Cover page, paste image over entire page

2019 Post-ASH Conference Report

American Society of Hematology Annual Meeting Orlando, Florida December 7–10, 2019

January 2020 / 1

Information Classification: General

Summary The 2019 American Society of Hematology (ASH) Annual Meeting was held in Orlando, Florida from December 7-10, 2019. The meeting included findings from early clinical results to updated results from key trials. Selected conference highlights include:

• Johnson & Johnson presented new data for the BCMA-targeting CAR-T therapy LCAR-B38M for the treatment of relapsed/refractory multiple myeloma. Encouraging efficacy results from the Phase Ib/II CARTITUDE-1 study showed patients achieving a 100% overall response rate (ORR) and 66% complete response (CR) rate. • Top-line results from the Phase II ZUMA-2 study of Gilead’s anti-CD19 CAR-T, KTE-X19, support a Biologics License Application (BLA) for relapsed/refractory mantle cell lymphoma with an impressive 93% ORR and 67% CR rate. • Bristol-Myers presented long-term follow-up results for the CD19 directed CAR-T therapy lisocabtagene maraleucel for the treatment of relapsed/refractory large B-cell lymphoma. The Phase I TRANSCEND NHL 001 study met both its primary and secondary endpoints. • Roche’s mosunetuzumab is a CD20-CD3 T-cell engaging bispecific antibody being evaluated in people with relapsed or refractory B-cell NHL. Results from a Phase I/Ib showed efficacy with an ORR of 63% in slow-growing NHL and 37% in aggressive NHL, CR rates were 43% and 19% respectively. Mosunetuzumab continues to be evaluated in several Phase I/II trials including in combination with Polivy and as first-line therapy. • The first numerical results for the Phase III AALL1331 study of Blincyto in relapsed ALL patients were presented in a late breaking abstract. The Blincyto arm demonstrated significantly improved two-year overall survival compared to the chemotherapy arm. These data support the use of Blincyto as a superior alternative to chemotherapy consolidation following re-induction therapy in pediatric patients at first-relapse. • Amgen and Janssen presented results for CANDOR, a Phase III study of Kyprolis combined with dexamethasone and Darzalex (KdD) vs Kyprolis and dexamethasone (Kd) in second-line or later multiple myeloma. This combination of two powerful targeted agents did not disappoint and the study met its primary endpoint of improving progression free survival with a 37% reduction in the risk of progression or death. The results from CANDOR suggest that the KdD regimen may be an alternative to the Darzalex/Velcade/dexamethasone (DVd) regimen for patients that relapsed, were refractory to or intolerant of a regimen containing an immunomodulatory agent such as Revlimid. We now await regulatory submissions for this new treatment option for relapsed/refractory multiple myeloma. • Notable findings from the Phase I/II study of the triple combination of TG-1303 (ublituximab, umbralisib; TGTX) and Venclexta for relapsed/refractory chronic lymphocytic leukemia (CLL) demonstrated a well-tolerated option for patients. Efficacy results of 100% ORR and 44% CR rate were promising and showed potential as the triple combination is being further studied in the Phase II ULTRA-V trial. • AstraZeneca presented data from the ELEVATE-TN trial which supported approval for CLL of the second generation BTK inhibitor Calquence. Calquence combined with Gazyva showed a median progression-free survival of 22.6 months in previously untreated patients. • Cerdulatinib (PTLA) is being studied in a Phase I/IIa study for patients with specific subtypes of T- cell Non-Hodgkin Lymphoma. The SYK/JAK inhibitor showed encouraging results for patients

January 2020 / 2

Information Classification: General

with angioimmunoblastic T-cell lymphoma (AITL) and cutaneous T-cell lymphoma (CTCL) with a 52% ORR and 37% CR rate in the AITL cohort and a favorable 25.8% ORR and 10.8% CR rate was seen in the PTCL cohort. • In the Phase III ASCERTAIN study, Otsuka’s ASTX727, an oral formulation of decitabine, was evaluated for the treatment of intermediate and high-risk (MDS). The study revealed a 5-day decitabine AUC equivalence of 98.9%, leading the company to move forward on a new drug application (NDA) filing to the U.S. Food and Drug Administration (FDA) with this data.

About the Author Biomedtracker is an independent research service that offers proprietary clinical assessments and patient-based revenue forecasts of developmental drugs within a comprehensive and intuitive drug information database. Clients from the pharmaceutical, biotech, and investment industries rely on Biomedtracker for its insight on the likelihood of approval, commercial potential, and future data and regulatory catalysts for drugs within the competitive landscape of every important disease and indication. Over the last several years, Biomedtracker has become the leader in providing objective information alongside evidence based clinical assessments and investment research on pipeline drugs worldwide. For more information on getting direct access to Biomedtracker, please email [email protected].

Datamonitor Healthcare provides a total business information solution to the pharmaceutical and healthcare industries. We provide expertise in therapeutic, strategic, and company market analysis and competitive intelligence to the global pharmaceutical and healthcare markets, enabling them to ultimately make valuable and profitable decisions. For more information about our products or to arrange a demo of our online service, please contact: [email protected].

Disclaimer Copyright © 2020 Sagient Research

This report is published by Sagient Research (the Publisher). This report contains information from reputable sources and although reasonable efforts have been made to publish accurate information, you assume sole responsibility for the selection, suitability and use of this report and acknowledge that the Publisher makes no warranties (either express or implied) as to, nor accepts liability for, the accuracy or fitness for a particular purpose of the information or advice contained herein. The Publisher wishes to make it clear that any views or opinions expressed in this report by individual authors or contributors are their personal views and opinions and do not necessarily reflect the views/opinions of the Publisher.

January 2020 / 3

Information Classification: General

Contents Summary ...... 2 About the Author ...... 3 Disclaimer...... 3 ASH 2019 Overview ...... 6 Drug Abstracts ...... 15 Acute Lymphoblastic Leukemia (ALL) ...... 15 Blincyto for Acute Lymphoblastic Leukemia (ALL) (AMGN, Approved) ...... 15 GC022 for Acute Lymphoblastic Leukemia (ALL) (Gracell; Development Outside U.S.) ...... 17 Acute Myelogenous Leukemia (AML) ...... 20 APR-246 for Acute Myelogenous Leukemia (AML) (APRE; Phase II) ...... 20 APR-246 for Acute Myelogenous Leukemia (AML) (APRE; Phase II) ...... 23 BST-236 for Acute Myelogenous Leukemia (AML) (BioSight, Phase II) ...... 25 Cusatuzumab for Acute Myelogenous Leukemia (AML) (JNJ; Phase I/II) ...... 27 Flotetuzumab for Acute Myelogenous Leukemia (AML) (MGNX; Phase I) ...... 29 Keytruda for Acute Myelogenous Leukemia (AML) (MRK; Phase II) ...... 31 Magrolimab for Acute Myelogenous Leukemia (AML) (FTSV; Phase I) ...... 33 MBG453 for Acute Myelogenous Leukemia (AML) (NVS; Phase I) ...... 36 Oral Azacitidine for Acute Myelogenous Leukemia (AML) (BMY, Phase III) ...... 38 Anemia Due to Oncology Treatment ...... 42 Roxadustat for Anemia Due to Oncology Treatment (AZN; Phase III) ...... 42 Autoimmune Hemolytic Anemia (AIHA) ...... 45 BIVV009 for Autoimmune Hemolytic Anemia (AIHA) (SNY, Phase III) ...... 45 Chronic Lymphocytic Leukemia (CLL)/Small Cell Lymphocytic Lymphoma (SLL) - NHL) ...... 49 Calquence for Chronic Lymphocytic Leukemia (CLL)/Small Cell Lymphocytic Lymphoma (SLL) – NHL (AZN; Approved) ...... 49 LOXO-305 for Chronic Lymphocytic Leukemia (CLL)/Small Cell Lymphocytic Lymphoma (SLL) – NHL (LLY; Phase I/II) ...... 52 TG-1303 for Chronic Lymphocytic Leukemia (CLL)/Small Cell Lymphocytic Lymphoma (SLL) – NHL (TGTX; Phase III) ...... 55 Diffuse Large B-Cell Lymphoma (DLBCL) - NHL ...... 58 AUTO3 for Diffuse Large B-Cell Lymphoma (DLBCL) – NHL (AUTL; Phase I/II) ...... 58

January 2020 / 4

Information Classification: General

Lisocabtagene Maraleucel for Diffuse Large B-Cell Lymphoma (DLBCL) – NHL (BMY; BLA) ...... 61 Indolent Non-Hodgkin's Lymphoma (Including Follicular Lymphoma) - NHL ...... 64 Mosunetuzumab for Indolent Non-Hodgkin's Lymphoma (Including Follicular Lymphoma) – NHL (RHHBY; Phase I) ...... 64 Polivy for Indolent Non-Hodgkin's Lymphoma (Including Follicular Lymphoma) – NHL (RHHBY, Phase II) ...... 67 REGN1979 for Indolent Non-Hodgkin's Lymphoma (Including Follicular Lymphoma) – NHL (REGN; Phase II) ...... 69 Tazemetostat for Indolent Non-Hodgkin's Lymphoma (Including Follicular Lymphoma) – NHL (Royalty Pharma; NDA) ...... 72 Mantle Cell Lymphoma - NHL ...... 75 KTE-X19 for Mantle Cell Lymphoma – NHL (GILD, BLA) ...... 75 Multiple Myeloma (MM) ...... 78 CC-93269 for Multiple Myeloma (MM) (BMY; Phase I) ...... 78 C-CAR088 for Multiple Myeloma (MM) (CBMG; Phase I) ...... 80 Darzalex for Multiple Myeloma (MM) (JNJ, Approved) ...... 83 ide-cel for Multiple Myeloma (MM) (BMY; Phase III) ...... 87 LCAR-B38M for Multiple Myeloma (MM) (JNJ, Phase II) ...... 90 Myelodysplastic Syndrome (MDS) ...... 92 APR-246 for Myelodysplastic Syndrome (MDS) (APRE, Phase III) ...... 92 ASTX727 for Myelodysplastic Syndrome (MDS) (Otsuka, Phase III) ...... 94 Venclexta for Myelodysplastic Syndrome (MDS) (ABBV, Phase II) ...... 97 Vidaza for Myelodysplastic Syndrome (MDS) (BMY, Approved) ...... 99 Myelofibrosis (MF) ...... 102 Reblozyl for Myelofibrosis (MF) (XLRN; Phase II) ...... 102 Peripheral T-Cell Lymphoma (PTCL) - NHL ...... 105 Cerdulatinib for Peripheral T-Cell Lymphoma (PTCL) – NHL (PTLA; Phase I/II) ...... 105 List of Biomedtracker ASH Events …………………………………………………………………………………..………….… 109

January 2020 / 5

Information Classification: General

ASH 2019 Overview

CAR-T therapy and Bispecific Antibodies

Immunotherapies, particularly chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies, were again a hot topic at this year’s meeting. Although the uptake for CAR-T therapies has not been strong thus far, companies are hoping that updated results will persuade providers and patients to try these new therapies. At this year’s conference, it became clear that bispecific antibodies could become significant competition for the CAR-T therapies.

In addition to response rates, the focus this year was on safety, namely the rates of cytokine release syndrome and neurotoxicity. With multiple therapies demonstrating dramatic efficacy, the long-term success of these immunotherapies will likely come down to the safety profiles.

CAR-T Therapies

CD19-directed CAR-T therapy

Bristol-Myers Squibb presented updated results for its CD19-targeting CAR-T therapy lisocabtagene maraleucel (JCAR017, liso-cel) in relapsed and refractory B-cell lymphoma (Abstract 241). Liso-cel demonstrated an overall response rate (ORR) of 73% and a complete response (CR) rate of 53% in the efficacy-evaluable population, results that compare favorably with historical results for Yescarta and Kymriah, the two CAR-T therapies already approved in this setting. Liso-cel will also likely distinguish itself based on the relatively promising safety profile, which included a 2% rate of Grade 3/4 cytokine release syndrome and 10% rate of Grade 3/4 neurotoxicity. A regulatory filing has been submitted to the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after at least two prior therapies. A decision is expected by August 2020.

Results were also presented from a Phase I/II trial of liso-cel for the treatment patients with relapsed/refractory chronic lymphocytic leukemia (Abstract 503). The study enrolled 23 patients with CLL/SLL who had received at least three (standard-risk disease) or two (high-risk disease) prior treatments with 22 patients evaluable for efficacy. At a median follow-up of 11 months, the ORR for patients receiving liso-cel was 81% with 45% of patients achieving a CR. In the nine patients that had failed a BTK inhibitor and Venclexta, the ORR was 89% with 67% achieving a CR. Cytokine release syndrome of any grade was seen in 79% of patients with 9% of patients experiencing grade 3 cytokine release syndrome. Thirty-nine percent of patients had neurological events (NE) of any grade, while 22% of patients had grade 3 or higher NE. There were no grade 5 events. The Phase II portion of this study continues to enroll patients.

January 2020 / 6

Information Classification: General

In the pivotal Phase II ZUMA-2 study of KTE-X19, a CD19 CAR-T therapy, in relapsed or refractory mantle cell lymphoma, KTE-X19 demonstrated an impressive ORR of 93%, with a CR rate of 67% (Abstract 754). At the time of data cut-off, 57% of the ITT population remained in remission while 78% of the CR population remained in remission. Additionally, 47% of all patients were alive at the two-year follow-up. In terms of safety, grade 3 or higher cytokine release syndrome was seen in 15% of patients and grade 3 or higher neurotoxic adverse events were seen in 31% of patients. A regulatory filing has been submitted to the FDA for the treatment of adult patients with relapsed or refractory mantle cell lymphoma. A decision is expected by August 2020.

BCMA-directed CAR-T therapy

Janssen presented results from two Phase Ib/II studies evaluating BCMA-directed CAR-T therapy JNJ- 4528 (also known as LCAR-B38M) in the treatment of relapsed or refractory multiple myeloma: LEGEND- 2, a Chinese study initiated in October 2015 and CARTITUDE-1 a US study initiated in June 2018. With a median follow-up of 25 months for the LEGEND-2 trial (Abstract 579), treatment with JNJ-4528 resulted in an ORR and CR rate of 88% and 74%, respectively and 93% of patients with a CR response were negative for minimal residual disease (MRD). Impressively, 46% of all-treated patients and 64% percent of MRD-negative patients with CR remained progression-free. The median progression-free survival (PFS) for all-treated patients was 20 months (range, 10–28); median PFS for MRD-negative patients with CR was 28 months (range, 20–31).

For the CARTITUDE-1 study (Abstract 577), patients had a median of five prior lines of therapy (range, 3– 18) and 86% of patients were triple-refractory to a protease inhibitor, immunomodulator, and anti-CD38 antibody; 72% were penta-exposed, and 31% were penta-refractory. In 29 patients with a median follow-up of six months, the ORR and CR or better rate was 100% and 86%, respectively. In addition, 100% of evaluable patients (15 of 29 patients) were MRD negative at the latest sample available. With a median follow-up of six months, 27 of 29 patients were progression-free.

These initial results show that despite enrolling a more heavily pretreated population, CARTITUDE-1 showed responses comparable to the LEGEND-2 study. While Bristol Myers Squibb idecabtagene vicluecel (ide-cel) is expected to reach the market first, these results suggest that JNJ-4528, structurally differentiated by its two BCMA targeting single domain antibodies, may beat ide-cel on efficacy. We now await results for the Phase II portion of this trial as well as from two recently initiated trials: a Phase II trial (CARTITUDE-2) and a Phase III trial (CARTITUDE-4) that will compare JNJ-4528 to standard of care therapies for multiple myeloma.

January 2020 / 7

Information Classification: General

Dual Targeted CAR-T therapy

Dual targeted CAR-T therapies, such as Gracell Biotechnologies’ CD19/CD22 dual CAR-T therapy GC022, made their debuts at ASH 2019 (Abstract 284). GC022 was evaluated in relapsed/refractory acute lymphocytic leukemia (ALL) patients; 35% had previously been treated with CD19 CAR-T cells and 30% had previously received an allogeneic hematopoietic stem cell transplant. Although the data is still preliminary, GC022 demonstrated an excellent safety profile, with no incidence of Grade 2 or higher neurotoxicities or cytokine release syndrome. With 93.8% of patients achieving a complete response or a complete response with incomplete hematologic recovery and a promising safety profile, GC022 is an example of how next generation CAR-T therapies could be game-changers.

Bispecific Antibodies

Non-Hodgkin’s Lymphoma (NHL)

Mosunetuzumab is a CD20-CD3 T-cell engaging bispecific antibody being evaluated in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL). Results from a Phase I/Ib study, GO29781, were presented at the ASH plenary session (Abstract 6) and included data from patients previously treated with CAR-T therapy. Results from this dose-escalation study showed efficacy with an ORR of 63% (n=42/67) in slow-growing NHL (mostly follicular lymphoma) and 37% (n=46/124) in aggressive NHL (mostly DLBCL with some transformed follicular lymphoma and mantle-cell lymphoma). Additionally, the CR rate was 43% (29/67) in slow-growing NHL and 19% (24/124) in aggressive NHL. CRs showed durability, with 83% (24/29) of patients with slow-growing NHL remaining in remission up to 26 months off initial treatment and 71% (17/24) of patients with aggressive NHL remaining in remission up to 16 months off initial treatment. For participants who received prior CAR T-cell therapy, the ORR was 39% (7/18) with 22% (4/18) achieving a CR. Adverse reactions included cytokine release syndrome in 29% of patients (21% had a Grade 1 event, 6% Grade 2 and 1% Grade 3). Grade 3 neurological adverse events occurred in 4% of patients. Mosunetuzumab continues to be evaluated in several Phase I/II trials including in combination with Polivy (polatuzumab vedotin; Roche) and as first-line therapy.

Updated results from the dose-escalation Phase I study of REGN1979, an anti-CD20 and anti-CD3 bispecific antibody, in relapsed/refractory follicular lymphoma (FL) patients were presented at the meeting (Abstract 762). The overall response rate (ORR) was 95.5% in the evaluable FL patients (n=14) with a complete response (CR) rate of 77.3%. However, there was a concerning 50% rate of any grade infection, which included 2 instances of an infection-related Grade 5 adverse event.

January 2020 / 8

Information Classification: General

Multiple Myeloma

CC-93269 is a bi-specific antibody targeting BCMA and CD3. A dose-escalation Phase I trial enrolled 30 third-line or later relapsed/refractory multiple myeloma patients (Abstract 143). The median number of prior regimens was 5 (range 3–13) with all patients refractory to their last line of therapy (80% refractory to their last anti-CD38 antibody, 77% to their last proteasome inhibitor, and 80% to their last immunomodulatory agent).

Cytokine release syndrome was reported in 77% of patients with only one patient reporting Grade 3 or higher cytokine release syndrome. This patient died in the setting of cytokine release syndrome, with a potential infection as a contributing factor.

Of nine patients treated with 10 mg CC-93269, the overall response rate was 89% with a very good partial response rate of 33% and a stringent complete response/complete response (sCR/CR) rate of 44%. Impressively, all patients achieving a sCR/CR response were MRD negative in the bone marrow. These encouraging, early results in heavily pretreated patients suggest that the positive results seen with AMG 420, Amgen’s bispecific antibody targeting BCMA, were not an anomaly and that bispecific antibodies targeting BCMA may prove to be valuable in treating relapsed/refractory multiple myeloma.

Acute Myeloid Leukemia

Flotetuzumab is a bispecific DART (dual-affinity re-targeting antibody) targeting CD123 and CD3 and is currently being tested in a Phase I/II study in patients with relapsed/refractory AML. At ASH, Macrogenics presented results from patients with primary refractory and early relapsed AML, a difficult to treat population with historical CR/CRh rates of 12.5%. With 30 patients treated at the recommended Phase II dose (given by continuous infusion), the CR/CRh rate was 26.7% (16.6% CR rate) in the ITT population (28 evaluable). Cytokine release syndrome was seen in all 30 patients however events were of short duration and mild to moderate in severity (30% of patients had a Grade 1 event, 67% Grade 2), with only one Grade 3 event reported in one patient. A Phase I trial evaluating flotetuzumab combined with an immune checkpoint was initiated in Q3 2019 and a pivotal trial is expected to initiate in 2020.

Summary

In 2020 we expect to see the first-approval of CAR-Ts for multiple myeloma and mantle-cell lymphoma. While CAR-Ts remain expensive, difficult to manufacture and complicated to deliver, they offer strong efficacy. There are ongoing efforts to address mechanisms of resistance and to reduce toxicity. At ASH there was discussion that as doctors become more familiar with them, uptake will continue to grow. We also expect that as they enter earlier lines of therapy, safety will continue to improve and outpatient treatment will become feasible.

January 2020 / 9

Information Classification: General

Interest continues to grow in bispecific antibodies as an off-the-shelf alternative to CAR-Ts. While first- generation bispecific antibodies had to be given by continuous infusion due to their short half-life, second generation bi-specifics are larger with longer half-lives. Bi-specific antibodies have shown utility as a bridge to CAR-T therapy and for patients who either relapse or never respond to CAR-T therapy. Bi- specific antibodies may also find use in earlier lines of therapy perhaps in combination with established or novel agents.

New standards of care are emerging

Several of the presentations at ASH 2019 described clinical trial results with practice-changing data, expected to result in new standard-of-care treatments. Other important presentations included results for treatments designed for patients who had progressed after receiving multiple novel therapies. These included important trials in acute myeloid leukemia, myelodysplastic syndrome, multiple myeloma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia.

Acute Lymphoblastic Leukemia (ALL)

At ASH, the first numerical results for the Phase III AALL1331 study of Blincyto in high- and intermediate- risk relapsed ALL patients (aged 1-30 years) were presented in a late breaking abstract (LBA1). Although there was a strong trend towards improved disease-free survival (DFS) for the Blincyto arm compared to the chemotherapy arm (DFS at 2 years was 59.3% vs 41.0%) this primary endpoint was not met (one- sided p=0.050). However, the Blincyto arm demonstrated significantly improved two-year overall survival (79.4% vs 59.3%, one-sided p=0.005) compared to the chemotherapy arm and a higher rate of patients receiving an allogeneic hematopoietic stem cell transplant (73% vs 45%, p<0.0001). Blincyto also had markedly lower toxicity and significantly fewer Grade 3 or higher cytotoxicites. These data support the use of Blincyto as a superior alternative to chemotherapy consolidation following re- induction therapy in pediatric patients at first-relapse.

Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

A new standard of care for AML maintenance therapy

Results from the placebo-controlled Phase III QUAZAR trial evaluating CC-486 (an oral formulation of azacitidine) as maintenance therapy in patients aged ≥55 years with AML in first remission following intensive chemotherapy showed showing significant improvements in both overall survival (24.7 months vs 14.8 months; hazard ratio 0.69) and relapse-free survival (10.2 months vs 4.8 months; hazard ratio 0.65) compared to the placebo arm. With the QUAZAR trial having achieved both its primary and

January 2020 / 10

Information Classification: General

secondary endpoints, CC-486 is set to receive FDA approval and become the new standard of care for AML patients in remission (Abstract LBA-3).

Aspacytarabine, a prodrug of cytarabine, for patients unfit for standard therapy

Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine (BST-236) evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Aspacytarabine was evaluated in a completed Phase I/IIa study and an ongoing Phase IIb study with the two studies enrolling newly diagnosed AML patients not suited for intensive chemotherapy. Across both studies, the CR rate was 30% (including once case of CRp) in all patients (n=23), 57% in de novo AML patients (n=7) and 19% in secondary AML patients (n=16). For the seven patients with a CR/CRp response, the one-year survival rate was 67%. We now await MRD assessment of patients in the Phase IIb trial as well as additional trials evaluating aspacytarabine either as single agent or in combination with targeted therapy.

Targeting CD70 with cusatuzumab eliminates AML stem cells

Leukemia stem cells (LSCs) resistant against conventional chemotherapy represent the major cause of relapse in AML. Preclinical work has shown that CD34+ AML cells (progenitors and LSC) consistently express the tumor necrosis factor family ligand CD70 as well as its receptor CD27 and that cell- autonomous CD70/CD27-signaling propagates the disease. The clinical relevance of these findings was determined in a Phase I trial in previously untreated elderly AML patients with a single dose of cusatuzumab monotherapy followed by a combination therapy with azacitidine. A single dose of cusatuzumab reduced bone marrow blasts in just two weeks in all patients on average by 32%. Cusatuzumab monotherapy significantly reduced LSC numbers and frequencies in all patients analyzed in the bone marrow as assessed in limiting dilution colony assays. In combination with azacitidine, cusatuzumab induced a response in 100% of 12 patients (67% CR, 17% CRi, 17% PR). Four of nine patients with a CR/CRi (44%) were MRD negative. For now, we await results from a Phase II confirmation and expansion study AML2001 CULMINATE which is actively recruiting patients. A Phase Ib platform study will explore combinations with standard AML therapies in different AML settings and subpopulations.

Immune Checkpoint Inhibitors for AML

A session on checkpoint inhibitors in AML was notable for two presentations. The first presentation, Abstract 829, convincingly showed that Imfinzi (durvalumab) combined with azacitidine did not significantly improve response rates or survival when compared to azacitidine alone in patients with newly diagnosed AML or high-risk MDS.

January 2020 / 11

Information Classification: General

The second presentation, Abstract 831, showed encouraging results for a single arm Phase II trial of Keytruda (pembrolizumab) combined with high-dose cytarabine (HiDAC) in relapsed/refractory AML. The overall response (ORR: CR+CRi+PR+MLFS) and composite CR (CR+CRi) rates were 46% and 38%, respectively, meeting the primary endpoint of the study. Outcomes remain dismal for patients with relapsed/refractory AML. Historical response rates with high dose cytarabine (HiDAC) salvage chemotherapy are approximately 20% which makes the 38% composite CR rate reported here encouraging. We now await announcement of a randomized Phase II trial comparing salvage chemotherapy with and without checkpoint inhibition.

New treatments for myelodysplastic syndrome (MDS) and TP53 mutated AML

Multiple presentations focused on high-risk myelodysplastic syndrome (MDS) and untreated acute myeloid leukemia (AML) with TP53 mutations, bringing hope of new treatment strategies for these patient populations with few efficacious treatment options.

The first of these presentations, which was featured in the Best of ASH, examined the combination of venetoclax + azacitidine in a Phase Ib study in treatment-naïve patients with higher-risk myelodysplastic syndrome (Abstract 568). The observed complete response (CR) with venetoclax monotherapy was 39%, although the venetoclax and azacitidine combination demonstrated a combined CR and marrow CR rate of 77%. This study determined that the recommended dosing is 400 mg venetoclax for days 1-14 of a 28- day cycle combination with azacitidine 75mg delivered on days 1-7.

Another presentation focused on updated results from the Phase Ib study of Forty Seven’s macrophage immune checkpoint inhibitor magrolimab in combination with azacitidine in untreated patients with AML or high-risk MDS (Abstract 569). In patients with high-risk MDS, the overall response rate (ORR) of 92% and the complete response (CR) rate of 50% seen with the magrolimab and azacitidine combination compare very favorably to azacitidine monotherapy, the current standard of care. Additionally, the ORR of 78%, CR rate of 44%, and CR with complete blood count recovery (CRi) rate of 33% in the subset of AML patients with TP53 mutations compare favorably to the CR/CRi rate of 47% seen in the same patient population in a Phase Ib study of Venclexta.

Finally, Aprea Therapeutics presented results from the Phase Ib/II clinical trial of APR-246, a small molecule that restores transcriptional activity of unfolded or mutant p53, in combination with azacitidine in TP53 mutant MDS and AML (Abstract 637). The APR-246 trial enrolled 33 TP53 mutated MDS patients and reported an ORR and CR rates of 88% and 61%, respectively. Although the results in the AML cohort were preliminary, 7 of the 8 evaluable patients responded to treatment for an ORR of 88%.

January 2020 / 12

Information Classification: General

Chronic Lymphocytic Leukemia (CLL)

Triple combination in CLL

A Phase I/II study in relapsed/refractory CLL (including patients refractory to Imbruvica) evaluated a debulking/induction regimen consisting of ublituximab, a glycoengineered anti-CD20 monoclonal antibody, combined with umbralisib, a dual inhibitor of PI3K delta and CK1 epsilon, given for three cycles. After induction the ORR was 87% in 23 patients and induction appeared to reduce Venclexta tumor lysis syndrome risk. Induction was followed by consolidation with umbralisib combined with Venclexta starting in cycle 4. Patients who were bone marrow MRD negative after cycle 12 stopped all therapy while those who were MRD positive continued on umbralisib maintenance therapy. For the first nine patients who completed cycle 12, the ORR and CR rate was 100% and 44%, respectively. All nine patients (100%) had undetectable MRD in the peripheral blood while 78% had undetectable MRD in the bone marrow and have stopped therapy. With a median follow-up of 6.4 months, no patients (n=27) have progressed to date. Only 2 patients (7%) have discontinued due to adverse events (one with grade 3 rash the other with grade 3 diarrhea). This regimen has the potential to offer patients with CLL a highly active, time-limited, and generally well tolerated treatment option. A Phase II study (ULTRA-V) in treatment naïve and relapsed/refractory CLL is ongoing.

Numerical results for Calquence, a new inhibitor of Bruton’s Tyrosine Kinase approved for CLL

An interim analysis of results from the Phase III ELEVATE TN trial in patients with previously untreated chronic lymphocytic leukemia (CLL) showed that Calquence plus Gazyva significantly extended PFS compared with Gazyva plus chlorambucil (median not reached vs. 22.6 months; HR = 0.1). Calquence monotherapy also significantly prolonged PFS (median not reached) compared with Gazyva plus chlorambucil (HR = 0.2). A subgroup analysis showed that the Calquence/Gazyva combination yielded a significant PFS benefit compared with the control in patients with unmutated (HR =0.08) or mutated (HR = 0.15) IGHV.

These findings, along with previously reported data from the Phase III ASCEND trial in relapsed or refractory CLL, supported the November 2019 FDA approval of Calquence for CLL. Imbruvica (ibrutinib; Jannsen) combined with Gazyva is currently a preferred treatment option for CLL. Compared to Imbruvica, Calquence is a more selective Bruton’s tyrosine kinase (BTK) inhibitor and may have an improved safety profile and thus represents an important new treatment option for CLL.

Preliminary results from LOXO-305, a next generation BTK inhibitor

Although preliminary, the first results from the dose-escalation Phase I/II BRUIN trial of Eli Lilly’s LOXO- 305, a non-covalent inhibitor of both wild-type and C481-mutated BTK, for the treatment of patients

January 2020 / 13

Information Classification: General

with chronic lymphocytic leukemia (CLL) or patients with mantle cell lymphoma (MCL) are encouraging (Abstract 501). All patients with CLL, including those with C481 mutations, experienced a reduction in tumor burden. The overall response rate (ORR) in this cohort was 77%, which included a partial response (PR) rate of 62% and a partial response with ongoing lymphocytosis (PR-L) rate of 15%. In the small MCL cohort, the ORR was 50%, with one complete response (CR) and two PRs. These are promising results because many of the patients had progressed on other novel therapies, including covalent BTK inhibitors, and had subsequently developed resistance to those therapies.

Multiple Myeloma

At ASH, Amgen and Janssen presented results for CANDOR, a Phase III study of Kyprolis (carfilzomib) combined with dexamethasone and Darzalex (daratumumab) (KdD) vs Kyprolis and dexamethasone (Kd) in second-line or later multiple myeloma. This combination of two powerful targeted agents did not disappoint and the study met its primary endpoint of improving progression free survival (PFS). Compared to Kd, the KdD regimen resulted in a 37% reduction in the risk of progression or death (HR=0.630; p=0.0014). The median PFS for patients treated with KdD had not been reached by the cut- off date compared to a median PFS of 15.8 months for patients who received Kd alone. The study also met key secondary endpoints with improvements in overall response rate (84.3% vs 74.7%, p=0.0040), complete response (including stringent complete response) rate at 12 months (28.5% vs 10.4%) and MRD-negative complete response rate at 12 months (12.5% vs 1.3%) favoring the KdD arm compared to Kd alone. Median overall survival has not yet been reached in either arm, but the hazard ratio indicated a trend in favor of the KdD arm (HR=0.75; P=0.08). The results from CANDOR suggest that the KdD regimen may be an alternative to the Darzalex/Velcade/dexamethasone (DVd) regimen for patients that relapsed, were refractory to or intolerant of a regimen containing an immunomodulatory agent such as Revlimid. For now, we await regulatory submissions for this new treatment option for relapsed/refractory multiple myeloma.

Peripheral T-Cell Lymphoma

Updated results from the peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) cohorts of the Phase IIa part of a Phase I/IIa study of Portola Pharmaceutical’s dual SYK/JAK inhibitor cerdulatinib were presented at ASH (Abstract 466). The overall response rates (ORR) and complete response (CR) rates differed widely among the PTCL subtypes, with the most promising results (ORR: 52%; CR: 37%) seen in the subset of patients in the PTCL cohort with angioimmunoblastic T-cell lymphoma (AITL). In the CTCL cohort, the ORR was 43% with a CR rate of 8% and a PR rate of 35%, and the average duration of response was 4 months (range 1-8). However, the study investigator reported ten cases of Epstein-Barr Virus reactivation in patients being treated with cerdulatinib, which is concerning and should be investigated further.

January 2020 / 14

Information Classification: General

Drug Abstracts

Acute Lymphoblastic Leukemia (ALL)

Blincyto for Acute Lymphoblastic Leukemia (ALL) (AMGN, Approved)

Phase III - COG AALL1331 (1st Relapse) Trial Data – Updated Results

Change to LOA: 0%

Abstract LBA-1: A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy As Post-Reinduction Therapy in High and Intermediate Risk (HR/IR) First Relapse of B-Acute Lymphoblastic Leukemia (B-ALL) in Children and Adolescents/Young Adults (AYAs) Demonstrates Superior Efficacy and Tolerability of Blinatumomab: A Report from Children’s Oncology Group Study AALL1331

Context During a planned interim analysis (data cut-off 6/30/19) by the Data Safety and Monitoring Committee, the HR/IR randomization was stopped early. While the improvement in DFS for Arm B did not cross the predefined superiority threshold at the time of interim analysis, the combination of improved DFS, superior OS, lower toxicity, and superior MRD clearance for Arm B relative to Arm A was judged to provide sufficiently compelling evidence to establish a new standard of care.

Design HR/IR first relapse B-ALL patients aged 1-30 years were randomized following re-induction chemotherapy (Block 1 of UKALLR3/mitoxantrone arm) to receive either two intensive chemotherapy blocks (Blocks 2 and 3 of UKALLR3; Control Arm A) or two 4-week blocks of blinatumomab, each followed by one week of rest (Blina cycles 1 and 2; Experimental Arm B). Patients with ≥25% marrow blasts after Block 1 were ineligible for randomization. After randomized therapy, patients on both arms proceeded to HSCT.

Endpoints The primary aim of this study was to compare disease-free survival (DFS) between arms. Secondary aims included comparisons of the following between Arms A and B: AEs, MRD response (by flow cytometry, central lab), overall survival (OS) and ability to proceed to HSCT.

January 2020 / 15

Information Classification: General

Results A total of 208 HR/IR patients were randomized (Arm A: 103, Arm B: 105). Baseline characteristics were comparable between arms. With median follow up of 1.4 years, the intent-to-treat (ITT) 2-year DFS (% ± standard error) was 41.0 ± 6.2% for Arm A vs. 59.3 ± 5.4% for Arm B (p=0.05, 1-sided per pre-specified statistical plan). The ITT 2-year OS was 59.2 ± 6.0% for Arm A vs. 79.4 ± 4.5% for Arm B (p=0.005, 1- sided). Among patients with detectable MRD (≥0.01%) at the completion of Block 1 chemotherapy, the proportion that achieved undetectable MRD (<0.01%) after Block 2 (Arm A) vs. Blina cycle 1 (Arm B) was 21% vs. 79% (p<0.0001). The rates of MRD response were similar with Block 3 or Blina cycle 2. The rate of patients successfully proceeding from randomization to HSCT (data cut-off 9/30/19) was strikingly different between arms. On Arm A, only 45% (44 of 98 who received randomized therapy) proceeded to HSCT. On Arm B, 73% (75 of 103 who received randomized therapy) proceeded to HSCT (p<0.0001).

Most Common Adverse Events Post-induction toxic deaths occurred in 4 patients on Arm A (all infections) vs. none on Arm B (p=0.05). Relative rates of CTCAEv4 grade ≥3 febrile neutropenia, infections, sepsis and mucositis were strikingly higher for Block 2/3 (Arm A) vs. Blina cycle 1/2 (Arm B): 44%/46% vs. 4%/0%, 41%/61% vs. 10%/11%, 14%/21% vs. 1%/2%, and 25%/7% vs. 0/1% respectively (p<0.001 for all comparisons except mucositis for Block 3 vs. Blina cycle 2, p=0.16). For Arm B, the rate of selected blinatumomab-related AEs in cycle 1/2 were: Cytokine release syndrome (CRS) 22%/1% (grade ≥3 1%/0%); seizure 4%/0% (1%/0%); other neurotoxicity (e.g., cognitive disturbance, tremor, ataxia, dysarthria) 14%/11% (2%/2%). All blinatumomab-related AEs fully resolved.

Conclusion For children and AYA patients with HR/IR first relapse of B-ALL, blinatumomab is superior to standard chemotherapy as post-reinduction consolidation prior to HSCT, resulting in fewer and less severe toxicities, higher rates of MRD response, greater likelihood of proceeding to HSCT and improved disease-free and overall survival.

Comment Results from Phase III trial (AALL1331), which was conducted by the Children's Oncology Group (COG), of Blincyto in pediatric patients with high-risk, B-cell acute lymphoblastic leukemia (B-ALL) at first relapse showed that Blincyto demonstrated significantly improved event-free survival over the conventional consolidation chemotherapy arm. With the Phase III 20120215 trial of Blincyto for pediatric patients with high-risk relapsed B-ALL also reporting positive results, these data support the use of Blincyto as a superior alternative to chemotherapy consolidation following re-induction therapy in pediatric patients at first-relapse.

