Late-breaking positive Phase 2 result at ACC.26 for difficult-to-treat Group 2 PH subgroup; Merck press release; high unmet need drives buzz; potential expansion of sotatercept (WINREVAIR) indications.
Sotatercept 0.3 mg/kg significantly reduced pulmonary vascular resistance compared to placebo at 24 weeks in patients with CpcPH-HFpEF (shift -1.02 WU; 95% CI -1.81 to -0.23; P=0.004).
RCT
54:55:55
Yes
Does sotatercept improve pulmonary vascular resistance in adults with combined post- and pre-capillary pulmonary hypertension associated with heart failure with preserved ejection fraction?
164 adults with combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction (CpcPH-HFpEF)
Sotatercept 0.3 mg/kg or 0.7 mg/kg every 3 weeks
Placebo every 3 weeks
Change in pulmonary vascular resistance at week 24surrogate
Sotatercept provides proof of concept for improving pulmonary vascular and cardiac hemodynamics in patients with combined post- and pre-capillary pulmonary hypertension associated with HFpEF.
Background: Combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction (CpcPH–HFpEF) involves remodeling in both the heart and pulmonary vasculature. Despite significant mortality, there are no proven therapies. Methods: In this multicenter, randomized, placebo-controlled, phase 2 trial, adults received sotatercept (0.3 or 0.7 mg/kg) or placebo every 3 weeks. The primary end point was change in pulmonary vascular resistance at week 24. Hodges–Lehmann shift estimates described placebo-adjusted changes. Results: 164 patients were randomized 54:55:55 to sotatercept 0.3 mg/kg, 0.7 mg/kg, and placebo, and baseline median pulmonary vascular resistance was 5.2 (interquartile range IQR 4.0–6.9) Wood units. The median change from baseline in pulmonary vascular resistance at week 24 was –0.67 Wood units in the sotatercept 0.3 mg/kg group, –0.33 Wood units in the sotatercept 0.7 mg/kg group, and 0.26 Wood units in the placebo group. The Hodges–Lehmann shift estimates in pulmonary vascular resistance were –1.02 Wood units (95% CI, –1.81 to –0.23; P =0.004) for 0.3 mg/kg and –0.75 Wood units (95% CI, –1.52 to 0.03; P =0.024) for 0.7 mg/kg sotatercept. Reductions were observed in mean pulmonary arterial pressure (0.3 and 0.7 mg/kg: –9.19 mm Hg 95% CI, –13.00 to –5.38 and –9.22 95% CI, –12.97 to –5.46) and pulmonary arterial wedge pressure (0.3 and 0.7 mg/kg: –3.04 mm Hg 95% CI, –5.77 to –0.32 and –2.53 95% CI, –5.33 to 0.28). Changes in 6-minute walk distance were 20.3 meters (95% CI, 1.5–39.1) for 0.3 mg/kg and 5.8 meters (95% CI, –17.3 to 28.9) for 0.7 mg/kg sotatercept. The most common adverse events with sotatercept (both groups) were increased hemoglobin and diarrhea. Conclusions: These findings provide proof of concept for improved pulmonary vascular and cardiac hemodynamics following activin signalling inhibition with sotatercept in patients with CpcPH–HFpEF.
“Similar to PAH trials, the benefits of sotatercept transcend the relatively modest reductions in resting PVR and highlight the importance of targeting inflammation, cell proliferation and endothelial function in HFpEF. As the biology of ligand traps evolves, sotatercept marks the first step in leveraging the power of signaling networks to reverse fibrosis and cellular hypertrophy. Notably, the CADENCE trial emphasizes the importance of targeting underlying biologic mechanisms responsible for disease, versus focusing solely on improving hemodynamic parameters.”
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Mardi Gomberg-Maitland
Ryan J. Tedford
David Langleben
Circulation
George Washington University
Medical University of South Carolina
Merck & Co., Inc., Rahway, NJ, USA (United States)
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Gomberg-Maitland et al. (Sun,) conducted a rct in Combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction (CpcPH-HFpEF) (n=164). Sotatercept vs. Placebo was evaluated on Change in pulmonary vascular resistance at week 24 (Hodges-Lehmann shift -1.02 Wood units (0.3 mg/kg), 95% CI -1.81 to -0.23, p=0.004). Sotatercept 0.3 mg/kg significantly reduced pulmonary vascular resistance compared to placebo at 24 weeks in patients with CpcPH-HFpEF (shift -1.02 WU; 95% CI -1.81 to -0.23; P=0.004).
www.synapsesocial.com/papers/69cb6526e6a8c024954b9309 — DOI: https://doi.org/10.1161/circulationaha.126.079918
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