Verastem, Inc. · NASDAQ:VSTM
Verastem — Investor Presentation (April 2023)
58 slides from Verastem's investor presentation, April 2023
Slide 1: Corporate Presentation
Corporate Presentation April 2023
Slide 2: Safe Harbor Statement
Safe Harbor Statement This presentation includes forward-looking statements about, among other things,Verastem Oncology’s programs and product candidates, including anticipated regulatory submissions, approvals, performance and potential benefits of Verastem Oncology’s product candidates, as well as
Slide 3: Well Positioned to Capitalize on Growth Opportunities
Verastem Oncology Well Positioned to Capitalize on Growth Opportunities Lead clinical program has Avutometinib (VS-6766; RAF/MEK clamp) and defactinib (FAK best-in-class potential inhibitor) are clinically active against RAS pathway-driven cancers FDA Breakthrough Therapy Designation; Interim analys
Slide 4: Key VSTM Achievements 2022 & Anticipated Milestones 2023
Key VSTM Achievements 2022 & Anticipated Milestones 2023 1H2022 2H2022 1Q2023 2Q2023 2H2023 RAMP 201 Selection Phase Complete; Initiated enrollment of RAMP 201 Second RAMP 201 Complete Present updated results Interim Update target enrollment of of Part A RAMP 201 Initiate confirmatory Expansion
Slide 5: Avutometinib is a Differentiated Agent with Potential to Serve as Backbone
Avutometinib is a Differentiated Agent with the Potential to Serve as the Backbone for Combinations Across RAS Pathway-Driven Cancers • Unique RAF/MEK clamp mechanism of action • Novel intermittent dosing schedule; convenient oral regimen • Breakthrough Therapy Designation in recurrent low-grade ser
Slide 6: Strong Scientific Rationale for Avutometinib and FAK Inhibitor Combination
Strong Scientific Rationale for Avutometinib and FAK Inhibitor Combination Anti-Tumor Efficacy in KRAS Mutant and Wild-Type LGSOC models Growth factors Extracellular Matrix pFAK KRAS mutant LGSOC PDX model RTK Integrin 150 300 vehicle α Tumor volume (mm3 +/- SEM) β 200 FAKi FAK defactinib avutometin
Slide 7: LGSOC Unmet Need & Opportunity
LGSOC Unmet Need & Opportunity • LGSOC is a less common type of ovarian cancer that is often diagnosed in younger women o LGSOC is a unique disease that is distinct from high-grade serous ovarian cancer (HGSOC) in its pathology, protracted clinical course and low response to chemotherapy and thus re
Slide 8: RAMP 201: Registration-Directed Phase 2 Trial in Recurrent LGSOC
RAMP 201 (ENGOTov60/GOG3052): Registration-Directed Phase 2 Trial of Avutometinib ± Defactinib in Patients with Recurrent LGSOC Part A Part B Selection Phase* Expansion Phase** Avutometinib + Defactinib Avutometinib + Defactinib Avutometinib + Defactinib KRAS mt n +20 KRAS mt n +40** KRAS mt (n=16)
Slide 9: RAMP 201: Planned Interim Analysis
RAMP 201 (ENGOTov60/GOG3052): Registration-Directed Phase 2 Trial of Avutometinib ± Defactinib in Patients with Recurrent LGSOC Planned Interim Analysis: Initial Efficacy Data: Part A (Evaluable Patients) Part A Selection Phase* Safety Data: All Treated Patients Avutometinib + Defactinib • Heavi
Slide 10: Efficacy and Tolerability of Avutometinib and Defactinib in LGSOC
