MDACC: CLL14: Trial Design

Safety Run-in Phase* Venetoclax–

Venetoclax– Venetoclax Follow-up Phase Obinutuzumab Previously untreated 6 cycles 6 cycles Primary endpoint: patients with CLL and Progression-free coexisting medical survival conditions 1:1 Key secondary endpoints: randomization CIRS > 6 and/or CrCl < Response, Minimal 70mL/min Residual Disease, Overall Chlorambucil– Chlorambucil Survival Obinutuzumab 6 cycles 6 cycles

* Fischer K et al. Venetoclax and Obinutuzumab in chronic lymphocytic , Blood 11 May 2017 Análise Primária: SLP avaliada pelo investigador (população ITT) Mediana de tempo fora de 100 tratamento: 17.1 meses (0.0–30.4) VenG (N=216) Mediana de duração do tratamento 11.1 meses (0.0–14.1) 80 Mediana de seguimento 28.1 meses 60 (0.0–35.9)

GCIb (N=216) VenG GClb

SLP (%) SLP (n=216) (n=216) 40 Mediana de tempo fora de tratamento : Eventos, n (%) 30 (13.9) 77 (35.6) 17.9 meses (0.0–30.2) HR (IC 95%), 0.35 (0.23–0.53) Mediana de duração do tratamento Valor de p 20 estratificado p<0.001* 10.8 meses ( 0.0–13.6) SLP 2 anos, 88.2 64.1 % (IC95%) (83.7–92.6) (57.4–70.8) 0 0 6 12 18 24 30 36 Tempo (Meses) No. of Pacientes com risco: VenG 216 195 192 183 153 25 0 GClb 216 194 184 152 110 21 0

O desfecho primário de SLP pelo invstigador foi atingido; pacientes que receberam VenG tiveram 65% menos risco de progressão ou morte em relação aos pacientes que receberam GClb (IC95% 0.23–0.53), p<0.001

O valor de p mostrado se refere ao valor de p controlado por alfa do teste log-rank estratificado pela classificação de Binet e região geográfica. IC – interval de confiança, SLP sobrevida livre de progressão Fischer K, et al. N Engl J Med 2019; DOI: 10.1056/NEJMoa1815281. A Novel Concept: Mimicking Autoinhibition of ABL1 by Myristate Binding to an Allosteric Site

ABL1 kinase BCR-ABL1 kinase

Hantschel O. Haematologica. 2012;97:195-97 Asciminib: Allosteric BCR-ABL1 Inhibition

▪ Binds with high affinity to the myristoyl pocket of ABL1 kinase to mimic the native myristate ligand

▪ Ba/F3 BCR-ABL1 IC50: ~3 nM (!) ▪ Demonstrates an extremely selective kinase profile ▪ Currently in Phase 1/2

Wylie et al. Nature. 2017;543(7647):733-737. Asciminib: Selectivity in Comparison

Wylie et al. Nature. 2017;543(7647):733-737. CASSIOPEIA Study Design • Phase 3 study of D-VTd versus VTd in transplant-eligible NDMM (N = 1,085), 111 sites from 9/2015 to 8/2017

Induction Consolidation Maintenance

D-VTd D-VTd D monotherapy D: 16 mg/kg IV QW Cycles 1-2, Q2W D: 16 mg/kg IV Q2W T ) D 16 mg/kg IV Q8W until

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4 Cycles of 28 days 2 Cycles of 28 days Part 1 Part 2

D-VTd, /bortezomib/thalidomide/dexamethasone; VTd, bortezomib/thalidomide/dexamethasone; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; QW, weekly; Q2W, every 2 weeks; SC, subcutaneous; PO, oral; PR, partial response; Q8W, every 8 weeks; PD, progressive disease. aDexamethasone 40 mg on Days 1, 2, 8, 9, 15, 16, 22, 23 of Cycles 1-2 and Days 1 & 2 of Cycles 3-4; 20 mg on Days 8, 9, 15, 16 of Cycles 3-4; 20 mg on Days 1, 2, 8, 9, 15, 16 of Cycles 5-6. 6 Moreau P, Attal M, Hulin C, et al, The Lancet 394:29-38, 2019 Winship Cancer Institute | Emory University 8 PFS and OS PFS OS

