Gossamer's PAH Candidate Meets Primary Endpoint, Stumbles on Secondary Measure

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Topline results from a Phase II study showed Gossamer Bio’s seralutinib met its primary efficacy endpoint in pulmonary arterial hypertension, the company announced Tuesday.

However, Gossamer’s compound fell short of its key secondary functional endpoint of a 6-minute walk distance. Compared with placebo, seralutinib treatment improved 6MWD by 2.4 meters at week 12 and 6.5 meters at week 24. Both failed to meet statistical significance, with p-values of 0.8273 and 0.5972, respectively. 6MWD is slated to be the primary endpoint in the upcoming Phase III study of seralutinib. 

Gossamer’s stock dropped 65% in reaction to the data. 

In an investor call Tuesday morning, company representatives said the Phase II TORREY study was neither sufficiently powered nor explicitly designed to assess this endpoint. 

“The TORREY study was designed as a hemodynamic study, first and foremost, and was not designed as an exercise capacity improvement study,” said Faheem Hasnain, co-founder, chairman and chief executive officer of Gossamer in a statement. Rather than being powered to see statistical significance, the study was intended to show trends that would help Gossamer design the Phase III program. 

Gossamer also pointed to a strong placebo effect in the overall population, which explained the apparent null effect of seralutinib treatment on 6MWD.

Focusing on patients with functional class III pulmonary hypertension - indicative of marked limitations in physical activity - treatment with Gossamer’s candidate induced an approximately 37-meter improvement in 6MWD, an effect that was found to be statistically significant. 

With nearly 90 patients enrolled, TORREY is a double-blinded and placebo-controlled trial that runs for 24 weeks, after which patients are given the option to continue treatment in an open-label extension phase. 

The study’s primary endpoint is change from baseline value in pulmonary vascular resistance, which measures the degree of resistance that blood must overcome as it passes through the pulmonary vasculatures. High PVR is a leading cause of pulmonary hypertension.

In the intention-to-treat analysis, seralutinib successfully and significantly reduced PVR at the 24-week follow-up as opposed to placebo. The treatment difference was 96.1 dyne*s/cm5, which was statistically significant in favor of seralutinib. This effect was even more pronounced in patients with more severe disease at baseline.

Regarding safety, 93.2% of the seralutinib-treated patients experienced a treatment-emergent adverse event, the most frequent of which was cough. Other common side effects included COVID-19, diarrhea and headache.

Based on these findings, Gossamer plans to complete its Phase II regulatory interactions by early 2023 and start registration for its Phase III program in the latter half of the year.

That 6MWD was significantly improved in PAH patients with severe disease “provides a clear path forward” for the Phase III study, Gossamer representatives noted on the call.

A Tough Act to Follow

Tuesday’s data brings seralutinib in direct competition with Merck’s sotatercept, which is also being developed for PAH.

Whereas Gossamer attacks the disease by targeting the PDGFR/CSF1R/c-Kit kinase pathway, thereby limiting the hyperactive cell growth in PAH, Merck has taken a different approach, focusing on the TGF-β family of molecules. The intention is to restore the balance of pro- and anti-proliferative signaling pathways.

Ardeschir Ghofrani, M.D., and Raymond Benza, M.D. said during the call that there would be space for both seralutinib and sotatercept in the PAH treatment space. This is particularly as both act through different and complementary pathways. Both PAH thought leaders were invited as guest speakers on the investor call.

In October, early data from the Phase III STELLAR study showed sotatercept could induce a significant and clinically meaningful improvement in 6MWD, as well as in other disease markers such as N-terminal pro-B-type natriuretic peptide levels and functional class.