Efficacy and Tolerability of Avutometinib and Defactinib in LGSOC A Head-to-Head Study Has Not Been Performed Median Number Prior Prior Discontinuation Response Rate Image Median PFS Trial of Prior MEK Bevaciz Therapy Rate ORR Assessment Months (95% CI) lines of Allowed umab Due to AEs Therapy GOG 3
Slide 11: RAMP 201: Safety and Tolerability Profile
RAMP 201: Safety and Tolerability Profile of Avutometinib + Defactinib No New Safety Signals; Few Discontinuations Due to Adverse Events Avutometinib + Defactinib Most Common Treatment-Related Adverse Any Grade Grade ≥3 Events (>20%) in All Treated Patients KRAS mt KRAS wt Total KRAS mt KRAS wt Tota
Slide 12: RAMP 201 Part A Results and FDA Feedback Establish Path to Filing
RAMP 201 Part A Results and FDA Feedback Establish Path to Filing for Accelerated Approval Update Next Steps • Combination of avutometinib with defactinib selected • Target enrollment for primary analysis (n=72) in as go forward treatment regimen combination has been achieved • Combination developme
Slide 13: Comprehensive approach to establish more complete blockade of RAS pathway
Comprehensive approach to establish more complete blockade of RAS pathway & resistance pathways Incidence/ Indication Regimen Setting Prevalence Prevalence1: LGSOC 6K Avutometinib + defactinib Relapsed Refractory molecularly profiled LGSOC Gynecologic Cancers Gynecologic Incidence6-10: Recurrent RAS
Slide 14: Broad Development Opportunities Across RAS/MAPK Pathway-Driven Cancers
Broad Development Opportunities Across Multiple RAS/MAPK Pathway-Driven Cancers High Priority Registration Indication Key Signal Finding Registration-Directed Trial Initiated in 4Q20 Avutometinib + G12Ci in KRAS G12C NSCLC2 (RAMP 203 - sotorasib) & (RAMP 204 - adagrasib) LGSOC1,2 (RAMP 201)-Targ
Slide 15: Robust Clinical Program: Avutometinib in Multiple Combinations
Robust Clinical Program: Avutometinib in multiple combinations across RAS/MAPK pathway-driven tumors CLINICAL STUDY COLLABORATION INDICATION REGIMEN NAME PRECLINICAL PHASE 1 PHASE 2 PHASE 3 WITH LGSOC1 Avutometinib + defactinib RAMP 201 Registration-directed trial: accelerated approval cohort fully
Slide 16: Key Financial Statistics
Key Financial Statistics As of and for the quarter ended December 31, 2022 Cash, cash equivalents & investments $87.9M Pro-forma cash, cash equivalents, & investments $132.9M^ Non-GAAP Operating Expenses* $15.6M Shares Outstanding 200.5M ^ Pro-forma cash, cash equivalents & investments includes Q1 2
Slide 17: Avutometinib RAF/MEK Clamp Program Overview
Avutometinib RAF/MEK Clamp Program Overview
Slide 18: Avutometinib is a Unique Small Molecule RAF/MEK Clamp
Avutometinib is a Unique Small Molecule RAF/MEK Clamp Growth factors Avutometinib inhibits MEK, RTK BRAF & CRAF by trapping these molecules in inactive complexes MEK inhibitors paradoxically % Inhibition % Inhibition induce MEK phosphorylation RAS (pMEK) by relieving ERK-dependent feedback inhib
Slide 19: Avutometinib Induces Inactive Complexes of MEK with ARAF, BRAF & CRAF
Avutometinib is a Unique RAF/MEK Clamp which Induces Inactive Complexes of MEK with ARAF, BRAF & CRAF Contrasting mechanism of action vs. trametinib DMSO Tram Avuto + Avutometinib + Trametinib Growth factors Growth factors RTK RTK RAS RAS Formation of DMSO Tram Avuto inactive RAF/MEK RAF complex to
Slide 20: Avutometinib Inhibits Cell Proliferation Across RAS/MAPK Alterations
