Inhaled Imatinib, AV-101, Tolerated Well at All Doses in Phase 1 Trial

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Aerovate Therapeutics‘ AV-101, an inhaled formulation of imatinib for treating pulmonary arterial hypertension (PAH), was well tolerated in healthy adult volunteers enrolled in a Phase 1 trial.

Study data also indicate AV-101, which delivers the medication directly to the lungs, reduced its systemic (whole body) exposure.

This is expected to limit the side effects seen with the oral formulation of imatinib in PAH patients enrolled in the Phase 3 IMPRES trial (NCT00902174) led by Novartis. Although oral imatinib improved exercise capacity and blood flow in people with advanced PAH, it was poorly tolerated due to its side effects. As a result, its development for PAH was discontinued.

“We are pleased these Phase 1 data showed that AV-101 was generally well-tolerated in this trial of healthy adult volunteers across a dose range we believe may overlap or exceed lung exposures from 400 mg of oral imatinib, the dose used in the Novartis global Phase 3 IMPRES trial, while simultaneously reducing systemic exposure,” Timothy Noyes, CEO at Aerovate, said in a press release.

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Hunter Gillies, Aerovate’s chief medical officer, presented the results in the poster “A Phase 1 Single and Multiple Ascending Dose (SAD/MAD) Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of AV-101, a Novel Inhaled Dry Powder Formulation of Imatinib in Healthy Adults” at the 2022 American Thoracic Society (ATS) International Conference in San Francisco.

Imatinib works by blocking cell growth. In PAH, abnormal cell growth is known to drive disease progression. AV-101 was designed to deliver the therapeutic benefits of imatinib directly to blood vessels in the lungs, thereby limiting the oral formulation’s associated side effects, which included gastrointestinal distress (vomiting, diarrhea, etc.), swelling, and fatigue.

“Formulated as a dry powder for inhalation, AV-101 is designed to deliver high concentrations of imatinib throughout the airways and straight to diseased blood vessels,” Gillies said. “By limiting systemic exposure and directly targeting the disease process of hyperproliferation [overgrowth] in the pulmonary vasculature, AV-101 has the potential to make a meaningful difference for the PAH community.”

The Phase 1 trial assessed the safety, tolerability, and pharmacokinetics of five single ascending doses (SAD) and multiple ascending doses (MAD) of AV-101 in healthy adult volunteers. Pharmacokinetics refers to the movement of a medicine into, through, and out of the body.

The SAD part of the trial randomly assigned participants to AV-101 — a planned progression of 1 mg, 3 mg, 10 mg, 30 mg, and 90 mg — or a placebo. Each dosing group was composed of eight participants and the results were compared to an additional group that received 400 mg oral imatinib, the dose used in the IMPRES trial.

The MAD part tested three doses of AV-101 — 10 mg, 30 mg, or 90 mg — vs. a placebo, delivered twice daily for seven days to three groups. Each group had 12 participants, nine were randomly assigned to AV-101 and three to a placebo.

On day seven, participants received a single dose in the morning to assess the therapy’s pharmacokinetics profile.

Results showed AV-101 was generally well tolerated at all doses, with no serious treatment-emergent adverse events (TEAEs) reported. Dizziness and headache were the most common TEAEs in the SAD part. Short periods of cough and headache were reported in the MAD part, mainly at the highest dose (90 mg). Only one participant discontinued the treatment, due to vomiting.

In both SAD and MAD, all AV-101 doses significantly reduced systemic exposure to imatinib compared with oral imatinib.

According to the poster, the amount of dry powder in the 90 mg dose will be reduced to mitigate coughing.

The ongoing Phase 2b/3 IMPAHCT (NCT05036135) trial will continue to evaluate the safety and effectiveness of AV-101 in PAH patients. The trial is currently enrolling patients, ages 18 to 75, at the University of Kansas Medical Center in Kansas City, Kansas and Indiana University Health in Indianapolis, Indiana. More information is available here.

Overall, “these findings represent an important step forward in our clinical development of AV-101, and support the selection of doses being evaluated in our ongoing Phase 2b/Phase 3 IMPAHCT trial,” Noyes said.

A Conversation With Rare Disease Advocates