Phase 1 inhaled imatinib data buoy upcoming Phase 2 trial design
Therapy safe, well-tolerated in healthy people; has few systemic side effects
An inhaled formulation of imatinib in development by Aerami Therapeutics to treat pulmonary arterial hypertension (PAH), was safe and well tolerated with few systemic side effects among healthy adults in a Phase 1 trial.
AER-901, which is delivered via a smart, breath-activated nebulizer, also showed a distinct absorption profile over oral imatinib, suggesting efficient concentrations in the lung tissue and little swallowing.
These findings were presented at the 2023 European Respiratory Society (ERS) International Congress, which was held Sept. 9-13 in Milan, Italy. The talk was titled, “Low Systemic Exposure With Targeted Administration of AER-901 (Inhaled Imatinib): Results of a Phase 1 Clinical Trial.”
“The data from our Phase 1 clinical trial demonstrate that the AER-901 drug-device combination can efficiently deliver imatinib directly to the lung with a potentially improved systemic safety profile,” Gary Burgess, MD, chief medical officer of Aerami, said in a company press release.
The findings support the design of the planned uniPHied Phase 2 trial that will evaluate AER-901 along with standard of care therapy among people with PAH or PAH associated with interstitial lung disease (PAH-ILD), according to Burgess. No information is available on when that trial will begin enrollment.
How does imatinib work against PAH?
In PAH, the abnormal growth of the cells that line blood vessels — called pulmonary vascular remodeling — contributes to the blood vessel narrowing that characterizes the disease. Some cases are caused by interstitial lung disease, which is marked by scarring and inflammation that damage the lungs, a condition known as PAH-ILD.
Imatinib inhibits enzymes called tyrosine kinases that contribute to the abnormal cell growth in PAH. In animal models of pulmonary hypertension, it reversed pulmonary vascular remodeling.
An oral formulation, marketed as Gleevec by Novartis, is approved to treat certain types of cancer. A Novartis-sponsored Phase 3 trial (NCT00902174) tested this oral version in PAH patients. It had a beneficial effect on exercise capacity and vascular function, but caused serious side effects and was deemed to have an unacceptable safety profile.
AER-901 is an inhaled version of imatinib, delivered directly into the lungs via a handheld inhalation device called a nebulizer that turns liquid medicine into a mist that can be inhaled.
By targeting the medication right where it’s needed and avoiding broad systemic exposure, Aerami believes it will offer Gleevec’s therapeutic benefits and minimize the side effects.
Phase 1 trial results of inhaled imatinib
Preclinical data indicates the therapy reached about 10 times higher concentrations in the lungs than the oral formulation in a rat model of pulmonary hypertension, meaning about a tenfold lower dose of the inhaled formulation may be required for therapeutic effect.
The Phase 1 trial (NCT04903730) enrolled 84 healthy volunteers, ages 18-60, at a single site in Australia to test the safety of single or multiple doses of AER-901 (5-80 mg) against a placebo. It also compared AER-901 to oral imatinib and evaluated single or twice daily dosings of AER-901 against a placebo.
AER-901 was found to be generally well tolerated with mostly mild side effects. Low rates of gastrointestinal and systemic side effects were observed.
The therapy was rapidly absorbed, consistent with preclinical studies, and had a distinct absorption profile from oral imatinib. AER-901 was well-distributed in the lungs and wasn’t associated with the medicine being inadvertently swallowed that could lead to systemic exposure.
“These data are consistent with our hypothesis that AER-901 has the potential to achieve efficacy with improved safety and tolerability relative to oral imatinib and we believe that they strongly support the design of our planned platform Phase 2 trial, uniPHied,” Burgess said.
In uniPHied, PAH or PAH-ILD patients will be randomly assigned to AER-901 or a placebo, delivered twice daily via a nebulizer. The main goal is to assess the percentage reduction in pulmonary vascular resistance, a measure of the resistance to blood flow in the vessels of the lungs, after about six months.
The company also plans to open a long-term extension study wherein all participants will continue receiving AER-901 after completing the main trial. AER-901 currently holds orphan drug status in the U.S., a designation intended to speed clinical development by offering financial incentives and regulatory support.
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