Epigenetic Drugs in Oncology: Current Clinical Landscape and Emerging Trends 2 / January 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) Rachel Meighan-Mantha PhD, Principal Oncology, Pharma Intelligence, Informa

Introduction “Epigenetics is the study of heritable, reversible Genome Project was completed in 2003 judging forms of gene regulation that are not dependent by the epigenetic international initiatives launched on the DNA sequence. This regulation includes DNA since then, including GWAS, ENCODE, TCGA, AHEAD, methylation and histone methylation, acetylation, ICGC, Roadmap Epigenomics and IHEC among ubiquitination, and phosphorylation.”1 While others2. Preclinical and clinical research over the epigenetic modifications are crucial for normal past 30 years point to the therapeutic potential of functioning in all stages in life, from embryonic epigenetic drugs, both alone and combination, in development through adulthood, these events correcting epigenetic dysregulation associated with are also associated with many cardiovascular, various types of malignancies. This report analyzes metabolic and neurological diseases as well as the current clinical landscape and some emerging .1 Epigenetics has become an area of trends for epigenetic drugs in oncology. extensive interest in the years since the Human

Methodology Data was retrieved from Informa’s Pharma dehydrogenase inhibitor, methyltransferase inhibitor Intelligence services in mid to late October as or methyltransferase stimulant follows. Strategic Transactions – a search of deal records Biomedtracker – a drug search with the (acquisitions, alliances and mergers) using keywords epigenetic-associated targets: BET Proteins/ or phrases related to epigenetics (e.g. bromodomain, Bromodomains, Isocitrate Dehydrogenase (IDH), “DNA methylation”, “epigenetic”, HDAC, “isocitrate Histone Methyltransferase (HMT), Lysine-Specific dehydrogenase” or “lysine-specific demethylase”) Demethylase-1 (LSD1)/KDM1A or SIRT1 Trialtrove – an oncology trials search of primary Pharmaprojects – a drug search of pipeline and drugs with the epigenetic-associated mechanisms of approved cancer drugs (global status of preclinical action: BET protein inhibitor, demethylase inhibitor, to launched) with the epigenetic-associated DNA methylase inhibitor, histone acetyltransferase mechanisms of action: BET protein inhibitor, inhibitor, inhibitor, histone demethylase inhibitor, DNA methylase inhibitor, deacetylase stimulant, histone methyltransferase histone acetyltransferase inhibitor, histone inhibitor, isocitrate dehydrogenase inhibitor or deacetylase inhibitor, histone deacetylase stimulant, methyltransferase inhibitor histone methyltransferase inhibitor, isocitrate

1 Heerboth S, Lapinska K, Snyder N, Leary M, Rollinson S, Sarkar S. Use of Epigenetic Drugs in Disease: An Overview. Genetics & Epigenetics. 2014;6:9-19. 2 Bae, JB. Perspectives of International Human Epigenome Consortium. Genomics & Informatics. 2013;11(1):7-14.

© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) January 2017 / 3 Approved Drugs Seven epigenetic drugs, two DNA methyltransferase and romidepsin (only approved in the USA) and (DNMT) inhibitors and five histone deacetylase chidamide (only approved in China). Not shown (HDAC) inhibitors have been approved in several in this table is a HDAC inhibitor, valproic acid/ different hematological malignancies as shown , which has been approved for decades in Table 1. While approvals date back to 2004, to treat epilepsy, bipolar disorder and migraines. It three drugs were approved just in the past three continues to be evaluated in oncology clinical trials years. Most of these drugs have been approved in as a repurposed drug. multiple countries with the exception of

Table 1: Approved Epigenetic Drugs in Oncology

Epigenetic Earliest Approved Drug Name Mechanism of Originator Approval Indications Action Date

azacitidine (Vidaza) DNMT inhibitor Celgene May 2004 AML, CML and MDS*

Astex Pharmaceuticals decitabine (Dacogen) DNMT inhibitor May 2006 AML, CML and MDS (Otsuka)

Cutaneous T-cell vorinostat (Zolinza) HDAC inhibitor Merck & Co. Oct 2006

Cutaneous/Peripheral romidepsin (Chromadax) HDAC inhibitor /Celgene Nov 2009 T-cell Lymphoma

Peripheral T-cell belinostat (Beleodaq) HDAC inhibitor TopoTarget Jul 2014 Lymphoma

