Model predicts sotatercept will extend survival in PAH patients

Add-on investigational therapy estimated to prolong life by over 11 years

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Add-on treatment with sotatercept, an investigational therapy for pulmonary arterial hypertension (PAH) now under regulatory review in the U.S., was predicted to prolong survival by about threefold relative to standard of care therapy alone in a recent analysis.

The prediction model was built using short-term data from the Phase 3 STELLAR clinical trial (NCT04576988) of sotatercept as well as real-world outcomes from PAH patient registries.

While long-term information about the effects of sotatercept is not yet available, the analysis informs on its possible survival benefits for people with PAH. Other anticipated benefits of sotatercept included fewer hospitalizations and less of a need for infused prostacyclin therapy — treatments such as Flolan (epoprostenol GM), Veletri (epoprostenol AS), and Remodulin (treprostinil).

The findings serve only as a prediction and will “need to be confirmed by longer-term real-world studies,” the researchers wrote.

The study, “Population Health Model Predicting the Long-Term Impact of Sotatercept on Morbidity and Mortality in Patients with Pulmonary Arterial Hypertension (PAH),” was published in Advances in Therapy. It was funded by Merck, sotatercept’s developer.

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Predicting disease progression with and without sotatercept

Sotatercept is designed to reduce the abnormal growth of blood vessel cells that contribute to the narrowing of the vessels carrying blood from the heart to the lungs in PAH. It’s thought to do so by restoring a more normal balance of signaling molecules involved in cell growth.

The Phase 3 STELLAR trial that’s backing Merck’s regulatory application for the therapy evaluated the effects of sotatercept against a placebo among 323 adults with PAH.

Participants received subcutaneous or under-the-skin injections of sotatercept or a placebo once every three weeks on top of background PAH therapy for about six months.

Data indicated that sotatercept significantly increased exercise capacity in trial participants relative to the placebo. It also improved measures of heart health and blood flow, and prolonged the time to overall clinical worsening.

However, because of the trial’s short-term nature, it was difficult for the researchers to determine the add-on therapy’s effects on disease progression and survival.

As such, the scientists developed a computational model to simulate the long-term disease course for PAH patients when using background therapy with or without sotatercept.

Validated risk stratification tools were used to classify STELLAR participants’ risk level of disease progression, including heart or lung transplant or death, at the trial’s start. These tools rely on clinical factors like exercise capacity, markers of heart function, and other prognostic indicators.

Changes in risk stratification throughout treatment were assessed and used to predict risk beyond the trial period. Mortality and transplant probabilities also were based on data from a real-world PAH patient registry called COMPERA.

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Sotatercept predicted to extend survival in PAH by 11.5 years

Overall, predicted survival with background therapy alone was 5.1 years. Add-on sotatercept was associated with a predicted survival of 16.5 years, amounting to an estimated survival benefit of 11.5 years.

“The longer life expectancy in sotatercept-treated patients was primarily driven by patients remaining in the low-risk health state for a longer duration,” the researchers wrote.

Moreover, the experimental treatment was linked to a greater number of years in which patients could live without needing infusions of prostacyclin therapies.

Specifically, patients using sotatercept were predicted to live about 14.7 prostacyclin-free years, whereas those on background therapy alone were predicted to live 3.1 such years.

Sotatercept also was associated with a predicted reduction of 683 PAH hospitalizations and four heart or lung transplants per 1,000 PAH patients.

The researchers noted that because the analysis relied heavily on STELLAR data, “the model’s predictions may be more informative for PAH populations with patient characteristics similar to those of the STELLAR trial population but may not be fully representative of all the patients with PAH.”

Factors such as geography, disease severity, or age could influence the findings. Nevertheless, previous trial analyses indicated that the benefits of sotatercept were consistent across most patient subgroups, according to the authors.

The study also did not account for potential broader long-term impacts of the treatment, including changes in life quality or costs of PAH care.

“Future research may be warranted to assess these broader implications related to sotatercept and other emerging novel therapies,” the researchers wrote.

An approval decision on sotatercept in the U.S. is due next March.

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