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 held in Palm Beach, FL May 7-9

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<ul><li> 1. BiomarkerstoOptimizeDrug Development in Hematology OncologyDevelopmentinHematologyOncology Steven M Fruchtman MDStevenMFruchtman,MD CMOSpectrumandSyndaxPharmaceuticals (Formerly)( y) AssociateProfessorofMedicine MountSinaiMedicalCenter;NewYork l i iEvolutionSummit May8,2014 </li></ul><p> 2. Dual Epigenetic TherapyDualEpigeneticTherapy LungCancer 3rd /4th LineNSCLC:Azacitidine+entinostatNCI 2 3. Oncogenic Mechanisms DNA GENETIC Chromatin EPIGENETIC DNA M i / l i Replication errors O / l d h i Enzymemodificationerrors Mutations/translocations Open/closedchromatin DNAsequence altered DNAsequence notaltered Altered DNA/mRNA/proteins Altered mRNA/proteins Transformedcells Oncogenesis Canbecausedby: Modificationstohistone proteins ModificationsofDNA Thecontentsofthisslideareconfidentialandforinternaltrainingpurposesonly.Notfordistribution. 3 methylation 4. Definitions TERM DEFINITIONTERM DEFINITION 1. Biologicalmarker Acharacteristic thatis objectivelymeasuredand evaluatedasan indicatorofnormalbiologicor pathogenicprocessesor pharmacologicresponsetoan intervention 2. Clinicalendpoint Acharacteristicorvariablethatreflects onafunctionorsurvival 3 Surrogate endpoint A biomarker intended to substitute for a3. Surrogateendpoint Abiomarkerintendedtosubstitutefora clinicalendpoint.Aninvestigatoruses epidemiological,therapeutic,pathophysiologic orotherscientificevidencetoselecta surrogateendpointthatisexpectedtopredict clinicalbenefitorharm 4 U f l bi k I f i k/b fi i h h i4. Usefulbiomarker Informsrisk/benefitratiowhenthereisa decisiontobemade.Doessoinabetter/ faster/cheaperwaythanexistingapproaches. Generallyapplicable:sampleandtechnologymustbeavailableandaccessible. 5. BIOMARKERS inHematology/Oncology ( l l )(partiallist) Biomarker INDICATION BCR/ABLCML ER/PR/HER2BreastCancer /ALK PTCL/Lung EGFR Lung JAK2/CALR MPNJAK2/CALR MPN BRAF Melanoma KRAS CRC HDACi ?? 6. HDAC Inhibitor Classes ClassIIHDACs ClassIHDACs S O S d NONHISTONE proteinslocatedin h l ( HISTONESand TRANSCRIPTION FACTORSlocated in the nucleus HDAC1 HDAC2 HDAC3 HDAC4 thecytoplasm(e.g. HDAC6) inthenucleus 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 7. 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 tubulin HSP90HIF1 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 8. Mechanism of ActionMechanismofAction 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. 9. HDACi inClinicalDevelopment Name Company DevStatus Formulation LeadIndication(s) Structure/Class vorinostat Merck Launched Oral/IV CTCL;BCellLymphomas Hydroxamic Acid/Pan romidepsin Gloucester NDAfiled IV PTCL;CTCL CyclicPeptide/Pan panobinostat NovartisAG PhaseII Oral/IV CTCL;CML;HL HydroxamicAcid/Pan belinostat TopoTarget UKLtd PhaseII IV/Oral PTCL Hydroxamic Acid/Pan entinostat Syndax PhaseII Oral Breast,NSCLC,HL Benzamide /Selective givinostat ItalfarmacoSpA PhaseII Oral HL HydroxamicAcid/Pan PCI24781 Pharmacyclics PhaseII Oral Sarcoma/NHL HydroxamicAcid/Pan CS 055 Huya / Chipscreen Phase I Oral CTCL; NHL Benzamide / SelectiveCS055 Huya /Chipscreen PhaseI Oral CTCL;NHL Benzamide/Selective 4SC201 4SC PhaseI Oral TBD HydroxamicAcid/Pan CHR2845 Chroma PhaseI Oral TBD ProDrugHydroxamicAcid/Pan JNJ26481585 J&amp;J PhaseI Oral TBD HydroxamicAcid/Pan SB939 S*BIOPteLtd PhaseI Oral TBD Hydroxamic Acid/Pan 10. 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. 11. 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. 12. BreakthroughDesignatedOncology Drug Company Stage Indication Mechanism Ofatumumab Genmab/GSK Ph 3/ d Chroniclymphocyticleukemia AntiCD20 Drugs approved Ibrutinib Pharmacyclics / J&amp;J Ph3 1. Chroniclymphocyticleukemia, 2. relapsedorrefractoryMantlecelllymphoma(MCL) 3. Waldenstrom's macroglobulinemia (WM). BTKinhibitor Obinutuzumab Roche Ph 3 Chronic lymphocytic leukemia AntiCD20Obinutuzumab Roche Ph3 Chroniclymphocyticleukemia Anti CD20 Palbociclib Pfizer Ph2/3 MetastaticER+breastcancer CDK4/6 inhibitor Volasertib Boerhinger Ingelheim Ph2/3 AML PLKinhibitor Ingelheim Entinostat Syndax Ph2/3 MetastaticER+breastcancer HDACinhibitor LDK378 Novartis Ph2 ALK+NSCLC ALK inhibitor Al ti ib R h Ph 2 ALK NSCLC ALK i hibitAlectinib Roche Ph2 ALK+NSCLC ALKinhibitor Lambrolizumab Merck Ph1/2 Advanced melanoma AntiPD1 Daratumumab Genmab/J&amp;J Ph1/2 Multiplemyeloma AntiCD38 SyndaxPharmaceuticals Confidential 13. 