Highest Dose Bexotegrast Found to Improve Lung Function in IPF
Data from Phase 2a trial suggest therapy has dose-dependent benefits
The highest tested dose of bexotegrast, an anti-fibrotic treatment candidate from Pliant Therapeutics, was found to best — and safely — improve lung function in people with idiopathic pulmonary fibrosis (IPF), outperforming all lower doses in a Phase 2a trial.
Three-month data from the INTEGRIS-IPF trial (NCT04396756) also showed that the high dose treatment of 320 mg daily slowed the progression of lung fibrosis, or scarring, and reduced disease-associated biomarkers.
Taken together with findings from the lower dose groups (40, 80, or 160 mg daily), the data suggest a dose-dependent anti-fibrotic effect of the treatment, according to Pliant.
The company now plans to start a Phase 2b trial of bexotegrast for IPF later this year.
“Data from the INTEGRIS-IPF trial have far exceeded our expectations, supporting bexotegrast’s favorable safety profile and demonstrating a statistically significant treatment response … at 320 mg,” Éric Lefebvre, MD, chief medical officer at Pliant, said in a press release. “We look forward to advancing bexotegrast into Phase 2b clinical development.”
Testing bexotegrast in trial
First, participants in the 320 mg group will continue treatment until all have been treated for at least 24 weeks (about six months). Final trial data is expected by the middle of this year.
Pliant designed bexotegrast, formerly known as PLN-74809, to block the activity of two integrin proteins, called alpha v beta 6 and alpha v beta 1, that are thought to contribute to fibrosis in IPF and other fibrotic conditions. The goal is to improve lung function in IPF patients.
Phase 1 trials demonstrated that the small molecule therapy was well-tolerated and had promising anti-fibrotic effects in healthy volunteers.
INTEGRIS-IPF initially enrolled 90 IPF patients, ages 40 and older, who were randomly assigned to receive one of three bexotegrast oral doses — 40, 80, or 160 mg — or a placebo, taken once daily for 12 weeks or about three months.
About 80% of participants also were using standard of care IPF medications, such as Ofev (nintedanib) or Esbriet (pirfenidone).
The study’s main goal was to assess the treatment’s safety and tolerability, with a secondary goal of assessing its absorbance, movement through the body, and elimination. This is known as a medication’s pharmacokinetics.
Results showed that bexotegrast was well-tolerated, with no deaths or treatment-related serious side effects. The therapy also showed a good pharmacokinetic profile, meeting both goals.
Exploratory efficacy was assessed using forced vital capacity (FVC), a measure of lung function that evaluates how much air a person can forcibly exhale after a deep breath.
Bexotegrast-treated patients experienced slower declines in FVC compared with the placebo group, the results showed. Moreover, the proportion of patients with a percent predicted FVC decline of 10% or more — a predictor of disease progression and mortality in IPF — was reduced in a dose-dependent manner.
Higher doses of the treatment also were associated with less progression of lung fibrosis, as assessed with the Quantitative Lung Fibrosis imaging score (QLF). In addition, levels of disease-associated biomarkers were reduced with bexotegrast.
Based on the safety of those tested doses, dosing was initiated in the 320 mg group. A total of 29 people were included, 21 of whom received bexotegrast and eight who were given a placebo.
As in the low dose groups, about 80% of patients were using another standard of care IPF medication.
Bexotegrast continued to demonstrate a favorable safety profile at its highest dose, with no drug-related severe or serious side effects reported, Pliant now reports. Its pharmacokinetic profile was similar to previous findings.
The statistically significant increase in mean FVC versus placebo seen throughout the 12-week treatment period of the INTEGRIS-IPF trial at 320 mg is unprecedented in clinical trials observed to date.
Patients in the bexotegrast-treated group experienced significant improvements in lung function after four, eight, and 12 weeks compared with a placebo, regardless of whether they were using standard of care medications.
At week 12, treated patients had a mean FVC increase of 29.5 mL relative to the study’s start — an improvement in lung function — compared with a decline of 110.7 mL in the placebo group.
Moreover, no patients treated with 320 mg bexotegrast experienced at least a 10% decline in the percent predicted FVC for their age.
This performance was superior to the previous analyses in the lower dose groups, according to Pliant.
“The statistically significant increase in mean FVC versus placebo seen throughout the 12-week treatment period of the INTEGRIS-IPF trial at 320 mg is unprecedented in clinical trials observed to date,” said Lisa H. Lancaster, MD, the study’s principal investigator and a professor of medicine at Vanderbilt School of Medicine.
QLF imaging indicated that 320 mg bexotegrast also led to a slower change in lung fibrosis (0.2%) compared with placebo (1.46%).
PRO-C3 and integrin beta-6, two biomarkers of IPF progression, also were decreased with 320 mg bexotegrast, which “aligned with changes in FVC and the antifibrotic mechanism of action of bexotegrast,” Lancaster said.
Bexotegrast has been granted orphan drug designation in Europe and the U.S., as well as fast track designation in the U.S., all of which are intended to facilitate its clinical development.
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