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The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman
 

The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

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The Importance of Biomarkers in Hematology/Oncology Drug Development - Presentation by Steven Fruchtman, Former Chief Medical Officer, Syndax Pharmaceuticals, at the marcus evans Evolution Summit 2014 ...

The Importance of Biomarkers in Hematology/Oncology Drug Development - Presentation by Steven Fruchtman, Former Chief Medical Officer, Syndax Pharmaceuticals, at the marcus evans Evolution Summit 2014 held in Palm Beach, FL May 7-9

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    The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman Presentation Transcript

    • Biomarkers to Optimize Drug  Development in Hematology OncologyDevelopment in Hematology Oncology Steven M Fruchtman MDSteven M Fruchtman, MD CMO Spectrum and Syndax Pharmaceuticals  (Formerly)( y) Associate Professor of Medicine Mount Sinai Medical Center; New York l i iEvolution Summit  May 8, 2014
    • Dual Epigenetic TherapyDual Epigenetic Therapy Lung Cancer 3rd / 4th Line NSCLC: Azacitidine + entinostatNCI 2
    • Oncogenic Mechanisms DNA GENETIC Chromatin EPIGENETIC DNA M i / l i Replication errors O / l d h i Enzyme modification errors Mutations/translocations Open/closed chromatin DNA sequence  altered DNA sequence not altered Altered  DNA/mRNA/proteins Altered  mRNA/proteins Transformed cells Oncogenesis Can be caused by: • Modifications to histone proteins • Modifications of DNA  The contents of this slide are confidential and for internal training purposes only.   Not for distribution. 3 methylation
    • Definitions TERM DEFINITIONTERM DEFINITION 1. Biological marker A characteristic that is  objectively measured and  evaluated  as an  indicator of normal biologic or  pathogenic processes or  pharmacologic response to an  intervention  2. Clinical endpoint A characteristic or variable that reflects  on a function or survival 3 Surrogate endpoint A biomarker intended to substitute for a3. Surrogate endpoint A biomarker intended to substitute for a  clinical endpoint. An investigator uses  epidemiological, therapeutic, pathophysiologic  or other scientific evidence to select a  surrogate endpoint that is expected to predict  clinical benefit or harm 4 U f l bi k I f i k/b fi i h h i4. Useful biomarker Informs risk/benefit ratio when there is a  decision to be made. Does so in a better/ faster/cheaper way than existing approaches. Generally applicable: sample and technology must be available and accessible.
    • BIOMARKERS in Hematology/Oncology ( l l )(partial list) Biomarker INDICATION BCR/ABL                                             CML ER/PR/HER2                                       Breast Cancer /ALK PTCL/Lung EGFR Lung JAK2/CALR MPNJAK2/CALR MPN BRAF   Melanoma KRAS CRC HDACi ??
    • HDAC Inhibitor Classes Class II HDAC’s Class I HDAC’s S O S d NON‐HISTONE  proteins located in  h l ( HISTONES and TRANSCRIPTION FACTORS located in the nucleus HDAC1 HDAC2 HDAC3 HDAC4 the cytoplasm (e.g.  HDAC6) in the nucleus HDAC3 HDAC8 HDAC5 HDAC7 HDAC6 HDAC7HDAC7 HDAC9 HDAC10 HDAC7 The contents of this slide are confidential and for internal training purposes only. Not for distribution. 6
    • Pan-HDAC Inhibition HDAC depicts individual deacetylases, e.g. HDAC1, HDAC4, HDAC6 Proteins d l d b HDAC6 HDAC HDAC HDAC HDAC HDAC modulated by DACs Histone α‐tubulin HSP90HIF‐1α p53 Tumor suppressor gene activity Loss of tumor suppressor function Microtubule depolymerization/ aggresome formation VEGF OncoproteinsDownstream effects p53 Cell-cycle arrest Cell motility and Invasion Cell proliferation and survival Tumor effects The contents of this slide are confidential and for internal training purposes only. Not for distribution. 7 Apoptosis Angiogenesis
    • Mechanism of ActionMechanism of Action Cell transformation from normal to cancerous requires shutdown of tumor suppressor genes. Belinostat restores aberrant cellular control inBelinostat restores aberrant cellular control in tumour cells by reactivation of tumor suppressor genes.
