Verastem, Inc. · NASDAQ:VSTM
Verastem — Investor Presentation (October 2022)
52 slides from Verastem's investor presentation, Oct 4, 2022
Slide 1: Corporate Presentation October 2022
Corporate Presentation October 2022
Slide 2: Safe Harbor Statement
2 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
Slide 3: Verastem Oncology Well Positioned to Capitalize on Growth Opportunities
3 We are a biopharmaceutical company committed to developing and commercializing new medicines for patients battling cancer Verastem Oncology Well Positioned to Capitalize on Growth Opportunities VS - 6766 (RAF/MEK clamp) and defactinib (FAK inhibitor) are clinically active against RAS mutant cancer
Slide 4: Key VSTM Milestones 2021-2022
4 Key VSTM Milestones 2021 - 2022 LGSOC NSCLC 1H2021 2H2021 1H2022 RAMP 201 Amended to Include KRAS wt patients in Selection Phase RAMP 201 Target enrollment of Selection Phase Complete Initiated enrollment of Expansion Phase RAMP 202 Complete enrollment of Selection Phase Updated data from FRAME NS
Slide 5: VS-6766 is a Differentiated, Potentially Best-in-Class Asset
5 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 canc
Slide 6: Robust Clinical Program
6 INDICATION REGIMEN STUDY NAME PRECLINICAL PHASE 1 PHASE 2 PHASE 3 CLINICAL COLLABORATION WITH LGSOC 1,2 VS - 6766 +/ - defactinib RAMP 201 R/R LGSOC VS - 6766 + defactinib FRAME R/ R endometrioid cancer (RAS/RAF mt) VS - 6766 + defactinib FRAME Gynecological Cancers (RAS Pathway - driven) 4 VS - 6
Slide 7: Key Financial Statistics
7 Key Financial Statistics Cash, cash equivalents & investments $94.3M ($110.4M as of August 31, 2022) Non - GAAP Operating Expenses $19.6M Shares Outstanding 187.6M (210.0M as of August 31, 2022) As of and for the quarter ended June 30, 2022 Oxford Finance LLC Credit Facility Loan Tranches Event A
Slide 8: RAF/MEK Clamp Program Overview
VS - 6766 RAF/MEK Clamp Program Overview
Slide 9: Broad Development Opportunities Across RAS/MAPK Pathway-Driven Cancers
9 Broad Development Opportunities Across Multiple RAS/MAPK Pathway - Driven Cancers VS - 6766 High Priority Registration Indication Registration - Directed Trial Initiated in 4Q20 LGSOC 1,2 (RAMP 201) Key Signal Finding VS - 6766 + G12Ci KRAS G12C mt NSCLC 2 (RAMP 203 - sotorasib) & (RAMP 204 -
Slide 10: VS-6766 is a Unique Small Molecule RAF/MEK Clamp
10 VS - 6766 is a Unique Small Molecule RAF/MEK Clamp VS - 6766 (RAF/MEKi) Mirdametinib (MEKi) 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
Slide 11: VS-6766 Induces Inactive Complexes of MEK with ARAF, BRAF & CRAF
11 VS - 6766 is a Unique RAF/MEK Clamp which Induces Inactive Complexes of MEK with ARAF, BRAF & CRAF Contrasting mechanism of action vs. trametinib Deborah Morrison unpublished RTK RAS RAF MEK ERK Tumor Growth Growth factors + VS - 6766 Improved ERK blockade Feedback reactivation is blocked; Sustai
Slide 12: Inhibits Cell Proliferation Across Multiple RAS/MAPK Pathway Alterations
12 VS - 6766 Inhibits Cell Proliferation Across Multiple RAS/MAPK Pathway Alterations and Multiple Solid Tumor Histologies Reference: Adapted from Pachter RAS - Targeted Drug Discovery , Sep 2021 3D proliferation assay SW1463 MIAPACA2 H358 H1373 SW837 H2122 H2030 SW1573 HPAC ASPC1 HPAFII SNU-C2B LS5
