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

Idiopathic Pulmonary Fibrosis (IPF) is a rare interstitial lung disease that typically occurs in adults over 60 years old. It is characterized by cough, breathlessness, and fatigue. This disease leads to progressive loss of lung function, decreased exercise tolerance, and a decline in health-related quality of life. The global prevalence of IPF is estimated to be between 0.33 to 4.51 per 10,000 people, with an annual incidence of 0.09 to 1.30 per 10,000 people. Without treatment, the prognosis for IPF is poor, with an average survival time of about 3 to 5 years.

Currently, two antifibrotic drugs approved for treating IPF are Pirfenidone and Nintedanib, which have become the global standard of care. These drugs have shown efficacy in slowing the rate of lung function decline, but individual responses vary widely and are difficult to predict. Patients’ symptoms and health-related quality of life have not significantly improved. Additionally, these drugs can cause adverse reactions affecting the gastrointestinal tract, liver, and skin, leading up to 40% of patients to discontinue treatment. Therefore, more effective treatment options are needed.

Pamrevlumab is a fully human monoclonal antibody that exerts its pharmacological effect by binding to and inhibiting the activity of Connective Tissue Growth Factor (CTGF). In phase 2 trials, it showed good tolerability and significantly slowed the decline in lung function and the degree of lung fibrosis.

Authors and Source

This study was conducted by Ganesh Raghu (MD), Luca Richeldi (MD), Evans R. Fernández Pérez (MD), Maria Cristina De Salvo (MD), Rafael S. Silva (MD), Jin Woo Song (MD), Takashi Ogura (MD), Zuo Jun Xu (MD), Elizabeth A. Belloli (MD), Xueping Zhang (PhD), Lorilyn L. Seid (MD), and Lona Poole (MD), representing the ZEPHYRUS-1 study group. The paper was published online in JAMA on May 19, 2024.

Study Objectives and Methods

The study aimed to evaluate the efficacy and safety of Pamrevlumab in patients with IPF. It was designed as a phase 3 randomized, double-blind, placebo-controlled clinical trial involving 356 IPF patients aged between 40 and 85 years who had not been treated with Nintedanib or Pirfenidone at the time of enrollment. Patients were recruited from 117 research sites in nine countries, with recruitment from July 18, 2019, to July 29, 2022, and the last follow-up on August 28, 2023.

Patients were randomly assigned in a 1:1 ratio to receive Pamrevlumab (181 patients, 30 mg/kg intravenous infusion every 3 weeks) or placebo (175 patients) for 48 weeks. The primary endpoint was the change in lung capacity from baseline to week 48. Secondary endpoints included time to disease progression and patient-reported symptoms. Exploratory endpoints included patient-reported symptoms and adverse events.

Study Process

Patient Selection and Randomization

The study included 356 eligible patients diagnosed with IPF within the past seven years, meeting high-resolution CT imaging requirements, and with lung function parameters within the specified range. Exclusion criteria included a significant history of obstructive lung disease, other interstitial lung diseases, pregnancy, and smoking. Randomization was stratified by gender, age, and lung function.

Study Design and Implementation

The entire study included a 6-week screening period, a 48-week treatment period, and a safety assessment period lasting until 60 days after the last dose. Patients received drug or placebo infusions every three weeks, with regular lung function monitoring and symptom questionnaire assessments.

Data Collection and Analysis

The primary endpoint was the absolute change in lung capacity over 48 weeks. Secondary endpoints included time to disease progression, time to first acute exacerbation of IPF, and changes in quantitatively analyzed lung fibrosis volume. Exploratory endpoints included changes in patient-reported symptoms. Safety analysis covered the incidence and severity of adverse events.

Results

Of the 356 randomized patients, 277 completed the entire trial. Baseline conditions and demographic characteristics were balanced between the two groups. For the primary endpoint, no significant difference was found between the Pamrevlumab and placebo groups in the absolute change in lung capacity (mean decrease of 260 ml in the Pamrevlumab group versus 330 ml in the placebo group, p=0.29). There were no significant differences between the two groups on all secondary and exploratory endpoints.

In terms of safety, the incidence of adverse events was similar between the Pamrevlumab and placebo groups. Treatment-related adverse events occurred in 88.4% of patients in the Pamrevlumab group and 86.3% in the placebo group. The incidence of serious adverse events was 28.2% and 34.3%, respectively. Each group had 23 patients who died during the trial.

Conclusion

This study indicates that Pamrevlumab did not show statistically significant superiority in slowing lung function decline in IPF patients. Despite its good safety profile, it did not demonstrate significant benefits in improving patients’ symptoms or quality of life, contrasting with earlier phase 2 trial results.

Significance and Value

The importance of this study lies in its rigorous evaluation of the efficacy of Pamrevlumab as a potential new treatment for IPF. Although the results did not demonstrate significant efficacy, the study provides valuable clinical trial data for future drug development for IPF. It also reminds researchers of the differences between small-scale trials and real-world clinical applications when conducting large-scale clinical trials. Furthermore, the study emphasizes the importance of multiple endpoint evaluations, providing methodological references for future related research.