Inhaled Seralutinib Shows Promise in 2 PAH Animal Models
Seralutinib (GB002), an investigational inhaled treatment for pulmonary arterial hypertension (PAH), effectively treated severe disease in two animal models, a study demonstrated.
Further, when compared directly, inhaled seralutinib showed greater efficacy than imatinib, an approved cancer therapy also being investigated for PAH.
Gossamer Bio, seralutinib’s developer, now is testing the therapy in a Phase 2 study (NCT04456998) called TORREY. That trial, conducted at 71 sites worldwide, enrolled 86 adults with PAH.
The results of the animal studies were reported in “Inhaled Seralutinib Exhibits Potent Efficacy in Models of Pulmonary Arterial Hypertension,” a study published in the European Respiratory Journal.
“We are excited to share some of the preclinical foundations for the seralutinib program in such a high impact scientific journal,” Faheem Hasnain, Gossamer’s co-founder, chairman, and CEO, said in a press release, with the company noting that the research findings support seralutinib’s potential as a treatment for pulmonary arterial hypertension.
“The studies included in the publication are part of the reason why we, along with the broader PAH community, are eagerly anticipating the topline results of the Phase 2 TORREY Study in the fourth quarter of this year,” Hasnain said.
In PAH, abnormal cell growth narrows the small blood vessels, called the pulmonary arteries, that transport blood through the lungs. This leads to high blood pressure and makes the heart work harder to pump blood through the body.
An oral formulation of imatinib is sold as Gleevec, by Novartis. The therapy is approved to treat certain types of cancers, and works by blocking the activity of signaling proteins involved in driving the growth of specific types of cells. It also has been shown to reduce the tightening and stiffness of pulmonary arteries associated with PAH.
However, imatinib’s development was hindered by serious side effects, according to researchers. The team noted that “serious adverse events and discontinuations were common” in clinical trials testing the therapy.
One such trial was IMPRES, a Phase 3 clinical study launched by Novartis to evaluate imatinib as an add-on PAH therapy. Although the treatment led to clinically meaningful improvements in blood flow and exercise abilities, almost half of those who received the therapy experienced serious side effects, possibly due to the high study dose. As a result, oral imatinib development for PAH has been discontinued.
Seralutinib, formerly called PK10571, is a molecule with a similar mechanism of action as imatinib. It was designed to minimize body-wide side effects and formulated as a dry powder for inhalation delivery directly to blood vessels in the lungs.
In advance of clinical trials, scientists at Gossamer, with researchers at the University of Colorado School of Medicine, conducted preclinical studies to compare seralutinib versus imatinib in cells and animal models of PAH.
In human pulmonary artery smooth muscle cells (PASMCs) and lung fibroblasts — cell types that grow abnormally in PAH — seralutinib was 13 to 20 times more potent than imatinib. Seralutinib also worked better than imatinib in blocking the cKIT and CSF1R kinases, two enzymes that play a role in PAH development.
Next, two rat PAH models were used to evaluate the efficacy of the inhaled formulation of seralutinib.
In rats exposed to the compound SU5416 and low oxygen (hypoxia) to induce PAH, inhaled seralutinib reduced pulmonary blood pressure by 43% relative to untreated animals. With seralutinib, the blood pressure in the right heart ventricle, responsible for pumping blood through the lungs, decreased in a dose-dependent manner compared with controls.
Enlargement of the right ventricle, a sign of PAH, was reduced in seralutinib-treated rats, and there was a significant decrease in the number of lesions in the small pulmonary arteries.
In the second model, in which one of the rats’ lungs was surgically removed to trigger PAH, seralutinib stabilized pulmonary blood pressure, which continued to rise in untreated animals. After 11 days, the blood pressure was 41% lower in treated rats.
The right heart ventricle pressure and enlargement were reduced by about half in seralutinib-treated rats, with fewer lesions in small blood vessels. Seralutinib also reduced scarring in the tissue surrounding blood vessels and significantly improved lung function.
SU5416/hypoxia-induced rats were then treated with inhaled seralutinib or orally administered imatinib. Seralutinib reduced the mean pulmonary arterial pressure more than imatinib, by 37% versus 27%. It also lowered right ventricle pressure by 45% versus 28%. These differences, however, were not statistically significant.
Compared with imatinib, seralutinib had a significantly greater effect on measures of heart function. It also lowered the levels of heart-damage marker NT-proBNP by 55%, which was unaffected by imatinib. A decrease in small pulmonary artery muscularization, an early feature of PAH, was seen in the seralutinib group compared with both the vehicle and imatinib-treated groups.
An analysis of biomarkers showed that seralutinib decreased bloodstream levels of pro-inflammatory TNF-alpha and increased anti-inflammatory interleukin-10 compared with untreated animals. In contrast, imatinib did not significantly alter these markers.
Additionally, seralutinib significantly increased the protein receptor BMPR2 — the loss of which promotes PAH — whereas no effect on BMPR2 was seen with imatinib. Two microRNAs, small RNA molecules that control protein production, were reduced following treatment with seralutinib, in line with the increase of BMPR2 protein.
The “restoration of lung BMPR2 expression in the rat PAH models suggest that seralutinib may impact underlying causes of PAH,” the researchers noted.
Lastly, to demonstrate clinical relevance, seralutinib was associated with a decreased signal for PAH-related receptors and enzymes in lung tissue isolated from PAH patients.
“Seralutinib delivered as an inhaled dry powder was shown to be effective in two preclinical models of PAH,” the authors concluded. “As these animal models of PAH replicate different features of the human disease, the fact that seralutinib demonstrated robust efficacy in both models increases the likelihood of seralutinib’s efficacy as a treatment in human PAH.”
Of note, AV-101, an inhaled version of imatinib developed by Aerovate Therapeutics, was well-tolerated in a Phase 1 study in healthy volunteers and now is being evaluated in a Phase 2b/3 trial in up to 462 adults with PAH.
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