Bexotegrast reverses signs of IPF lung scarring in Phase 2a trial
Benefits seen in lung function, cough severity of patients over 3 months
Pliant Therapeutics’ bexotegrast reversed the signs of lung scarring, while improving lung function and easing cough severity in people with idiopathic pulmonary fibrosis (IPF), according to top-line data from a small Phase 2a imaging trial.
Using positron emission tomography (PET) scans, researchers at Massachusetts General Hospital were able to directly see a decrease in lung collagen, the primary protein within scar tissue, in patients treated with bexotegrast for 12 weeks, or three months. At the same time, those who received a placebo saw an increase in total lung collagen over the same period.
“Results from this first study using collagen PET imaging to assess a therapeutic intervention highlight the possible utilization of this novel technology to identify potentially disease-modifying antifibrotic IPF therapies in short-term studies,” Sydney Montesi, MD, clinician-researcher in the division of pulmonary and critical care medicine at Massachusetts General Hospital and the trial’s principal investigator, said in a company press release.
Bexotegrast designed to block two proteins to slow, reverse fibrosis
Bexotegrast, formerly known as PLN-74809, is a small molecule designed to block two proteins — alpha v beta 6 and alpha v beta 1 — found at high levels in the lungs of IPF patients. Because these proteins are thought to contribute to scar tissue formation, blocking them is expected to slow, halt, or even reverse fibrosis.
The Phase 2a imaging study (NCT05621252) enrolled 10 IPF patients. Participants were randomly assigned, with seven receiving 160 mg of once-daily bexotegrast, and three given a matching placebo for 12 weeks. Six bexotegrast-treated patients and two given the placebo also received standard of care treatment with either Ofev (nintedanib) or Esbriet (pirfenidone).
Participants underwent PET scans before and after treatment, as well as assessments of lung function, fibrosis markers, and cough severity. For collagen to be visible on a PET scan, patients were first injected with a radiotracer, called 68Ga-CBP8, which selectively binds to type 1 collagen, the main type of collagen found in the lungs of IPF patients.
After 12 weeks, bexotegrast-treated patients showed a reduced standardized uptake value of the radiotracer, “suggesting potential reversal of fibrosis,” according to Pliant. In comparison, those given a placebo saw an increase in radiotracer uptake, consistent with more type 1 collagen and disease progression.
In line with PET scans, lung function rapidly improved in bexotegrast-treated patients and gradually worsened in placebo-treated patients, representing an overall 4% difference by week 12. Lung function was measured by forced vital capacity, which is the maximum amount of air a person can forcibly exhale after a deep breath.
Likewise, cough severity, as assessed by a patient-rated visual analog scale, lessened over time with bexotegrast and worsened with a placebo.
Reduction in 2 biomarkers of fibrosis in bexotegrast-treated patients
Blood tests taken at weeks four and 12 also showed a reduction in two biomarkers of fibrosis, PRO-C3 and integrin beta-6, in bexotegrast-treated patients compared with those on the placebo.
Bexotegrast was well tolerated when given at a dose of 160 mg for 12 weeks, with no serious adverse events reported. The most frequently reported treatment-related adverse events were mild in severity, and no participant discontinued the trial.
These findings were consistent with data from a Phase 2a trial called INTEGRIS-IPF (NCT04396756), which tested multiple doses of bexotegrast versus a placebo in 119 IPF patients over nearly one year. Six-month data showed a 320 mg daily dose of bexotegrast, given in combination with standard of care, prevented lung function decline and eased cough.
In particular, based on CT scans, the extent of fibrosis with bexotegrast was below the minimally clinically important difference of 2%, whereas it was above this threshold with a placebo. By six months, bexotegrast-treated patients were more than twice as likely to show stable or improved lung fibrosis as compared with the placebo group.
“These imaging data continue to demonstrate the antifibrotic mechanism of action of bexotegrast and build on previous results, including from our INTEGRIS-IPF Phase 2a trial,” said Éric Lefebvre, MD, Pliant’s chief medical officer.
Last year, Pliant launched a Phase 2b study called BEACON-IPF (NCT06097260) to assess whether 160 or 320 mg of bexotegrast can improve lung function in about 360 IPF patients, 40 and older, compared with a placebo. Recruitment has begun at some sites across the globe and is expected to open soon at others.
In April, BEACON-IPF became a pivotal, adaptive Phase 2b/3 trial after the European Union and global health authorities accepted the change. This adaptive design is expected to shorten bexotegrast’s late-stage development over a traditional Phase 3 trial. A pivotal trial is designed to demonstrate the safety and efficacy of a therapy to support its potential marketing approval.
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