    • HDACi in Clinical Development Name Company Dev Status Formulation Lead Indication(s) Structure / Class vorinostat  Merck Launched Oral / IV CTCL; B Cell Lymphomas Hydroxamic Acid / Pan romidepsin Gloucester  NDA filed  IV PTCL; CTCL Cyclic Peptide / Pan panobinostat  Novartis AG Phase II Oral / IV CTCL; CML; HL Hydroxamic Acid / Pan belinostat  TopoTarget UK Ltd Phase II IV / Oral PTCL Hydroxamic Acid / Pan entinostat Syndax Phase II  Oral Breast, NSCLC, HL Benzamide / Selective givinostat Italfarmaco SpA Phase II  Oral HL Hydroxamic Acid / Pan PCI‐24781 Pharmacyclics Phase II  Oral Sarcoma/NHL Hydroxamic Acid / Pan CS 055 Huya / Chipscreen Phase I Oral CTCL; NHL Benzamide / SelectiveCS‐055 Huya / Chipscreen Phase I  Oral CTCL; NHL Benzamide / Selective 4SC‐201 4SC Phase I  Oral TBD Hydroxamic Acid / Pan CHR‐2845 Chroma  Phase I  Oral TBD Pro‐Drug Hydroxamic Acid / Pan JNJ‐26481585 J & J Phase I  Oral TBD Hydroxamic Acid / Pan SB‐939 S*BIO Pte Ltd Phase I Oral TBD Hydroxamic Acid / Pan
    • Accelerating the Approval Process • Fast track is the process to get important new drugs to the patient earlier by facilitating the development and expediting the review of cce e at g t e pp o a ocess earlier by facilitating the development, and expediting the review of drugs to treat serious diseases and fill an unmet medical need. • Accelerated Approval allows earlier approval of drugs to treatAccelerated Approval allows earlier approval of drugs to treat serious diseases that fill an unmet medical need based on a surrogate endpoint provided that post marketing clinical trials verify the anticipated clinical benefit. • Priority Review is given to drugs offering major advances in t t t id t t t h d t th i ttreatment, or provide a treatment where no adequate therapy exists with the goal for completing FDA Review in 6 months.
    • Breakthrough Therapyea t oug e apy • A novel category of “breakthrough drugs” was established by the FDA as part of legislation that became law in July 2012of legislation that became law in July, 2012. • Companies can request the agency designate their experimental treatments for life threatening diseases as breakthrough therapies, which affords them advice and guidance from the FDA staff to optimize development. – Requests must identify the indication under study, provide evidence that the drug is intended, alone or in combination, to treat a serious or life-threatening disease or condition. – Preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development, are required. • As of Dec 10 2012, the FDA received 7 breakthrough requests; 2 were granted,, g q ; g , 1 denied and 4 are pending.
