Verastem, Inc. · NASDAQ:VSTM
Verastem — Investor Day (July 2013)
88 slides from Verastem's investor day presentation, Jul 11, 2013
Slide 1: Research and Development Day
RESEARCH AND DEVELOPMENT DAY JULY 11, 2013 NASDAQ: VSTM Confidential Page
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation and other matters discussed today, or answers that may be given to questions asked, include forward-looking statements about the Company’s strategy, future plans and prospects, including statements regarding the development of the Company’s compounds, inc
Slide 3: Agenda
Agenda • 12:45 Introduction • 1:00 Focal Adhesion Kinase (FAK) and Cancer Stem Cells • 1:20 FAK Program Status: VS-6063 + Paclitaxel in Ovarian Cancer • 1:40 Mesothelioma and the VS-6063 Registration-Directed Trial • 2:30 FAK Portfolio Expansion: VS-6063 into Lung Cancer and VS-4718 into Phase 1 • 2
Slide 4: Today's Speakers
Today’s Speakers José Baselga, M.D., Ph.D. Robert Weinberg, Ph.D. Richard Gralla, M.D. Physician in Chief, Memorial Sloan- Founding Member, Whitehead Albert Einstein College of Medicine Kettering Cancer Center Institute President, NY Lung Cancer Alliance Verastem scientific advisory board Verastem s
Slide 5: Cancer Stem Cells are a Reason for Failure of Current Therapies
Cancer Stem Cells are a Reason for Failure of Current Therapies Current cancer treatments Cancer stem cells resist Cancer stem cells drive often fail to cure chemotherapy disease progression 5-year relative survival rate 5-year relative survival rate 99% 99% 100% 100% 84% 84% (breast cancer) (breast
Slide 6: Verastem is at the Forefront of Cancer Stem Cell Biology
Verastem is at the Forefront of Cancer Stem Cell Biology Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening Gupta, Weinberg, Lander, et al. 2009 The Epithelial-Mesenchymal Transition Generates Cells With Properties of Stem Cells Mani, Weinberg, et al. 2008 Hallm
Slide 7: Targeting Cancer Stem Cells For a Durable Clinical Response
Targeting Cancer Stem Cells For a Durable Clinical Response Current cancer Problem: treatments Initial Tumor Tumor reduction but Recurring Tumor CSCs survive CSC drugs + current cancer treatments Solution: Durable clinical response Initial Tumor Tumor reduction and elimination of CSCs Page 7 Novel D
Slide 8: Platform to Discover Drugs Targeting Cancer Stem Cells
Platform to Discover Drugs Targeting Cancer Stem Cells High-Throughput Screening Candidate Drug Selection In vitro characterization In vivo tumor models Page 8 Novel Drugs Targeting Cancer Stem Cells July 11, 2013
Slide 9: Portfolio of Product Candidates Targeting Cancer Stem Cells
Portfolio of Product Candidates Targeting Cancer Stem Cells PreClin Phase 1 Phase 2 Phase 3 Focal Adhesion Kinase (FAK) VS-6063 Mesothelioma Registration-directed trial Japanese Development Phase 1 Lung (KRASm NSCLC) Phase 2 Planned Ovarian Phase 1/1b in combo with paclitaxel Ongoing VS-4718 Solid T
Slide 10: Upcoming Milestones
Upcoming Milestones Regulatory Clinical Trial Initiations Data H1 2013 H2 2013 2014 FDA Meeting VS-5584 IND VS-4718 Phase 1 EU Meeting VS-6063 US Orphan VS-6063 Phase 1b combo biomarkers VS-6063 Meso trial and activity VS-4718 IND VS-6063 EU Orphan VS-5584 Phase 1 VS-4718 Phase 1b biomarkers VS-4718
Slide 11: Agenda
Agenda • 12:45 Introduction • 1:00 Focal Adhesion Kinase (FAK) and Cancer Stem Cells • 1:20 FAK Program Status: VS-6063 + Paclitaxel in Ovarian Cancer • 1:40 Mesothelioma and the VS-6063 Registration-Directed Trial • 2:30 FAK Portfolio Expansion: VS-6063 into Lung Cancer and VS-4718 into Phase 1 • 2
Slide 12: Robert Weinberg, Ph.D.