While there was a strong trend towards improved disease-free survival (DFS) for the Blincyto arm compared to the chemotherapy arm (DFS at 2 years was 59.3% vs 41.0%), the primary endpoint was not

January 2020 / 16

Information Classification: General

met (one-sided p=0.050). However, the Blincyto arm demonstrated significantly improved two-year overall survival (79.4% vs 59.2%, one-sided p=0.005) compared to the chemotherapy arm and a higher rate of patients receiving an allogeneic hematopoietic stem cell transplant (73% vs 45%, p<0.0001). Also, for patients with detectable MRD (≥0.01%) at the completion of induction chemotherapy, the proportion that achieved undetectable MRD (<0.01%) was higher for patients treated with a cycle of Blincyto compared to patients treated with a cycle of chemotherapy (79% vs 21%, p<0.001).

Additionally, Blincyto also had markedly lower toxicity and significantly fewer Grade 3 or higher cytotoxicites. There was a statistically significant lower risk of death than the chemotherapy arm (0 patients vs 4 patients).

Blincyto previously received accelerated approval for the treatment of adults or children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL) based on single arm trials in adult and pediatric patients. Full approval was granted based on the Phase III TOWER study which enrolled adults ≥18 years and showed an improvement in overall survival.

Source: American Society of Hematology (ASH) 12/10/2019 (Abstract LBA-1) Sagient Analysis

GC022 for Acute Lymphoblastic Leukemia (ALL) (Gracell; Development Outside U.S.)

Phase I - PGC0003 Trial Data – Top-Line Results

Change to LOA: 0%

Abstract 284: Anti-CD19/CD22 Dual CAR-T Therapy for Refractory and Relapsed B-Cell Acute Lymphoblastic Leukemia

Design The CD19/CD22 dual CAR-T cells were manufactured in a cGMP facility. Patients’ peripheral blood (PB) mononuclear cells were first collected, and CD3+ T cells were separated. The cells were then transfected by lentivirus encoded with CD19 CD22 bispecific scFv sequences. The CAR-T cells produced in this way contained a 4-1BB co-stimulatory signal domain. The CAR-T cells were then cultured for 8-14 days until sufficient cells were harvested for infusion.

All pts received conditioning regimen of fludarabine and cyclophosphamide intravenously for 3

January 2020 / 17

Information Classification: General

consecutive days with doses of 30 mg/m2/day and 250 mg/m2/day, respectively before a single infusion of CAR-T cells. The level of infused CAR-T cell proliferation in PB was analyzed by qPCR and flow cytometry.

Endpoints The primary end points were to evaluate feasibility and toxicity, and the secondary end points included disease response and engraftment/persistence of infused CD19/CD22 dual CAR-T cells.

Results The treatment efficacy was assessed in 20 patients with a 28-day follow-up, of which: • 4 in the low dose group reported no response; • 15 of 16 (93.8%) in mid and high dose groups achieved complete remission, and confirmed with MRD-CR, with or without complete blood count recovery (CR/CRi) on Day 28. Dual CAR-19-22 proved effective on patients who had previously been treated with CD19 CAR-T cells and/or received allogeneic hematopoietic stem cell transplantation (allo-HSCT) for r/r B-ALL but failed to benefit from prior treatments. Among these five patients, four (80%) patients achieved MRD-CR with a 28-day follow-up. Surpassing the 3-month durable remission period, fifteen patients still retain ongoing response.

Per the abstract, from February 2019 to July 23, 2019, 17 patients (pts) with relapsed/refractory B-ALL including 4 pts who previously treated with CD19 CAR-T cells were enrolled and pts were treated with CD19/CD22 dual CAR-T GC022. Four were adults, 13 pediatrics (age 1-45). The median bone marrow (BM) blasts was 19.09 (0.36-87.82) %. Four patients received a low-dose (2.5-5×105/kg) dual CAR-T, 7 received a medium-dose (1-2.5×106/kg) and 5, a high-dose (3-5×106/kg). One patient withdrew immediately before CAR-T infusion due to his personal issue. Anti-leukemic efficacy was evaluated in 11/16 pts (5 pts have not yet reached D15). The 3/4 pts received low dose of GC022 had no response to treatment and 1 had MRD-positive CR. Seven patients who received medium dose achieved 100% CR on D15, highlighting the dose-dependent anti-leukemic activity. Six out of seven pts had MRD negative CR in this medium dose group. Five pts in high dose group have not reached the time for evaluation. No one relapsed with a median observation time of 60 (7-139) days. Cellular kinetic data was analyzed. Median peak of CAR-T copies was 1.09 (0.0022-4.98) x105 copy number/µg PB genomic DNA. The proliferation of medium or high dose groups was significantly better than the low dose group 3.47(0.43-4.98) x105 vs. 0.023(0.0022-0.81) x105(P=0.02) and 2.02(1.89-2.16) x105 vs. 0.023(0.0022-0.81) x105(P=0.004). The peaks of IL-6, IFN-γ, IL-10, and CD25 were observed around day 7-10.

Most Common Adverse Events Furthermore, Dual CAR-19-22 demonstrated an excellent safety profile, with 6/20 (30%) patients indicating no CRS, 14/20 (70%) reporting Grade 1 CRS. No ICANS events were reported.

January 2020 / 18

Information Classification: General

Per the abstract, sixteen out of seventeen pts had grade 0-1 cytokine release syndrome (CRS) and only 1 patient experienced grade 2 CRS. None developed neurotoxicity.

Conclusion The study demonstrates safety and technical feasibility of CD19 and CD22 dual CAR-T in treating patients with CD19+CD22+ relapsed/refractory B-ALL. A low toxicity with dose-dependent high CR rate including pts who previously treated with CD19 CAR-T cells were observed. Longer observation time and more patients are needed to evaluate a beneficial advantage of the CD19/CD22 dual CAR-T over CD19 CAR-T product.

Comment These top-line results from the Phase I study of GC022, a dual CD19/CD22 CAR-T therapy, are promising. Dual CAR-T cells are designed to mitigate relapse due to antigen loss and this Phase I study evaluated the safety and technical feasibility of GC022 as a treatment for both pediatric and adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL).

Data from the study showed that GC022 has surprisingly low toxicity for a CAR-T therapy, with none of the 24 patients presenting with neurotoxicity, which has been a significant issue for other CAR-T therapies. Additionally, 70% of the patients experienced a Grade 1 adverse event (AE), with no Grade 2 or higher AEs reported in this analysis. Although these safety results are promising, a detailed and longer-term safety analysis is still needed.

Of the patients enrolled, 35% had previously been treated with CD19 CAR-T cells and 30% had previously received an allogeneic hematopoietic stem cell transplant (HSCT). The response rates for the three dosing groups indicate that efficacy of this therapy is likely dose-dependent. None of the four patients treated with the lowest dose of GC022 responded to treatment. However, 93.8% of the sixteen patients in the medium or high dose groups achieved a complete response (CR) or a complete remission with incomplete hematologic recovery (CRi). Additionally, there have been no relapses in the 11 patients who subsequently received an allogenic HSCT. Only 1 of the 4 patients who did not undergo HSCT after treatment with GC022 relapsed within approximately 2 months.

This preliminary analysis showed that this CD19/CD22 dual CAR-T therapy had low toxicity while maintaining a promising initial CR rate in this highly pre-treated patient population, particularly those who have been previously treated with both CD19 CAR-T cells and allogenic hematopoietic stem cell transplants. However, data from a longer follow-up period and from additional patients are still needed in order to determine how this therapy will compare with CD19 or CD22 single CAR-T products. Given that this product is only in development in China at this point, we are leaving the LOA unchanged.

January 2020 / 19

Information Classification: General

Source: PR Newswire 12/09/2019 American Society of Hematology (ASH) 12/07/2019 (Abstract 284) Sagient Analysis

Acute Myelogenous Leukemia (AML)

APR-246 for Acute Myelogenous Leukemia (AML) (APRE; Phase II)

Phase Ib/II - w/Azacitidine Trial Data - Updated Results

Change to LOA: 0%

Abstract 676: Phase 2 Results of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML)

Design The trial is evaluating the safety and efficacy of APR-246 in combination with azacitidine for the treatment of TP53 mutated MDS and AML. Eligible patients in the Phase Ib/II clinical trial include HMA- naïve, TP53 mutated MDS, oligoblastic acute myeloid leukemia (AML, ≤ 30% blasts), MDS- myeloproliferative neoplasm (MDS-MPN) overlap and chronic myelomonocytic leukemia (CMML). In the Phase Ib part of the clinical trial, patients received APR-246 in a 3+3 dose escalation design (50, 75, 100 mg/kg lean body weight) IV daily over 4 days in a lead-in phase (days -14 to -10), followed by the same dose of APR-246 (days 1-4) and AZA 75 mg/m2 SC/IV daily for 7 days (days 4-10 or 4-5 and 8-12) in 28- day cycles. In the Phase II part of the clinical trial, patients receive APR-246 as a 4,500 mg fixed dose IV daily (days 1-4) and AZA daily for 7 days (days 4-10 or 4-5 and 8-12) in 28-day cycles. Primary objective in Phase Ib part of the clinical trial was safety, with AEs graded by CTCAE v4.03 and DLT assessment over 6 weeks.

Per the abstract, this is a multicenter Phase Ib/II trial of APR-246+AZA in HMA-naïve mTP53 higher risk MDS, MDS/MPN and oligoblastic AML (≤ 30% blasts) pts. P2 pts received APR-246 4500mg IV (days 1-4) + AZA 75 mg/m2 SC/IV x 7 days (days 4-10 or 4-5 and 8-12) in 28 day cycles. Primary objective was CR rate by International Working Group (IWG) 2006 criteria. Secondary objectives included ORR, OS, outcome following allogeneic hematopoietic stem cell transplant (allo-HSCT), and both next generation sequencing (NGS) and p53 immunohistochemistry (IHC) to monitor clonal suppression and remission depth as prognostic covariates. For minimal residual disease (MRD) analysis, a custom target-capture

January 2020 / 20

Information Classification: General

NGS assay was developed using unique molecular Identifiers for error correction with a 0.1% limit of detection.

Endpoints Secondary endpoints included response rate by IWG 2006 criteria, PFS, OS, as well as serial next generation sequencing and p53 immunohistochemistry for evaluation of clonal suppression and depth of remission. In the Phase II part of the clinical trial the primary endpoint is CR rate.

Results As of the data cutoff, the overall response rate (ORR) in 33 evaluable MDS patients was 88%, with a 61% complete remission (CR) rate, by International Working Group (IWG) criteria. With a median duration of follow-up of 10.8 months, the median duration of response was 8.4 months and the median duration of CR was 7.3 months. Seventeen (52%) evaluable MDS patients discontinued therapy to pursue stem cell transplant. Median overall survival (OS) for all enrolled patients (n=55) was 10.8 months. Median OS in responding patients versus non-responders was 13.7 vs. 3.9 months.

Per the abstract, as of July 15, 2019, 55 pts were enrolled (6 P1; 49 P2) with a median age 66 years (34- 85; 47% male). By WHO, 40 pts had MDS, 11 AML-MRC and 4 CMML/MDS-MPN; 85% had complex cytogenetics and 33% TR-MDS/AML. All pts had higher risk disease by IPSS-R (7% Intermediate, 24% High, 69% Very High). Fifty pts (91%) had a TP53 missense mutation in the DNA binding domain with multiple mutations in 18 (33%), and median variant allele frequency (VAF) of 25%. In 34 pts (62%), TP53 was the sole mutation. Median time on treatment is 154 days (11-392) with 8 pts ongoing. Eighteen pts (33%; 40% of evaluable pts) discontinued study treatment to proceed to allo-HSCT.

At data cutoff, 45pts were response evaluable with a median follow up of 10.5 months. ORR by IWG was 87% (39/45) with 24 CR (53%), 8 marrow CR (mCR)+HI (18%), 3 HI alone (7%), and 4 with mCR (9%). Of 6 non-responders, 4 had stable disease and 2 pts had progressive disease. Median time to response was 2.1 months (0.1-5.4) and median duration of response of 6.5 months. CR rate for MDS was 61% (20/33), 50% for AML (4/8) and 0% for MDS/MPN (0/4) with an 88% ORR rate for MDS/AML and 75% for MDS/MPN. An isolated mTP53 was predictive for a higher CR rate (69% vs 25%; P=.006) with a trend for higher ORR (93% vs 75%; P=.17). Additionally, pts with >10% p53 IHC+ BM-MNC was a covariate associated with higher CR rate (66% vs 13%; P=.01). Complete and partial cytogenetic response occurred in 41% (n=18) and 18% (n=8) of pts, respectively. On serial TP53 NGS using a VAF cutoff of 5%, 39% (n=21) of patients achieved NGS negativity, which was associated with improved OS (12.8 vs 9.2 months; P=.02). In NGS- pts, the median MRD VAF at maximum clearance was 0.63% (0.0%-5%) with 5 pts (11%) MRD negative. By intention-to-treat analysis, median OS was 11.6 months (95% CI 9.2-14) with significantly longer OS in responding pts (12.8 vs 3.9 months; P<.0001). Pts undergoing allo-HSCT had improved median OS (16.1 [95% CI 11.6-NE] vs 9.2 [95% CI 6.3-13.7] months), with a 1-year OS of 66% vs 29% in pts who were not transplanted (P=.002). All NGS- pts prior to allo-HSCT remain alive at date

January 2020 / 21

Information Classification: General

cutoff.

Most Common Adverse Events Adverse events, regardless of causality, were mostly grade 1/2. Grade 3+ adverse events occurring in ≥20% of patients were limited to cytopenias and infection, consistent with underlying hematopoietic malignancies, and no exacerbation of the expected AZA-related safety profile has been observed.

Per the abstract, treatment (Tx)-related AEs in ≥ 20% of pts included nausea/vomiting (58%), dizziness (31%), constipation (24%), neuropathy (22%), leukopenia (22%) and thrombocytopenia (20%; all G1/G2 except cytopenias (G3/G4). Tx-related febrile neutropenia and anemia occurred in 9% and 5% of pts with no other G3/G4 event in >1 pt. Thirty and 60 day mortality was 2% (n=1) and 6% (n=3), respectively.

Conclusion Per the abstract, APR-246+AZA is a well-tolerated combination with high response rates in mTP53 MDS/AML. Response durations are promising accompanied by a high fraction of cytogenetic and deep molecular remissions leading to encouraging outcomes post-HSCT. These data support the ongoing, randomized Phase III study of APR-246+AZA versus AZA alone in mTP53 MDS.

Comment Results from both the US and French Phase Ib/II studies of APR-246 in combination with azacitidine in patients with hypomethylating agent-naïve TP53 mutant myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) were presented at ASH 2019. In the US study, the overall response rate (ORR) of 88% and the complete response (CR) rate of 50% were promising. The ORR for AML patients with 20-30% blasts in the French study was 55% while the ORR for patients with greater than 30% blasts was 50%.

However, the safety profile for the APR-246 and azacitidine combination is slightly concerning due to high rates of serious adverse events and a 60-day mortality rate of 5%. With only 8 evaluable patients in the US Study and 11 evaluable patients in the French study, it is difficult to arrive at any definitive conclusions regarding the benefit/risk profile based on these preliminary data from the TP53 mutant acute myelogenous leukemia (AML) cohorts at this time.Thus, we are leaving the likelihood of approval unchanged pending additional data.

Aprea Therapeutics is also investigating APR-246 as a post-stem cell transplant maintenance therapy in TP53 mutant MDS and AML. The combination of APR-246, azacitidine, and venetoclax is also being testing in relapsed/refractory AML patients in a recently initiated Phase I/II study.

January 2020 / 22

Information Classification: General

Source: Press Release 12/09/2019 American Society of Hematology (ASH) 12/09/2019 (Abstract 676) Sagient Analysis

APR-246 for Acute Myelogenous Leukemia (AML) (APRE; Phase II)

Phase Ib/II - w/Azacitidine (France) Trial Data – Top-Line Results

Change to LOA: 0%

Abstract 677: APR-246 Combined with Azacitidine (AZA) in TP53 Mutated Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). a Phase 2 Study By the Groupe Francophone Des Myélodysplasies (GFM)

Context Per the abstract, a Phase III international trial comparing AZA alone and AZA+ APR 246 in TP53m MDS is ongoing.

Design The trial is evaluating the safety and efficacy of APR-246 in combination with azacitidine for the treatment of patients with TP53 mutated MDS and AML. The clinical trial is sponsored by the Groupe Francophone des Myélodysplasies.

Eligible patients in the Phase Ib/II clinical trial include HMA naïve, TP53 mutated MDS and acute myeloid leukemia (AML). All enrolled patients were to receive APR-246 as a 4,500 mg fixed dose IV daily (days 1- 4) and AZA over 7 days (days 4-10 or 4-5 and 8-12) in 28-day cycles.

Endpoints The primary endpoint of the trial is CR rate.

Results As of the data cutoff, the overall response rate (ORR) in 24 evaluable MDS patients was 74%, with a 66% complete remission (CR) rate, based on International Working Group criteria. With a median duration of follow-up of 6.4 months, the median overall survival (OS) for all enrolled patients (n=53) had not been reached. In addition, all responding patients were alive at data cutoff. Relative to baseline, mutant TP53 variant allele frequency (VAF) was significantly decreased in responding patients and undetectable in all

January 2020 / 23

Information Classification: General

patients who achieved a CR.

Per the abstract, 53 patients were enrolled between September 2018 and July 2019 in 7 GFM centers, with a median age of 73 years (range 44-87), and M/F: 28/25. 34 patients had MDS (including 74% very high IPSS-R) and 19 had AML. IPSS-R cytogenetic risk was very poor in 30/34 MDS, and unfavorable in 18/19 AML, complex in 89% of the patients. Median baseline mutated TP53 VAF was 21% (range 3-76).

Nineteen of the 53 patients had been included at least 7 months before date of analysis (July 25, 2019), had received protocol treatment and were thus potentially evaluable for response after 6 treatment cycles (ITT population). One of them died after only one cycle from an unrelated cause (cerebral ischemic stroke), and 2 during the third cycle (from bleeding and sepsis, respectively). In the remaining 16 patients (evaluable population per protocol), the response rate was 75% including 9 (56%) CR, 3 (19%) marrow CR or stable disease with hematological improvement (HI), and 4 treatment resistance. In the ITT population, the response rate was 63%, including 47% CR, and 16% stable or marrow CR+ HI. Among CR patients, complete cytogenetic CR and negative NGS for TP53 mutation (VAF cutoff of 2%) were achieved in 7/9 (78%) and 8/8 (100%), respectively. So far, 1 patient has undergone allo-SCT.

Most Common Adverse Events Per the abstract, treatment related AEs observed in ≥ 20% of patients were febrile neutropenia in 19 (36%) and neurological AEs in 21 (40%) of the patients. The latter, reviewed with a neurological team, were mainly grade 1 or 2 and consisted of ataxia (n=13), sometimes associated with cognitive impairment (n=4), suggesting a cerebellar origin. Other patients experienced acute confusion (n=4), isolated dizziness (n=3) and facial paresthesia (n=1). Neurological AEs reached grade III in 3 cases (1 acute confusion, 2 ataxia). Occurrence of neurological AEs was correlated with lower glomerular filtration rate at treatment onset (p<0.01) and higher age (p=0.05). Neurological symptoms spontaneously regressed within 5 days of drug discontinuation (after a median of 1 day). They did not recur in the following cycles after per protocol APR 246 dose reductions.

Conclusion Per the abstract, in this very high-risk elderly population of TP53m MDS and AML, generally with complex karyotype, a promising 56% CR rate at 6 cycles was reached in the evaluable population with AZA+ APR 246 combination, with deep molecular remission in all CR patients. Manageable neurologic AEs were observed, mainly in elderly patients with reduced renal function, who therefore require close monitoring and dose reduction if necessary. An update regarding safety and efficacy in the 53 patients, including survival data, will be available at the meeting.

Comment For comment, please see the APR-246 and azacitidine US study event.

January 2020 / 24

Information Classification: General

Source: Press Release 12/09/2019 American Society of Hematology (ASH) 12/09/2019 (Abstract 677) Sagient Analysis

BST-236 for Acute Myelogenous Leukemia (AML) (BioSight, Phase II)

Phase IIb - ELPIS (Newly Diagnosed) Trial Data – Top-Line Results

Change to LOA: 1%

Abstract 179: Aspacytarabine (BST-236) Is Safe and Efficacious As a Single-Agent, First-Line Therapy for Patients with Acute Myeloid Leukemia Unfit for Standard Chemotherapy. Integrated Results from a Phase 1/2a and an Ongoing Phase 2b

Design A completed Phase I/IIa study and an ongoing Phase IIb study evaluate the efficacy and safety of aspacytarabine as a single-agent therapeutic for AML. The Phase I/IIa, dose-escalation study enrolled newly-diagnosed patients unfit for standard therapy and patients with relapsed/refractory AML. Patients were treated with 0.3-6 g/m2/d aspacytarabine in 6 dose-escalating cohorts.

The ongoing multi-center Phase IIb study expands the subgroup of newly-diagnosed AML patients unfit for standard therapy, to evaluate the efficacy and safety of aspacytarabine as a first-line therapy for this population. Secondary AML patients, treated with HMA, chemotherapy, or radiotherapy for a prior condition, are allowed. Patients in the Phase IIb study are treated with the selected aspacytarabine dose of 4.5 g/m2/d, containing approximately 3 g/m2/d of cytarabine. Each aspacytarabine treatment course (induction and consolidation) consists of 6 1-hour daily intravenous infusions.

Results To date, 34 AML patients, median age 76 years, received at least 1 dose of aspacytarabine, including 30 patients unfit for standard induction therapy due to age or comorbidities. Twenty-one patients were newly-diagnosed with AML, either de novo or secondary to MDS or therapy. The patient population was characterized by older age (median 76 years, range 67-88 years), and the majority (67%) of patients had secondary AML, including 10 patients (48%) who were previously treated with HMA (median of 10 courses) or radiotherapy. The median baseline bone marrow blast percentage of this population was 75, and 43% and 48% had intermediate or adverse European LeukemiaNet (ELN) cytogenetic score, respectively.

January 2020 / 25

Information Classification: General

Despite these poor-prognostic characteristics, the 30-day mortality rate in the group of patients receiving ≥4.5 g/m2/d aspacytarabine was 7%. The combined complete remission (CR) rate of all doses was 33%, including 1 patient reaching a CR with partial platelet recovery (CRp). The CR rate in patients treated with at least 4.5 g/m2/d aspacytarabine is 36%, with median time for complete hematological recovery of 27 days (range 21-30) following induction and consolidation. Notably, among the 7 patients who reached a CR/CRp (median age 77), 3 secondary AML patients reached a CR, including 2 patients with prior exposure to HMA (5 and 10 courses) and 1 with prior exposure to radiotherapy. Duration of response and overall survival follow up is ongoing

Most Common Adverse Events Aspacytarabine was safe and well-tolerated in repeated-course administration, including in older and unfit patients. Adverse events included mainly hematological “on-target” events with no drug-related mucositis or cerebellar toxicity.

Conclusion The accumulating clinical data suggest that aspacytarabine is safe and efficacious for the treatment of AML patients who are unfit for standard induction therapy, including patients with prior exposure to HMA, which may establish aspacytarabine as a new therapeutic backbone for AML, either as a single agent or in combination with targeted therapy.

Comment Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine (BST-236) evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Aspacytarabine was evaluated in a completed Phase I/IIa study and an ongoing Phase IIb study with the two studies enrolling newly diagnosed AML patients not suited for intensive chemotherapy. Across both studies, the CR rate was 30% (including once case of CRp) in all patients (n=23), 57% in de novo AML patients (n=7) and 19% in secondary AML patients (n=16). For the seven patients with a CR/CRp response, the one-year survival rate was 67%.

As we await MRD assessment of patients in the Phase IIb trial as well as additional trials evaluating aspacytarabine either as single agent or in combination with targeted therapy, we are raising the LOA by 1%.

Source: American Society of Hematology (ASH) 12/07/2019 (Abstract 179) Sagient Analysis

January 2020 / 26

Information Classification: General

Cusatuzumab for Acute Myelogenous Leukemia (AML) (JNJ; Phase I/II)

Phase I/II – CULMINATE Trial Data – Updated Results

Change to LOA: 2%

Abstract 234: Targeting CD70 with Cusatuzumab Eliminates Acute Myeloid Leukemia Stem Cells in Humans

Context In addition to the CULMINATE trial in the newly diagnosed unfit AML population, cusatuzumab is also being evaluated in a Phase Ib platform study to explore combinations with standard AML therapies with the first trial exploring combinations of venetoclax, cusatuzumab and azacytidine.

Design Per the abstract, the effect of HMA treatment on the expression of CD70 on primary human CD34+CD38- AML LSCs was determined in vitro cultures and in patients treated with HMA in vivo. The therapeutic potential of targeting CD70-expressing LSCs in presence and absence of HMA was assessed using the anti-CD70 ADCC-optimized monoclonal antibody (mAb), cusatuzumab, and an effector-dead anti-CD70 mAb in colony formation and re-plating assays as well as patient-derived xenograft models (Silence et al, 2014). The clinical relevance of the findings was determined in a clinical Phase I trial in previously untreated elderly AML patients with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine. Four different dose levels of cusatuzumab (1, 3, 10 and 20 mg/kg Q2W) were studied; AZA was administered at 75 mg/m² for 7 days every 28 days.

Results • 100% of patients achieved a response including eight with a complete response (CR), two with a complete response with incomplete hematologic recovery (CRi), and two with a partial response (PR); 83% of patients achieved either a CR or CRi • Of the nine CR/CRi patients evaluable for minimal residual disease (MRD) negativity, four achieved MRD negativity using a threshold of 10-3 which is consistent with the previous data cut-off in October 2018 • Four patients have remained in the study for at least 12 months • Three patients from the study have been re-classified with risk category based on new mutation information or a reassessment of existing mutation information Per the abstract, the Company found that resistance of AML LSCs to HMA treatment is mediated by the up-regulation of the CD70. The up-regulation of CD70 triggered cell-autonomous CD70/CD27 signaling on AML LSCs. Based on these findings we hypothesized that the upregulation of CD70 by HMA may

January 2020 / 27

Information Classification: General

render LSCs more susceptible to CD70-targeting interventions. Targeting CD70-expressing LSCs by a blocking anti-CD70 mAb and the anti-CD70 mAb cusatuzumab, which blocks CD70/CD27-signaling and additionally mediates ADCC and CDC, eradicated LSCs in colony and re-plating assays in vitro and in xenotransplantation experiments in vivo. HMA in combination with blocking αCD70 mAb synergistically reduced LSC numbers in vivo and this was even more efficient when ADCC-enhanced αCD70 mAb cusatuzumab was added in the presence of NK cells.

In order to test the hypothesis that targeting CD70 in combination with HMA eliminates LSCs in AML patients, the Company initiated a Phase I dose-escalation trial in previously untreated elderly AML patients with a single dose of cusatuzumab monotherapy followed by a combination therapy with azacitidine. No dose-limiting toxicities (DLT) were observed in the dose-escalation Phase I trial and responses were observed across the dose levels (1-20 mg/kg). A single dose of cusatuzumab reduced bone marrow blasts in just two weeks in all patients on average by 32%. Cusatuzumab monotherapy significantly reduced LSC numbers and frequencies in all patients analyzed in the bone marrow as assessed in limiting dilution colony assays. Single cell sequencing analysis revealed that cusatuzumab induced gene signatures related to myeloid differentiation and apoptosis in LSCs. In combination with azacitidine, cusatuzumab induced CR/CRi in 10 out of 12 patients. Responses were observed at all dose levels of cusatuzumab and median time to response was 3.3 months.

Most Common Adverse Events Cusatuzumab continued to be well-tolerated in patients with AML across the different doses.

Conclusion Per the abstract, blocking CD70/CD27-signaling and targeting CD70-expressing LSCs by the ADCC- optimized mAb, cusatuzumab, eliminated LSCs in vitro and in xenotransplantation experiments. In a Phase I study promising activity of cusatuzumab in combination with HMA was observed in AML patients, in which translational data indicate that cusatuzumab selectively eliminates CD70-expressing LSCs.

Comment Leukemia stem cells (LSCs) resistant against conventional chemotherapy represent the major cause of relapse in AML. Preclinical work has shown that CD34+ AML cells (progenitors and LSC) consistently express the tumor necrosis factor family ligand CD70 as well as its receptor CD27 and that cell- autonomous CD70/CD27-signaling propagates the disease.

The clinical relevance of these findings was determined in a Phase I trial in previously untreated elderly AML patients with a single dose of cusatuzumab monotherapy followed by a combination therapy with azacitidine. A single dose of cusatuzumab reduced bone marrow blasts in just two weeks in all patients on average by 32%. Cusatuzumab monotherapy significantly reduced LSC numbers and frequencies in all

January 2020 / 28

Information Classification: General

patients analyzed in the bone marrow as assessed in limiting dilution colony assays. In combination with azacitidine, cusatuzumab induced a response in 100% of 12 patients (67% CR, 17% CRi, 17% PR). Four of nine patients with a CR/CRi (44%) were MRD negative. For now, we await results from a Phase II confirmation and expansion study AML2001 CULMINATE which is actively recruiting patients. A Phase Ib platform study will explore combinations with standard AML therapies in different AML settings and subpopulations.

Based on these encouraging results for cusatuzumab combined with azacitidine, we are increasing the LOA by 2%.

Source: Press Release 12/07/2019 (ARGX) American Society of Hematology (ASH) 12/07/2019 (Abstract 234) Sagient Analysis

Flotetuzumab for Acute Myelogenous Leukemia (AML) (MGNX; Phase I)

Phase I - MGD006-01 Trial Data – Updated Results

Change to LOA: 1%

Treatment Treatment Description Flotetuzumab Number of Patients 30 Number of Evaluable Patients 28 CR 17.900 % CR + CRh 28.600 % CR + CRh +CRi 32.100 %

Abstract 733: Flotetuzumab, an Investigational CD123 x CD3 Bispecific Dart Protein, in Salvage Therapy for Primary Refractory and Early Relapsed Acute Myeloid Leukemia (AML) Patients

Context The study is currently ongoing, with additional patients being enrolled. Based on the data from this study, and pending anticipated discussions with the FDA in the first half of 2020, the company is planning for a potential registration-enabling study of flotetuzumab in this population of patients with refractory AML, who have limited treatment options.

January 2020 / 29

Information Classification: General

Design In the Phase I/II open-label, dose expansion study, 30 patients classified as primary induction failure or early relapsed AML who had received a median of four prior therapies were treated with flotetuzumab at the recommended Phase II dose (RP2D) of 500 ng/kg/day by continuous infusion. Data were reported as of the cut-off date of November 1, 2019.

Results Responses, including complete remission (CR), CRh (CR with partial hematological recovery) and CRi (CR with incomplete hematological improvement) per a modified International Working Group (IWG) Response Criteria for AML, are summarized in the tabled results. Four responders received allogeneic hematopoietic stem cell transplantation as consolidation therapy and remain in remission after 6 to 21 months.

Most Common Adverse Events The most common treatment-related adverse event (TRAE) was infusion-related reaction/cytokine release syndrome (IRR/CRS) that occurred in all (30/30) patients. However, most CRS events observed were of short duration and mild to moderate (grade 1 or 2) in severity, with only one grade 3 event reported in one patient.

Conclusion In conclusion, the data shows that FLZ elicits clinical response in heavily treated patients with poor response rates to primary therapy.

Comment Flotetuzumab is a bispecific DART (dual-affinity re-targeting antibody) targeting CD123 and CD3 and is currently being tested in a Phase I/II study in patients with relapsed/refractory AML. At ASH, Macrogenics presented results from patients with primary refractory and early relapsed AML, a difficult to treat population with historical CR/CRh rates of 12.5%. With 30 patients treated at the recommended Phase II dose (given by continuous infusion), the CR/CRh rate was 26.7% (16.6% CR rate) in the ITT population (28 evaluable). Cytokine release syndrome was seen in all 30 patients however events were of short duration and mild to moderate in severity (30% of patients had a Grade 1 event, 67% Grade 2), with only one Grade 3 event reported in one patient.

Based on these promising results and as we await a pivotal trial to initiate in 2020, we are increasing the LOA by 1%.

Source: Press Release 12/09/2019 (MGNX) American Society of Hematology (ASH) 12/09/2019 (Abstract 733)

January 2020 / 30

Information Classification: General

American Society of Hematology (ASH) 12/09/2019 (MGNX, Presentation) Company Conference Call Slides 12/09/2019 (MGNX) Sagient Analysis

Keytruda for Acute Myelogenous Leukemia (AML) (MRK; Phase II)

Phase II - LCCC 1522 Trial Data – Final Results

Change to LOA: 2%

Treatment Treatment Description HiDAC + Pembrolizumab Number of Patients 37 Number of Evaluable Patients N/A CR 35.000 % (Endpoint=Primary) Overall CR 38.000 % CR+CRi (Endpoint=Primary) PR 5.000 % MLFS 3.000 % Overall Response 46.000% CR + Cri + PR + MLFS

Abstract 831: Final Clinical Results of a Phase II Study of High Dose Cytarabine Followed By Pembrolizumab in Relapsed/Refractory AML

Design Eligibility for this study included R/R AML 18-70 years, ECOG PS 0-1 and adequate organ function. Treatment consisted of HiDAC (<60 years: 2 gm/m2 IV Q12hours days 1-5; >60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14. Overall responders were eligible to receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until progression. Allogeneic stem cell transplant (alloSCT) was permissible before or after maintenance phase.

Endpoints The primary objective of this study was to estimate the overall complete remission (CR + CRi) rate. Secondary objectives included assessment of safety, durability of CR, overall survival (OS) and biomarker correlates of response.

January 2020 / 31

Information Classification: General

Results Thirty-seven pts were enrolled and evaluable. Sixteen (43%) pts had refractory disease and 16 (43%) pts had relapsed AML with CR1 duration <1 year. The overall response (ORR: CR+CRi+PR+MLFS) and composite CR (CR+CRi) rates were 46% [29%,63%] and 38% [22%,55%], respectively, meeting the primary endpoint of the study. Seven of 14 patients (50%) with a CR/CRi response were MRD negative.

Rates of CR/CRi responses for different subpopulations were as follows: patients >60 years, 4/15 (27%); refractory patients, 6/16 (38%); adverse-risk patients, 6/19 (32%); secondary AML patients, 4/13 (31%). Notably, 13/28 (46%) pts receiving HiDAC + pembrolizumab as their first salvage regimen achieved CR/CRi. Two pts refractory to HiDAC (administered within past 6 months) achieved CR including one pt who was refractory to HiDAC salvage 1 month prior to enrollment and ultimately achieved CR without evidence of minimal residual disease.

Nine (24%) pts received an alloSCT. There were no instances of Grade >3 acute GVHD or veno-occlusive disease post-alloSCT. Nine (24%) pts received maintenance phase pembrolizumab (median # of cycles = 3; range: 1-12) for CR (n=8) or PR (n=1). Seven out of 9 pts relapsed/progressed after maintenance phase. Median follow-up among survivors, and median OS, event-free survival and disease-free survival was 7.8 months, 8.9 months [6.0,13.1], 6.9 months [4.2,11.5], and 5.7 months [1.9,7.3], respectively.

Most Common Adverse Events Excluding electrolyte abnormalities, the most common pembrolizumab-related toxicities were febrile neutropenia (57%), ALT elevation (43%; Grade >3: n=1), AST elevation (32%; Grade >3: n=1), fatigue (27%), alkaline phosphatase elevation (24%), and maculopapular rash (19%; Grade >3: n=2). Sixty-day mortality was 3% (1/37) due to progressive AML. Median time to full neutrophil (>1x109/L) and platelet (>100x109/L) recovery was 32 and 31 days, respectively.

Grade >3 immune-related adverse events (iRAE) were rare (maculopapular rash: n=2, AST/ALT increase: n=2, right upper quadrant pain with lymphocytic infiltrate in liver: n=1) and self-limiting. Five (14%) pts required steroid administration for grade 2 hyperbilirubinemia (n=1), grade 3 ALT elevation (n=1), grade 3 AST elevation with liver biopsy revealing no evidence of iRAE (n=1), grade 3 bilirubin subsequently deemed to be a delayed hemolytic transfusion reaction (n=1), and grade 3 systolic dysfunction without evidence of myocarditis by endomyocardial biopsy or cardiac MRI (n=1).

Conclusion Pembrolizumab can be safely administered after HiDAC salvage in R/R AML. Severe iRAE’s were uncommon despite administration after cytotoxic chemotherapy. The addition of pembrolizumab to HiDAC led to an overall CR rate meeting the primary endpoint of the study. Immunogenomic biomarker analyses consisting of B cell receptor amplicon sequencing, RNA-seq of blasts and CD8+ T cells, CD8+ T cell receptor repertoire, whole exome sequencing and flow cytometry analyses are ongoing to

January 2020 / 32

Information Classification: General

determine predictors of response. These results warrant further investigation of IR blockade and other immunomodulatory therapeutic strategies after intensive cytotoxic chemotherapy in AML.

Comment These are encouraging results for a single arm Phase II trial of Keytruda combined with high-dose cytarabine (HiDAC) in relapsed/refractory AML. ORR and composite CR (CR+CRi) rates were 46% and 38%, respectively, meeting the primary endpoint of the study. Median OS, event-free survival and disease-free survival were 10.5 months, 6.9 months, and 5.7 months, respectively. Outcomes remain dismal for patients with relapsed/refractory AML. Historical response rates with high dose cytarabine (HiDAC) salvage chemotherapy are approximately 20% which makes the 38% composite CR rate reported here encouraging.

There is an ongoing effort to determine if there are immunogenomic biomarkers measured pre- treatment that correlate with response. A preliminary analysis suggests that increased CD8+ve TCR diversity pre-treatment is associated with a response.

As we await announcement of a randomized Phase II trial comparing salvage chemotherapy with and without checkpoint inhibition, we are increasing the LOA by 2%.

