Sotatercept Safely Maintains Efficacy in PAH Up to 2 Years: New Data
Patients switching to sotatercept also saw gains in heart function
Up to two years of treatment with sotatercept safely maintained gains in heart function and physical abilities in people with pulmonary arterial hypertension (PAH), according to details of the PULSAR study extension phase.
Further, participants who were initially assigned a placebo in the Phase 2 controlled trial, and switched to sotatercept in the extension study, demonstrated significant improvements across all primary and secondary efficacy measures. The results for these patients matched those of participants who had continued sotatercept for up to two years, the data showed.
“These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension,” the researchers wrote.
“Notably, 97/106 (92%) [of trial] participants continued into the extension period, highlighting the tolerability of sotatercept and the desire to receive therapy among this heavily treated participant population,” the team wrote.
Data were published in the European Respiratory Journal, in the study “Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension.” The study was funded by Acceleron Pharma, owned by Merck, which is developing sotatercept.
The BMP signaling pathway — a group of structurally related proteins that perform key cellular regulatory functions — plays an essential role in maintaining blood vessel function. But it also is responsible for vascular remodeling that contributes to PAH development.
Sotatercept is designed to sequester certain molecules in order to balance pro- and anti-proliferative signaling.
Testing sotatercept in PULSAR
The Phase 2 PULSAR study (NCT03496207), launched in 2018, compared sotatercept to a placebo in 106 PAH patients over 24 weeks, or about six months. It was designed to assess the therapy’s safety and efficacy.
In addition to standard-of-care therapy, sotatercept was administered every 21 days as an under-the-skin (subcutaneous) injection at a dose of 0.3 mg/kg or 0.7 mg/kg.
Top-line data after 24 weeks showed that sotatercept treatment led to clinically meaningful improvements in functional capacity and reductions in heart strain.
After completing six months of treatment, the patients given sotatercept had the option to continue receiving the therapy for an additional 18 months in an open-label extension study. Additional data showed that, after a further 24 weeks of treatment — for a total of 48 weeks, or roughly one year — extension study participants continued to show improvements in physical abilities and reduced PAH severity.
In this report, scientists at Acceleron Pharma, alongside PULSAR clinical investigators, now described the impact of 18–24 months (two years) of treatment, including an analysis of those who switched from a placebo to sotatercept.
Among the 106 PULSAR participants, a total of 97 (92%) entered the open-label extension study. Among them, 31 participants continued receiving the 0.3 mg/kg therapy dose while 36 received 0.7 mg/kg of sotatercept. From the placebo group, 15 patients were randomly assigned to the therapy’s low dose and 15 to the high dose.
Compared with before treatment (baseline), those who switched from the placebo demonstrated statistically significant improvements across all primary and secondary efficacy measures at 18–24 months. The mean pulmonary vascular resistance (PVR), the primary efficacy outcome, and a measure of heart strain, each decreased significantly.
Among secondary assessments, the mean distance walked in six minutes (6MWT) increased from 409 meters (about 1,340 feet) to 480 meters (approximately 1,575 feet). The mean levels of heart disease marker NT-proBNP decreased from 840 to 363 picograms/mL.
There also were significant improvements in the World Health Organization functional class (WHO FC), another measure of PAH severity.
In addition, sotatercept significantly reduced mean pulmonary arterial pressure and right atrial pressure from baseline to months 18–24. The researchers reported that no significant changes were seen in the cardiac index and cardiac output, two measures of heart function, nor in the pulmonary arterial wedge pressure, an estimate of left atrial pressure.
Compared with participants who continued to receive sotatercept, those who switched from the placebo had similar measures of PVR, 6MWD, WHO FC, and NT-proBNP at months 18–24. The magnitudes of these improvements were similar between the two groups.
Any improvement in WHO FC was achieved in 27 of 66 (40.9%) of the continued-sotatercept participants and 16 of 29 (55.2%) of the placebo-switched group. Overall, 82 of 91 patients (90.1%) were classified as WHO FC I or II at months 18–24, defined as without or with minimal physical activity limitations.
Pulmonary vascular resistance improvements seen at six months were maintained throughout the entire 18–24–month extension period. Improvements in 6MWD, WHO FC, and NT-proBNP were at least sustained from the end of the placebo-controlled period throughout the entire extension study.
Regarding safety, the number of treatment-emergent adverse events (TEAEs) — side effects not occurring prior to treatment, or those present that worsen in intensity or frequency after treatment — decreased with more prolonged use of sotatercept
During months 1–6, 17.3% of participants reported headaches, 15.4% had diarrhea, and 14.4% developed a common cold. During months 7–12, 12.2% had headaches, 10.2% reported diarrhea, and 10.2% developed a cold. None of these TEAEs were experienced by any participants between months 13 to 24. The TEAEs were comparable regardless of sotatercept dose.
The majority of patients (61%) tolerated their dose without reduction; three-quarters experienced at least one dose delay, with about half of them due to problems related to the COVID-19 pandemic.
Among the 41 patients who needed a lower dose, 20 were due to TEAEs, and the rest to changes in hemoglobin, the protein that carries oxygen throughout the body. Within this group, 22 (21.2%) returned to a higher dose.
Stopping treatment due to TEAEs occurred in 10 (9.6%) of participants, and three deaths were reported (2.9%) but were not considered related to sotatercept by investigators.
During the extension phase, after about 1.5 years of treatment, on average, telangiectasia, or small, widened blood vessels on the skin, was seen in 11 (10.6%) of patients. These were mostly mild in all cases. There were no signs of internal blood vessel abnormalities in those with telangiectasia.
“Treatment with sotatercept in the PULSAR open-label extension period suggests a clinical benefit in participants re-randomised from placebo to sotatercept treatment,” the researchers concluded. “In those who continued sotatercept for 24 months, the initial benefits were maintained.”
Overall, researchers said the results support the therapy’s use and durability.
“This report characterises the longer-term safety and efficacy of sotatercept in adult participants with pulmonary arterial hypertension from the PULSAR open-label extension period,” the team wrote.