GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - VERASTEM INC

Financial Performance:

• No specific revenue, earnings, or cash flow figures disclosed; company is in clinical-stage biotech.
• Recent capital raise secured to fund clinical development programs.
• Commercial asset (AbMak, a Raf-MEK and FAC inhibitor approved in May 2025) reached break-even status, with sales revenue covering commercial force costs.

Guidance and Future Outlook:

• Targeting accelerated FDA approval for VS-7375 (KRAS G12D inhibitor) in second-line Pancreatic Ductal Adenocarcinoma (PDAC) via Target 201 study.
• Aiming for potential NDA submission in Q2 2026, with approval possible by year-end 2026.
• Full enrollment in PDAC and Colorectal Cancer (CRC) Phase 2 studies expected end of year; Non-Small Cell Lung Cancer (NSCLC) enrollment starting early next year.
• Three Phase 3 confirmatory trials in the frontline setting for PDAC, CRC, and NSCLC planned.
• Long-term goal to achieve durable disease control (6-month PFS rate of 67% in PDAC) and extend patient survival beyond the current standard of 12 months.

Business Segments and Product Lines:

• VS-7375 (KRAS G12D Inhibitor):
  • Positioned as "best-in-class" for KRAS G12D-driven cancers (PDAC, CRC, NSCLC) due to dual "on/off" inhibition and long residence time.
  • Selected dosage of 900 mg/day (vs. partner GenFleet's 600 mg) based on superior dose-proportional exposure and identical safety/tolerability profile.
  • PDAC Phase 1 data (intention-to-treat, n=22) shows 41% Overall Response Rate (ORR) in pre-treated patients, with two Complete Responses (CRs).
  • Target 201 study includes a randomization arm comparing single-agent VS-7375 vs. combination with Cetuximab (anti-EGFR) in second-line PDAC.
  • Phase 3 frontline PDAC study (Target 301) uses a three-arm design combining with Gemcitabine/Nab-paclitaxel (GMP) or S-1/S-1/5-FU/Leucovorin, excluding FOLFIRINOX to maximize tolerability.
  • CRC development path includes Phase 2 single-arm studies aiming for accelerated approval in 3rd line+ (benchmark: ~30% ORR) and Phase 3 frontline confirmatory trials starting H1 2026.
  • NSCLC development includes Target D202 (pre-treated) and upcoming frontline combo trials; includes cohort for patients with asymptomatic brain metastases.
• AbMak (Raf-MEK/FAC Inhibitor): Approved and commercialized; revenue covers operational costs.
• Partnerships: Collaboration with GenFleet (China, 600 mg dose); partnership with Eraska for Pan-RAS combination preclinical studies; upcoming announcement for PRMT5 inhibitor partner in PDAC.

Market and Competitive Landscape:

• VS-7375 differentiated from competitors (e.g., Zolifon-Mod, ERAS-001) by demonstrating superior molecular response at 900 mg and clinically meaningful 6-month PFS (67%) in PDAC.
• First G12D inhibitor to report durable PFS in second-line PDAC; competitors often lack single-agent PFS data.
• Unique combination strategy in CRC with Cetuximab in both late-line (Target 201) and frontline settings, capitalizing on preclinical synergy with EGFR inhibition.
• Competitor failure (CRYSTAL-10) in second-line without chemo combination viewed as setting different benchmarks; Veristem focuses on frontline chemo-combo and late-line settings.
• Market opportunity includes large pools of patients in PDAC, CRC, and NSCLC with KRAS G12D mutations.

Risks and Challenges:

• Clinical trial execution risks: Need to mature data for durability (DOR) and confirmatory Phase 3 success to support accelerated approval and subsequent full approval.
• Safety profile management: Ensuring tolerability remains high when combining with chemotherapy in frontline settings (avoiding FOLFIRINOX toxicity).
• Resistance mechanisms: Potential for resistance to G12D monotherapy, necessitating combo strategies (e.g., Pan-RAS, PRMT5 inhibitors).
• Competition: Active space with multiple G12D inhibitors and pan-RAS inhibitors; risk of lower response rates if single-agent efficacy is not robust enough.
• Brain metastasis efficacy: While a cohort exists, ensuring efficacy in patients with brain mets is critical for NSCLC positioning.

Management Commentary and Tone:

• Leadership Transition: Dan Patterson (CEO since 2011) stepping down; Michael Bailey to assume CEO role Jan 1st, selected for expertise in commercializing G12D inhibitors.
• Confidence: Management expressed high confidence in the 900 mg dose optimization and the "best-in-class" potential of VS-7375 based on consistent clinical data.
• Tone: Optimistic and aggressive regarding development timelines ("full steam ahead"), emphasizing rigorous data reporting (intention-to-treat, confirmed responses) to validate efficacy.
• Strategic Focus: Shift from purely preclinical/early clinical to commercialization and accelerated regulatory pathways.

Analyst Questions and Answers:

• Q: Dose selection (900 mg vs. 600 mg)? A: 900 mg chosen for optimal exposure based on preclinical models; safety profile identical to 600 mg (mostly Grade 1 GI disorders), no difference in durability.
• Q: PDAC response rate robustness? A: Data reported on 900 mg only (no dose pooling), including all treated patients; consistent 41% ORR across 2nd and 3rd line; two CRs observed (rare in G12D PDAC).
• Q: Timeline to market in PDAC? A: Aiming for submission in Q2 2026, with potential approval by late 2026; Target 201 enrollment completion expected end of current year.
• Q: Rationale for Cetuximab combination in PDAC? A: Preclinical data (CRISPR screen) identified EGFR as the strongest potentiator; clinical observations show deeper responses; Phase 2 randomized study to establish contribution for registration.
• Q: Frontline PDAC Phase 3 design (why no FOLFIRINOX)? A: FOLFIRINOX is too toxic; Veristem's single-agent potency with GMP is expected to yield similar ORR while preserving tolerability and single-agent activity which drives PFS after chemo stops.
• Q: CRC third-line approval benchmarks? A: Benchmark is ~30% ORR (vs. 6% for monotherapy); Target 201 has >50 patients; partner GenFleet reported 44% ORR.
• Q: NSCLC brain metastasis data? A: Phase 2 includes 25 patients with brain mets; data anticipated to be a differentiator as competitors lack blood-brain barrier penetration.
• Q: Future combination partners? A: Announcing PRMT5 partner soon (PDAC focus); partnered with Eraska for Pan-RAS combination (preclinical).

Other Key Points:

• Veristem highlights the "on/off" dual inhibition mechanism as a key driver for efficacy and resistance management compared to traditional tricomplex inhibitors.
• Management emphasized the need to improve survival outcomes in pancreatic cancer from the current median of 12 months.
• The company is prioritizing single-agent activity as the primary driver for PFS in randomized Phase 3 trials, rather than relying solely on combination synergy.
• Target 201 study allows for accelerated approval of both the single-agent and the Cetuximab combination if Phase 2 data supports it.