Source: American Society of Hematology (ASH) 12/09/2019 (Abstract 831) Sagient Analysis

Magrolimab for Acute Myelogenous Leukemia (AML) (FTSV; Phase I)

Phase Ib - w/Azacitidine (AML/MDS) Trial Data – Updated Results

Change to LOA: 1%

Treatment Treatment Treatment Treatment Description Margolimab + AZA Margolimab + AZA Margolimab + AZA 1L MDS 1L AML TP53 Mutant AML Number of Patients 24 22 9 Number of Evaluable Patients N/A N/A N/A ORR 92.000 % 64.000 % 78.000 % CR 50.000 % 41.000 % 44.000 % CRi N/A 14.000 % 33.000 % PR 0.000 % 5.000 % N/A

January 2020 / 33

Information Classification: General

MLFS/Marrow CR 33.000 % 5.000 % N/A Hematologic Improvement 8.000 % N/A N/A Stable disease 8.000 % 32.000 % N/A Progressive disease 0.000 % 5.000 % N/A RBC transfusion independence 44.000 % 73.000 % N/A Complete cytogenetic response in 26.000 % 60.000 % 67.000 % responders MRD negativity in responders 23.000 % 57.000 % 57.000 %

Abstract 569: The First-in-Class Anti-CD47 Antibody Magrolimab (5F9) in Combination with Azacitidine Is Effective in MDS and AML Patients: Ongoing Phase 1b Results

Context Forty Seven also announced it achieved alignment with the FDA on the final design of its potentially registration-enabling clinical development program for magrolimab in higher-risk MDS.

Design Forty Seven’s Phase Ib trial, which is being funded in part by the California Institute of Regenerative Medicine (CIRM), is designed to evaluate magrolimab in combination with azacitidine in untreated patients with higher risk MDS and untreated patients with AML, who are ineligible for induction chemotherapy. All patients received a 1 mg/kg priming dose of magrolimab, coupled with intrapatient dose escalation, to mitigate on-target anemia. Patients were then treated with full doses of azacitidine and a magrolimab maintenance dose of 30 mg/kg once weekly.

Endpoints The primary objects were safety of magrolimab alone or with AZA and efficacy of magrolimab + AZA in untreated AML/MDS.

Results As of the data cutoff of November 18, 2019, 62 patients had been treated with the combination in the Phase Ib portion of the trial, including 35 patients with MDS and 27 patients with AML. • In higher-risk MDS, the overall response rate (ORR) was 92%, with 12 patients (50%) achieving a complete response (CR), eight patients (33%) achieving a marrow CR and two patients (8%) achieving hematologic improvement. Additionally, two patients (8%) achieved stable disease. • In untreated AML, the ORR was 64%, with nine patients (41%) achieving a CR, three patients (14%) achieving a CR with complete blood count recovery (CRi) and one patient (5%) achieving a morphologic leukemia-free state (MLFS). Additionally, seven patients (32%) achieved stable disease (SD) and one patient (5%) had progressive disease. • The median time to response among MDS and AML patients treated with the combination was 1.9 months.

January 2020 / 34

Information Classification: General

• No median duration of response or overall survival has been reached for either MDS or AML patients, with a median follow-up of 6.4 months (range 2.0 to 14.4 months) for MDS and 8.8 months (range 1.9 to 16.9 months) for AML. Additionally, mutational analyses are ongoing to correlate subgroups with response. Seven of nine (78%) evaluable TP53 mutant AML patients achieved an objective response, with 44% achieving CR and 33% achieving CRi. TP53 mutations are often associated with a poor prognosis and patients with TP53 mutant disease are refractory to existing therapies.

Lastly, in AML patients who achieved an objective response, a significant increase in CD4 and CD8 T cell infiltration was observed in the bone marrow while on therapy, demonstrating that magrolimab and azacitidine can induce an adaptive T cell response.

Most Common Adverse Events As of the data cutoff, the combination of magrolimab and azacitidine was well-tolerated, with no evidence of increased toxicities compared to azacitidine alone. Adverse events (AEs) were consistent with prior clinical experience. No deaths were observed in the first 60 days on combination treatment and only one patient out of 62 (1.6%) discontinued treatment due to a treatment-related AE.

Comment Updated results from the Phase Ib study of magrolimab in combination with azacitidine in untreated patients with high-risk myelodysplastic syndrome (MDS) and untreated patients with acute myeloid leukemia (AML) showed that the combination demonstrated high efficacy rates in both cohorts. Following discussions with the FDA, Forty Seven announced that a path to submission for accelerated approval for MDS had been identified and that this Phase Ib study will serve as the basis for the submission.

The data in the MDS cohort compared favorably to azacitidine, the current standard of care for MDS. The overall response rate (ORR) of 92% and complete response (CR) rate of 50% seen with the magrolimab and azacitidine combination are higher than the ORR of 29% and CR rate of 17% seen with azacitidine monotherapy in Phase III/IV study in a similar patient population, although it remains to be seen if magrolimab’s high response rates will translate into an overall survival benefit.

For the general AML cohort, the CR/CRi rate of 55% for the combination therapy does not compare favorably with Venclexta, which demonstrated a CR/CRi response rate of 66% in the same setting. However, Forty Seven also presented very encouraging results for a subgroup of AML patients with TP53 mutations. Patients with TP53 mutant AML are often refractory to existing therapies and TP53 mutations are associated with significantly worse overall and event-free survival rates. In this subgroup, the magrolimab and azacitidine combination demonstrated an ORR of 78%, a CR rate of 44%, and a CRi rate of 33%. These response rates are significantly higher than the CR/CRi rate of 47% seen in patients

January 2020 / 35

Information Classification: General

with TP53 mutations in a subgroup analysis of the Phase Ib study of Venclexta.

Based on these results, we are raising our likelihood of approval in MDS by 4% and in AML by 1%.

The MDS and AML expansion cohorts of this Phase Ib study are ongoing, with the AML cohort focused on enrolling additional TP53 patients. Additionally, enrollment will begin soon in the Phase III ENHANCE study, which will evaluate the magrolimab and azacitidine combination against azacitidine monotherapy in patients with high risk MDS.

Source: Press Release 12/09/2019 (FTSV) American Society of Hematology (ASH) 12/09/2019 (Abstract 569) American Society of Hematology (ASH) 12/09/2019 (FTSV, Presentation Slides) Company Conference Call 12/09/2019 (FTSV) Company Conference Call Slides 12/09/2019 (FTSV) Sagient Analysis

MBG453 for Acute Myelogenous Leukemia (AML) (NVS; Phase I)

Phase Ib - w/PDR001 Trial Data – Top-Line Results

Change to LOA: 0%

Treatment Treatment Treatment Treatment Description MBG453 + Decitabine MBG453 + Decitabine MBG453 + Decitabine HR-MDS AML R/R AML Number of Patients N/A N/A N/A Number of Evaluable Patients 16 14 17 CR 8 Patients 2 Patients N/A PR N/A 2 Patients N/A CRi N/A N/A 5 Patients

Abstract 570: Phase Ib Study of the Anti-TIM-3 Antibody MBG453 in Combination with Decitabine in Patients with High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Design Patients with Revised International Prognostic Scoring System (IPSS-R) high or very high-risk (HR) MDS and newly diagnosed, or relapsed/refractory (R/R), AML following ≥ 1 prior therapy who were not

January 2020 / 36

Information Classification: General

candidates for standard chemotherapy and who were HMA naive were enrolled in this multi-center, open label phase Ib dose-escalation study (NCT03066648). Escalating doses of MBG453 were administered i.v. every 2 weeks (Q2W; days 8, 22) or every four weeks (Q4W; day 8) in combination with decitabine (20 mg/m2; i.v. days 1–5). Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs). Adverse events (AEs) were graded using NCI-CTCAE v4.03. The International Working Group criteria for MDS (Cheson et al, 2006) or AML (Cheson et al, 2003) were used to assess efficacy.

Endpoints The primary objectives were to characterize the safety and tolerability of MBG453 in combination with decitabine and to identify recommended doses for future studies. Secondary objectives included assessing preliminary efficacy and pharmacokinetics of the combination.

Results As of March 25, 2019, 17 HR-MDS, 4 chronic myelomonocytic leukemia (CMML), and 38 AML patients have received decitabine and MBG453 at 240 mg Q2W (n=22), 400 mg Q2W (n=21), or 800 mg Q4W (n=16). MTD has not been reached. Median age was 70 years (range 23–87 years). 24 patients are ongoing (duration of exposure 1.1 to 18.6 months) with 35 patients discontinued (disease progression [n=19, 32%], AE [n=1, 2%], patient/physician decision [n=13, 22%], death [n=2, 3%]).

16 HR-MDS and 31 AML patients have had post-baseline disease response assessments. Median duration of decitabine and MBG453 is 3.9 months (range 0.7–18.6 months). Evidence of activity with MBG453 in combination with decitabine has been seen at doses ranging from 240 mg Q2W to 800 mg Q4W. 8 of 16 (50%) HR-MDS patients achieved mCR or CR. None of the responding HR-MDS patients has had disease recurrence with exposure durations currently ranging from 3.4 to 18.6 months; two patients in mCR underwent allogeneic stem cell transplant. 4 of 14 (29%) newly diagnosed AML patients have achieved a response of PR or better (2 PR, 2 CR), with 3 additional patients exhibiting ≥ 50% bone marrow blast reduction, and 10 of 14 (71%) continuing on study. 5 of 17 (29%) R/R AML patients have achieved a response of CRi, with 5 additional patients exhibiting ≥ 50% bone marrow blast reduction. Exposure durations for all AML responders currently range from 2.1 to 17.9 months. Median onset of response among all patients was 2.0 months. TIM-3 expression was detected on leukemic cells, with modulation of TIM-3 expression following treatment with decitabine.

Most Common Adverse Events There was one DLT consisting of a grade 3 ALT elevation that was corticosteroid responsive. The most common treatment emergent grade 3/4 AEs were febrile neutropenia (39%), neutropenia (34%), thrombocytopenia (31%), and anemia (29%). A total of 8 patients (14%) developed ≥ grade 2 suspected immune related AEs (irAEs) considered to be MBG453 related; 4 of whom (7%) presented with grade 3/4 events: ALT elevation (n=2), arthritis (n=1), and GGT increase (n=1). No study treatment-related deaths

January 2020 / 37

Information Classification: General

were observed.

Conclusion In this ongoing study in patients with HR-MDS and AML, the combination of MBG453 and decitabine was safe and well tolerated, and exhibited evidence of anti-leukemic activity with encouraging preliminary response rates occurring at a median of 2 cycles, with durability in both HR-MDS and AML.

Comment Unfortunately, the overall response rate (ORR) of 41.2% and complete response (CR) rate of 17.6% seen in the previously untreated acute myeloid leukemia (AML) cohort do not compare favorably with Venclexta, which demonstrated a CR/CRi response rate of 66% in the same setting. However, the company has previously announced that they will soon initiate a Phase II study of MBG453 in combination with both azacitidine and Venetoclax, a decision that was likely made after seeing the poor response rates for the combination with decitabine. Given the decision to move forward with a different combination, we are leaving the likelihood of approval unchanged.

Also of note is that the presenter mentioned that baseline TIM-3 expression was correlated with a reduction in bone marrow blasts following treatment. This will likely help identify the subset of patients that will benefit the most from the combination treatment of MBG453 and hypomethylating agents in the future.

Source: American Society of Hematology (ASH) 12/09/2019 (Abstract 570) Sagient Analysis

Oral Azacitidine for Acute Myelogenous Leukemia (AML) (BMY, Phase III)

Phase III - QUAZAR (Maintenance) Trial Data – Updated Results

Change to LOA: 0%

Difference Between Placebo Treatment Treatment and Placebo Treatment Description Placebo CC-486 CC-486 vs. Placebo Number of Patients N/A N/A 472 Number of Evaluable Patients 234 238 N/A Median Overall Survival 14.800 Months 24.700 Months N/A (Endpoint=Primary) (P= 0.0009)

January 2020 / 38

Information Classification: General

Median Relapse-Free Survival 4.800 Months 10.200 Months N/A (Endpoint=Secondary) (P= 0.0001) Median Overall Survival HR N/A N/A 0.690 Median Relapse-Free Survival HR N/A N/A 0.640

Abstract LBA-3: The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia (AML) in First Remission

Context Based on the results of QUAZAR AML-001, Bristol-Myers Squibb is planning regulatory submissions in the first half of 2020.

Design QUAZAR AML-001 is a Phase III, international, randomized, double-blind, placebo-controlled study of CC-486 as AML maintenance therapy in patients who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy (with or without consolidation). The study enrolled 472 patients, randomized 1:1 to receive initially either oral CC-486 300mg or placebo once daily for 14 days of a 28-day cycle plus best supportive care. Patients remained on treatment until unacceptable toxicity or disease progression.

Patients in the Phase III, international, randomized, double-blind, placebo-controlled study QUAZAR AML-001 were at least 55 years old, had de novo or secondary AML with intermediate or poor-risk cytogenetics and had achieved their first complete remission (CR) or complete remission with incomplete count recovery (CRi) after intensive induction chemotherapy. Patients had received intensive induction chemotherapy, with or without consolidation chemotherapy per investigator’s choice and were deemed not candidates for hematopoietic stem-cell transplant prior to study entry.

Per the abstract, eligible pts had de novo or secondary AML, intermediate- or poor-risk cytogenetics, and Eastern Cooperative Oncology Group performance status (ECOG PS) scores of ≤3; had achieved first complete remission (CR) or CR with incomplete count recovery (CRi) after IC, with or without consolidation chemotherapy; and were not candidates for hematopoietic stem-cell transplant (HSCT). Within 4 months of attaining CR/CRi, pts were randomized 1:1 to receive CC-486 300 mg or PBO once- daily on days 1–14 of repeated 28-day Tx cycles. A 21-day dosing schedule was permitted for pts who experienced AML relapse with 5–15% blasts in blood or bone marrow while on-study. Tx could continue indefinitely until the presence of >15% blasts, unacceptable toxicity, or HSCT. Hazard ratios (HRs) and 95% confidence intervals (CIs) were generated using a stratified Cox proportional hazards model.

Endpoints The primary endpoint of the study was overall survival. Secondary endpoints included relapse-free

January 2020 / 39

Information Classification: General

survival (RFS), safety and tolerability, healthcare resource utilization and patient-reported outcomes per the FACIT-Fatigue Scale and EQ-5D questionnaire.

Results Following intensive induction chemotherapy, 81% of patients had achieved a CR and 19% of patients had achieved a CRi. Eighty percent of patients had received at least one cycle of consolidation therapy prior to enrollment in the study. Four hundred seventy-two patients were then randomized 1:1 to receive initially either investigational CC-486 300mg (n=238) or placebo (n=234) once daily for 14 days of each 28-day cycle. Patients remained on treatment until unacceptable toxicity or disease progression.

At a median follow-up of 41.2 months, the primary endpoint of OS was significantly improved for patients receiving CC-486 compared to placebo. Median OS from time of randomization was 24.7 months in the CC-486 arm compared to 14.8 months for placebo (p=0.0009; HR 0.69 [95% CI: 0.55, 0.86]). Median RFS, the key secondary endpoint, was 10.2 months for those receiving CC-486 compared to 4.8 months for those receiving placebo (p=0.0001; HR 0.65 [95% CI: 0.52, 0.81]). Improvements in OS and RFS for those treated with CC-486 compared to placebo were demonstrated, regardless of cytogenetic risk category, prior consolidation or CR/CRi status at enrollment. Health-related quality of life (HRQoL) was preserved from baseline for patients receiving CC-486 compared to placebo during treatment.

The median duration of treatment was 12 cycles (1-80) for CC-486 and 6 cycles with placebo (1-73).

Per the abstract, between May 2013 and October 2017, 472 pts were randomized to receive CC-486 (n=238) or PBO (n=234). Baseline characteristics were balanced between Tx arms. Median age was 68 years (range 55–86), 91% of pts had de novo AML, and 86% and 14% of pts, respectively, had intermediate-risk or poor-risk cytogenetics. Following induction, 81% of pts achieved a CR and 19% achieved CRi; 80% of pts had received consolidation chemotherapy (45% received 1 consolidation cycle and 31% received 2 consolidation cycles). At a median follow-up of 41.2 months, OS was significantly improved with CC-486 vs. PBO: median OS was 24.7 months vs. 14.8 months from time of randomization, respectively (P=0.0009; HR 0.69 [95%CI 0.55, 0.86]). RFS was also significantly prolonged: median RFS was 10.2 months in the CC-486 arm, compared with 4.8 months in the PBO arm (P=0.0001; HR 0.65 [95%CI 0.52, 0.81]). OS and RFS benefits of CC-486 were demonstrated regardless of baseline cytogenetic risk, the number of prior consolidation cycles received, and CR/CRi status. CC-486 did not adversely impact overall HRQoL vs. PBO, as assessed by mean changes from baseline in HRQoL measures during Tx.

Most Common Adverse Events The most commonly occurring adverse events (AEs) of all grades with CC-486 and placebo, respectively, were nausea (65% vs. 24%), vomiting (60% vs. 10%) and diarrhea (50% vs. 22%). The most common

January 2020 / 40

Information Classification: General

grade 3-4 AEs for CC-486 and placebo, respectively, were neutropenia (41% vs. 24%), thrombocytopenia (23% vs. 22%) and anemia (14% vs. 13%). Serious AEs were reported in 34% of CC-486 patients and 25% of placebo patients, and were mainly infections, which occurred in 17% and 8% of CC-486 and placebo patients, respectively. There were 13% of CC-486 patients and 4% of placebo patients who discontinued treatment due to AEs.

Per the abstract, CC-486 had a manageable safety profile generally consistent with that of injectable azacitidine. Median exposure to CC-486 was 12 cycles (range 1–80) and to PBO was 6 cycles (1–73). The most frequently reported adverse events (AEs) with CC-486 and PBO were grade 1 or 2 gastrointestinal (GI) events, including nausea (64% and 23%, respectively), vomiting (59% and 10%), and diarrhea (49% and 21%). The most common grade 3–4 AEs were neutropenia (CC-486, 41%; PBO, 24%), thrombocytopenia (23% and 22%), and anemia (14% and 13%). Serious AEs were infrequent, mainly infections, which occurred in 17% of pts in the CC-486 arm and 8% of pts in the PBO arm. Few AEs led to Tx discontinuation, most often GI events (CC-486, 5%; PBO, 0.4%).

Conclusion Per the abstract, CC-486 is the first therapy used in the maintenance setting to provide statistically significant and clinically meaningful improvements in both OS and RFS in pts with AML in remission following induction chemotherapy, with or without consolidation. Oral CC-486 has a manageable safety profile and represents a new therapeutic standard for pts with AML in remission.

Comment Since 2017 there has been an explosion of newly approved treatments for AML and CC-486, an oral formulation of azacytidine, has the potential to add to this armamentarium. At ASH, Bristol-Myers presented the first numerical results from the placebo-controlled Phase III QUAZAR trial evaluating CC- 486 as maintenance therapy in patients aged ≥55 years with AML in first remission following intensive chemotherapy. With the CC-486 arm showing significant improvements in both overall survival (24.7 months vs 14.8 months; hazard ratio 0.69) and relapse-free survival (10.2 months vs 4.8 months; hazard ratio 0.65) compared to the placebo arm, these are impressive results and herald the likely approval of yet another treatment option for AML.

Intensive chemotherapy is a standard of care for newly diagnosed AML patients and induces complete remission in 60-80% of patients < 60 years and in 40-60% of patients older than 60 years but most of these patients, especially the older patients or those with a CRi, will relapse. Post-remission therapy with bone marrow transplant is desirable in higher-risk patients such as those with poor cytogenetic risk or those who are MRD-positive but transplant is not feasible for the majority of older individuals. The QUAZAR trial enrolled patients with intermediate- or poor-risk cytogenetics who were not eligible for a bone marrow transplant.

January 2020 / 41

Information Classification: General

At ASH, the presenter mentioned that 40-50% of patients were MRD-positive at enrollment and that the conversion rate to MRD-negativity was 39% in the CC-486 arm versus 20% in the placebo arm. The presenter also mentioned that CC-486 has a PK/PD profile distinct from injectable azacitidine.

Currently the only approved maintenance therapy for AML is Rydapt which is approved in this setting only in the EU and only for patients with a FLT3 mutation. Apart from CC-486, the only other therapies being investigated in registration trials for the first-relapse maintenance setting are the FLT3 inhibitors Xospata and quizartinib and the IDH1 inhibitor FT-2102. If successful, these other agents will be indicated only for patients with mutations in the targeted protein (FLT3 or IDH1). Zeltherva, a therapeutic vaccine targeting the Wilms tumor 1 (WT1) antigen, is being evaluated in a pivotal Phase III trial as maintenance therapy for patients in second complete remission (CR2) ineligible for allogeneic stem cell transplantation.

The primary completion date for a pivotal Phase III trial evaluating CC-486 for low-risk MDS was January 2019. at ASH, the investigator said that the MDS trial is no longer ongoing although no further details were provided.

With the QUAZAR trial having achieved both its primary and secondary endpoints, CC-486 is set to receive FDA approval and become the new standard of care for AML patients in remission. As we await an NDA submission expected in 1H of 2020, we are increasing the LOA by 4%.

Source: Press Release 12/10/2019 American Society of Hematology (ASH) 12/10/2019 (Abstract LBA-3) Sagient Analysis

Anemia Due to Oncology Treatment

Roxadustat for Anemia Due to Oncology Treatment (AZN; Phase III)

Phase III - MDS (US) Trial Data – Top-Line Results

Change to LOA: 2%

January 2020 / 42

Information Classification: General

Treatment Treatment Treatment Treatment Treatment Description Roxadustat 1.5 Roxadustat 2.0 Roxadustat 2.5 Roxadustat mg/kg mg/kg mg/kg Number of Patients 8 8 8 24 Number of Evaluable Patients N/A N/A N/A N/A Transfusion Independence (TI) 3 Patients 1 Patients 5 Patients 9 > 56 Consecutive Days within the First Patients 28 Weeks (Endpoint=Primary) At the Time of Achieving TI 1 Patients 1 Patients 7 Patients N/A Patients who Remainded on TI for >20 1 Patients 3 Patients N/A N/A Weeks > 50% Reduction in RBC Units in Any 8- N/A 12 Patients N/A 14 Week Period Compared to Baseline Patients

Abstract 843: Roxadustat (FG4592; ASP1517; AZD9941) in the Treatment of Anemia in Patients with Lower Risk Myelodysplastic Syndrome (LR-MDS) and Low Red Blood Cell (RBC) Transfusion Burden (LTB)

Design This is a two-part study; an open-label (OL), dose-finding segment (N=24) followed by a randomized double-blind (DB) placebo-controlled segment (N=156, 3:2 ratio of roxadustat to placebo). The primary goal of the OL segment is to identify the starting roxadustat dose-level for the DB segment. A total 24 patients in the OL segment have been enrolled in three sequential cohorts with 8 patients in each starting dose cohort (1.5, 2.0, or 2.5 mg/kg). RBC transfusion has been allowed per institutional criteria. Eligible patients were very low, low or intermediate risk primary MDS patients based on the International Prognostic Scoring System Revised classification with <5% bone marrow blasts; had baseline Hb < 10.0 g/dL; were >18 years old; and had LTB defined as receiving 1-4 RBC units per 8 week period. Patients were ineligible if they used an ESA within 8 weeks of the study start; had endogenous EPO levels >400 mIU/mL, or had a del(5q) cytogenetic abnormality. Roxadustat was administered TIW with doses titrated every 8 weeks per a dosing algorithm based on Hb response and transfusion need. Data from the OL segment were evaluated to identify the starting dose for the DB segment (currently enrolling). The proportion of patients who achieve ≥50% reduction in RBC transfusion over any 8 weeks compared to baseline (8 weeks prior to Day 1) and proportion of patients who achieve TI for ≥20 consecutive weeks are evaluated. Safety and tolerability are assessed by adverse event reporting, percentage of patients progressing to acute myeloid leukemia (AML), and clinical laboratory values.

Endpoints The primary endpoint is transfusion independence (TI) for ≥56 consecutive days during the first 28 weeks of treatment.

January 2020 / 43

Information Classification: General

Results Twenty-four transfusion dependent, LR-MDS patients were enrolled in the OL segment of this global Phase III trial. Nine patients (38%) achieved TI for at least 56 consecutive days within the first 28 weeks. Three of 9 patients started at 1.5 mg/kg dose, 1 patient started at 2.0 mg/kg dose and 5 patients started at 2.5 mg/kg dose. At the time of achieving TI, 7 of 9 patients (78%) were on 2.5 mg/kg dose, 1 patient (11%) was on 2.0 mg/kg dose (started with 1.5 mg/kg dose) and one patient (11%) was on 1.5 mg/kg dose. Four patients remained TI for >20 weeks (one at 1.5 mg/kg dose level and three at 2.5 mg/Kg dose-level). One additional patient achieved TI after the initial 28-week dosing period at a dose-level of 3.5 mg/kg (starting dose 2.0 mg/kg). A total of 14 patients (58%) achieved a ≥50% reduction in RBC units in any 8-week period compared to baseline (range of 2-4 RBC units in 8 weeks before dosing); 12 of these patients were at ≥ 2.5 mg/kg dose level when achieving a 50% reduction in transfusion without need for IV iron.

Most Common Adverse Events The overall safety profile observed is consistent with the patient population under study. Six patients reported 8 treatment-emergent SAEs with none being fatal. No patient has progressed to AML.

Conclusion Based on the observed response (TI and transfusion reduction) and safety profile in LR-MDS patients, 2.5 mg/kg was selected as the starting dose for the ongoing 156-patient DB portion of the trial.

Comment These top-line results are positive for Astellas' and Astrazeneca’s roxadustat for the treatment of anemia in patients with lower risk myelodysplastic syndrome (LR-MDS) and low red blood cell transfusion burden (LTB). While these dose-ranging data are preliminary and the sample size is small, they suggest that roxadustat is capable of reducing requirement for blood transfusions, and thus we are increasing our LOA by 2%.

Roxadustat is a first-in-class inhibitor for hypoxia-inducible factor prolyl hydroxylase (HIF-PH) and is used in the treatment of anemia. The current results demonstrated that 2.5mg/kg is the optimal dose since it had the best response from patients, as measured by transfusion independence for at least 56 days (eight weeks) in the first 28 weeks of treatment. In the overall roxadustat-treated population, the primary endpoint, of transfusion independence within the 28 weeks period, was achieved by 38% of patients, with 56% (5/9) achieving the endpoint in the 2.5mg/kg arm. Additionally, 58% of roxadustat- treated patients had a lower requirement for red blood cell transfusions, with the majority of these patients (12/14) receiving the higher 2.5mg/kg dose. The safety profile was in line with the patient population, with six patients reporting severe adverse events, none of which were fatal.

Roxadustat is forecast to reach blockbuster sales and has already achieved approvals in China for the

January 2020 / 44

Information Classification: General

treatment of dialysis patients and those with chronic kidney disease. The orally-delivered drug represents a significant threat to current therapies such as erythropoiesis-stimulating agents (ESAs) like Epogen and ProCrit, which are expensive biologics that are administered via intravenous injection. Additionally, the drug is positioned to launch in Japan a year ahead of GlaxoSmithKline’s rival drug daprodustat.

Source: American Society of Hematology (ASH) 12/09/2019 (Abstract 843) Sagient Analysis

Autoimmune Hemolytic Anemia (AIHA)

BIVV009 for Autoimmune Hemolytic Anemia (AIHA) (SNY, Phase III)

Phase III - Cardinal (Cold Agglutinin Disease) Trial Data – Updated Results

Change to LOA: 4%

Treatment Treatment Description BIVV009 Number of Patients 24 Number of Evaluable Patients N/A Patients with Composite of an Increase in Hemoglobin >2 54 % g/dL from baseline at Week 26 (Endpoint=Primary) Patients with Hemoglobin level >12 g/dL at Week 26 62.5 % (Endpoint=Primary) Patients remaining Transfusion-Free after Week 5 71 % (Endpoint=Primary) Patients achieving a Clinically Significant Mean Hemoglobin 83 % Improvement of >1 g/dL (Endpoint=Secondary) Overall Mean FACIT Fatigue Score Increase from Baseline at 10.9 points Week 26 (Endpoint=Secondary)

Abstract LBA-2: Inhibition of Complement C1s with Sutimlimab in Patients with Cold Agglutinin Disease (CAD): Results from the Phase 3 Cardinal Study

January 2020 / 45

Information Classification: General

Design Context Sanofi intends to submit a Biologics License Application for sutimlimab, for which it has received Breakthrough Therapy designation, to the US Food and Drug Administration in the near future.

Design Cardinal is a pivotal Phase III, open-label, single-arm, multicenter study of 26 weeks’ duration (Part A) with an ongoing extension (Part B). Data is available from Part A. Patients with confirmed diagnosis of CAD were enrolled. Eligibility criteria included baseline hemoglobin (Hb) ≤10 g/dL, total bilirubin level above normal, and ≥1 blood transfusion in the prior 6 months. Sutimlimab was administered intravenously on Days 0 and 7, followed by biweekly infusions. Patients weighing <75 kg or ≥75 kg received a 6.5 g or 7.5 g dose, respectively.

Endpoints The primary efficacy outcome was a responder rate based on a composite of an increase in hemoglobin ≥2 g/dL from baseline or reaching a hemoglobin level ≥12 g/dL at the 26-week treatment assessment timepoint and the absence of transfusions from Weeks 5 to 26, further, patients were not allowed to receive other CAD-related treatments. The secondary efficacy measures assessed improvement in key indicators of the disease process: hemoglobin, bilirubin (a measure of red blood cell destruction in CAD), Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score (a quality of life measure of fatigue), lactate dehydrogenase (LDH), and transfusion usage.

Results Twenty-four patients enrolled and received at least one dose of sutimlimab (mean age of 71.3 years). 62.5% of patients (n=15) had received ≥1 prior targeted therapy within the last 5 years. Two patients withdrew from the study early for reasons unrelated to study drug. All 22 patients who completed Part A of the study elected to continue sutimlimab in Part B, an ongoing safety and durability of response extension study. • The pre-specified primary endpoint was met. 54% (n=13) of patients met the composite endpoint criteria, with 62.5% (n=15) of patients achieving a hemoglobin ≥ 12 g/dL or an increase of at least 2 g/dL and 71% (n=17) of patients remaining transfusion-free after week 5. • The study showed an overall mean increase in hemoglobin of 2.6 g/dL at treatment assessment timepoint; 83% (n=20) of the 24 patients enrolled achieved a clinically significant mean hemoglobin improvement of ≥1 g/dL. • Hemoglobin improved rapidly, with a mean increase from baseline of ≥1 g/dL by week 1 and ≥2 g/dL by week 3. Mean hemoglobin levels were maintained at >11 g/dL (from a mean baseline 8.6 g/dL) after week 3, demonstrating a sustained effect throughout the remainder of the treatment period.

January 2020 / 46

Information Classification: General

• Mean total bilirubin, a key marker of hemolysis in CAD, achieved near normalization after the first week of treatment (24.6 µmol/L; upper limit of reference range 20.5 µmol/L), with normalized bilirubin levels (< upper limited of reference range) maintained from week 3 through the remainder of the study. • Mean FACIT-Fatigue score demonstrated a clinically meaningful improvement in fatigue by week 1 of treatment with an increase of 7.2 points. The overall mean FACIT Fatigue score increase from baseline at the 26-week treatment assessment timepoint was 10.9 points. Per the abstract, the estimated mean (standard error [SE]) Hb increase at treatment assessment time point was 2.6 (0.4) g/dL. Hb improved rapidly after the first dose of sutimlimab with 1.2 g/dL and 2.3 g/dL increases by Weeks 1 and 3, respectively. Mean overall Hb was maintained above 11 g/dL after Week 3. Twenty (83.3%) patients had a mean Hb increase ≥1 g/dL. Mean total bilirubin was normalized by Week 3. Seventeen (70.8%) patients remained free of transfusions from Weeks 5 to 26. FACIT-F scores improved within 1 week, peaking by Week 5, and remained stable through Week 26. The estimated mean (SE) FACIT-F score increase at the treatment assessment time point was 10.9 (1.4), consistent with a clinically meaningful response. Hb, bilirubin, and FACIT-F improvements correlated with rapid normalization of complement C4 and near-complete inhibition of CP activity. The prespecified primary endpoint was met (13 [54.2%] patients).

Most Common Adverse Events • 22 patients (91.7%) experienced at least 1 treatment-emergent adverse event. • 7 patients (29.2%) experienced at least 1 treatment-emergent serious adverse event (TESAE) of which none were assessed by the investigator as related to sutimlimab. • 2 patients (8.3%) experienced at least 1 TESAE of infection, of which none were assessed by the investigator as related to sutimlimab. No patient discontinued sutimlimab due to infection and there were no meningococcal infections identified. Per the abstract, twenty-two (91.7%) patients experienced ≥1 treatment-emergent adverse event (TEAE), with 7 (29.2%) patients experiencing a serious TEAE (TESAE). There were no TESAEs assessed as related to sutimlimab. There was 1 death in a patient with hepatic cancer that was assessed as unrelated to the study drug. Serious infections were reported, but no meningococcal infections were identified. There were no thromboembolisms and decreases in mean D-dimer and thrombin- antithrombin III complex thrombotic markers were observed. All 22 patients that completed Part A enrolled in Part B.

Conclusion The Phase III Cardinal study shows that sutimlimab, a first-in-class selective inhibitor of the CP, has a rapid and sustained treatment effect in CAD by preventing hemolysis, significantly increasing Hb, and improving QOL (FACIT-F). These results demonstrate that targeting the CP represents a novel, effective therapeutic approach for the management of CAD and indicate that sutimlimab has the potential to change treatment practices for patients with this condition.

January 2020 / 47

Information Classification: General

Comment Sanofi presented the first numeric data from the pivotal, single-arm, Phase III Cardinal study of sutimlimab, a monoclonal antibody that inhibits C1s in the classical complement pathway, in a late- breaking abstract at ASH 2019. The efficacy results shown are likely to pave the path for approval, particularly since there are currently no approved treatments for primary cold agglutinin disease (CAD), a form of autoimmune hemolytic anemia.

Both rituximab and rituximab in combination with fludarabine are currently used off-label for the treatment of CAD. Rituximab monotherapy has demonstrated an overall response rate (ORR) of 45% to 54%, consisting primarily of partial responses (PRs), while the combination of rituximab and fludarabine has demonstrated an ORR of 76%, including a 21% complete response (CR) rate and a 55% PR rate. However, the toxicity of the combination regimen severely limits its use in CAD.

The results seen with sutimlimab are relatively in line with those seen with the off-label treatments, although longer term follow-up is needed to determine how the duration of response will compare. The primary endpoint in CARDINAL, which corresponded roughly to the criteria used for a partial response in the rituximab trial, was met in 54.2% of patients. Additionally, patients responded quickly to treatment with sutimlimab, demonstrating increases in both mean hemoglobin and mean total bilirubin, a biomarker used for detecting hemolysis in CAD, within the first weeks of treatment. Furthermore, treatment with sutimlimab was associated with clinically meaningful improvements in quality of life, as measured by the FACIT-Fatigue score. The side-effect profile was relatively safe, with few investigator- assessed serious treatment-emergent adverse events due to sutimlimab.

Sanofi has already announced plans to file for approval in 2020. In addition to Breakthrough designation in the United States, sutimlimab has received Orphan Drug Designation in the US, Europe, and Japan.

Based on these results and the high unmet need for additional treatments in this indication, we are raising the likelihood of approval by 4%.

Source: Press Release 12/10/2019 (SNY) American Society of Hematology (ASH) 12/10/2019 (Abstract LBA-2) Sagient Analysis

January 2020 / 48

Information Classification: General

Chronic Lymphocytic Leukemia (CLL)/Small Cell Lymphocytic Lymphoma (SLL) - NHL)

Calquence for Chronic Lymphocytic Leukemia (CLL)/Small Cell Lymphocytic Lymphoma (SLL) – NHL (AZN; Approved)

Phase III - ELEVATE-TN (vs. Obinutuzumab) (First-Line) Trial Data – Updated Results

Change to LOA: 0%

Difference Between Difference Between Treatment Treatment Treatment and Treatment and Comparator Comparator Comparator Treatment Description Calquence + Calquence Calquence + Calquence Chlorambucil + Obinutuzumab Monotherapy Obinutuzumab vs. Monotherapy vs. Obinutuzumab Chlorambucil + Chlorambucil + Obinutuzumab Obinutuzumab Number of Patients 179 179 N/A N/A 177 Number of Evaluable N/A N/A N/A N/A N/A Patients Median Progression- 22.600 Months N/A N/A N/A N/A Free Survival (PFS) (Endpoint=Primary) Hazard Ratio - PFS N/A N/A N/A 0.100 0.200 (Endpoint=Primary) (P< 0.0001) (P< 0.0001) Estimated PFS at 24 47.000 % 93.000 % 87.000 % N/A N/A Months Overall Response Rate 78.500 % 93.900 % 85.500 % N/A N/A (ORR) (P< 0.0001) (P= 0.0763) (Endpoint=Secondary)

Abstract 31: ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL)

Context These findings, along with previously reported data from the Phase III ASCEND trial in relapsed or refractory CLL, support the recent approvals of Calquence by the US FDA and the Australian Therapeutic Goods Administration for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) and by Health Canada for CLL.

January 2020 / 49

Information Classification: General

Design ELEVATE TN (ACE-CL-007) is a randomised, multicentre, open-label Phase III trial evaluating the safety and efficacy of Calquence in combination with obinutuzumab, a CD20 monoclonal antibody, or Calquence alone versus chlorambucil, a chemotherapy, in combination with obinutuzumab in previously untreated patients with CLL. Patients 65 years of age or older, or between 18 and 65 years of age with a total Cumulative Illness Rating Scale (CIRS) >6 or creatinine clearance of 30 to 69 mL/min, were enrolled. In the trial, 535 patients were randomised (1:1:1) into three arms. Patients in the first arm received chlorambucil in combination with obinutuzumab. Patients in the second arm received Calquence (100mg approximately every 12 hours until disease progression or unacceptable toxicity) in combination with obinutuzumab. Patients in the third arm received Calquence monotherapy (100mg approximately every 12 hours until disease progression or unacceptable toxicity).

Endpoints The primary endpoint is PFS in the Calquence and obinutuzumab arm compared to the chlorambucil and obinutuzumab arm, assessed by an independent review committee (IRC), and a key secondary endpoint is IRC-assessed PFS in the Calquence monotherapy arm compared to the chlorambucil and obinutuzumab arm. Other secondary endpoints include objective response rate, time to next treatment and overall survival.

Results At a median follow-up of 28.3 months, Calquence in combination with obinutuzumab or as a monotherapy significantly reduced the risk of disease progression or death by 90% and 80%, respectively, vs. chlorambucil plus obinutuzumab.

In an exploratory analysis, Calquence in combination or alone demonstrated consistent PFS improvements across most pre-specified subgroups of patients with high-risk disease characteristics, including the unmutated immunoglobulin heavy-chain variable gene (IGHV), del(11q) and complex karyotype.