Robert Weinberg, Ph.D. Page 12 Novel Drugs Targeting Cancer Stem Cells July 11, 2013
Slide 13: The invasion-metastasis cascade
primary tumor formation. The complexity of the invasion- metastasis cascade rivals that of the earlier steps of primary tumor formation. The invasion-metastasis cascade 13 Page 13 Figure 14.4 The Biology of Cancer (© Garland Science 2007)
Slide 14: Induction of EMT by Snail and Twist
Induction of EMT by Snail and Twist EMT-inducing TFs CD44hi/CD24lo also generates CD44 CD24 cells hi lo (position of stem cells) HMLE HMLE-Snail HMLE-Twist CD44 CD44lo/CD24hi (position of non- stem cells) CD24 Vector Snail Twist S.A.Mani & W. Guo Page 14 14
Slide 15: How does the EMT create cancer stem cells?
Filopodium-like structures contribute to cell-matrix adhesions in 3D nonmetastatic cells metastatic cells few/no FLP abundant FLPs EMT How does the EMT few/no mature abundant mature create cancer stem cells? adhesion adhesion plaque plaques FLPs = filopodium-like minimal FAK potent FAK structures ac
Slide 16: Abundant FLP formation is a common attribute of metastatic cells
Abundant FLP formation is a common attribute of metastatic cells Tsukasa Shibue Page 16
Slide 17: EMT induction elevates FLP-forming ability
EMT EMT induction elevates FLP-forming ability 0.5 3.1 2.8 (average # FLPs/cell) EMT EMT induction in HMLER cells stimulate their FLP-forming and tumor-initiating abilities, which is attributable in part to the elevated b-parvin expression. Page 17 Tsukasa Shibue
Slide 18: EMT promotes metastasis via FLP-dependent FAK activation
EMT promotes metastasis via FLP-dependent FAK activation EMT FAK activation FLP formation assembly of mature (within mature adhesion plaques adhesion plaques) ERK activation proliferation (driven by FAK signaling) macrometastasis EMT FAK signaling serves as a key intermediary in EMT- formation depen
Slide 19: FLP formation empowers initial proliferation of cancer cells
FLP formation empowers initial proliferation of cancer cells proliferation following implantation tumor- Initiating ability EMT The formation of FLPs predicts, and contributes functionally to, the subseqent proliferation of cancer cells both after metastatic dissemination and orthotopic Page 19 Tsuk
Slide 20: FAK Inhibition Preferentially Reduces CSCs in Multiple Assays
FAK Inhibition Preferentially Reduces CSCs in Multiple Assays HMLE: Selective for CSCs Tumorsphere Formation 125 non-CSCs S e c o n d a ry S p h e re s CSCs 100 % Cell Viability 100 ( % o f C o n t r o l) 75 50 50 25 0 0 l M M o 0.01 0.1 1 10 100 tr 1 3 n o VS-4718, M C V S -4 7 1 8 Aldefluor-Pos
Slide 21: Targeting Cancer Stem Cells For a Durable Clinical Response
Targeting Cancer Stem Cells For a Durable Clinical Response Current cancer Problem: treatments Initial Tumor Tumor reduction but Recurring Tumor CSCs survive CSC drugs + current cancer treatments Solution: Durable clinical response Initial Tumor Tumor reduction and elimination of CSCs Page 21 Novel
Slide 22: Combination of CSC Drug & Chemotherapy Reduces Tumor-Initiating Capability
Combination of Cancer Stem Cell Drug & Chemotherapy Reduces Tumor-Initiating Capability • Ovarian cancer cells treated in vitro & allowed to recover for 4 days • 1,000 cells from each treatment arm were implanted into immunodeficient mice No tumors initiated in combination-treatment arm 120 100 % Tu
Slide 23: Agenda
Agenda • 12:45 Introduction • 1:00 Focal Adhesion Kinase (FAK) and Cancer Stem Cells • 1:20 FAK Program Status: VS-6063 + Paclitaxel in Ovarian Cancer • 1:40 Mesothelioma and the VS-6063 Registration-Directed Trial • 2:30 FAK Portfolio Expansion: VS-6063 into Lung Cancer and VS-4718 into Phase 1 • 2