Avutometinib Inhibits Cell Proliferation Across Multiple RAS/MAPK Pathway Alterations and Multiple Solid Tumor Histologies KRAS G12C KRAS G12D KRAS G12V Other KRAS mt BRAF mt NRAS mt NF1 mt Other mt Avutometinib IC50 (µM) 10 1 0.1 0.01 SW837 SKLU1 SW403 SW620 SW480 CFPAC1 H358 A427 H441 HCT 116 HCT-
Slide 21: Optimized Dosing Schedule Defined
Optimized Dosing Schedule Defined: Favorable Tolerability Profile with Novel Intermittent Dosing Regimen Summary of Adverse Events Grade ≥ 3 Occurring in ≥ 5% of patients Avutometinib monotherapy RP2D RP2D Daily at MTD Avutometinib monotherapy (Avutometinib 3.2mg twice N=6 4mg twice weekly weekly +
Slide 22: Avutometinib Patent Exclusivity
Avutometinib Patent Exclusivity Composition of Matter PTE Feb 2027 + 5 yrs (PTE) = 2032 Method of Making Sept 2032 Dosing Protocol May 2038 Combination w/ Defactinib Sept 2040 Methods of Treating 2041 - 2042 if issued Combinations 2041 - 2042 if issued 22
Slide 23: Avutometinib ± Defactinib in Low-Grade Serous Ovarian Cancer
Avutometinib ± Defactinib in Low-Grade Serous Ovarian Cancer
Slide 24: LGSOC is a Unique RAS Pathway-Driven Cancer with a High Unmet Need
LGSOC is a Unique RAS Pathway-Driven Cancer with a High Unmet Need ~30% of LGSOC Patients Have KRAS mt LGSOC is a type of ovarian cancer that disproportionately ~70% of LGSOC Shows RAS Pathway-Associated mts affects younger women 1,000 to 2,000 patients in the U.S. and 15,000 to 30,000 worldwide dia
Slide 25: Low-Grade and High-Grade Serous Ovarian Cancer Are Different Diseases
Low-Grade and High-Grade Serous Ovarian Cancer Are Different Diseases Variable LGSOC HGSOC Nuclear atypia Uniform round to +++ oval with little Marked variation variation Mitotic Index <12 mitoses per >12 mitoses per 10 hpf 10 hpf Chromatin and Little Marked (nuclear LGSOC variation in size of size
Slide 26: Recurrent LGSOC: High Medical Need
Recurrent LGSOC: High Medical Need No Approved Treatment Options – Limited Benefit from Available Therapies Recurrent Low-Grade Ovarian Cancer – Treatment Guidelines 1 No Category 1 recommendations (high-level evidence). Category 2a (lower-level evidence with uniform NCCN consensus) unless otherwise
Slide 27: Recent LGSOC Trials Highlight High Unmet Need
Recent LGSOC Trials Highlight High Unmet Need Number of Prior Prior Response Discontinuation Systemic Prior Image Median PFS Trial MEK Therapy Rate Rate Therapies Bevacizumab Assessment Months (95% CI) allowed ORR due to AEs Median (range) GOG 3 SoC 6% INV 7.2 (5.6-9.9) 13% No * Low % 2811 (1-10) Tr
Slide 28: FRAME Study: Foundation for Avutometinib plus Defactinib in Recurrent LGSOC
FRAME Study: Solid Foundation for the Development of Avutometinib in Combination with Defactinib in Recurrent LGSOC (n=24) Response by RECIST Best response by RECIST KRAS D57-T58ins 20 KRAS D33E, I24N Undocumented Undocumented Undocumented Undocumented 10 Continuing on treatment KRAS G12D KRAS G12D
Slide 29: RAMP 201: Registration-Directed Phase 2 Trial in Recurrent LGSOC
RAMP 201 (ENGOTov60/GOG3052): Registration-Directed Phase 2 Trial of Avutometinib ± Defactinib in Patients with Recurrent LGSOC Part A Part B Selection Phase* Expansion Phase** Avutometinib + Defactinib Avutometinib + Defactinib Avutometinib + Defactinib KRAS mt n +20 KRAS mt n +40** KRAS mt (n=16)