Most Common Adverse Events Overall, the safety and tolerability profile of Calquence observed in the ELEVATE TN trial was consistent with its known profile. Adverse events (AEs) led to treatment discontinuation in 11.2% of patients treated with Calquence in combination with obinutuzumab and 8.9% of patients treated with Calquence monotherapy versus 14.1% of patients treated with chlorambucil plus obinutuzumab.

With over two years of follow-up, 79% of patients in both the Calquence-containing arms remain on Calquence as a monotherapy. In the Calquence combination arm (n=178), the most common AEs of any grade (≥30%) included headache (39.9%), diarrhoea (38.8%) and neutropenia (31.5%). In the Calquence

January 2020 / 50

Information Classification: General

monotherapy arm (n=179), the most common AEs of any grade (≥30%) included headache (36.9%) and diarrhoea (34.6%). In the chlorambucil plus obinutuzumab arm (n=169), the most common AEs of any grade (≥30%) included neutropenia (45.0%), infusion-related reaction (39.6%) and nausea (31.4%).

Comment This interim analysis of results from the Phase III ELEVATE TN trial in patients with previously untreated CLL show that Calquence + Gazyva significantly extended PFS compared to Gazyva + chlorambucil (median not reached vs. 22.6 months; HR = 0.10). Calquence monotherapy also significantly prolonged PFS (median not reached) compared with Gazyva + chlorambucil (HR = 0.20). A subgroup analysis showed that Calquence + Gazyva yielded a significant PFS benefit compared with the control in patients with unmutated (HR = 0.08) or mutated (HR = 0.15) IGHV.

Although there was no significant improvement in overall survival, this may be because the trial allowed patients in the Gazyva + chlorambucil arm with disease progression to crossover to Calquence. With a median follow-up of 28.3 months, 82 of 177 patients (46%) randomized to Gazyva + chlorambucil had disease progression and 45/82 (55%) crossed over to receive Calquence monotherapy. Nevertheless, fewer deaths were seen with Calquence + Gazyva and Calquence monotherapy (5% and 6% of enrolled patients, respectively) compared to Gazyva + chlorambucil (9.6% of enrolled patients). Longer follow-up may be needed to detect a significant difference in overall survival.

In a cross-trial comparison, the 87% PFS rate at 24 months for Calquence monotherapy compares well to similar data for Imbruvica (89%). Similarly, the 90% PFS rate at 30 months for Calquence + Gazyva compares well to the corresponding 79% PFS rate reported for Imbruvica + Gazyva.

In the conference call, officials noted that both Calquence and Imbruvica are efficacious but that Calquence, a more selective inhibitor of BTK, appears safer. Indeed, the rate of Grade III or higher atrial fibrillation was lower in the ELEVATE TN trial (1% for Calquence + Gazyva and 0% for Calquence monotherapy) than for Imbruvica (5% for Imbruvica + Gazyva and 3% for Imbruvica monotherapy). Furthermore, while the Imbruvica FDA label lists hypertension and tumor lysis syndrome in the warnings and precautions, they are not listed in the Calquence label.

The approval of Venclexta in combination with Gazyva as a 12-month, fixed duration treatment for front-line CLL has generated a lot of excitement. The pivotal trial used the same comparator as the ELEVATE-TN trial (Gazyva + chlorambucil) and the PFS rate at 24 months for Venclexta + Gazyva (88.2%) was slightly lower than for Calquence + Gazyva (93%). Moreover, the hazard ratio for the latter regimen was more impressive (0.1 vs 0.35).

In the call, Dr. John Byrd, lead investigator for the ELEVATE TN trial, noted that most CLL patients are in in their seventies and being treated in the community and that for such patients a well-tolerated

January 2020 / 51

Information Classification: General

regimen such as Calquence monotherapy may be optimal. Dr. Byrd stated that the fixed duration option of Venclexta combined with Gazyva may be best suited for younger patients in their sixties who are fitter and have a longer life expectancy. Dr. Byrd also commented that he thought chemoimmunotherapy such as FCR may be reserved only for very young patients (in their fifties) with IGHV mutated CLL.

Looking to the future, we await results from ELEVATE-RR, a Phase III trial comparing Calquence to Imbruvica in patients with previously treated CLL. There is also a Phase III trial evaluating Calquence +Venclexta with and without Gazyva in newly diagnosed CLL with chemoimmunotherapy as the comparator.

Source: Press Release 12/07/2019 (AZN) American Society of Hematology (ASH) 12/07/2019 (Abstract 31) American Society of Hematology (ASH) 12/10/2019 (AZN, Presentation Slides) Company Conference Call 12/10/2019 (AZN) Sagient Analysis

LOXO-305 for Chronic Lymphocytic Leukemia (CLL)/Small Cell Lymphocytic Lymphoma (SLL) – NHL (LLY; Phase I/II)

Phase I/II – BRUIN Trial Data – Top-Line Results

Change to LOA: 2%

Abstract 501: Results from a First-in-Human, Proof-of-Concept Phase 1 Trial in Pretreated B-Cell Malignancies for Loxo-305, a Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor

Design The BRUIN Phase I/II trial, which began enrolling patients in March 2019, contains a dose escalation phase and a dose expansion phase. The dose escalation phase follows a "3+3" design. LOXO-305 is dosed orally in 28-day cycles. As dose cohorts are cleared, additional patients can enroll in cleared cohorts and intra-patient dose escalation is permitted.

The data presented at ASH were based on patients treated as of September 27, 2019, with follow-up as of November 5, 2019. Twenty-eight total patients had been enrolled to five dose escalation cohorts: 25 mg QD (n=5), 50 mg QD (n=6), 100 mg QD (n=9), 150 mg QD (n=5), and 200 mg QD (n=3). There were 16

January 2020 / 52

Information Classification: General

patients with CLL, eight patients with MCL, two patients with Waldenstrom macroglobulinemia, one patient with diffuse large B-cell lymphoma (DLBCL), and one patient with marginal zone lymphoma (MZL). The CLL patients had received a median of four prior systemic therapy regimens and 75% had received at least one prior BTK inhibitor. The MCL patients had received a median of three prior systemic therapy regimens and 88% had received at least one prior BTK inhibitor.

Endpoints The primary endpoint of the trial is the determination of the maximum tolerated dose (MTD) or recommended dose for further study. Secondary endpoints include safety, overall response rate (by disease-specific criteria) and duration of response.

Results The efficacy data presented at ASH are based on investigator response assessments. Responses were observed across all dose levels. • Of 16 CLL patients enrolled, there were 10 responders (8 partial responses, 2 partial response with ongoing lymphocytosis) among 13 patients eligible for response assessment, resulting in a 77% ORR. All patients with CLL have demonstrated tumor reduction, with evidence of deepening response over time. Responses were observed in patients with acquired resistance to prior BTK therapy (those with and without C481S mutations), in patients who were intolerant to prior BTK therapy, and in patients with acquired resistance to prior BCL2 therapy (including one with a known BCL G101V mutation). As expected, LOXO-305 treatment causes acute lymphocytosis, which resolves over time—a well described pharmacodynamic response associated with effective BTK inhibition. Of the three CLL patients not yet eligible for response assessment (one with the BTK C481S mutation), all three have demonstrated lymphocytosis early in cycle 1. All CLL responding patients remain in response and all CLL patients remain on study. • Of eight MCL patients enrolled, there were three responses (1 complete response, 2 partial responses) among six patients eligible for response assessment, resulting in a 50% ORR. Two of the responders had progressed on prior BTK therapy (but without a documented C481x mutation). All MCL responding patients remain in response and on study. Three MCL patients discontinued therapy in cycle 1 due to progressive disease.

Most Common Adverse Events Most treatment-emergent adverse events were Grade 1 in severity with the most commonly reported events, regardless of attribution, being fatigue (25% total: 21% Grade 1, 4% Grade 2) and diarrhea (18% total: 14% Grade 1, 4% Grade 2). Two adverse events ≥Grade 3 were attributed to LOXO-305 (Grade 3 leukocytosis and Grade 3 transient neutropenia). No dose limiting toxicities were reported and an MTD had not been reached.

Conclusion

January 2020 / 53

Information Classification: General

At all doses studied, LOXO-305 delivered objective responses in patients who had received diverse prior therapies and had exhibited varied molecular mechanisms of acquired resistance.

Comment Although preliminary, these first results from the dose-escalation Phase I/II BRUIN trial of LOXO-305 for the treatment of patients with chronic lymphocytic leukemia (CLL) or patients with mantle cell lymphoma (MCL) are promising. Bruton's tyrosine kinase (BTK) is a validated molecular target found across many B-cell leukemias and lymphomas. However, the use of currently approved BTK inhibitors such as ibrutinib and acalabrutinib is limited by patient intolerance, likely caused by off-target inhibitor of other cellular targets, and acquired resistance, usually caused by the development of BTK C481 mutations. Eli Lilly’s LOXO-305 is a highly selective, non-covalent inhibitor of both wild-type and C481- mutated BTK.

In terms of safety, there were no observations of atrial fibrillation or major bleeding, both of which are adverse events typically associated with the covalent BTK inhibitor class. There were also no dose limiting toxicities seen with LOXO-305 and the maximum tolerated dose has not yet been reached. Moreover, there were only two Grade 3 or higher adverse events in this study. LOXO-305 had an excellent safety profile, which supports its use both as a monotherapy and as part of a potential combination regimen in the future.

The responses rates in the CLL cohort were promising, with an overall response rate (ORR) of 77%, a partial response (PR) rate of 62%, and a partial response with ongoing lymphocytosis (PR-L) rate of 15%. All patients with CLL, including those with C481 mutations, experienced a reduction in tumor burden with LOXO-305 regardless of starting dose or prior therapy and currently remain on treatment. Additionally, there was evidence that patient response deepened over time, although confirmatory longer-term follow-up in additional patients is needed. There was also evidence of BTKi-induced lymphocytosis, an expected pharmacodynamic response associated with effective BTK inhibition, in 12 patients.

In the small MCL cohort, the ORR was 50%, with one patient achieving a CR and two patients with PRs. As in the CLL cohort, the responses were observed in patients who had previously progressed on a BTK inhibitor. The MCL responders all remain on the study and have not yet experienced any progression. While these early efficacy results look good, data from additional patients are needed to fully elucidate LOXO-305’s role in MCL.

These encouraging, preliminary results in heavily pretreated patients suggest that LOXO-305 may be an effective and safe treatment for both CLL and MCL, particularly for patients who have progressed other novel therapies. Of note, LOXO-305 demonstrated anti-tumor activity in patients who had progressed after prior treatment with covalent BTK inhibitors, suggesting that BTK remains an actionable target in

January 2020 / 54

Information Classification: General

those patients. The BRUIN trial is continuing to enroll patients.

Based on both the efficacy and safety results in this difficult-to-treat relapsed/refractory population, we are raising the likelihood of approval by 2%.

Source: Press Release 12/08/2019 (LLY) American Society of Hematology (ASH) 12/08/2019 (Abstract 501) Sagient Analysis

TG-1303 for Chronic Lymphocytic Leukemia (CLL)/Small Cell Lymphocytic Lymphoma (SLL) – NHL (TGTX; Phase III)

Phase I/II - w/Venetoclax Trial Data – Updated Results

Change to LOA: 3%

Treatment Treatment Treatment Description Induction with Induction with Ublituximab + Ublituximab + Umbralisib Umbralisib Followed by Consolidation with Umbralisib + Venetoclax Number of Patients N/A N/A Number of Evaluable Patients 23 9 ORR at cycle 3 87.000 % N/A ORR after Cycle 12 N/A 100.000 % CR after Cycle 12 N/A 44.000 % (Endpoint=Secondary) PB MRD-negativity after Cycle 12 N/A 100.000 % (Endpoint=Secondary) BM MRD-negativity after Cycle 12 N/A 78.000 % (Endpoint=Secondary)

Abstract 360: A Phase 1/2 Study of Umbralisib, Ublituximab and Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Context TG Therapeutics expects to see data in the Phase III UNITY trial in the coming weeks or months. An open-label, multicenter, Phase II study evaluating U2 (TG-1303) plus venetoclax (ULTRA-V) in treatment naïve and previously treated CLL is now open for enrollment.

January 2020 / 55

Information Classification: General

TG Therapeutics announced top-line results from the Phase I study of TG-1701 for the treatment of relapsed/refractory B-cell malignancies. The abstract entitled "Phase 1 Study of TG-1701, a Selective Irreversible Inhibitor of Bruton's Tyrosine Kinase (BTK), in Patients with Relapsed/Refractory B-Cell Malignancies" will be presented at the American Society of Hematology annual meeting on December 9, 2019.

Design Regimen was administered with 3 cycles of U2 induction/debulking to reduce the risk of tumor lysis syndrome (TLS), followed by the combination of umbralisib and venetoclax starting in cycle 4. Patients who were bone marrow MRD negative after cycle 12 stopped all therapy.

Results This oral presentation includes data from patients with relapsed or refractory CLL treated with the triple combination of ublituximab, umbralisib, and venetoclax. Twenty-seven patients were evaluable for safety and 23 were evaluable for efficacy.

• Overall response rate (ORR) of 87% (20/23) after U2 induction period at cycle 3, prior to introduction of venetoclax, in relapsed/refractory CLL patients, including patients refractory to ibrutinib. • U2 induction appeared to reduce venetoclax TLS risk, with no patients remaining as TLS high-risk following 3 cycles of U2. • 13 patients treated for > 7 cycles and 9 patients >12 cycles: o 100% ORR (13/13) after cycle 7 for the triple combination o 100% ORR (9/9) including 44% Complete Response (CR) after cycle 12 for the combination o 100% (9/9) of patients had undetectable minimal residual disease (MRD) (<0.01%) in peripheral blood after 12 cycles of therapy; and o 78% (7/9) of patients who completed 12 cycles of therapy had undetectable MRD in bone marrow and have stopped therapy • No patients (n = 27) have progressed to date with a median follow-up of 6.4 months.

Most Common Adverse Events Triple combination was generally well tolerated with no events of TLS observed.

Conclusion • Umbralisib, ublituximab and venetoclax is well tolerated at the Phase II doses o U2 induction mitigates TLS risk

January 2020 / 56

Information Classification: General

o Manageable myelosuppression and GI effects resulting in low rate (7%) of discontinuation due to AE • Early evidence of MRD negativity with 12 cycles of therapy o 9/9 and 7/9 undetectable in peripheral blood and marrow respectively • Relapsed/refractory CLL enrollment is ongoing in BTK inhibitor treated patients o Expansion cohorts for Richters transformation and mantle cell lymphoma • ULTRA-V Phase II Study of U2-Ven regimen ongoing in treatment naïve and relapsed/refractory CLL

Comment These positive results in relapsed/refractory CLL (including patients refractory to Imbruvica) suggest that a debulking/induction regimen consisting of ublituximab, a glycoengineered anti-CD20 monoclonal antibody, combined with umbralisib, a dual inhibitor of PI3K delta and CK1 epsilon, given for three cycles, can lower the risk of tumor lysis syndrome during consolidation treatment with umbralisib + Venclexta. Patients who were bone marrow MRD negative after cycle 12 stopped all therapy while those who were MRD positive continued on umbralisib maintenance therapy.

The 100% ORR, 44% CR rate and 100% peripheral blood (PB) MRD-negativity rate in the first nine patients to complete 12 cycles are encouraging when compared to Phase III data for rituximab + Venclexta (93% ORR, 27% CR rate and 83.5% PB MRD-negativity). In MURANO, the pivotal trial that led to approval of the rituximab + Venclexta for relapsed/refractory CLL, this regimen was evaluated as a fixed-duration treatment.

Interestingly, induction with ublituximab + umbralisib resulted in an ORR of 87%. The ublituximab + umbralisib combination is currently being evaluated in the pivotal UNITY-CLL trial in treatment-naïve or relapsed/refractory CLL and results are expected in early 2020. The primary endpoint is PFS with ORR as the secondary endpoint and Gazyva + chlorambucil the comparator.

While PI3K inhibitors have gotten a black eye for their poor tolerability, umbralisib has so far shown a favorable tolerability profile. A key advantage of PI3K inhibitors is that they target the BTK pathway and so offer an alternative to BTK inhibitors which could be useful for patients that cannot tolerate these inhibitors or who have developed resistance.

The triple combination of ublituximab, umbralisib and Venclexta has the potential to offer patients with CLL a highly active, time-limited, and generally well tolerated treatment option. A Phase II study (ULTRA- V) in treatment naïve and relapsed/refractory CLL is ongoing. As we await results from the UNITY-CLL trial, we are increasing the LOA for TG-1303 by 3% bringing it to 1% above average.

January 2020 / 57

Information Classification: General

Source: Press Release 12/08/2019 (TGTX) American Society of Hematology (ASH) 12/08/2019 (Abstract 360) American Society of Hematology (ASH) 12/08/2019 (Presentation Slides) Sagient Analysis

Diffuse Large B-Cell Lymphoma (DLBCL) - NHL

AUTO3 for Diffuse Large B-Cell Lymphoma (DLBCL) – NHL (AUTL; Phase I/II)

Phase I/II - ALEXANDER - w/Keytruda Trial Data – Updated Results

Change to LOA: 0%

Abstract 246: Phase 1/2 Study of AUTO3 the First Bicistronic Chimeric Antigen Receptor (CAR) Targeting CD19 and CD22 Followed By an Anti-PD1 in Patients with Relapsed/Refractory (r/r) Diffuse Large B Cell Lymphoma (DLBCL): Results of Cohort 1 and 2 of the Alexander Study

Context The company expects to progress AUTO3 to a decision point in relapsed/refractory DLBCL by the mid- point of 2020.

Design ALEXANDER is a Phase I/II study of AUTO3 in Diffuse Large B Cell Lymphoma (DLBCL). The trial is divided into a Phase I safety cohort and a Phase II efficacy cohort.

Per the abstract, investogators constructed a novel bicistronic retroviral vector encoding both an anti- CD19 CAR and an anti-CD22 CAR. Antigen binding domains were humanized incorporating an OX40 co- stimulatory domain for the CD19 CAR and a 41BB co-stimulatory domain for the CD22 CAR. The CD22 CAR was enhanced by incorporating a novel pentameric spacer. The cell product was manufactured in a semi-automated and closed process. Patients (≥ 18 years) with r/r DLBCL not otherwise specified (NOS), high grade, or transformed from indolent histology; Eastern Cooperative Oncology Group Performance Status <2, adequate renal, hepatic, cardiac function and an absolute lymphocyte count ≥0.5 x 109/L are eligible. Patients with CNS disease, prior allogeneic stem cell transplant, prior CD19 or CD22 directed therapy are excluded, as well as patients with any contraindication to receiving Pem.

January 2020 / 58

Information Classification: General

All patients received lymphodepletion with 30 mg/m2/day fludarabine and 300 mg/m2/day cyclophosphamide for 3 days prior to AUTO3 infusion. Patients in cohort 1 received 50 x 106 and patients in cohort 2 received 150 x 106 transduced CAR T-cells. The first 3 patients in lowest dose cohort received AUTO3 alone, subsequently all patients should receive AUTO3 followed by 3 doses of Pem 200 mg given every 3 weeks starting day 14.

Endpoints Per the abstract, the primary endpoints of Phase I are frequency of dose-limiting toxicities (DLTs) and grade (G) 3-5 toxicity. Key secondary endpoints include overall response rate, complete response rate, duration of response, disease free survival, overall survival, and biomarker endpoints such as the level of AUTO3 cells in blood and duration of B cell aplasia.

Results In the dose escalation phase, 16 patients were treated, with 4 patients dosed at 50 x 106 cells without pembrolizumab; 11 patients were dosed at escalating doses of AUTO3 with pembrolizumab administered at day 14 as follows: 3 at 50 x 106 cells, 4 at 150 x 106 cells, and 4 at 450 x 106 of AUTO3; and 1 patient was dosed with 450 x 106 cells with pembrolizumab administered 1 day before AUTO3 infusion. Fourteen patients were evaluable at one month. Across all tested doses 5 patients achieved a complete response, with 4 of 5 complete responses ongoing, the longest at 18 months. All CRs were achieved without need for steroid or tocilizumab-based management of the patients or ICU level care.

Per the abstract, as of the data cut-off date (July 5, 2019), 24 patients have been enrolled, 4 patients were screen failures, 1 patient is in screening, and 19 patients underwent leukapheresis. 16/16 patients had product manufactured and 3 patient products in the manufacturing process. 5/16 patients discontinued before dosing and 11 patients were dosed with AUTO3 in cohort 1 and 2. Four with AUTO3 alone, and 7 with AUTO3 followed by Pem. Seven patients received 50x106 AUTO3, and 4 patients received 150 x 106 AUTO3. Median age was 49, median 3 prior lines of treatment, and 27% had prior autologous transplant. Seven patients had DLBCL NOS and 4 patients had transformed DLBCL from marginal zone or follicular lymphoma. Eleven patients in cohort 1 and 2 had a minimum of 4 week follow up and were evaluable for safety and efficacy analysis.

At the lowest dose level of 50 x 106 cells, the objective response rate (ORR) was 57% and complete remission rate (CRR) was 29%. The ORR and CRR at dose 150 x 106 cells was 50%. Updated follow up and additional patient data at higher dose levels as well as cellular kinetics, product characteristics and relevant biomarkers was presented.

Most Common Adverse Events AUTO3 was well-tolerated, with no patients experiencing ≥ Grade 3 cytokine release syndrome (CRS) with primary infusion and 1 of 14 experiencing Grade 3 neurotoxicity that resolved swiftly with steroids.

January 2020 / 59

Information Classification: General

There were no pembrolizumab immune-related toxicities and the majority of grade 3 or higher adverse events were hematological. Low levels of serum cytokines are consistent with the observed low levels of CRS and neurotoxicity.

Per the abstract, no AUTO3 related deaths and no DLTs were observed. G > 3 treatment emergent adverse events > 10 % were neutropenia (73%), thrombocytopenia (64%), anemia (64%), and infection (18%). Treatment emergent adverse events > 25% regardless of grades were pyrexia (82%), thrombocytopenia (82%), neutropenia (73%), anemia (64%), nausea (36%), vomiting (36%), fatigue (36%), headache (36%), constipation (36%), dyspnea (27%), and cough (27%). 27% experienced cytokine release syndrome (CRS), all were grade 1, no ≥ G2 CRS were noted. Only one case (9%) of neurotoxicity was noted which was grade 3 and treated with steroids and tocilizumab. Dose levels 50 and 150 x 106 have been cleared without DLTs.

Conclusion Per the abstract, AUTO3 has a manageable safety profile in combination with Pem. Notable is the lack of severe CRS (0%). The efficacy data with 2/4 patients achieving CR at dose 150 x 106 cells is promising. The study continues to enroll patients at higher dose levels of AUTO3 followed by Pem.

Comment The response rates from the Phase I/II ALEXANDER study of AUTO3 have decreased from those previously reported at ASH 2018, although the 50%-57% overall response rates (ORR) and the 29%-50% complete response (CR) rates remain somewhat promising for this treatment strategy. The CRs have been robust, with 80% of the responses ongoing at the time of this analysis.

However, there is no evidence of a dose-response as the ORR and CR rates have remained relatively consistent across the various doses that have been tested thus far. Additionally, while the higher CR rates are in line with historical results from ZUMA-1 for Gilead’s Yescarta and JULIET for Novartis’ Kymriah (51% and 40% respectively), it remains to be seen how they will compare to newly presented data from other CAR T-cell therapies such as lisocabtagene maraleucel.

The preliminary tolerability of AUTO3 also remains promising. Most importantly, the rates of cytokine release syndrome (CRS) and neurotoxicity (NT) have not increased with the higher doses of AUTO3. No instances of grade 3 or higher CRS have been observed. For NT, only one instance of grade 3 neutrotoxicity occurred and was resolved quickly with steroids.

In addition to antigen loss, upregulation of PD-L1 is thought to play a role in relapse. At this point, 12 patients have received pembrolizumab preconditioning, although it is difficult to determine if the inclusion of pembrolizumab consolidation therapy has any effect on response rates given the small number of patients in each cohort.

January 2020 / 60

Information Classification: General

Determining the patient population most likely to respond to AUTO3 and pembrolizumab treatment will play an important role in the ongoing clinical study, particularly as AUTO3 seeks to differentiate itself from the other CAR T-cell therapies currently in development for this patient population. As we await further updates for AUTO3 in DLBCL, we are leaving the likelihood of approval unchanged based on these results.

Source: Press Release 12/08/2019 American Society of Hematology (ASH) 12/07/2019 (Abstract 246) Investor Presentation 12/09/2019 (AUTL) Sagient Analysis

Lisocabtagene Maraleucel for Diffuse Large B-Cell Lymphoma (DLBCL) – NHL (BMY; BLA)

Phase I - TRANSCEND Trial Data – Updated Results

Change to LOA: 1%

Abstract 241: Pivotal Safety and Efficacy Results from Transcend NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed/Refractory (R/R) Large B Cell Lymphomas

Context Based on results from TRANSCEND NHL 001, Bristol-Myers Squibb expects to complete the submission of a Biologics License Application to the U.S. FDA by the end of 2019.

Design TRANSCEND NHL 001 is an open-label, multicenter, pivotal Phase I study to determine the safety, pharmacokinetics, and antitumor activity of liso-cel in patients with relapsed/refractory B-cell non- Hodgkin lymphoma, including diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B and mantle cell lymphoma.

Endpoints The primary outcome measures were treatment-related adverse events, dose-limiting toxicities and objective response rate. Secondary outcome measures included complete response rate, duration of response and progression-free survival.

January 2020 / 61

Information Classification: General

Results In the study, 344 patients were leukapheresed and 269 patients received liso-cel at one of three dose levels (50 x 106 n=51; 100 x 106 n=177; and 150 x 106 n=41). There were 25 patients that received nonconforming product and there were two instances where product could not be manufactured. Patients were heavily pretreated and had aggressive disease with a median of three prior therapies including 35% with prior autologous or allogeneic hematopoietic stem cell transplant (HSCT) and 67% with chemotherapy-refractory disease. Bridging therapy was administered to 59% of patients.

Among patients evaluable for efficacy (n=256), the overall response rate (ORR) was 73% (187/256, 95% CI: 67 – 78) with 53% of patients (136/256, 95% CI: 47 – 59) achieving a complete response (CR). Responses were similar across all patient subgroups. The median duration of response (DOR) for all patients was not reached (95% CI: 8.6 months – NR) at a median follow-up of 12 months (95% CI: 11.2 – 16.7). Median progression-free survival (PFS) was 6.8 months (95% CI: 3.3 – 14.1) and median overall survival (OS) was 21.1 months (95% CI: 13.3 – NR). The median PFS and OS for patients who achieved a CR was not reached with 65.1% of patients progression free and 85.5% of patients alive at 12 months, respectively.

Most Common Adverse Events Among all patients, 79% (213/269) had grade 3 or higher treatment-emergent adverse events (TEAE) including neutropenia (60%, 161/269), anemia (38%, 101/269) and thrombocytopenia (27%, 72/269). Instances of any grade cytokine release syndrome (CRS) occurred in 42% (113/269) of patients at a median onset of 5 days and grade 3 or higher CRS occurring in 2% (6/269) of patients. There were neurologic events (NEs) that occurred in 30% of patients (80/269) with grade 3 or higher NEs occurring in 10% (27/269) of patients at a median onset of 9 days. Nineteen and 21% of patients received tocilizumab and corticosteroids, respectively. There were four grade 5 TEAEs related to liso-cel in the study from diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome or cardiomyopathy. There were three grade 5 TEAEs considered unrelated to liso-cel from fludarabine leukoencephalopathy, septic shock and progressive multifocal leukoencephalopathy. Eight patients had ongoing CRS/NE at the time of death from other reasons. Prolonged grade 3 or higher cytopenias were reported in 37% (100/269) of patients.

Conclusion Longer-term follow-up from the TRANSCEND study shows that liso-cel resulted in a rapid, high rate of durable complete responses with low incidence of severe cytokine release syndrome and neurologic events in two and ten percent, respectively, among patients with relapsed/refractory large B-cell lymphomas. Additionally, responses with liso-cel were seen across patient groups including high-risk patients such as those with refractory disease, older patients and those with high tumor burden.

January 2020 / 62

Information Classification: General

Comment Updated results from the Phase I TRANSCEND NHL 001 study for the CD19-directed CAR T-cell therapy lisocabtagene maraleucel (liso-cel) showed that TRANSCEND NHL 001 met its primary and secondary endpoints of safety and efficacy while demonstrating a rapid rate of durable response in patients with relapsed/refractory B-cell non-Hodgkin lymphomas.

Liso-cel demonstrated an overall response rate (ORR) of 73% and a complete response (CR) rate of 53% in the efficacy-evaluable population. These CR rate results compare well to historical results from ZUMA-1 for Gilead’s Yescarta and JULIET for Novartis’ Kymriah (51% and 40% respectively). Of note is that the median time to first CR or partial response (PR) was 1.0 months and that the duration of response (DOR) was 60.4% at 6 months and 54.7% at 12 months. As with the other CAR-T trials, results were not presented for the ITT population. However, the presentation did include the first efficacy results for different subtypes, which showed that the longest progression free survival was seen in primary mediastinal large B-cell lymphoma and transformed follicular lymphoma patients.

The low rates of Grade 3/4 cytokine release syndrome (CRS) remain impressive. Only 6 patients (2%) experienced Grade 3 or Grade 4 CRS, which still compares very favorably to the 13% seen with Yescarta and the 23% seen with Kymriah. The rate of Grade 3 or 4 neurotoxicity was 10%, lower than the 15% previous seen in the dose-finding and dose expansion cohorts.

However, some questions still remain regarding manufacturing. Of the 294 liso-cel-treated patients, 25 received non-conforming product. This 10% nonconforming rate is relatively high and is unchanged from the dose-finding and dose expansion cohorts. The presenter did note that the efficacy among patients who received the non-conforming liso-cel was similar to those who received conforming liso-cel, although no comparative data was shown for these two groups.

Bristol Myers Squibb has announced that it will submit a Biologics License Application to the U.S. Food and Drug Administration by the end of the year based on these data. Two other CAR-T therapies, Gilead’s Yescarta and Novartis’ Kymriah, are currently approved in this setting. If approved, liso-cel will likely seek to differentiate itself based on safety, particularly the low rate of Grade 3 or higher CRS.

Based on these results, we are raising the likelihood of approval a further 1%.

Source: Press Release 12/07/2019 (BMS) American Society of Hematology (ASH) 12/07/2019 (Abstract 241) American Society of Hematology (ASH) 12/08/2019 (BMY, Slide 5) Sagient Analysis

January 2020 / 63

Information Classification: General

Indolent Non-Hodgkin's Lymphoma (Including Follicular Lymphoma) - NHL

Mosunetuzumab for Indolent Non-Hodgkin's Lymphoma (Including Follicular Lymphoma) – NHL (RHHBY; Phase I)

Phase I - Dose Escalation and Expansion Trial Data – Updated Results

Change to LOA: 2%

Abstract 6: Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After Chimeric Antigen Receptor T-Cell (CAR-T) Therapies, and Is Active in Treatment through Multiple Lines

Context Additionally, results from the Phase I/Ib NP30179 study evaluating CD20-TCB as a combination therapy with Gazyva (obinutuzumab) for people with R/R NHL was presented at ASH.

Design The GO29781 study is a Phase I/Ib, multicenter, open-label, dose-escalation study evaluating the safety and pharmacokinetics of mosunetuzumab in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma, including patients who have relapsed following, or are resistant to, CAR T-cell therapy.

Per the abstract, mosunetuzumab (M) is administered with step-up dosing on Days 1, 8, and 15 of Cycle 1, and then as a fixed dose on Day 1 of each subsequent 21-day cycle (maximum 17 cycles).

Endpoints Outcome measures include best objective response rate by revised International Working Group criteria, maximum tolerated dose, and tolerability.

Results Results from this dose-escalation study showed efficacy with an objective response rate (ORR) of 62.7 percent (n=42/67) in slow-growing NHL and 37.1 percent (n=46/124) in aggressive NHL. Additionally, data demonstrated a complete response (CR) rate of 43.3 percent (n=29/67) in slow-growing NHL and 19.4 percent (n=24/124) in aggressive NHL. CRs showed durability, with 82.8 percent (n=24/29) of patients with slow-growing NHL remaining in remission up to 26 months off initial treatment and 70.8 percent (n=17/24) of patients with aggressive NHL, remaining in remission up to 16 months off initial

January 2020 / 64

Information Classification: General

treatment. Of the participants who received prior CAR T-cell therapy, the ORR was 38.9 percent (n=7/18), and 22.2 percent (n=4/18) achieved a CR.

Per the abstract, as of June 4, 2019, 218 pts in Group B had received any amount of M. Indolent NHL (iNHL) pts (n=72) were mainly follicular lymphoma (FL, n=69). Aggressive NHL (aNHL) pts (n=141) were mainly diffuse large B-cell lymphoma (DLBCL, n=87) or transformed FL (trFL, n=29). Median prior systemic therapies was 3 (range: 1–14). Twenty-three pts had prior CAR-T therapy (12 DLBCL, 6 trFL, 5 FL), and 16 were efficacy evaluable (7 DLBCL, 5 trFL, 4 FL). ORR and CR rates were 43.8% (7/16) and 25.0% (4/16, 2 DLBCL and 2 FL), respectively. Expansion of previously administered CAR-Ts after M administration was detected by quantitative PCR, in line with the mechanism of action of M.

Dose escalation is ongoing, supported by a positive exposure-response relationship for efficacy and broad therapeutic window with step-up dosing. Among efficacy-evaluable pts across all dose levels, ORR and CR rates were 64.1% (41/64) and 42.2% (27/64) in iNHL pts and 34.7% (41/119) and 18.6% (22/119) in aNHL pts, respectively.

CRs appeared durable, with 25/27 (92.6%) iNHL pts (median time from first CR: 5.8 months; range: 0.2– 28.9) and 15/22 (68.2%) aNHL pts (median time from first CR: 8.8 months; range: 0.0–25.4) who achieved CR remaining in remission. Re-treatment with M was allowed in CR pts who relapsed. Four pts, including 1 in Group A who was initially treated with a fixed, non-step-up dosing schedule, received M re-treatment. One CR and 2 partial responses were observed. All three responses are ongoing, with the CR pt in second remission for 314 days. The MTD of M has not been reached at doses up to 1/2/60mg (Cycle 1 Day 1, 8, and 15).

Most Common Adverse Events Adverse reactions included cytokine release syndrome (CRS) in 28.9 percent of patients with 20.0 percent at Grade 1 and 1.1 percent at Grade 3. Grade 3 neurological adverse events occurred in 3.7 percent of patients.

Per the abstract, adverse events (AEs) leading to treatment withdrawal were uncommon (12/218, 5.5%). Cytokine release syndrome (CRS), graded by Lee criteria, was observed in 28.4% of pts, and was mostly Grade (Gr) 1 (21.1%) or Gr 2 (6.0%); Gr 3 CRS occurred in 1.4% of pts. Most CRS events occurred in Cycle 1; 5 pts (2.7%) had CRS during or after Cycle 2. Three of 218 pts (1.4%) received tocilizumab for CRS management; all 3 events resolved without sequelae (for 1 pt, CRS resolved after the cutoff date). Neurological AEs (NAEs) were reported in 44% of pts (Gr 1, 28.0%; Gr 2, 12.8%; Gr 3, 3.2%). Common NAEs were headache (14.7%), insomnia (10.1%), and dizziness (9.2%). Potential immune effector cell- associated neurotoxicity syndrome (ICANS)-like NAEs of Gr 1 or Gr 2 confusional state occurred in 3 pts (1.4%) during cycles 1 and 2. The frequency of CRS and NAEs did not correlate with M exposure, likely due to step-up dosing, which effectively mitigates acute toxicities and allows administration of higher

January 2020 / 65

Information Classification: General

doses. Among the 4 pts who were re-treated with M, no CRS was observed and NAEs were reported in 1 pt (Gr 1 headache and insomnia). Among the 23 pts who were R/R to CAR-T therapy, CRS occurred in 5 pts (21.7%; Gr 1, 13.0%; Gr 2, 4.3%; Gr 3, 4.3%) and NAEs in 8 pts (34.8%; Gr 1, 17.4%; Gr 2, 13.0%; Gr 3, 4.3%), with no ICANS-like events.

Conclusion Per the abstract, M has favorable tolerability and durable efficacy in pts with heavily pre-treated R/R B- cell NHL, including CRs in pts with disease progression after CAR-T therapies. Preliminary data support the possibility for re-treatment with M.

Comment Genentech announced new data for mosunetuzumab, a CD20-CD3 T-cell engaging bispecific antibody, in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL). Results from a Phase I/Ib study, GO29781, were presented at the ASH plenary session and included data from people previously treated with chimeric antigen receptor (CAR) T-cell therapy.

During the introduction to the plenary session, Dr. Georg Lenz from the University of Muenster noted that while follicular lymphoma patients have an overall survival of approximately 15 years, response duration and survival shorten with each line of therapy and there is a need for new therapy. Similarly, while 5-year survival rates for DLBCL in the first-line setting range from 60% to 70%, patients with refractory DLBCL have a median overall survival of just 6.3 months. While CAR-T therapies represent an effective approach for DLBCL, not all patients respond and some patients who respond eventually relapse. Dr. Lenz proposed that bispecific antibodies represent a novel therapeutic strategy for relapsed/refractory NHL.

Results from this dose-escalation study showed efficacy with an objective response rate (ORR) of 63% (n=42/67) in slow-growing NHL (mostly follicular lymphoma) and 37% (n=46/124) in aggressive NHL (mostly DLBCL with some transformed follicular lymphoma and mantle-cell lymphoma). Additionally, data demonstrated a complete response (CR) rate of 43% (n=29/67) in slow-growing NHL and 19% (n=24/124) in aggressive NHL. CRs showed durability, with 83% (n=24/29) of patients with slow-growing NHL remaining in remission up to 26 months off initial treatment and 71% (n=17/24) of patients with aggressive NHL remaining in remission up to 16 months off initial treatment. Of the participants who received prior CAR T-cell therapy, the ORR was 39% (n=7/18), and 22% (n=4/18) achieved a CR.

