Inhaled imatinib therapy for PAH shows promise in animal models

Safety, efficacy of Aerovate's AV-101 also tested in clinical trials

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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AV-101, an inhaled formulation of imatinib for people with pulmonary arterial hypertension (PAH) now being tested in clinical trials, was found in a series of experiments in animal models to result in better lung exposure than oral formulations of the medication.

By offering direct delivery to the lungs, AV-101’s developer, Aerovate Therapeutics, believes the therapy will minimize side effects of imatinib associated with broader systemic exposure.

“Direct pulmonary delivery of imatinib demonstrates greater lung and lower systemic exposure than can be achieved with oral imatinib,” Ralph Niven, PhD, chief scientific officer at Aerovate, said in a company press release.

Findings from the preclinical experiments were presented at the American Thoracic Society (ATS) 2023 International Conference, held May 19-24, in Washington, D.C. The data were outlined in a poster, titled “The Influence of Route of Delivery and Formulation on the Pulmonary Pharmacokinetics of Imatinib in Nonclinical Species.”

“The results from these nonclinical studies further support our development of AV-101, a dry powder formulation of imatinib administered by inhalation for the treatment of PAH,” Niven said.

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Both animal studies and clinical trials used to test AV-101

AV-101 had already demonstrated that it reduces systemic exposure compared with oral imatinib in a Phase 1 trial involving healthy volunteers. That trial also showed the inhaled therapy had a favorable safety and tolerability profile.

Now, the IMPAHCT Phase 2b/3 clinical trial (NCT05036135) is evaluating AV-101’s safety and efficacy in up to 462 adults with PAH. Participants ages 18-75 are being recruited for that study — already underway at most of its 100 sites worldwide. Top-line data from the Phase 2b part of the trial are expected in 2024.

PAH is marked by an increased pressure in the pulmonary arteries sending blood from the heart to the lungs.

Abnormal cell growth in the blood vessels of the lungs — the pulmonary vasculature — is one factor known to contribute to its progression. Imatinib, which belongs to a class of molecules called tyrosine kinase inhibitors, works to block such abnormal cell growth.

An oral formulation of imatinib developed by Novartis was able to improve exercise capacity and blood flow in people with advanced PAH. Those results were seen among participants in the Phase 3 IMPRES trial (NCT00902174), completed in 2011.

Still, the oral therapy was poorly tolerated, accompanied by side effects such as nausea, swelling, diarrhea, and fatigue, and the treatment’s development for PAH was discontinued.

Now, Aerovate has designed AV-101, a dry powder formulation of imatinib that’s delivered directly to the small blood vessels in the lungs that are affected in PAH. With its direct delivery, it is expected to bypass the side effects associated with systemic exposure, as found with an oral formulation. The inhaled formulation also has the potential to reduce the therapeutic dose of the medication.

In a series of preclinical experiments, researchers now explored the pharmacological properties of the dry powder formulation. They used mice, rats, and monkeys in these studies.

Overall, the company found that the inhaled therapy exhibited a promising pharmacological profile.

A single administration of AV-101 directly into the airways of mice and rats led to significantly higher lung exposure to imatinib compared with into-the-vein (intravenous) or oral administration.

With repeated daily inhalation of the therapy for about a month in rats and monkeys, measurable concentrations of AV-101 were maintained in the lungs for 24 hours after a dose.

Moreover, the ratio of the therapy in the lungs relative to that in the bloodstream was significantly higher than with oral administration, suggesting minimal systemic exposure.

The multi-national IMPAHCT trial will continuously enroll participants as it moves from its Phase 2b to Phase 3 portion. The trial is expected to run though January 2025.

In the Phase 2b, dose-finding portion, participants will receive one of three doses of AV-101 or a placebo for 24 weeks, or about six months. The goal is to select the optimal dose of the therapy for the Phase 3 portion.

During the Phase 3 part, participants will be randomly assigned to receive this optimal dose of AV-101 or a placebo for 24 weeks. The main goal is to evaluate changes in exercise capacity, as evaluated by the six-minute walk distance test.

Data on other measures related to disease progression and quality of life also will be collected.

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