Introduction
Idiopathic Pulmonary Fibrosis (IPF) is a progressive and often fatal interstitial lung disease marked by chronic fibrosis and inflammation of lung tissue. IPF remains a significant therapeutic challenge despite the availability of antifibrotic agents like pirfenidone and nintedanib. Recent attention has turned toward inflammation-modulating and immunoregulatory therapies. One of the more promising investigational compounds is nerandomilast, a selective PDE4B inhibitor, which has shown potential in preclinical and early clinical studies for treating fibrotic lung diseases.
What is Nerandomilast?
Nerandomilast is a highly selective phosphodiesterase 4B (PDE4B) inhibitor. PDE4 enzymes degrade cyclic adenosine monophosphate (cAMP), a key regulator of inflammation. PDE4B is believed to play a key role in promoting lung inflammation. By inhibiting PDE4B, nerandomilast reduces pro-inflammatory mediators, including TNF-α, IL-1β, and IL-6—molecules that contribute to the scarring process in IPF.
Mechanism of Action in Pulmonary Fibrosis
Although the precise causes of IPF and progressive pulmonary fibrosis are not well understood, a growing body of data points to abnormal wound healing responses following lung injury. This process involves activation of fibroblasts, cells that are involved in scar formation. Nerandomilast’s anti-inflammatory effects, via PDE4B inhibition, may:
- Suppress the release of cell signaling molecules that promote scar formation (e.g., TGF-β, IL-13)
- Inhibit fibroblast function
- Reduce oxidative stress and improve lung cellular response to injury
In preclinical models, nerandomilast reduced lung inflammation, fibrosis, and immune cell migration into the lung, positioning it as a disease-modifying candidate rather than merely a symptom-reliever.
Clinical Trials and Evidence
Two phase 3 studies were recently published, one in IPF and one in progressive pulmonary fibrosis. These trials were called FIBRONEER IPF and FIBRONEER PPF.
FIBRONEER IPF
In this 52-week study comparing nerandomilast 9mg, 18mg and placebo, active treatment with nirandomilast significantly reduced the rate of decline in lung function compared to placebo. Overall, there was about a 40% decrease in the decline in lung function. Study participants were allowed to be on either of the approved therapies for IPF (nintandenib or pirfenidone). Nerandomilast was effective in patients taking background antifibrotic therapy as well as in patients not on any other therapy for their IPF. Among patients taking pirfenidone, only the 18mg dose was effective due to a drug interaction that led to lower levels of nerandomilast when used at the same time as pirfenidone.
Unfortunately, other endpoints such as time to first exacerbation and hospitalization rates were not improved by nerandomilast. Side effects were common among subjects taking nerandomilast. Overall, 40% of subjects on nerandomilast experienced diarrhea and this increased to 60% in subjects on background nintandenib. The 18mg dose was more likely to cause diarrhea than the 9mg dose.
FIBRONEER PPF
This 52-week study compared nerandomilast 9mg and 18mg to placebo in subjects with progressive pulmonary fibrosis. Nerandomilast led to slower loss of lung function. There was about a 40% reduction in the rate of decline in lung function. The benefits were seen both in subject taking background nintendanib and in those not on any other antifibrotic therapy. There was a strong trend towards a reduced rate of disease exacerbation, hospitalization or death.
Side effects were common among study participants. The most common side effect was diarrhea, occurring in 36% of subject on the 18mg dose. Among participants on background nintendanib, approximately 50% experience diarrhea.
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Conclusions
Nerandomilast slows the progression of both IPF and progressive pulmonary fibrosis. In IPF it did not improve other endpoints. In progressive pulmonary fibrosis there was a stronger suggestion that it may reduce disease exacerbations and hospitalizations but more data is needed. Unfortunately, the major side effect is diarrhea. I expect this drug to be approved by the FDA and be available for patients in the next six to 12 months. The optimal way in which nerandomilast will be used will require more experience with the medication.