    • Breakthrough Designated Oncology  Drug Company Stage Indication Mechanism Ofatumumab Genmab/GSK Ph 3 /  d Chronic lymphocytic leukemia  Anti‐CD20 Drugs approved Ibrutinib Pharmacyclics /  J&J Ph 3 1. Chronic lymphocytic leukemia , 2. relapsed or refractory Mantle cell lymphoma (MCL) 3. Waldenstrom's macroglobulinemia (WM).  BTK inhibitor Obinutuzumab Roche Ph 3 Chronic lymphocytic leukemia Anti‐CD20Obinutuzumab Roche Ph 3 Chronic lymphocytic leukemia Anti CD20 Palbociclib Pfizer Ph 2/3 Metastatic ER+ breast cancer CDK4/6  inhibitor Volasertib Boerhinger Ingelheim Ph 2/3 AML PLK inhibitor Ingelheim Entinostat Syndax Ph 2/3 Metastatic ER+ breast cancer HDAC inhibitor LDK378 Novartis Ph 2 ALK+ NSCLC ALK inhibitor Al ti ib R h Ph 2 ALK NSCLC ALK i hibitAlectinib Roche Ph 2 ALK+ NSCLC ALK inhibitor Lambrolizumab Merck Ph 1/2 Advanced melanoma Anti‐PD‐1 Daratumumab Genmab/J&J Ph 1/2 Multiple myeloma Anti‐CD38 Syndax Pharmaceuticals ‐ Confidential
    • Cost of Drug DevelopmentCost o ug e e op e t • Over the past generation, the economics burden of drug development has grown substantially. • It is estimated that the costs of developing an approved drug has i d 10 f ld j i f $199 illi t $1 9 billionincreased 10-fold, jumping from $199 million to $1.9 billion since the 1970s!!!! • The Office of Health Economics identified 4 key factors:The Office of Health Economics identified 4 key factors: 1. soaring out of pocket research costs 2. a success rate cut in half 3. a vastly longer time spent in the clinic 4. an increased cost of capital as regulatory demands grew alongside scientific complexity.
    • 14
    • Factors Contributing to Rising Costsacto s Co t but g to s g Costs • The average time to acquire the data needed for an approval jumped from 6 to 13 513.5 years. • High priced drugs listed in 2012 were: – Gattex for short bowel syndrome (>$200k per patient per year ) – Kalydeco for CF (>$200k per patient per year ) – Elelyso for Gaucher’s (>$200k per patient per year ) – Juxtapid for homozygous familial hypercholesterolemia (>$200k per patient per year ) – Soliris for PNH ($440,000/year.) • In 2012, 10% of the approved drugs by the FDA cost more than a house, with a 44% increase in the number of such high priced rare disease drugs on theg p g market. • The cost of Zaltrap ($9600/week) decreased 50% after an article in NYT by MSKCC physicians stated the drug would not be used due to cost.
    • Biomarkers/Correlates/Pharmacodynamics Lysine acetylation • Histone H3 and H4 lysine acetylation may be viewed as PD endpoint but has not correlated with efficacywith efficacy • Most analysis done in PBMCs so may not reflect tumor activity/concentration • Unclear how lysine acetylation relates to various MOA, i.e. apoptosis requires higher doses than histone hyperacetylation • Acetylation of specific proteins may provide insight into clinical responses i e HSP90 tubulin• Acetylation of specific proteins may provide insight into clinical responses, i.e. HSP90, tubulin, p53, etc Cell cycle / DNA damage markers • p21 induction a consistent marker of HDACi activity • γH2AX induction as marker of DNA damage effects (or attenuation of DNA repair) HDAC expression • Histone and tubulin acetylation reduced in DCIS, IDC vs normal epithelium (Suzuki et al 2009 Clin Canc Res)Clin Canc Res) • Class 1 HDAC protein expression may be linked to tumor progression (reviewed Weichert Canc Lett 2009) Question still remains for whether HDAC expression levels or its inhibition correlate with response to HDACi Overview Presentation5/14/2014 © 2009. Syndax. All rights reserved.16 correlate with response to HDACi