Slide 24: Portfolio of Product Candidates Targeting Cancer Stem Cells
Portfolio of Product Candidates Targeting Cancer Stem Cells PreClin Phase 1 Phase 2 Phase 3 Focal Adhesion Kinase (FAK) VS-6063 Mesothelioma Registration-directed trial Japanese Development Phase 1 Lung (KRASm NSCLC) Phase 2 Planned Ovarian Phase 1/1b in combo with paclitaxel Ongoing VS-4718 Solid T
Slide 25: FAK Program Summary
FAK Program Summary • FAK is a critical regulator of cancer stem cells and disease progression • Strong pre-clinical evidence and initial clinical proof-of-concept for targeting FAK in mesothelioma, ovarian and lung cancer • Two candidates in clinical development with 5 clinical trials ongoing/plann
Slide 26: VS-6063 – First in Class FAK Inhibitor
VS-6063 – First in Class FAK Inhibitor • Oral compound with good safety profile and initial signs of activity in Phase 1 • USAN name: defactinib • Orphan designation in European Union for mesothelioma • Two clinical FAK competitors • Boehringer Ingelheim: Phase 1 • GlaxoSmithKline: Phase 1 VS-6063 p
Slide 27: VS-6063 Phase 1 Study in 46 Patients: Good Safety Profile
VS-6063 Phase 1 Study in 46 Patients with Advanced Solid Tumors: Good Safety Profile and Stable Disease in 43% of Patients >100mg BID Primary Endpoint: Safety and Tolerability Initial Signs of Clinical Activity Grade Stable disease of circa 6 months + 1 2 3 4 Total Adverse Events* NSCLC (425 mg BID;
Slide 28: Clinical Trial Designs for Drugs Targeting Cancer Stem Cells
Clinical Trial Designs for Drugs Targeting Cancer Stem Cells Theoretical Result Concurrent: CSC Drugs + Chemo More Durable Clinical Response Initial Tumor Tumor Reduction & Elimination of CSCs Maintenance: Chemo CSC Drugs More Durable Clinical Response Initial Tumor Tumor Reduction but CSCs are Enri
Slide 29: VS-6063 Concurrently with Weekly Paclitaxel (Phase 1/1b)
VS-6063 Concurrently with Weekly Paclitaxel (Phase 1/1b) • Targeting cancer stem cells concurrently with chemotherapy, to reduce both cancer stem cells and tumor bulk • Initial target population – recurrent ovarian cancer • Signs of clinical activity in the single-agent Phase 1 study • Recurrent tum
Slide 30: VS-6063 and Weekly Paclitaxel can be Combined
VS-6063 and Weekly Paclitaxel can be Combined • Expansion into other indications where paclitaxel is standard of care • Dose escalation portion of study enrollment complete Q2 2013 • Subjects with advanced ovarian cancer and ≤4 prior therapies • No DLTs observed • No exacerbation of paclitaxel AE pr
Slide 31: Ongoing Trial Narrative: Encouraging in-progress Data
Ongoing Trial Narrative: Encouraging in-progress Data • 59 year old white female, diagnosed Jan 2012 with stage 4 serous ovarian cancer Duration Prior Treatment Setting Status (months) Completed course, relapsed Carboplatin, paclitaxel Adjuvant following surgery ~ 7.4 ~3 months later Doxorubicin (Do
Slide 32: VS-6063: Phase 1b Stage of Combination with Weekly Paclitaxel in Ovarian Cancer
VS-6063: Phase 1b Stage of Combination with Weekly Paclitaxel in Ovarian Cancer • VS-6063 400mg BID + weekly paclitaxel • 10-day single agent VS-6063 run-in to measure CSC biomarkers and pFAK • Continue on combination until progression • May continue on VS-6063 alone if experiencing paclitaxel toxic
Slide 33: Agenda