Slide 30: RAMP 201: Planned Interim Analysis
RAMP 201 (ENGOTov60/GOG3052): Registration-Directed Phase 2 Trial of Avutometinib ± Defactinib in Patients with Recurrent LGSOC Planned Interim Analysis: Initial Efficacy Data: Part A (Evaluable Patients) Part A Selection Phase* Safety Data: All Treated Patients Avutometinib + Defactinib • Heavi
Slide 31: RAMP 201 Part A: Heavily Pre-Treated Patient Population
RAMP 201 Part A: Heavily Pre-Treated Patient Population Prior Platinum-Based Chemotherapy, Endocrine Therapy, Bevacizumab in Most Patients; Prior MEK Inhibitor Therapy was Permitted Avutometinib Monotherapy Avutometinib + Defactinib KRAS mt KRAS wt Total KRAS mt KRAS wt Total (n=16) (n=17) (n=33) (n
Slide 32: RAMP 201 Part A: Evaluable Patient Population
RAMP 201 Part A: Evaluable Patient Population* Positive ORR Confirmed by Blinded Independent Central Review (BICR) Support Avutometinib + Defactinib as Go Forward Regimen in LGSOC - Regardless of KRAS Status Avutometinib Avutometinib + Defactinib KRAS mt KRAS wt Total KRAS mt KRAS wt Total (n=15) (n
Slide 33: Go Forward Regimen: High Disease Control Rate + Tumor Reduction
Go Forward Regimen: Combination of Avutometinib and Defactinib High Disease Control Rate + Tumor Reduction in Recurrent LGSOC 20 RAMP 201 (Part A) Part A (Evaluable for Efficacy *) N=29 Evaluable for Efficacy * Confirmed ORR: 28% 0 (% change from baseline) * * * Confirmed/Unconfirmed ORR: 38% * Best
Slide 34: Initial Data from RAMP 201 Reinforce Findings from FRAME
Go Forward Regimen: Combination of Avutometinib and Defactinib Initial Data from RAMP 201 Trial Reinforce Findings from FRAME Trial RAMP 201 (Part A) FRAME Interim Analysis - Blinded ICR Investigator Assessment N=29 20 N=24 0 (% change from baseline) * * * Best Response -20 * -40 * * * * * * * -60 K
Slide 35: RAMP 201: Safety and Tolerability Profile
RAMP 201: Safety and Tolerability Profile of Avutometinib + Defactinib No New Safety Signals; Few Discontinuations Due to Adverse Events Avutometinib + Defactinib Most Common Treatment-Related Adverse Any Grade Grade ≥3 Events (>20%) in All Treated Patients KRAS mt KRAS wt Total KRAS mt KRAS wt Tota
Slide 36: RAMP 201 Part A Results and FDA Feedback Establish Path to Filing
RAMP 201 Part A Results and FDA Feedback Establish Path to Filing for Accelerated Approval Update Next Steps • Combination of avutometinib with defactinib selected • Target enrollment for primary analysis (n=72) in as go forward treatment regimen combination has been achieved • Combination developme
Slide 37: Efficacy and Tolerability of Avutometinib and Defactinib in LGSOC
Efficacy and Tolerability of Avutometinib and Defactinib in LGSOC A Head-to-Head Study Has Not Been Performed Median Number Prior Prior Discontinuation Response Rate Image Median PFS Trial of Prior MEK Bevaciz Therapy Rate ORR Assessment Months (95% CI) lines of Allowed umab Due to AEs Therapy GOG 3
Slide 38: RAMP 201 Interim Data Support Market Potential for All Recurrent LGSOC
RAMP 201 Part A Interim Data Support Meaningful Market Potential for All Recurrent LGSOC Regardless of KRAS Status with Long Duration of Therapy Prevalence Patient-months of Therapy Per Year2 (across all 2L+ patients) ~6K - 50,000 100,000 150,000 patients US1 NSCLC KRAS G12C3 Pancreatic Cancer3 LGSO