Re-treatment with mosunetuzumab was allowed in CR pts who relapsed, and four patients received re- treatment. One CR (25%) and 2 partial responses were observed. All three responses are ongoing, with the CR patient in second remission for 314 days. At ASH, the speaker also discussed a patient with rapidly progressing follicular lymphoma with an urgent need for therapy who was administered mosunetuzumab prior to CD-19 CAR-T therapy indicating that in this case, mosunetuzumab was safely

January 2020 / 66

Information Classification: General

and successfully sequenced prior to CAR-T therapy.

Adverse reactions included cytokine release syndrome (CRS) in 29% of patients with 20% at Grade 1 and 1% at Grade 3. Grade 3 neurological adverse events occurred in 4% of patients.

Mosenutuzumab continues to be evaluated in several Phase I/II trials including in combination with Polivy (see here) and as first-line therapy (see here).

Based on these positive results, we are increasing the LOA by 2%.

Source: Press Release 12/07/2019 (Genentech) Press Release 12/07/2019 (RHHBY) Press Release 12/09/2019 (City of Hope) American Society of Hematology (ASH) 12/08/2019 (Abstract 6) Sagient Analysis

Polivy for Indolent Non-Hodgkin's Lymphoma (Including Follicular Lymphoma) – NHL (RHHBY, Phase II)

Phase Ib/II - w/Obinutuzumab + Lenalidomide Trial Data – Updated Results

Change to LOA: 4%

Abstract 126: Polatuzumab Vedotin Plus Obinutuzumab and Lenalidomide in Patients With Relapsed/Refractory Follicular Lymphoma: Primary Analysis of the Full Efficacy Population in a Phase Ib/II Trial

Design GO29834 is an open-label, multicenter study of pts with R/R FL (excluding grade 3b) who had received ≥1 prior anti-CD20-containing chemo-immunotherapy regimen. An initial 3+3 dose-escalation phase to define the recommended Phase II dose (RP2D) combination for Pola + Len was expanded into Phase II. Pts in the expansion cohort received induction treatment with six 28-day cycles of: G 1000mg IV (Cycle [C]1: Day [D] 1, D8, D15; C2–6: D1); Pola 1.4mg/kg IV (D1), and Len 20mg PO (D1–21). Responders received maintenance treatment for 24 months (G 1000mg on D1 every 2 months and Len 10mg on D1– 21 during Months 1–12).

Endpoints

January 2020 / 67

Information Classification: General

The primary endpoint was complete response (CR) at end of induction (EOI), as determined by the Independent Review Committee (IRC) based on positron emission tomography–computed tomography (PET–CT) scans (by modified Lugano 2014 criteria). In addition, progression-free survival (PFS) was determined by the investigator.

Results At the time of the primary analysis (March 12, 2019), a total of 56 pts from the Phase Ib and Phase II populations were enrolled and had entered induction; the median duration of follow-up was 11.79 months. Baseline characteristics were: median age, 62 years; male, 59%; Ann Arbor Stage III–IV, 88%; Follicular Lymphoma International Prognostic Index high-risk (≥3), 55%; bulky disease (≥7cm), 16%; ≥2 prior lines of therapy, 77%; refractory to last line of prior regimen, 50%; and refractory to last line of anti-CD20 treatment, 45%.

In the primary efficacy population (n=46), the IRC-assessed modified Lugano objective response rate was 76%, with a CR rate of 65%. A sub-group analysis showed that 71% (15/21) of pts who were refractory to their last treatment achieved a CR. In total, five pts experienced PD, three in C1 or C2 and two at the month 12 response assessment. With a median follow-up duration of 11.27 months, median PFS was not reached.

Most Common Adverse Events All pts had at least one adverse event (AE), 31 (55%) had a serious AE, and 44 (79%) had a grade 3–4 AE. The most common grade 3–4 AEs were neutropenia (28 pts, 50%), thrombocytopenia (13 pts, 23%), infections (9 pts, 16%), and anemia (8 pts, 14%). AEs leading to a dose reduction or interruption of any drug occurred in 19 (34%) and 41 (73%) of pts, respectively; the majority were modifications of Len. In addition, 14 (25%) pts had an AE that led to the discontinuation of any study drug. One grade 5 AE was reported (septic shock); however, it was not considered to be related to study treatment as the pt was receiving a new anti-lymphoma treatment after experiencing disease progression (PD).

Conclusion The study of the novel triplet combination, Pola-G-Len, demonstrates a safety profile consistent with the known profiles of the individual drugs. This first report of the full efficacy population showed high CR rates at EOI in a heavily pre-treated and refractory population, which compares favorably with currently available R/R FL therapies. These findings support the further investigation of this triplet combination in a larger pt population. To determine the median PFS, a longer period of follow-up, through and beyond maintenance treatment, is ongoing.

Comment These are promising results for a novel combination of Polivy, Gazyva, and Revlimid in relapsed/refractory follicular lymphoma (r/r FL). Cross-trial comparisons suggest that the addition of

January 2020 / 68

Information Classification: General

Polivy could add additional efficacy and point to a potential role for the triple combination in r/r FL. However, this trial’s single-arm design makes it difficult to predict if the triple combination has the potential to generate data that could support approval in an eventual pivotal trial.

In the ROMULUS trial, the combination of Polivy and rituximab showed a 45% complete response rate (CRR) in r/r FL. The present trial’s CRR of 65% therefore appears improved over ROMULUS. Furthermore, the 71% CRR in patients who were refractory to their last treatment is impressive. In a previous Phase Ib/II trial, the combination of Polivy, bendamustine, and rituximab showed a CRR of 69%. However, this CRR was similar to the CRR for the combination of bendamustine and rituximab, which was 63%. In the r/r FL group in the GALEN trial, the combination of Gazyva and Revlimid showed a 38% CRR. Therefore, if the Polivy/Gazyva/Revlimid combination was to be studied in a pivotal trial with an active comparator, it is reasonable to think that it could show CRR benefit over Gazyva/Revlimid. However, given that the present study is a single-arm Phase Ib/II trial, we remain cautiously optimistic about the triple combination at this time.

In terms of safety, with 34% of patients undergoing dose reduction and 25% having an adverse event that led to discontinuation of any study drug, safety will be something to keep an eye on. The presenter mentioned that in many cases, patients were able to tolerate the regimen once Revlimid dosage had been reduced, and that even in cases where patients had to discontinue treatment, many still derived benefit from therapy. Given these comments, it seems unlikely that the starting dose for the three drugs will be changed going forward, but rather that investigators will need to carefully consider the adverse events associated with Revlimid if a pivotal trial is to be initiated.

Nevertheless, with Roche currently planning on submitting an application for approval of Polivy in r/r FL sometime in 2022 or beyond, we are raising our likelihood of approval by 4% to reflect the potential of Polivy in this space.

Source: American Society of Hematology (ASH) 12/07/2019 (Abstract 126) Sagient Analysis

REGN1979 for Indolent Non-Hodgkin's Lymphoma (Including Follicular Lymphoma) – NHL (REGN; Phase II)

Phase I - B-Cell Malignancies Trial Data – Updated Results

Change to LOA: 1%

January 2020 / 69

Information Classification: General

Abstract 762: Clinical Activity of REGN1979, a Bispecific Human, Anti-CD20 x Anti-CD3 Antibody, in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL)

Context Dose escalation is complete and a recommended Phase II dose has been determined. Based on these efficacy findings, a global Phase II study is underway to evaluate REGN1979 monotherapy in R/R FL Gr 1- 3a, R/R DLBCL, and other R/R B-NHL subtypes.

Design Eligible pts with R/R B-NHL must have received prior CD20-directed therapy. Treatment consists of 12 weekly intravenous doses of REGN1979 followed by every 2-week dosing for 12 doses (36 weeks total).

Endpoints Primary objectives are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives are to assess antitumor activity, pharmacokinetics (PK), and pharmacodynamics.

Results As of June 3, 2019, 96 pts (diffuse large cell B-cell lymphoma [DLBCL] [n=53], follicular lymphoma [FL] grade [Gr] 1-3a [n=25], mantle cell lymphoma [n=6], marginal zone lymphoma [n=6], or other [FL Gr 3b, FL unknown, FL ungraded, or Waldenström macroglobulinemia ] [n=6]) were treated with REGN1979 0.03–320 mg and received a median of 9 doses (range 1–24). Pts had a median of 3 prior lines of therapy (range 1-11); 12 pts with prior CAR T therapy were included in the safety analysis of which 6 were included in the efficacy analysis. Twenty-four pts remain on treatment; 18 completed treatment; 54 discontinued early (35 due to progressive disease [PD]).

Emerging data suggest increasing efficacy with higher doses in R/R DLBCL, with 5 of 8 pts treated at 80/160/320 mg achieving CR; at these doses 2 of 3 pts achieved CR after failure of CAR T therapy. Data also suggest increasing efficacy with increasing doses in R/R FL, but maximum efficacy appears to be achieved at lower doses than in DLBCL; in pts with FL Gr 1-3a treated at ≥5 mg, the ORR was 93% (13/14), and the CR rate was 71.4% (10/14).

REGN1979 concentrations in serum increased linearly with dose during the first five weeks. Elevated levels of serum cytokines were observed, mostly in week 1, and no correlation was observed with clinical efficacy. Immunohistological analysis of malignant lymph node tissue demonstrated that pts with high and low CD20 expression achieved clinical response. Relapse among responders was seen with either maintenance or loss of CD20 expression, suggesting antigen-dependent and independent disease escape mechanisms.

January 2020 / 70

Information Classification: General

Most Common Adverse Events No pts with B-NHL experienced a DLT. The most common treatment-emergent adverse events (AEs) were pyrexia (n=74), CRS (n=55), chills (n=49), infections and infestations (n=47), fatigue (n=36), increased C-reactive protein (n=32), and anemia (n=32). Seven pts experienced Gr 3 CRS. The severity of CRS symptoms declined through optimized pre-medication even with REGN1979 dose escalation. Most common Gr 3 or 4 AEs were anemia (n=19), decreased lymphocytes/lymphopenia (n=19), infections and infestations (n=18), decreased neutrophils/neutropenia (n=17), and hypophosphatemia/decreased blood phosphorus (n=16). No pts had seizures or grade 4/5 neurologic AEs. Gr 3 neurologic AEs included depressed level of consciousness (unrelated), somnolence, and syncope (n=1 each). Neurological events were transient and none required permanent treatment termination. Five pts discontinued due to AEs: Gr 3 hemolysis; Gr 3 fatigue; Gr 2 and Gr 3 pneumonia; and Gr 3 neck abscess (1 each). Eleven pts died on study: PD (n=6), gastric perforation (n=1), cardiac arrest (n=1), lung infection (n=1), multi-organ failure (n=1), pneumonia (n=1).

Conclusion Tolerability of REGN1979 has been demonstrated at doses up to the final dose level of 320 mg weekly, with no observed DLTs in pts with B-NHL. No pts discontinued due to neurologic AE. Activity was observed broadly in heavily pretreated R/R B-NHL pts treated with REGN1979. With increasing dose, more resistant tumors such as R/R DLBCL are showing benefit, even in pts with prior CAR T therapy failure.

Comment These updated results from the dose-esclataion Phase I study of REGN1979, an anti-CD20 and anti-CD3 bispecific antibody, show very promising response rates in relapsed/refractory follicular lymphoma (FL) patients. The overall response rate (ORR) was 95.5% in the evaluable FL patients with a complete response (CR) rate of 77.3%. These results compare favorably to historical results for CR rates from ROMULUS for the combination of Polivy and rituximab and GALEN for Gazyva and Revlimid (45% and 38% respectively).

Additionally, REGN1979 demonstrated an ORR of 50% and a CR of 25% in the subset of twelve BLBCL patients who had previously received CAR T-cell therapy. While these preliminary results are promising, it is difficult to get an accurate picture of the efficacy of REGN1979 in this patient population given the limited duration of follow-up.

Additionally, the potential toxicity of the drug is a concern. 59.1% of patients experienced any grade cytokine release syndrome (CRS), with 6.4% experiencing grade 3 or 4 CRS. The rate of any grade infections was 50%, which is also concerning. Of note is that two of the three patients who experienced a treatment-related grade 5 adverse event died due to infections.

January 2020 / 71

Information Classification: General

A global Phase II pivotal trial is currently enrolling relapsed/refractory follicular lymphoma patients. Further information on the side effect profile is needed for REGN1979, but we are raising the likelihood of approval by 1% in light of the demonstrated efficacy in this highly pretreated population.

Source: American Society of Hematology (ASH) 12/09/2019 (Abstract 762) Sagient Analysis

Tazemetostat for Indolent Non-Hodgkin's Lymphoma (Including Follicular Lymphoma) – NHL (Royalty Pharma; NDA)

Phase II - Relapsed or Refractory DLBCL/FL Trial Data – Updated Results

Change to LOA: 4%

Treatment Treatment Treatment Treatment Treatment Description 800mg 800mg 800mg 800mg Tazemetostat Tazemetostat Tazemetostat Tazemetostat EZH2 MT Cohort EZH2 MT EZH2 WT Cohort EZH2 WT Response- Cohort Response- Cohort evaluable POD24 evaluable POD24 Population Subgroup Population Subgroup Number of Patients N/A N/A N/A N/A Number of Evaluable 43 17 53 30 Patients Objective Response 77.000 % 65.000 % 34.000 % 30.000 % Rate (Endpoint=Primary) Complete Response 7.000 % 6.000 % 6.000 % 0.000 % (Endpoint=Secondary) Partial Response 70.000 % 59.000 % 28.000 % 30.000 % (Endpoint=Secondary) Progression-Free 11.100 Months 13.800 5.700 Months 5.600 Survival Months Months (Endpoint=Secondary) Median Duration of 8.300 Months 8.200 Months 13.000 Months 7.300 Months Response (Endpoint=Secondary)

Abstract 123: Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients with Relapsed or Refractory Follicular Lymphoma

January 2020 / 72

Information Classification: General

Context NDA Submission for Accelerated Approval of Tazemetostat for Patients with Relapsed or Refractory Follicular Lymphoma on Track for December 2019. The IRC assessment was conducted for inclusion in Epizyme’s planned NDA submission to the U.S. Food and Drug Administration (FDA). NDA for epithelioid sarcoma is under review, and the Company have finalized commercial readiness plans in anticipation of an early 2020 launch.

Design Follicular lymphoma patients who had been previously treated with two or more systemic therapies were enrolled into two cohorts in the Phase II study. One cohort enrolled 45 patients with EZH2 activating mutations and a second enrolled 54 patients with wild-type EZH2. All patients were treated with 800 mg of tazemetostat, administered orally twice a day.

Per the abstract, this open-label, multicenter, Phase II study evaluated tazemetostat 800 mg administered orally twice daily in patients with MT or WT EZH2 R/R FL (Grade 1–3b). Key inclusion criteria included age ≥18 years, Eastern Cooperative Oncology Group performance status of 0–2, ≥2 prior treatment regimens, and measurable disease per 2007 IWG-NHL criteria. The POD24 subgroup was composed of patients experiencing disease progression or relapse within 24 months of diagnosis or the start of frontline treatment with immunochemotherapy.

Endpoints The primary endpoint of the study is ORR, as assessed by the investigator, and defined as a complete response or partial response according to 2007 Cheson criteria. Secondary endpoints include duration of response, progression free survival, overall survival and safety.

Results As assessed by the IRC, as of an August 9, 2019 data cutoff date, tazemetostat treatment resulted in: • Objective response rate (ORR) of 69% for patients with an EZH2 mutation and 35% for patients with wild-type EZH2 • Median duration of response of 11 months for patients with an EZH2 mutation and 13 months for patients with wild-type EZH2 • Median progression-free survival of 14 months for patients with an EZH2 mutation and 11 months for patients with wild-type EZH2 • Overall survival has not yet been reached for either FL patient population Per the abstract, as of June 7, 2019, interim data were available for 99 patients (MT EZH2, n=45 [POD24, n=17; 38%]; WT EZH2, n=54 [POD24, n=30; 56%]). Of the 33 patients in the MT cohort with an objective response, 15 (45%) had a response at ≥6 months, 7 (21%) at ≥12 months, and 4 (12%) at ≥16 months. Of the 18 patients in the WT cohort with an objective response, 15 (83%) had a response at ≥6 months, 9

January 2020 / 73

Information Classification: General

(50%) at ≥12 months, and 6 (33%) at ≥16 months. Data from the MT cohort continue to mature, with 11 (24%) patients enrolled in the past year and 17 (38%) patients still on treatment. Interim efficacy data from the response-evaluable population and POD24 subgroup of the MT and WT cohorts are presented in the table above.

Most Common Adverse Events Favorable safety and tolerability have been observed with tazemetostat in these ongoing Phase II study cohorts. The most frequently reported treatment-related treatment-emergent adverse events (TEAEs) of Grade 3 or higher included thrombocytopenia (3%), anemia (2%), asthenia (1%) and fatigue (1%). TEAEs led to only 8% of patients discontinuing tazemetostat treatment and 9% of patients requiring a dose reduction. There were no treatment-related deaths while on study.

Per the abstract, treatment-related Grade ≥3 adverse events (AEs) were reported in 17% of all patients and 15% of patients in the POD24 subgroup. The most frequently reported AEs were similar across the total population and the POD24 subgroup and included thrombocytopenia (3%), anemia (2%), asthenia (2%), vomiting (1%), and fatigue (1%). Five percent of all patients discontinued treatment, and 9% had dose reductions due to treatment-related AEs. No treatment-related Grade 5 AE and deaths were reported.

Conclusion Per the abstract, tazemetostat demonstrated clinically meaningful, durable, single-agent activity across a spectrum of patients with FL, including the POD24 subgroup, and pronounced responses in patients with EZH2 activating mutations.

Comment These mature results are positive ahead of the company’s planned registrational filing in December 2019. Following discussions with the FDA, Epizyme announced that a path to submission for accelerated approval had been identified for patients with relapsed and/or refractory follicular lymphoma (FL), both with and without EZH2 activating mutations, early in 2019.

Though Epizyme will seek approval in both EZH2 mutant and wild-type patients, the efficacy data is clearly improved in EZH2 mutant patients. Therefore, if approved, among the ~20-28% of patients with this mutation, tazemetostat is likely to be viewed as a preferred option. In contrast, historical overall response rate (ORR) data for Aliqopa, which holds an approval in the third-line or later setting, seems to be superior to tazemetostat in EZH2 wild-type patients. For example, Aliqopa showed a 58.7% ORR, compared to Tazemetostat’s ORR of 34% in EZH2 wild-type patients. Despite this lower ORR, the median duration of response (mDOR) in wild type patients is surprisingly long at 13 months, which compares favorably to Aliqopa, which showed a mDOR of just over a year. Taken together, even among patients without EZH2 mutations, tazemetostat (if approved) may still be considered, especially if options like

January 2020 / 74

Information Classification: General

Aliqopa have already been exhausted. Furthermore, the associated confirmatory trial is testing tazemetostat in combination with Revlimid and rituximab. If this approach is also successful, it could further build on tazemetostat’s utility in follicular lymphoma.

With this strong update, we are raising out likelihood of approval by 4%.

Source: Press Release 12/07/2019 (EPZM) American Society of Hematology (ASH) 12/07/2019 (Abstract 123) Sagient Analysis

Mantle Cell Lymphoma - NHL

KTE-X19 for Mantle Cell Lymphoma – NHL (GILD, BLA)

Phase II - ZUMA-2 (r/r MCL) Trial Data – Top-Line Results

Change to LOA: 6%

Treatment Treatment Description KTE-X19 Number of Patients N/A Number of Evaluable Patients 60 Best Objective Response 93.000 % Independent Radiologic Central Review (Endpoint=Primary) Complete Response Rate 67.000 % 12-Month Estimated Progression-Free-Survival 61.000 % 12-Month Estimated Overall Survival (OS) 83.000%

Abstract 754: KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients (Pts) With Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL): Results of the Phase 2 ZUMA-2 Study

Context Based on the results of the trial, Kite plans to submit a Biologics License Application (BLA) for KTE-X19 to the U.S. Food and Drug Administration (FDA) by the end of this year and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in the first quarter of 2020.

January 2020 / 75

Information Classification: General

KTE-X19 has been granted Breakthrough Therapy Designation (BTD) by the FDA and Priority Medicines (PRIME) by the EMA for relapsed or refractory MCL based on interim data from ZUMA-2.

Design ZUMA-2 is a single-arm, multicenter, open-label Phase II study involving 74 enrolled/leukapheresed adult patients (≥18 years old) with MCL whose disease is refractory to or has relapsed following up to five prior lines of therapy, including anthracycline or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy and the BTK inhibitors ibrutinib or acalabrutinib. The objectives of the study are to evaluate the efficacy (60 patients) and safety (68 patients) after a single infusion of KTE-X19 in this patient population.

Endpoints The primary endpoint for the study is objective response rate (ORR). ORR in this trial is defined as the combined rate of complete responses and partial responses as assessed by an Independent Radiology Review Committee.

Secondary endpoints include duration of response, best objective response, progression-free survival, overall survival, incidence of adverse events, incidence of anti-CD19 CAR antibodies, levels of anti-CD19 CAR T cells in blood, levels of cytokines in serum, and changes over time in the EQ-5D scale score and visual analogue scale score.

Results After a single infusion of KTE-X19, the best objective response via independent radiologic central review (n=60 evaluable for efficacy analysis) was 93 percent, with 67 percent of patients having achieved a complete response.

With a median follow-up of 12.3 months (range: 7.0 to 32.3 months) at the time of data cutoff, 57 percent of patients remained in an ongoing response. Of the first 28 patients treated (minimum follow- up of 24 months), 43 percent were alive and remained in continued remission without additional therapy. The 12-month estimates of progression-free survival (PFS) and overall survival (OS) were 61 percent and 83 percent, respectively. Median duration of response, PFS and OS were not yet reached.

Per the abstract, Investigator-assessed ORR was 86% (95% CI, 67% – 96%) with a CR rate of 57% (95% CI, 37% – 76%). As of May 30, 2018, 75% of responders remained in response and 64% of treated pts had ongoing responses. The 12-month estimates of DOR, PFS and OS were 83% (95% CI, 60% – 93%), 71% (95% CI, 50% – 84%), and 86% (95% CI, 66% – 94%), respectively and the medians were not reached.

Most Common Adverse Events

January 2020 / 76

Information Classification: General

Among the 68 patients evaluable for safety, cytokine release syndrome (CRS) and neurologic events were observed in 91 percent and 63 percent of patients, respectively. Grade 3 or higher CRS and neurologic events were seen in 15 percent and 31 percent of patients, respectively. No Grade 5 CRS or neurologic events occurred.

Per the abstract, the most common Grade ≥ 3 AEs (≥ 20% of pts) were anemia (54%), platelet count decreased (39%), neutropenia (36%), neutrophil count decreased (32%), white blood cell count decreased (29%), encephalopathy (25%), and hypertension (21%). Grade 3/4 cytokine release syndrome (CRS) assessed by Lee et al. (Blood. 2014) was reported in 18% of pts, most commonly manifesting as hypotension (14%), hypoxia (14%), and pyrexia (11%). Grade 3/4 neurologic events (NE) were reported in 46% of pts and included encephalopathy (25%), confusional state (14%), and aphasia (11%). No Grade 5 CRS or NE occurred. All CRS events and most NE (15/17 pts) were reversible. Median time to onset and resolution of CRS was 2 days (range, 1 – 7) and 13 days (range, 4 – 60), respectively. Median time to onset of NE was 6 days (range, 1 – 15) and median time to resolution was 20 days (range, 9 – 99). There was 1 Grade 5 AE of organizing pneumonia that was considered related to conditioning chemotherapy. Median CAR T cell levels as measured by peak and area under the curve were 99 cells/µL (range, 0.4 – 2589) and 1542 cells/µL (range, 5.5 – 27239), respectively. Peak CAR T cell expansion was observed between Days 8 and 15 and declined over time.

Conclusion ZUMA-2 is the first multicenter Phase II study of CAR T cell therapy in pts with R/R MCL. With ≥ 1 year of follow-up, KTE-X19 demonstrated significant and durable clinical benefit, including a majority of pts achieving CR, and a manageable safety profile in pts with R/R MCL for whom there are no curative treatment options.

Comment The first update from the Phase II ZUMA-2 trial justifies the BLA submission with impressive results in an area of unmet need. Based on these data we are raising the LOA 6%.

In heavily pretreated patients, including 68% that were de novo resistant to BTK inhibition, KTE-X19 achieved a 93% ORR and 67% CR. Additionally, 57% of the entire ITT population remain in remission, 78% of the CR population remain in remission, and 47% of all patients were alive at the two-year follow- up. Finally, the responses are impressive even in the ITT population that includes the six patients unable to receive KTE-X19 (three due to manufacturing failure, two due to progression, and one lost after the conditioning chemotherapy): 85% ORR and 59% CR. These results compare very well to historical overall response rates for post-BTK treatment that typically do not surpass 50%.

The safety and tolerability profile were as expected for a CAR-T regimen with CRS and neutropenia events a common reaction. There were two on-study deaths, but these were primarily related to side

January 2020 / 77

Information Classification: General

effects of the bridging chemotherapy regimens received prior to administration of KTE-X19. The median vein-to-vein time was 27 days. Improving this process, as with most CAR-T therapies, will improve the response rates even further by eliminating on-study progression from patients waiting for therapy.

Source: Press Release 12/09/2019 (GILD) Press Release 12/09/2019 (MD Anderson) American Society of Hematology (ASH) 12/09/2019 (Abstract 754) Sagient Analysis

Multiple Myeloma (MM)

CC-93269 for Multiple Myeloma (MM) (BMY; Phase I)

Phase I – RRMS Trial Data – Top-Line Results

Change to LOA: 2%

Abstract 143: First Clinical Study of the B-Cell Maturation Antigen (BCMA) 2+1 T-Cell Engager (TCE) CC- 93269 in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Interim Results of a Phase 1 Multicenter Trial

Design Eligible pts had RRMM and had received ≥ 3 prior regimens without prior BCMA-directed therapy. In dose escalation, CC-93269 was administered intravenously over 2 hours on Days 1, 8, 15, and 22 for Cycles 1–3; Days 1 and 15 for Cycles 4–6; and on Day 1 for Cycle 7 and beyond, all in 28-day cycles. Dose escalation involved 2 stages: in stage 1, CC-93269 was given in fixed doses; in stage 2, pts received a fixed first dose on Cycle 1 Day 1, followed by intrapatient dose escalation on Cycle 1 Day 8. Minimal residual disease (MRD) was assessed after clinical response in pt bone marrow aspirate samples by Next Generation Flow using the EuroFlow panel. MRD negativity was reported only if a minimum sensitivity of < 1 tumor cell in 105 nucleated cells was achieved.

Endpoints Primary objectives were to assess the safety and tolerability of CC-93269 and define the maximum tolerated dose (MTD), non-tolerated dose (NTD), and/or recommended Phase II dose (RP2D).

January 2020 / 78

Information Classification: General

Results As of May 24, 2019, 19 pts had received CC-93269. Median age was 64 years (range 51–78), with a median of 6.2 years (range 1.4–13.9) since initial diagnosis. The median number of prior regimens was 6 (range 3–12) and included treatment with autologous stem cell transplantation (73.7%), allogenic stem cell transplantation (10.5%), lenalidomide (100%), pomalidomide (84.2%), bortezomib (100%), carfilzomib (84.2%), and daratumumab (DARA; 94.7%). All pts had MM refractory to their last line of therapy, with 16 (88.9%) refractory to DARA, 17 (89.5%) to their last proteasome inhibitor, and 16 (84.2%) to their last immunomodulatory agent.

CC-93269 doses ranged from 0.15 to 10 mg; median duration of treatment was 14.6 weeks (range 1.6– 32.0) with pts receiving a median of 4 cycles (range 1–8). Dose-related pharmacodynamic activity, including peripheral blood immune cell redistribution and transient release of pro- and anti- inflammatory cytokines, was observed in pts.

Of the 12 pts treated with ≥ 6 mg CC-93269 in Cycle 1, 10 pts achieved a partial response (PR) or better (overall response rate; 83.3%), including 7 (58.3%) with a very good partial response (VGPR) or better and 4 (33.3%) with a stringent complete response (sCR); 9 (75.0%) pts achieved MRD negativity. The median time to response was 4.2 weeks (range 4.0–13.1), and 10 of 10 responses were ongoing with follow-up ranging from 2.1 to 4.7 months. The NTD, MTD, and RP2D have not yet been reached.

Most Common Adverse Events Grade 3–4 treatment-emergent adverse events were reported in 15 (78.9%) pts and included 10 (52.6%) pts with neutropenia, 8 (42.1%) with anemia, 5 (26.3%) with infections, and 4 (21.1%) with thrombocytopenia. No pt required dose modifications. Cytokine release syndrome (CRS) was reported in 17 (89.5%) pts, the majority of whom reported a maximum grade 1 (n = 11 [57.9%]) or grade 2 (n = 5 [26.3%]), and occurred most frequently with the first or second dose (n = 22 of 27 events [81.5%]). CRS prophylaxis was implemented with dexamethasone for first dose and dose increases in pts receiving ≥ 6 mg. Of 27 CRS events, 8 (29.6%) were managed with dexamethasone and 10 (37.0%) with tocilizumab. One pt receiving 6 mg CC-93269 as first dose and 10 mg on Cycle 1 Day 8 died on study in the setting of CRS, with a potential infection as a contributing factor.

Conclusion CC-93269, a 2+1 BCMA TCE, shows a manageable safety profile and promising efficacy, including MRD- negative sCRs, in pts with heavily pretreated RRMM. The study continues to enroll in the dose escalation phase.

Comment These are encouraging early results for CC-93269, a bi-specific antibody targeting BCMA and CD3. At ASH, the presenter mentioned that for nine patients treated with 10 mg CC-93269 (four patients

January 2020 / 79

Information Classification: General

received 10 mg as the intial dose, five patients received step-up dosing of 6 mg followed by 10 mg), the overall response rate (ORR) was 89% with a very good partial response (VGPR) rate of 33% and a stringent complete response/complete response (sCR/CR) rate of 44%. Impressively, all patients achieving a sCR/CR response were MRD negative in the bone marrow.

These results compare well to Amgen’s bispecific antibody AMG 420 which reported an ORR of 70% in ten patients treated at 400 mcg/day with a VGPR rate of 10% and an MRD-negative complete response rate of 50%. These results also compare well to BCMA directed CAR-Ts with ORRs of 81.5% and 100% for ide-cel (Bristol-Myers Squibb) and LCAR-B38M (Johnson & Johnson), respectively, and CR rates of 35.2% and 66%, respectively.

Unlike AMG 420 which must be administered daily, CC-93269 was administered once a week for the first three months, every other week for another three months and then once a month. The presenter mentioned that CC-93269 could potentially be given as outpatient therapy but that for now patients are closely observed for 72 hours following dosing.

With regards to safety, data presented at ASH showed cytokine release syndrome (CRS) in 76.7% of all patients (n=30) with one case of Grade 3 or higher CRS. This patient received step-up dosing and experienced Grade 3 CRS at the initial dose of 6 mg and then Grade 5 CRS at the 10 mg dose. Contributing factors to this death included myeloma progression with a high tumor burden (extensive extramedullary disease) and pre-existing infection. There were three other deaths within 35 days of dosing, but they were not treatment related (sepsis in the setting of advanced prostate cancer, sudden cardiac death and progressive disease). Infections and infestations occurred in 56.7% of all patients (30% Grade 3 or higher). Safety will be closely monitored as additional patients get treated with the 10 mg dose.

As we await further dose optimization and expansion, we are raising the LOA by 2%.

Source: American Society of Hematology (ASH) 12/07/2019 (Abstract 143) American Society of Hematology (ASH) 12/08/2019 (BMY, Slide 13) Sagient Analysis

C-CAR088 for Multiple Myeloma (MM) (CBMG; Phase I)

Phase I - C-CAR088 Trial Data – Top-Line Results

January 2020 / 80

Information Classification: General

Change to LOA: 0%

Abstract 50: Developing a Novel Anti-BCMA CAR-T for Relapsed or Refractory Multiple Myeloma

Design A Phase I, 3+3 dose escalation trial is being conducted in patients with r/r MM (≥ 3 prior lines, having received treatment and proteasome inhibitors (PI) and IMiD or double refractory) to assess the safety and efficacy of C-CAR088. Patients are apheresed to harvest T cells. C-CAR088 is then manufactured and administered to patients as a single intravenous dose after a standard 3-day cyclophosphamide/fludarabine conditioning regimen.

Results As of the end of November the Company has enrolled eleven patients, of which eight were infused with C-CAR088, and five patients were evaluable for clinical response. Three of the five patients were treated with C-CAR088 at the dose of 1.0 x 106 CAR-T cells/kg, and the other two patients treated at 3.0x106 CAR-T cells/kg. All five patients showed clinical improvement as early as two weeks post treatment. By 4 weeks, one patient achieved a complete response (CR), three patients reached a very good partial response (VGPR), and one patient reached a partial response (PR) post C-CAR088 infusion. Furthermore, the Company observed that C-CAR088 proliferation & expansion in the peripheral blood correlated with the decrease of tumor burden in all patients.

Per the abstract, in preclinical study, the human T cells transduced with the lentiviral vector encoding C- CAR088 exhibited specific functions in vitro including CAR-T proliferation, cytokine production, cytotoxicity to BCMA positive tumor cells. C-CAR088 cells were not activated by soluble BCMA protein and MM patient serums. However, they can eradicate BCMA positive tumor cells in vivo including BMCA positive multiple myeloma tumor model RPMI-8226. C-CAR088 is manufactured in a serum free, automated and digital, closed system which produce CAR-T cells with stable and high percentage of Tcm phenotype. C-CAR088 showed a very good dose dependent tumor inhibition effect and survival benefit in animal studies.

Per the abstract, as of July 5, 2019 cutoff date, 3 patients have been treated with C-CAR088 at the dose of 1.0 x 106 CAR-T cells/kg. Patients were heavily pre-treated (7 prior lines of therapy), and all failed IMiDs and proteasome inhibitor therapies. After C-CAR088 treatment, all three patients showed clinical improvement as early as two weeks post treatment. Furthermore, C-CAR088 proliferation & expansion in the peripheral blood correlated with the decrease of tumor burden. Two patients reached VGPR at 4 weeks and 8 weeks respectively, and the third patient reached PR as early as 2 weeks post C-CAR088 infusion.

January 2020 / 81

Information Classification: General

Most Common Adverse Events C-CAR088 treatment showed to be well tolerated. There were no dose-limiting toxicities (DLTs). Reversible Grade 1 and Grade 2 Cytokine release syndrome (CRS) were observed in four and one patient respectively.

Per the abstract, C-CAR088 treatment was well tolerated, no dose-limiting toxicities (DLTs), reversible Grade 1~2 CRS observed.

Conclusion In conclusion, early clinical trial results in patients with r/r MM for C-CAR088 support preclinical findings that the drug shows promising efficacy and manageable safety profile.The very early clinical efficacy signal at low, suboptimal dose is encouraging and compares favorably to many other anti-BCMA CAR-T products at similar dose. The promising trend needs to be confirmed by the ongoing clinical trial.

Comment With results from only five patients in the first two dose escalation cohorts of this Phase I study, it is difficult to arrive at any definitive conclusions based on these data. The 100% overall response rate seen with C-CAR088 in this heavily pre-treated population is promising. However, two patients experienced progressive disease within 24 weeks of treatment, which may indicate a short duration of response. The safety profile was relatively standard for a CAR T-cell therapy. Although there was no incidence of Grade 3 or 4 cytokine release syndrome, 100% of patients experienced Grade 3 or 4 neutropenia and 80% experience Grade 3 or 4 thrombocytopenia, which is somewhat concerning.

The study is continuing to enroll patients at the higher dose levels and it will be interesting to see how the response rates and safety profile change over time. Additionally, even if C-CAR088 demonstrates similar efficacy results at a higher dose level, it will have to compete with more advanced CAR T-cell therapies in development for a similar patient population in multiple myeloma. Given this, we are leaving the likelihood of approval unchanged pending additional efficacy and safety data.

Source: PR Newswire 12/07/2019 Press Release 12/07/2019 (Multiple Myeloma Research Foundation) American Society of Hematology (ASH) 12/07/2019 (Abstract 50) American Society of Hematology (ASH) 12/07/2019 (Slide Deck) Sagient Analysis

January 2020 / 82

Information Classification: General

Darzalex for Multiple Myeloma (MM) (JNJ, Approved)

Phase III - CANDOR (w/Kyprolis+Dex) Trial Data – Updated Results

Change to LOA: 0%

Difference Between Treatment Comparator Treatment and Comparator Treatment Description Carfilzomib + DARZALEX + Carfilzomib DARZALEX + Carfilzomib + Dexamethasone + Dexamethasone Dexamethasone vs. Carfilzomib + Dexamethasone Alone Number of Patients N/A N/A N/A Number of Evaluable Patients N/A N/A N/A Progression-Free Survival (PFS) 15.8 Months N/A N/A (Endpoint=Primary) Hazard Ratio - PFS N/A N/A 0.63 (Endpoint=Primary) (P=0.0014) Rate of Minimal Residual 1.3 % 12.5 % N/A Disease (MRD)-Negativity (P<0.0001) (Endpoint=Secondary) Overall Response Rate (ORR) 75 % 84 % N/A (Endpoint=Secondary) (P=0.0040) Complete Response (CR) or 10 % 29 % N/A Better Median Treatment Duration 10.1 Months 17.5 Months N/A

Abstract LBA-6: Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor (NCT03158688)

Design CANDOR is an Amgen-sponsored study and is co-funded by Janssen Research & Development. The study included patients who had received 1–3 prior lines of therapy for multiple myeloma. Of the patients randomized in the study, 42 percent and 90 percent had previous exposure to lenalidomide and bortezomib, respectively; 33 percent were lenalidomide-refractory and 29 percent were bortezomib- refractory.

CANDOR is a randomized, open-label Phase III study of DARZALEX (daratumumab), carfilzomib and dexamethasone (DKd) compared to carfilzomib and dexamethasone (Kd) alone. The study evaluated 466 relapsed or refractory patients with multiple myeloma from 120 global sites who had received 1-3 prior

January 2020 / 83

Information Classification: General

therapies. Patients were treated until disease progression. The primary endpoint was PFS and the key secondary endpoints were overall response rate, minimal residual disease and overall survival. PFS was defined as time from randomization until disease progression or death from any cause.

