Sotatercept, Fixed-Dose Combo Therapy on the Right Path for PAH

NEW ORLEANS -- The limited clinical evidence thus far supports investigational compounds for addition to or simplification of existing frontline therapies for pulmonary arterial hypertension (PAH), according to two trials presented here at the American College of Cardiology (ACC) annual meeting.

The activin signaling inhibitor biologic sotatercept showed promise as an add-on to usual treatment for PAH by conferring additional improvements in 6-minute walk distance (6MWD) 24 weeks into the STELLAR trial, reported Marius Hoeper, MD, a respiratory and ICU physician at Hannover Medical School in Germany.

Sotatercept, which targets the pro-proliferative and anti-proliferative signaling associated with pulmonary arterial wall and right ventricular remodeling in the rare disease, was also tied to short-term reductions in clinical worsening events among PAH patients with slight to marked functional limitations and shortness of breath during some activities at baseline (WHO functional class II or III).

In a similar population in the A DUE trial, macitentan (Opsumit)/tadalafil (Adcirca), a fixed-dose combination pill, reduced pulmonary vascular resistance (PVR) over monotherapy with either agent. This could improve treatment adherence, especially since PAH is commonly accompanied by lung disease and heart disease, creating a large pill burden, according to Kelly Chin, MD, a pulmonary and critical care specialist at UT Southwestern Medical Center in Dallas.

Sotatercept in STELLAR

Sotatercept improved exercise capacity for PAH patients on background therapy in the dose-ranging STELLAR study, earning further investigation in a larger phase III program.

Hoeper told the audience at ACC that the biologic induced greater improvements in 6MWD from baseline to week 24 compared with placebo (+34.4 vs +1.0 m), in addition to a broader multicomponent endpoint (38.9% vs 10.1%, P<0.001) counting patients who met the criteria for improvements in:

• 6MWD (better by ≥30 m)
• NT-proBNP level (decrease of ≥30% or maintenance/achievement of NT-proBNP <300 pg/mL)
• WHO functional class (downward shift or maintenance of class II)

Notably, sotatercept recipients were much less likely to die or experience a clinical worsening event over a median 32.7 weeks (5.5% vs 26.3% for placebo, HR 0.16, 95% CI 0.08-0.35).

"These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH," Hoeper said.

He nevertheless emphasized that endothelin receptor antagonist (ERA) treatment or a phosphodiesterase-5 (PDE5) inhibitor should still remain upfront therapy for these PAH patients, even if sotatercept makes it to the market. "That's not going to change," he said.

Results from STELLAR were also published in the New England Journal of Medicine.

In the trial, treatment-emergent adverse event rates were over 90% in both study groups. However, sotatercept was associated with more nose bleeds, dizziness, telangiectasia, increased hemoglobin, thrombocytopenia, and increased blood pressure.

Julia Grapsa, MD, PhD, a heart failure specialist at Guy's and St. Thomas' NHS Foundation Trust and King's College London, said she believed the overall benefit of sotatercept is greater than its risks.

"To me, this study is new hope for PAH patients," Grapsa, who was not involved in the STELLAR trial, said during a press conference.

Hoeper and team randomized 323 adults to placebo or sotatercept (0.3 mg/kg starting dose to 0.7 mg/kg) every 3 weeks. Mean age was 48, 80% were women, and 90% were white.

Background PAH therapy at baseline included triple therapy for 61% of patients and prostacyclin infusion therapy for 40%.

The study investigators were unable to identify predictors for patients most likely to respond to sotatercept, which performed similarly across subgroups of patients with idiopathic heritable PAH, connective tissue disease, and other forms of PAH, Hoeper said.

Another important unknown is what happens if PAH patients take sotatercept soon after diagnosis, not after 9 years, as was the case in the trial.

Dual Macitentan/Tadalafil in A DUE

Use of a macitentan/tadalafil fixed-dose combination single tablet was associated with better hemodynamics than either treatment alone, according to the small A DUE trial.

Change in PVR significantly favored the fixed-dose combination over macitentan monotherapy (-29%, P<0.0001) and tadalafil monotherapy (-28%, P<0.0001), Chin reported.

Exercise capacity by the 6MWD at week 16 was not significantly improved with the macitentan/tadalafil combination, though this particular analysis was not sufficiently powered, Chin told the audience.

A fixed-dose combination of macitentan and tadalafil would purportedly help PAH patients adhere to these medications. In the 2022 European guidelines, macitentan 10 mg and tadalafil 40 mg are recommended as combination therapy in newly diagnosed PAH patients and in most patients over follow-up.

Chin said that patients are usually on two or three medications for PAH, one or two diuretics, and potassium for some. That comes out to six to eight pills for pulmonary hypertension, not counting other medications for the typical comorbidities of diabetes, hypertension, and hyperlipidemia. The fixed-dose tablet would actually mean two fewer pills for patients, as tadalafil 40 mg comes in two pills, she told MedPage Today.

"The results from this study demonstrate that a single tablet combination has the potential to support initial dual combination therapy and rapid escalation from monotherapy, which may improve functional outcomes and help close the gap from guideline recommendations to clinical practice," Chin said in a press release.

As for safety, however, combination macitentan/tadalafil therapy was associated with increases in edema, anemia, and hypotension. Three patients in this arm died (judged unrelated to treatment).

Long-term efficacy and safety of this front-loaded combination therapy will need to be supported by all-cause mortality and readmission rates in future large studies, commented Biykem Bozkurt, MD, PhD, a heart failure specialist at Baylor College of Medicine in Houston, during a press conference.

Macitentan is available by itself to women only under an FDA-mandated Risk Evaluation and Mitigation Strategy due to a risk of embryo-fetal toxicity. Women with reproductive potential must comply with pregnancy testing and contraception requirements if they wish to receive the medication.

A DUE was a phase III trial conducted across 148 sites in 19 countries, and included 187 adults with PAH in WHO functional class II or III who were treatment naive or on a stable dose of an ERA or PDE5 inhibitor. Mean age was about 50, and over 70% were women. They were randomized to macitentan/tadalafil combination therapy or one of the two monotherapies.

Moving forward, Bozkurt said that a strategy of starting macitentan and tadalafil sequentially, whether within a week or 2 weeks, should be studied as a comparator to simultaneous initiation of agents.

In addition, real-world costs may be an issue for a polypill, as has been shown in the heart failure field, she said.