Long-term study findings reflect potential of sotatercept for PAH

The efficacy and safety of the novel, first-in-class, selective fusion protein sotatercept were sustained or enhanced for up to 48 weeks when added to standard of care (SOC) for the treatment of pulmonary arterial hypertension (PAH), according to interim findings of the ongoing open-label extension (OLE) period of the phase II PULSAR trial presented at ATS 2021.

“[This effect was seen] across multiple study endpoints,” said Dr David Badesch from the University of Colorado, Aurora, Colorado, US, during his presentation. “The improvements observed in patients rerandomized from placebo to sotatercept align with the initial results from the placebo-controlled treatment period.”

The findings come on the heels of PULSAR’s 24-week, placebo-controlled phase, which also revealed favourable results. A total of 106 participants were randomized 3:3:4 to receive placebo, sotatercept 0.3 mg/kg, or sotatercept 0.7 mg/kg every 21 days on top of SOC. Least-squares mean (LSM) changes from baseline 6MWD* were 58.1 and 50.1 meters with sotatercept 0.3 and 0.7 mg/kg, respectively. Both sotatercept doses also reduced NT-proBNP** levels vs baseline (LSM changes, –621.1 pg/mL and –340.6 pg/mL, respectively). [N Engl J Med 2021;384:1204-1215]

In the OLE phase, sotatercept recipients continued their regimen, while those initially on placebo were rerandomized 1:1 to receive sotatercept 0.3 or 0.7 mg/kg. [ATS 2021, abstract A1185]

Among those who transitioned from placebo to sotatercept 0.3 mg/kg, 6MWD and NT-proBNP values increased from week 24 to 48 (from +43.0 to +82.4 meters and +365.8 to –248.2 pg/mL, respectively). A similar trend was seen in the placebo-sotatercept 0.7-mg/kg arm (from +24.3 to +53.6 meters and +13.9 to –782.1 pg/mL, respectively). The fraction of participants who had WHO FC*** improvements also jumped from week 24 to 48, be it with sotatercept 0.3 or 0.7 mg/kg (from 13 percent to 29 percent and 13 percent to 53 percent, respectively).

Those on continued sotatercept had either sustained or improved endpoint values between weeks 24 and 48, both with the 0.3-mg/kg (from +57.4 to +67.7 meters [6MWD] and –689.2 to –655.5 pg/mL [NT-proBNP]) or the 0.7-mg/kg dose (from +53.9 to +66.5 meters and –246.2 to –433.3 pg/mL, respectively). There were also more patients in this group with WHO FC improvements vs week 24 (from 31 percent to 38 percent [0.3 mg/kg] and 17 percent to 33 percent [0.7 mg/kg]).

Safety-wise, more than a quarter (28 percent) of participants reported serious treatment-emergent adverse events (TEAEs). Nine patients withdrew from the study owing to TEAEs. The two deaths reported (ie, brain abscess, cardiac arrest) were not deemed drug-related. The safety profile of sotatercept aligns with that observed in the placebo-controlled phase and in previous studies.

PAH is characterized by pulmonary vascular remodelling, leading to increased pulmonary artery pressure and progressive right ventricular dysfunction. [Circ Res 2014;115:115-130] “Disruptions in transforming growth factor-β and bone morphogenetic protein signalling are associated with PAH. Novel therapies that target these underlying mechanisms of vascular remodelling are needed to attenuate disease development and progression,” noted Badesch and colleagues.

Evidence shows that sotatercept acts by rebalancing the pro- and anti-proliferative signalling pathways, thus exhibiting potential to reverse the vascular remodelling triggering PAH pathology. [Haematologica 2019;104:477-484; Sci Trans Med 2020;12:eaaz5660]

Overall, the findings imply that the initial placebo assignment did not influence the ability of participants to respond to sotatercept after 24 weeks, Badesch noted. “These longer-term results highlight the versatility of sotatercept as a new treatment for PAH.”

Further results from the ongoing OLE phase are in the offing. Sotatercept will be further evaluated in phase III trials, he added.