    • HDACi in Breast Cancer Clinical Trials Vorinostat Entinostat Single Agent P i l Combination • Pre-surgical • DCIS • Advanced breast cancer Combination • w/ chemotherapy Panobinostat • w/ endocrine therapy • w/ chemotherapy • w/ endocrine therapy • w/ TKIs • w/ monoclonal Abs Single Agent • Advanced breast cancer (+/- HER2) Combination • w/ monoclonal Abs 15 Trials Ongoing in Breast Cancer Overview Presentation5/14/2014 © 2009. Syndax. All rights reserved.17 w/ monoclonal Abs Includes only currently enrolling trials on clinical trials.gov
    • Breast Cancer
    • Metastatic Breast Cancer – Better Options Needed In 2012 it is estimated that there will be:  1.3 million women diagnosed worldwide 465,000 deaths worldwide Breast Cancer Subsets by M l l Bi k No gain in overall survival  in ER+ metastatic disease in 20 years Molecular Biomarkers ER / PgR Triple NegativeHer-2 Positive ~70-77% (ER‐, PR‐ and Her‐2‐) ~15% Positive ~25-30% Near‐term opportunity in ER+ hormone‐ Syndax Pharmaceuticals ‐ Confidential refractory breast cancer ‐ overall  program targets all subsets
    • Entinostat Overcomes Hormone Resistance Entinostat restores estrogen receptor sensitivity in vivo1, 2 2,000 Switch to exemestane 1 0 5 1 0 8 1 0 HER‐2 1 000 1,500 Volume(mm3) Continue letrozole Switch to entinostatControl 1.0 5.1 0.8 1.0 1.0 3.2 0.3 0.7 p‐HER‐2 1.0 3.2 0.8 0.9 p‐c‐Raf 500 1,000 Switch to exemestane / add entinostat Continue letrozole / add entinostat MeanTumorV ER 1.0 0.1 0.9 0.4 Protein expression   levels from tumors  From xenograft AI   00 Switch to exemestane / add entinostat Weeks resistant model,   Sabnis et al.1 1Sabnis et al Mol Canc Therap 2013 (accepted) Humanized mouse xenograft ER+ breast cancer model designed to study aromatase inhibitors (N=10 per group) Syndax Pharmaceuticals ‐ Confidential
    • Entinostat Restores ERα Expression Entinostat + Letrozole Effective in vivo in ER PR HER2 Tumors Entinostat Induces Expression of ERα and Aromatase in ER Tumors in vivo Entinostat + Aromatase Inhibitor Effective in vivo in ERα- model Control Entinostat (E) 2.5mg/kg/day po* Letrozole (L) 10ug/day sc* in vivo in ERα-, PR-, HER2- Tumorsand Aromatase in ERα- Tumors in vivo Entinostat + Letrozole* *Androstenedione added to treatment groups at 100ug/day sc Entinostat + Letrozole Effective in vivo in ERα-/PR-/HER2- Tumors Sabnis et al 2008 ENDO Overview Presentation5/14/2014 © 2009. Syndax. All rights reserved.21 Entinostat + Letrozole Effective in vivo in ERα-/PR-/HER2- Tumors
    • ENCORE 301 – Rigorous Ph 2 Study ENCORE  301 • Randomized, double-blind, placebo-controlled • Multi-center international study to ensure Ph 3-like populationMulti center, international study to ensure Ph 3 like population • Endpoints include: Progression-Free Survival, Overall Survival • Biomarker in subset: Protein lysine acetylation in blood cells Exemestane + entinostat (EE) PO 5 mg weeklyR O 5 g ee y N = 64A N D O M Post-menopausal women with metastatic or locally advanced ER+ Exemestane + placebo (EP) N = 66 M I Z E hormone refractory breast cancer Syndax Pharmaceuticals ‐ Confidential
