Combination therapy with sotatercept analog RAP-011 is superior to sildenafil alone in severe experimental PAH and RAP-011 benefits persist after treatment cessation

Background: Beneficial effects of sotatercept – an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that traps multiple members of the TGF-β superfamily, including activins and growth differentiation factors – have been reported in PAH patients treated with standard-of-care therapies in a recent phase 2 study (PULSAR). We previously reported that therapeutic treatment with a rodent analog of sotatercept (RAP-011) reverses vascular modeling in rats with established severe angio-obliterative PAH. Aims: To investigate: 1) whether RAP-011 adds therapeutic benefit when combined with sildenafil compared to sildenafil alone and 2) whether benefits of RAP-011 persist after monotherapy cessation. Methods: Sugen-hypoxia-normoxia rats were treated with RAP-011 or sildenafil as monotherapies, or in combination therapy, from weeks 5 to 9, after established disease. We evaluated structural and functional parameters for the pulmonary vasculature and right ventricle (RV) at week 9 and 4 weeks after treatment cessation. Results: Compared to vehicle controls, combination therapy yielded greater improvement than sildenafil alone for RV systolic pressure (↓65% vs 12%, P < 0.0001), total peripheral resistance index (↓83% vs 28%, P < 0.0001 ), RV hypertrophy (↓39% vs 4%, P < 0.0001), and RV fractional area change (↑72% vs ↓2%, P < 0.0001) at week 9. Improvements of this magnitude were maintained 4 weeks after cessation of RAP-011 monotherapy. Conclusions: Our results indicate that combination therapy with RAP-011 exerts effects superior to sildenafil alone and that benefits of RAP-011 persist 4 weeks after cessation of monotherapy.