Phase I studies of BI 1015550, a preferential phosphodiesterase 4B inhibitor, in healthy males and patients with idiopathic pulmonary fibrosis

Abstract

Introduction: BI 1015550 is a phosphodiesterase 4 (PDE4) inhibitor that has antifibrotic properties. Phase I and Ic studies were conducted to investigate the safety, tolerability and pharmacokinetics of BI 1015550 in healthy male subjects and patients with idiopathic pulmonary fibrosis (IPF).

Methods: In the phase I study, 42 subjects were partially randomised to receive placebo or BI 1015550 in single rising doses of 36 mg and 48 mg, or multiple rising doses of 6 mg and 12 mg twice daily over 14 days. In the phase Ic study, 15 patients with IPF were randomised to receive 18 mg BI 1015550 or placebo twice daily for up to 12 weeks. For both studies, the primary endpoint was the number of subjects with drug-related adverse events (AEs).

Results: In the Phase I study, drug-related AEs were reported for 50.0% of healthy male subjects treated with a single dose of BI 1015550, compared with 16.7% receiving placebo. For those receiving multiple doses, drug-related AEs were reported for 37.5% of those treated with BI 1015550 and 12.5% receiving placebo. The most frequently reported AEs by organ class were nervous system disorders, which were largely driven by headache. In the Phase Ic study, drug-related AEs were reported in 90.0% of patients treated with BI 1015550, compared with 60.0% of those receiving placebo. The most frequent AEs by organ class were gastrointestinal AEs.

Conclusions: BI 1015550 had an acceptable safety profile in healthy male subjects and male and female patients with IPF, supporting further development in larger trials.

FIGURE 1

Phase I study in healthy males: subject flow. ^#: one patient prematurely discontinued the study after taking 48 mg BI 1015550 due to an adverse event that was not considered drug-related (ligament sprain). SRD: single rising dose; MRD: multiple rising dose.

FIGURE 2

Geometric mean plasma concentration–time profiles of BI 1015550. Phase I study in healthy males after a) single oral administration of BI 1015550 36 mg or 48 mg under fasted conditions, and b) single and multiple oral administrations of 6 mg or 12 mg twice-daily BI 1015550 under fed conditions. c) Phase Ic study in patients with idiopathic pulmonary fibrosis after single and multiple oral administration of 18 mg twice-daily BI 1015550.

FIGURE 3

Phase Ic study in patients with idiopathic pulmonary fibrosis: patient flow. Of 10 patients treated with BI 1015550, seven were treated up to a maximum duration of 12 weeks and three up to a maximum of 4 weeks. Of five patients treated with placebo, four were treated up to a maximum duration of 12 weeks and one up to a maximum of 4 weeks. AE: adverse event; PK: pharmacokinetic. ^#: four patients were screened twice; ^¶: other reasons for discontinuations (n=1 each) included no longer willing to participate, administrative reason, randomisation timeline, study closed and unable to perform calprotectin retest.