ORIC® Enozertinib Program Update Call - ORIC PHARMACEUTICALS INC

Financial Performance:

• No specific quarterly financial metrics (revenue, net income, cash flow) were disclosed as ORIC Pharmaceuticals is a clinical-stage biopharmaceutical company.
• Management confirmed cash runway guidance remains on track to extend into the second half of 2028.
• The cash runway base case accounts for the initiation of two Phase 3 trials: "Himalaya 1" (RINDSY) and "Redwood 1" (Enozertinib).
• No debt disclosures or specific profitability timelines were provided beyond the standard development cost burn rate implied by the runway.

Guidance and Future Outlook:

• Redwood 1: Global Phase 3 trial initiation is targeted for the first half of 2027.
• Regulatory Alignment: End-of-Phase 1 meeting with the FDA confirmed the Recommended Phase 3 Dose (RP3D) of 80mg once daily and aligned on trial design, endpoints, and control arm.
• Redwood 2: Plans to initiate a Phase 3 trial for EGFR exon 20 mutations in the same population are anticipated following the sharing of monotherapy and combination data in mid-2027.
• Top-line Data: Specific timing for ORR (accelerated approval) and PFS (full approval) readouts for Redwood 1 was not provided, pending trial activation.
• Long-term Goal: To establish Enozertinib as the best-in-class, first-line therapy for EGFR atypical NSCLC.

Business Segments and Product Lines:

• Enozertinib (Lead Asset):
  • Phase 1b Data (First-line EGFR Atypical): Updated data presented at ESMO shows 84% confirmed systemic ORR, 70% confirmed CNS ORR, and 88% 6-month landmark PFS in 26 patients.
  • Patient Population: Enrolled a highly challenging cohort with 65% baseline CNS disease (double the competitor rate), including 46% with untreated brain metastases.
  • Safety: No treatment-related discontinuations; manageable toxicity profile (Grade 3 AEs in 23%); no significant off-target toxicities (cardiac, hepatic, hematologic).
  • Mechanism: High brain penetrance, strong potency against atypical mutations (exon 19-like/719/S768/L861Q), and kinase selectivity.
• Exon 20 Development:
  • Evaluating three regimens: monotherapy, combination with chemotherapy, and combination with amivantamab.
  • Data on all three cohorts expected to be shared in mid-2027 to inform the Phase 3 design for the "Exon 20" program.
• Other Programs: Mention of "RINDSY" (RINDSY-M) for CRPC is noted regarding cash runway but not detailed in this update.

Market and Competitive Landscape:

• Market Opportunity: Addressable market for first-line EGFR atypical NSCLC estimated at >$2.5 billion annually in the U.S. and >$5 billion globally.
• Unmet Need: Current approved therapies (Afatinib, Osimertinib) lack optimal balance of efficacy, CNS penetration, and tolerability for atypical mutations; late-stage competitors (Firminertinib, Silivertinib) show negative PFS outcomes or high toxicity.
• Competitive Differentiation: Unlike competitors requiring treated/stable brain mets, Enozertinib allowed untreated brain metastases, demonstrating efficacy in a "hardest-to-treat" population.
• Market Share Potential: Blinded market research with 75 oncologists suggests a differentiated CNS-active product could capture ~60% market share.
• Historical Precedent: Cites Osimertinib (EGFR) and Alectinib/Lorlatinib (ALK) as examples of "best-in-class" CNS-active drugs achieving market leadership despite being 3rd-5th to market.

Risks and Challenges:

• Clinical Trial Complexity: High baseline CNS disease burden may complicate control arm outcomes if control agents lack CNS activity in this specific mutation set.
• Competitor Landscape: Recent Phase 3 failures in EGFR Exon 20 (e.g., Vermetinib) highlight the difficulty of developing monotherapies for this population.
• Regulatory Timing: Global Phase 3 initiation requires completing ex-US regulatory interactions and operational site onboarding before H1 2027.
• Small Sample Size: Phase 1b data is from a small cohort (26 patients); median PFS and Duration of Response (DoR) are immature.

Management Commentary and Tone:

• Tone: Highly confident and optimistic; described data as setting a "new benchmark" and "best-in-class."
• Differentiation Strategy: Emphasized that physician-driven enrollment of patients with untreated brain mets validates the drug's CNS activity rather than selection bias.
• Safety Confidence: Highlighted the absence of off-target toxicities as a key differentiator from competitors like Firminertinib (high toxicity) and standard of care.
• Strategic Focus: Reiterated commitment to rapid progression through late-stage development to capture the underserved patient population.

Analyst Questions and Answers:

• Enrollment Bias: Management clarified that the high rate of CNS disease was driven by investigator preference due to the drug's preclinical CNS profile, not study design manipulation.
• PFS Expectations: Management expects PFS differentiation to mirror the pattern seen in ALK/EGFR history, where CNS activity drives PFS rather than just systemic ORR.
• Control Arm Composition: The Phase 3 control arm will be "Physician's Choice" (Osimertinib or Afatinib), stratified by therapy choice and geography; no cap on allocation expected.
• L861Q Subgroup: Despite small numbers in Phase 1b (3 patients), all responded (1 CR); this subgroup will be stratified in Phase 3.
• Cash Runway: Initiating Redwood 1 in H1 2027 is already factored into the previous cash guidance of H2 2028.
• Exon 20 Strategy: Will wait for mid-2027 data on monotherapy vs. combinations (with Amivantamab or Chemo) to determine the optimal Phase 3 path, noting the toxicity challenges of chemo-combos.
• Regulatory Milestones: Dual primary endpoints (ORR for accelerated approval, PFS for full approval) align with FDA's Project Accelerated Approval/Project Butt Runner.

Other Key Points:

• Preclinical Differentiation: Inzertinib demonstrates a favorable therapeutic index with high potency in mutants vs. wild-type and zero off-target kinase binding.
• CNS Response Metrics: BICR analysis using modified RANO-BM criteria confirmed 67% intracranial ORR (40% CR) in evaluable CNS patients, including those with non-measurable disease.
• Patient Vignettes: Two specific cases highlighted where patients with untreated brain mets achieved complete responses and have been on treatment for 18+ months.
• Global Footprint: Phase 1 conducted across 39 centers in 10 countries, supporting the feasibility of a global Phase 3 trial.
• Market Research: Independent study validated that the "Best-in-Class" profile (high efficacy + low toxicity + CNS activity) drives strong prescribing intent among oncologists.