Aerovate Therapeutics, Inc. announced the publication of Phase 1 study results evaluating AV-101, a novel dry powder inhaled formulation of imatinib, in ERJ Open Research. The results showed that AV-101 was generally well tolerated and inhaled administration significantly reduced systemic exposure compared to orally dosed imatinib with no serious adverse events reported. AV-101 is being developed to address abnormal cellular proliferation and resistance to apoptosis in the pulmonary vasculature, which are key features of the pathophysiology of pulmonary arterial hypertension (PAH).

Imatinib is an anti-proliferative drug initially approved for the treatment of chronic myeloid leukemia. It has previously demonstrated a statistically significant and clinically meaningful benefit in PAH patients in the global Phase 3 IMPRES trial, conducted by Novartis, when administered orally as a tablet but was poorly tolerated due to adverse events. The development of imatinib for PAH was discontinued.

Aerovate designed AV-101 to deliver imatinib throughout the airways to more directly access the diseased blood vessels in the lung, at or above concentrations observed with the oral dose while limiting systemic exposure. This allows for the potential to maximize efficacy while limiting the adverse events observed with oral imatinib. The Phase 1, placebo-controlled trial, with topline results previously reported at the American Thoracic Society 2022 International Conference, evaluated single and multiple ascending doses of AV-101, self-administered twice daily with an easy-to-use pocket-sized inhaler in 82 healthy adults.

The single ascending dose (SAD) portion of Aerovate's trial included 40 patients divided into 5 cohorts of 8 subjects each (6 randomized to AV-101, 2 placebo), who were administered a planned progression of 1 mg, 3 mg, 10 mg, 30 mg, and 90 mg single doses of inhaled AV-101 or placebo, compared to an additional cohort of 8 participants receiving 400 mg oral imatinib, the dose used in the IMPRES trial. The multiple ascending dose (MAD) portion included 34 patients divided into 3 cohorts of up to 12 subjects each (9 randomized to AV-101, 3 placebo) who received AV-101 or placebo at either 10 mg, 30 mg, or 90 mg twice daily for 7 days. At all doses, AV-101 demonstrated only moderate plasma accumulation and significantly lower systemic exposure compared to oral imatinib.

No serious treatment-emergent adverse events (TEAEs) were reported in either the SAD or the MAD cohorts. In the SAD portion of the trial, the most common TEAEs were dizziness and headache, whereas in the MAD portion of the trial, the most common TEAEs were short periods of cough and headache, primarily in the 90 mg cohort. Aerovate's Phase 2b/Phase 3 trial, called IMPAHCT (Inhaled iMatinib Pulmonary Arterial Hypertension Clinical Trial), is underway to evaluate the safety and efficacy of inhaled AV-101 in adults with PAH.

Enrollment is ongoing and topline data are expected from the Phase 2b portion of the trial in the fourth quarter of 2023 or first quarter of 2024.