Sotatercept Reduces Heart Strain, Improves Functional Capacity in PAH, Data Show

Sotatercept (ACE-011) leads to clinically meaningful reductions in heart strain and improvements in functional capacity in patients with pulmonary arterial hypertension (PAH), top-line data from a Phase 2 trial show.

The findings were presented in an oral presentation, titled “Sotatercept for the Treatment of Pulmonary Arterial Hypertension,” during the ‘Breaking News’ session of the American Thoracic Society 2020 Virtual Conference (ATS 2020 Virtual).

Sotatercept is an investigational compound being developed by Acceleron Pharma as a potential treatment for PAH. It is designed to bind and trap members of the transforming growth factor-beta (TGF-beta) family, which control multiple signaling cascades in the body, including the bone morphogenic protein (BMP) pathway.

BMP signaling is known to play a key role in the maintenance of healthy lung blood vessels. By binding and blocking the activity of TGF-beta proteins, sotatercept is thought to help restore the balance of BMP signals in the lungs, which are believed to be drivers of PAH development and progression.

A Phase 2 trial called PULSAR (NCT03496207) is currently investigating the safety and efficacy of sotatercept, when given alongside standard-of-care PAH therapies, in 106 PAH patients at 44 sites in eight countries.

In the trial, patients were randomly assigned to receive either sotatercept at a dose of 0.3 mg/kg or 0.7 mg/kg through a subcutaneous (under-the-skin) injection, or a placebo, every 21 days, for six months (24 weeks).

After completing the first six months of treatment, patients had the option to enroll in an extension study and continue receiving sotatercept for an additional 18 months.

The study’s main goal was to assess changes in pulmonary vascular resistance, a measure of heart strain, determined by right heart catheterization, from the start to the end of treatment. Secondary goals included assessing changes in the total distance covered in the six-minute walking test (6MWT), a classical measure of functional capacity or endurance.

Exploratory outcomes included evaluating changes in the levels of the N‐terminal pro‐brain natriuretic peptide (NT-proBNP) — a prognostic marker of pulmonary hypertension — mean pulmonary arterial pressure, and WHO functional class.

Top-line findings from PULSAR now announced by Acceleron showed the trial achieved its main goal, with sotatercept being superior to the placebo at reducing patients’ heart strain over a period of six months.

According to the new data, when given at a dose of 0.3 mg/kg or 0.7 mg/kg, sotatercept significantly reduced pulmonary vascular resistance by 20.5% and 33.9%, respectively. In the placebo group, pulmonary vascular resistance dropped by 2.1%.

Sotatercept was also superior to the placebo at improving patients’ functional capacity at 24 weeks. On average, those receiving sotatercept were able to walk 54 meters farther than at the beginning of the study, whereas those given the placebo were able to cover an additional 25 meters.

“We’re thrilled to report the impressive magnitude of the positive effects that sotatercept, in combination with current therapies, was able to achieve in patients with PAH,” Habib Dable, president and CEO of Acceleron, said in a press release. “As we work now with health authorities to move sotatercept into Phase 3 testing, we are increasingly encouraged that we will be able to deliver a truly innovative therapy to patients with this debilitating disease.”

Improvements in exploratory outcomes were also observed, with sotatercept lowering the levels of the NT-proBNP by 51%, and mean pulmonary arterial pressure by 20%. Additionally, approximately a fourth (23%) of the patients receiving sotatercept saw their WHO functional class improve (the higher the WHO functional class, the worse the patient’s condition).

Treatment was found to be safe and generally well-tolerated in the trial. Adverse events observed in patients treated with sotatercept were consistent with findings from previous studies in other patient populations.

Serious treatment-emergent adverse events were more common among patients who received the highest dose of sotatercept (24%), than in those treated with the lowest dose of the medication (6%) or the placebo (9%). The most common treatment-emergent adverse events included headache, diarrhea, peripheral edema (fluid accumulation and swelling), dizziness, fatigue, hypokalemia (low potassium levels), and nausea.

“These results, seen on top of existing therapies in heavily pretreated patients, are consistent with sotatercept exerting its effects through a mechanism distinct from currently approved agents,” said David Badesch, MD, professor of medicine and clinical director of the Pulmonary Hypertension Center at the University of Colorado, who presented the findings at ATS 2020 Virtual.

“If sotatercept’s efficacy and safety are confirmed in the next phase of clinical development, I believe it has the potential to substantially alter the way we treat patients with PAH,” Badesch added.

The team is now planning a Phase 3 program for sotatercept.

From the 106 patients who participated in PULSAR, 97 opted to enroll in the study’s extension study, with 94 of them still receiving treatment as of June 22. A total of 64 patients have now been receiving sotatercept for at least one year.