GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - C4 THERAPEUTICS INC

Explicit Guidance:

• MOMENTUM Study (Simcitomide + Dexamethasone): Enrollment expected to conclude in the first quarter of 2027; no changes to this timeline anticipated. Initial investigator-assessed data expected in the second half of 2027 (specifically the second half of next year).
• Combination Study (Simcitomide + L-RENATINAB/BITE): Full data from all evaluated cohorts expected in mid-year 2027.
• Molecular Dosing Targets: Targeting an overall response rate (ORR) of at least 40% for accelerated approval consideration in the late-line setting (targeting up to 40%+ to exceed the assumed 25% background efficacy of off-label lines).
• Phase 3 MRD Targets: Aiming for a Minimal Residual Disease (MRD) negative Complete Response (CR) rate of at least 40% (targeting a 47% benchmark based on recent ELRI data) to support accelerated approval in a future Phase 3 study.
• Dose Confirmation: 75 micrograms cleared for safety and expanded in an expansion cohort; 100 micrograms escalated in an escalation cohort for monotherapy.

Business-Segment Outlook:

• Core Product (Simcitomide): Vision to become a "backbone therapy" for myeloma across the evolving landscape. The molecule is positioned to capture the shift of immune-based strategies (like BITEs) into earlier lines of therapy (2nd line, potentially 1st line).
• Clinical Trial Expansion: Operational footprint expanding from 13 centers in the U.S. (First-in-Human) to 60 sites (MOMENTUM), including U.K. and Western Europe.
• Pipeline Strategy: Platform focus shifting from oncology to inflammation, neuroinflammation, and neurodegeneration. Future pipeline generation expected to be capital-efficient.
• Combination Strategy: Simcitomide positioned as a prime combination partner to augment efficacy of other agents (e.g., BITEs, CAR-Ts) via dual mechanisms (anti-proliferation + immune activation).

Market and Competitive Outlook:

• Therapeutic Landscape: Immune-based strategies are migrating earlier; BITEs moving from late-line to 2nd line (potentially 1st line), citing recent positive trials and ASCO guideline updates.
• Competitive Differentiation: Simcitomide claims "best-in-class" potential due to pharmacology allowing 14 days on/14 days off dosing, lower protein binding, and lower dose requirements compared to competitors.
• Pricing/Regulatory Bar: Accelerated approval will be judged against contemporaneous peers, not historical CAR-T benchmarks which are moving earlier. Safety profile (low neutropenia, low GCSF use) is a key regulatory differentiator expected to facilitate label expansion.
• Market Positioning: Differentiates from competitors (e.g., Bristol Myers Squibb) who are developing labels to replace IMiD franchises in current settings; C4 is targeting earlier lines to build on durability and depth of response.
• Unique Opportunity: No other entity is currently pursuing an IMiD-BITE combination in a formal regulatory study (others limited to Phase 1 or co-op studies with lower doses/safety signals).

Macro / Industry Outlook:

• Industry Trend: Industry consensus shifting toward "saving" high-response-rate drugs for earlier lines rather than late-line salvage.
• Practice Guidelines: ASCO guidelines released recently now recommend second-line refractory myeloma patients be first considered for BITE-based regimens or CAR-T, validating C4's development strategy.
• Regulatory Pathway: Anticipates FDA will accept MRD-negative CR as a surrogate endpoint for accelerated approval in Phase 3, similar to recent approvals in the space.

Strategic Initiatives:

• New Studies: Launching Phase 1b Dara-Carfilzomib combination study in the coming year to establish safety/predictability for combination dosing.
• Platform Expansion: Developing non-equity dilutive collaborations for new targets in inflammation and neurodegeneration (specific targets not disclosed).
• M&A/Partnership: Exploring potential partnership for Simcitomide to leverage external resources, but currently focused on advancing the asset internally.
• Operational Goals: Establish Simcitomide as a "predictable dose" combination partner through upcoming Phase 1b data, enabling easier integration with other potent degraders.

Risks and Headwinds to Outlook:

• Regulatory Uncertainty: Accelerated approval requires an efficacy signal "interesting beyond" the 25% assumed background rate of off-label use; safety and duration of response are equally critical hurdles.
• Data Interpretation: Agency only considers independent response criteria, not investigator-assessed, for approval; independent data must align with safety/duration metrics.
• Dose Escalation Risks: While 75mcg is cleared, 100mcg combination potential still carries risk, though current data suggests safety is manageable at higher exposures.
• Clinical Trial Execution: Enrollment and recruitment targets rely on broadening the prescriber base (community docs vs. major centers); patient eligibility criteria remain strict (4th line+ or 3rd line+).
• Competitive Migration: As CAR-T and BITEs move to earlier lines, Simcitomide must prove sufficient durability and depth of response to compete in those earlier settings.

Management Tone on the Future:

• Confidence Level: High confidence ("most robust de-risk proof-of-concept," "best of both worlds," "unique opportunity"). Management expresses strong belief that the field has evolved to validate their strategy ("field has evolved... to exactly where we thought it would be").
• Differentiation: Emphasizes a "stark differentiating fact" regarding safety and dose-escalation capabilities compared to class peers (e.g., no need for dose reduction to 0.6mcg like other agents).
• Forward-Looking Narrative: Tone suggests a strategic pivot to capitalize on the "migration" of immune therapies to earlier lines, viewing Simcitomide as the ideal vehicle to drive this shift.
• Hedges: Acknowledges the need for caution regarding small sample sizes regarding MRD-negative signals but relies on modeling and precedents to set targets.

Miscellaneous:

• Timeline Specifics: First-in-Human study (72 patients) completed; MOMENTUM enrollment to Q1 2027; MOMENTUM investigator data H2 2027; Combination data mid-2027; Phase 3/accelerated approval filing likely post-2028.
• Clinical Metrics: Current H1-Human data showed 53% ORR at 100mcg, 40% at 75mcg, and 36% across all doses in a heavily pre-treated population (75% CAR-T/BITE refractory).
• Safety Profile: Lowest rate of Grade 4 neutropenia and GCSF use in the class, with no dose reductions or treatment discontinuations due to safety in the H1 study.