Novel PDE4 inhibitor slows IPF progression

Treatment with BI 1015550, a novel investigational phosphodiesterase 4 (PDE4) inhibitor, slows lung function decline in patients with idiopathic pulmonary fibrosis (IPF) with or without background antifibrotic therapy, according to a 12-week phase II trial data presented at ATS 2022.

“Current antifibrotic agents slow down, but do not stop, the progression of fibrosis [or scarring] in the lungs,” said principal trial investigator Professor Luca Richeldi from Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore in Rome, Italy.  “There remains an unmet need for new treatments that can be used alone or [in combination] with current antifibrotic therapies [nintedanib and pirfenidone].”

Hence, Richeldi and his team sought to investigate the efficacy and safety of BI 1015550 for IPF, either taken alone or with background use of an antifibrotic agent.

This double-blind, placebo-controlled trial involved 147 patients (age ≥40 years) with IPF who had a baseline FVC* of ≥45 percent of the predicted value. Patients were randomized in a 2:1 ratio to receive BI 1015550 18 mg given orally twice daily (n=97) or placebo (n=50) for 12 weeks. Both treatment groups were stratified according to background antifibrotic use (BI 1015550: n=49; placebo: n=25) and nonusers (BI 1015550: n=48; placebo: n=25). [ATS 2022, abstract 423; N Engl J Med 2022;386:2178-2187]

Applying the Bayesian analysis, the overall treatment effect of BI 1015550, with or without background antifibrotic use, was 98.6 percent and 99.8 percent, respectively, with >98 percent probability that it was superior to placebo in slowing down IPF progression, said Richeldi.

Among those who were not on antifibrotics, the median change in FVC from baseline to week 12 was 5.7 mL and -81.7 mL in the BI 1015550 and placebo arms, respectively (median difference, 88.4 mL).

Similar benefits were observed in patients already on antifibrotic therapy, with a median change in FVC of 2.5 mL in the BI 1015550 arm and -59.2 mL in the placebo arm (median difference, 62.4 mL) at week 12 from baseline.

“Consistent effects of BI 1015550 treatment on FVC were [also] observed in the prespecified MMRM** analysis,” the researchers noted.

The most frequent adverse event (AE) reported was diarrhoea, which occurred in three patients taking the BI 1015550 along with background antifibrotics, resulting in treatment discontinuation.

Although more patients treated with BI 1015550 experienced any AEs than those on placebo, regardless of whether they are taking antifibrotics (73.5 percent vs 68.0 percent) or not (64.6 percent vs 52.0 percent), the overall tolerability of BI 1015550 was still acceptable.

Overall, treatment with BI 1015550, alone or with background antifibrotics, prevented lung function decline, in contrast with placebo which resulted in a marked decline in FVC, Richeldi summarized.

The safety profile of BI 1015550, in combination with its observed beneficial effects on FVC, warrants further investigation as a promising treatment for IPF and other forms of progressive pulmonary fibrosis, he added.

The phase II results reinforce the potential of BI 1015550 for IPF and will pave the way for acceleration into a phase III clinical trial. In February 2022, the novel investigational therapy was granted Breakthrough Therapy Designation by the US FDA, allowing for a priority review.

IPF is a debilitating lung disease, with an estimated mean survival of only 2–5 years from the time of diagnosis. [Curr Opin Pulm Med 2009;15:463-469] Given the grave prognosis of the disease, new therapies deserve to be investigated.

*FVC: Forced vital capacity