Shenzhen Chipscreen Peripheral T-cell chidamide (Epidaza) HDAC inhibitor Dec 2014 Biosciences Lymphoma

panobinostat (Farydak) HDAC inhibitor Feb 2015 Multiple Myeloma

*Acute Myelogenous (AML), Chronic Myelogenous Leukemia (CML) and Myelodysplastic Syndromes (MDS)

Source: Pharmaprojects®, October 2016

4 / January 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) Current Clinical Landscape In addition to the seven approved drugs described I-III) development (Figure 1). Almost all of drugs in above, the current clinical landscape, as of October clinical development were still in early-to mid-stage 2016, included 112 active drugs. Approximately 48% trials (phase I and II). Not shown are the inactive of the active drugs were in preclinical development drugs (suspended, no development reported, while approximately 46% were in clinical (phase discontinued or withdrawn).

Figure 1: Global Status of Active Epigenetic Drugs in Oncology

Preclinical 57 Phase I 27 Phase II Clinical Trial 25 Phase III Clinical Trial 3 Launched 7 0 5 10 15 20 25 30 35 40 45 50 55 60 Drugs by Global Status

Source: Pharmaprojects®, October 2016

Epigenetic drugs, active and currently inactive, were collaborator involvement relative to other types for evaluated in 1418 oncology clinical trials. Of these, each trial status remained relatively constant with 35% were ongoing (open, closed or temporarily slight increases in Industry and Industry-Generic closed) and planned while 65% were completed or involvement for planned trials and slight decreases terminated. Approximately 93% of the trials were in Government involvement for planned and open early- to mid-stage (phases I, I/II and II) while trials (Figure 2). Relative to the other types for each just over 6% were late-stage (phases II/III, III and phase, Industry involvement was highest in phases I IV). The remainder of the trials were not assigned and III and lowest in phase II (Figure 3). In contrast, a specific phase by the sponsor (data not shown). Academic involvement was highest in phase II Sponsors/collaborators of these trials were classified and lowest in phase III. Both Co-op Group and by type (Industry, Industry-Generic, Academic, Government involvement were similar in phases I to Co-op Group and Government) and examined II/III, yet in phase III, Co-op Group involvement was by trial status and phase. The ratios of sponsor/ highest while Government involvement dropped off.

© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) January 2017 / 5 Figure 2: Sponsor/Collaborator Type by Trial Status

Trial Count 0 200 400 600 800 1000 1200

Planned

Open

Closed

Temporarily Closed

Completed

Terminated

Industry Industry-Generic Academic Co-op Group Government

Source: Trialtrove®, October 2016

Figure 3: Sponsor/Collaborator Type by Trial Phase

Trial Count 0 200 400 600 800 1000 1200

I

I/II

II

II/III

III

IV

Industry Industry-Generic Academic Co-op Group Government

Source: Trialtrove®, October 2016

6 / January 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) By overall trial design, 42% of epigenetic drug approximately equivalent in their use. However trials in oncology evaluated single agents while in ongoing and planned trials, single agents were 58% evaluated combinations. In completed and evaluated in only 33% of trials and combinations terminated trials, these two study designs were increased to 67% from the overall trial design ratio.

Figure 4: Overall Trial Design by Trial Status

700

600

500

400

300 Trial Count Trial 200

100

0 Planned Open Closed Temporarily Completed Terminated Closed

Single Agent Combination

Source: Trialtrove®, October 2016

These trials were also assessed for attributes related rather than completed or terminated (Figure 5). to regulatory approvals, investigator involvement Additional differences between these two trial and biomarkers. Like oncology trials in general, status groups included increases in investigator- epigenetic drug trials supported the trend towards initiated and registration trials for ongoing and personalized medicine, especially in ongoing and planned versus completed and terminated trials. planned trials. Trials that preselected or stratified Trial statuses with the highest attribute percentage patients based on a pharmacogenomic (PGX) are boxed, and five temporarily closed trials are not biomarker were more likely to be ongoing or planned shown.