Agenda • 12:45 Introduction • 1:00 Focal Adhesion Kinase (FAK) and Cancer Stem Cells • 1:20 FAK Program Status: VS-6063 + Paclitaxel in Ovarian Cancer • 1:40 Mesothelioma and the VS-6063 Registration-Directed Trial • 2:30 FAK Portfolio Expansion: VS-6063 into Lung Cancer and VS-4718 into Phase 1 • 2
Slide 34: Cancer Stem Cells in Mesothelioma
Cancer Stem Cells in Mesothelioma • CSCs identified in 90% of human mesothelioma patient samples • Standard of care agents increase proportion of mesothelioma CSCs • FAK inhibitors reduce proportion of mesothelioma CSCs H2052 Human Mesothelioma % Change in CSCS from 700 500 Control 300 100 -100 Page
Slide 35: Low Merlin Expression Increases Sensitivity to VS-6063 in Mesothelioma Models
Low Merlin Expression Increases Sensitivity to VS-6063 in Mesothelioma Models Mesothelioma Cell Line Panel 125 M e ro -2 5 H 2452 100 H 226 Merlin High C e ll V ia b ilit y ( % ) M S T O -2 1 1 H 75 H 28 M M 87 50 M e ro -1 4 25 M e ro -4 1 Merlin Low M e ro -8 3 0 0 .0 0 1 0 .0 1 0 .1 1 10 100 V S
Slide 36: Initial Proof of Concept for FAK Inhibitors in Mesothelioma
Initial Proof of Concept for FAK Inhibitors in Mesothelioma: GSK2256098 Phase 1 Study – Recurrent Mesothelioma 30 Biomarker for patient stratification 25 24 weeks 2nd Line Treatment in Recurrent Median Progression Free Survival 20 Mesothelioma 20 18 18 weeks 15 16 11 weeks 14 10 (weeks) 12 10 5 8 6
Slide 37: Jocelyn Farrar Video Presentation
Jocelyn Farrar, DNP, CCRN, ACNP-BC Video Presentation Page 37 Novel Drugs Targeting Cancer Stem Cells July 11, 2013
Slide 38: Richard Gralla, M.D.
Richard Gralla, M.D. Page 38 Novel Drugs Targeting Cancer Stem Cells July 11, 2013
Slide 39: Principle Malignancies Treated by Thoracic Oncologists
Principle Malignancies Treated by Thoracic Oncologists Non-Small Cell Lung Cancer Small Cell Lung Cancer Mesothelioma Thymoma / Thymic Carcinoma
Slide 40: Selected Molecularly Targeted Agents in Thoracic Oncology
SELECTED MOLECULARLY TARGETED AGENTS IN THORACIC ONCOLOGY Number of Patients Potentially Agent Eligible for Agent / Year in the USA NSCLC Erlotinib 10,000 – 12,000 NSCLC Crizotinib 3000 - 4000 Mesothelioma VS-6063 2500 - 3000
Slide 41: Worldwide Incidence of Mesothelioma Continues to Increase
Worldwide Incidence of Mesothelioma Continues to Increase Asbestos Mining, Use & Danger Persists Page 41
Slide 42: Worldwide Incidence of Mesothelioma Continues to Increase
Worldwide Incidence of Mesothelioma Continues to Increase • WHO estimates total worldwide fatalities of 59,000/year – Britain: • Most rapidly increasing cancer in women and 3rd most rapid in men – Japan • New diagnoses almost tripled from 2006 – 2012 (500 – 1278 patients/per year) • Asbestos exposur
Slide 43: Mesothelioma is a Devastating Cancer
Mesothelioma is a Devastating Cancer • Highly aggressive and lethal cancer – Typically diagnosed late-stage (Stages III and IV) – There is no known effective screening method for early detection – 9 to 12 month survival from time of diagnosis in most studies • Tumor encases the lungs leading to pain
Slide 44: Pleural Nodules of Mesothelioma
Pleural Nodules of Mesothelioma Images reprinted with permission. © 2004 NJ Vogelzang, MD. Page 44
Slide 45: Current Therapy for Mesothelioma is Limited
Current Therapy for Mesothelioma is Limited • Surgery for resectable disease, but few patients are cured • First-line standard therapy for mesothelioma is combination pemetrexed + cisplatin – demonstrated 2-3 month overall survival benefit and symptom benefits versus single agent cisplatin • No stan
Slide 46: Pemetrexed + Cisplatin Versus Cisplatin
