Guggenheim 3rd Annual Healthcare Innovation Conference - EDGEWISE THERAPEUTICS INC

Financial Performance:

• No specific financial metrics (revenue, earnings, cash flow, or debt) were disclosed in the transcript as the company is in the clinical development phase (Phase 3 for 7500, Phase 2 for 5400).

Guidance and Future Outlook:

• Phase 2 "Equinox" trial for drug candidate 5400 has commenced, with data expected in the second half of next year.
• Phase 3 trials for drug candidate 7500 are designed to be flexible via an adaptive protocol; if efficacy signals are observed in the non-obstructive group, the trial may expand to potentially save six months compared to static designs.
• Management anticipates a significantly larger market opportunity than the current $2–3 billion cap seen with cardiac myosin inhibitors (CMIs), targeting a broader patient population including the 200,000 symptomatic HCM patients.
• Long-term goal is to establish a label without a Risk Evaluation and Mitigation Strategy (REMS), contingent on demonstrating no concentration-dependent drop in ejection fraction (EF) relative to placebo.

Business Segments and Product Lines:

• 7500 (Levosimendan-like mechanism): Phase 3 program designed for both obstructive and non-obstructive Hypertrophic Cardiomyopathy (HCM). The primary endpoint is Peak VO2; secondary endpoints include KCCQ and VE/VCO2 slope.
  • Mechanism targets a regulatory protein on the sarcomere lever arm, offering high potency (4–5x) on diastolic relaxation without suppressing systolic contraction (EF).
  • Protocol allows physicians to titrate to a target dose of 150mg based on tolerability without mandatory repeated echocardiograms during dose escalation.
• 5400: In Phase 2 (Equinox trial) for Heart Failure with Preserved Ejection Fraction (HFpEF).
  • Differentiated PK profile with a 60-hour half-life, <10% coefficient of variability, and low risk of drug-drug interactions, making it suitable for older patients on multiple background medications.

Market and Competitive Landscape:

• Competitive Advantage: Differentiates from Cardiac Myosin Inhibitors (CMIs) which carry Black Box warnings for heart failure and REMS requirements due to EF drops, limiting their uptake by community cardiologists.
• Market Size: Management estimates current CMI market cap at $2–3 billion due to safety monitoring burdens; 7500 aims to unlock a much larger market by removing these barriers.
• Regulatory Alignment: Successfully coordinated with FDA, EMA, and Japanese regulatory societies to agree on Peak VO2 as the primary endpoint.
• Trial Design: Separate statistical powering for obstructive and non-obstructive HCM populations to satisfy FDA requirements for significance in both groups within a single umbrella protocol.

Risks and Challenges:

• Ejection Fraction (EF): While no EF drop was observed in Phase 2 data (1,000+ measures), management acknowledges the need to monitor relative delta from placebo in the Phase 3 safety database to ensure no heart failure signals emerge.
• Recruitment Uncertainty: Recruitment rates for obstructive (competitive landscape) vs. non-obstructive populations are unknown, potentially affecting trial timelines.
• AFib Risk: Acknowledges Atrial Fibrillation is intrinsic to HCM phenotype; managing this risk in a placebo-controlled setting is difficult, and cross-trial comparisons with competitors are hindered by this shared phenotype.
• Endpoint Interpretation: Initial proposal for a composite Z-score was rejected by agencies as hard to interpret; management pivoted to separate measurement of Peak VO2.

Management Commentary and Tone:

• Confidence: Tone was confident and assertive, highlighting the "very different" and "highly differentiated" mechanism of 7500 compared to CMIs.
• Strategic Wins: Expressed strong satisfaction with FDA acceptance of the titration-to-tolerability approach, removing the need for echo monitoring during dose escalation.
• Defense: Firmly addressed competitive marketing claims regarding AFib risk, attributing them to a lack of placebo-controlled comparative data in the CMI space.

Analyst Questions and Answers:

• Q: Dose Titration Protocol: Management confirmed patients will start low and titrate up to 150mg based on symptom tolerance (NYHA class, side effects), with no mandatory echocardiograms required for titration decisions.
• Q: Trial Duration: 24-week duration deemed sufficient due to the rapid onset of diastolic improvement; maximum dose (150mg) will be reached 16 weeks prior to the primary endpoint.
• Q: REMS Likelihood: Management believes a REMS will not be required if the trial shows no concentration-dependent EF decline or heart failure signal relative to placebo.
• Q: EF Inclusion Criteria: Inclusion criteria set at EF ≥60 to minimize risk, noting that EF variability is typically ±10%.
• Q: 5400 Differentiation: 5400 offers a tight PK profile suitable for the complex HFpEF population, contrasting with 7500's specific HCM focus.

Other Key Points:

• Safety Data: A 12-week echo is included in the protocol for safety database support and label filing, read by a core lab, but explicitly excluded from patient dose titration decisions.
• Adaptive Design: The trial allows for sample size adjustment based on blinded interim data, particularly beneficial for the non-obstructive arm where variability might be higher.
• Mechanism Science: Published preclinical and clinical data (including a paper in the latest quarter) demonstrates exquisite pharmacological control via small chemical structure changes (enantiomers) to avoid the "zero contraction" risk seen with direct ATPase inhibitors.