Moreau P, Attal M, Hulin C, et al, The Lancet 394:29-38, 2019 Winship Cancer Institute | Emory University 9 Phase III ALCYONE Trial: VMP± Daratumumab in ASCT- Ineligible Patients With Newly Diagnosed Myeloma Daratumumab monotherapy phase 100 24 mos 30 mos

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% ( P 40 Dara-VMP arm 36% 28% VMP Median: 19.1 20 HR: 0.43 mos (95% CI: 0.35-0.54; P< .0001) 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Patients at Risk, n Mos VMP 356 304 277 262 245 206 169 127 102 59 27 5 0 0 D-VMP 350 322 312 298 292 265 243 220 203 138 73 31 9 0

Mateos MV, et al. N Engl J Med 2018; 378:518-52 Response Rates by Treatment Cohort

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N =1 4 5 n =2 9 n =3 1 n =3 7 n =3 7 * All doses includes 11 patients that received 1200 mg venetoclax C DiNardo et al, Blood 2018 Luspatercept forthe treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Platzbecker et al, Lancet Oncology, 2017

Sotatercept with long-term extension forthe treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial Komrokji, Garcia-Manero et al, Lancet Haematology, 2018

The Medalist Trial: Results of a Phase 3, Randomized, Double- Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions ASHPlenary, 2018

Luspatercept promotes late stages of erythroid differentiation by inhibiting SMAD2/3 activation

MDS

Collaboration with Ravi Kumar, Rajshekhar Suragini, Acceleron; Suragini et al, Nat Med 2014 C The Medalist Trial: Results of a Phase 3, Randomized, Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, orIntermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Ghia, EHA 2019 ASCEND Study Design (ACE-CL-309)

Primary endpoint: Acalabrutinib • PFS (assessed by Relapsed/Refract 100 mg PO BID IRC) Key secondary ory CLL (N= 310) R A endpoints: N • ORR (assessed by Stratification: D Idelalisib plus (IdR) IRC and O 1:1 del(17p), y vs n M Idelalisib 150 mg PO BID + rituximaba investigator) ECOG PS 0-1 vs 2 I - or - • Duration of Z response 1-3 vs ≥4 prior E Bendamustine plus Rituximab (BR) therapies • PFS (assessed by Bendamustine 70 mg/m2 IVb + investigator) c rituximab • OS

Crossover from IdR/BR arm allowed after confirmed disease progression

• Interim analysis was planned after occurrence of ~79 PFS events (2/3 of primary event goal)

Ghia et al, EHA2019 Ghia, EHA 2019 IRC-Assessed PFS Superior for Acalabrutinib vs IdR/BR

Ghia et al, EHA2019 ADMIRAL Global Phase 3 Randomized Study (NCT02421939)

Gilteritinib Resume HSCT 120 mg/day n=247 Adult subjects with FLT3mut+ R/R AML Randomization 2:1 N=371 Salvage * HSCT Key Eligibility Criteria: n=124 • Refractory to initial induction or untreated first relapse after prior CRc (defined as CR Co-Primary Endpoints: OS, plus CRi plus CRp) CR/CRh rate – Prior frontline or allowed Key Secondary Endpoints: EFS, – Prior gilteritinib or other FLT3 inhibitors CR rate excluded • Central laboratory-confirmed FLT3-ITD or *Salvage chemotherapy regimen was selected prior to randomization FLT3-TKD (D835/I836) by PCR MEC (mitoxantrone, etoposide, and cytarabine) • ECOG performance status <2 High intensity FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) (1–2 cycles) • Normal liver, renal function Low-dose cytarabine Low intensity (given until disease progression or intolerance) • QTcF <450 msec by central ECG reading Azacitidine Abbreviations: CR, complete remission; CRc, composite complete remission; CRh, complete remission with incomplete hematologic recovery; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EFS, event-free survival; G-CSF, granulocyte colony-stimulating factor; HSCT, hematopoietic stem cell transplantation; ITD, internal tandem duplication; OS, overall survival; PCR, polymerase chain reaction; QTcF, Fridercia-corrected QT interval; R/R, relapsed/refractory; TKD, tyrosine kinase domain. Perl et al. AACR 2019 Overall Survival (ITT Population: N=371) Median OS (95% CI) Gilteritinib 120 mg/day 9.3 months (7.7, 10.7) Salvage chemotherapy 5.6 months (4.7, 7.3) + Censored HR=0.637 (95% CI: 0.490, 0.830); P=0.0007

