Verastem, Inc. · NASDAQ:VSTM
Verastem — Investor Presentation (August 2022)
53 slides from Verastem's investor presentation, August 2022
Slide 1: Corporate Presentation
Corporate Presentation August 2022
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, that are
Slide 3: Verastem Oncology: Well Positioned to Capitalize on Growth Opportunities
Verastem Oncology Well Positioned to Capitalize on Growth Opportunities Lead clinical program has VS-6766 (RAF/MEK clamp) and defactinib (FAK inhibitor) are clinically best-in-class potential active against RAS mutant cancers FDA Breakthrough Therapy Designation in LGSOC; Supported Rapid development
Slide 4: Key VSTM Milestones 2021-2022
Key VSTM Milestones 2021-2022 1H2021 2H2021 1Q2022 2Q2022 2H2022 ✓ RAMP 201 ✓RAMP 201 Selection Amended to Include KRAS wt patients in ✓ Updated data ✓ RAMP 201 Target Phase Update* Selection Phase from FRAME enrollment of RAMP 201 Complete LGSOC cohort Selection Phase enrollment of LGSOC Complete E
Slide 5: VS-6766 is a Differentiated, Potentially Best-in-Class Asset
VS-6766 is a Differentiated, Potentially Best-in-Class Asset Applicable Across Multiple Patient Populations • Unique RAF/MEK clamp mechanism of action • Novel intermittent dosing schedule; convenient oral regimen • Breakthrough Therapy Designation in recurrent low-grade serous ovarian cancer • Poten
Slide 6: Robust Clinical Program in Two Lead Indications
Robust Clinical Program in Two Lead Indications: Gynecologic Oncology & Non-Small Cell Lung Cancer CLINICAL STUDY COLLABORATION INDICATION REGIMEN NAME PRECLINICAL PHASE 1 PHASE 2 PHASE 3 WITH LGSOC1,2 VS-6766 +/- defactinib RAMP 201 R/R LGSOC VS-6766 + defactinib FRAME R/R endometrioid cancer VS-67
Slide 7: Key Financial Statistics
Key Financial Statistics As of and for the quarter ended June 30, 2022 Cash, cash equivalents & investments $94.3M Non-GAAP Operating Expenses $19.6M Shares Outstanding 187.6M Oxford Finance LLC Credit Facility Loan Tranches Event A $25M At closing B $15M COPIKTRA PTCL approval in U.S. or $50M equit
Slide 8: VS-6766 RAF/MEK Clamp Program Overview
VS-6766 RAF/MEK Clamp Program Overview
Slide 9: Broad Development Opportunities Across Multiple RAS/MAPK Driven Cancers
Broad Development Opportunities Across Multiple RAS/MAPK Driven Cancers High Priority Registration Indications Key Signal Finding Registration-Directed Trials Initiated in 4Q20 VS-6766 + G12Ci KRAS G12C mt NSCLC2 (RAMP 203-sotorasib) & (RAMP 204-adagrasib) LGSOC1,2 (RAMP 201) KRAS non-G12V1,2
Slide 10: VS-6766 is a Unique Small Molecule RAF/MEK Clamp
VS-6766 is a Unique Small Molecule RAF/MEK Clamp VS-6766 inhibits MEK, BRAF & CRAF by trapping these molecules in inactive complexes MEK inhibitors paradoxically induce MEK phosphorylation (pMEK) by relieving ERK-dependent feedback inhibition of RAF By inhibiting RAF phosphorylation of MEK, VS
Slide 11: VS-6766 is a Unique RAF/MEK Clamp Inducing Inactive Complexes
VS-6766 is a Unique RAF/MEK Clamp which Induces Inactive Complexes of MEK with ARAF, BRAF & CRAF Contrasting mechanism of action vs. trametinib DMSO Tram VS-6766 + VS-6766 + Trametinib Growth factors Growth factors RTK RTK RAS RAS Formation of DMSO Tram VS-6766 inactive RAF/MEK RAF complex to block
Slide 12: VS-6766 Inhibits Cell Proliferation Across Multiple MAPK Pathway Alterations