    • ENCORE 301 Baseline Patient Characteristics EE N=64 EP N=66 Median Age (range) 63 (37 – 85) 62 (37 – 88) ECOG Performance Status , n (%) 0 1 40 (63%) 24 (38%) 50 (76%) 16 (24%) S i f AI P i (%)Setting of AI Progression, n (%) Adjuvant Advanced/ Metastatic 10 (16%) 54 (84%) 9 (14%) 57 (86%) Sites of Metastases, n (%) Bone 49 (77%) 47 (71%)Bone Bone Only Disease Lymph nodes Visceral Involvement 49 (77%) 13 (20%) 30 (47%) 34 (53%) 47 (71%) 11 (17%) 32 (48%) 44 (67%) Measurable Disease, n (%) 52 (81%) 54 (82%), ( ) ( ) ( ) Prior Chemotherapy, n (%) Adjuvant Disease Metastatic Disease 22 (34%) 22 (34%) 28 (42%) 21 (32%) Geographic Region, n (%) h iNorth America Central Europe/Russia 42 ( 66%) 22 ( 34%) 43 ( 65%) 23 ( 35%) Syndax Pharmaceuticals ‐ Confidential
    • Positive Phase 2 POC: PFS and OS ENCORE  301 EE: median PFS 4 3 months PFS ‐ Intent‐to‐treat population OS ‐ Intent‐to‐treat population EE: median PFS 4.3 months EP: median PFS 2.3 months Hazard ratio 0.73 (95% CI: 0.50, 1.07) P=0.055 (1‐sided) EE:  median OS 28.1 months EP:  median OS 19.8 months Hazard Ratio 0.59 (95% CI: 0.36, 0.97) P=0.04 (2‐sided) ; P=0.02 (1‐sided) Yardley et al. JCO Syndax Pharmaceuticals ‐ Confidential
    • Consistent PFS Benefit Across All Subsets ENCORE  301 1 AI iti ( i d i t ) d fi d CR PR SD > 6 th d i t t t ith i (l t) AI f ABC Syndax Pharmaceuticals ‐ Confidential 1 AI‐sensitive (acquired resistance) defined as CR, PR or SD > 6 months during treatment with prior (last) AI for ABC.  All other patients, including all those who received the AI as adjuvant therapy, defined as AI‐resistant (primary resistance).  Feb ‘12  data cut
    • Consistent Survival Benefit Across All Subsets ENCORE  301 1 AI iti ( i d i t ) d fi d CR PR SD > 6 th d i t t t ith i (l t) AI f ABC Feb ‘12  data cut 1 AI‐sensitive (acquired resistance) defined as CR, PR or SD > 6 months during treatment with prior (last) AI for ABC.  All other patients, including all those who received the AI as adjuvant therapy, defined as AI‐resistant (primary resistance).  Syndax Pharmaceuticals ‐ Confidential
    • Post Study Treatment Well Balanced ENCORE  301 First Subsequent Therapy All Subsequent Therapies Post Study Treatment Therapy EE EP Chemotherapy 48% 43% Post Study Treatment Therapy EE EP Chemotherapy 66% 71%py Hormone therapy 37% 35% Bisphosphonates 2% 0% py Hormone therapy 47% 45% Bisphosphonates 5% 2% Radiation 6% 5% Surgery 0% 2% Other 0% 6% Radiation 16% 8% Surgery 0% 2% Other 6% 11%Other 0% 6% Other 6% 11% *Patients may be counted under more than one category 81% of EE patients and 85% of EP patients confirmed to have received post study treatment Syndax Pharmaceuticals ‐ Confidential
    • Favorable Side Effect Profile ENCORE  301 Adverse Event1 EE (N=63) EP (N=66) Any G3 G4 Any G3 G4Any G3 G4 Any G3 G4 Fatigue 29 ( 46%) 7  11%  1   2%  17 ( 26%) 2   3%  ‐ Nausea 25 ( 40%) 3   5%  ‐ 10 ( 15%) 1   2%  ‐ Neutropenia2, 3 16 ( 25%) 7  11%  1 2%  0 (  0%) ‐ ‐ Oedema peripheral 13 ( 21%) ‐ ‐ 3 (  5%) ‐ ‐ Vomiting 13 ( 21%)  3   5%  ‐ 3 (  5%) ‐ ‐ Anemia2 12 ( 19%) 1   2%  ‐ 8 ( 12%) 1   2%  1   2%  Dyspnoea 12 ( 19%) 2   3%  ‐ 7 ( 11%) ‐ ‐ Weight decreased 11 ( 17%) ‐ ‐ 12 ( 18%) ‐ ‐ Thrombocytopenia2 11 ( 17%) ‐ ‐ 4 (  6%) ‐ 1   2%  Diarrhoea 10 ( 16%) ‐ ‐ 8 ( 12%) 1   2%  ‐ Pain 10 ( 16%)  1   2%  ‐ 4 (  6%) 1   2%  ‐ Back pain 9 ( 14%) ‐ ‐ 11 ( 17%) 1   2%  ‐ Arthralgia 7 ( 11%) 1   2%  ‐ 11 ( 17%) ‐ ‐ Constipation 6 ( 10%) ‐ ‐ 10 ( 15%) 1   2%  ‐ 1  Occurring in >15% in either Group ; Safety Population; Treatment‐emergent Adverse Events, regardless of treatment‐attribution.  