Pamrevlumab for Idiopathic Pulmonary Fibrosis: The ZEPHYRUS-1 Randomized Clinical Trial

Abstract

Importance: Current treatments for idiopathic pulmonary fibrosis slow the rate of lung function decline, but may be associated with adverse events that affect medication adherence. In phase 2 trials, pamrevlumab (a fully human monoclonal antibody that binds to and inhibits connective tissue growth factor activity) attenuated the progression of idiopathic pulmonary fibrosis without substantial adverse events.

Objective: To assess the efficacy and safety of pamrevlumab for patients with idiopathic pulmonary fibrosis.

Design, setting, and participants: Phase 3 randomized clinical trial including 356 patients aged 40 to 85 years with idiopathic pulmonary fibrosis who were not receiving antifibrotic treatment with nintedanib or pirfenidone at enrollment. Patients were recruited from 117 sites in 9 countries between July 18, 2019, and July 29, 2022; the last follow-up encounter occurred on August 28, 2023.

Interventions: Pamrevlumab (30 mg/kg administered intravenously every 3 weeks; n = 181) or placebo (n = 175) for 48 weeks.

Main outcomes and measures: The primary outcome was absolute change in forced vital capacity (FVC) from baseline to week 48. There were 5 secondary outcomes (including time to disease progression, which was defined as a decline of ≥10% in predicted FVC or death). The exploratory outcomes included patient-reported symptoms. Adverse events were reported.

Results: Among 356 patients (mean age, 70.5 years; 258 [72.5%] were men; 221 [62.1%] were White), 277 (77.8%) completed the trial. There was no significant between-group difference for absolute change in FVC from baseline to week 48 (least-squares mean, -260 mL [95% CI, -350 to -170 mL] in the pamrevlumab group vs -330 mL [95% CI, -430 to -230 mL] in the placebo group; mean between-group difference, 70 mL [95% CI, -60 to 190 mL], P = .29). There were no significant between-group differences in any of the secondary outcomes or in the patient-reported outcomes. In the pamrevlumab group, there were 160 patients (88.4%) with treatment-related adverse events and 51 patients (28.2%) with serious adverse events vs 151 (86.3%) and 60 (34.3%), respectively, in the placebo group. During the study, 23 patients died in each group (12.7% in the pamrevlumab group vs 13.1% in the placebo group).

Conclusions and relevance: Among patients with idiopathic pulmonary fibrosis treated with pamrevlumab or placebo, there was no statistically significant between-group difference for the primary outcome of absolute change in FVC from baseline to week 48.

Trial registration: ClinicalTrials.gov Identifier: NCT03955146.

Figure 1.. Patient Randomization and Follow-Up

^aThe most common reasons were (1) percent predicted forced vital capacity values did not meet inclusion criteria at screening and on day 1, (2) did not have a guideline-based diagnosis of idiopathic pulmonary fibrosis, (3) did not have a diagnosis of idiopathic pulmonary fibrosis confirmed by high-resolution computed tomography imaging scan, (4) had percent predicted values for diffusing capacity of the lungs for carbon monoxide that did not meet inclusion criteria, and (5) had evidence of significant obstructive lung disease. ^bIncluded all randomized patients during the 48-week study. ^cIncluded all randomized patients (1) who completed at least 36 weeks of treatment with a pulmonary function test assessment at baseline and at least once after baseline and (2) without major protocol deviations that significantly affected the efficacy analyses. ^dIncluded all patients who received at least 1 dose of study drug. ^eIncluded all patients who were in the safety population and who had at least 1 evaluable immunogenicity assessment after baseline.

Figure 2.. Change in Forced Vital Capacity From Baseline to Week 48 (Primary Outcome)

A, The boxes represent the IQRs, the horizontal lines within the boxes represent the medians, the error bars extending from the boxes indicate the minimum and maximum values, and the dots represent the means. B, The error bars represent the 95% CIs.