Slide 39: RAS Pathway-Driven Cancers and Rational Avutometinib Combinations
RAS Pathway-Driven Cancers and Rational Avutometinib Combinations
Slide 40: High Unmet Needs in Additional RAS/MAPK Pathway-Driven Cancers
High Unmet Needs in Additional RAS/MAPK Pathway-Driven Cancers KRAS-mutant NSCLC 31% Pancreatic Uterine 21% Colorectal 45% Incidence3,5: Incidence5: Endometrioid Incidence5: Cancers1 114K 58K 98% Incidence4,5: 59K 148K NRAS-mutant Melanoma 28% Multiple Myeloma 20% Incidence5: Incidence5: Cancers1 10
Slide 41: Vertical Blockade: Avutometinib as Backbone of Therapy
Vertical Blockade: Establishing Avutometinib as the Backbone of Therapy for RAS/MAPK Pathway-Driven Tumors Growth factors Current Challenges RTK • Blocking any single target in the pathway is insufficient for maximum depth and duration of anti-tumor efficacy EGFRi • e.g. SHP2i, KRAS-G12Ci, KRAS-G1
Slide 42: Parallel Pathway Inhibition: Avutometinib as Backbone of Therapy
Parallel Pathway Inhibition: Establishing Avutometinib as the Backbone of Therapy for RAS/MAPK Pathway-Driven Tumors Growth factors Extracellular Matrix Current Challenges RTK Integrin • Blocking RAS pathway can be circumvented through α parallel pathways EGFRi β • e.g. PI3K/AKT/mTOR, FAK, RhoA,YA
Slide 43: Preclinical Synergy of Avutometinib with Promising Agents
Preclinical Synergy of Avutometinib in Combination with Promising Agents for Clinical Investigation Vertical RAS/MAPK Pathway Inhibition Parallel Pathway Inhibition Avutometinib + pan-HERi (afatinib) Avutometinib + SHP2i (RMC-4550) Avutometinib + SOS1i (BI-3406) Avutometinib 100% (5/5)+ CDK4/6i 100%
Slide 44: Avutometinib Combinations in Non-Small Cell Lung Cancer
Avutometinib Combinations in Non-Small Cell Lung Cancer
Slide 45: High Unmet Need in Refractory KRAS & BRAF mt NSCLC Adenocarcinoma
High Unmet Need in Refractory KRAS & BRAF mt NSCLC Adenocarcinoma Advanced or Metastatic NSCL Cancer NSCLC Adenocarcinoma3 Recommend Histologic and Molecular Subtyping5 15 EGFR/ALK/ROS1/BRAF/ Non-targeted Non-Targeted KRAS G12C (targeted) PD-(L)1 ≥ 1% PD-(L)1 < 1% US Annual Incidence7,8: 114K WW Ann
Slide 46: Preclinical Synergy of Avutometinib + G12C Inhibitors in KRAS G12C Models
Preclinical Synergy of Avutometinib + G12C Inhibitors in KRAS G12C Models Avutometinib & FAKi potentiate sotorasib efficacy in KRAS G12C Synergy of avutometinib + G12C inhibitors across NSCLC in vivo; Tumor regression in all mice with triple combination G12C mutant NSCLC, CRC & Pancreatic cancer cel
Slide 47: Acquired Resistance Mechanisms to KRAS G12Ci Support Combination
Acquired Resistance Mechanisms to KRAS G12Ci Treatment in Patients Further Support Combination of KRAS G12Ci with Avutometinib Summary of Putative Mechanisms of Acquired • Mechanisms of acquired resistance to KRAS G12Ci Resistance to Adagrasib Treatment adagrasib treatment in patients recently repor
Slide 48: RAMP 203: Avutometinib + Sotorasib in KRAS G12C NSCLC
RAMP 203: Phase 1/2 Trial of Avutometinib + LUMAKRASTM (Sotorasib) in KRAS G12C Advanced NSCLC Part A: Dose Evaluation Part B: Dose Expansion at RP2D (3+3 DLT Assessment) (Primary endpoint ORR) Patients must have a KRAS G12C mutation determined using Cohort 1 validated test Patients without Prior