PEMETREXED + CISPLATIN versus CISPLATIN Phase III Study Design: Target of 6 Cycles Pemetrexed + Cisplatin R A 500 mg/m2 75 mg/m2 N D O M Versus I Z E Cisplatin 75 mg/m2 – All agents given on Day 1 every 3 weeks – KPS 70% – Unresectable MPM; no prior chemotherapy Page 46 Vogelzang et al, J Clin Onc
Slide 47: Survival and Response
PEMETREXED + CISPLATIN versus CISPLATIN Survival and Response 100 Pemetrexed + Cisplatin (n=226) Cisplatin (n=222) pem/cis cis 75 Median Survival (months) 12.1 9.3 Hazard Ratio 0.77 % Alive - Log-Rank P-value 0.020 Response Rate 41.3 16.7 50 Fisher’s Exact P-value <0.001 25 0 0 5 10 15 20 25 30 Meth
Slide 48: Thoracic Symptoms: 8-week Results
PEMETREXED + CISPLATIN versus CISPLATIN Thoracic Symptoms: 18-week Results 80 Pem + cis Cisplatin p<0.001 p<0.001 p<0.001 60 % Target AUC 40 20 0 Pain Dyspnea Cough Page 48 Reference: Vogelzang et al JCO 2003 100% = best score
Slide 49: Lung Function by Treatment
Lung Function by Treatment 2.70 P = .006 P/C C P = .034 2.65 NS Vital Capacity 2.60 NS (L) 2.55 2.50 2.45 2.40 0 2 4 6 Cycle Hollen P, Gralla RJ et al. Cancer 2004;101:587–95. Page 49
Slide 50: Lung Cancer Symptom Scale: Dyspnea
Lung Cancer Symptom Scale: Dyspnea P/C P = .004 40 C P = .476 P = .344 Baseline (mm) Change From 35 NS 30 25 0 2 4 6 Cycle Hollen P, Gralla RJ et al. Cancer 2004;101:587–95. Page 50
Slide 51: Lung Cancer Symptom Scale: Pain
Lung Cancer Symptom Scale: Pain 35 P/C C P = .017 Baseline (mm) Change From P = .064 P = .017 30 NS 25 20 0 2 4 6 Cycle Hollen P, Gralla RJ et al. Cancer 2004;101:587–95. Page 51
Slide 52: General Symptoms: 8-week Results
PEMETREXED + CISPLATIN versus CISPLATIN General Symptoms: 18-week Results 80 Pem + cis Cisplatin % Target AUC 60 p=0.010 p=0.017 p=0.058 40 20 0 Fatigue Anorexia Activity level Page 52 Reference: Vogelzang et al JCO 2003 100% = best score
Slide 53: Global Assessment: 8-week Results
PEMETREXED + CISPLATIN versus CISPLATIN Global Assessment: 18-week Results Pem + cis 80 Cisplatin % Target AUC 60 p=0.012 p=0.009 40 20 0 Global QoL Symptom distress Reference: Vogelzang et al JCO 2003 100% = best score Page 53
Slide 54: Patient-Determined Pain and Global Quality-of-Life Scores by Response
Patient-Determined Pain and Global Quality-of-Life (QoL) Scores by Response (model-based means— All Patients) Improvement Improvement Pain Global QoL Change From Baseline Change From Baseline (mm) 10 15 8 6 4 10 (mm) 2 0 5 -2 -4 -6 0 CR/PR SD (n = 171) PD (n = 128) -8 (n = 129) CR/PR (n = 129) SD (n
Slide 55: Endpoints and treatment: Relationships and role of PROs
Endpoints and treatment: Relationships and role of patient reported outcomes (“PROs”) Malignancy Survival Quality of life Tumor response & side effects Treatment Page 55
Slide 56: Clinical Trial Designs for Drugs Targeting Cancer Stem Cells
Clinical Trial Designs for Drugs Targeting Cancer Stem Cells Theoretical Result Concurrent: CSC Drugs + Chemo More Durable Clinical Response Initial Tumor Tumor Reduction & Elimination of CSCs Maintenance: Chemo CSC Drugs More Durable Clinical Response Initial Tumor Tumor Reduction but CSCs are Enri
Slide 57: Registration-Directed Study in Malignant Pleural Mesothelioma
Registration-Directed Study in Malignant Pleural Mesothelioma Sample Size for •350 – 400 PFS •Randomized, double blind, placebo Design controlled, no cross-over allowed •Central review of CT scans •Patients with good performance status, evaluable lesions and disease control Population immediately af
Slide 58: Registration-Directed Study Design in Malignant Pleural Mesothelioma
