Two new approaches show promise in PAH


By Michael Woodhead

14 Mar 2023

Prof. Marius Hoeper

Patients with pulmonary arterial hypertension (PAH) may benefit from a novel first-in-class medication sotatercept and from use of a fixed-dose combination pill of existing therapies, according to two studies presented at the American College of Cardiology’s Annual Scientific Session (ACC23).

Results from an international, multicentre phase 3 trial involving 323 patients with PAH showed that those assigned to receive sotatercept on top of existing therapy experienced significant improvements in six-minute walk distance test (6MWD), the study’s primary endpoint.

Patients who received sotatercept also had a lower risk of death or worsening of their condition compared with patients on standard therapy.

Sotatercept is a fusion protein activin signalling inhibitor that blocks abnormal patterns of growth differentiation factors involved in PAH.

The Phase 3 STELLAR trial enrolled 323 adult patients (median age 48 years, 79% women) with PAH (WHO functional class II or III) who were receiving stable background therapy, of whom 60% had severe symptoms despite maximal therapy with three medications.

After a median follow up of 7.5 months the average improvement in 6MWD among patients receiving sotatercept was 40.8 meters, while patients who received the placebo showed no improvement.

The change was statistically significant and exceeded the clinically relevant benchmark of a minimum of 33 meters at which patients report a noticeable improvement in their walking capacity, said study investigators.

Patients receiving sotatercept also showed improvements in eight of nine secondary endpoints, including functional class, proBNP levels and several measures of quality of life.

Nine patients (5.5%) in the sotatercept group died or experienced at least one clinical worsening event, compared with 42 (26.3%) in the placebo group, a risk reduction of 84%.

Patients in the sotatercept groups also had statistically significant improvements in symptoms such as shortness of breath and fatigue, as well as in the ability to perform activities such as light household chores, whereas patients on placebo showed no improvements.

In addition, the sotatercept group saw a reduction in pulmonary arterial pressure, or blood pressure in the lungs, that was 13.9 mmHg larger than was seen in the placebo group.

“This is the most impressive reduction in the pulmonary arterial pressure that we’ve ever seen in pretreated patients with PAH,” said study investigator Professor Marius Hoeper of Hannover Medical School, Germany. “For me, it’s one of the strongest signals suggesting that we truly achieved some regression of the disease’s adverse changes in the pulmonary vessels. However, this remains a hypothesis that we need to explore in future studies.”

Sotatercept appeared to be safe and well tolerated, with adverse events including mild nose bleeds and bleeding of the gums, telangiectasias, increases in haemoglobin levels and lower platelet counts.

Professor Hoeper said the results establish the clinical utility of sotatercept as a new approach to the treatment of PAH in combination with existing approved therapies.

“It’s really a paradigm shift in how we will treat PAH in the future … what we see in our clinic is fascinating—patients who have been evaluated for lung transplantations coming off the transplant list, patients returning to work, young patients who have been ill for most of their lives starting at their first jobs. [This treatment] opens the door to further research aiming at restoration of a normal pulmonary blood flow.”

The study was funded by Acceleron Pharma Inc., a subsidiary of Merck Sharp & Dohme.

‘More is better’

Prof. Kelly Chin

Meanwhile, a separate study presented at ACC 23 showed that patients with PAH had approximately double the reduction in pulmonary vascular resistance (PVR) if they took a fixed dose combination tablet of two recommended PAH medications macitentan (10 mg) and tadalafil (40 mg) rather than either drug alone.

The phase 3 A DUE study enrolled 187 adult patients with PAH (WHO class II and III).  About half of the study participants were not yet taking any medications for PAH.

At week 16, participants assigned to the fixed dose combination tablet showed a significantly greater reduction in PVR compared to baseline than participants taking either drug alone, meeting the trial’s primary endpoint.

In the portion of the study that compared the fixed-dose combination with macitentan monotherapy, PVR decreased by 45% in the fixed-dose combination arm and by 23% in the monotherapy arm. In a comparison with tadalafil monotherapy, PVR decreased by 44% in the fixed-dose combination arm and 22% in the monotherapy arm.

There was also a trend for clinically relevant improvement in 6MWD in favour of the fixed dose combination.

“We were very happy with the results,” said study investigator Professor Kelly Chin, director of the pulmonary hypertension program at UT Southwestern Medical Center in Dallas.

“PVR fell in both patients who were on one therapy and patients who were on two, but it was a much larger decrease with fixed-dose combination therapy.”

“Across many studies, we’re seeing that more is better in terms of lowering PVR, and what we get with one medication is, for many patients, just not enough,” said Professor Chin.

“I would strongly recommend combination therapy with two medications initially for the majority of patients, and this combination has significant evidence that it’s effective and well tolerated,” she added.

The study investigators noted that patients taking the two-drug combination therapy were more likely to discontinue their assigned therapy due to adverse events, with anaemia, hypotension and swelling being the most common side effects.

The study was funded by Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson.

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