Add-on sotatercept offers hope for rare heart-lung disorder

The phase III STELLAR trial lives up to its name, delivering stellar results and offering hope for patients with pulmonary arterial hypertension (PAH), a rare, progressive, life-threatening disorder affecting the heart and lungs, by adding sotatercept – a novel first-in-class activin signalling inhibitor – to background therapy.

“Our study met its primary endpoint [and] eight out of the nine prespecified secondary endpoints,” said principal study investigator Dr Marius Hoeper from Hannover Medical School, Hannover, Germany, at ACC.23/WCC.

A 40-m improvement from baseline 6MWD* was seen in the sotatercept arm at week 24, as opposed to a 1.4-m drop in the placebo arm. The Hodges-Lehmann location shift estimate yielded a statistically significant difference of 40.8 m (p<0.001), representing a profound improvement in exercise capacity. [ACC.23, abstract LBA 410-14]

 

Secondary, exploratory endpoints

The six secondary outcomes that were highly statistically significant were multicomponent improvement**, PVR, NT-pro BNP, WHO FC***, French low-risk score, and TTCW^# or all-cause death (p<0.001 for all).

The TTCW finding was remarkable, said Hoeper, considering the difference between sotatercept and placebo in terms of the number of patients who died or experienced at least one clinical worsening event (n=9 vs 42). “Basically, all components^## of this endpoint were in favour of sotatercept, leading to an overall hazard ratio of 0.16, representing an 84-percent risk reduction with sotatercept vs placebo.”

The other two secondary outcomes that improved with sotatercept were the Physical Impacts (p=0.010) and Cardiopulmonary domains (p=0.028) of the PAH-SYMPACT^®### tool.

Moreover, a 14-mm Hg decline in mean pulmonary artery pressure was seen between arms on exploratory analysis. “[This is] something we have never seen before with any drug that has been used as add-on therapy in patients with PAH,” underlined Hoeper. “For me, [this is] 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.”

 

Reverse remodeling agent

Based on the disease regression seen in animal models, it is proposed that reverse remodelling in humans may also be achieved with this drug, Hoeper noted. Their team set off to ascertain the benefit of sotatercept with STELLAR, which included 323 PAH patients (mean age 48 years, 79 percent female) who were on stable background therapy.

About two-thirds of participants were on triple therapy, a third on doublet, and 40 percent were receiving prostacyclin infusions. Participants were randomized 1:1 to receive placebo or SC sotatercept at a target dose of 0.7 mg/kg (starting dose 0.3 mg/kg) Q3W.

More than half of participants had idiopathic PAH. Eighteen percent had heritable PAH, while 15 percent had connective tissue disease-associated PAH. The rest either had drug- or toxin-induced PAH, or PAH associated with corrected congenital stunts.

Compared with placebo, sotatercept was tied to more treatment-related adverse events (AEs; 47 percent vs 27 percent) but fewer serious treatment-emergent AEs (TEAEs; 22 percent vs 28 percent), severe TEAEs (13 percent vs 18 percent), and TEAEs leading to drug discontinuation (4 percent vs 7 percent).

Bleeding events (mostly epistaxis, gum bleeds) were the most common TEAEs of interest with sotatercept (32 percent), followed by telangiectasia (14 percent). Haemoglobin level increased in 6 percent of sotatercept recipients, but Hoeper noted that this was expected. About 10 percent of those on sotatercept had thrombocytopenia, but cases were mostly mild.

 

A paradigm shift

“[Taken together, STELLAR shows] that sotatercept, the first activin signalling inhibitor that we have, [delivered] a significant and clinically relevant improvement in 6MWD [for] adult patients with PAH who presented with WHO FC II or III and were on background therapy,” said Hoeper. “This came along with a broad clinical benefit across multiple domains, including haemodynamics, WHO FC, biomarkers, NT-proBNP, risk scores, and patient-reported outcomes.”

Sotatercept also reduced the risk of death and nonfatal clinical worsening events and was generally well tolerated.

“Overall, I believe these results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” Hoeper concluded. “It’s really a paradigm shift in how we will treat PAH in the future.”

It remains to be seen though how this drug can fit in the current PAH treatment landscape, Hoeper stressed. “This is one of the key questions that we still need to answer. In STELLAR, the average time between PAH diagnosis and study inclusion was 9 years, [yet we saw] such an impressive response … I believe the combination of an ERA⁺ and a PDE5⁺ inhibitor will still be the standard upfront therapies … but I think we are not going to wait 9 years before we start this drug. I think we should introduce this drug … more or less right after [the standard therapy].”

Most participants are now enrolled in the long-term extension phase wherein those originally on placebo shall cross over to sotatercept.

Sotatercept has received Breakthrough Therapy Designation and Orphan Drug designation (US FDA), and Priority Medicines designation and Orphan Drug designation (EMA), for the treatment of PAH. [merck.com/news/mercks-investigational-activin-signaling-inhibitor-sotatercept-improved-six-minute-walk-distance-by-40-8-meters-at-week-24-versus-placebo-in-adults-with-pulmonary-arterial-hypertension-on-bac]