Figure 5: Trial Tags by Trial Status

Trial Tags Planned Open Closed Completed Terminated Biomarker/Efficacy 14% 38% 50% 43% 44% Investigator-initiated 8% 12% 16% 5% 3% PGX – Biomarker Identification/Evaluation 7% 22% 37% 28% 26% PGX – Patient Preselection/Stratification 10% 22% 13% 4% 9% Registration 7% 3% 1% 2% 0%

Source: Trialtrove®, October 2016

© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) January 2017 / 7 Locations for epigenetic drug trials in oncology 1% in Africa (data not shown). The geographical encompass several different geographical regions. representation of the top countries in each region Overall, 70% of the trials were conducted at sites did not change much from one status to the next, in North America, 27% in (eastern and except for an increase in ongoing and planned trials western), 15% in Asia, 5% in Australia/New Zealand, conducted in China (Figure 6). 2% in both South America and the Middle East and

Figure 6: Top Trial Locations by Country

100% 90% 80% Spain 70% Singapore Russia 60% Netherlands 50% Japan 40% Italy 30% Trial Count (Normalized) Count Trial France 20% China 10% Canada

0% Belgium Austrialia

Open Closed Planned Completed Terminated

Source: Trialtrove®, October 2016

8 / January 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) Epigenetic drug trials in oncology span a indications also contained the most ongoing and wide variety of malignancies, both solid and planned trials. Relative to the total number of trials hematological (Figure 7). Diseases that included within each indication, glioblastoma, AML, Hodgkin’s more than 100 trials were acute myelogenous lymphoma, multiple myeloma and myelproliferative leukemia (AML), myelodysplastic syndromes (MDS), (MPN) had the most ongoing and non-Hodgkin’s lymphoma (NHL), non-small cell planned trials. (NSCLC) and . These same

Figure 7: Diseases with Ten or More Trials by Trial Status

Trial Count 0 50 100 150 200 250 300 350 400 Bladder Breast Planned CNS, Glioblastoma Open CNS, Medulloblastoma Colorectal Closed Esophageal Completed Gastric Terminated Head/Neck Leukemia, Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, Chronic Lymphocytic Leukemia, Chronic Myelogenous Liver Lung, Non-Small Cell Lung, Small Cell Lymphoma, Hodgkin’s Lymphoma, Non-Hodgkin’s Mesothelioma Multiple Myeloma Myelodysplastic Syndrome Myeloproliferative Neoplasms Osteosarcoma Ovarian Pancreas Prostate Renal Soft Tissue Sarcoma Thyroid

Source: Trialtrove®, October 2016

© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) January 2017 / 9 Emerging Trends A few emerging trends should be noted for recognized epigenetic mechanisms only dated the clinical development of epigenetic drugs in back five years. These newer mechanisms include oncology. Already discussed was the use of PGX bromodomain and extraterminal protein (BET) biomarkers to preselect or stratify patients in inhibitors, lysine-specific demethylase 1A (LSD1/ ongoing and planned trials (Figure 5). Other trends KDM1A) inhibitors, isocitrate dehydrogenase (IDH) to be examined include historical changes in the mutant inhibitors, histone methyltransferase (HMT) clinical evaluation of epigenetic drug targets, the and protein arginine methyltransferase (PRMT) types of combinations in ongoing and planned trials inhibitors. The total number of trials evaluating and sponsor/collaborator involvement in ongoing DNMT inhibitors and HDAC inhibitors were 552 and and planned trials. 839 trials, respectively. The total number of trials evaluating epigenetic drugs acting via these newer Clinical trial activity of epigenetic drugs in mechanisms constituted just a small percentage of oncology as determined by start year over the these totals. Only 32 trials with BET inhibitors, six past three decades is shown in Figure 8. Trial with LSD1A/KDM1A inhibitors, 26 with IDH mutant activity of the DNMT inhibitors and histone HDAC inhibitors and 12 with HMT/PRMT inhibitors have inhibitors dated back to 1987 while trial activity been conducted (data not shown). for epigenetic drugs acting via more newly-

Figure 8: Clinical Trial Starts for Epigenetic Inhibitors 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

BET

LSD1/KDM1A

DNMT

HDAC

IDH

HMT or PRMT

*BET – bromodomain and extraterminal protein; LSD1/KDM1A – lysine-specific demethylase 1A; DNMT – DNA methyltransferase; HDAC – histone deacetylase; IDH – isocitrate dehydrogenase mutant; HMT – histone methyltransferase; PRMT – protein arginine methyltransferase

