Sotatercept Improves Exercise Capacity in PAH, Early SPECTRA Data Show

Treatment with Acceleron Pharma’s sotatercept leads to substantial improvements in cardiac parameters, as well as exercise tolerance and capacity, in people with pulmonary arterial hypertension (PAH) on standard therapies, early data from the SPECTRA Phase 2 trial show.

The findings, “SPECTRA and Beyond: Signs of Disease Modification? Preliminary Interim Data from the SPECTRA Phase 2 Trial of Sotatercept in Pulmonary Arterial Hypertension,” were presented by Aaron B. Waxman, MD, PhD, the lead investigator of the SPECTRA trial and a consultant to Acceleron, at the American Heart Association (AHA) 2020 Scientific Sessions virtual meeting. 

“The SPECTRA trial’s innovative design is meant to help us better understand and detect sotatercept’s potential effects on underlying disease pathology,” Waxman, director of the pulmonary vascular disease program at Boston’s Brigham and Women’s Hospital, said in a press release. “Despite the limited number of patients evaluated to date, it’s difficult not to be encouraged by the range and extent of positive changes seen in key hemodynamic [blood] and exercise capacity measures thus far.”

The open-label, multicenter study (NCT03738150) is currently investigating the effects of sotatercept given for 24 weeks in up to 25 adults with advanced PAH (World Health Organization functional class III). Patient recruitment is open at four locations in the U.S.; more information is available here.

Sotatercept (ACE-011) is designed to bind and trap members of the TGF-beta superfamily, including those involved in bone morphogenic protein (BMP) signaling — known to play a key role in the maintenance of healthy lung blood vessels.

Participants receive sotatercept by subcutaneous (under-the-skin) injections at a starting dose of 0.3 mg/kg, increasing to 0.7 mg/kg. During the study, patients are allowed to continue receiving stable background PAH therapies.

After completing the first 24 weeks (about six months) of treatment, participants have the option to enroll in an extension study and continue receiving sotatercept for an additional 18 months.

The study’s main goal is to assess changes in peak oxygen uptake or VO₂ max after six months of treatment. VO₂ max, measured using invasive cardiopulmonary exercise testing (iCPET), measures the maximal consumption of oxygen during exercise. In turn, iCPET has been a standard approach to evaluate treatment efficacy or prognosis in people with pulmonary hypertension and other conditions.

Additional goals include measurements of exercise capacity and tolerance, assessed by iCPET and right heart catheterization, such as pulmonary vascular resistance — which evaluates the internal resistance to blood flow within pulmonary arteries — and mean pulmonary artery pressure (PAP).

Preliminary findings from the first 10 patients in SPECTRA (six women, four men, median age 45) showed that treatment with sotatercept resulted in marked improvements in cardiac parameters, exercise tolerance, and exercise capacity.

According to the new data, at resting, the patients’ mean PAP decreased from 43.4 mmHg at the start of the trial (baseline) to 30.6 mmHg after three doses of sotatercept, representing a reduction of 29.5%. Significant improvements also were seen in pulmonary vascular resistance.

In his talk, Waxman highlighted the case of a 25-year-old woman who had been diagnosed with idiopathic PAH almost five years prior to joining the trial.

The woman, who was the first patient enrolled in the study, had advanced PAH and was taking a combination therapy of Adcirca (tadalafil) and Letairis (ambrisentan, marketed as Volibris in Europe).

At the start of the trial, the patient’s total distance covered in the six-minute walking distance test (6MWD) — a classic measure of functional capacity or endurance — was 285.5 meters or 936.7 feet.

As of Sept. 21, her functional class had improved from class III to class I following 24 weeks of treatment with sotatercept. The functional class I status was retained at follow-up testing at 48 weeks.

Her performance in the 6MWT increased by 183.2 meters (601 feet) from the start of the trial, from the initial 285.5 meters distance to 468.7 meters (1,537.7 feet). At the 48-week follow-up, the distance covered in the 6MWT was 443.7 meters (1,455.7 feet).

Overall, sotatercept was generally well-tolerated. The adverse events were consistent with those previously reported for sotatercept in PAH.

“We’re thrilled to see such positive preliminary outcomes from the SPECTRA trial, which serves as another important exploration of sotatercept and the potential of its unique mechanism to alter the course and treatment of PAH,” said Habib Dable, president and CEO of Acceleron.

In another presentation at the Scientific Sessions meeting, researchers shared data from an analysis of 51 participants in the PULSAR Phase 2 trial (NCT03496207), which investigated the effect of sotatercept — when given alongside standard PAH therapies — on a key measure in PAH called right ventricle–pulmonary artery (RV-PA) coupling.

Impaired function of the heart’s right ventricle is a central feature of PAH and the main factor affecting patients’ prognoses. RV-PA is estimated by the ratio of tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP),  and measures energy transfer between the right ventricle and the pulmonary artery. According to the researchers, a TAPSE/PASP ratio of 0.31 mm/mm Hg or higher is associated with a better prognosis and lower risk of clinical worsening.

The new data showed that, compared with the placebo, treatment with sotatercept led to statistically significant improvements in RV–PA coupling and RV function. After 24 weeks, both sotatercept dose groups (0.3 mg/kg and 0.7 mg/kg) had mean TAPSE/ PASP values above the cut-off limit of 0.31 mm/mm Hg, a benefit not seen in patients on the placebo.

“These results, combined with new PULSAR trial data presented at AHA and the topline PULSAR findings announced earlier this year, position us well to initiate a robust Phase 3 development program to realize our vision of sotatercept as a backbone therapy for patients with PAH across all stages of disease,” Dable said.

In fact, Acceleron recently announced plans to launch STELLAR, a Phase 3 trial of sotatercept in people with PAH before the end of the year. Two other Phase 3 studies in expanded PAH patient populations are expected to begin in mid-2021.