Slide 13: Vertical Blockade: Backbone of Therapy for RAS/MAPK Tumors
13 Vertical Blockade: Establishing VS - 6766 as the Backbone of Therapy for RAS/MAPK Pathway - Driven Tumors ▪ Current Challenges • Blocking any single target in the pathway is insufficient for maximum depth and duration of anti - tumor efficacy • e.g., SHP2i, KRAS - G12Ci, RAFi, MEKi, ERKi • Vertic
Slide 14: Parallel Pathway Inhibition: Backbone of Therapy
14 Parallel Pathway Inhibition: Establishing VS - 6766 as the Backbone of Therapy for RAS/MAPK Pathway - Driven Tumors ▪ Current Challenges • Blocking Ras pathway can be circumvented through parallel pathways • e.g., PI3K/AKT/mTOR, FAK, RhoA, YAP • Combinations of MEKi + AKTi have shown poor tolerab
Slide 15: Favorable Tolerability Profile with Novel Intermittent Dosing Regimen
15 Favorable Tolerability Profile with Novel Intermittent Dosing Regimen VS - 6766 monotherapy Daily at MTD N=6 28 - day cycle RP2D VS - 6766 monotherapy 4mg twice weekly N=26 28 - day cycle RP2D (VS - 6766 3.2mg twice weekly + defactinib 200mg twice daily) N=38 21 days of 28 - day cycle Treatment R
Slide 16: Favorable Tolerability Profile for VS-6766 plus Defactinib
16 Favorable Tolerability Profile at Recommended Phase 2 Dose for VS - 6766 plus Defactinib Combination Regimen Treatment Related Adverse Events Details* (≥10% patients in cohort 3.2mg 6766 and Def 200mg ) VS - 6766 4mg Twice Weekly (4 wks of every 4 wks) 1 n=22 VS - 6766 3.2mg Twice Weekly Def 200m
Slide 17: VS-6766 +/- Defactinib in Low-Grade Serous Ovarian Cancer
VS - 6766 +/ - Defactinib in Low - Grade Serous Ovarian Cancer
Slide 18: 70% of LGSOC Tumors Driven by Mutations in the RAS/MAPK Pathway
18 70% of LGSOC Tumors Driven by Mutations in the RAS/MAPK Pathway LGSOC is a type of ovarian cancer that disproportionately affects younger women Patients often experience significant pain and suffering from their disease over time A slow growing cancer, that has a median survival of almost 10 year
Slide 19: LGSOC: Limited Treatment Options with High Unmet Need
19 LGSOC: Limited Treatment Options with High Unmet Need References: 1 NCCN guidelines v1.2022 2 No standard sequencing of drugs for recurrence disease Low - Grade Ovarian Cancer – Treatment Algorithm 1 Observe only Carbo - Pt + Paclitaxel + hormonal (2b) OR Chemo + Beva for Stage II - IV (2a) OR Ho
Slide 20: VS-6766 with Defactinib (FRAME) Shows Promising ORR in Refractory LGSOC
20 VS - 6766 in Combination with Defactinib (FRAME) Shows Promising ORR with Durability in Refractory LGSOC with Expanded Number of Patients (n=24) Reference: Banerjee et al., ESMO Sept 2021 Data cut off April 2021 PFS: Progression free survival NR: Not reached • Overall response rate (ORR) = 46% (1
Slide 21: RAMP 201 Registration-Directed Trial in Recurrent LGSOC
21 RAMP 201 Registration - directed Phase 2 Trial of VS - 6766 +/ - Defactinib in Recurrent LGSOC - KRAS Mutant (mt) and Wild Type ( wt ) *Dosing: Defactinib + VS - 6766 combo: Defactinib 200mg PO BID: 21/28 days + VS - 6766 3.2mg PO 2x/wk 21/28 days; VS - 6766 monothera py: VS6766 4.0 mg PO 2x/wk 2