All patients received carfilzomib as a 30-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter) and received 40 mg dexamethasone oral or IV weekly (20 mg/m2 for patients >75 years). In the treatment arm, DARZALEX (8 mg/kg) was administered via IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks for 4 cycles (Cycles 3‒6), and every 4 weeks thereafter.

Per the abstract, RRMM pts with measurable disease who had received 1–3 prior lines of therapy, with partial response or better to ≥1 line of therapy were eligible. Pts were randomized 2:1 to KdD or Kd. All pts received carfilzomib (K) as a 30-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). Daratumumab (8 mg/kg) was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 wks for 4 cycles (cycles 3 to 6), and every 4 wks thereafter. All pts received 40 mg dexamethasone oral or IV weekly (20 mg for pts >75 years).

Endpoints Per the abstract, the primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), minimal residual disease (MRD) negative-complete response at 12 months (threshold, 10-5 cells), overall survival (OS), time to response, and safety.

Results Results from the study show addition of DARZALEX (daratumumab) to carfilzomib (Kyprolis) and dexamethasone (DKd), compared to carfilzomib and dexamethasone (Kd) alone, significantly improved progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma, resulting in a 37 percent reduction in the risk of progression or death (HR, 0.63; 95 percent CI, 0.46–0.85; P=0.0014). Compared to Kd alone, DKd resulted in significantly longer PFS rates and response rates. The primary endpoint of PFS was met after a median follow-up of 16.9 months and 16.3 months for the DKd and Kd arms, respectively. Median PFS was not reached in the DKd arm versus 15.8 months in the Kd arm. At 12 months, patients in the DKd arm had a 10 times higher rate of minimal residual disease (MRD)-negativity compared to patients treated with Kd alone (12.5 percent vs. 1.3 percent; P<0.0001). Overall response rate (ORR) was 84 percent in the DKd arm, compared to 75 percent in the Kd arm (P=0.0040). The rate of complete response (CR) or better was 29 percent (DKd) and 10 percent (Kd). Median treatment duration was longer in the DKd arm than in the Kd arm (17.5 vs. 10.1 months, respectively).

Median overall survival (OS) was not reached in either arm at a median follow-up time of 17 months

January 2020 / 84

Information Classification: General

(HR, 0.75; 95 percent CI, 0.49–1.13; P=0.08).

Per the abstract, 466 pts (KdD: 312; Kd: 154) from 102 sites worldwide were randomized. Baseline characteristics were balanced between the two arms. Median age was 64 years. Of the randomized pts, 42.3% and 90.3% received previous LEN- and BTZ-containing regimens, respectively. 33% of pts were LEN-refractory. The primary endpoint of PFS was met after a median follow-up of 16.9 mo and 16.3 mo for the KdD and Kd arms, respectively. Median PFS was not reached for the KdD arm vs 15.8 mo for the Kd arm (HR, 0.63; 95% CI, 0.46–0.85; P=0.0014). PFS HRs favored KdD vs Kd across prespecified subgroups. Importantly, median PFS (KdD vs Kd) was not reached vs 12.1 mo in the LEN-exposed group (HR, 0.52; 95% CI, 0.34–0.80), and was not reached vs 11.1 mo in the LEN-refractory group (HR, 0.45; 95% CI, 0.28–0.74). Median time to first response was 1 mo in the KdD and Kd arms. ORR was 84.3% vs 74.7% (P=0.0040), and the rate of complete response or better was 28.5% vs 10.4%. MRD-negative complete response rate at 12 mo was 12.5% for KdD vs 1.3% for Kd (P<0.0001). Median OS was not reached in either arm at a median follow-up time of 17 mo (HR, 0.75; 95% CI, 0.49–1.13; P=0.08). Median treatment duration was longer in the KdD than Kd arm (70.1 vs 40.3 wks).

Most Common Adverse Events In general, the safety profile of DKd was consistent with the known safety profiles of daratumumab and Kd, with the exception of treatment emergent fatal adverse events which were higher in the DKd arm compared to the Kd arm. The incidence of Grade 3 and above adverse events (AEs) was 82 percent and 74 percent of patients in DKd and Kd, respectively, while serious AEs (SAEs) occurred in 56 percent and 46 percent of patients, respectively. The frequency of Grade 3 and above cardiac failure was 4 percent (DKd) and 9 percent (Kd); rate of cardiac failure event leading to discontinuation of carfilzomib was similar in both arms at 4 percent (DKd) and 5 percent (Kd). The rate of treatment discontinuation due to AEs was similar in both arms (DKd, 22 percent vs. Kd 25 percent). Five deaths were reported as treatment-related in the DKd arm (pneumonia, sepsis, septic shock, acinetobacter infection and cardio- respiratory arrest, n=1 each).

Per the abstract, the incidence of grade ≥3 AEs was 82.1% and 73.9% in the KdD and Kd arms, respectively. Serious AEs occurred in 56.2% (KdD) and 45.8% (Kd). The rate of treatment discontinuation due to AEs was similar in both arms (KdD, 22.4%; Kd, 24.8%). The frequency of grade ≥3 cardiac failure was 3.9% (KdD) and 8.5% (Kd); rate of cardiac failure event leading to K discontinuation was similar in the arms (3.9% and 4.6%). 5 deaths were reported as treatment-related, all in the KdD arm (pneumonia, sepsis, septic shock, acinetobacter infection, and cardio-respiratory arrest [n=1 each]).

Conclusion Per the abstract, KdD resulted in a significant PFS benefit over Kd, with a 37% reduction in the risk of progression or death. Pts treated with KdD achieved deeper responses, with a nearly 10-times higher MRD negative-complete response rate vs Kd-treated pts. The PFS benefit of KdD was maintained across

January 2020 / 85

Information Classification: General

prespecified clinically important subgroups, particularly among LEN-exposed and LEN-refractory pts. AEs were generally manageable and the incidence of AEs leading to treatment discontinuation was similar in the arms. Overall, KdD was associated with a favorable benefit-risk profile and represents an efficacious new regimen for RRMM, including for LEN-exposed and/or LEN-refractory pts.

Comment At ASH, Amgen and Janssen presented positive results for CANDOR, a Phase III study of Kyprolis combined with dexamethasone and Darzalex (KdD) vs Kyprolis and dexamethasone (Kd) in second-line or later multiple myeloma. This combination of two powerful targeted agents, Darzalex and Kyprolis, did not disappoint and the study met its primary endpoint of improving progression free survival (PFS). Compared to Kd, the KdD regimen resulted in a 37% reduction in the risk of progression or death. The median PFS for patients treated with KdD had not been reached by the cut-off date compared to a median PFS of 15.8 months for patients who received Kd alone. The treatment effect on PFS was generally consistent across prespecified clinically important groups such as patients with prior lenalidomide exposure (HR 0.52; 95% CI 0.34-0.80) and patients refractory to lenalidomide (HR 0.45; 95% CI: 0.28-0.74).

The study also met key secondary endpoints with improvements in overall response rate (84.3% vs 74.7%), complete response (including stringent complete response) rate at 12 months (28.5% vs 10.4%) and MRD-negative complete response rate at 12 months (12.5% vs 1.3%) favoring the KdD arm compared to Kd alone. Median overall survival has not yet been reached in either arm, but the hazard ratio indicated a trend in favor of the KdD arm (HR=0.75; 95% CI, 0.49–1.13; P=0.08).

Notwithstanding the improvement in PFS, there were some safety concerns as all five treatment-related deaths occurred in the KdD arm. Most of these deaths were related to infection. Multiple myeloma profoundly suppresses the immune system and Darzalex is known to impair cellular immunity which may deepen that suppression further and lead to a higher susceptibility to infection. At ASH the presenter mentioned that acyclovire prophylaxis was mandated but that antimicrobial prophylaxis was left to the choice of the investigator. A Phase III study showed that addition of prophylactic antibiotic treatment with levofloxacin to active myeloma treatment of newly diagnosed patients could reduce deaths in these patients. Such an approach may also be useful in relapsed/refractory patients being treated with KdD.

Kyprolis is currently approved for second-line or later multiple myeloma as a triplet, in combination with Revlimid (lenalidomide) and dexamethasone. Similarly, Darzalex is approved in this setting in combination with Revlimid and dexamethasone (based on the POLLUX trial) as well as in combination with Velcade (bortezomib) and dexamethasone (based on the CASTOR trial). The results from CANDOR suggest that the KdD regimen may be an alternative to the Darzalex/Velcade/dexamethasone (DVd) regimen for patients that relapsed, were refractory to or intolerant of a regimen containing an

January 2020 / 86

Information Classification: General

immunomodulatory agent such as Revlimid. Cross-trial comparisons of CANDOR and CASTOR suggest greater efficacy for the KdD regimen compared to the DVd regimen as KdD reported improved overall response rates (84.3% vs 79.3%) and complete response or better rates (28.5% vs 18.3%). Although median PFS has not yet been reached for either the KdD regimen or the DVd regimen in their respective trials, the median PFS for the comparator arms (15.8 months for Kd vs 7.2 months for Vd) indicate that the bar was set higher for the KdD regimen.

For now, we await regulatory submissions for this new treatment option for relapsed/refractory multiple myeloma.

Source: Press Release 12/10/2019 (JNJ) Press Release 12/10/2019 (Janssen) Press Release 12/10/2019 (AMGN) American Society of Hematology (ASH) 12/10/2019 (Abstract LBA-6) Press Release 12/10/2019 (Multiple Myeloma Research Foundation) Sagient Analysis

ide-cel for Multiple Myeloma (MM) (BMY; Phase III)

Phase II – KarMMa Trial Data – Top-Line Results

Change to LOA: 3%

Treatment Treatment Treatment Treatment Ide-cel Ide-cel Ide-cel Ide-cel Treatment Description 150 x 106 CAR+ T 300 x 106 CAR+ T 450 x 106 CAR+ T 150-450 x 106 CAR+ cells cells cells T cells Number of Patients N/A N/A N/A N/A Number of Evaluable 4 70 54 128 Patients Overall Response Rate 50.000 % 68.600 % 81.500 % 73.400 % (Endpoint=Primary) Complete Response Rate 25.000 % 28.600 % 35.200 % 31.300 % (Endpoint=Secondary) Median Duration of Response N/A 9.900 Months 11.300 Months 10.600 Months (Endpoint=Secondary)

January 2020 / 87

Information Classification: General

Median Progression-Free Survival N/A 5.800 Months 11.300 Months 8.600 Months (Endpoint=Secondary)

Context More comprehensive data from KarMMa will be submitted for presentation at a future medical meeting. Bristol-Myers Squibb is actively preparing for submission of these data to Health Authorities for proposed initial registration of ide-cel as a first-in-class BCMA-targeted CAR T cell therapy.

Design KarMMa is a pivotal, open-label, single-arm, multi-center Phase II study evaluating the efficacy and safety of ide-cel in adult patients with relapsed and refractory multiple myeloma, in North America and Europe. All enrolled patients had received at least three prior treatment regimens, including an IMiD agent, a PI and an anti-CD38 antibody, and were refractory to their last regimen, defined as progression during or within 60 days of their last therapy.

KarMMa enrolled 140 patients, of whom 128 patients were treated with ide-cel across the target dose levels of 150-450 x 106 CAR+ T cells. All treated patients were exposed to at least three prior therapies, including an immunomodulatory (IMiD) agent, a proteasome inhibitor (PI) and an anti-CD38 antibody, and all were refractory to their last regimen. Ninety-four percent of patients were refractory to an anti- CD38 antibody and 84% percent were triple refractory (refractory to an IMiD agent, PI and anti-CD38 antibody).

Endpoints The primary endpoint of the study is overall response rate as assessed by an independent review committee (IRC) according to the International Myeloma Working Group (IMWG) criteria. Complete response rate is a key secondary endpoint. Other efficacy endpoints include time to response, duration of response, progression-free survival, overall survival and minimal residual disease evaluated by Next- Generation Sequencing (NGS) assay.

Results Results for the primary endpoint (overall response rate [ORR]) and key secondary endpoint (complete response rate [CR]), as well as duration of response (DoR) and progression-free survival (PFS) across the target dose levels and at each of the three target doses explored in the study are presented in the table above. The median follow-up duration for all subjects was 11.3 months. Median DOR and median PFS are not reported for the 150 x 106 CAR+ T cells dose group due to the small number of evaluable patients.

Most Common Adverse Events Overall, the safety results were consistent with those observed in the Phase I CRB-401 study, which

January 2020 / 88

Information Classification: General

evaluated the preliminary safety and efficacy of ide-cel. Instances of grade 3 or higher cytokine release syndrome (CRS) occurred in 5.5% (7/128) of patients, including one fatal CRS event. Investigator identified grade 3 or higher neurotoxicity events (iiNT) occurred in 3.1% (4/128) of patients and there were no Grade 4 iiNT events reported. Grade 3 or higher CRS and iiNT events were reported in <6% of subjects at each target dose. CRS of any grade occurred in 83.6% (107/128) of patients and iiNT of any grade occurred in 18% (23/128) of patients.

Conclusion Study met its primary endpoint and key secondary endpoint, demonstrating deep and durable responses in a heavily pre-treated multiple myeloma patient population.

Comment Strong first results from the Phase II KarMMa study show the majority of relapsed/refractory multiple myeloma patients respond to ide-cel treatment, with a 73.4% overall response rate (ORR) across all dose levels. Particularly impressive are the data from the highest dose cohort (450 x 106 CAR+ T-cells), which achieved a 35%+ complete response rate. These results show ide-cel is able to replicate earlier positive results from the Phase I CRB-401 study in a larger patient cohort and potentially improve upon results from available therapies such as Darzalex and Pomalyst, which have previously demonstrated ORRs of 29.2% and 32.6% in relapsed/refractory patients, respectively.

The safety and tolerability profile of ide-cel administration was adequate and in line with previous results from the CRB-401 trial. Both the KarMMa and CRB-401 studies demonstrated serious (grade 3 or higher) cytokine release syndrome and neurotoxicity in approximately 6% and 3% of cases, respectively.

Bristol-Myers Squibb and bluebird bio plan to file a regulatory submission based on the KarMMa study in H1 2020, and are also studying the BCMA-directed therapy in earlier treatment lines in the Phase II KarMMa-2 and Phase III KarMMa-3 trials.

Based on these positive results, we are raising the LOA an additional 3%.

Source: Press Release 12/06/2019 (BMY) Press Release 12/06/2019 (BLUE) American Society of Hematology (ASH) 12/08/2019 (BMY, Slide 11) Sagient Analysis

January 2020 / 89

Information Classification: General

LCAR-B38M for Multiple Myeloma (MM) (JNJ, Phase II)

Phase Ib/II - CARTITUDE-1 (Dose Finding) Trial Data – Top-Line Results

Change to LOA: 2%

Treatment Treatment Description JNJ-4528 Number of Patients 29 Number of Evaluable Patients N/A Overall response rate 100.000 % (Endpoint=Primary) Stringent complete response 66.000 % Very good partial response or better 86.000 % Partial response 14.000 % MRD-negative disease status at day 28 100.000 %

Abstract 577: Results from CARTITUDE-1: A Phase 1b/2 Study of JNJ-4528, a CAR-T Cell Therapy Directed Against B-Cell Maturation Antigen (BCMA), in Patients with Relapsed and/or Refractory Multiple Myeloma (R/R MM)

Context These data also supported the recently announced U.S. Food and Drug Administration Breakthrough Therapy Designation for JNJ-4528.

Design CARTITUDE-1 is an ongoing Phase Ib/II, open-label, multicenter study evaluating the safety and efficacy of JNJ-68284528 in adults with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy or are double refractory to a PI and an IMiD; have received a PI, IMiD and an anti-CD38 antibody; and who progressed on or within 12 months of their last line of therapy.

Endpoints The primary objective of the Phase Ib portion of the study is to characterize the safety and confirm the dose of JNJ-68284528, which was informed by the first-in-human study with LCAR-B38M CAR-T cells (LEGEND-2). The primary objective for the Phase II portion of the study is to evaluate the efficacy of JNJ- 68284528 (primary endpoint: overall response rate as defined by the International Myeloma Working Group response criteria).

Results Results from the Phase Ib portion of the CARTITUDE-1 study showed early and deep responses among

January 2020 / 90

Information Classification: General

patients (n=29) with a median of five prior multiple myeloma treatment regimens (range, 3-18) treated with JNJ-4528 (median administered dose 0.73x106 CAR+ viable T cells/kg), with 100 percent of patients achieving a response (95 percent confidence interval [CI], 76-95) at a median six-month follow-up. The overall response rate (ORR) included 69 percent of patients achieving a complete response (CR) or better (66 percent achieving a stringent CR); 86 percent of patients achieving a very good partial response (VGPR) or better; and 14 percent of patients achieving a partial response (PR). In addition, 100 percent of evaluable patients achieved early minimal residual disease (MRD)-negative disease status at day 28 post-infusion. At the six-month follow-up, 27 of 29 patients were progression-free. Based on the Phase Ib results, a recommended Phase II dose of 0.75x106 CAR+ viable T cells/kg was confirmed.

Most Common Adverse Events The most common adverse events (AEs) observed in the CARTITUDE-1 study were cytokine release syndrome (CRS) (93 percent); neutropenia (93 percent); anemia (86 percent); and thrombocytopenia (86 percent). In patients who experienced grade 3 and above AEs (25 percent), the most common were neutropenia (93 percent); thrombocytopenia (69 percent); and anemia (55 percent). A majority of patients (86 percent) experienced grade 1-2 CRS. One patient experienced grade 3 CRS and one patient died of complications from grade 5 CRS at day 99. The median onset of CRS was generally predictable at seven days (range, 2-12) post-infusion, with a median duration of four days (range, 1-60).

Conclusion Collectively these results demonstrate that JNJ-4528 at a target dose of 0.75x106 CAR+ cells/kg delivers early and deep responses, including MRD negativity in all evaluable pts tested, with a manageable safety profile in pts with refractory MM. The safety and efficacy results from the ongoing CARTITUDE-1 study are consistent with the LEGEND-2 study and confirm the 0.75x106 CAR+ cells/kg dose as the RP2D for further clinical development.

Comment First results from the CARTITUDE-1 trial show this BCMA-directed CAR-T is effective in heavily pretreated multiple myeloma. The 100%% ORR and 66% CR rate for LCAR-B38M are decidedly positive considering patients included in the study had a median of 5 prior lines of therapy with 86% and 31% of patients categorized as triple- and penta-refractory, respectively. Of note, 27 of the 29 patients that achieved a CR were still in remission at the six-month follow-up and the two that relapsed had extramedullary disease. These results are slightly less impressive than those for ide-cel, which achieved a 94% ORR and 56% CR rate after approximately nine months of follow-up in the Phase I CRB-401 study in a somewhat sicker population that had a median of seven prior lines of therapy. LCAR-B38M’s efficacy does compare well to BCMA-directed ADC, belantamab mafodotin, which reached an ORR of 60% in the Phase I DREAMM-1 Study.

The safety and tolerability of LCAR-B38M seems to be average for a CAR-T regimen. There were

January 2020 / 91

Information Classification: General

relatively few neurotoxicity events, but CRS was common. There was one grade 3 and one grade 5 CRS event on LCAR-B38M treatment and 76% of patients required tocilizumab intervention. The vein-to-vein time of 43 days is somewhat long compared to other CAR-T assets. Ide-cel’s vein-to-vein time while in Phase I was 30 days. The presenter noted that of the 35 enrolled patients, six were unable to be dosed due to progression while waiting for the therapy.

The average tolerability and long manufacture time are a detriment in this increasingly crowded development space heavily focused on BCMA therapies. However, the positive efficacy results are encouraging and certainly warrant further investigation. We are raising the LOA an additional 2%.

Source: Press Release 12/07/2019 (JNJ) Press Release 12/07/2019 (Janssen) Press Release 12/11/2019 (Multiple Myeloma Research Foundation) American Society of Hematology (ASH) 12/09/2019 (Abstract 577) Sagient Analysis

Myelodysplastic Syndrome (MDS)

APR-246 for Myelodysplastic Syndrome (MDS) (APRE, Phase III)

Phase Ib/II - w/Azacitidine (US) Trial Data – Updated Results

Change to LOA: 3%

Abstract 676: Phase 2 Results of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML)

Design Eligible patients in the Phase Ib/II clinical trial include HMA-naïve, TP53 mutated MDS, oligoblastic acute myeloid leukemia (AML, ≤ 30% blasts), MDS-myeloproliferative neoplasm (MDS-MPN) overlap and chronic myelomonocytic leukemia (CMML). In the Phase Ib part of the clinical trial, patients received APR-246 in a 3+3 dose escalation design (50, 75, 100 mg/kg lean body weight) IV daily over 4 days in a lead-in phase (days -14 to -10), followed by the same dose of APR-246 (days 1-4) and AZA 75 mg/m2 SC/IV daily for 7 days (days 4-10 or 4-5 and 8-12) in 28-day cycles. In the Phase II part of the clinical trial, patients receive APR-246 as a 4,500 mg fixed dose IV daily (days 1-4) and AZA daily for 7 days (days 4-10

January 2020 / 92

Information Classification: General

or 4-5 and 8-12) in 28-day cycles.

Endpoints Primary objective in Phase Ib part of the clinical trial was safety, with AEs graded by CTCAE v4.03 and DLT assessment over 6 weeks. Secondary endpoints included response rate by IWG 2006 criteria, PFS, OS, as well as serial next generation sequencing and p53 immunohistochemistry for evaluation of clonal suppression and depth of remission. In the Phase II part of the clinical trial the primary endpoint is CR rate.

Results As of the data cutoff, the overall response rate (ORR) in 33 evaluable MDS patients was 88%, with a 61% complete remission (CR) rate, by International Working Group (IWG) criteria. With a median duration of follow-up of 10.8 months, the median duration of response was 8.4 months and the median duration of CR was 7.3 months. Seventeen (52%) evaluable MDS patients discontinued therapy to pursue stem cell transplant. Median overall survival (OS) for all enrolled patients (n=55) was 10.8 months. Median OS in responding patients versus non-responders was 13.7 vs. 3.9 months.

Most Common Adverse Events Adverse events, regardless of causality, were mostly grade 1/2. Grade 3+ adverse events occurring in ≥20% of patients were limited to cytopenias and infection, consistent with underlying hematopoietic malignancies, and no exacerbation of the expected AZA-related safety profile has been observed.

Conclusion Per the abstract, APR-246+AZA is a well-tolerated combination with high response rates in mTP53 MDS/AML. Response durations are promising accompanied by a high fraction of cytogenetic and deep molecular remissions leading to encouraging outcomes post-HSCT. These data support the ongoing, randomized Phase III study of APR-246+AZA versus AZA alone in mTP53 MDS.

Comment These are encouraging results from both the US and French Phase Ib/II studies of APR-246 in combination with azacitidine in patients with hypomethylating agent-naïve TP53 mutant myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). In MDS, a TP53 mutation is associated with lower overall survival and more complex cytogenetics. The overall response rate (ORR) of 88% and complete response (CR) rate of 61% seen in the MDS cohort of the Phase Ib/II US trial compare favorably to the response rates seen with the current standard of care, azacitidine monotherapy (29% and 17%, respectively). Although the French Phase Ib/II trial results seen in a separate presentation were lower, the ORR of 63% and the CR rate of 48% are still promising. Additionally, this lower rate could have been due to the higher median age of participants (73 years vs. 68 years) in the French study.

January 2020 / 93

Information Classification: General

The data from the US Phase Ib/II study are comparable to the updated results for magrolimab, an anti- CD47 monoclonal antibody, in combination with azacitidine that were also presented at ASH 2019. The magrolimab and azacitidine combination showed an ORR of 92% and a CR of 50%. However, it is worth nothing that the APR-246 studies had a much higher percentage of patients with TP53 mutations than the magrolimab study (100% vs 11%), which complicates comparison between the two drugs.

Unfortunately, the safety profile for the APR-246 and azacitidine combination is slightly concerning. In terms of serious adverse events, APR-246 had a 25% rate of febrile neutropenia, a 20% rate of lung infection, a 7% rate of respiratory failure, and a 7% rate of sepsis. The 30- and 60-day mortality rates were 2% and 5%, respectively. However, there was a relatively low discontinuation rate due to adverse events (5%).

Given these positive preliminary efficacy results and the high unmet need of this patient population, we are raising our likelihood of approval by 3% in MDS as we await results, particularly an update regarding the safety profile, from the pivotal Phase III study.

Aprea Therapeutics is also investigating APR-246 as a post-stem cell transplant maintenance therapy in TP53 mutant MDS and AML. The combination of APR-246, azacitidine, and venetoclax is also being testing in relapsed/refractory AML patients in a recently initiated Phase I/II study. These expansions into other therapy lines for both MDS and AML will potentially increase the available patient population, thus significantly increasing the commercial potential of this drug.

Source: Press Release 12/09/2019 (APRE) American Society of Hematology (ASH) 12/09/2019 (Abstract 637) Company Conference Call 12/09/2019 (APRE) Company Conference Call Slides 12/09/2019 (APRE) Sagient Analysis

ASTX727 for Myelodysplastic Syndrome (MDS) (Otsuka, Phase III)

Phase III - ASCERTAIN (vs. Decitabine) Trial Data – Updated Results

Change to LOA: 2%

January 2020 / 94

Information Classification: General

Treatment Treatment Description Oral ASTX727 + IV Decitabine Number of Patients N/A Number of Evaluable Patients N/A Total 5-Day Decitabine AUC 98.900 % (Endpoint=Primary) Complete Response (CR) 12.000 % (Endpoint=Secondary) Overall Response Rate (ORR) 64.000 % (Endpoint=Secondary)

Abstract 846: Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross over Phase 3 Study (ASCERTAIN study) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine

Context Based on the data from the ASTX727 clinical program, including the ASCERTAIN Phase III study, Astex is moving ahead with plans to file a New Drug Application (NDA) with the US Food & Drug Administration (FDA).

Design The study was designed as a randomized crossover study comparing oral ASTX727 (100mg cedazuridine and 35mg decitabine fixed dose combination tablet given once daily for 5 days on a 28-day cycle) to intravenous (IV) decitabine (20mg/m2 administered as a daily 1-hour IV infusion for 5 days on a 28 day cycle) in the first 2 cycles with patients continuing to receive oral ASTX727 from Cycle 3 onward.

Endpoints Per the presentation, primary endpoints include total 5-d decitabine AUC equivalence. Secondary endpoints include efficacy (response rate; transfusion, independence; duration of response), leukemia- free and overall survival, safety of ASTX727, and Max LINE-1 demethylation.

Results The data presented demonstrated that the ASCERTAIN study met the primary endpoint of total 5-Day decitabine Area-Under-The-Curve (AUC) equivalence of oral ASTX727 and IV decitabine. The oral/IV decitabine 5-day AUC was 98.9% (with a 90% Confidence Interval between 92.7% and 105.6%). Preliminary clinical activity as of the data cutoff was also consistent with published data for IV decitabine. In evaluable patients, the Complete Response (CR) rate was 12%, with an overall response rate, including hematological improvement, of 64%.

Most Common Adverse Events Safety findings from the study were consistent with those anticipated with IV decitabine, with no

January 2020 / 95

Information Classification: General

significant differences in the incidence of most common adverse events between ASTX727 and IV decitabine in the first 2 randomized cycles. The most common adverse events (AEs) of any grade >20% regardless of causality in patients in the first 2 randomized cycles who received ASTX727 were thrombocytopenia (43.8%); neutropenia (35.4%); anemia (36.9%); and fatigue (23.8%).

Conclusion The ASCERTAIN Phase III study data confirms the hypothesis that by inhibiting cytidine deaminase in the gut, systemic therapeutic concentrations of decitabine can be delivered orally to achieve decitabine systemic exposure equivalent to IV dosing.

Comment The first numerical results from the Phase III ASCERTAIN study of ASTX727 showed that the study met the primary endpoint, demonstrating an oral/intravenous (IV) ratio 5-day decitabine AUC ratio of approximately 99% with a 90% confidence interval of 93% to 106%. This equivalence to decitabine, which is an FDA approved intravenous (IV) therapy for myelodysplastic syndrome (MDS) International Prognostic Scoring System (IPSS) int-1, int-2, or high-risk MDS patients and patients with chronic myelomonocytic leukemia (CMML), was confirmed through findings from sensitivity and secondary pharmacokinetic AUC analyses. In terms of pharmacodynamics, comparison of hypomethylating activity as measured by LINE-1 demethylation showed no statistically significant difference between the two drugs.

Oral ASTX727 also demonstrated promising results for the secondary endpoints of safety and efficacy. There were no statistically significant differences seen in the adverse event rates for IV decitabine and oral ASTX727 during the first two randomized cycles. Although the efficacy data is somewhat immature, the results seem to be relatively in line with those seen with IV decitabine. The overall response rate (ORR) in the MDS and CMML evaluable patients was 64.4%, with a complete response (CR) rate of 11.9%.

Astex Pharmaceuticals will be moving forward with plans to file a New Drug Application (NDA) for ASTX727 with the US Food & Drug Administration (FDA) based on these data. If approved, ASTX727 will be a convenient option for patients that does not require 5-day IV infusions every month, which will also likely reduce the costs associated with treatment. Furthermore, the oral formulation allows for the possibility of an all-oral combination therapy in the future.

Based on these bioequivalence data, we are increasing the likelihood of approval by an additional 2%.

Source: Press Release 12/09/2019 (Astex)

January 2020 / 96

Information Classification: General

American Society of Hematology (ASH) 12/09/2019 (Abstract 846) American Society of Hematology (ASH) 12/09/2019 (Company Presentation) Sagient Analysis

Venclexta for Myelodysplastic Syndrome (MDS) (ABBV, Phase II)

Phase Ib - w/Azacitidine Trial Data – Top-Line Results

Change to LOA: 3%

Abstract 568: A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Azacitidine in Treatment-Naïve Patients with Higher-Risk Myelodysplastic Syndrome

Design The study initially included a 3-arm randomized cohort. Data from this cohort included 10 pts treated with Ven (400 mg or 800 mg for 28 days) + Aza and 2 pts treated with Aza alone. Following two deaths (Ven 400 mg=1/5 and Ven 800 mg=1/5), the study was amended to a dose-escalation and safety expansion design to determine the recommended Phase II dose (RP2D) of Ven+Aza. Key inclusion criteria were age ≥18 yrs, no prior therapy for MDS, IPSS score of ≥1.5, bone marrow blasts <20%, ECOG score of ≤2, and excluded pts with chronic myelomonocytic leukemia and pts who were candidates for undergoing intensive chemotherapy or allogeneic HSCT. In the dose escalation portion, cohorts were enrolled with escalating doses of Ven administered orally for the first 14 days of each 28-day cycle with cohorts from 100 mg daily up to 400 mg daily. Pts started at 100% of the prescribed Ven dose without intraindividual ramp up. Aza was administered at the std dose (75 mg/m2, subcutaneously or IV) from Day 1-7 per 28-day cycle. Primary study objectives were to evaluate safety and determine the RPTD schedule of Ven+Aza. Key secondary efficacy outcomes include objective response rate (ORR[complete remission (CR) + marrow complete remission (mCR) + partial remission]), progression free survival (PFS), time to response (TTR), duration of response (DOR), and overall survival (OS).

Results As of April 9, 2019, 59 pts have been treated and dose-escalation is complete. These included 12 pts in the initial randomized cohort. The dose-escalation cohort included 25 pts (Ven 100 mg=8, Ven 200 mg=9, Ven 400 mg=8) and the safety expansion included 22 pts. Results are presented for all 59 pts [75% male, median age 71 yrs (range 26-85)]. At baseline, 15 (25%) pts had an overall IPSS score of 1.5, 29 (49%) had a score of 2, 8 (14%) had a score of 2.5, 6 (10%) had a score of 3.0, and 1 (2%) pt had a score of 3.5. Eleven (19%) pts had intermediate and 24 (41%) pts had poor baseline cytogenetic risk.

January 2020 / 97

Information Classification: General

Among 57 pts evaluable for response, the ORR with (CR) was documented in 18, mCR in 22 , and stable disease (SD) in 11. Disease progression was observed in 2 pts. Median TTR for ORR was 1.0 mos (range 0.7-3.5 mos). At this data cut, the median time to FU was 4.3 mos (range 3.3-6.5 months). Median DOR, PFS and OS were not reached. With this short follow up, the 12-mo estimates for DOR for ORR was 74% (95% CI: 34%, 92%) and PFS was 59% (95% CI: 31%, 79%). The 18-mo estimate for OS was 74% (95% CI: 50%, 87%). Among 56 pts eligible for hematological improvement (HI), 28 (50%) patients achieved HI as either HI-erythroid, HI-platelet, or HI-neutrophil.

Most Common Adverse Events In treated pts, the most common treatment-emergent adverse events (TEAE’s) were anemia, neutropenia, and thrombocytopenia (Table). Common gastrointestinal symptoms were constipation, nausea, diarrhea, and vomiting. Infection was predominantly febrile neutropenia. Predominant Grade 3 or 4 AEs included neutropenia (61%), thrombocytopenia (39%), leukopenia (31%), and anemia (20%). Major SAEs were febrile neutropenia (31%). There were 10 deaths of which 4 were due to infections (pneumonia-2, neutropenic sepsis-1 and septic shock- 1). Other causes of death were multiorgan failure (n=1), respiratory failure (n=1), progressive disease (n=3), and unexplained death (n=1). Twenty pts discontinued the study including 10 who underwent transplantation.

Conclusion The combination therapy of Ven+Aza demonstrated a tolerable safety profile and promising efficacy in pts with HR-MDS. The maximum tolerated dose of Ven without dose-limiting toxicities was determined to be 400 mg in this HR-MDS population.

Comment These top-line results from the Phase Ib study of the combination of venetoclax and azacitidine for the treatment of higher-risk myelodysplastic syndrome (MDS) are impressive, with an overall response rate (ORR) of 77.2%, which was composed of a complete response (CR) rate of 38.6% and a marrow complete response (mCR) rate of 38.6%, and a 12-month overall survival (OS) estimated rate of 76.9%.

The preliminary overall survival (OS) rates at this point also appear durable, although longer term follow-up is still needed. Among the 22 patients who achieved a CR and the 22 patients who achieved a mCR, the 12-month OS estimates were 93.8% and 85.9%, respectively. Additionally, 67% of all patients on the study had an eight week or greater transfusion-free interval from both RBC and platelet transfusions.

In terms of serious adverse events, 40% of patients experienced febrile neutropenia and 7% of patients developed pneumonia. Dr. Andrew Wei mentioned during his presentation that the safety profile was manageable with the truncated dosing schedule and, if neutrophil counts drop below 0.5, the recommended anti-bacterial prophylaxis. Dr. Wei also noted that there was no significant exposure-

January 2020 / 98

Information Classification: General

safety relationship in terms of neutropenia or thrombocytopenia incidence across the venetoclax exposure range.

Although the ORR is relatively in line with the results seen at ASH 2019 from the Phase Ib/II studies of APR-246 and azacitidine and the Phase Ib study of magrolimab in combination with azacitidine, venetoclax may ultimately distinguish itself based on overall survival. Based on these results, we are increasing the likelihood of approval by 3%.

Source: American Society of Hematology (ASH) 12/09/2019 (Abstract 568) Sagient Analysis

Vidaza for Myelodysplastic Syndrome (MDS) (BMY, Approved)

Phase II - w/Durvalumab Trial Data – Top-Line Results

Change to LOA: 0%

Treatment Treatment Treatment Treatment Treatment Description Azacitidine + Azacitidine Azacitidine + Azacitidine Durvalumab MDS Cohort Durvalumab AML Cohort MDS Cohort Arm B AML Cohort Arm B Arm A Arm A Number of Patients 42 42 64 65 Number of Evaluable Patients N/A N/A N/A N/A Overall Response Rate (ORR) 61.9 % 47.6 % N/A N/A CR + PR + mCR + HI (Endpoint=Primary) Complete Remission (CR) 7.1 % 9.5 % 17.2 % 21.5 % (Endpoint=Primary) Partial Remission (PR) 0 % 0 % N/A N/A (Endpoint=Primary) Marrow Complete Remission (cMR) 35.7 % 19.0 % N/A N/A (Endpoint=Primary) Hematological Improvement (HI) Only 19.0 % 19.0 % N/A N/A (Endpoint=Primary) Stable Disease (SD) 14.3 % 7.1 % N/A N/A Overall Response Rate (ORR) N/A N/A 31.3 % 35.4 % CR + CRi (Endpoint=Primary)

January 2020 / 99

Information Classification: General

Complete Remission with Incomplete N/A N/A 14.1 % 13.8 % Blood Recovery (CRi) (Endpoint=Primary) Median Overall Survival (OS) 11.6 Months 11.7 Months 13.0 Months 14.4 Months (Endpoint=Secondary) Median Progression-Free Survival (PFS) 8.7 Months 8.6 Months 8.1 Months 7.2 Months (Endpoint=Secondary)

Abstract 829: Efficacy and Safety of Azacitidine (AZA) in Combination with the Anti-PD-L1 Durvalumab (durva) for the Front-Line Treatment of Older Patients (pts) with Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy (IC) and Pts with Higher-Risk Myelodysplastic Syndromes (HR- MDS): Results from a Large, International, Randomized Phase 2 Study

Design This randomized, open-label, international, multicenter study enrolled untreated pts in 2 cohorts: 1) MDS (aged ≥18 years; IPSS-R intermediate, high, and very high) and 2) older AML pts (aged ≥65 years) who were ineligible for IC. All pts had ECOG performance status 0–2 and were separately randomized (1:1) to receive SC AZA 75 mg/m2 Days 1–7 and durva 1500 mg IV on Day 1 Q4W (Arm A) or AZA alone (Arm B) and stratified according to cytogenetic risk (MDS, very good/good/intermediate vs. poor/very poor; AML, intermediate vs. poor). Treatment was planned to continue until progression or unacceptable toxicity. Disease status was evaluated every third treatment cycle. Peripheral blood samples were collected to assess changes in DNA methylation using the EPIC methylation array (Illumina). Bone marrow (BM) aspirates were obtained for quantitation of PD-L1 surface expression by flow cytometry and values are reported as molecules of equivalent soluble fluorochrome.

Endpoints Primary MDS endpoints included overall response rate (ORR, defined as complete remission [CR], marrow [m]CR, partial response [PR], or hematologic improvement [HI]) based on IWG 2006 response criteria, while for AML ORR was defined as CR or CR with incomplete blood recovery (CRi) based on modified IWG 2003 response criteria. Secondary endpoints included PFS, OS, and safety.

