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The fully human monoclonal antibody pamrevlumab failed to improve lung function among patients with idiopathic pulmonary fibrosis (IPF) in the randomized ZEPHYRUS-1 trial, despite showing positive results in a phase II study.

Among 356 patients with IPF, there was no statistically significant difference in absolute change in forced vital capacity (FVC) at 48 weeks versus baseline between those who took pamrevlumab and those in the placebo group (least-squares mean -260 mL vs -330 mL; P=0.29), reported Ganesh Raghu, MD, of the University of Washington in Seattle, at the annual meeting.

The study was also published simultaneously in .

The results "did not demonstrate significant benefit compared with placebo," Raghu said in his presentation. "No significant differences were found in secondary or exploratory endpoints. [The drug] was safe and well-tolerated."

An open-label extension trial and an ongoing companion trial known as ZEPHYRUS-2 were cancelled due to the results.

These findings emphasize the importance of changing the way that IPF drugs are studied, said Victor E. Ortega, MD, PhD, of the Mayo Clinic in Phoenix, who co-authored a , at the ATS meeting. "We have to think about more efficient, adaptive ways to conduct clinical trials where the patient and the biomarkers are being interrogated in real time ... The current approach isn't working."

Currently, the anti-fibrotic drugs pirfenidone (Esbriet) and nintedanib (Ofev) are the standard of care for patients with IPF. But Raghu and team pointed out that the efficacy of these drugs is limited, and many patients can't tolerate them.

Enter pamrevlumab, which inhibits connective tissue growth factor, "a central mediator of fibrosis and remodeling in IPF," Raghu said. The drug has been investigated for the treatment of pancreatic cancer, as well as Duchenne muscular dystrophy, for which a .

A phase II trial previously suggested that the drug had promise in IPF.

Raghu and colleagues speculated that the study failed to replicate these previous results because it included more patients with more advanced disease. They also noted that, unlike the previous trial, this one allowed patients to take pirfenidone or nintedanib.

In the accompanying commentary, Eva M. Carmona, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and colleagues wrote that "the failure of different investigational drugs to successfully progress from phase II to phase III is a fundamental problem limiting the development of much-needed effective treatments for IPF."

While the use of highly variable FVC as a primary outcome is controversial, reducing the target difference in trials "would be a step in the wrong direction," they added. Moving forward, "adaptive trial designs that consider complex factors will enhance the understanding of IPF and its subtypes while accelerating the development of much-needed therapeutics for appropriate patients."

During the presentation, Ortega, who is also an associate editor for JAMA, noted that the study initially didn't allow treatment with IPF drugs. "We're going to have to live with the fact that we can't really withdraw standards of care while [patients are] undergoing trials."

Moving forward, Raghu said, future IPF studies "should consider multiple endpoints, including a change in efficiency, the structural health provision, mortality, and patient-reported outcomes, to assess treatment efficacy according to how the patient feels, [and] how the person functions and survives."

For this study, 356 patients with IPF were recruited from 117 sites in nine countries from July 2019 to July 2022. Mean age was 70.5, 72.5% were men, and 62.1% were white.

They were assigned to receive 30 mg/kg of intravenous pamrevlumab (n=181) or placebo (n=175) every 3 weeks for 48 weeks. All patients had been diagnosed with IPF within 7 years, had a predicted FVC that was greater than 45% to less than 95%, and had evidence of parenchymal fibrosis (reticulation) that was 10% or greater to less than 50% and honeycombing within the whole lung of less than 25% on a high-resolution CT scan (confirmed by an independent central reviewer before randomization).

Exclusions included significant obstructive lung disease and use of nintedanib or pirfenidone at screening or within 1 week (patients could have received treatment but stopped it for various reasons), although, as previously noted, a mid-trial protocol amendment allowed participants to take one or both drugs if their status worsened.

Most patients in both groups finished the 48-week trial.

There were no significant between-group differences in any of the secondary outcomes, including time to disease progression, change in quantitative lung fibrosis volume from baseline to week 48, time to all-cause mortality, and time to first respiratory hospitalization, or in patient-reported outcomes.

Treatment-emergent adverse events (TEAEs) occurred in 88.4% of the patients who received pamrevlumab, and 28.2% had serious TEAEs, compared with 86.3% and 34.3% of those in the placebo group; 8.8% and 8.6% of patients in the two groups died.