VS-6766 Inhibits Cell Proliferation Across Multiple MAPK Pathway VS-6766 IC50 Alterations and Multiple Solid Tumor Histologies (3D proliferation assay) KRAS G12C KRAS G12D KRAS G12V Other KRAS mt BRAF mt NRAS mt NF1 mt Other mt 10 VS-6766 IC50 (M) 1 0.1 0.01 H358 SW837 SKLU1 A427 H441 SW403 SW620 S
Slide 13: Vertical Blockade: VS-6766 as Backbone of Therapy
Vertical Blockade: Establishing VS-6766 as the Backbone of Therapy for RAS Pathway-Driven Tumors Growth factors ▪ Current Challenges RTK • Blocking any single target in the pathway is insufficient for maximum depth and EGFRi duration of anti-tumor efficacy FGFRi • e.g., SHP2i, KRAS-G12Ci, RAFi, MEKi
Slide 14: Parallel Pathway Inhibition: VS-6766 as Backbone of Therapy
Parallel Pathway Inhibition: Establishing VS-6766 as the Backbone of Therapy for RAS Pathway-Driven Tumors Growth factors Extracellular Matrix ▪ Current Challenges RTK Integrin • Blocking Ras pathway can be circumvented through EGFRi α parallel pathways β FGFRi • e.g., PI3K/AKT/mTOR, FAK, RhoA,YAP F
Slide 15: VS-6766 +/- Defactinib in Low-Grade Serous Ovarian Cancer
VS-6766 +/- Defactinib in Low-Grade Serous Ovarian Cancer
Slide 16: Favorable Tolerability Profile with Novel Intermittent Dosing Regimen
Favorable Tolerability Profile with Novel Intermittent Dosing Regimen Summary of Adverse Events Grade ≥ 3 Occurring in ≥ 5% of patients VS-6766 monotherapy RP2D RP2D Daily at MTD VS-6766 monotherapy (VS-6766 3.2mg twice weekly + N=6 4mg twice weekly defactinib 200mg twice daily) 28-day cycle N=26 N=
Slide 17: Favorable Tolerability Profile at Recommended Phase 2 Dose
Favorable Tolerability Profile at Recommended Phase 2 Dose for VS-6766 plus Defactinib Combination Regimen VS-6766 3.2mg Twice VS-6766 4mg Weekly Treatment Related Adverse Twice Weekly Def 200mg BID Summary of FRAME Safety Profile Events Details* (4 wks of (3 wks of Most Adverse Events (AE) were G
Slide 18: 70% of LGSOC Tumors Driven by Mutations in the RAS Pathway
70% of LGSOC Tumors Driven by Mutations in the RAS Pathway ~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 diagnosed w
Slide 19: LGSOC: Limited Treatment Options with High Unmet Need
LGSOC: Limited Treatment Options with High Unmet Need Low-Grade Ovarian Cancer – Treatment Algorithm1 Recent Clinical Trials in Recurrent LGSOC Stage IA-IB Stage IC Stage II-IV Response Rate Median PFS Discontinuation Therapy ORR Months (95% CI) Rate due to AEs Carbo-Pt + Paclitaxel + hormonal (2b)
Slide 20: VS-6766 with Defactinib Shows Promising ORR with Durability in Refractory LGSOC
Best response by RECIST KRAS D57-T58ins KRAS D33E, I24N VS-6766 in Combination with Defactinib Shows Promising ORR with Undocumented Undocumented Undocumented Undocumented KRAS G12D KRAS G12D KRAS G12D KRAS G12D KRAS G12D KRAS G12D KRAS G12V Durability in Refractory LGSOC with Expanded Number of Pat
Slide 21: RAMP 201 Registration-directed Phase 2 Trial in Recurrent LGSOC
RAMP 201 Registration-directed Phase 2 Trial of VS-6766 +/- Defactinib in Recurrent LGSOC - KRAS Mutant (mt) and Wild Type (wt): adaptive design modified based on interim analysis findings Completed Enrollment Now Enrolling Expansion Phase Selection Phase* Expansion Phase** Defactinib + VS-6766 Defa
Slide 22: RAMP 201 Selection Phase: Interim Analysis Findings - June 2022