Source: Trialtrove®, October 2016

10 / January 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) Another emerging trend in Figure 9: Top Drug Types in Epigenetic Drug Combinations by the clinical development of Trial Counts epigenetic drugs in oncology is the prevalence of combination Angiogenesis, Targeted trials in ongoing and planned trials (Figure 4). To aid in the 6 2 Cytotoxic analysis of the types of epigenetic 4 Cytotoxic, Immunotherapy drug combinations, drugs were 12 categorized as Angiogenesis, Cytotoxic, Other Cytotoxic, Epigenetic, Hormonal, Planned Cytotoxic, Targeted Immunotherapy, Targeted or Other. Combinations of up to 12 3 Epigenetic seven types were evaluated Immunotherapy in 332 ongoing and planned 5 Other trials, although the majority 4 2 was combinations of two or Targeted three drug types (62% and 30%, respectively). The top combinations with epigenetic Angiogenesis drugs for 56 planned, 193 open 6 6 Angiogenesis, Cytotoxic and 80 closed trials are shown 23 7 in Figure 9. Relatively consistent Angiogenesis, Targeted between trials in these three trial 16 Cytotoxic statuses was the use of cytotoxic 41 and targeted drugs, alone in Open Cytotoxic, Other combination with epigenetic 17 Cytotoxic, Targeted drugs, together in combination with epigenetic drugs or in 9 Epigenetic combination with another drug 9 22 Hormonal 11 type and epigenetic drugs. Immunotherapy Notable differences include the increasing use from closed to Other planned of Immunotherapy Targeted combinations, the decreasing use from closed to planned of Angiogenesis combinations and inclusion of Hormonal Angiogenesis combinations as a top drug type 8 8 Angiogenesis, Cytotoxic only in open trials. 4 5 Angiogenesis, Targeted Cytotoxic 8 4 Closed Cytotoxic, Other Cytotoxic, Targeted 4 13 Cytotoxic, Targeted, Other 6 9 Epigenetic Other Targeted

Source: Trialtrove®, October 2016

© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) January 2017 / 11 Immense interest and investment has been devoted Trials with the more popular immunotherapy to the clinical development of immunotherapy drugs are represented by disease in Figure 10. drugs within the past several years. Combination Not shown are eight trials evaluating epigenetic trials with immunotherapy drugs, both approved drugs and peptide vaccines, peptide-pulsed and unapproved for any disease, are being explored cellular therapies or general immunostimulants. as a means to extract benefit for patients that Epigenetic and immunotherapy combination trials did not/will not benefit from single agent therapy occurred most frequently in diseases with approved in diseases in which immunotherapy drugs are immunotherapy drugs (e.g. NSCLC and melanoma) already approved or for patients in diseases that but also in diseases without any approved are historically difficult to treat successfully. Since immunotherapy drugs (e.g. MDS, AML and breast epigenetic and immunotherapy combinations are an cancer). Most widespread was the combination emerging trend in ongoing and planned trials, these of pembrolizumab and an epigenetic drug in 18 combinations were examined more thoroughly. different diseases, followed by nivolumab in nine and ipilimumab and durvalumab in six each.

Figure 10: Epigenetic and Immunotherapy Combination Trials by Disease and Immunotherapy Drug

Unspecified Solid Tumor avelumab Renal atezolizumab Pancreas durvalumab Ovarian ipilimumab Myeloproliferative Neoplasms lirilumab Myelodysplastic Syndrome nivolumab Melanoma pembrolizumab Lymphoma, Non-Hodgkin’s Lymphoma, Hodgkin’s Lung, Small Cell Lung, Non-Small Cell Liver Leukemia, Chronic Myelogenous Leukemia, Acute Myelogenous Head/Neck Gastric Esophageal Colorectal Breast Bladder 0 5 10 15 Trial Count

Source: Trialtrove®, October 2016

12 / January 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) Sponsors/collaborators for ongoing and planned collaborators by trial count included Celgene, NIH/ trials included a wide mix of large pharmaceutical NCI, MD Anderson Cancer Center, Novartis and Merck companies, small pharmaceutical/biotech & Co. Among these top sponsors/collaborators, companies, university-affiliated medical centers all had trials that were recruiting patients (open), and the National Cancer Institute at the National while five had no trials that were ongoing but Institutes of Health. Industry and non-industry not recruiting patients (closed) and seven had no players that were involved with five or more trials planned trials. are shown in Figure 11. The top five sponsors/

Figure 11: Ongoing and Planned Trials by Sponsor/Collaborator*

Trial Count 0 10 20 30 40 50 60 70 80 Celgene NIH/NCI MD Anderson Cancer Center Novartis Merck & Co. Otsuka Pharmaceutical Agios Pharmaceuticals GlaxoSmithKline Acetylon Roche Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Syndax S*BIO HUYA Bioscience Memorial Sloan-Kettering Cancer Center Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute Epizyme Fred Hutchinson Cancer Research Center Mirati Therapeutics Shenzhen Chipscreen Biosciences Weill Medical College of Cornell University 4SC Amgen Bristol-Myers Squibb H. Lee Moffitt Cancer Center and Research Institute Incyte Corporation Johnson & Johnson Servier Planned UC San Francisco Open Virginia Commonwealth University Closed Washington University School of Medicine