Slide 22: RAMP Update - October 2022
22 RAMP 201 Update - October 2022 • Full enrollment based on the study protocol on track and expected by the end of the year • FDA meeting 4Q - 22 to align on regulatory path forward and go forward regimen • Completed second planned interim analysis • Encouraging efficacy results include independent
Slide 23: LGSOC Market Opportunity vs Other KRAS Opportunities
23 LGSOC Market Opportunity Larger or Comparable to Other High Unmet Need KRAS Opportunities NSCLC KRAS G12C 3 Pancreatic 3 LGSOC 3 Endometrioid 3 Metastatic uveal melanoma 3 ~6K patients US 1 ~80K patients WW 1 Patient - months of Therapy Per Year 2 (across all 2L+ patients) 1 References : Monk, Ra
Slide 24: VS-6766 +/- Defactinib in NSCLC
VS - 6766 +/ - Defactinib in NSCLC
Slide 25: High Unmet Need in Refractory mt NSCLC
25 High Unmet Need in Refractory mt NSCLC Adenocarcinoma Advanced or Metastatic NSCL Cancer Recommend Histologic and Molecular Subtyping 5 Appropriate targeted agent Chemotherapy Docetaxel Gemcitabine Pemetrexed Prior PD - (L)1 No Prior PD - (L)1 PD - (L)1 Chemo PD - (L)1 PD - (L)1 single ag
Slide 26: RAMP 202: Phase 2 Trial in Advanced NSCLC
26 RAMP 202: Phase 2 Trial of VS - 6766 +/ - Defactinib in Advanced NSCLC Primary Cohort: KRAS G12V mt NSCLC References: 1 Defactinib 200 mg PO BID (21/28 days) + VS - 6766 3.2 mg PO 2x/wk (21/28 days) 2 VS - 6766 4.0 mg PO 2x/wk (21/28 days) Advanced NSCLC 1 - 2 prior regimens 1 prior platinu
Slide 27: RAMP Results - August 2022
27 RAMP 202 Results – August 2022 • Results of Part A of RAMP 202 trial in KRAS - G12V mt NSCLC show VS - 6766 ± defactinib did not meet criteria to continue to expansion phase • Continue to analyze the results of the trial and integrate the findings into our development plans moving forward • Conti
Slide 28: RAMP 202: VS-6766 + Defactinib in BRAF mt NSCLC
28 RAMP 202: VS - 6766 + Defactinib in BRAF mt NSCLC References: 1 Defactinib 200 mg PO BID (21/28 days) + VS - 6766 3.2 mg PO 2x/wk (21/28 days) Advanced NSCLC 1 - 2 prior regimens 1 prior platinum - containing chemo; Prior CPI unless contraindicated Measurable disease (RECIST 1.1) Appr
Slide 29: Preclinical Synergy of VS-6766 + G12C Inhibitors in KRAS G12C Models
29 Preclinical Synergy of VS - 6766 + G12C Inhibitors in KRAS G12C mt Models Synergy of VS - 6766 + G12C inhibitors across G12C mutant NSCLC, CRC & Pancreatic cancer cell lines Doses Tested Trametinib: 0.3 mg/kg QD VS - 6766: 0.3 mg/kg QD FAKi: 50 mg/kg BID Sotorasib: 30 mg/kg QD Response @ Day 10 V
Slide 30: Acquired Resistance Mechanisms to KRAS G12Ci Support Combination
30 Acquired Resistance Mechanisms to KRAS G12Ci Treatment in Patients Further Support Combination of KRAS G12Ci with VS - 6766 Summary of Putative Mechanisms of Acquired Resistance to Adagrasib Treatment • Mechanisms of acquired resistance to KRAS G12Ci adagrasib treatment in patients recently repor
Slide 31: RAMP 203: Trial of VS-6766 + Sotorasib in KRAS G12C NSCLC
31 Patients must have known G12C KRAS mutation determined using validated test Treatment with at least 1 but no more than 3 prior systemic regimens, for Stage 3B - C or 4 NSCLC* Patient may have previously received adjuvant chemotherapy for earlier - stage disease Measurable disease accordin