RAMP 201 Selection Phase: Interim Analysis Findings - June 2022 Findings Next Steps • Support continued evaluation of both VS-6766 • All four cohorts from Selection Phase will be monotherapy and VS-6766 + defactinib enrolled for Expansion Phase (add ~ 20 combination therapy treatment arms patients/c
Slide 23: LGSOC Market Opportunity Larger or Comparable to Other KRAS Opportunities
LGSOC Market Opportunity Larger or Comparable to Other High Unmet Need KRAS Opportunities Prevalence Patient-months of Therapy Per Year2 (across all 2L+ patients) ~6K - 50,000 100,000 150,000 patients US1 NSCLC KRAS G12C3 Pancreatic3 LGSOC3 ~4k ~2k Endometrioid3 wild KRAS type mutation Metastatic uv
Slide 24: VS-6766 +/- Defactinib in NSCLC
VS-6766 +/- Defactinib in NSCLC
Slide 25: High Unmet Need in Refractory mt NSCLC Adenocarcinoma
High Unmet Need in Refractory mt NSCLC Adenocarcinoma Advanced or Metastatic NSCL Cancer NSCLC Adenocarcinoma3 Recommend Histologic and Molecular Subtyping5 15 EGFR/ALK/ROS1/BRAF/KR Non-targeted Non-Targeted AS-G12C (targeted) PD-(L)1 1% PD-(L)1 1% US Annual Incidence1,2: 92K WW Annual Incidence
Slide 26: VS-6766 Inhibits CRAF - The Key Driver of KRAS G12V mt NSCLC
VS-6766 Inhibits CRAF - The key driver of KRAS G12V mt NSCLC A Precision Approach to KRAS G12V Driven NSCLC CRAF Drives KRAS G12V mt NSCLC1 CRAF KO Shows Strong KRAS G12V Efficacy CRAF BRAF PI3K +83% OS MEK/ERK AKT/mTOR BRAF KO Has No Effect Tumor Growth KRAS G12V signals mainly through RAF/MEK i
Slide 27: VS-6766 +/- FAKi Induces Tumor Regression in KRAS G12V mt NSCLC Model
VS-6766 +/- FAKi Induces Significant Tumor Regression in KRAS G12V mt NSCLC in vivo Model, with Clear Differentiation from Trametinib KRAS G12V mutant;Tp53 KO NSCLC 80 Doses Tested Tumor volume fold change 60 Trametinib: 0.1 mg/kg QD (5 days/week) VS-6766: 0.1 mg/kg QD (5 days/week) 40 FAKi: 50 mg/k
Slide 28: Case Study: Response in a Patient with KRAS G12V mutant NSCLC
Case Study: Response to VS-6766 + Defactinib in a Patient with KRAS G12V mutant NSCLC VS-6766 + Defactinib May 2019: Diagnosed with NSCLC June 2019 - Sept 2019: Treated with first line Carboplatin + Pemetrexed + Pembrolizumab Oct 2019: Progression, palliative RT to right hip Nov 2019 – present: On t
Slide 29: Strong Signal Identified in KRAS G12V NSCLC
Strong Signal Identified in KRAS G12V NSCLC VS-6766 ± Defactinib Has Shown a 57% ORR in KRAS G12V mt NSCLC in Integrated Analysis Best Response by RECIST in KRAS G12V mt NSCLC Time on Treatment for KRAS G12V mt NSCLC Time on Treatment NSCLC (57% ORR; N=7) Weeks on treatment Mono 216 Combo 70 * Mono
Slide 30: RAMP 202: Registration-directed Phase 2 Trial in Advanced NSCLC
RAMP 202: Registration-directed Phase 2 Trial of VS-6766 +/- Defactinib in Advanced NSCLC Primary Cohort: KRAS G12V mt NSCLC Selection Phase Expansion Phase Advanced NSCLC 1-2 prior regimens 1 prior platinum- containing chemo; Completed Enrollment Prior CPI unless contraindicated Defactinib
Slide 31: RAMP 202: Additional Cohorts in KRAS non-G12V & BRAF mt NSCLC
RAMP 202: Additional Cohorts of VS-6766 + Defactinib in KRAS non-G12V mt & BRAF mt NSCLC Advanced NSCLC Initial Phase Analysis 1-2 prior regimens Completed Enrollment 1 prior platinum- Non-G12V Cohort containing chemo; Defactinib + VS-67661 KRAS Mutant – non-G12V Expansion TBD based Prior
Slide 32: Preclinical Synergy of VS-6766 + G12C Inhibitors
Preclinical Synergy of VS-6766 + G12C Inhibitors in KRAS G12C mt Models Synergy of VS-6766 + G12C inhibitors across VS-6766 & FAKi potentiate sotorasib efficacy in KRAS G12C mutant G12C mutant NSCLC, CRC & Pancreatic cancer cell lines NSCLC in vivo; Tumor regression in all mice with triple combinati
