ZEPHYRUS-1: Pamrevlumab fails in IPF

Pamrevlumab did not slow down lung function impairment in patients with idiopathic pulmonary fibrosis (IPF) in a phase 3 study, while phase 2 trials had suggested that this agent could be efficacious in this population. Are there lessons to be learned for the design of future trials in IPF?

The phase 3 ZEPHYRUS-1 trial (NCT03955146) enrolled patients with IPF who were not being treated with antifibrotic therapy (n=356). Participants were randomised 1:1 to pamrevlumab or a placebo, to assess whether this connective tissue growth factor inhibitor can slow down the deterioration of lung function in this patient population [1].

At week 48, the FVC change from baseline was -260 mL in the pamrevlumab arm and -330 mL in the control arm, a non-significant difference (95% CI -60 to +90; P=0.29). Similarly, secondary and exploratory endpoints revealed no substantial differences between the pamrevlumab arm and the placebo arm.

“Although this was a well-designed trial, with a large, diverse population, and using modern technologies such as machine learning to quantify imaging of fibrosis, the results are disappointing,” commented Dr Ganesh Raghu (UW Medical Center, WA, USA). “In previous phase 2 studies, pamrevlumab had displayed promising signs of clinical activity.” Dr Raghu reasoned that the smaller cohorts of the phase 2 studies, the fact that patients in the ZEPHYRUS-1 study had more lung function impairment, and the permission of concomitant pirfenidone or nintedanib during the phase 3 trial, as opposed to the phase 2 trials, may have contributed to the contrasting results.

“Phase 2 trials should be representative of the general population from which phase 3 trials should be drawn, and test similar outcomes,” argued Dr Raghu. “Next to that, we should consider using composite endpoints in future IPF trials, including ‘feels’, functions, and survive measures, mirroring the lived experience of patients with IPF.”

1. Raghu G, et al. Pamrevlumab for idiopathic pulmonary fibrosis: results of the phase 3 ZEPHYRUS-1 study. C95: New clinical trial results in chronic lung disease. ATS 2024, 17–22 May, San Diego, USA.

Medical writing support was provided by Robert van den Heuvel.

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Posted on 11 June 202412 June 2024