Slide 32: RAMP 204: Trial of VS-6766 + Adagrasib in KRAS G12C NSCLC
32 RAMP 204: Phase 1/2 Trial of VS - 6766 + Adagrasib in KRAS G12C - mutated Advanced NSCLC Patients must have a KRAS G12C mutation determined using validated test Treatment with at least 1 but no more than 3 prior systemic regimens, for Stage 3B - C or 4 NSCLC Patient must have received prior
Slide 33: Future Opportunities: VS-6766 as Backbone of RAS Therapy
Future Opportunities: VS - 6766 as Backbone of RAS Therapy
Slide 34: High Unmet Needs in RAS/MAPK Pathway-Driven Cancers
34 High Unmet Needs in RAS/MAPK Pathway - Driven Cancers NSCLC Incidence 3,5 : 194K Colorectal Incidence 5 : 148K Pancreatic Incidence 5 : 58K Uterine Endometrioid Incidence 4,5 : 59K Melanoma Incidence 5 : 108K Multiple Myeloma Incidence 5 : 32K Melanoma Incidence 5 : 108K Colorectal Incidence 7 :
Slide 35: Preclinical Synergy of VS-6766 in Combination with Promising Agents
35 Preclinical Synergy of VS - 6766 in Combination with Promising Agents for Clinical Investigation H2122 SW837 H1373 SW1573 H358 H2030 MIAPACA2 0 10 20 30 40 50 VS-6766 + AMG 510 Combined Synergy Score NSCLC Panc Synergy Antagonism Indication CRC VS - 6766 + G12Ci (sotorasib) H2122 SW837 SW1573 H35
Slide 36: VS-6766 + Everolimus Clinical Data Presented at ASCO
36 VS - 6766 + Everolimus Clinical Data Presented at ASCO • Well - tolerated RP2D established for VS - 6766 + everolimus with intermittent dosing of both agents (twice weekly; 3 wks on/1 wk off) o No DLTs reported at RP2D • VS - 6766 + everolimus combo induced PRs in patients with various RAS mutati
Slide 37: VS-6766 with anti-EGFR mAb Induces Tumor Regression in KRAS mt CRC Model
37 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 • G12Ci + anti - EGFR (sotorasib + panitumumab and adagrasib + cetuxima
Slide 38: Patent Exclusivity
38 VS - 6766 Patent Exclusivity Composition of Matter Method of Making Sept 2032 Dosing Protocol May 2038 Combination w/ Defactinib 2041 - 2042 if issued Feb 2027 + 5 yrs (PTE) = 2032 Sept 2040 Methods of Treating PTE 2041 - 2042 if issued Combinations
Slide 39: Backup Slides
Backup Slides
Slide 40: VS-6766 Inhibits CRAF - Key Driver of KRAS G12V mt NSCLC
40 VS - 6766 Inhibits CRAF - The key driver of KRAS G12V mt NSCLC References: Ishii et al. Cancer Res (2013), Blasco, R. B. et al. Cancer Cell (2011), Lito, P. et al. Cancer Cell (2014), Sanclemente, M. et al. Cancer Cell (2018) A Precision Approach to KRAS G12V Driven NSCLC CRAF, but not BRAF, abla
Slide 41: VS-6766 +/- FAKi Induces Tumor Regression in KRAS G12V mt NSCLC
41 VS - 6766 +/ - FAKi Induces Significant Tumor Regression in KRAS G12V mt NSCLC in vivo Model, with Clear Differentiation from Trametinib Doses Tested Trametinib: 0.1 mg/kg QD (5 days/week) VS - 6766: 0.1 mg/kg QD (5 days/week) FAKi: 50 mg/kg BID (5 days/week) KRAS G12V mutant; Tp53 KO NSCLC • VS
Slide 42: Case Study: Response to VS-6766 + Defactinib in KRAS G12V NSCLC
42 Case Study: Response to VS - 6766 + Defactinib in a Patient with KRAS G12V mutant NSCLC Reference: Krebs et al. AACR 2021 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 20
