Confirmed benefits seen with Winrevair in trial for PH linked to heart failure
Approved therapy tested for CpcPH-HFpEF in proof-of-concept CADENCE study
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In a large clinical trial, treatment with Winrevair (sotatercept-csrk) significantly reduced pressure in the lungs’ blood vessels among adults with a form of pulmonary hypertension associated with heart failure, according to newly published data.
The injection therapy, approved in the U.S. for people with pulmonary arterial hypertension, was tested in the Phase 2 CADENCE clinical trial (NCT04945460) as a possible treatment for individuals with combined post- and precapillary and heart failure with preserved ejection fraction (CpcPH-HFpEF).
A complex condition, CpcPH-HFpEF is marked by dysfunction of the left side of the heart, which is normally responsible for pumping oxygen-rich blood out to the body. In CpcPH-HFpEF, the left heart beats normally but doesn’t adequately fill with blood between heartbeats. This leads to pulmonary hypertension — elevated pressure in the vessels that carry blood from the heart to the lungs — which strains the right side of the heart.
Merck, which sells Winrevair and sponsored the study through its subsidiary Acceleron, announced late last year that the trial testing the therapy for CpcPH-HFpEF had hit its main goal. Now, the findings have undergone peer review — a quality control process in which independent scientists review data for technical issues — and were detailed in a paper titled “Sotatercept for Combined Post- and Pre-capillary Pulmonary Hypertension Associated With Heart Failure: Results from the Phase 2, Randomized, Placebo-Controlled CADENCE Study.” The paper was published in the journal Circulation.
Mardi Gomberg-Maitland, MD, coauthor of the study at George Washington University School of Medicine and Health Sciences, said in a press release from Merck that the results “suggest that Winrevair has direct pulmonary vascular and cardiac [heart and lung] effects in this distinct population, which may translate to clinically meaningful improvements.”
According to Gomberg-Maitland, “these proof-of-concept data provide strong rationale for further evaluation in a Phase 3 study.”
Gomberg-Maitland noted that CpcPH-HFpEF “is a distinct, identifiable and well-characterized condition that develops in people with advanced heart failure and typically impacts people who are older and have other [coexisting] conditions.”
Though it is “an uncommon condition and underdiagnosed, it is associated with a high … mortality rate,” Gomberg-Maitland said, adding that “there are no approved treatment options specifically for CpcPH-HFpEF.”
CADENCE tested Winrevair for possible use in CpcPH-HFpEF
Winrevair is approved in the U.S. to boost exercise capacity, improve functional class, and reduce the risk of clinical worsening events in adults with PAH. It works by inhibiting certain signaling molecules that contribute to the abnormal growth of blood vessel cells.
The CADENCE trial enrolled 164 adults with CpcPH-HFpEF. Participants were randomly assigned to receive Winrevair at one of two maintenance doses (0.3 or 0.7), or a placebo, administered every three weeks for 24 weeks, or nearly six months. Data from CADENCE indicated that Winrevair was generally well tolerated, with a safety profile similar to what is seen in PAH patients.
The study’s main goal was to show that Winrevair would reduce pulmonary vascular resistance (PVR), a measure of how difficult it is for the heart to pump blood to the lungs. The trial hit this goal: Median PVR decreased by 0.67 and 0.33 Wood units in the low- and high-dose Winrevair groups, respectively. By contrast, in patients given the placebo, median PVR increased by 0.26 Wood units.
In other words, over the course of the trial, PVR on average improved for people given Winrevair but worsened for those given the placebo.
“Both [Winrevair] doses … demonstrated statistically significant reductions in PVR compared with placebo over a 24-week treatment period,” the researchers wrote.
Improvements with Winrevair relative to the placebo were also observed in other measures of lung blood vessel pressure, namely mean pulmonary arterial pressure and pulmonary arterial wedge pressure.
Treatment was also associated with benefits in a range of other secondary endpoints, including reductions in levels of a heart damage marker called NT-proBNP and delayed clinical worsening. Improvements were also seen in six-minute walk distance, which is a common measure of exercise capacity.
Differences in these secondary endpoints weren’t consistently statistically significant, however, meaning it’s mathematically plausible these differences are just random chance.
Planning underway for registrational study to test therapy
Merck is now planning a Phase 3 clinical trial to further evaluate Winrevair as a potential treatment for CpcPH-HFpEF. Because the lower 0.3 mg/kg dose of Winrevair showed a more potent effect on PVR and other endpoints, the new study will likely test this dose.
“The totality of evidence and consistency in trends across multiple endpoints from the CADENCE study support advancement of Winrevair into a registrational Phase 3 program in CpcPH-HFpEF,” said Mahesh Patel, MD, vice president of global clinical development at Merck Research Laboratories. Patel noted that while both doses were to some degree effective, the 0.3 mg/kg dose “may optimize the benefit-risk profile of Winrevair” in this specific patient group.
According to Patel, the company is now “working with regulatory agencies to design a Phase 3 registrational study with endpoints that focus on clinical outcomes most relevant to the needs of this population, with the ultimate goal of providing the first treatment option for CpcPH-HFpEF.”
