Nerandomilast: PDE4B Inhibitor Rewrites IPF Standard of Care

Ofev/Esbriet Don't Stop It—That's the Reality

IPF's standard-of-care drugs—Pirfenidone and Nintedanib—only "slow progression." Patients still lose lung function. And many discontinue due to side effects.

Enter Nerandomilast (Jascayd), a PDE4B-selective inhibitor. By sparing PDE4D (the vomiting center trigger) and hitting only PDE4B (the lung fibrosis driver), it achieved add-on efficacy in FIBRONEER-IPF—cleared for FDA approval in 2025.

BI 1015550 (Nerandomilast): Precise Molecular Design

BI 1015550 (Nerandomilast), under development by Boehringer Ingelheim, is an oral drug that selectively inhibits phosphodiesterase 4B (PDE4B).

Why PDE4"B"? The Key to Overcoming Side Effect Barriers

PDE4 inhibitors themselves are not a new concept (e.g., the COPD drug roflumilast). They exert anti-inflammatory effects by increasing cAMP levels, but traditional "non-selective" PDE4 inhibitors had a dilemma where severe central side effects such as nausea and vomiting became dose-limiting factors, preventing the administration of sufficiently effective doses.

BI 1015550 broke through this barrier with "selectivity."

• PDE4B: A subtype expressed in inflammatory cells and fibroblasts, involved in pathogenesis.
• PDE4D: A subtype expressed in the vomiting center of the brain, involved in side effects such as nausea.

BI 1015550 possesses the characteristic of having about 9 times higher inhibitory activity against PDE4B than PDE4D. This made it possible to exert potent anti-inflammatory and anti-fibrotic effects only in the lung lesions (PDE4B) without stimulating the vomiting center (PDE4D).

Clinical Trial Data: Statistical Significance and Its Meaning

Phase 2 Trial Results (The NEJM)

It showed dramatic improvement compared to the placebo group in the effect of inhibiting FVC decline.

• FVC Change (at 12 weeks):
  • In the BI 1015550 monotherapy group, no decline in FVC was observed, suggesting Stabilization of disease activity (+5.7 mL vs placebo -81.7 mL).
• Proof of Combination Effect:
  • Even when BI 1015550 was added on to patients taking existing standard of care drugs (pirfenidone or nintedanib), further FVC decline inhibitory effects were confirmed. This is important data suggesting the possibility of future Add-on therapy to standard of care.

Phase 3 Trial (FIBRONEER-IPF)

In the Phase 3 FIBRONEER-IPF trial, for which results were reported in 2025, 1,177 IPF patients (about 80% concurrently using pirfenidone or nintedanib) were compared between Nerandomilast 9 mg / 18 mg and placebo.

• Primary Endpoint (FVC change at 52 weeks):
  • Nerandomilast 18 mg group: -114.7 mL (vs placebo -183.5 mL, difference +68.8 mL, relative reduction 38%, p<0.001)
  • Nerandomilast 9 mg group: -138.6 mL (vs placebo -183.5 mL, difference +44.9 mL, relative reduction 24%, p=0.02)
  • Both doses showed significant FVC decline inhibitory effects regardless of the presence or absence of background therapy.
• Safety: The most frequent adverse event was diarrhea, but most cases were mild to moderate, confirming tolerability in long-term administration.
• Secondary Endpoints: On the other hand, no significant difference was observed in the composite endpoint of "acute exacerbation, respiratory hospitalization, or death," and future verification with long-term follow-up and real-world data is expected.

Others: Challenge of Local Delivery by Inhaled Drugs

Another approach to avoid systemic side effects is "inhaled drugs."

• Inhaled Pirfenidone (Avalyn Pharma, etc.):
  • Development is progressing as an approach to avoid systemic side effects. It is a strategy aiming to reduce gastrointestinal symptoms and maximize efficacy by keeping blood concentrations low while increasing concentrations in lung tissue, and is expected as a distinct option from oral drugs.

Conclusion

IPF drug discovery has entered a new phase with the appearance and approval (October 7, 2025, US FDA) of the PDE4B inhibitor Nerandomilast (Brand name Jascayd). From "slowing progression" to "maintaining function and improving QOL." Following approval in the US, applications for approval are also underway in domestic markets (Japan), and it is expected that this new option will reach Japanese patients in the near future. The era where many patients can receive combination therapy adding Nerandomilast to existing anti-fibrotic drugs is already beginning. It is expected that this will be even better news for patients as guidelines in each country are revised and "treatment algorithms" regarding which patient groups should be introduced early are reconstructed in the future.