Slide 33: Acquired Resistance Mechanisms to KRAS G12Ci Support Combination with VS-6766
Acquired Resistance Mechanisms to KRAS G12Ci Treatment in Patients Further Support Combination of KRAS G12Ci with VS-6766 Summary of Putative Mechanisms of Acquired • Mechanisms of acquired resistance to KRAS G12Ci Resistance to Adagrasib Treatment adagrasib treatment in patients recently reported1,
Slide 34: RAMP 203: Phase 1/2 Trial of VS-6766 + Sotorasib
RAMP 203: Phase 1/2 Trial of VS-6766 + LUMAKRASTM (sotorasib) in KRAS G12C-mutated Advanced NSCLC Part A: Dose Evaluation Part B: Dose Expansion at RP2D Patients must have (3+3 DLT Assessment) (Primary endpoint ORR) known G12C KRAS mutation determined using validated test Cohort 1 Treatment with
Slide 35: RAMP 204: Phase 1/2 Trial of VS-6766 + Adagrasib
RAMP 204: Phase 1/2 Trial of VS-6766 + Adagrasib in KRAS G12C-mutated 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 than 3 pri
Slide 36: Future Opportunities: VS-6766 as Backbone of RAS Therapy
Future Opportunities: VS-6766 as Backbone of RAS Therapy
Slide 37: High Unmet Needs in RAS/RAF/MEK/ERK-Driven Cancers
High Unmet Needs in RAS/RAF/MEK/ERK-Driven Cancers KRAS-mutant NSCLC 31% Pancreatic Uterine 21% Colorectal Ovarian 45% 5% Incidence3,5: Incidence5: Endometrioid Incidence5: Incidence5: Cancers1 194K 58K 98% Incidence4,5: 59K 148K 22K NRAS-mutant Melanoma 28% Multiple Myeloma 20% Incidence5: Incidenc
Slide 38: Preclinical Synergy of VS-6766 with Promising Agents
Preclinical Synergy of VS-6766 in Combination with Promising Agents for Clinical Investigation Vertical MAPK Pathway Inhibition Parallel Pathway Inhibition VS-6766 + Palbociclib VS-6766 + pan-HERi (Afatinib) VS-6766 + SHP2i (RMC-4550) VS-6766 + SOS1i (BI-3406) VS-6766 100%+ CDK4/6i (5/5) 100% (5/5)(
Slide 39: VS-6766 + Everolimus Clinical Data Presented at ASCO
VS-6766 + Everolimus Clinical Data Presented at ASCO Pre-treatment VS-6766 + Everolimus • Well-tolerated RP2D established for VS-6766 + everolimus with intermittent dosing of both NRAS Q61K agents (twice weekly; 3 wks on/1 wk off) Anaplastic o No DLTs reported at RP2D thyroid cancer (lung metastasis
Slide 40: VS-6766 with anti-EGFR mAb Induces Regression in KRAS mt Colorectal PDX Model
Combination of VS-6766 with anti-EGFR mAb Induces Tumor Regression in a KRAS mt Colorectal PDX Model • VS-6766 + anti-EGFR (panitumumab) induces tumor regression in a KRAS G12V mt CRC patient-derived xenograft model Vehicle • G12Ci + anti-EGFR (sotorasib + panitumumab and adagrasib + cetuximab) have
Slide 41: Backup Slides
Backup Slides
Slide 42: Verastem Oncology Strategic Transformation
Verastem Oncology Strategic Transformation Q1 2020: In-licensed global rights to VS-6766, best-in-class RAF/MEK inhibitor, from Chugai PIPE financing based on data for new clinical program Q3 2020: Divested global rights to Copiktra to Secura Bio Q4 2020: Initiated registration-directed ph. 2 study
Slide 43: VS-6766 Monotherapy Has Shown Clinical Activity in RAS/RAF Mutant Cancers
VS-6766 Monotherapy Has Shown Clinical Activity in Several RAS/RAF Mutant Cancer Indications, Including NSCLC and Gynecologic Cancers Confirmed responses especially in patients with KRAS G12V mutation KRAS G12R 43 Guo et al., Lancet Oncology 2020
