Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis

At December 17, 2024

Abstract:

Background:

Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis.

Methods:

In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent.

Results:

A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, –39.1 to 50.5) in the BI 1015550 group and –81.7 ml (95% credible interval, –133.5 to –44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, –32.8 to 38.2) in the BI 1015550 group and –59.2 ml (95% credible interval, –111.8 to –17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 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 event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups.

Conclusions:

In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.)

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible lung disease with high mortality.1,2 Currently, there are two approved antifibrotic drugs — nintedanib and pirfenidone — that slow, but do not stop, the progression of fibrosis.3-5 Therefore, there is a need for additional treatments that can be used alone or with existing antifibrotic therapies.6
Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic properties.7,8 Preferential inhibition of the PDE4B subtype may be beneficial in the treatment of IPF because it may harness these properties9,10 and is also associated with a more acceptable safety profile than nonselective PDE4 inhibitors.7,10

IPF is a rare disease, which makes the recruitment of large numbers of patients in early-phase clinical trials a challenge. In this trial, we used Bayesian analysis11,12 to incorporate informative historical data from phase 2–4 clinical trials of nintedanib for the control groups. Consistent decreases in the forced vital capacity (FVC) that have been observed in the placebo groups of these trials3,4,13–16 make such an approach suitable for proof-of-concept studies of new drug candidates for the treatment of IPF. In this multicenter, randomized, double-blind, phase 2 trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of PDE4B,17 in patients with IPF according to background nonuse or use of an antifibrotic agent.

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