Registration-Directed Study Design in Malignant Pleural Mesothelioma Key Eligibility Criteria • Performance status ≥70% Karnofsky Performance Criteria 1:1 Randomization • Measurable or Evaluable Disease CT scan at treatment start and every 6 weeks RECIST v1.1 • Tumor material for Merlin Status • Ade
Slide 59: Adaptive Design Enables Two Paths to Registration
Adaptive Design Enables Two Paths to Registration •90% power Powering for PFS •Potential for accelerated approval on PFS •Resize at primary PFS analysis to achieve Powering for OS adequate power for OS •Potential for full approval on OS •Pre-planned interim evaluation by DSMB at 128 PFS events Inter
Slide 60: VS-6063: Adaptive Design Enables Multiple Paths to Registration
VS-6063: Adaptive Design Enables Multiple Paths to Registration Enroll Enroll Merlin Merlin Low/High Low Only Primary PFS Analysis Sample Size Re- Interim Estimation for PFS Analysis PFS Significant 50% PFS Events PFS not Significant Enrich Enroll Merlin Sample Size Continue Low/High Re-Estimation f
Slide 61: Clinical Assay for Merlin Expression in Mesothelioma
Clinical Assay for Merlin Expression in Mesothelioma Merlin-High max H score or Biopsy Immunohistochemistry on tissue sections min Merlin-Low Determining Binary Cut-off Clinical Assay Validation • Assay validated by Labcorp 1 Clinical specimens retrospectively analyzed from • H – Score [0-300] from
Slide 62: Site Qualification and Regulatory Progress on Schedule
Site Qualification and Regulatory Progress on Schedule • ~35 sites qualified to date in 11 countries • Regulatory submissions/allowances on track • US Investigator meeting held. Others shortly New Australia Belgium Canada France Netherlands Zealand Allowed South Spain Sweden UK USA Africa • Estimate
Slide 63: VS-6063: Japanese Development Strategy
VS-6063: Japanese Development Strategy • Facilitate Japanese inclusion into global mesothelioma trial • Create a path to possible Japanese approval • Phase 1 bridging study –Dose escalation as a single agent –Patient population: advanced solid tumors • 3-5 expansion sites for global mesothelioma stu
Slide 64: Team to Execute the Global Regulatory Study
Team to Execute the Global Regulatory Study • Leadership with extensive late-stage development experience – Joanna Horobin, M.B., Ch.B. – Chief Medical Officer • Syndax Pharmaceuticals, Rhone-Poulenc Rorer, EntreMed • 10 marketed compounds including Taxotere and Camptosar – Mitchell Keegan, Ph.D. –
Slide 65: Agenda
Agenda • 12:45 Introduction • 1:00 Focal Adhesion Kinase (FAK) and Cancer Stem Cells • 1:20 FAK Program Status: VS-6063 + Paclitaxel in Ovarian Cancer • 1:40 Mesothelioma and the VS-6063 Registration-Directed Trial • 2:30 FAK Portfolio Expansion: VS-6063 into Lung Cancer and VS-4718 into Phase 1 • 2
Slide 66: Mesothelioma is a Potentially Rapid Path to Regulatory Filing: Expansion
Mesothelioma is a Potentially Rapid Path to Regulatory Filing: Expansion to Additional Tumor Types Mesothelioma Ovarian Breast Lung WW Incidence WW Incidence ~59,000 ~225,000 WW Incidence ~1,400,000 Targeting cancer stem cells that are WW Incidence implicated in epithelial solid tumors: ~1,600,000 8
Slide 67: Potential Indication Expansion to Non-Small Cell Lung Cancer
Potential Indication Expansion to Non-Small Cell Lung Cancer • Lung cancer with KRAS mutation accompanied by 2nd mutation in INK4a/ARF or p53 shown to be especially sensitive to FAK inhibition • Sensitivity determined by both FAK genetic knockdown and in vivo xenograft experiments with small-molecul
Slide 68: VS-6063: Phase 2 Study in KRAS-mutated NSCLC