*Any collaborative trials were counted once for each sponsor/collaborator. Source: Trialtrove®, October 2016

© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) January 2017 / 13 Epigenetic Drugs and Companies to Watch Drugs acting on newly-recognized epigenetic targets development. Notable among these drugs are have only been in clinical development since 2012 two IDH mutant inhibitors, in clinical development (Figure 8). One method to predict their progress by Agios Pharmaceuticals in collaboration with is to follow their likelihood of approval (LOA) Celgene, that have a higher LOA than other drugs relative to competing drugs during their clinical in their respective phases of clinical development. development. Shown in Table 2 are epigenetic Enasidenib (AG-221) and AG-120 have a 7% and 3% drugs acting on newly-recognized epigenetic targets above average LOA for AML, respectively. that have progressed beyond phase I in clinical

Table 2: Likelihood of Approval for Epigenetic Drugs in Oncology

Sub Disease Indication Current Likelihood Drug Name Lead Company Target Group Name Phase of Approval Acute Isocitrate Celgene Myelogenous 42% (7% enasidenib Hematologic III Dehydrogenase Corporation Leukemia Above Avg.) (IDH) (AML) Acute Myelogenous 10% (Same BET Proteins/ birabresib Merck & Co. Hematologic II Leukemia As Avg.) Bromodomains (AML) 10% (Same BET Proteins/ birabresib Merck & Co. Solid Solid Tumors II As Avg.) Bromodomains Brain Cancer (Malignant 10% (Same BET Proteins/ birabresib Merck & Co. Solid II Glioma; AA As Avg.) Bromodomains and GBM) Acute Isocitrate Agios Myelogenous 13% (3% AG-120 Hematologic I/II Dehydrogenase Pharmaceuticals Leukemia Above Avg.) (IDH) (AML) Isocitrate Celgene 10% (Same enasidenib Solid Solid Tumors I/II Dehydrogenase Corporation As Avg.) (IDH) Bristol-Myers 10% (Same BET Proteins/ BMS-986158 Solid Solid Tumors I/II Squibb As Avg.) Bromodomains 10% (Same BET Proteins/ GSK-525762 GlaxoSmithKline Solid Solid Tumors I/II As Avg.) Bromodomains Hematologic 10% (Same BET Proteins/ INCB-54329 Incyte Corporation Hematologic I/II Cancer As Avg.) Bromodomains Lysine-specific 10% (Same INCB-59872 Incyte Corporation Solid Solid Tumors I/II demethylase-1 As Avg.) (LSD1)/KDM1A

Source: Biomedtracker®, October 2016

14 / January 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) Companies that are pursuing clinical development deal activity include companies of various sizes of epigenetic drugs with newly-recognized targets and those with approved or just pipeline epigenetic are part of an upswing in interest and investment in drugs. These include Epigenomics, Syndax, Roche, this area. Evidence of this upswing is the escalating Onxeo/TopoTarget, MDxHealth, Mirati Therapeutics, number of deals (acquisitions, alliances and Celgene, GlaxoSmithKline, Epizyme and Merck & Co. financing) as well as the potential deal value from (data not shown). 2000-2016 (Figure 12). The top ten companies in

Figure 12: Epigenetic Deal Activity and Potential Value

25 3000 Acquisition

Alliance 2500 20 Financing 2000 15 Potential Deal Value ($M) 1500 10 1000

Trial Count (Normalized) Count Trial 5 500

0 0

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

Source: Strategic Transactions®, October 2016

Conclusions Investment and interest in epigenetic drugs has clinically evaluated in both solid and hematological dramatically increased since 2000, but only in malignancies, especially in AML, NHL, MDS, NSCLC the past several years has clinical development and breast cancer. Emerging trends in ongoing and begun for drugs of newly-recognized epigenetic planned trials include the use of pharmacogenomic targets. Overall, only seven epigenetic drugs have biomarkers to preselect and stratify patients, been approved in oncology, and the vast majority the prevalence of combinations, especially with of clinical development is still considered early to immunotherapy drugs and the wide mix of mid-stage. Clinical trials have been conducted all sponsors/collaborators that are pursuing clinical geographic regions, but 70% of these trials occurred development. in North America. Epigenetic drugs are being

© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.) January 2017 / 15 [email protected]

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