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Novel Tx Shows Early Promise for Pulmonary Arterial Hypertension

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Novel Tx Shows Early Promise for Pulmonary Arterial Hypertension

Patients with pulmonary arterial hypertension (PAH) treated with the investigational drug sotatercept showed significant improvements in pulmonary vascular resistance (PVR) and 6-minute walk distance in phase II findings from the PULSAR study.

At week 24, patients treated with 0.7 mg/kg of the drug had a 33.9% reduction in PVR values, compared with a 2.1% reduction in patients in the placebo group (P<0.0001), reported David Badesch, MD, of the University of Colorado in Aurora.

  • This research was presented at a conference and has not yet been published in a peer-reviewed journal.

And patients treated with a lower dosage of the drug for 24 weeks (0.3 mg/kg) had a 20.5% reduction in PVR (P=0.0027), according to findings presented at an American Thoracic Society virtual session on clinical trials held in advance of the full virtual program scheduled for August.

Currently available treatments for PAH generally promote pulmonary vessel dilation without addressing the underlying cause of the disease, Badesch noted.

Research has implicated imbalances in the bone morphogenetic protein and transforming growth factor (TGF)-beta as a key driver of PAH in all forms of the disease.

Sotatercept is a novel, first-in-class fusion protein designed as a selective ligand trap for the TGF-beta superfamily to rebalance pro- and anti-signaling pathways for the serine receptor kinase bone morphogenetic protein receptor type II (BMPR-II), a key molecular driver of PAH.

In a recent preclinical study, sotatercept showed consistent effects on key components of PAH, including pulmonary arterial smooth muscle cells and microvascular endothelial cell suppression.

“Sotatercept is proposed to act by re-balancing signaling between pro- and anti-proliferative pathways, thereby reversing the characteristic vascular remodeling seen in pulmonary arterial hypertension,” Badesch said.

The investigational drug has been granted breakthrough therapy designation from the FDA.

The PULSAR phase II trial was designed to evaluate the efficacy and safety of sotatercept in PAH, with the primary endpoint being change from baseline pulmonary vascular resistance over 24 weeks of treatment.

The study included 106 patients randomized to standard-of-care treatment plus placebo (32 patients), sotatercept 0.3 mg/kg (32 patients), or sotatercept 0.7 mg/kg (42 patients) subcutaneously every 21 days.

Just over a third of patients (35%) were receiving double background PAH-specific treatments and 56% were receiving triple background PAH-specific therapies.

In addition to achieving the primary endpoint, the phase II trial also met the protocol-defined improvement in the key secondary endpoint of 6-minute walk distance at 24 weeks, Badesch said.

He confirmed that both sotatercept dose groups showed at least a 50-meter (LS mean) increase from baseline, as demonstrated in the 0.3 mg/kg group (58 meters) and 0.7 mg/kg group (50 meters), allowing for a pre-specified pooled analysis.

Treatment with sotatercept (pooled analysis) achieved a 54-meter (LS mean) change from baseline and a placebo-corrected (LS mean) difference of 25 meters (nominal P=0.03).

NT-terminal pro-hormone B natriuretic peptide (N-proBNP) declined by 51% in the pooled sotatercept group versus the placebo group (P=0.0001), while right arterial pressure declined by 12% (P=0.03) and pulmonary arterial pressure by 20% (P=0.0001). Cardiac output (L/min) increased by 2% (absolute change +0.1).

“The PULSAR study achieved the objectives of demonstrating improvement in pulmonary vascular resistance and 6 minute walk distance at week 24 versus placebo,” he said. “Subgroup analysis favored sotatercept at both dose levels and in patients receiving mono, double, or triple (background) therapy.”

The drug was generally well tolerated, with a safety profile similar to that seen in other PAH-treatment populations, he reported, adding that a phase III study is in the planning stages.

The facilitator for the presentation, Steven Kawut, MD, director of the Pulmonary Hypertension/Pulmonary Vascular Disease Program at Penn Medicine in Philadelphia, said he was surprised that the drug did not appear to have a positive impact on cardiac output.

Badesch said the echocardiographic data is still being analyzed but suggests a possible improvement in right ventricular function with sotatercept use over time.

“The study was 6 months in duration, and we were using a drug that affects vascular structure as opposed to vasodilatation,” he said. “It is possible that we will see an effect on cardiac output later, but I think the principal effect is within the small vessels and pulmonary vasculature.”

Disclosures

The research was funded by Acceleron, which is developing sotatercept.

Badesch reported serving as a consultant and serving on advisory boards and steering committees for Acceleron; he also reported financial relationships with Actelion, Arena, Liquidia, Eiger, Complexa, and United Therapeutics.

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