Slide 44: Overcoming Key Resistance Mechanisms to MEK Inhibitors
Overcoming Key Resistance Mechanisms to MEK Inhibitors p-FAK • MEK inhibition induces 150 compensatory activation of pFAK preclinically and clinically o Trametinib induced ↑ pFAK (Y397) 100 preclinically in KRAS mt NSCLC cell lines H-Score o Also observed in patients 50 • VS-6766 induced ↑ pFAK (Y39
Slide 45: VS-6766 and FAK Inhibitor Combination Leads to More Robust Anti-Tumor Efficacy
VS-6766 and FAK Inhibitor Combination Leads to More Robust Anti-Tumor Efficacy in vivo KRASmt Ovarian TOV-21G Tumor growth in vivo Model1 KRASmt NSCLC H358 in vivo Model2 VS-4718 + CH5126766 500 Tumor growth Vehicle 600 400 Vehicle (mm3 +/- SEM) Tumor volume Trametinib 0.3 mg/kg QD Tumor volume (mm3
Slide 46: Pharmacokinetic Profiles of VS-6766 + Defactinib in Combination
Pharmacokinetic Profiles of VS-6766 + Defactinib in Combination Similar to that Seen in Single Agent Studies VS-6766 Defactinib Dose AUC0-24h Cmax AUClast Cmax Cohort N Subject Cohort Dose (mg) N Subject (mg) (h*ng/mL) (ng/mL) (h*ng/mL) (ng/mL) 3.2 Mean 6179 354 Mean 2071 273 1 3 200 (with 200mg VS)
Slide 47: NSCLC Responses with VS-6766 + Defactinib Combination (n=20)
NSCLC Responses with VS-6766 + Defactinib Combination (n=20) Confirmed responses Best response inin2/2 by RECIST KRASpatients mt NSCLC with KRAS G12V mt NSCLC Tumor reduction in 4/6 patients with KRAS G12C mt NSCLC G12D G12C G12D G12C G12D G12D G12D G12D G12C G12C G12D G12C G12C G12A Q61H G12A G12V
Slide 48: Target Exposure for Preclinical Tumor Regression Covered by Twice Weekly Dosing
Target Exposure for Preclinical Tumor Regression is Covered by Twice Weekly Dosing of 4 mg VS-6766 3 wks on/1 wk off Cav for tumor regression from KRAS G12V mt NSCLC GEMM model Modeling of PK for 4 mg VS-6766 2/wk, 3 wks on/1 wk off, based on 4 mg single dose PK data (study NO21895) Relationship
Slide 49: VS-6766 Upregulates MHC Class I Antigens on Tumor Cells
VS-6766 Upregulates MHC Class I Antigens on Tumor Cells: a mechanism for potentiation of I/O efficacy B2M HLA-A 6 8 DMSO Relative mRNA Levels DMSO Relative mRNA Levels VS-6766 VS-6766 6 4 4 RAS/RAF mutation 2 Cell Line Tumor type 2 status 0 A549 TOV21g SKMEL5 IGR1 WM115 0 A549 TOV21g SKMEL5 IGR1 WM1
Slide 50: VS-6766 Enhances Tumor Growth Inhibition with Anti-PD-1
VS-6766 Enhances Tumor Growth Inhibition when Combined with Anti-PD-1 in the CT26 KRAS (G12D) Syngeneic Model Tumor growth Survival 1200 100 Vehicle 1000 80 VS-6766 0.5 mg/kg QD x 28 days Vehicle Percent survival anti-PD-1 3 mg/kg 2xW x 4 doses Tumor volume (mm3 +/- SEM) 800 VS-6766 0.5 mg/kg QD 60
Slide 51: Strong Patent Protection
Strong Patent Protection • COM for VS-6766 to 2027 & defactinib to 2028, Hatch Waxman should extend to 2032 • VS-6766 intermittent dosing regimen until 2038 • FAK/MEK combination to 2035 • VS-6766/defactinib combination until 2040 if granted • Method of manufacture for VS-6766 to 2032 • Other activi
Slide 52: Experienced Senior Management Team
Experienced Senior Management Team Brian Stuglik Daniel Paterson Rob Gagnon President and Chief Operating Chief Business and Chief Executive Officer Officer Financial Officer Global VP & Chief Marketing CEO – The DNA Repair Co. (now CFO – Harvard Bioscience, Clean Officer – Lilly Oncology On-Q
Slide 53: Thank You
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