Following a phase 3 randomized controlled trial, researchers reported that sotatercept, when added to background therapy, reduced the risk of clinical worsening by 76% in patients with pulmonary arterial hypertension who were diagnosed within the past year. They also observed a clinical benefit after three doses.
Vallerie V. McLaughlin, MD, of the University of Michigan Medical School in Ann Arbor, and colleagues also found, "that treatment with sotatercept prevented one additional clinical worsening event for every five patients treated over a 12-month period, as compared with placebo." They added, “By improving the balance between proliferative and antiproliferative signaling, sotatercept is proposed to address one of the underlying causes of [pulmonary arterial hypertension (PAH)].”
Sotatercept is an activin-signaling inhibitor that targets a different pathway than existing PAH therapies, and the trial—called HYPERION—included a more real-world patient population than previous trials for the drug.
Among 320 patients, clinical worsening occurred in 11% of those who received sotatercept compared with 37% of those who received placebo during a median 13 months of follow-up. Deterioration in exercise performance was the most common event: it affected 5% of patients in the sotatercept group and 29% in the placebo group. Unplanned hospitalization for worsening PAH occurred in 2% and 9% of patients, respectively. "Such events are considered to be important because nonfatal clinical worsening events in patients with pulmonary arterial hypertension are associated with an increased risk of subsequent death, a relationship underscoring the need to monitor and prevent disease progression in these patients," the authors wrote. Death from any cause was reported in 4% of patients receiving sotatercept and 4% receiving placebo. No patients required atrial septostomy or lung transplantation.
Secondary outcomes also favored sotatercept. At 24 weeks, multicomponent improvement was observed in 29% of the sotatercept group compared with 15% of the placebo group. A low REVEAL Lite 2 risk score was achieved in 60% and 48%, respectively. Median change in 6-minute walk distance was 29 meters with sotatercept compared with 16 meters with placebo. Reductions in NT-proBNP levels were greater in the sotatercept group. Further, treatment effect was consistent across subgroups, "including patients with connective-tissue disease, those receiving double therapy for pulmonary arterial hypertension, and those at intermediate risk according to the REVEAL Lite 2 risk score or at intermediate–low risk according to the COMPERA 2.0 risk score," the authors wrote.
While the overall safety profile was similar between groups, treatment-related adverse events occurred more frequently with sotatercept (about 58% vs 30% of patients). More specifically, epistaxis occurred in 32% of patients receiving sotatercept compared with 7% receiving placebo, and serious bleeding events occurred in 4% (sotatercept) vs 2% (placebo) of patients. Telangiectasia was reported in 26% and 11% of patients, respectively. Serious adverse events were reported in about one quarter of each group. Discontinuation due to adverse events occurred in 3% of sotatercept patients and none of those receiving placebo. The authors noted that median duration of follow-up was longer in the sotatercept group than in the placebo group (about 15 months vs 12 months).
Patients were randomly assigned in a 1:1 ratio to sotatercept or placebo, given every 21 days by subcutaneous injection. Sotatercept was administered at a starting dose of 0.3 mg/kg and then escalated to 0.7 mg/kg. All patients had World Health Organization functional class II or III PAH diagnosed within 1 year and were on stable dual or triple background therapy for at least 90 days. The trial was stopped early because results from earlier sotatercept studies raised concerns about clinical equipoise. This early termination shortened follow-up and reduced the number of events, and therefore limited assessment of long-term safety and mortality. Thirty-three patients did not reach the 24-week visit due to early closure. Longer follow-up is needed to determine durability of benefit and long-term safety, the researchers wrote.
The trial was funded by Merck Sharp and Dohme, a subsidiary of Merck (Rahway, NJ). According to the report, the sponsor participated in study design, monitoring, and analysis. Academic authors had full access to the data and vouch for the completeness and fidelity of the trial to the protocol