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. 14 15. 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 (&gt;$200k per patient per year ) Kalydeco for CF (&gt;$200k per patient per year ) Elelyso for Gauchers (&gt;$200k per patient per year ) Juxtapid for homozygous familial hypercholesterolemia (&gt;$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. 16. 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 H2AX 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 17. 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 18. Breast Cancer 19. Metastatic Breast Cancer Better Options Needed In2012itisestimatedthattherewillbe: 1.3millionwomendiagnosedworldwide 465,000deathsworldwide BreastCancerSubsetsby M l l Bi k Nogaininoverallsurvival inER+metastaticdiseasein20years MolecularBiomarkers ER / PgR TripleNegativeHer-2 Positive ~70-77% (ER,PR andHer2) ~15% Positive ~25-30% NeartermopportunityinER+hormone SyndaxPharmaceuticals Confidential refractorybreastcancer overall programtargetsallsubsets 20. 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 HER2 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 pHER2 1.0 3.2 0.8 0.9 pcRaf 500 1,000 Switch to exemestane / add entinostat Continue letrozole / add entinostat MeanTumorV ER 1.0 0.1 0.9 0.4 Proteinexpression levelsfromtumors Fromxenograft AI 00 Switch to exemestane / add entinostat Weeks resistantmodel, Sabnis etal.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) SyndaxPharmaceuticals Confidential 21. Entinostat Restores ER Expression Entinostat + Letrozole Effective in vivo in ER PR HER2 Tumors Entinostat Induces Expression of ER and Aromatase in ER Tumors in vivo Entinostat + Aromatase Inhibitor Effective in vivo in ER- model Control Entinostat (E) 2.5mg/kg/day po* Letrozole (L) 10ug/day sc* in vivo in ER-, PR-, HER2- Tumorsand Aromatase in ER- Tumors in vivo Entinostat + Letrozole* *Androstenedione added to treatment groups at 100ug/day sc Entinostat + Letrozole Effective in vivo in ER-/PR-/HER2- Tumors Sabnis et al 2008 ENDO Overview Presentation5/14/2014 2009. Syndax. All rights reserved.21 Entinostat + Letrozole Effective in vivo in ER-/PR-/HER2- Tumors 22. 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 SyndaxPharmaceuticals Confidential 23. 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%) SyndaxPharmaceuticals Confidential 24. Positive Phase 2 POC: PFS and OS ENCORE 301 EE: median PFS 4 3 months PFS Intenttotreatpopulation OS Intenttotreatpopulation EE:medianPFS4.3months EP:medianPFS2.3months Hazardratio0.73(95%CI:0.50,1.07) P=0.055(1sided) EE:medianOS28.1months EP:medianOS19.8months HazardRatio0.59(95%CI:0.36,0.97) P=0.04(2sided);P=0.02(1sided) Yardleyetal.JCO SyndaxPharmaceuticals Confidential 25. Consistent PFS Benefit Across All Subsets ENCORE 301 1 AI iti ( i d i t ) d fi d CR PR SD &gt; 6 th d i t t t ith i (l t) AI f ABC SyndaxPharmaceuticals Confidential 1 AIsensitive(acquiredresistance)definedasCR,PRorSD&gt;6monthsduringtreatmentwithprior(last)AIforABC. Allotherpatients,includingallthosewhoreceivedtheAIasadjuvanttherapy,definedasAIresistant(primaryresistance). Feb12datacut 26. Consistent Survival Benefit Across All Subsets ENCORE 301 1 AI iti ( i d i t ) d fi d CR PR SD &gt; 6 th d i t t t ith i (l t) AI f ABC Feb12datacut 1 AIsensitive(acquiredresistance)definedasCR,PRorSD&gt;6monthsduringtreatmentwithprior(last)AIforABC. Allotherpatients,includingallthosewhoreceivedtheAIasadjuvanttherapy,definedasAIresistant(primaryresistance). SyndaxPharmaceuticals Confidential 27. Post Study Treatment Well Balanced ENCORE 301 FirstSubsequentTherapy AllSubsequentTherapies 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% *Patientsmaybecountedundermorethanonecategory 81%ofEEpatientsand85%ofEPpatientsconfirmedtohavereceivedpoststudytreatment SyndaxPharmaceuticals Confidential 28. Favorable Si...</p>

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