Idiopathic pulmonary fibrosis (IPF) has proved to be a tough disease to crack, as last year’s trial failures from Galecto Inc. and FibroGen, Inc. have shown. But Boehringer Ingelheim GmbH has defied precedent, touting a hit in the Phase III FIBRONEER-IPF trial of nerandomilast.
Key Takeaways
- Boehringer Ingelheim’s nerandomilast has hit in a Phase III trial in idiopathic pulmonary fibrosis, though whether it improved patients’ lung function or simply slowed decline compared with placebo is not clear.
- Secondary endpoints and safety will be crucial, and are expected to be revealed next year.
- Bristol Myers Squibb and United Therapeutics/Mannkind also have IPF candidates in Phase III.
The oral phosphodiesterase 4B inhibitor produced a significantly greater change in forced vital capacity (FVC), a measure of lung function, at one year than placebo in the study. But the extent of the hit, and the performance of the two doses tested, have not been disclosed. Neither has nerandomilast’s safety record in the trial, and given that it had marked gastrointestinal side-effects in Phase II this is a material consideration.
The study was the largest IPF trial conducted to date, signing up 1,177 patients who took nerandomilast, formerly known as BI 1015550, at either 9mg or 18mg twice-daily or placebo. The 18mg dose was that used in nerandomilast’s Phase II IPF study. Boehringer added the lower dose in the hope that it would be less toxic, as well as to provide further dose- and exposure-response data.
In its Phase II trial, nearly a third of patients taking nerandomilast 18mg twice-daily on top of background antifibrotic therapy had diarrhea. The background antifibrotics used in the trial – Boehringer’s own Ofev (nintedanib) and Roche Holding AG’s Esbriet (pirfenidone) – are known to cause gastrointestinal side-effects themselves, and it is likely that nerandomilast would be added on top of these approved drugs in real-world use.
Among the Phase II patients taking nerandomilast as monotherapy, 17% had diarrhea (Also see "Boehringer Bids To Go Beyond Slowing IPF" - Scrip, 16 May, 2022.). Overall 13 patients quit nerandomilast treatment owing to adverse events; there were no discontinuations in the placebo group. That trial only lasted three months, so side-effects could be higher in FIBRONEER-IPF.
Efficacy
In Phase II, nerandomilast monotherapy boosted patients’ FVC by 5.7mL versus a decline of 81.7mL for placebo at three months. In patients on antifibrotics nerandomilast increased FCV by 2.7mL, versus a drop of 59.2mL in the placebo group.
If nerandomilast can match these figures in Phase III it might have a good shot at approval. The current biggest-selling IPF drug, Ofev, was not able to improve FVC in its Phase III trials, only managing to slow decline compared with placebo.
Investors will also want to see nerandomilast’s showing on the main secondary endpoint of FIBRONEER-IPF. This is how long it takes before patients experience any of the components of the composite endpoint: time to first acute IPF exacerbation; first hospitalization for respiratory cause; or death, whichever occurs first.
Boehringer plans to present the full FIBRONEER-IPF data in the first half of 2025, and to file nerandomilast with regulatory bodies worldwide.
There are, however, a handful of other companies aiming to contest this market. The most immediate threat to Boehringer here is Tyvaso (treprostinil), being developed by United Therapeutics Corporation and MannKind Corporation. Two Phase III studies of the inhaled product could read out next year, and since they have the same primary endpoint as FIBRONEER-IPF comparisons should be fairly straightforward.
Bristol Myers Squibb Company is also active in Phase III here. Its second-generation LPA1 antagonist BMS-986278 is in a 1,185-patient placebo-controlled trial, and again change in FVC at one year is a primary endpoint. If nerandomilast is approved in IPF, Boehringer might be wise to act fast to capitalize on the first IPF success story for ten long years.
