With the emergence of pirfenidone and nintedanib over the past decade or so, pulmonologists now have at their disposal two breakthrough antifibrotic agents for the treatment of idiopathic pulmonary fibrosis.
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But these two drugs have a number of shortcomings that a host of investigative agents are aiming to address. For one, while pirfenidone and nintedanib have been shown to slow disease progression and improve symptoms, they don’t stop or reverse the disease. Also, a large number of patients with IPF don’t tolerate these drugs well. And, their high cost is a barrier for many patients.
Joyce Lee, MD
Dr. Joyce Lee
in terms of therapies or interventions that have better efficacy, better long-term tolerability, and that improve symptoms and quality of life for our patients with IPF disease,” said Joyce Lee, MD, associate professor of medicine–pulmonary at the University of Colorado at Denver, Aurora, and senior medical adviser for research and health care quality for the Pulmonary Fibrosis Foundation.
The National Institutes of Health estimates that more than 30,000 new cases of IPF are diagnosed in the United States annually, and as many as 3 million people have the disease worldwide. The 5-year survival rate is less than 40% after diagnosis. Bloomberg News reported that more than 80 pharmaceutical companies are working on IPF treatments. iHealthcareAnalyst estimates the global market for IPF will reach $10.1 billion by 2029 thanks to rapidly increasing prevalence and incidence with age, premium-priced drugs, and rapid approval of new treatments.
The perils of phase 3 studies
A search on ClinicalTrials.gov turned up 89 investigative IPF treatments in human trials. However, the search for alternatives can be perilous. “In the field, we have gotten used to promising phase 2 studies that failed in the phase 3 stage of development,” Dr. Lee said. “I don’t hold my breath these days just in terms of trying to predict whether or not the efficacy will be present in the phase 3 clinical trial.”
Three notable phase 3 flops include the ISABELA 1 and 2 trials of the autotaxin inhibitor ziritaxestat, which failed to meet their primary endpoint and were halted early (JAMA. 2023;329:1567-78). The phase 3 ZEPHYRUS-1 trial failed to show any benefit of pamrevlumab to improve percent predicted force vital capacity (ppFVC) at week 48, causing discontinuation of a second phase 3 trial. The phase 3 STARSCAPE-OLE study of intravenous recombinant human pentraxin-2 was terminated earlier this year when the sponsor, Hoffmann-LaRoche, decided it was unable to meet its primary objective (NCT04594707).
In the meantime, these six other phase 3 programs in IPF are still in the field:
Anlotinib. A phase 2 and 3 trial in China is evaluating 1-year outcomes of once-daily oral anlotinib for treatment of IPF/progressive fibrosis-interstitial lung disease (PF-ILDS) (NCT05828953). Anlotinib is a tyrosine kinase inhibitor (TKI) that targets four factors: vascular endothelial growth factor receptor (VEGR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. It’s approved in China as a third-line therapy for non–small cell lung cancer (NSCLC).
BI 101550. Enrollment in the FIBRONEER-IPF trial commenced last fall (NCT05321069), with completion scheduled for late next year. BI 1015550 is an oral phosphodiesterase 4B (PDE4B) inhibitor. FIBRONEER-ILD is a separate phase 3 trial in fibrosing idiopathic lung disease (NCT05321082). In both trials, the primary endpoint is the absolute change from baseline in FVC at week 52.
BMS-986278. Results of a phase 2 trial showed that twice-daily treatment with oral BMS-986278 60 mg over 26 weeks reduced the rate of decline in ppFVC by 69% vs. placebo. The phase 3 ALOFT trial has been approved but hasn’t yet started recruiting patients (NCT06003426). BMS-986278 is a lysophosphatidic acid receptor 1 (LPA1) antagonist.
Lanxoprazole. Commonly used to treat and prevent gastrointestinal problems like stomach ulcers and esophagitis, this oral proton pump inhibitor (PPI) is the focus of a trial in the United Kingdom evaluating if PPIs can slow the progression of IPF (NCT04965298).
N-acetylcysteine (NAC). The PRECISIONS trial is evaluating the effect of NAC plus standard-of-care treatment in IPF patients who have the TOLLIP rs3750910 TT genotype (NCT04300920). Participants receive 600 mg NAC orally or matched placebo three times daily for 24 months. Trial completion is scheduled for 2025.
Treprostinil. Already approved to treat pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease, inhaled Treprostinil is the subject of the TETON 1 and 2 trials evaluating its impact on ppFVC after 52 weeks of treatment (NCT04708782, NCT05255991).