Slide 43: Strong Signal Identified in KRAS G12V NSCLC
43 Strong Signal Identified in KRAS G12V NSCLC Preclinical evidence suggests combination with Defactinib may improve efficacy in KRAS G12V mt NSCLC Activity of VS - 6766 as a single agent and in combo with Defactinib in KRAS G12V mt NSCLC VS - 6766 ± Defactinib Has Shown a 57% ORR in KRAS G12V m
Slide 44: VS-6766 Monotherapy Has Shown Clinical Activity in RAS/RAF Mutant Cancers
44 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 Guo et al., Lancet Oncology 2020 KRAS G12R
Slide 45: Overcoming Key Resistance Mechanisms to MEK Inhibitors
45 Overcoming Key Resistance Mechanisms to MEK Inhibitors • MEK inhibition induces compensatory activation of pFAK preclinically and clinically Pre dose Post VS-6766 Post combination 0 50 100 150 p-FAK H-Score o Trametinib induced ↑ pFAK (Y397) preclinically in KRAS mt NSCLC cell lines o Also observ
Slide 46: VS-6766 and FAK Inhibitor Combination Leads to Robust Anti-Tumor Efficacy
46 VS - 6766 and FAK Inhibitor Combination Leads to More Robust Anti - Tumor Efficacy in vivo KRAS mt Ovarian TOV - 21G in vivo Model 1 KRAS mt NSCLC H358 in vivo Model 2 0 5 10 15 0 100 200 300 400 500 Tumor growth VS-4718 + CH5126766 Days on treatment Tumor volume (mm 3 +/- SEM) Vehicle Trametinib
Slide 47: NSCLC Responses with VS-6766 + Defactinib Combination (FRAME)
47 0 10 20 30 40 50 60 70 FRA101017 FRA102005 FRA101043 FRA101040 FRA101034 FRA101018 FRA102016 FRA101026 FRA101020 FRA101036 FRA102004 FRA101010 FRA102008 FRA102006 FRA102007 FRA101041 FRA102017 FRA102002 FRA102009 FRA101031 Time on Treatment (weeks) Unconfirmed PR Partial response Stable disease P
Slide 48: Target Exposures Covered by Twice Weekly Dosing of 3.2 mg
48 Target exposures for preclinical tumor regression & pERK inhibition in human subjects are covered by twice weekly dosing of 3.2 mg VS - 6766, 3 wks on/1 wk off Modeling of PK for 3 .. 2 mg VS - 6766 2 /wk, 3 wks on/ 1 wk off, based on 3 .. 2 mg single dose PK data (study CCR 3808 ) Relationsh
Slide 49: VS-6766 Upregulates MHC Class I Antigens on Tumor Cells
49 VS - 6766 Upregulates MHC Class I Antigens on Tumor Cells: a mechanism for potentiation of I/O efficacy Cell Line Tumor type RAS/RAF mutation status A549 Lung KRASmt G12S TOV21g Ovarian KRASmt G13C SKMEL5 Melanoma BRAFmt V600E IGR - 1 Melanoma BRAFmt V600E WM115 Melanoma BRAFmt V600E A549 TOV21g
Slide 50: VS-6766 Enhances Tumor Growth Inhibition with Anti-PD-1
50 VS - 6766 Enhances Tumor Growth Inhibition when Combined with Anti - PD - 1 in the CT26 KRAS (G12D) Syngeneic Model Reference: Pachter, RAS - Targeted Drug Development, Sept 2020 -100 0 100 200 300 400 Response at Day 13 % Change in Tumor Volume Vehicle VS-6766 anti-PD-1 VS-6766 + anti-PD-1 20 40
Slide 51: Experienced Senior Management Team
51 Experienced Senior Management Team Brian Stuglik Chief Executive Officer Cathy Carew Chief Organizational Effectiveness Officer Louis Denis, M.D. Chief Medical Officer Principal – HR Collaborative Ironwood, ActiveBiotics, Dynogen, Tufts Health Plan CMO, Asana BioSciences Boehringer - Inge
Slide 52: Verastem Oncology
\W VERASTEM ONCOLOGY