Oral PDE4 Inhibitor Halts IPF Progression in Trial

SAN FRANCISCO — Patients with idiopathic pulmonary fibrosis (IPF) had no disease progression when they took a novel agent targeting phosphodiesterase (PDE) 4B in a short-term study, researchers reported.

Those receiving the oral drug, called BI 1015550, showed a slight increase in forced vital capacity (FVC) after 12 weeks, whereas it declined significantly in a placebo group for a median difference of 88.4 mL (95% credible interval 29.5-154.2), according to Luca Richeldi, MD, PhD, of Università Cattolica del Sacro Cuore in Rome, and colleagues.

With the active agent, median change in FVC was 5.7 mL (95% CI -39.1 to 50.5); with placebo, the median change was -81.7 mL (95% CI -133.5 to -44.8), they wrote in the New England Journal of Medicine (NEJM). The findings were simultaneously presented at the American Thoracic Society annual meeting.

The drug’s efficacy was similar whether or not patients were also taking conventional antifibrotic drugs, Richeldi and colleagues indicated, and whether statistical analysis were based on data only from patients randomized in the trial or through Bayesian methods that also included some historical controls (patients taking placebo in previous IPF drug trials).

When viewed over time, it appeared that BI1015550 induced a small spike in mean FVC in the first 2 weeks, about 30 mL, which then declined gradually over succeeding weeks to leave the small net increase at week 12. The placebo group, meanwhile, showed decreases in FVC at every time point.

Inhibiting PDE4B is a promising approach in IPF, the group asserted, based on studies in animal models and human tissues in vitro. Inflammation, in which PDE4 enzymes are heavily involved, is seen as a key driver of IPF progression. Richeldi’s group also suggested that targeting PDE4B specifically may come with fewer side effects than seen with PDE4 inhibitors that don’t discriminate among the enzyme’s subtypes. (Several are currently approved for psoriasis and related conditions.)

For the current phase II study, 147 patients were enrolled, split about equally between those receiving antifibrotics including nintedanib (Ofev) and pirfenidone (Esbriet) and those not. Patients in both groups were randomized 2:1 to BI 1015550 or placebo.

Mean patient age was about 70, while about three-quarters were men; the majority were white. Those on antifibrotics had lived with IPF for a mean of about 4 years; for those not taking these agents, time since diagnosis was closer to 2 years.

Baseline FVC stood at approximately 2,700-2,900 mL; these values were roughly 70%-80% of predicted for the patients’ demographics, with the antifibrotic-using patients at the lower end. Diffusing capacity of carbon monoxide (DLCO) was even more deficient, at about 50% of predicted after adjusting for hemoglobin levels in all groups.

BI 1015550 was administered at 18 mg twice daily.

Change in FVC was the primary efficacy endpoint reported in NEJM, with DLCO and quality of life assessed as well. The last measurements were taken 1 week after completing the 12 weeks of treatment. No significant differences between BI 1015550 and placebo groups were noted at week 13 for either of these secondary outcomes.

Every group showed a high rate of adverse events, though most were not considered serious or severe. The most common type that occurred more frequently with the active drug was diarrhea, seen in 17% of patients not using antifibrotics and 31% of those taking them. Fatigue was also seen in seven patients but was not noticeably more common with BI 1015550 than placebo, and thus may have simply stemmed from patients’ lung disease.

Study limitations included the small number of patients and “limited duration,” according to the authors. “A phase III trial will be necessary to evaluate these preliminary findings and assess additional outcomes that are relevant to patients with IPF,” they stated.