Inhaled form of approved treatment boosts lung drug levels in IPF trials

AP02, an inhaled form of nintedanib being developed by Avalyn Pharma for idiopathic pulmonary fibrosis (IPF), was generally well tolerated and resulted in higher lung levels of the drug than oral nintedanib, according to findings from two Phase 1 trials.

An oral formulation of nintedanib, sold as Ofev, with generic formulations available, is approved for the treatment of IPF.

The two Phase 1 trials, AP02-001 (ACTRN12620001141932) and AP02-002 (ACTRN12624000825550), evaluated AP02 in healthy volunteers, with AP02-001 also including six people with IPF. By delivering nintedanib directly to the lungs, AP02 is designed to increase local drug exposure while limiting drug levels elsewhere in the body.

“The data … demonstrate substantially higher predicted lung exposure alongside significantly lower systemic exposure than oral nintedanib, supporting AP02’s potential to improve the therapeutic profile of this important medicine,” Melissa Rhodes, PhD, Avalyn’s chief operative officer, said in a company press release.

The trials’ results were described in “Nebulized nintedanib (AP02) for idiopathic pulmonary fibrosis demonstrates favorable safety and lung lining fluid exposures: results from two phase I safety, tolerability, and pharmacokinetics studies,” which was published in Respiratory Research.

Based on these findings, Avalyn advanced AP02 into the Phase 2 AURA trial (NCT07194382). The study will assess the treatment’s safety and efficacy in an estimated 160 adults with IPF, who are currently being enrolled at 24 sites worldwide. Participants will receive one of two AP02 doses, or a placebo, twice daily for about three months. According to the company, top-line data are expected in late 2027.

“We are encouraged by the continued progress of our AURA Phase 2 trial and the strong interest we have seen from investigators and patients across participating sites. We look forward to Phase 2 clinical data from AURA further evaluating AP02’s potential to deliver meaningful benefit for people living with IPF,” Rhodes said.

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AP02 led to higher nintedanib exposure in the lung lining fluid

Pulmonary fibrosis is marked by lung inflammation and fibrosis, or scarring, leading to symptoms such as shortness of breath and dry cough. In IPF, the cause of the disease is unknown.

Nintedanib inhibits multiple receptor tyrosine kinases that have been shown to contribute to the cellular mechanisms involved in lung fibrosis.

AP02 is an inhaled formulation of nintedanib, available as a liquid solution that can be inhaled using the PARI eFlow Nebulizer System. The AP02-001 trial tested single ascending doses up to 2 mg in 32 healthy volunteers and six IPF patients, while AP02-002 evaluated single and multiple ascending doses up to 8 mg, twice daily for seven days, in 60 healthy volunteers.

Participants had a mean age in the early 30s. Males represented 47.4% of the participants in the first trial and 90% in the second. Of the six IPF patients enrolled, four had been treated with salbutamol, a fast-acting bronchodilator that is used to widen the airways.

Both Phase 1 studies compared AP02 to a placebo. In addition, the AP02-001 trial also assessed the approved 150 mg oral dose of nintedanib in four healthy volunteers.

AP02 was generally well tolerated in both Phase 1 studies, with no serious adverse events reported. The most common treatment-related events included headache, nausea, and mild cough in the first study, and dizziness in the second. None of the treatment-related side effects led to study discontinuation.

We believe this lung-targeted approach may ultimately help patients derive greater benefits from treatment, with fewer side effects that can limit adherence to long-term therapy and impact quality of life.

AP02 was absorbed rapidly after inhalation, with nintedanib reaching peak blood levels within minutes. However, exposure in the bloodstream was substantially lower than with the approved oral formulation, with a single 2 mg dose of AP02 resulting in about 68 times lower overall exposure over 24 hours and 15 times lower peak blood levels than the 150 mg oral formulation.

With repeated dosing, blood exposure remained considerably lower than the levels expected with oral nintedanib.

At the same time, AP02 led to substantially higher nintedanib exposure in the lung lining fluid than the oral formulation. The drug remained detectable in the lungs for up to 12 hours after inhalation and reached levels higher than those seen with the oral formulation.

“Subsequent clinical development will include more dedicated safety and tolerability studies in a larger number of patients with IPF. These findings support the further clinical advancement of AP02 and suggest that an inhaled delivery of a proven efficacious agent may be a promising new treatment option for IPF,” the team wrote.

Added Rhodes: “We believe this lung-targeted approach may ultimately help patients derive greater benefits from treatment, with fewer side effects that can limit adherence to long-term therapy and impact quality of life.”