Boehringer Ingelheim has ended a decade of industrywide failures in idiopathic pulmonary fibrosis (IPF) by reporting a phase 3 win for a potentially first-in-class candidate and outlining plans to seek approval.
Physicians already have Boehringer’s Ofev and Roche’s Esbriet to manage IPF patients. However, those drugs only slow the progression of fibrosis. Attempts to develop molecules that further slow, or ideally stop, progression have failed to establish an alternative to Ofev and Esbriet. Boehringer tried to end the losing streak by moving its PDE4B inhibitor nerandomilast into a phase 3 program in 2022.
Patients on nerandomilast performed better on the forced vital capacity test, a measure of lung function, than subjects on placebo after 52 weeks, causing the study to hit its primary endpoint. Boehringer is yet to share the numbers behind the primary endpoint hit.
The decision to hold back data for presentation in the first half of 2025 makes it impossible to gauge how well nerandomilast performed. Boehringer is yet to comment on how the two different doses, the lower of which wasn’t tested in phase 2, fared or to say anything about secondary endpoints. The study has a key secondary that is tracking time to any of a set of negative events such as hospitalization and death.
There are also unanswered questions about the patient population and how nerandomilast performed in different subgroups. The study accepted patients who were either on stable therapy with Ofev or Esbriet or hadn’t received either drug for at least eight weeks. Data on the subgroups could help unpick the level of benefit nerandomilast provides as an add-on drug and its potential to become the first-choice agent.
Nerandomilast has a potential mechanistic advantage over the incumbent products. The candidate has a different target, PDE4B, than the existing drugs. Targeting PDE4 drives anti-inflammatory and antifibrotic effects, but attempts to develop oral inhibitors of the enzyme in respiratory diseases have been hindered by class-related systemic adverse events such as diarrhea and headaches.
Boehringer designed nerandomilast to overcome those problems by preferentially targeting PDE4B over PDE4D. Hitting PDE4B, a subtype of the enzyme that is found at high levels in the lungs, could enable the molecule to cause anti-inflammatory and antifibrotic effects without the side effects associated with less selective inhibitors. Boehringer’s data drop lacks any comment on nerandomilast’s safety and tolerability.
While the drugmaker is giving little away, its actions suggest it believes nerandomilast has a future in IPF. Boehringer plans to seek approval for the molecule in the U.S. and other parts of the world. Work on a second phase 3 trial, which is testing nerandomilast in progressive fibrosing interstitial lung diseases, is continuing. The study is scheduled to reach primary completion in December.