2 Composed of combined MedDRA preferred terms. 3   None of these 8 grade 3/4 patients experienced febrile neutropenia or associated infections during the time of the neutropenia. 1 patient with  non‐measurable bone‐only disease given a myeloid growth factor for neutrophil support; patient had history of neutropenia & growth factor usage Syndax Pharmaceuticals ‐ Confidential 1° data cut
    • ENCORE 301 Pharmacodynamic Analysis ENCORE  301 HDACi induce hyperacetylation of lysines on histones and a number of other proteins as their mechanism of actionof other proteins as their mechanism of action We hypothesized that HDACi-induced hyperacetylation will be associated with lower risk of disease progression Cycle 1 Exemestane daily Cycle 1 D22 D28D1  Entinostat Entinostat Entinostat Entinostat C1D0 P C1D8 7 d D8 D15 C1D15 7 dC1D0 Pre‐ treatment  baseline C1D2 4‐36hrs  C1D8 ~7 days  after previous  entinostat C1D15 ~7 days  after previous  entinostat after entinostat Syndax Pharmaceuticals ‐ Confidential
    • Patient Enrichment Strategy Identified ENCORE  301 Hyperacetylation associated with prolonged PFS in entinostat treated patients EE HA-: median PFS 2.76 months EE HA+: median PFS 8.55 months 1.00 EE HA+ (n=13) : median PFS 8.5 months EE HA‐ (n=14) : median PFS 2.8 months Kaplan-Meier Estimates of PFS by Acetylation at Day 15 (n=27) Hazard ratio 0.317 (95% CI: 0.127, 0.787) Probability 0.75 Hazard ratio 0.32 (95% CI: 0.13, 0.79) Progression 0.25 0.50 Potential to benefit may be determined by  blood test within 1st two weeks of treatment 8.5 months 2.8 months P 0.00 0 2 4 6 8 10 12 14 16 18 Months Ordentlich AACR‐NCI‐EORTC Molecular Targets 2011 1° data cut Syndax Pharmaceuticals ‐ Confidential
    • Ph 3 Registration Study ECOG 2112ECOG 2112
    • Clinical Development Plan in ER+ MBC • Ph 3 E2112 – to start Q1 2014 – Conducted by ECOG-ACRIN Cancer Research Group (ECOG) and sponsored by the Division of Cancer Treatment and Diagnosis National Cancer Institute (NCI)Treatment and Diagnosis, National Cancer Institute (NCI). – Incorporates FDA input on patient population, statistics, design • Syndax applying for SPA – Randomized, 600 pts in hormone refractory ER+ post- menopausal metastatic breast cancermenopausal metastatic breast cancer – Endpoints: Co-primary PFS and/or OS – 1st data in Q4 2016 – PFS Syndax Pharmaceuticals ‐ Confidential
    • ECOG E2112 – Ph 3 Study Design E2112 A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo  in Patients with Hormone Receptor‐Positive Metastatic Breast Cancer R Exemestane + entinostat 5mg wkly p A N D O M Advanced breast cancer ER+/PR+, HER2- Progression on prior Exemestane + entinostat 5mg wkly  N  ≈ 300 1 Refractory  setting N=600M I Z E non-steroidal AI Exemestane + placebo  N ≈ 300 1 N 600 Co‐1° Endpoints: PFS (in first 360 patients) and/or OS (N=600)  Other 2° Endpoints: ORR, Safety Biomarkers: Protein lysine acetylation; molecular and genomic tumor characterizationBiomarkers: Protein lysine acetylation; molecular and genomic tumor characterization Syndax Pharmaceuticals ‐ Confidential
    • THANK YOUTHANK YOU • Organizers – MarcusevansOrganizers  Marcusevans • Audience i h i i i h i l• Patients who participate in research trials • QUESTIONS???