CR/CRh Gilteritinib vs SC: 37% 34.0% vs. 15.3%

17%

Two-sided P-values were determined according to the log-rank test; the Kaplan-Meier method in combination with the Greenwood formula were used to determine overall survival and corresponding 95% confidence intervals. Abbreviations: CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival. Perl et al. AACR 2019 What if the Patient has an IDH mutation?  Ivosedinib and enasedinib effective alone and in combination with HMA in relapsed and de novo disease  Data on HMA/VEN in patients with IDH mutations very encouraging as well

Pollyea et al, ASH 2018 Mutation # CR/CRi %(N) Duration of response Overall Survival (mo) FLT3 18 72 (13) 11(6.5,NR) NR(8-NR) IDH ½ 35 71(25) NR(6.8,NR) 24.4 (12.3-NR)

NPM1 23 91(21) NR(6.8, NR) NR (11-NR)

ATdapPted5fr3om DiNardo et al, Blood 03186 47(17) 5.6(1.2,9.4) 7.2(3.7-NR) 2 JAKARTA-2: Open-Label, Phase 2 Studyof Fedratinib

• Aged ≥18 years Fedratinib • Intermediate-2 or high-risk status – Primary MF Once daily, starting dose 400 mg – Post–PVMF Consecutive 4-week cycles – Post–ET MF • Platelet count ≥50 x 109/L • Permitted dose adjustments = 200-600 mg/day • Received RUX for ≥14 days • Dose up-titration permitted if <50%reduction in • Discontinued RUX ≥14 days prior to spleen volume by palpation to ECO6 starting fedratinib • Dose-titration permitted in event of toxicity • Patients who continued to benefit clinically could remain on study until the occurrence of disease RUX RUX progression or unacceptable toxicity resistant intolerant

Classification made by treating physician Harrison CNet al. Lancet Haematol. 2017;4:e317-e324. JAKARTA: SPLEEN VOLUME AND SYMPTOM RESPONSES

• Among all patients, SVRR was significantly higher with fedratinib 400 mg/day vs. placebo (47% vs. 1%, respectively; P<0.0001) • Symptom RR was also significantly improved with fedratinib overall • There was no statistically significant difference in SVRR or symptom RR between BL platelet count subgroups within the fedratinib 400 mg treatment arm

JAKARTA

BL Platelet Count BL Platelet Count 50 to <100 × 109/L ≥100 × 109/L

Placebo Fedratinib 400 mg Placebo Fedratinib 400 mg n = 18 n = 14 n = 77 n = 82

SVRR: 0% SVRR: 35.7% SVRR: 1.3% SVRR: 48.8% [95%CI NE] [95%CI 11%, 61%] [95%CI 0%, 4%] [95%CI 38%, 60%]

Symptom RR (n=16): Symptom RR (n=13): Symptom RR (n=65): Symptom RR (n=76): 0% 30.8% 10.8% 42.1% [95%CI NE] [95%CI 6%, 56%] [95%CI 3%, 18%] [95%CI 31%, 53%]

Statistical comparisons between BL platelet count subgroups should be interpreted with caution due to small sample sizes. 6 BL, baseline; ITT, intention-to-treat; NE, not estimable; RR, response rate; SVRR, spleen volume response rate. Fedratinib Is Effective in Patients With MFPreviously Treated With : Results From JAKARTA-2

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Harrison CNet al. Lancet Haematol. 2017;4:e317-e324.