Inhaled pirfenidone AP01 for IPF may have fewer side effects: Data
Like approved oral therapy, AP01 seen to slow lung function decline
AP01, Avalyn Pharma’s pirfenidone solution for inhalation, may have fewer side effects than the oral formulation now used to treat idiopathic pulmonary fibrosis (IPF) — while helping keep lung function from declining as quickly.
That’s according to data from the company-sponsored Phase 1b ATLAS trial (ACTRN12618001838202), which is testing how safe and effective AP01 is when given to IPF patients for up to 72 weeks, or nearly 17 months. The experimental treatment was given as either a low dose of 50 mg, once daily, or a high dose of 100 mg, twice daily.
Most of those who received high-dose AP01 had relatively stable lung function at weeks 24 and 48 — roughly the six-month and one-year marks — meaning that their lung function did not decline as much as expected.
“Although the ATLAS study’s primary endpoint was safety, secondary measures of efficacy showed a trend towards disease stabilization in participants with IPF who administered high-dose AP01,” Lyn Baranowski, Avalyn’s CEO, said in a company press release, adding, “We believe AP01 has the potential to meet or exceed the efficacy of oral pirfenidone without the systemic toxicities that limit its adoption.”
Findings from ATLAS were reported in the study, “Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose–response trial,” published in the journal Thorax.
Inhaled pirfenidone may have fewer side effects than oral therapy
While final data from week 72 are awaited, the company is getting ready to start the next phase of its clinical program, with an aim to further test AP01 in patients.
“We are eager to explore this hypothesis in a larger, controlled efficacy trial that we plan to begin later this year,” Baranowski said.
When fibrous scar tissue forms in the lungs of people with pulmonary fibrosis (PF), breathing becomes harder, causing patients to experience shortness of breath and fatigue. Over time, scarring (fibrosis) can get worse and make it more difficult for patients to do everyday activities like walking or climbing stairs. In people with IPF, the reason why the disease occurs is unknown.
Esbriet (pirfenidone), an oral medication approved to treat IPF, can help slow the progression of lung fibrosis. But because it’s taken by mouth, it often requires larger doses, which can lead to systemic or whole-body toxicities.
“While oral pirfenidone has the potential to improve lung function by reducing fibrosis, its utility is limited by its poor tolerability profile,” Baranowski said. Possible side effects include liver problems, sun sensitivity and rash, diarrhea, vomiting, and nausea.
Because AP01 is given as a solution for delivery as a soft mist using a nebulizer, more of it can reach the lungs. In theory, smaller doses would be needed to achieve a therapeutic effect, and systemic toxicities would be avoided.
Of the 91 patients who took part in the ATLAS study, 46 were assigned to receive 50 mg of AP01 once daily; the remaining 45 were assigned to receive 100 mg of the therapy twice daily. Most patients (84.6%) completed the first 24 weeks of the study, and three-quarters (74.7%) reached week 48.
An earlier report noted that AP01 was safe and tolerated well over the first 24 weeks of the study, and that a higher dose kept lung function from declining.
New data on inhaled pirfenidone covers nearly one year
The new report, which covers the first 48 weeks, confirmed that the most common side effects were all mild or moderate in severity.
“Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01,” the researchers wrote.
They included cough (15.4%), rash (12.1%), nausea (8.8%), throat irritation (5.5%), and fatigue (4.4%). One patient experienced liver problems, which resolved after treatment was interrupted.
“The tolerability profile we saw with AP01 in this study is really important because we see so many patients who may try to take the oral antifibrotics but eventually stop as the side-effects become increasingly difficult to bear as their disease progresses, and others who cannot tolerate them for even a short time,” said Alex West, clinic lead for interstitial lung diseases at Guy’s and St. Thomas’ Hospital in London and an investigator in the ATLAS study.
“AP01 has the potential to keep patients on effective therapy longer, which might translate into increased life expectancy and quality of life,” West said.
The tolerability profile we saw with AP01 in this study is really important because we see so many patients who may try to take the oral antifibrotics but eventually stop as the side-effects become increasingly difficult to bear as their disease progresses, and others who cannot tolerate them for even a short time.
At study entry (baseline), mean percent predicted forced vital capacity (FVC%), a measure of lung function, was about 72%. In those who received low-dose AP01, the change in FVC% had a negative slope of 2.5 at week 24, and 4.9 at week 48. A negative slope means that lung function worsened over time.
In those who received high-dose AP01, the slope of FVC% was 0.6, which means it trended upward over the first 24 weeks; at week 48, it had a negative slope of 0.4, that is, lung function was relatively stable.
These findings mirrored changes in lung fibrosis scores, as measured by high-resolution computed tomography (HRCT), the researchers noted.
Of the 54 patients who reached week 72, 47 (87%) continued into the open-label extension, where 100 participants are now receiving high-dose AP01. It’s expected that those findings will be presented along with data from week 72 at upcoming medical meetings.
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