Novel PDE4B inhibitor offers breakthrough for IPF

Findings from a phase 2, randomised, placebo-controlled trial in patients with idiopathic pulmonary fibrosis (IPF) showed that the investigational drug BI 1015550, either alone or with background use of an anti-fibrotic agent, significantly prevented a decrease in lung function.

The anti-inflammatory and immunomodulatory abilities of oral, selective phosphodiesterase 4B (PDE4B) inhibition has not yet been explored clinically for IPF. However, in a late-breaking session, Prof. Luca Richeldi (Università Cattolica del Sacro Cuore, Italy) presented the first clinical results of the novel, investigational, preferential, oral PDE4B inhibitor BI 015550 [1] in a phase 2 study (NCT04419506), either in the presence or absence of background anti-fibrotics. The findings were simultaneously published in the New England Journal of Medicine [2].

IPF is a progressive, irreversible lung disease with high mortality. Currently there are 2 approved anti-fibrotic drugs (nintedanib and pirfenidone) which slow, but do not stop fibrotic progression [3,4]. There remains an unmet need for additional treatments that can be used alone or with existing antifibrotic therapies. In preclinical studies, the preferential PDE4B inhibitor BI1015550 demonstrated anti-inflammatory and anti-fibrotic effects [5].

Patients were randomised in a 2:1 ratio to an arm which either received 18 mg of the investigational drug oral twice daily (n=97), or placebo (n=50) for 12 weeks, with an additional 1 week of follow-up. Randomisation was based on stratification of use of anti-fibrotics. The primary endpoint was change in baseline in forced vital capacity (FVC) at 12 weeks. The secondary endpoint was percentage of patients with treatment-emergent adverse events.

The primary endpoint was evaluated separately in patients with and without background anti-fibrotic therapy at baseline in a 2-step procedure. Firstly, data from the current trial were analysed with a restricted maximum likelihood-based approach using an MMRM (mixed model with repeated measurements). Secondly, the pre-specified primary analysis of FVC change was based on a Bayesian approach combining MMRM estimates and historical data for the placebo arm, Of the original 233 patients screened, 147 were ultimately randomised. Of those participants, 97 were randomised to the investigational arm (48 were not taking concomitant anti-fibrotic therapy, 49 were), and 50 assigned to the placebo comparator arm (25 were not taking concomitant anti-fibrotic therapy, 25 were).

The primary endpoint was met; the change in FVC at week 12 and over time in all patients showed a remarkable improvement in the patients taking the investigational drug with an adjusted mean of +4.6 mL versus -83.8 mL for the placebo arm (D88.4 mL; 95% CI 40.7–136.0). When stratifying the groups based on background anti-fibrotic therapy, the effect was maintained; using Bayesian modelling, patients without background anti-fibrotics showed a +5.7 mL mean improvement in FVC vs -81.4 mL (D87.1 mL) and those with background antifibrotics had a +2.9 mL FVC improvement on the drug as opposed to a -59.2 mL decrease in the placebo (D62.1 mL). Both calculations predicted a >98% probability that BI 101550 is superior to placebo. The trial also met the secondary endpoint, as BI 1015550 demonstrated acceptable safety and tolerability in trial participants over 12 weeks.

In conclusion, compared with placebo, treatment with the investigational PDE4B inhibitor BI 1015550, either alone or concomitant with background anti-fibrotic agents, prevented a decline in lung function in patients with IPF. The observed safety and tolerability of BI 1015550 were acceptable and, in combination with the beneficial effects on FVC, warrant further clinical development as a treatment for IPF, and possibly other forms of progressive pulmonary fibrosis.

1. Richeldi L et al, Phosphodiesterase Inhibition as a Novel Strategy to Stop Fibrosis in the Lung. Session B12, ATS International Conference 2022, San Francisco, CA, USA, 13–18 May.


2. Richeldi L, et al. N Engl J Med. 2022 May 15. doi: 10.1056/NEJMoa2201737.


3. Richeldi L, et al. N Engl J Med. 2014 May 29;370(22):2071–82.


4. Noble PW, et al. Eur Respir J. 2016 Jan;47(1):243–53.


5. Herrmann FE, et al. Front Pharmacol. 2022 Apr 20;13:838449.

 

 

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Posted on 17 May, 2022