Sotatercept Eases Heart Strain, Improves Exercise Capacity in PAH, Trial Shows

Treatment with sotatercept (ACE-011) eased heart strain and improved exercise capacity in individuals with pulmonary arterial hypertension (PAH) participating in the Phase 2 PULSAR trial, according to Acceleron Pharma, the therapy’s manufacturer.

Sotatercept is an investigational compound designed to bind and entrap proteins from the transforming growth factor-beta (TGF-beta) family. These proteins help regulate the bone morphogenic protein (BMP) pathway, which is thought to be a key driver of PAH when dysregulated.

By trapping TGF-beta proteins, sotatercept aims to restore the balance of BMP signaling in the lungs, and potentially reverse the process of blood vessel remodeling associated with PAH.

“We’re thrilled to report such positive topline results from the PULSAR trial,” Habib Dable, president and CEO of Acceleron, said in a press release.

“PAH is a debilitating disease of high unmet medical need, so we’re encouraged by these data that signal that sotatercept could deliver added benefit to patients,” Dable said. “We look forward to upcoming interactions with health authorities as we plan to globally develop and, if approved, commercialize sotatercept in PAH.”

PULSAR (NCT03496207) is a randomized, double-blind, placebo-controlled study that is currently assessing the efficacy and safety of sotatercept in people with PAH.

The trial enrolled 106 participants, who were randomly assigned to receive one of two doses of sotatercept — 0.3 or 0.7 mg/kg — or a placebo. All were given by subcutaneous (under-the-skin) injections, every 21 days, for six months. During the trial, patients were allowed to continue receiving stable background PAH therapies.

Topline data from PULSAR showed the trial met its primary efficacy endpoint by demonstrating that those treated with sotatercept had a statistically significant reduction in pulmonary vascular resistance — a measure of heart strain — compared with those treated with a placebo. Pulmonary vascular resistance was measured by right heart catheterization,

The findings also revealed that participants receiving sotatercept experienced significant improvements in exercise tolerance as assessed by the Six-Minute Walk Test, and in World Health Organization functional class, a measure of disease severity. The patients on sotatercept also saw significant improvement in the levels of amino-terminal brain natriuretic propeptide (NT-proBNP), a prognostic biomarker of PAH.

Sotatercept was generally well-tolerated, and had a safety profile consistent with previous reports.

“As a selective ligand trap for members of the TGF-beta superfamily, sotatercept is designed to rebalance [BMP] signaling, which is a key molecular driver of PAH,” said Marc Humbert, MD, PhD, professor at the Université Paris-Saclay and an investigator on the PULSAR trial.

“The PULSAR data demonstrate that this novel approach has the potential to provide significant benefit on top of currently available therapies,” Humbert added.

Vallerie McLaughlin, MD, professor at the University of Michigan and an investigator on PULSAR, said the results were “particularly impressive” given that patient population had advanced hemodynamics, or bood circulation issues, and lengthy disease duration.

“These clinically meaningful data raise the exciting possibility that sotatercept could potentially shift the treatment paradigm for patients with PAH,” McLaughlin said.

Acceleron plans to present detailed results from the study at a medical conference later this year.

In the meantime, the company already has started enrolling the patients who completed PULSAR, and wished to continue treatment with sotatercept, into the study’s 18-month trial extension period. Among the 106 participants originally enrolled in PULSAR, 97 chose to proceed to the extension period. So far, none of the patients enrolled in the extension study have discontinued treatment.

In addition to PULSAR, Acceleron is conducting another Phase 2 study called SPECTRA (NCT03738150), evaluating sotatercept in PAH. That trial is currently recruiting participants at several locations in the U.S.