Inhaled Seralutinib Shows Potential to Treat PAH in Phase 2 Trial
Better blood pressure in lungs, exercise capacity in those on PAH treatment
Treatment with seralutinib (GB002), an inhaled investigational therapy, significantly improved measures of blood pressure in the lungs of people with pulmonary arterial hypertension (PAH) in the Phase 2 TORREY study, meeting the trial’s main goal.
Promising effects also were seen on measures of exercise capacity and heart structure, with these benefits generally more pronounced among patients with more severe disease at the trial’s start, according to top-line results announced by Gossamer Bio, seralutinib’s developer.
“We are very pleased to share that seralutinib significantly improved hemodynamic [blood flow], biomarker, and right heart structural and functional measures in a heavily treated PAH patient population,” Faheem Hasnain, co-founder, chairman and CEO of Gossamer, said in a press release.
Reasonable safety seen with seralutinib, a tyrosine kinase inhibitor
Safety results were generally positive, unlike those of prior studies in an oral therapy with similar mechanisms of action.
“Importantly, these efficacy results were paired with a favorable safety and tolerability profile, something that has challenged past development of tyrosine kinase inhibitors in PAH,” Hasnain said.
Seralutinib is designed to block the activity of certain signaling proteins that play roles in the abnormal cell growth that drives PAH. The therapy’s mechanism of action is similar to that of imatinib, which is approved to treat certain cancers and is sold by Novartis under the name Gleevec.
Novartis sponsored PAH trials of imatinib as a potential oral treatment, and efficacy results were generally positive. However, many patients reported substantial side effects such as nausea, vomiting, diarrhea, and swelling. Novartis ultimately stopped developing imatinib for PAH due to the poor safety profile. Studies are underway by others of imatinib in an inhaled formulation.
Seralutinib, inhaled directly into to the lungs, is expected to cause fewer digestive side effects than oral imatinib. The experimental therapy has shown promising results in preclinical studies in animal disease models.
The Phase 2 TORREY study (NCT04456998) enrolled 86 patients with World Health Organization (WHO) functional class 2 or 3. Participants were randomly assigned to take seralutinib or a placebo twice daily for 24 weeks, or about six months.
Enrolled patients also remained on their standard-of-care background therapies. Most (57%) were on a combination of three PAH medications.
The study’s main goal was to determine the effect of treatment on pulmonary vascular resistance (PVR), a measure of the pressure in the lungs’ blood vessels. Results showed that, after 24 weeks, the average reduction in PVR was significantly lower — by 14.3% — in patients on seralutinib compared with those on placebo.
The mean distance participants could walk in six minutes (6MWD, a common measure of exercise capacity) increased by over six meters (more than 19 feet) in the seralutinib relative to the placebo group, though this difference did not reach statistical significance.
Notably, more pronounced improvements in PVR and 6MWD were generally seen among patients with more severe disease upon starting the trial, Gossamer reported. For example, among people with WHO functional class 3, the average PVR improvement was 21% and 6MWD increase was 37 meters with seralutinib’s use compared with placebo. Both differences reached statistical significance in this subgroup.
Potential for seralutinib as ‘anti-inflammatory and anti-fibrotic’ PAH treatment
Seralutinib treatment also led to a statistically significant reduction of NT-proBNP, a marker of heart damage. This decrease was apparent as early as 12 weeks after starting treatment, and was accompanied by “clinically relevant and statistically significant changes” in heart structure and function, according to Gossamer.
“The strong concordance of the results generated in the TORREY study, particularly the impact seen on cardiac measures of disease progression, suggest that seralutinib could be an important future therapy for patients with PAH,” said Raymond Benza, MD, a cardiologist and professor of internal medicine at The Ohio State University, a trial site.
Adverse events — safety-related findings, including but not limited to treatment side effects — were reported in most patients in both the seralutinib and placebo groups. These were generally mild or moderate in severity. The most common was coughing, reported in 43% of patients on seralutinib and 38% of those on placebo.
One serious adverse event was deemed related to seralutinib treatment. Gossamer did not provide details on this event.
Of note, side effects like vomiting and swelling, were “observed at substantially lower frequency in the TORREY study” compared to the IMPRES Phase 3 study of oral imatinib in PAH (NCT00902174). Gossamer did not report exact frequencies for these side effects.
“The TORREY results represent a significant step forward in unlocking the promise of safely using tyrosine kinase inhibitors to treat PAH,” said Ardeschir Ghofrani, MD, a professor of pulmonary vascular research at Justus Liebig University in Germany.
“The efficacy results generated with seralutinib in the context of a favorable safety and tolerability profile highlight compelling potential differentiation for seralutinib as an anti-proliferative, anti-inflammatory, and anti-fibrotic [scarring] therapeutic candidate with possible reverse remodeling effects,” Ghofrani said.