Patient Response to Pirfenidone, Nintedanib for IPF Differs in Real World vs Trials

Real-world data demonstrated that both pirfenidone and nintedanib are tolerable and effective at slowing down the decline of lung function in patients with idiopathic pulmonary fibrosis (IPF)—an idea that was supported by several randomized controlled studies but with limited meta-analyses of these studies.¹

However, both drugs were also associated with higher mortality rates and acute exacerbation of IPF (AE-IPF) incidence in real-world settings compared with previous clinical trials, with a higher mortality rate among patients taking pirfenidone. These findings were published in the European Journal of Clinical Pharmacology and were based on a review of 74 studies with more than 23,000 total participants.

Over 12 months of treatment, the review authors measured a –0.75% decline in percent predicted forced vital capacity (%FVC) for pirfenidone and a –1.43% decline for nintedanib. These relatively small declines in %FVC suggest that both medications are somewhat effective at preserving lung function over the course of a year, with pirfenidone showing a slightly better outcome.

Meanwhile, the decline in percent predicted diffusing capacity for carbon monoxide (%DLCO) was –2.32% for pirfenidone and –3.95% for nintedanib. DLCO measures how well the lungs can transfer gas from inhaled air to the bloodstream, and a decline in %DLCO indicates a reduction in the lungs' ability to transfer gases, an important function in respiratory health. These declines again indicate that both medications are working to slow the progression of IPF, though nintedanib shows a slightly larger decline in this function compared with pirfenidone.

“Clinical trials often exclude patients with severe and combined IPF with severe lung function impairment such as lung cancer and emphysema, whereas our study demonstrated that patients were able to benefit from both drugs with similar rates of %FVC and %DLCO decline regardless of their baseline %FVC status,” the review authors said.

Despite these promising results in slowing disease progression, the real-world incidence of AE-IPF was higher at 12.5% for pirfenidone and 14.4% for nintedanib. According to the authors, this discrepancy may be due to the inclusion of patients who were in poorer health at the start of the study, as lower FVC is a known risk factor for AE-IPF. Additionally, since acute exacerbations of IPF share similarities with other respiratory diseases, the accuracy of diagnostic criteria significantly influences AE-IPF incidence rates. Notably, only 9 studies in this meta-analysis provided clear definitions for AE-IPF, suggesting that variations in diagnostic criteria could have led to the misclassification of patients with suspected AE-IPF, contributing to the higher incidence observed in this real-world review compared with clinical trials.

The meta-analysis also highlighted a significant rate of adverse events, occurring in 56.4% of patients on pirfenidone and 69.7% of patients on nintedanib. The most common adverse reactions to pirfenidone, with incidence above 10%, were:

Antifibrotics pirfenidone and nintedanib slowed down lung function decline in patients with idiopathic pulmonary fibrosis, but real-world data showed other associations as well | Image credit: doucefleur – stock.adobe.com

• Anorexia
• Appetite loss
• Epigastric discomfort
• Fatigue
• Nausea
• Dyspepsia
• Weight loss
• Rash
• Photosensitivity reactions

Meanwhile, the most common adverse reactions to nintedanib were:

• Diarrhea
• Weight loss
• Nausea
• Fatigue
• Anorexia
• Appetite loss
• Liver dysfunction

The discontinuation rates due to adverse reactions were 16.6% for pirfenidone and 16.2% for nintedanib, aligning with previous clinical trial data and suggesting good tolerability.

Mortality rates were also concerning, with IPF-related deaths at 13.4% for pirfenidone and 7.2% for nintedanib, while all-cause mortality was 20.1% for pirfenidone and 16.6% for nintedanib. In comparison, prior clinical trials demonstrated IPF-related mortality rates of 4% and 1.4% for pirfenidone and nintedanib, respectively, as well as all-cause mortality rates of 5.8% and 3.6%. Mortality rates are a key measure of IPF treatment, but the authors noted that the short time frame of clinical trials has made it difficult to fully understand how pirfenidone and nintedanib affect survival rates in patients with IPF.

“Further large-sample studies are needed to investigate the risks of these drugs in these aspects,” the authors said regarding the higher mortality and AE-IPF rates in real-world settings compared with clinical trials. “Additionally, we recommend that future real-world studies pay more attention to patients’ subjective symptoms and conduct stratified analyses of the efficacy and safety of pirfenidone and nintedanib based on factors such as patients’ baseline lung function, comorbidities, and age, in order to provide more personalized medication advice for IPF patients in clinical practice.”

Antifibrotic drugs pirfenidone and nintedanib have been approved and commonly used to treat IPF since 2014, and have demonstrated varied long-term results in other studies.² While these medications have been linked to improved lung function decline, real-world registry data showed no significant difference in transplant-free survival or time to pulmonary function decline with these drugs compared with placebo. Data also indicated that most patients with newly diagnosed IPF continued antifibrotic treatment for at least 6 months, with an average duration of over 3 years. Together, these findings show high patient utilization of these 2 antifibrotic drugs, but more research is needed on patient outcomes.

References

1. Kou M, Jiao Y, Li Z, et al. Real-world safety and effectiveness of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Eur J Clin Pharmacol. Published online July 4, 2024. doi:10.1007/s00228-024-03720-7
2. Klein HE. Many patients with IPF continue on antifibrotics for 3 years. AJMC^®. June 28, 2024. Accessed July 24, 2024. https://www.ajmc.com/view/many-patients-with-ipf-continue-on-antifibrotics-for-3-years