Sotatercept cuts death, clinical worsening by 84% in pulmonary arterial hypertension
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NEW ORLEANS — Sotatercept, a novel activin signaling inhibitor, reduced risk for death and clinical worsening by 84% in patients with pulmonary arterial hypertension compared with placebo, according to results of the STELLAR trial.
“I am convinced that this is going to be a paradigm shift in the way we treat pulmonary hypertension patients,” Marius M. Hoeper, MD, deputy director of the department of respiratory medicine and head of the pulmonary hypertension program at Hannover Medical School, Germany, told Healio. “We will continue to use the currently available treatments as background therapy, but most physicians will use sotatercept early on in the course of the disease, and patients will advocate for it.”
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For the phase 3, randomized, double-blind, placebo-controlled STELLAR trial, the researchers randomly assigned 323 patients (mean age, 47.9 years; 79.3% women; mean time between PAH diagnosis and enrollment, 8.8 years) with WHO group I and WHO functional class II or III PAH taking background PAH therapy to sotatercept (Acceleron Pharma/Merck) or placebo. The dosages were 0.3 mg/kg at the start, followed by 0.7 mg/kg every 3 weeks. Hoeper presented the findings at the American College of Cardiology Scientific Session, and they also were published simultaneously in The New England Journal of Medicine.
“Years ago, we thought pulmonary hypertension was basically pulmonary vasoconstriction,” Hoeper told Healio. “We learned that that is not the case. It’s remodeling caused by hyperproliferation of the endothelial and smooth-muscle cells lining the vessel. This hyperproliferation is caused by dysbalance of anti-proliferative and pro-proliferative signaling mediators and among the proliferative pathway activins and related proteins or ligands. Sotatercept is a fusion protein that contains the Fc domain of human immunoglobulin G1, which is bound to human activin-type IIa receptors. It acts as a ligand trap that binds to activins and other ligands, thereby restoring this balance. The beauty is that once you do this ... you can reopen the vessels, at least partly. We believe this is reverse remodeling. We cannot prove it in humans, but we see it in animal models, and all the data we have from human studies suggest reversal, or at least partial reversal, of the disease is also the case in humans.”
The primary endpoint was change in 6-minute walk distance between baseline and 24 weeks. Among the secondary endpoints was time to death or first clinical worsening event through the study completion on Aug. 26, 2022.
“Once the week 24 visit was reached, the patients continued to be in the study, blinded and taking the original treatment, up to the cutoff date, which was when the last patient completed the 24-week visit,” Hoeper told Healio. “At that time, most of the patients had been in the study much longer, so we have more signals of safety, tolerability and disease progression.”
The sotatercept group improved in 6-minute walk distance by 40.1 m between baseline and 24 weeks (95% CI, 29.9-50.2), compared with a decline of –1.4 m in the placebo group (95% CI, –13.2 to 10.3; P < .001), Hoeper said during the presentation.
The time to clinical worsening or all-cause death at a median follow-up of 32.7 weeks was dramatically lower in the sotatercept group compared with the placebo group (Hodges-Lehmann estimator of location shift = 0.16; 95% CI, 0.08-0.35; P < .001), he said.
“This is something we have never seen before,” Hoeper told Healio. “We usually see 40% to 50% risk reduction. This 84% is something unheard of.”
The sotatercept group also outperformed the placebo group in the following secondary endpoints:
- multicomponent improvement at 24 weeks, defined as improved 6-minute walk distance of at least 30 m; decrease of N-terminal pro-B-type natriuretic peptide levels by at least 30% or maintenance of achieved NT-proBNP level of less than 300 pg/mL; and improvement of WHO functional class, defined as shift from class III to class II or I, shift from class II to class I or maintenance of class II (P < .001);
- pulmonary vascular resistance (P < .001);
- NT-proBNP level (P < .001);
- WHO functional class (P < .001);
- French low-risk score (P < .001);
- PAH-SYMPACT Physical Impacts score (P = .01); and
- PAH-SYMPACT Cardiopulmonary score (P = .028).
“What was really special was the reduction in the mean [pulmonary artery] pressure, which was about 14 mm Hg, which is much more than any other drug,” Hoeper told Healio.
The proportion of patients who died or experienced a clinical worsening event was 26.3% in the placebo group and 5.5% in the sotatercept group, Hoeper said, noting the most common worsening events were the need to initiate rescue therapy or need to increase dose of infusion prostacyclin by 10% or more (placebo, 10.6%; sotatercept, 1.2%) and deterioration of PAH (placebo, 9.4%; sotatercept, 2.5%), and that death was the first event in 3.8% of the placebo group and 1.2% of the sotatercept group.
More than 90% of patients in both groups experienced treatment-emergent adverse events. The sotatercept group had more events related to treatment (47.2% vs. 26.9%), but fewer events leading to treatment discontinuation, events leading to study discontinuation, events leading to death, severe events, serious events and serious events related to treatment compared with the placebo group, Hoeper said.
The most common events in the sotatercept group were epistaxis (20.2%), dizziness (14.7%) and telangiectasia (14.1%), he said.
“The side-effect profile is quite different from all other drugs,” Hoeper told Healio. “We interfere with a system that we have never interfered with in medicine, a very tightly balanced angiogenesis system, and we did see systemic side effects, especially the development of telangiectasia ... and nosebleeds; I think these are related to the kind of mechanism. It’s not in everybody, but some patients do develop that. We also need to follow very closely the effect on internal organs.”
Sotatercept is not yet approved for commercial use in the United States.
“The company will seek approval, and I have little doubt, given the efficacy and the safety profile, that the drug will be approved and, hopefully, on the global market in the near future,” Hoeper told Healio. “I wonder what will happen when we use this compound in patients newly diagnosed. I would expect an even stronger response, but that needs to be demonstrated.”
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Julia Grapsa, MD, PhD, FACC
What I would tell a patient who is very keen to take this medicine is that they should be very careful if they had any bleeding incidents in the past. They need to advise their cardiologist and PAH specialist of this so they can balance the risks vs. the benefits. But overall, this is a promising agent for patients with PAH.
From the phase 2 trial, we knew that the drug reduces pulmonary vascular resistance and BNP, so there was already evidence that this is a promising agent. Now that we have these results from phase 3, I cannot wait to see it on the market. We need to use it in more patients and to see the long-term effects. I would be interested in getting more details about whether the drug is indeed causing reverse remodeling in the right ventricle and reversing the hypertrophy. I would like to see whether a patient with very heavy remodeling can get back to normal. If a patient sees benefit but the RV remains static, how long will that benefit last?
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Hoeper MM, et al. Late-Breaking Clinical Trials V. Presented at: American College of Cardiology Scientific Session; March 4-6, 2023; New Orleans (hybrid meeting).
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