Novel Therapy Shows Promise for Treatment of Idiopathic Pulmonary Fibrosis

Phase II trial findings show stabilized lung function with PDE4 inhibition

05/16/2022
Salynn Boyles, Contributing Writer, BreakingMED™
Kevin Rodowicz, DO, Assistant Professor, St. Luke’s University/Temple University
Take Away
  1. Significantly less change was observed in forced vital capacity (FVC) exhaled lung volume during the 12-week trial among idiopathic pulmonary fibrosis patients receiving the PDE4B inhibitor BI 101550 compared to placebo.

  2. BI 101550 is not yet approved for clinical use; based on data from this phase II trial, the U.S. Food and Drug Administration granted breakthrough drug status to the investigational oral treatment in late February 2022.

Phosphodiesterase 4 (PDE4) inhibition with an investigational oral therapy appeared to stabilize lung function in patients with the progressive and irreversible lung disease idiopathic pulmonary fibrosis (IPF) in a phase II, randomized trial, regardless of whether they were receiving antifibrotic treatments.

Significantly less change was observed in forced vital capacity (FVC) exhaled lung volume during the 12-week trial among patients receiving the PDE4B inhibitor BI 101550 compared to patients randomized to the placebo arm of the trial.

The between-group differences were shown in both Bayesian and mixed model with repeat measure (MMRM) analysis.

The phase II trial data were published online May 15 in The New England Journal of Medicine, and the findings were scheduled for presentation May 16 in San Francisco at the international conference of the American Thoracic Society, ATS 2022.

Based on data from the trial, the U.S. Food and Drug Administration granted breakthrough drug status to the oral treatment in late February.

In a press release issued by the drug’s manufacturer at the time, a company spokesperson noted that BI 1015550 is the first in a class of PDE4 inhibitors under development for the treatment of IPF and other progressive, fibrosing interstitial lung diseases.

Phase II data from the study showed daily treatment with the PDE4 inhibitor prevented decline in lung function.

"Although this trial was only 12 weeks long, it appeared to show the stabilization of FVC with BI 1015550 therapy, which was replicated in patients regardless of background antifibrotic use and thus provides a proof of concept for longer-term phase III trials," wrote researcher Luca Richeldi, MD, PhD, of Rome, Italy’s Catholic University of Sacred Heart, and colleagues.

Idiopathic pulmonary fibrosis is a rare disease, which presents a challenge for recruiting sufficient numbers of patients for randomized trials. For this reason, Richeldi and colleagues used Bayesian analysis which incorporated historical data for the study’s control group from prior clinical trials of the antifibrotic therapy nintedanib.

Nintedanib and pirfenidone are the only approved antifibrotic therapies, but neither drug has been shown to stop the progression of fibrosis.

The use of Bayesian analysis in the BI 1015550 trial "allowed more patients to be randomly assigned to active treatment; because of the use of historical data, this approach reduced the number of patients who were assigned to the placebo group for the 12-week duration of the trial," the researchers wrote.

The study included 147 patients with IPF randomized in a 2:1 ratio to treatment with the experimental PDE4 inhibitor (18 mg twice daily) or placebo for 12 weeks. The study’s primary endpoint was change in FVC from baseline at the end of the treatment period. All patients were included in the safety analysis, which recorded adverse events occurring during the treatment period and one week of follow-up.

In patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% confidence interval [CI], –39.1 to 50.5) in the PDE4 inhibitor group and –81.7 ml (95% CI, –133.5 to –44.8) in the placebo group (median difference, 88.4 ml; 95% CI, 29.5 to 154.2; probability that treatment with the PDE4 inhibitor was superior to placebo, 0.998).

Among the other main findings:

  • "In patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% CI, –32.8 to 38.2) in the PDE4 inhibitor group and –59.2 ml (95% CI, –111.8 to –17.9) in the placebo group (median difference, 62.4 ml; 95% CI, 6.3 to 125.5; probability that the PDE4 inhibitor was superior to placebo, 0.986).
  • "A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis."
  • The most frequent adverse events were gastrointestinal, reported in 27% of the experimental-treated and 16% of the placebo-treated groups.
  • Thirteen patients treated with the PDE4 inhibitor, and none in the placebo group, discontinued treatment during the study due to adverse events. Diarrhea was the most frequent adverse event leading to treatment discontinuation (three patients).
  • The percentage of reported serious adverse events or severe adverse events were similar in the two treatment groups.

Study limitations cited by the researchers included the relatively short 12-week treatment period and small sample size.

"Although the size and duration of the trial were sufficient for the determination of changes in the FVC, these factors did not permit the meaningful collection of data relating to clinically important events, including acute exacerbations or death, or the determination of changes in patients’ quality-of-life measures," Richeldi and colleagues wrote.

Disclosures

This research was funded by Boehringer Ingelheim. Richeldi reported serving as a paid consultant for Boehringer Ingelheim, Bristol-Myers Squibb, CLS Behring, Biogen Idec, F. Hoffmann-LaRoche, FibroGen, Nitto, Pliant Therapeutics, RespiVant, Toray Industries, and Zambon. Other study researchers reported receiving consulting fees from Boehringer Ingelheim and others or being employed by Boehringer Ingelheim.

Sources

Richeldi L, et al. "Trial of a preferential phosphodiesterase 4B inhibitor for idiopathic pulmonary fibrosis" N Engl J Med 2022; DOI: 10.1056/NEJMoa2201737.