Results A total of 213 pts, 84 with MDS (each arm, n=42) and 129 with AML (Arm A, n=64; Arm B, n=65) were randomized. As of October 31, 2018, 32 pts (MDS, n=14; AML, n=18) continued to receive trial treatment while 181 (MDS, n=70; AML, n=111) had discontinued. Baseline demographics and disease characteristics were generally balanced across treatment groups in both cohorts. Median number of treatment cycles for AML Arm A vs. B, 6.5 vs. 6.7; for MDS Arm A vs. B, 7.9 vs. 7.0. No statistically significant differences in ORR between treatment arms were observed in either cohort. In MDS Arm A vs. B, median OS was 11.6 vs. 16.7 months (mo) and PFS was 8.7 vs. 8.6 mo. In the AML cohort, median OS was 13.0 vs. 14.4 mo and PFS was 8.1 vs. 7.2 mo. Caution should be used when interpreting results

January 2020 / 100

Information Classification: General

because >50% of patients were censored. AZA induced similar trends in global hypomethylation, along with focal hypomethylation of PD-L1 and PD-L2 gene loci, at the end of treatment cycle 1 in all treatment groups and cohorts. Mean PD-L1 surface expression in BM immune cells at baseline was highest in monocytes (MDS=1,425; AML=1,536), followed by granulocytes (MDS=550; AML=758) and myeloid blasts (MDS=532; AML=735). Increased surface expression of PD-L1, but not PD-L2, was observed at the end of treatment cycle 3 on BM granulocytes and monocytes from MDS pts and on BM monocytes from AML pts, but no increase was detected on myeloid blasts.

Most Common Adverse Events The most frequent TEAEs (≥15%) were hematologic and GI toxicity. In the MDS and AML cohorts, 7 and 17, respectively, immune-mediated AEs were observed; all were treated and resolved.

Conclusion No clinically meaningful difference in efficacy was observed between treatments for either cohort. No new safety signals or potential overlapping risks were identified with the combination. While the hypomethylating activity of AZA on PD-L1 gene was confirmed, no treatment-mediated induction of PD- L1 surface expression was observed on myeloid blasts.

Comment These disappointing results show that Imfinzi combined with azacitidine did not significantly improve response rates or survival when compared to azacitidine alone in patients with newly diagnosed AML or high-risk myelodysplastic syndrome (MDS).

Preclinical work has shown that azacitidine increases PD-L1 expression. While the hypomethylating activity of azacitidine on PD-L1 gene was confirmed, no treatment-mediated induction of PD-L1 surface expression was observed on myeloid blasts.

Checkpoint inhibitors such as Imfinzi may eventually find success when combined with intensive chemotherapy as encouraging results were presented for Keytruda combined with high-dose cytarabine in relapsed/refractory AML.

Source: American Society of Hematology (ASH) 12/09/2019 (Abstract 829) Sagient Analysis

January 2020 / 101

Information Classification: General

Myelofibrosis (MF)

Reblozyl for Myelofibrosis (MF) (XLRN; Phase II)

Phase II - MF-001 Trial Data – Top -Line Results

Change to LOA: 1%

Treatment Treatment Treatment Treatment Treatment Description Luspatercept Luspatercept + Luspatercept Luspatercept + Cohort 1 Ruxolitinib Cohort 2 Ruxolitinib Cohort 3A Cohort 3B Number of Patients N/A N/A N/A N/A Number of Evaluable Patients 20 14 20 19 Mean Hb increase of > 1.5 g/dL 15.000 % 57.000 % N/A N/A (Endpoint=Primary) RBC-TI > 12 weeks N/A N/A 10.000 % 32.000 % (Endpoint=Primary) > 50% reduction in RBC N/A N/A 38.000 % 53.000 % transfusion burden from baseline (Endpoint=Secondary)

Abstract 557: A Phase 2 Study of Luspatercept in Patients with Myelofibrosis-Associated Anemia

Design Per the abstract, 74 patients with myelofibrosis (MF) and anemia were enrolled, including 41 not receiving concomitant ruxolitinib at study entry who received either no red blood cell (RBC) transfusions (n = 20; Cohort 1) or 2–4 RBC U/28 d in the 12 weeks prior to treatment (n = 21; Cohort 2). Thirty-three enrolled patients were receiving a stable dose of ruxolitinib for at least 16 weeks, of which 14 were not receiving RBC transfusions (Cohort 3A) and 19 were (Cohort 3B). Patients in Cohorts 3A and 3B received a median dose of ruxolitinib of 20 mg/d (range, 5–50 mg/d) for a median of 41 and 43 weeks, respectively. Patients received luspatercept every 21 days at a starting dose of 1.0 mg/kg in doses escalating up to 1.75 mg/kg. Intent-to-treat (ITT) data were analyzed as of May 10, 2019.

Endpoints The primary endpoint in patients not receiving transfusions was a hemoglobin (Hb) increase ≥ 1.5 g/L at every assessment from baseline for ≥ 12 consecutive weeks within the first 24 weeks on study. In patients receiving RBC transfusions, the primary endpoint was RBC transfusion-independence (RBC-TI)

January 2020 / 102

Information Classification: General

for ≥ 12 consecutive weeks within the first 24 weeks on study. Additional endpoints included proportion of patients achieving mean Hb increase ≥ 1.5 g/dL in Cohorts 1 and 3A, and ≥ 50% decrease in RBC transfusions (minimum 4 RBC U decrease from baseline) in Cohorts 2 and 3B, with both responses lasting ≥ 12 consecutive weeks within 24 weeks of study entry.

Results Patients with MF receiving a stable dose of ruxolitinib in combination with luspatercept treatment: • 8 of 14 (57%) non-transfusion-dependent (NTD) patients (trial Cohort 3A) achieved a mean hemoglobin (Hb) increase of ≥ 1.5 grams per deciliter (g/dL) • 6 of 19 (32%) transfusion-dependent (TD) patients (trial Cohort 3B) achieved RBC-TI over any consecutive 12 weeks o 10 (53%) TD patients achieved a ≥ 50% reduction in RBC transfusion burden from baseline. Patients with MF receiving luspatercept without concomitant treatment with ruxolitinib: • 3 of 20 (15%) NTD patients (trial Cohort 1) achieved a mean Hb increase of ≥ 1.5 g/dL • 2 of 20 (10%) TD patients (trial Cohort 2) achieved RBC-TI over any consecutive 12 weeks. Per the abstract, median age was 71 years (range, 50–88 years), and 42 (57%) were male. Median interval from MF diagnosis to study entry was 3.3 years (range, 19 days to 13.5 years). Seven patients were Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, 58 were intermediate-2, and eight were high risk. Median Hb concentration at study entry was 8.8 g/dL (range, 6.7–9.8 g/dL) for Cohort 1, and 8.6 g/dL (range, 6.7–9.1 g/dL) for Cohort 3A. Patients in Cohort 2 received a median of 2.7 RBC U/28 d (range, 1–5 U/28 days), and patients in Cohort 3B received a median of 2.3 RBC U/28 d (range, 2–4 U/28 d). Patients received a median of eight cycles of luspatercept (range, 1–24 cycles).

Efficacy data are displayed in the table, per ITT data. Two of 20 (10%) and 3/14 (21%) patients in Cohorts 1 and 3A, respectively, achieved an absolute Hb increase ≥ 1.5 g/dL at every measurement from baseline over any consecutive 12 weeks. Two of 21 (10%) and 6/19 (32%) patients in Cohorts 2 and 3B, respectively, achieved RBC-TI over any consecutive 12 weeks. Median duration of Hb response was 20 weeks (range, 12–27 weeks) in Cohort 1, and 12 weeks (range, 12–13 weeks) in Cohort 3A. Median duration of RBC-TI was 23 weeks (range, 16–31 weeks) in Cohort 2, and 32 weeks (range, 12–65 weeks) in Cohort 3B. Three (15%) and eight (57%) patients in Cohorts 1 and 3A, respectively, achieved a mean Hb increase of ≥ 1.5 g/dL. Eight (38%) and 10 (53%) patients in Cohorts 2 and 3B, respectively, achieved a ≥ 50% reduction in RBC transfusion burden from baseline. Ruxolitinib exposure remained stable throughout the 24-week treatment period in both Cohorts 3A and 3B. There was no difference in spleen size between responders and non-responders.

Most Common Adverse Events Per the abstract, four patients (5%) had grade 3–4 treatment-related adverse events (AEs). There were no treatment-related deaths. Treatment-related AEs occurring in ≥ 3% of patients were hypertension

January 2020 / 103

Information Classification: General

(11%), bone pain (8%), and diarrhea (4%). Seven patients (9%) had ≥ 1 AE resulting in treatment discontinuation; 23 (31%) remain on study.

Conclusion Per the abstract, the initial results from this ongoing study suggest clinically significant activity of luspatercept in patients with MF-associated anemia, including those receiving concomitant ruxolitinib. A minority of AEs were grade 3–4 in severity, consistent with previous studies in MDS and beta- thalassemia.

Comment These are encouraging results for luspatercept. While Jakafi can improve splenomegaly symptoms and even prolong survival, there are no approved therapies for alleviating anemia, which is considered a negative prognostic risk factor for survival in patients with myelofibrosis (MF). Symptomatic anemia is observed in more than 50% of patients at the time of diagnosis, and treatment with Jakafi is associated with an increased incidence of grade 3/4 anemia. The 2019 NCCN MF guidelines recommend anemia be treated with red blood cell (RBC) transfusions; however, these transfusions greatly diminish quality of life.

Erythropoiesis-stimulating agents (ESAs), androgens (danazol), and immunomodulatory agents (thalidomide, Revlimid, and Pomalyst) are used off-label for the management of MF-associated anemia. In several small studies, ESAs reported week 12 anemia responses (transfusion independence, sustained increase in hemoglobin levels [>2g/dL] or >50% reduction in transfusion requirements) in 45–60% of patients with MF. ESAs are only recommended for MF where serum erythropoietin levels are not elevated, and they have been associated with venous thromboembolism and increased mortality.

Danazol reported anemia responses in 30% of patients, while thalidomide, Revlimid, and Pomalyst regimens (often in combination with corticosteroids) reported anemia responses of 62%, 19–32%, and 39%, respectively, according to the 2019 NCCN guidelines. We are therefore encouraged that luspatercept given concomitantly with Jakafi showed complete responses (RBC transfusion- independence) in 32% of patients, and partial responses (>50% reduction in RBC transfusions) in 53% of patients. Also encouraging is that 57% of patients who were not yet transfusion-dependent had increases in hemoglobin following treatment with luspatercept and Jakafi.

A potential pipeline competitor is Constellation Pharmaceuticals’ CPI-0610. At ASCO 2019, it was reported that CPI-0610 reduced spleen volume, and when CPI-0610 was combined with Jakafi, two of three transfusion-dependent patients became transfusion-independent. Updated data for CPI-0610 will be presented at ASH (Abstract 670).

As we await announcement of a Phase III trial for luspatercept, we are increasing the LOA by 1%.

January 2020 / 104

Information Classification: General

Source: Press Release 11/06/2019 (XLRN) American Society of Hematology (ASH) 12/08/2019 (BMY, Slide 16) American Society of Hematology (ASH) 12/09/2019 (Abstract 557) Sagient Analysis

Peripheral T-Cell Lymphoma (PTCL) - NHL

Cerdulatinib for Peripheral T-Cell Lymphoma (PTCL) – NHL (PTLA; Phase I/II)

Phase I/IIa - Two Part Dose Escalation Trial Data – Updated Results

Change to LOA: 2%

Treatment Treatment Treatment Treatment Description Cerdulatinib Cerdulatinib Cerdulatinib PTCL PTCL - AITL Subset CTCL Number of Patients 64 27 40 Number of Evaluable Patients 64 27 40 Overall Response Rate (ORR) 34.000 % 52.000 % 43.000 % (Endpoint=Primary) Complete Response Rate (CR) 22.000 % 37.000 % 8.000 % Partial Response (PR) 12.000 % 15.000 % 35.000 % Median Duration of Response (DOR) 8 months 9 months N/A

Abstract 466: A Phase 2 Study of the Dual SYK/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability and Clinical Response in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T- Cell Lymphoma

Design The Phase IIa, open-label study was designed to assess the safety and efficacy of cerdulatinib in patients with specific subtypes of relapsed/refractory T-cell Non-Hodgkin Lymphoma – including PTCL and CTCL, B-cell Non-Hodgkin lymphoma alone or in combination with rituximab, chronic lymphocytic leukemia, and small lymphocytic lymphoma.

Per the abstract, patients with relapsed/refractory PTCL or CTCL who received at least 1 prior systemic therapy were eligible to be treated with cerdulatinib at 30 mg orally BID. These expansion cohorts were

January 2020 / 105

Information Classification: General

enrolled in 2 stages: initially 20 patients accrued and, if ≥3 responses were observed, the cohort was expanded. Patients are treated until progression, intolerance, or response adequate to allow stem cell transplantation. All patients receive antimicrobial prophylaxis (typically sulfamethoxazole and trimethoprim [Bactrim]).

Endpoints Per the abstract, the primary endpoint is response according to either the Lugano criteria (PTCL) or Global Assessment (CTCL).

Results As of the November 12, 2019 cut-off date, 64 PTCL patients and 40 CTCL patients treated with cerdulatinib as a single agent were evaluable for response. The overall response rate (ORR) was 34% in the PTCL cohort and 43% in the CTCL cohort. Among the subset of patients in the PTCL cohort with AITL, the ORR was 52% and the complete response rate (CR) was 37%.

Among the 64 patients in the PTCL cohort, 14 patients (22%) achieved a CR and eight patients (12%) achieved a partial response (PR). In the subgroup of 27 patients with AITL, 10 patients (37%) achieved a CR, and four patients (15%) achieved a PR. The median duration of response is eight months for all PTCL patients and is greater than nine months in AITL patients. Follow-up is ongoing.

Among the 40 patients in the CTCL cohort, three patients (8%) achieved a CR and 14 patients (35%) achieved a PR. Rapid improvements in pruritus, or severe itching – a common and often serious condition associated with CTCL – have been observed, as measured by the Likert scale.

Per the abstract, an interim analysis of 61 patients with PTCL and 37 with CTCL who received cerdulatinib as a single agent was performed on July 18, 2019. Patient characteristics: median (range) age: PTCL: 65 (21-85) years and CTCL: 62 (24-80) years; median prior systemic therapies: PTCL: 2 (1-12) and CTCL: 5 (1-16); refractory to last therapy: PTCL: 48% and CTCL: 62%. For PTCL and CTCL combined, 41% of patients received prior romidepsin, 5% received prior belinostat, 12% received prior pralatrexate, and 32% received prior brentuximab.

In the PTCL cohort, 60 patients were evaluable for response (overall response rate [ORR] of 35%). Responses were primarily seen in AITL/TFH subtype (ORR of 55% [12 of 22], of which 41% of patients achieved a complete response [CR]). Responses have additionally been observed in patients with PTCL- NOS, ATLL, ALCL, and gamma-delta TCL. The ORR in CTCL patients was 35%, with the greatest activity observed in mycosis fungoides (ORR of 45%, of which 9% of patients achieved CR) versus Sezary syndrome (ORR of 17%, with no CR). Rapid improvements in pruritus have been observed in CTCL patients, independent of tumor response. Median duration of response is pending for both cohorts, but several patients have been in response for over a year.

January 2020 / 106

Information Classification: General

Most Common Adverse Events Cerdulatinib demonstrated good tolerability in both PTCL and CTCL. The most common Grade 3 or greater adverse events across the PTCL and CTCL cohorts with a frequency > 5% were lipase increase (25%), amylase increase (19%), neutropenia (12%), anemia (10%), diarrhea (8%), sepsis/bacteremia (6%), and febrile neutropenia (4%). The lipase and amylase changes were generally asymptomatic and not associated with pancreatitis.

Per the abstract, among all patients, the most common (>5% incidence) treatment-emergent grade 3+ adverse events were lipase increase (21%) and amylase increase (18%), diarrhea (8%), neutropenia (8%), anemia (7%), and fatigue (6%). Grade 3+ infections occurred in 29% of patients, which were generally managed by standard care. The amylase and lipase increases occurred without clinical pancreatitis and resolved irrespective of dose modification.

Conclusion Per the abstract, cerdulatinib has shown good tolerability and clinical activity in PTCL and CTCL. Complete and durable responses across a spectrum of PTCL and CTCL subtypes were observed. Correlative studies are aimed at identifying predictors of response and resistance. This Phase IIa study will inform the design of a pivotal trial in T-cell lymphoma.

Comment Updated results from the relapsed/refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) cohorts of the Phase IIa part of a Phase I/IIa study showed that the dual SYK/JAK inhibitor cerdulatinib demonstrated promising results in angioimmunoblastic T-cell lymphoma (AITL) and CTCL patients.

On the whole, the overall response rate (ORR) and the complete response (CR) rates differed widely among the subtypes in the PTCL cohort. None of the 11 patients with PTCL not otherwise specified (PTCL-NOS) achieved a complete or partial response. But, among the subset of patients in the PTCL cohort with AITL, the ORR was 52% and the CR rate was 37%. The rates seen in the PTCL cohort of cerdulatinib compare favorably with the 25.8% ORR and the 10.8% CR rates seen in the Phase II pivotal trial of Beleodaq, a Class I and II histone deacetylase (HDAC) inhibitor that was approved for relapsed/refractory PTCL in 2014. However, the varying response rates seen with cerdulatinib in the different PTCL subgroups may limit its potential use to certain subtypes.

The efficacy results in the CTCL cohort, which consisted of 40 patients with either mycosis fungoides or Sezary syndrome, were also promising, with an impressive overall response rate of 43%, including an 8% CR rate. These responses compare very favorably with the rates seen in the pivotal Phase III study of Kyowa Kirin’s Poteligeo, which had an ORR of 28.0%. Of note is that 55% of patients in the CTCL group

January 2020 / 107

Information Classification: General

experienced a 50% reduction of their Modified Severity Weighted Assessment Tool (mSWAT) score, indicating that the cytokine JAK/STAT pathway may be important in pruritis, a common symptom of CTCL.

Additionally, the study investigators noticed Epstein-Barr virus (EBV) reactivation, which is associated with lower survival, in patients being treated with cerdulatinib. This reactivation was initially seen in conjunction with progress of disease in several patients with AITL, although additional cases were seen in patients with three other subtypes, for a total of 10 cases identified throughout the study. This EBV reactivation is somewhat concerning and will need to be monitored in future studies.

Portola Pharmaceuticals has indicated that it will initiate a registrational study of cerdulatinib for PTCL in the coming months. Based on these preliminary results, we are raising the likelihood of approval by an additional 2%.

Source: Press Release 12/08/2019 American Society of Hematology (ASH) 12/08/2019 (Abstract 466) Sagient Analysis

January 2020 / 108

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Acute Lymphoblastic Trial Data - Updated AUTO1 Autolus Therapeutics plc AUTL Phase I - ALLCAR19 (Adults; UK) 360853 Leukemia (ALL) Results Acute Lymphoblastic Trial Data - Updated AUTO1 Autolus Therapeutics plc AUTL Phase I - ALLCAR19 (Adults; UK) 360853 Leukemia (ALL) Results Acute Lymphoblastic Trial Data - Updated AUTO1 Autolus Therapeutics plc AUTL Phase I - CARPALL (Pediatric; UK) 360861 Leukemia (ALL) Results Acute Lymphoblastic Trial Data - Updated AUTO3 Autolus Therapeutics plc AUTL Phase I/II - AMELIA 360834 Leukemia (ALL) Results Acute Lymphoblastic Trial Data - Updated Blincyto Amgen, Inc. AMGN Phase III - COG AALL1331 (1st Relapse) 361104 Leukemia (ALL) Results Acute Lymphoblastic Gracell Biotechnologies Co., Trial Data - Updated GC007F Phase I - PGC0002 (Relapsed/Refractory) 360990 Leukemia (ALL) Ltd. Results Acute Lymphoblastic Gracell Biotechnologies Co., Trial Data - Top-Line GC007G Phase I - Donor-derived CAR-T cells 360986 Leukemia (ALL) Ltd. Results Acute Lymphoblastic Gracell Biotechnologies Co., Trial Data - Top-Line GC022 Phase I - PGC0003 360663 Leukemia (ALL) Ltd. Results Acute Lymphoblastic Trial Data - Updated JZP-458 Jazz Pharmaceuticals plc JAZZ Phase I - Healthy Volunteers 360964 Leukemia (ALL) Results Acute Lymphoblastic Trial Data - Top-Line PBCAR0191 Precision BioSciences Inc. DTIL Phase I/IIa - Dose Escalation 363634 Leukemia (ALL) Results Acute Lymphoblastic Trial Data - Preclinical S81694 Les Laboratoires Servier Preclinical Studies 360772 Leukemia (ALL) Results Acute Lymphoblastic Trial Data - Preclinical UCART19 Allogene Therapeutics, Inc. ALLO Preclinical Studies 360662 Leukemia (ALL) Results Acute Myelogenous Trial Data - Preclinical AB8939 AB Science S.A. AB:FP Preclinical Studies 360610 Leukemia (AML) Results Acute Myelogenous Actinium Pharmaceuticals, Trial Data - Top-Line Actimab-A ATNM Phase I - w/CLAG-M 357305 Leukemia (AML) Inc. Results Acute Myelogenous Actinium Pharmaceuticals, Trial Data - Updated Actimab-A ATNM Phase I - w/CLAG-M 360781 Leukemia (AML) Inc. Results Acute Myelogenous Trial Data - Preclinical ALLO-819 Allogene Therapeutics, Inc. ALLO Preclinical Studies 361009 Leukemia (AML) Results Acute Myelogenous Trial Data - Top-Line AMG 673 Amgen, Inc. AMGN Phase I - First-In-Human 361039 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated APR-246 Aprea Therapeutics, Inc. APRE Phase Ib/II - w/Azacitidine 361308 Leukemia (AML) Results Acute Myelogenous Trial Data - Top-Line APR-246 Aprea Therapeutics, Inc. APRE Phase Ib/II - w/Azacitidine (France) 361301 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated Phase Ib - Dose Escalation APTO-253 Aptose Biosciences Inc. APTO 360753 Leukemia (AML) Results (AML/MDS/MM/Lymphomas) Acute Myelogenous Trial Data - Top-Line AZD2811 AstraZeneca PLC AZN Phase I/II - HEMREF 41 361300 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated Bemcentinib BerGenBio AS BGBIO:NO Phase Ib/II - BGBC003 (Norway) 360864 Leukemia (AML) Results Acute Myelogenous Trial Data - Top-Line BST-236 BioSight Ltd. Phase IIb - ELPIS (Newly Diagnosed) 360792 Leukemia (AML) Results Acute Myelogenous Bristol-Myers Squibb Trial Data - Top-Line CC-90009 BMY Phase I - Dose Finding 360666 Leukemia (AML) Company Results Acute Myelogenous Takeda Pharmaceutical Trial Data - Preclinical CTX-712 TAK Preclinical Studies 360680 Leukemia (AML) Company Ltd Results Acute Myelogenous Trial Data - Updated Cusatuzumab Johnson & Johnson JNJ Phase I/II - CULMINATE 360653 Leukemia (AML) Results Acute Myelogenous Trial Data - Top-Line Cusatuzumab Johnson & Johnson JNJ Phase I - W/Azacitidine + Venetoclax 361075 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated CX-01 Chimerix, Inc. CMRX Phase I - w/Azacitidine 361027 Leukemia (AML) Results

January 2020 / 109

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Acute Myelogenous Trial Data - Updated CYAD-01 Celyad CYAD Phase I - DEPLETHINK 360969 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated CYAD-01 Celyad CYAD Phase Ib - THINK (AML/MM/Solids) 360959 Leukemia (AML) Results Acute Myelogenous Trial Data - Preclinical CYAD-02 Celyad CYAD Preclinical Studies 360983 Leukemia (AML) Results Acute Myelogenous Cyclacel Pharmaceuticals, Trial Data - Top-Line CYC065 CYCC Phase I - CYC065-03 360930 Leukemia (AML) Inc. Results DC Vaccines Acute Myelogenous Trial Data - Updated MediGene AG MDG:GR Phase I/II - Norway 361023 (Cytovant/Medigene) Leukemia (AML) Results Acute Myelogenous Trial Data - Updated DCP-001 DCPrime B.V. Phase I/II - DCOne-1 (Netherlands) 358392 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated Flotetuzumab MacroGenics, Inc. MGNX Phase I - MGD006-01 360906 Leukemia (AML) Results Acute Myelogenous Trial Data - Top-Line FT-1101 FORMA Therapeutics Phase I - HEM-101 (AML/MDS) 361012 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated FT-2102 FORMA Therapeutics Phase I/II - w/Azacitidine or Cytarabine 360633 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated Idasanutlin Roche Holding AG RHHBY Phase Ib/II - w/Venetoclax 360627 Leukemia (AML) Results Acute Myelogenous Bristol-Myers Squibb Trial Data - Updated Idhifa BMY Phase Ib/II - w/Azacitidine 360958 Leukemia (AML) Company Results Acute Myelogenous Trial Data - Preclinical IMGN632 ImmunoGen, Inc. IMGN Preclinical Studies 360973 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated IMGN632 ImmunoGen, Inc. IMGN Phase I - 0801 360960 Leukemia (AML) Results Acute Myelogenous Actinium Pharmaceuticals, Trial Data - Updated Iomab-B ATNM Phase III - SIERRA 357296 Leukemia (AML) Inc. Results Acute Myelogenous Trial Data - Final Keytruda Merck & Co., Inc. MRK Phase II - LCCC 1522 363452 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated Magrolimab Forty Seven Inc. FTSV Phase Ib - w/Azacitidine (AML/MDS) 360795 Leukemia (AML) Results Acute Myelogenous Trial Data - Top-Line MBG453 Novartis AG NVS Phase Ib - w/PDR001 361287 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated Onvansertib Trovagene, Inc. TROV Phase Ib/II - w/Cytarabine or Decitabine 360636 Leukemia (AML) Results Acute Myelogenous Bristol-Myers Squibb Trial Data - Updated Oral Azacitidine BMY Phase III - QUAZAR (Maintenance) 361108 Leukemia (AML) Company Results Acute Myelogenous Trial Data - Updated ORY-1001 Oryzon Genomics S.A. ORY:SM Phase IIa - ALICE 360933 Leukemia (AML) Results Acute Myelogenous Trial Data - Preclinical PRGN-3006 Precigen, Inc. PGEN Preclinical Studies 363010 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated Tibsovo Agios Pharmaceuticals, Inc. AGIO Phase Ib/II - w/Azacitidine 360855 Leukemia (AML) Results Acute Myelogenous Phase I - C-001 (Hematologic Malignancies Tibsovo Agios Pharmaceuticals, Inc. AGIO Trial Data 360863 Leukemia (AML) w/IDH1 Mutation) Acute Myelogenous Trial Data - Updated Uproleselan GlycoMimetics, Inc. GLYC Phase I/II - w/Chemo 360728 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated Venclexta AbbVie Inc. ABBV Phase I - Pediatric 360773 Leukemia (AML) Results Acute Myelogenous Bristol-Myers Squibb Trial Data - Updated Vidaza BMY Phase Ib/II - w/ AG-120 or AG-221 363636 Leukemia (AML) Company Results Acute Myelogenous Bristol-Myers Squibb Trial Data - Top-Line Vidaza BMY Phase II - w/Durvalumab 363645 Leukemia (AML) Company Results Acute Myelogenous Trial Data - Updated Vyxeos Jazz Pharmaceuticals plc JAZZ Phase III - 301 - Secondary AML 360650 Leukemia (AML) Results

January 2020 / 110

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Acute Myelogenous Trial Data - Top-Line Vyxeos Jazz Pharmaceuticals plc JAZZ Phase II - w/Gemtuzumab 360704 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated Vyxeos Jazz Pharmaceuticals plc JAZZ Phase III - 301 - Secondary AML 361002 Leukemia (AML) Results Acute Myelogenous Trial Data - Updated Xospata Astellas Pharma, Inc. 4503:JP Phase III - ADMIRAL 360761 Leukemia (AML) Results Acute Myelogenous Trial Data - Top-Line Xospata Astellas Pharma, Inc. 4503:JP Phase Ib - w/Venetoclax 360997 Leukemia (AML) Results Acute Myelogenous Trial Data - Xospata Astellas Pharma, Inc. 4503:JP Phase III - ADMIRAL 360991 Leukemia (AML) Retrospective Analysis Adult T-cell Trial Data - Updated Valemetostat Leukemia/Lymphoma Daiichi Sankyo Co., Ltd. DSKYF Phase I - A-J101 361164 Results (ATL) Amyloid light-chain (AL) Takeda Pharmaceutical Trial Data - Updated Phase III - TOURMALINE-AL1 Ninlaro TAK 360638 Amyloidosis Company Ltd Results (w/Dexamethasone) Anaplastic Large Cell Trial Data - Updated Adcetris Seattle Genetics, Inc. SGEN Phase III - ECHELON-2 360935 Lymphoma (ALCL) - NHL Results Trial Data - Top-Line Phase I - Faconi Anemia Subtype A (Pediatric, RP-L102 Anemia Rocket Pharmaceuticals Inc. RCKT 360703 Results US) Trial Data - Updated RP-L102 Anemia Rocket Pharmaceuticals Inc. RCKT Phase I/II - FANCOLEN-1 (Spain) 361010 Results Anemia Due to Oncology Trial Data - Top-Line Roxadustat AstraZeneca PLC AZN Phase III - MDS (US) 361006 Treatment Results Autoimmune Hemolytic Trial Data - Top-Line BIVV009 Sanofi SNY Phase III - Cardinal (Cold Agglutinin Disease) 359188 Anemia (AIHA) Results Autoimmune Hemolytic Trial Data - Updated BIVV009 Sanofi SNY Phase III - Cardinal (Cold Agglutinin Disease) 361029 Anemia (AIHA) Results Autoimmune Hemolytic Trial Data - Updated BIVV009 Sanofi SNY Phase Ia/Ib - TNT009-01 361038 Anemia (AIHA) Results Autoimmune Hemolytic Trial Data - Final Tavalisse Rigel Pharmaceuticals, Inc. RIGL Phase II - SOAR (AIHA) 361262 Anemia (AIHA) Results Blastic Plasmacytoid Trial Data - Updated IMGN632 Dendritic Cell Neoplasm ImmunoGen, Inc. IMGN Phase I - 0801 361319 Results (BPDCN) Bone Complications Trial Data - Xgeva (Including Bone Amgen, Inc. AMGN Phase III - SRE in MM (study 482) 361011 Retrospective Analysis Metastases) Bone Marrow and Stem Cell Transplant - Graft vs. Trial Data - Updated Phase II - Canada/Belgium (CR-AIR-007), Phase ATIR101 Kiadis Pharma N.V. KIADF 360980 Host Disease (GVHD) Results II - Repeat-Dosing (AML/ALL/MDS) Prophylaxis Bone Marrow Transplant Trial Data - Preclinical C200 Magenta Therapeutics MGTA Preclinical Studies 360995 and Stem Cell Transplant Results Bone Marrow Transplant Trial Data - Top-Line MGTA-145 Magenta Therapeutics MGTA Phase I - +/- Plerixafor 360654 and Stem Cell Transplant Results Trial Data - Updated ALX148 Cancer ALX Oncology, Inc. Phase I - AT148001 360626 Results Trial Data - Preclinical KZR-8834 Cancer Kezar Life Sciences, Inc. KZR Preclinical Studies 361195 Results Trial Data - Preclinical KZR-8834 Cancer Kezar Life Sciences, Inc. KZR Preclinical Studies 361198 Results Sleeping Beauty CAR- T Program Trial Data - Preclinical Cancer ZIOPHARM Oncology, Inc. ZIOP Preclinical Studies 360679 (Ziopharm/Eden Results Biocell)

January 2020 / 111

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link T-Cell Immunotherapy Trial Data - Preclinical Cancer Amgen, Inc. AMGN Preclinical Studies 360786 Program Results (Immatics/Amgen) Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated ARQ 531 ArQule, Inc. ARQL Phase I/II - 101 (B-Cell Malignancies) 357322 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated ARQ 531 ArQule, Inc. ARQL Phase I/II - 101 (B-Cell Malignancies) 360759 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Top-Line Brukinsa BeiGene, Ltd. BGNE Phase III - SEQUOIA 360709 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Brukinsa BeiGene, Ltd. BGNE Phase I - B-Cell Malignancies (Australia) 360726 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Phase III - ELEVATE-TN (vs. Obinutuzumab) Calquence AstraZeneca PLC AZN 357476 Lymphocytic Lymphoma Results (First-Line) (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Phase III - ELEVATE-TN (vs. Obinutuzumab) Calquence AstraZeneca PLC AZN 360621 Lymphocytic Lymphoma Results (First-Line) (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Top-Line Calquence AstraZeneca PLC AZN Phase II - AVO 360655 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Calquence AstraZeneca PLC AZN Phase I/II - ACE-CL-001 360722 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Preclinical CG-806 Aptose Biosciences Inc. APTO 360701 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated CG-806 Aptose Biosciences Inc. APTO Phase Ia/b - Dose Escalation 360751 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Cirmtuzumab Oncternal Therapeutics, Inc. ONCT Phase Ib/II - CIRLL Study (w/ Ibrutinib) 360749 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Top-Line Copiktra Verastem, Inc. VSTM Phase I/II - w/Venetoclax (Dana-Farber) 357390 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Copiktra Verastem, Inc. VSTM Phase III - DUO 360634 Lymphocytic Lymphoma Results (SLL) - NHL

January 2020 / 112

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Copiktra Verastem, Inc. VSTM Phase I/II - w/Venetoclax (Dana-Farber) 360629 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Cyclacel Pharmaceuticals, Trial Data - Top-Line CYC065 CYCC Phase Ib - 065-02 (w/Venetoclax) 360908 Lymphocytic Lymphoma Inc. Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Gazyva Roche Holding AG RHHBY Phase III - CLL14 (w/Venclexta) 360667 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated ICP-022 InnoCare Phase I/II - ICP-CL-00103 (China) 362946 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Phase III - RESONATE, Phase III - RESONATE-2 Imbruvica AbbVie Inc. ABBV 360750 Lymphocytic Lymphoma Results (Elderly) (PCYC-1115) (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Imbruvica AbbVie Inc. ABBV Phase II - CAPTIVATE (w/Venetoclax) 360622 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Imbruvica AbbVie Inc. ABBV Phase III - NCI (ECOG1912) IR vs FCR 360623 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Lisocabtagene Leukemia (CLL)/Small Cell Bristol-Myers Squibb Trial Data - Updated BMY Phase I/II - TRANSCEND-CLL-004 360740 Maraleucel Lymphocytic Lymphoma Company Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Preclinical LOXO-305 Eli Lilly & Company LLY Preclinical Studies 360684 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Top-Line LOXO-305 Eli Lilly & Company LLY Phase I/II - BRUIN 360721 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Phase II - COSMOS (w/Idelalisib or MOR208 MorphoSys AG MOR 360763 Lymphocytic Lymphoma Results w/Venetoclax) (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Top-Line TG-1303 TG Therapeutics, Inc. TGTX Phase I/II - w/Venetoclax 363394 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated TG-1303 TG Therapeutics, Inc. TGTX Phase I/II - w/Venetoclax 363395 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Top-Line Ublituximab TG Therapeutics, Inc. TGTX Phase I/II - w/Venetoclax+TGR-1202 357578 Lymphocytic Lymphoma Results (SLL) - NHL

January 2020 / 113

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Ublituximab TG Therapeutics, Inc. TGTX Phase I/II - w/Venetoclax+TGR-1202 363526 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Top-Line Umbralisib TG Therapeutics, Inc. TGTX Phase I/II - w/Venetoclax+Ublituximab 357580 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Umbralisib TG Therapeutics, Inc. TGTX Phase I/II - w/Venetoclax+Ublituximab 363527 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Top-Line Venclexta AbbVie Inc. ABBV Phase I/II - w/Ublituximab+TGR-1202 360711 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Venclexta AbbVie Inc. ABBV Phase I/II - w/Ublituximab+TGR-1202 360715 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Lymphocytic Leukemia (CLL)/Small Cell Trial Data - Updated Venclexta AbbVie Inc. ABBV Phase III - MURANO (w/Rituximab) 360669 Lymphocytic Lymphoma Results (SLL) - NHL Chronic Myelogenous Ascentage Pharma Group Trial Data - Updated APG-1351 Phase I - China 360720 Leukemia (CML) Corporation Results Chronic Myelomonocytic Trial Data - Top-Line Lenzilumab Humanigen, Inc. HGEN Phase I - Dose Escalation (CMML) 360955 Leukemia (CMML) Results Chronic Myelomonocytic Trial Data - Preclinical Lenzilumab Humanigen, Inc. HGEN Preclinical Studies 361288 Leukemia (CMML) Results Diffuse Large B-Cell Trial Data - Updated ADCT-402 ADC Therapeutics SA Phase II - 201 360948 Lymphoma (DLBCL) - NHL Results Diffuse Large B-Cell Trial Data - Updated ARQ 531 ArQule, Inc. ARQL Phase I/II - 101 (B-Cell Malignancies) 359601 Lymphoma (DLBCL) - NHL Results Diffuse Large B-Cell Trial Data - Updated ARQ 531 ArQule, Inc. ARQL Phase I/II - 101 (B-Cell Malignancies) 360972 Lymphoma (DLBCL) - NHL Results Diffuse Large B-Cell Trial Data - Updated AUTO3 Autolus Therapeutics plc AUTL Phase I/II - ALEXANDER - w/Keytruda 360828 Lymphoma (DLBCL) - NHL Results Diffuse Large B-Cell Trial Data - Preclinical Betalutin Nordic Nanovector ASA NANO:NO Preclinical Studies 360448 Lymphoma (DLBCL) - NHL Results Diffuse Large B-Cell Trial Data - Updated DPX-Survivac IMV Inc. IMV Phase II - SPiReL (Triple Combination) 360725 Lymphoma (DLBCL) - NHL Results Diffuse Large B-Cell Trial Data - Updated Fimepinostat Curis, Inc. CRIS Phase I - Dose-escalation (Study 101) 360943 Lymphoma (DLBCL) - NHL Results Diffuse Large B-Cell Shanghai Henlius Biotech Co. Trial Data - Updated HLX01 Phase III - HLX01-NHL03 361086 Lymphoma (DLBCL) - NHL Ltd. Results Diffuse Large B-Cell Trial Data - Updated Phase III - PHOENIX (w/R-CHOP) (Non-GCB Imbruvica AbbVie Inc. ABBV 360717 Lymphoma (DLBCL) - NHL Results DLBCL) Diffuse Large B-Cell Trial Data - Updated Imbruvica AbbVie Inc. ABBV Phase I/II - PCYC-1123 360947 Lymphoma (DLBCL) - NHL Results Lisocabtagene Diffuse Large B-Cell Bristol-Myers Squibb Trial Data - Updated BMY Phase I - TRANSCEND 360658 Maraleucel Lymphoma (DLBCL) - NHL Company Results Phase I - TRANSCEND, Phase II - OUTREACH, Lisocabtagene Diffuse Large B-Cell Bristol-Myers Squibb Trial Data - Updated BMY Phase II - PILOT (2nd Line Non-Transplant 360819 Maraleucel Lymphoma (DLBCL) - NHL Company Results Eligible)