Slide 49: RAMP 204: Avutometinib + Adagrasib in KRAS G12C NSCLC
RAMP 204: Phase 1/2 Trial of Avutometinib + KRAZATITM (Adagrasib) in KRAS G12C Advanced NSCLC Part A: Dose Evaluation Part B: Dose Expansion Patients must have a (3+3 DLT Assessment) (Primary endpoint ORR) KRAS G12C mutation determined using validated test Treatment with at least 1 but no more S
Slide 50: RAMP 202: Avutometinib + Defactinib in BRAF mt NSCLC
RAMP 202: Phase 2 Trial of Avutometinib + Defactinib in BRAF mt NSCLC Initial Phase Analysis Patients with Advanced NSCLC 1-2 prior regimens 1 prior platinum-containing Avutometinib + chemo Defactinib1 Prior CPI unless BRAF V600E contraindicated BRAF Mutant n=15 Expansion TBD Measurable di
Slide 51: Additional Avutometinib Combinations for Pancreatic, Colorectal and Melanoma
Additional Avutometinib Combinations for Pancreatic, Colorectal and Melanoma
Slide 52: Preclinical Synergy of Avutometinib/FAK Inhibition + Chemotherapy in Pancreatic Model
Preclinical Synergy of Avutometinib/FAK Inhibition + Chemotherapy in a KRAS/p53 pancreatic cancer mouse model vehicle gemcitabine/paclitaxel avutometinib/FAKi avutometinib/FAKi + gemcitabine/paclitaxel The combination of avutometinib + FAKi induces tumor growth inhibition and increases survival bu
Slide 53: RAMP 205: Avutometinib/Defactinib + Gemcitabine/Nab-paclitaxel in Pancreatic Cancer
RAMP 205: Phase 1/2 Trial of Avutometinib/Defactinib + GEMZARTM (Gemcitabine)/ABRAXANETM (Nab-paclitaxel) in Front Line Metastatic Pancreatic Cancer Part A: Dose Evaluation Part B: Dose Expansion at RP2D (3+3 DLT Assessment) (Primary endpoint ORR) Patients with confirmed metastatic pancreatic duct
Slide 54: Avutometinib with anti-EGFR mAb Induces Regression in KRAS mt Colorectal Model
Combination of Avutometinib with anti-EGFR mAb Induces Tumor Regression in a KRAS mt Colorectal PDX Model • Avutometinib + anti-EGFR (panitumumab) induces tumor regression in a KRAS mutant CRC patient-derived xenograft model vehicle • G12Ci + anti-EGFR (sotorasib + panitumumab and adagrasib + cetuxi
Slide 55: Avutometinib + FAK Inhibition with Checkpoint Inhibitor in Melanoma Model
Combination of Avutometinib + FAK Inhibition with Checkpoint Inhibitor Induces Tumor Regression in an IO-resistant BRAF V600E melanoma model • Avutometinib + IO (anti-PD-1 + anti-CTLA-4) induces tumor regression in an IO-resistant vehicle IO (anti-PD-1 + anti-CTLA-4) syngeneic BRAF V600E melanoma mo
Slide 56: Avutometinib Development in Multiple Combinations with Potential Early Read-Outs
Avutometinib Development in Multiple Combinations Across RAS Pathway- Driven Tumors with Potential Early Read-Outs in 2H 2023 Indication Study KRAS G12C NSCLC RAMP 203: Avutometinib/Sotorasib combo KRAS G12C NSCLC RAMP 204: Avutometinib/Adagrasib combo Pancreatic RAMP 205: Avutometinib/Gem/Abraxane/
Slide 57: Experienced Senior Management Team
Experienced Senior Management Team Brian Stuglik Daniel Paterson Cathy Carew President and Chief Operating Chief Organizational Chief Executive Officer Officer Effectiveness Officer Global VP & Chief Marketing CEO – The DNA Repair Co. (now Principal – HR Collaborative Officer – Lilly Oncology
Slide 58: Thank You
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