VS-6063: Phase 2 Study in KRAS-mutated NSCLC • Endpoints: PFS at 12 weeks, ORR and OS • Increase safety database for VS-6063 • Targeted initiation Q3 2013 • 8-10 clinical sites Interim analysis KRAS INK4a p53 Cohort A VS-6063 400mg BID VS-6063 400mg BID Cohort B VS-6063 400mg BID VS-6063 400mg BID C
Slide 69: VS-4718: Second FAK Inhibitor in Clinical Development
VS-4718: Second FAK Inhibitor in Clinical Development • Orally available, potent and selective inhibitor of FAK kinase • Targets cancer stem cells in in vitro & in vivo cancer models • Phase 1 first-in-human study open and enrolling patients Biochemical Properties Cancer Stem Cells 125 Aldefluor-Pos
Slide 70: VS-4718: Dose Escalation Scheme
VS-4718: Dose Escalation Scheme • Phase 1 dose escalation in patients with advanced cancers initiated Q2 2013 • 3+3 modified Fibonacci design • Pre/post treatment biopsies • Expansion at recommended Phase 2 dose • Clinical sites • Sarah Cannon, Cedars Sinai and Florida Cancer Specialists • Up to 30
Slide 71: FAK Program Summary
FAK Program Summary • FAK is a critical regulator of cancer stem cells and disease progression • Strong pre-clinical evidence and initial clinical proof-of-concept for targeting FAK in mesothelioma, ovarian and lung cancer • Two candidates in clinical development with 5 clinical trials ongoing/plann
Slide 72: Agenda
Agenda • 12:45 Introduction • 1:00 Focal Adhesion Kinase (FAK) and Cancer Stem Cells • 1:20 FAK Program Status: VS-6063 + Paclitaxel in Ovarian Cancer • 1:40 Mesothelioma and the VS-6063 Registration-Directed Trial • 2:30 FAK Portfolio Expansion: VS-6063 into Lung Cancer and VS-4718 into Phase 1 • 2
Slide 73: Jose Baselga, M.D., Ph.D.
Jose Baselga, M.D., Ph.D. Page 73 Novel Drugs Targeting Cancer Stem Cells July 11, 2013
Slide 74: Lack of inhibition of mTOR correlates with resistance to PI3K inhibitors
Lack of inhibition of mTOR correlates with resistance to PI3K inhibitors Page 74 Elkabets et al. Science Transl Med. In press
Slide 75: Lack of inhibition of mTOR in patients resistant to PI3K inhibitors
Lack of inhibition of mTOR in patients resistant to PI3K inhibitors Science Transl Med. In press Page 75
Slide 76: Synergism between mTOR and PI3K inhibitors
Synergism between mTOR and PI3K inhibitors 700 CAL51 400 600 Tumor volume (mm3) Tumor volume (mm3) 500 300 400 200 300 200 * ** ** 100 100 0 0 0 10 20 30 40 50 0 20 40 60 80 100 120 140 160 Days of treatment Days after treatment Vehicle Vehicle RAD001 0.5mg/kg BYL719 25mg/kg BYL719 25mg/kg BYL719 50
Slide 77: Portfolio of Product Candidates Targeting Cancer Stem Cells
Portfolio of Product Candidates Targeting Cancer Stem Cells PreClin Phase 1 Phase 2 Phase 3 Focal Adhesion Kinase (FAK) VS-6063 Mesothelioma Registration-directed trial Japanese Development Phase 1 Lung (KRASm NSCLC) Phase 2 Planned Ovarian Phase 1/1b in combo with paclitaxel Ongoing VS-4718 Solid T
Slide 78: VS-5584: Dual mTORC1/2 and pan-PI3K Inhibitor
VS-5584: Dual mTORC1/2 and pan-PI3K Inhibitor • Potent against mTORC1/2 & all Class 1 PI3K PI3K/mTOR isoforms • Oral formulation RTKs • IND-enabling toxicity studies ongoing • Phase 1 dose escalation in patients with advanced cancers planned to initiate Q4 2013 PI3K – Solid tumors and lymphomas T AK
Slide 79: VS-5584 Potently Targets Human B-Cell Lymphoma Cell Lines
VS-5584 Potently Targets Human B-Cell Lymphoma Cell Lines • PI3K-delta inhibitors CAL-101 and IPI-145 have shown promising clinical activity in patients with B-cell malignancies IC50 (nM) mTOR PI3Ka PI3Kb PI3Kg PI3Kd VS-5584 3.4 2.6 21 2.7 3.0 CAL-101 > 10,000 8500 840 550 11 IPI-145 9,800 243 97 3.