January 2020 / 114

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Diffuse Large B-Cell Trial Data - Subgroup MOR208 MorphoSys AG MOR Phase II - L-MIND (w/Lenalidomide) 360632 Lymphoma (DLBCL) - NHL Analysis Diffuse Large B-Cell Trial Data - Final MOR208 MorphoSys AG MOR Phase IIa - Monotherapy 360954 Lymphoma (DLBCL) - NHL Results Diffuse Large B-Cell Trial Data - Updated Mosunetuzumab Roche Holding AG RHHBY Phase I - Dose Escalation and Expansion 360644 Lymphoma (DLBCL) - NHL Results Phase Ib/II - Diffuse Large B-Cell Trial Data - Updated Polivy Roche Holding AG RHHBY w/Rituximab/Obinutuzumab/Bendamustine 361058 Lymphoma (DLBCL) - NHL Results (Follicular/Diffuse) Diffuse Large B-Cell Trial Data - Updated RG-6026 Roche Holding AG RHHBY Phase I/Ib - w/Gavyza 360642 Lymphoma (DLBCL) - NHL Results Diffuse Large B-Cell Trial Data - Updated Yescarta Gilead Sciences, Inc. GILD Phase I/II - ZUMA-1 (DLBCL/PMBCL/TFL) 360639 Lymphoma (DLBCL) - NHL Results Fungal Infections - Trial Data - Preclinical Rezafungin Cidara Therapeutics, Inc. CDTX Preclinical Studies 360778 Systemic Results Trial Data - Preclinical FLT200 Gaucher's Disease Freeline Therapeutics Preclinical Studies 360682 Results Graft vs. Host Disease ALPN-101 Alpine Immune Sciences, Inc. ALPN Trial Announcement Phase I/II - BALANCE (Grade II-IV aGVHD) 357475 (GVHD) - Treatment Graft vs. Host Disease Trial Data - Updated KD025 Kadmon Holdings, Inc. KDMN Phase IIa - cGVHD-208 360951 (GVHD) - Treatment Results Graft vs. Host Disease Trial Data - Top-Line MaaT013 MaaT Pharma SA Phase II - HERACLES 363092 (GVHD) - Treatment Results Trial Data - Updated Lumoxiti Hairy Cell Leukemia Innate Pharma S.A. IPHA Phase III - PLAIT 360698 Results CD19 Non-Viral CAR- Trial Data - Preclinical Hematologic Cancer ZIOPHARM Oncology, Inc. ZIOP Preclinical Studies 360775 T Program Results CD19-Anti-CD20 Trial Data - Preclinical Hematologic Cancer Aleta Biotherapeutics, Inc. Preclinical Studies 360611 Bridging Protein Results Trial Data - Updated CLR 131 Hematologic Cancer Cellectar Biosciences, Inc. CLRB Phase II - CLOVER-1 360929 Results Trial Data - Preclinical DT2216 Hematologic Cancer Pfizer Inc. PFE Preclinical Studies 360618 Results Trial Data - Updated ECT001 Hematologic Cancer ExCellThera Inc. Phase I/II - Maisonneuve-Rosemont Hospital 359668 Results Trial Data - Top-Line ET019003 Hematologic Cancer Eureka Therapeutics, Inc. Phase I - China 360788 Results Trial Data - Preclinical FSI-174 Hematologic Cancer Forty Seven Inc. FTSV Preclinical Studies 361005 Results Trial Data - Preclinical FT596 Hematologic Cancer Fate Therapeutics, Inc. FATE Preclinical Studies 360673 Results Trial Data - Preclinical FT819 Hematologic Cancer Fate Therapeutics, Inc. FATE Preclinical Studies 361167 Results Trial Data - Top-Line GEN3013 Hematologic Cancer Genmab A/S GMAB Phase I/II - GCT3013-01 360949 Results Trial Data - Preclinical KYM-003 Hematologic Cancer Kymera Therapeutics, LLC. 360953 Results Trial Data - Top-Line MGTA-456 Hematologic Cancer Magenta Therapeutics MGTA Phase II - Masonic Cancer Center 361019 Results Trial Data - Preclinical NRX0492 Hematologic Cancer Nurix Therapeutics, Inc. Preclinical Studies 360616 Results Trial Data - Preclinical NRX0492 Hematologic Cancer Nurix Therapeutics, Inc. Preclinical Studies 360977 Results Trial Data - Updated Tabelecleucel Hematologic Cancer Atara Biotherapeutics, Inc. ATRA Expanded Access Protocol (after HCT or SOT) 357423 Results

January 2020 / 115

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Trial Data - Updated Tabelecleucel Hematologic Cancer Atara Biotherapeutics, Inc. ATRA Expanded Access Protocol (after HCT or SOT) 360890 Results Trial Data - Top-Line TG-1701 Hematologic Cancer TG Therapeutics, Inc. TGTX Phase I -101 (Australia) 357355 Results Trial Data - Updated TG-1701 Hematologic Cancer TG Therapeutics, Inc. TGTX Phase I -101 (Australia) 360755 Results Trial Data - Updated Vecabrutinib Hematologic Cancer Sunesis Pharmaceuticals, Inc. SNSS Phase Ib/II - B-Cell Malignancies (U.S.) 360437 Results Trial Data - Updated Phase Ib/II - Epstein-Barr Virus-Associated VRx-3996 Hematologic Cancer Viracta Therapeutics, Inc. 360687 Results Lymphoid Malignancies Trial Data - Top-Line XmAb13676 Hematologic Cancer Xencor, Inc. XNCR Phase I - XmAb13676-01 (Multidose) 357326 Results Trial Data - Updated XmAb13676 Hematologic Cancer Xencor, Inc. XNCR Phase I - XmAb13676-01 (Multidose) 360905 Results Hemolytic Uremic Trial Data - Updated Phase III - Pediatric, Phase III - Treatment- Ultomiris Alexion Pharmaceuticals, Inc. ALXN 360625 Syndrome (HUS) Results Naïve Trial Data - Final BIVV 001 Hemophilia A Sanofi SNY Phase I/IIa - EXTEN-A 361269 Results Trial Data - Subgroup Hemlibra Hemophilia A Roche Holding AG RHHBY Phase III - HAVEN 3 360688 Analysis Trial Data - Hemlibra Hemophilia A Roche Holding AG RHHBY Phase III - HAVEN 3 360967 Retrospective Analysis Trial Data - Jivi Hemophilia A Bayer AG BAYRY Phase II/III - PROTECT-VIII 360766 Retrospective Analysis Trial Data - Updated Jivi Hemophilia A Bayer AG BAYRY Phase II/III - PROTECT-VIII 360981 Results Trial Data - Preclinical Mim8 Hemophilia A Novo Nordisk A/S NVO Preclinical Studies 360615 Results Trial Data - Updated SB-525 Hemophilia A Pfizer Inc. PFE Phase I/II - Alta (Study 1603) 357364 Results Trial Data - Updated SB-525 Hemophilia A Pfizer Inc. PFE Phase I/II - Alta (Study 1603) 360661 Results Trial Data - Preclinical Sig001 Hemophilia A Sigilon Therapeutics, Inc. Preclinical Studies 360620 Results Hemophilia A and B - Trial Data - Updated Fitusiran Sanofi SNY Phase I/II - OLE 360647 General Clotting Products Results Hemophilia A and B - Trial Data - Preclinical Marzeptacog alfa Catalyst Biosciences, Inc. CBIO Preclinical Studies 360765 General Clotting Products Results Hemophilia A and B - Trial Data - Preclinical Marzeptacog alfa Catalyst Biosciences, Inc. CBIO Preclinical Studies 360700 General Clotting Products Results Trial Data - Updated AMT-060 Hemophilia B uniQure N.V. QURE Phase I/II - CT-AMT-060-01 360936 Results Etranacogene Trial Data - Updated Hemophilia B uniQure N.V. QURE Phase IIb - Dose-Confirmation 360932 Dezaparvovec Results Trial Data - Updated Adcetris Hodgkin's Lymphoma Seattle Genetics, Inc. SGEN Phase II - Elderly Front-Line 360681 Results Trial Data - Updated Adcetris Hodgkin's Lymphoma Seattle Genetics, Inc. SGEN Phase I/II - w/Opdivo 360683 Results Trial Data - Updated Adcetris Hodgkin's Lymphoma Seattle Genetics, Inc. SGEN Phase III - ECHELON-1 360928 Results Immune Trial Data - Top-Line BIVV009 Thrombocytopenic Sanofi SNY Phase I - PK/PD Study 362656 Results Purpura (ITP) Immune Swedish Orphan Biovitrum Trial Data - Updated Doptelet Thrombocytopenic STO:SOBI Phase III - Study 302 360830 AB Results Purpura (ITP)

January 2020 / 116

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Immune Swedish Orphan Biovitrum Trial Data - Updated Doptelet Thrombocytopenic STO:SOBI Phase III - Study 302 360842 AB Results Purpura (ITP) Immune Trial Data - Updated Efgartigimod Thrombocytopenic argenx N.V. ARGX Phase II - Low Platelet Count 361087 Results Purpura (ITP) Immune Trial Data - Updated PRN1008 Thrombocytopenic Principia Biopharma, Inc. PRNB Phase I/II - Relapsed 360677 Results Purpura (ITP) Immune Trial Data - Final Rozanolixizumab Thrombocytopenic UCB SA UCB:BB Phase IIa - TP0001 361018 Results Purpura (ITP) Immune Trial Data - Updated Tavalisse Thrombocytopenic Rigel Pharmaceuticals, Inc. RIGL Phase III - Study 049 - Ext. 360660 Results Purpura (ITP) Indolent Non-Hodgkin's Lisocabtagene Lymphoma (Including Bristol-Myers Squibb Trial Data - Updated BMY Phase I - TRANSCEND 360659 Maraleucel Follicular Lymphoma) - Company Results NHL Indolent Non-Hodgkin's Lisocabtagene Lymphoma (Including Bristol-Myers Squibb Trial Data - Updated BMY Phase I - TRANSCEND 361277 Maraleucel Follicular Lymphoma) - Company Results NHL Indolent Non-Hodgkin's Lymphoma (Including Trial Data - Updated Mosunetuzumab Roche Holding AG RHHBY Phase I - Dose Escalation and Expansion 362773 Follicular Lymphoma) - Results NHL Indolent Non-Hodgkin's Lymphoma (Including Trial Data - Updated Polivy Roche Holding AG RHHBY Phase Ib/II - w/obinutuzumab + lenalidomide 360645 Follicular Lymphoma) - Results NHL Indolent Non-Hodgkin's Lymphoma (Including Regeneron Pharmaceuticals, Trial Data - Updated REGN1979 REGN Phase I - B-Cell Malignancies 361297 Follicular Lymphoma) - Inc. Results NHL Indolent Non-Hodgkin's Lymphoma (Including Bristol-Myers Squibb Trial Data - Subgroup Phase III - AUGMENT - w/Rituximab (R/R Revlimid BMY 360742 Follicular Lymphoma) - Company Analysis Indolent) NHL Indolent Non-Hodgkin's Lymphoma (Including Trial Data - Updated Tazemetostat Royalty Pharma AG Phase II - Relapsed or Refractory DLBCL/FL 360635 Follicular Lymphoma) - Results NHL Kidney Transplant Trial Data - Updated FCR001 Talaris Therapeutics, Inc. Phase I/II - University of Louisville 360581 Rejection Results Mantle Cell Lymphoma - Trial Data - Preclinical BI-1206 BioInvent International AB BINV.ST Preclinical Studies 357702 NHL Results Mantle Cell Lymphoma - Trial Data - Preclinical CG-806 Aptose Biosciences Inc. APTO Preclinical Studies 360904 NHL Results Mantle Cell Lymphoma - Trial Data - Updated ICP-022 InnoCare Phase I/II - ICP-CL-00102 (China) 362950 NHL Results Phase II - PCYC-1104-CA - MCL, Phase II - Mantle Cell Lymphoma - Trial Data - Imbruvica AbbVie Inc. ABBV SPARK, Phase III - RAY - vs. Temsirolimus (ex- 360697 NHL Retrospective Analysis US) Mantle Cell Lymphoma - Trial Data - Top-Line KTE-X19 Gilead Sciences, Inc. GILD Phase II - ZUMA-2 (r/r MCL) 360939 NHL Results

January 2020 / 117

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Lisocabtagene Mantle Cell Lymphoma - Bristol-Myers Squibb Trial Data - Updated BMY Phase I - TRANSCEND 361275 Maraleucel NHL Company Results Marginal Zone Lymphoma Bristol-Myers Squibb Trial Data - Subgroup Phase III - AUGMENT - w/Rituximab (R/R Revlimid BMY 361354 - NHL Company Analysis Indolent) Blueprint Medicines Trial Data - Top-Line Ayvakit Mastocytosis BPMC Phase II - PIONEER 360716 Corporation Results Mucopolysaccharidosis I Orchard Therapeutics Trial Data - Updated OTL-203 ORTX Phase I/II - TigetT10_MPSIH 360743 (MPS I; Hurler Syndrome) Limited Results Trial Data - Preclinical ALLO-715 Multiple Myeloma (MM) Allogene Therapeutics, Inc. ALLO Preclinical Studies 360612 Results Trial Data - Preclinical AMG 701 Multiple Myeloma (MM) Amgen, Inc. AMGN 360785 Results Trial Data - Top-Line AUTO2 Multiple Myeloma (MM) Autolus Therapeutics plc AUTL Phase I/II - APRIL 362523 Results Bristol-Myers Squibb Trial Data - Updated bb21217 Multiple Myeloma (MM) BMY Phase I - CRB-402 357440 Company Results Bristol-Myers Squibb Trial Data - Updated bb21217 Multiple Myeloma (MM) BMY Phase I - CRB-402 361045 Company Results Bristol-Myers Squibb Trial Data - Top-Line CC-93269 Multiple Myeloma (MM) BMY Phase I - RRMS 360672 Company Results Cellular Biomedicine Group, Trial Data - Top-Line C-CAR088 Multiple Myeloma (MM) CBMG Phase I - C-CAR088 360664 Inc. Results CD38-ARM Program Trial Data - Preclinical Multiple Myeloma (MM) Kleo Pharmaceuticals Inc. Preclinical Studies 360927 (Kleo/PeptiDream) Results Trial Data - Updated Phase Ib/II - PoC (+/- Dexamethasone), Phase CLR 131 Multiple Myeloma (MM) Cellectar Biosciences, Inc. CLRB 360747 Results II - CLOVER-1 Trial Data - Updated CT-103A Multiple Myeloma (MM) Nanjing IASO Biotherapeutics Phase I - China 361077 Results Daratumumab- Trial Data - Updated rHuPH20 Multiple Myeloma (MM) Johnson & Johnson JNJ Phase II - PLEIADES 360730 Results (Subcutaneous) Trial Data - Updated Darzalex Multiple Myeloma (MM) Johnson & Johnson JNJ Phase III - MAIA (MMY3008) 361000 Results Trial Data - Updated Darzalex Multiple Myeloma (MM) Johnson & Johnson JNJ Phase II - LYRA (w/CyBorD) 360996 Results Trial Data - Updated Darzalex Multiple Myeloma (MM) Johnson & Johnson JNJ Phase II - GRIFFIN (vs. RVd) 360992 Results Phase III - Cassiopeia - Trial Data - Updated Darzalex Multiple Myeloma (MM) Johnson & Johnson JNJ w/Bortezomib/Thalidomide/Dexamethasone 360988 Results (MMY3006) Trial Data - Top-Line Phase II - w/Carfilzomib, Lenalidomide, Darzalex Multiple Myeloma (MM) Johnson & Johnson JNJ 361279 Results Dexamethasone Trial Data - Top-Line Darzalex Multiple Myeloma (MM) Johnson & Johnson JNJ Phase II - MASTER 361283 Results Trial Data - Top-Line Phase II - w/Ixazomib, Lenalidomide, Darzalex Multiple Myeloma (MM) Johnson & Johnson JNJ 361266 Results Dexamethasone Trial Data - Updated Darzalex Multiple Myeloma (MM) Johnson & Johnson JNJ Phase III - CANDOR (w/Kyprolis+Dex) 361014 Results Trial Data - Preclinical Descartes-08 Multiple Myeloma (MM) Cartesian Therapeutics, Inc. Preclinical Studies 358585 Results Trial Data - Updated Eltanexor Multiple Myeloma (MM) Karyopharm Therapeutics KPTI Phase I/II - Relapsed/Refractory Cancers 360784 Results Trial Data - Top-Line Elzonris Multiple Myeloma (MM) Stemline Therapeutics, Inc. STML Phase I/II - w/Pomalidomide/Dexamethasone 360708 Results Bristol-Myers Squibb Trial Data - Updated Phase II - w/Lenalidomide/Dexamethasone Empliciti Multiple Myeloma (MM) BMY 361232 Company Results (Japan)

January 2020 / 118

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Gracell Biotechnologies Co., Trial Announcement - GC012 Multiple Myeloma (MM) Phase I - Relapsed/Refractory 358509 Ltd. Initiation Gracell Biotechnologies Co., Trial Announcement - GC012 Multiple Myeloma (MM) Phase I - Relapsed/Refractory 358512 Ltd. Trial Completed Gracell Biotechnologies Co., Trial Data - Top-Line GC012 Multiple Myeloma (MM) Phase I - Relapsed/Refractory 360702 Ltd. Results Trial Data - Preclinical GEN3014 Multiple Myeloma (MM) Genmab A/S GMAB Preclinical Studies 361342 Results Bristol-Myers Squibb Trial Data - Updated Iberdomide Multiple Myeloma (MM) BMY Phase Ib/IIa - MM-001 (w/Dexamethasone) 360670 Company Results Bristol-Myers Squibb Trial Data - Top-Line ide-cel Multiple Myeloma (MM) BMY Phase II - KarMMa 360567 Company Results Bristol-Myers Squibb Trial Data - Updated ide-cel Multiple Myeloma (MM) BMY Phase I - CRB-401 361306 Company Results Trial Data - Top-Line Kyprolis Multiple Myeloma (MM) Amgen, Inc. AMGN Phase II - FORTE 361251 Results Trial Data - Updated Kyprolis Multiple Myeloma (MM) Amgen, Inc. AMGN Phase III - CANDOR (w/Darzalex+Dex) 361021 Results Trial Data - Updated LCAR-B38M Multiple Myeloma (MM) Johnson & Johnson JNJ Phase I/II - LEGEND-2 360774 Results Trial Data - Top-Line LCAR-B38M Multiple Myeloma (MM) Johnson & Johnson JNJ Phase Ib/II - CARTITUDE-1 (Dose Finding) 360770 Results LCAR-B38M Multiple Myeloma (MM) Johnson & Johnson JNJ Trial Data Phase Ib/II - CARTITUDE-1 (Dose Finding) 360779

Trial Data - Top-Line LY3039478 Multiple Myeloma (MM) Eli Lilly & Company LLY Phase I - w/BCMA 363455 Results Trial Data - Updated MP0250 Multiple Myeloma (MM) Molecular Partners AG MOLN.SW Phase II - MiRRoR 360699 Results Takeda Pharmaceutical Trial Data - Updated Ninlaro Multiple Myeloma (MM) TAK Phase II - w/Lenalidomide/Dexamethasone 361217 Company Ltd Results SpringWorks Therapeutics, Trial Data - Preclinical Nirogacestat Multiple Myeloma (MM) SWTX 360925 Inc. Results Trial Data - Preclinical NKTR-255 Multiple Myeloma (MM) Nektar Therapeutics NKTR Preclinical Studies 360942 Results Trial Data - Preclinical NKTR-255 Multiple Myeloma (MM) Nektar Therapeutics NKTR Preclinical Studies 360950 Results Trial Data - Preclinical Pelareorep Multiple Myeloma (MM) Oncolytics Biotech, Inc. ONCY Preclinical Studies 360617 Results Regeneron Pharmaceuticals, Trial Data - Top-Line REGN5458 Multiple Myeloma (MM) REGN Phase I/II - First-In-Human 360671 Inc. Results Trial Data - Sarclisa Multiple Myeloma (MM) Sanofi SNY Phase III - ICARIA-MM (w/PomDex) 360646 Retrospective Analysis Trial Data - Updated Sarclisa Multiple Myeloma (MM) Sanofi SNY Phase III - ICARIA-MM (w/PomDex) 360640 Results Trial Data - Updated Sarclisa Multiple Myeloma (MM) Sanofi SNY Phase III - ICARIA-MM (w/PomDex) 360686 Results Trial Data - Updated STRO-001 Multiple Myeloma (MM) Sutro Biopharma Inc. STRO Phase I - BCM1 357331 Results Takeda Pharmaceutical Trial Data - Top-Line TAK-079 Multiple Myeloma (MM) TAK Phase I/IIa - Study 1501 360651 Company Ltd Results Trial Data - Updated Venclexta Multiple Myeloma (MM) AbbVie Inc. ABBV Phase I - Relapsed/Refractory 361291 Results Trial Data - Updated Xpovio Multiple Myeloma (MM) Karyopharm Therapeutics KPTI Phase Ib/II - STOMP 360656 Results Trial Data - Xpovio Multiple Myeloma (MM) Karyopharm Therapeutics KPTI Phase IIb - STORM 360657 Retrospective Analysis

January 2020 / 119

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Trial Data - Updated Xpovio Multiple Myeloma (MM) Karyopharm Therapeutics KPTI Phase Ib/II - STOMP 360782 Results Regulatory - Meeting Ygalo Multiple Myeloma (MM) Oncopeptides AB ONKO:SS 361180 with FDA Trial Data - Updated Ygalo Multiple Myeloma (MM) Oncopeptides AB ONKO:SS Phase II - HORIZON 360630 Results Trial Data - Updated Ygalo Multiple Myeloma (MM) Oncopeptides AB ONKO:SS Phase I/IIa - ANCHOR 360727 Results Myelodysplastic Trial Data - Updated APR-246 Aprea Therapeutics, Inc. APRE Phase Ib/II - w/Azacitidine (US) 360957 Syndrome (MDS) Results Myelodysplastic Trial Data - Top-Line APR-246 Aprea Therapeutics, Inc. APRE Phase Ib/II - w/Azacitidine (France) 360961 Syndrome (MDS) Results Myelodysplastic Trial Data - Updated ASTX727 Otsuka Holdings Co., Ltd. 4768:JP Phase III - ASCERTAIN (vs. Decitabine) 361020 Syndrome (MDS) Results Myelodysplastic Trial Data - Top-Line AZD2811 AstraZeneca PLC AZN Phase I/II - HEMREF 41 361434 Syndrome (MDS) Results Estybon Myelodysplastic Onconova Therapeutics, Inc. ONTX Trial Data Phase III - INSPIRE (HR-MDS) 360978 (Intravenous) Syndrome (MDS) Myelodysplastic Trial Data - Updated Estybon (Oral) Onconova Therapeutics, Inc. ONTX Phase I/II - 09-08 (MDS/AML/CMML) 360944 Syndrome (MDS) Results Myelodysplastic Trial Data - Top-Line FT-1101 FORMA Therapeutics Phase I - HEM-101 (AML/MDS) 361001 Syndrome (MDS) Results Myelodysplastic Trial Data - Updated FT-2102 FORMA Therapeutics Phase I/II - w/Azacitidine or Cytarabine 361016 Syndrome (MDS) Results Myelodysplastic Trial Data - Updated FT-2102 FORMA Therapeutics Phase I/II - w/Azacitidine or Cytarabine 361026 Syndrome (MDS) Results Myelodysplastic Trial Data - Updated Magrolimab Forty Seven Inc. FTSV Phase Ib - w/Azacitidine (AML/MDS) 360813 Syndrome (MDS) Results Myelodysplastic Trial Data - Top-Line MBG453 Novartis AG NVS Phase Ib - w/PDR001 360979 Syndrome (MDS) Results Myelodysplastic Trial Data - Updated Reblozyl Acceleron Pharma, Inc. XLRN Phase III - MEDALIST 357301 Syndrome (MDS) Results Myelodysplastic Trial Data - Updated Reblozyl Acceleron Pharma, Inc. XLRN Phase III - MEDALIST 360956 Syndrome (MDS) Results Myelodysplastic Trial Data - Updated Reblozyl Acceleron Pharma, Inc. XLRN Phase III - MEDALIST 360963 Syndrome (MDS) Results Myelodysplastic Trial Data - Top-Line Telaglenastat Calithera Biosciences, Inc. CALA Phase Ib/II - w/Azacitidine 361296 Syndrome (MDS) Results Myelodysplastic Trial Data - Top-Line Venclexta AbbVie Inc. ABBV Phase Ib - w/Azacitidine 361325 Syndrome (MDS) Results Myelodysplastic Bristol-Myers Squibb Trial Data - Top-Line Vidaza BMY Phase II - w/Durvalumab 361028 Syndrome (MDS) Company Results Constellation Trial Data - Updated CPI-0610 Myelofibrosis (MF) CNST Phase I/II - MANIFEST (+/- Ruxolitinib) 360790 Pharmaceuticals, Inc. Results Trial Data - Updated Elzonris Myelofibrosis (MF) Stemline Therapeutics, Inc. STML Phase I/II - HES/MF/CMML (Mayo) 361024 Results Trial Data - Updated Phase I/IIb - IMG-7289-CTP-102 IMG-7289 Myelofibrosis (MF) Imago BioSciences, Inc. 360970 Results (Australia/US/EU) Trial Data - Momelotinib Myelofibrosis (MF) Sierra Oncology, Inc. SRRA Phase III - Simplify 1 (vs. Ruxolitinib) 360641 Retrospective Analysis Trial Data - Top-Line Navitoclax Myelofibrosis (MF) AbbVie Inc. ABBV Phase II - w/Ruxolitinib 361290 Results Trial Data - Phase III - PERSIST-1, Phase III - PERSIST-2 Pacritinib Myelofibrosis (MF) CTI BioPharma Corporation CTIC 360914 Retrospective Analysis (PAC326) Trial Data - Top-Line Pacritinib Myelofibrosis (MF) CTI BioPharma Corporation CTIC Phase II/III - PAC203 360899 Results

January 2020 / 120

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Trial Data - Phase III - PERSIST-1, Phase III - PERSIST-2 Pacritinib Myelofibrosis (MF) CTI BioPharma Corporation CTIC 360918 Retrospective Analysis (PAC326) Trial Data - Top-Line Reblozyl Myelofibrosis (MF) Acceleron Pharma, Inc. XLRN Phase II - MF-001 357323 Results Trial Data - Updated Reblozyl Myelofibrosis (MF) Acceleron Pharma, Inc. XLRN Phase II - MF-001 360934 Results BeyondSpring Plinabulin Neutropenia / Leukopenia BYSI Trial Data Phase II/III - Protective-1 360812 Pharmaceuticals, Inc. Non-Hodgkin's Trial Data - Updated ACTR707 Unum Therapeutics, Inc. UMRX Phase I - ATTCK-20-03 (w/Rituximab) 360675 Lymphoma (NHL) Results Non-Hodgkin's Trial Data - Preclinical CA-4948 Dr. Reddy's Laboratories RDY Preclinical Studies 360594 Lymphoma (NHL) Results Lisocabtagene Non-Hodgkin's Bristol-Myers Squibb Trial Data - Top-Line Phase II - PILOT (2nd Line Non-Transplant BMY 360719 Maraleucel Lymphoma (NHL) Company Results Eligible) Lisocabtagene Non-Hodgkin's Bristol-Myers Squibb Trial Data - Updated Phase I - TRANSCEND, Phase II - PILOT (2nd BMY 361278 Maraleucel Lymphoma (NHL) Company Results Line Non-Transplant Eligible) Non-Hodgkin's Trial Data - Updated MT-3724 Molecular Templates Inc. MTEM Phase I/Ib - NHL001 360915 Lymphoma (NHL) Results Non-Hodgkin's Trial Data - Updated NAM-NK Cells Gamida Cell Ltd. GMDA Phase I - R/R MM + R/R CD20+ NHL 360888 Lymphoma (NHL) Results Non-Hodgkin's Trial Data - Top-Line PBCAR0191 Precision BioSciences Inc. DTIL Phase I/IIa - Dose Escalation 360776 Lymphoma (NHL) Results Non-Hodgkin's Trial Data - Updated RG-6026 Roche Holding AG RHHBY Phase I/Ib - w/Gavyza 360643 Lymphoma (NHL) Results Non-Hodgkin's Trial Data - Top-Line RG-6026 Roche Holding AG RHHBY Phase Ib - w/Tecentriq 360705 Lymphoma (NHL) Results Non-Hodgkin's Trial Data - Updated Valemetostat Daiichi Sankyo Co., Ltd. DSKYF Phase I - A-J101 361177 Lymphoma (NHL) Results Paroxysmal Nocturnal Achillion Pharmaceuticals, Trial Data - Updated Danicopan ACHN Phase II - Add-On to Eculizumab (Study 101) 360901 Hemoglobinuria (PNH) Inc. Results Paroxysmal Nocturnal Regeneron Pharmaceuticals, Trial Data - Updated REGN-3918 REGN Phase I - HV-1659 360741 Hemoglobinuria (PNH) Inc. Results Paroxysmal Nocturnal Trial Data - Updated RG-6107 Roche Holding AG RHHBY 361274 Hemoglobinuria (PNH) Results Paroxysmal Nocturnal Trial Data - Updated Phase III - Naïve Study (vs. Eculizumab), Phase Ultomiris Alexion Pharmaceuticals, Inc. ALXN 360624 Hemoglobinuria (PNH) Results III - Switch Study (vs. Eculizumab) Paroxysmal Nocturnal Trial Data - Updated Ultomiris Alexion Pharmaceuticals, Inc. ALXN Phase III - Switch Study (vs. Eculizumab) 360718 Hemoglobinuria (PNH) Results Peripheral T-Cell Trial Data - Adcetris Seattle Genetics, Inc. SGEN Phase III - ECHELON-2 360685 Lymphoma (PTCL) - NHL Retrospective Analysis Peripheral T-Cell Trial Data - Updated Cerdulatinib Portola Pharmaceuticals, Inc. PTLA Phase I/IIa - Two Part Dose Escalation 360738 Lymphoma (PTCL) - NHL Results Peripheral T-Cell Trial Data - Updated Cerdulatinib Portola Pharmaceuticals, Inc. PTLA Phase I/IIa - Two Part Dose Escalation 360885 Lymphoma (PTCL) - NHL Results Peripheral T-Cell Trial Data - Top-Line Copiktra Verastem, Inc. VSTM Phase II - PRIMO 357383 Lymphoma (PTCL) - NHL Results Peripheral T-Cell Trial Data - Updated Copiktra Verastem, Inc. VSTM Phase II - PRIMO 360631 Lymphoma (PTCL) - NHL Results Peripheral T-Cell Trial Data - Top-Line CPI-818 Corvus Pharmaceuticals, Inc. CRVS Phase I/Ib - 001, Preclinical Studies 360613 Lymphoma (PTCL) - NHL Results Peripheral T-Cell CStone Pharmaceuticals Trial Data - Top-Line CS1001 HKEX: 2616 Phase II - CS1001-201 357657 Lymphoma (PTCL) - NHL (Suzhou) Co., Ltd Results Peripheral T-Cell CStone Pharmaceuticals Trial Data - Updated CS1001 HKEX: 2616 Phase II - CS1001-201 361258 Lymphoma (PTCL) - NHL (Suzhou) Co., Ltd Results Peripheral T-Cell Trial Data - Updated Tipifarnib (Oncology) Kura Oncology, Inc. KURA Phase II - 002 360710 Lymphoma (PTCL) - NHL Results

January 2020 / 121

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Primary Central Nervous Trial Data - Top-Line Tirabrutinib System Lymphoma Gilead Sciences, Inc. GILD Phase I/II - ONO-4059-02 (Japan) 360767 Results (PCNSL) - NHL Primary Trial Data - Top-Line JSP-191 Jasper Therapeutics, Inc. Phase I - CP-001 361017 Immunodeficiencies Results Primary Trial Data - Updated MB-107 Fortress Biotech, Inc. FBIO Phase I/II - LVXSCID-ND 360637 Immunodeficiencies Results Primary Trial Data - Top-Line MB-107 Fortress Biotech, Inc. FBIO Phase I/II - LVXSCID-OC 360849 Immunodeficiencies Results Primary Orchard Therapeutics Trial Data - Top-Line Phase I/II - UCLA Cryo (ADA-SCID), Phase I/II - OTL-101 ORTX 357410 Immunodeficiencies Limited Results UCLA Fresh (ADA-SCID) Primary Orchard Therapeutics Trial Data - Updated Phase I/II - UCLA Cryo (ADA-SCID), Phase I/II - OTL-101 ORTX 360733 Immunodeficiencies Limited Results UCLA Fresh (ADA-SCID) Pyruvate Kinase Trial Data - Updated Mitapivat Agios Pharmaceuticals, Inc. AGIO Natural History Studies 360971 Deficiency Results Pyruvate Kinase Trial Data - Updated Mitapivat Agios Pharmaceuticals, Inc. AGIO Phase II - DRIVE PK 360966 Deficiency Results Trial Data - Adakveo Sickle Cell Anemia Novartis AG NVS Phase II - SUSTAIN 361256 Retrospective Analysis Trial Data - Preclinical AXA4010 Sickle Cell Anemia Axcella Health, Inc. AXLA Preclinical Studies 360614 Results Trial Data - Updated BCL11a shRNA(miR) Sickle Cell Anemia bluebird bio BLUE Phase I - SCD 361171 Results Trial Data - Preclinical BIVV-003 Sickle Cell Anemia Sanofi SNY Preclinical Studies 360619 Results Trial Data - Preclinical EDIT-301 Sickle Cell Anemia Editas Medicine EDIT Preclinical Studies 361155 Results Trial Data - Top-Line FT-4202 Sickle Cell Anemia FORMA Therapeutics Phase I - SAD/MAD 360998 Results Global Blood Therapeutics, Trial Data - Updated Oxbryta Sickle Cell Anemia GBT Phase III - HOPE 360648 Inc. Results Global Blood Therapeutics, Trial Data - Updated Oxbryta Sickle Cell Anemia GBT Phase III - HOPE 360745 Inc. Results Global Blood Therapeutics, Trial Data - Updated Oxbryta Sickle Cell Anemia GBT Phase IIa - HOPE-KIDS 1 (GBT 440-007) 360783 Inc. Results Trial Data - Updated Zynteglo Sickle Cell Anemia bluebird bio BLUE Phase I/II - HGB-206 360628 Results Trial Data - Updated Phase I/II - ß-Thalassemia/Severe Sickle Cell - Zynteglo Sickle Cell Anemia bluebird bio BLUE 360737 Results HGB-205 (France) NYESO-1 TCR Trial Data - Top-Line Solid Tumors Tmunity Therapeutics ,Inc. Phase I - 25416 360649 Program (Tmunity) Results Protagonist Therapeutics, Trial Data - Preclinical PTG-300 Thalassemia PTGX Preclinical Studies 361186 Inc. Results Trial Data - Updated Reblozyl Thalassemia Acceleron Pharma, Inc. XLRN Phase III - BELIEVE (Global) 357317 Results Trial Data - Updated Reblozyl Thalassemia Acceleron Pharma, Inc. XLRN Phase III - BELIEVE (Global) 360945 Results Trial Data - Updated Reblozyl Thalassemia Acceleron Pharma, Inc. XLRN Phase III - BELIEVE (Global) 360952 Results Trial Data - Updated ST-400 Thalassemia Sanofi SNY Phase I/II - THALES 357367 Results Trial Data - Updated ST-400 Thalassemia Sanofi SNY Phase I/II - THALES 360883 Results Trial Data - Updated Phase I/II - Northstar - Beta-Thalassemia (HGB- Zynteglo Thalassemia bluebird bio BLUE 360965 Results 204; US)

January 2020 / 122

Information Classification: General

Biomedtracker 2019 ASH Events

Drug Indication Lead Company Ticker Event Type Trial Name Link Trial Data - Updated Zynteglo Thalassemia bluebird bio BLUE Phase III - NorthStar-2 (HGB-207) 360968 Results Trial Data - Updated Zynteglo Thalassemia bluebird bio BLUE Phase III - Northstar-3 (HGB-212) 360974 Results Orchard Therapeutics Trial Data - Final OTL-103 Thrombocytopenia ORTX Phase I/II - TIGET-WAS (Wiskott-Aldrich) 357408 Limited Results Orchard Therapeutics Trial Data - Updated OTL-103 Thrombocytopenia ORTX Phase I/II - TIGET-WAS (Wiskott-Aldrich) 360729 Limited Results CRISPR Base Editing Trial Data - Preclinical Undisclosed Beam Therapeutics BEAM Preclinical Studies 360746 Program (Beam) Results Venous Trial Data - Updated Xarelto Johnson & Johnson JNJ Phase III - EINSTEIN JR (Children) 360652 Thromboembolism (VTE) Results Waldenstrom Macroglobulinemia (WM) Trial Data - Updated Brukinsa BeiGene, Ltd. BGNE Phase Ib - w/BGB-A317 360723 / Lymphoplasmacytic Results Lymphoma (LPL) - NHL Waldenstrom Macroglobulinemia (WM) Trial Data - Top-Line Tirabrutinib Gilead Sciences, Inc. GILD Phase II - ONO-4059-05 (Japan) 360769 / Lymphoplasmacytic Results Lymphoma (LPL) - NHL

January 2020 / 123

Information Classification: General