Guggenheim 3rd Annual Healthcare Innovation Conference - EDGEWISE THERAPEUTICS INC

Explicit Guidance:

• No financial guidance (revenue, earnings, capex, or margins) provided; focus remains on clinical milestones.
• 7500 Primary Endpoint: Expected to be read out at 24 weeks from the start of dosing in the Phase 3 trial (implying patients reach max dose ~16 weeks prior to readout).
• 5400 Data Readout: Phase 2 Equinox trial data expected in the second half of next year.

Business-Segment Outlook:

• 7500 (Obstructive & Non-Obstructive HCM):
  • Market Expansion Potential: Management estimates current market cap for competitive Myosin Inhibitors (CMIs) at $2–$3 billion due to safety monitoring (REMS) requirements; anticipates potential for a "much broader market" by targeting 200,000 symptomatic patients and enabling treatment in community cardiology practices without restrictive monitoring.
  • Trial Structure: Will run as two separate trials (obstructive and non-obstructive) under one umbrella protocol, powered for statistical significance in both populations individually.
  • Adaptive Design: Protocol includes an adaptive feature to potentially increase sample size (N), particularly for the non-obstructive arm, if early efficacy signals are observed; estimated to potentially save six months if non-obstructive efficacy is confirmed.
  • Enrollment: Internal estimates suggest the non-obstructive population may recruit faster than the obstructive population, though competitive landscape dynamics may alter this.
  • Efficacy Profile: 7500 is hypothesized to act 4–5 times more potently on diastolic relaxation than systolic contraction, driving a "more rapid response" compared to CMIs.
• 5400 (HFpEF):
  • Target Population: Designed specifically for older HFpEF patients on multiple background medications; differentiated metabolic properties avoid difficult drug-drug interactions.
  • PK Profile: 60-hour half-life with low coefficient of variability (<10%) and steady-state accumulation in ~3.5 days, ensuring reproducible dosing.

Market and Competitive Outlook:

• Competitive Landscape (CMIs): Identifies a significant liability in current Myosin Inhibitors regarding dose-dependent reduction in ejection fraction (EF), leading to REMS requirements and black box warnings that limit community uptake.
• Differentiation: 7500 targets a regulatory protein on the sarcomere lever arm rather than binding directly to ATPase/actin, theoretically avoiding the "contraction down to zero" risk and allowing dose titration based on tolerability rather than EF monitoring.
• Regulatory Path: Anticipates alignment across FDA, EMA, and Japanese regulators on "Peak VO2" as the primary endpoint, though a composite "Z-score" endpoint was rejected by agencies as difficult to interpret for efficacy levels.

Macro / Industry Outlook:

• Regulatory Environment: Management expresses confidence that the specific trial design (no mandatory monitoring during titration, 12-week and 24-week core lab echos only for safety/labeling support) will preclude a requirement for a Risk Evaluation and Mitigation Strategy (REMS) label, unlike current CMIs.
• Safety Thresholds: Anticipates inclusion criteria for Ejection Fraction (EF) at 60% to minimize risk; notes that while some patients may dip below 50% in large trials (~800 patients), the key metric will be the delta relative to placebo rather than absolute values.

Strategic Initiatives:

• Trial Execution: Implementing an adaptive design to re-size the non-obstructive arm based on real-world data from the first 200–400 patients, rather than relying on pre-trial guesses.
• Dosing Strategy: Plan to titrate patients to a target maximal dose of 150 mg based on tolerability (NYHA status) rather than stopping at lower effective doses, aiming to maximize the clinical differential in peak VO2 and KCCQ.
• Pipeline Progression: Moving 5400 into Phase 2 Equinox trial; dosing initiated with healthy volunteer data already published confirming PK consistency.

Risks and Headwinds to Outlook:

• Enrollment Uncertainty: Recruitment rates for obstructive vs. non-obstructive populations remain unknown due to competing agents and a potentially approving competitor in non-obstructive HCM; one arm could outpace the other.
• Endpoint Interpretation: The primary endpoint (Peak VO2) is a single measure rather than a composite, which management believes is a "lowest common denominator" but may limit statistical power compared to the previously proposed Z-score.
• Safety Signals: Potential for patients to dip below EF 50% in the large Phase 3 cohort; management monitors the relative delta from placebo to determine safety.
• Market Size: While the 200,000 patient pool exists, actual uptake relies on overcoming the "gatekeeping" of cardiologists currently accustomed to monitoring requirements for CMIs.
• Atrial Fibrillation (AFib): Acknowledges AFib as a significant part of the HCM phenotype; notes that without a placebo arm in the trial design, it is "impossible to determine what the level of AFib is" or if it differs from the natural history of the disease.

Management Tone on the Future:

• Confidence: High confidence in the differentiated mechanism of action and the ability to avoid REMS requirements. Describes the FDA alignment on trial design as a "very important win."
• Cautious Optimism: Acknowledges the "long-winded" nature of regulatory coordination but remains confident in the "cleaner" approach of two separate powered trials.
• Strategic Clarity: Explicitly states that the goal is to "move the drug into the community cardiologist community" to unlock a larger market than competitors, though financial impact remains unquantified.

Miscellaneous:

• Echocardiography Usage: No echos required for dose titration; a 12-week echo is collected by a core lab solely to support the safety database for filing and is not used for label decisions or patient dosing adjustments.
• Mechanism Specifics: 7500 is a regulated regulator of the lever arm, distinguishing it from CMIs; the mirror image enantiomer (7500, 7,499) was noted to mimic CMI behavior, highlighting the "exquisite control of pharmacology" via small structural changes.