PI-079 - PHARMACOKINETICS OF EDG-7500, A FIRST-IN-CLASS CARDIAC SARCOMERE MODULATOR FOR THE TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY
Wednesday, May 28, 2025
5:00 PM - 6:30 PM East Coast USA Time
M. Mok1, M. Madden1, J. Silverman1, C. Dufton1, D. Gretler1, J. MacDougall1, M. Evanchik1, M. Semigran1, A. Hunt2, M. Valentine3; 1Edgewise Therapeutics, Boulder, CO, United States, 2Celerion, Lincoln, NE, USA, 3Celerion, Lincoln, NE, United States.
Associate Director, DMPK Edgewise Therapeutics Boulder, Colorado, United States
Background: Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiac sarcomere characterized by excessive contraction and impaired relaxation of the heart. EDG-7500 is a first-in-class, oral (PO) small molecule cardiac sarcomere modulator being developed for the treatment of HCM. The compound acts through a novel calcium-dependent mechanism that allows it to slow the rate of myocardial contraction and improve cardiac relaxation. The pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of EDG-7500 were assessed in a Phase 1, randomized, double-blinded, placebo-controlled, single and multiple-ascending dose study in healthy adults. The relative bioavailability (rBA) and potential effect of food on the PK/PD of EDG-7500 were also assessed in an open-label, three-period, randomized crossover study. Methods: 48 healthy subjects (6 EDG-7500, 2 placebo per cohort) received a single PO suspension of EDG-7500 (5, 15, 50, 100, 200, and 300 mg), while 24 subjects received once-daily (QD) PO suspension of EDG-7500 (25, 50, 100 mg) for 14 days. In the rBA/FE study, 12 subjects received a single dose of EDG-7500 (50 mg) as a solid tablet or PO suspension on three occasions under fed and fasting conditions. Echocardiographic monitoring of LVEF was used to evaluate cardiovascular safety. Serial blood and urine samples were collected for PK/PD assessments Results: EDG-7500 exposure was generally linear and dose-proportional from 5 – 200 mg. Steady-state PK was achieved in the MAD cohorts with EDG-7500 (100 mg) PO QD x 14 days, resulting in a mean area under the curve (AUCINF) of 19,285 h∙ng/mL, Tmax of ~2 h, terminal half-life of ~30 h, and ~2-fold accumulation. All adverse events (AEs) were mild, except for one (moderate medical device site reaction), and resolved by the end of each study. No significant difference in Cmax or AUC exposures were observed between the tablet and suspension. No dose-response AEs, food effect, or clinically significant changes in LVEF were observed. Conclusion: EDG-7500 was well-tolerated in healthy subjects, and these results support its development as a potential first-in-class, cardiac sarcomere modulator, once-daily oral drug for HCM and other diseases of diastolic dysfunction.