Slide 80: VS-5584: Robust Tumor Growth Inhibition in Preclinical Models
VS-5584: Robust Tumor Growth Inhibition in Preclinical Models Superior to Everolimus Taxane-Resistant Breast Ca in Xenograft Model Patient-Derived Xenograft Page 80 Novel Drugs Targeting Cancer Stem Cells July 11, 2013
Slide 81: VS-5584: Preferential Effects on Cancer Stem Cells
VS-5584: Dual mTORC1/2 and PI3K Inhibitor with Preferential Effects on Cancer Stem Cells Proliferation Apoptosis 12 Aldefluor- Non-CSCs CSCs % Annexin-V Positive Aldefluor+ 10 Non-CSCs 8 Cells 6 CSCs 4 2 0 Control 0.2 µM 0.5 µM VS-5584 • VS-5584 is ~30-fold more potent vs CSCs than non-CSCs SUM159 T
Slide 82: VS-5584 Reduces CSCs in MCF7 Breast Cancer Model
VS-5584 Reduces CSCs in MCF7 Breast Cancer Model: Contrast to mTORC1 inhibitor, Everolimus MCF7 BrCa Liberase CSC assays Viable cells 1 .5 ALDH CSC assay Tumor Initiation in 2o Mice % ALDH+ CSCs T u m o r In itia tin g F r e q u e n c y 200 1 .0 (% o f C o n t r o l) 0 .5 p = 0 .0 0 7 4 150 ** 0 .0
Slide 83: VS-5584 Extends Efficacy of Chemotherapy in SCLC Model
VS-5584 Extends Efficacy of Chemotherapy in SCLC Model VS-5584 Extends Cisplatin Efficacy SCLC Cell Line Panel in SCLC Xenograft Model Cisplatin VS-5584 Page 83 Novel Drugs Targeting Cancer Stem Cells
Slide 84: Clinical Trial Designs for Drugs Targeting Cancer Stem Cells
Clinical Trial Designs for Drugs Targeting Cancer Stem Cells Theoretical Result Concurrent: CSC Drugs + Chemo More Durable Clinical Response Initial Tumor Tumor Reduction & Elimination of CSCs Maintenance: Chemo CSC Drugs More Durable Clinical Response Initial Tumor Tumor Reduction but CSCs are Enri
Slide 85: VS-5584: Phase 1 Dose Escalation and Schedule Finding Study
VS-5584: Phase 1 Dose Escalation and Schedule Finding Study • Phase 1 dose escalation in patients with advanced solid tumors including lymphomas • Pre/post treatment biopsies • Expansion at recommended Phase 2 dose/schedule into cancer stem cell-driven tumors • Targeted initiation – YE 2013 • Clinic
Slide 86: Agenda
Agenda • 12:45 Introduction • 1:00 Focal Adhesion Kinase (FAK) and Cancer Stem Cells • 1:20 FAK Program Status: VS-6063 + Paclitaxel in Ovarian Cancer • 1:40 Mesothelioma and the VS-6063 Registration-Directed Trial • 2:30 FAK Portfolio Expansion: VS-6063 into Lung Cancer and VS-4718 into Phase 1 • 2
Slide 87: Upcoming Milestones
Upcoming Milestones Regulatory Clinical Trial Initiations Data H1 2013 H2 2013 2014 FDA Meeting VS-5584 IND VS-4718 Phase 1 EU Meeting VS-6063 US Orphan VS-6063 Phase 1b combo biomarkers VS-6063 Meso trial and activity VS-4718 IND VS-6063 EU Orphan VS-5584 Phase 1 VS-4718 Phase 1b biomarkers VS-4718
Slide 88: Portfolio of Product Candidates Targeting Cancer Stem Cells
Portfolio of Product Candidates Targeting Cancer Stem Cells PreClin Phase 1 Phase 2 Phase 3 Focal Adhesion Kinase (FAK) VS-6063 Mesothelioma Registration-directed trial Japanese Development Phase 1 Lung (KRASm NSCLC) Phase 2 Planned Ovarian Phase 1/1b in combo with paclitaxel Ongoing VS-4718 Solid T