PDE4 inhibitor(Joincare)

Boehringer Ingelheim has peeled back the curtain on its late-stage pulmonary fibrosis programme, revealing the data behind two Phase III wins at the American Thoracic Society (ATS) meeting on Sunday.The German drugmaker previously reported that nerandomilast, its oral phosphodiesterase 4 (PDE4) inhibitor, met the primary endpoint of each trial by significantly improving absolute change from baseline in forced vital capacity (FVC) versus placebo at week 52. FIBRONEER-IPF enrolled 1,177 patients with idiopathic pulmonary fibrosis (IPF), and FIBRONEER-ILD recruited 1,176 individuals with progressive pulmonary fibrosis (PPF).A marketing application for nerandomilast in IPF is currently under priority review at the FDA, with a decision expected in the fourth quarter. Boehringer has also submitted a US regulatory filing for the PDE4 inhibitor to treat PPF.Diarrhoea drawbacksIn the two studies, patients were randomised to receive either a 9-mg or 18-mg dose of nerandomilast twice-daily, or placebo. Both the low and high dose, in each trial, met the primary endpoint. In FIBRONEER-IPF, patients in the 18-mg dose group and 9-mg dose group saw an adjusted mean change in FVC of -114.7 ml and -138.6 ml, respectively, compared with -183.5 ml for placebo. However, 41.3% of patients in the high-dose cohort, and 31.1% who received the low-dose, reported diarrhoea, versus 16% in the placebo group. The side effect led to study discontinuation in 6.1% of patients in the 18-mg group, 1.8% of the 9-mg recipients, and 0.5% of those on placebo. Oppenheimer analyst Jeff Jones previously suggested that gastrointestinal tolerability could be an issue with nerandomilast (see – Spotlight On: Another ILD win raises stakes on Boehringer’s looming full reveal).The incidence of diarrhoea was lower in the FIBRONEER-ILD trial. In the 18-mg cohort, 36.6% of patients reported the symptom, which led to a 2.6% discontinuation rate; the 9-mg cohort saw 29.5% of patients experience diarrhoea, leading to discontinuation in 1.3% of the group. Of those who received placebo, 24.7% reported diarrhea, and 0.5% discontinued treatment due to the symptom.Patients with PPF also experienced a greater benefit from nerandomilast. The 9-mg and 18-mg cohorts saw an adjusted mean change in FVC of -84.6 ml and -98.6 ml, respectively, compared with −165.8 ml for placebo. While the experimental treatment did not meet, in either trial, its composite secondary endpoint of time to first acute exacerbation, hospitalisation for a respiratory cause, or death Boehringer noted that in FIBRONEER-ILD, there were numerically fewer deaths in both treatment groups: 33 in the 9-mg cohort, 24 in the 18-mg cohort, versus 50 in the placebo arm. Shashank Deshpande, Boehringer's head of human pharma, said that IPF and PPF are "devastating conditions," with half of those diagnosed with IPF dying within five years. "Despite this stark reality…there remains a need for additional therapies," he said. "The latest efficacy, safety and tolerability data on nerandomilast points to its potential in addressing the needs of those impacted by IPF and PPF."