Positive results from the FIBRONEER trials of nerandomilast in idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) have sent the phosphodiesterase 4B inhibitor to the US Food and Drug Administration (FDA) for marketing approval. If approved, nerandomilast would be the first new antifibrotic agent for interstitial lung disease (ILD) in more than a decade.
“There is a lot of excitement about nerandomilast, but we have to be patient and let the approval process play out,” said Barry Shea, MD, Associate Physician at Massachusetts General Hospital and Assistant Professor of Medicine at Harvard Medical School. “Assuming the drug is approved and becomes available later this year or perhaps early next year, we will have another option for pulmonary fibrosis.”
Additionally, how the drug is approved will make a significant difference in how it is used.
Nerandomilast slowed decline in FVC both as monotherapy and as an add-on to existing antifibrotic agents nintedanib and pirfenidone for IPF, as well as nintedanib and selected immunosuppressant background therapies for PPF.
“What the trials have shown us is that we now have a third antifibrotic agent,” said Adrian Shifren, MBBCh, FCCP, Professor of Medicine and Director of the Interstitial Lung Diseases Program at Washington University School of Medicine. “As monotherapy, it could be prescribed as first-line therapy or to replace an existing drug if patients aren’t tolerating it. It could also be considered for upfront combination therapy, but the indications for this are still uncertain. So, we aren’t sure how the FDA is going to approve it for use, but we hope it will be approved as both monotherapy and add-on therapy.”
FIBRONEER-ILD is the second phase 3 study of nerandomilast. The FIBRONEER-ILD study, which randomized patients with PPF in a 1:1:1 ratio to receive 18 mg of nerandomilast twice daily, 9 mg of nerandomilast twice daily, or placebo, met its primary end point of absolute change in FVC from baseline at 52 weeks compared with placebo. Previously, FIBRONEER-IPF, which studied nerandomilast in patients with IPF, also showed positive top-line results.
Nerandomilast 18 mg slowed FVC decline by 67.2 ml compared with placebo (95% CI, 31.9-102.5; P < .001) in patients with PPF. Nerandomilast 9 mg slowed FVC decline by 81.1 ml compared with placebo (95% CI, 46.0-116.3; P < .001). The most common adverse event was diarrhea, reported by one-third of patients receiving nerandomilast.
The key secondary end point in the PPF trial was a composite of time to first acute exacerbation of ILD, hospitalization for a respiratory cause, or death, whichever occurred first. Other secondary end points included each of the components separately or in combination.
Neither dose of nerandomilast showed a benefit compared with placebo with respect to the key composite secondary end points of the study. However, the hazard ratio for the secondary end point of death alone compared with placebo was 0.48 (95% CI, 0.30-0.79) for the 18 mg dose and 0.60 (95% CI, 0.38-0.95) for the 9 mg dose.
“The potential mortality benefit identified in people with PPF taking nerandomilast is intriguing,” Dr. Shifren said. “However, caution needs to be exercised, as it was not the key secondary end point, so it needs to be explored in more detail. If the mortality benefit were confirmed, however, its use as a first-line agent would be compelling.”
The open label extension portion of the trial may provide additional mortality data and insight.
What nerandomilast did not demonstrate was any improvement in patients’ quality of life.
Changes in the Living with Pulmonary Fibrosis questionnaire, dyspnea score, cough score, and fatigue score were similar across both nerandomilast groups and the placebo group.
“There is still a lot to be done,” said Tejaswini Kulkarni, MBBCh, FCCP, Director of the Interstitial Lung Disease Program at the University of Alabama at Birmingham. “The field is excited and optimistic that having another approved medication will help our patients. But, at the same time, the quest for newer therapies that might impact patients’ quality of life and not just slow down FVC decline needs to continue.”
The biggest limiting factor for now is waiting for approval and distribution. Clinicians and patients know nerandomilast is effective and better tolerated than either nintedanib or pirfenidone, but it is not available outside clinical trial settings.
“Patients who participated in the parent clinical trials have been given the opportunity to enroll in the open label phase of FIBRONEER and are currently receiving study medication,” Dr. Kulkarni said. “Decisions from the FDA are anticipated later this year, hopefully in October. Unfortunately, this medication is not approved for use for patients anywhere in the world until then.”
For now, Dr. Kulkarni is talking patients through the FIBRONEER findings, assessing their current medication regimen, and discussing tolerability. Existing medications can slow the decline in lung function, but side effects can be intolerable limiting factors for some patients. Assuming nerandomilast is approved, patients who cannot tolerate existing agents or who are not on any antifibrotic therapy will likely be first in line for prescribing.
“I think our threshold for prescribing antifibrotic therapy is going to be lower because we will have an option with fewer side effects,” Dr. Shea said. “It also doesn’t have the risk of liver toxicity, so it’s not going to require liver monitoring. This is going to be a relatively easy medication to start and will lower the threshold to antifibrotic therapy for people who might have been on the fence previously.”
This article was originally published in the Fall 2025 issue of CHEST Physician.
