Researchers from a large number of international institutions have published an integrated analysis showing that long-term treatment with pirfenidone (Esbriet, Genentech, Roche) in patients with idiopathic pulmonary fibrosis (IPF) can be considered safe.
The study, “Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials“ by Dr. Lisa Lancaster and colleagues, was published in the journal BMJ Open Respiratory Research on Jan. 12, 2016.
The analysis builds on data from five international clinical trials: the two Phase 3 CAPACITY studies and the Phase 3 ASCEND study, and two open-label trials named RECAP. The analysis included data from 1,299 patients with a cumulative total exposure to pirfenidone of 3,160 person exposure years (PEY). The median duration of exposure was 1.7 years (range 1 week to 9.9 years). In total, 42 percent of patients received pirfenidone for more than two years, and 25 percent received the drug for more than four years.
Included in the analysis were treatment-emergent adverse events (TEAEs), or events with an initial onset or worsening following the first dose and within 28 days after the last dose, along with treatment-emergent death rates.
Almost all the patients experienced at least one TEAE, with 38.1 percent of the pirfenidone-treated patients stopping the treatment due to an adverse event. The most common adverse events leading to treatment discontinuation were IPF (11.5 percent), followed by nausea (1.7 percent), rash (1.5 percent), and respiratory failure (1.3 percent). No other reason was reported in more than 1 percent of the pirfenidone group.
Among pirfenidone-treated patients, nausea (37.6 percent), diarrhea (28.1 percent), dyspepsia (18.4 percent), vomiting (15.9 percent) and rash (25.0 percent) were the most commonly reported adverse events. These side effects were generally mild to moderate in severity and rarely led to treatment discontinuation. Their frequency in the study did not differ from earlier reports from the Phase 3 clinical trials, suggesting that the risk of gastrointestinal or skin-related adverse effects does not increase with long-term treatment.
On the contrary, respiratory adverse events such as cough, dyspnea and IPF were more common in the integrated analysis than in the Phase 3 trials — an expected finding in a population with a chronic progressive respiratory disease studied over a long period of time.
In the analysis, serious adverse events were reported by 49.2 percent of the pirfenidone group. When adjusted for the longer duration of exposure, the rate of serious adverse events was comparable to the rates in the pooled pirfenidone and placebo groups in the Phase 3 trials: 49.8 per 100 PEY compared to 41.7 and 44.2 per 100 PEY, respectively.
The most common serious adverse events reported across all the trials were worsening IPF (17.5 percent), pneumonia (7.9 percent), respiratory failure (3.2 percent), atrial fibrillation (2.8 percent) and bronchitis (2.7 percent).
With the exception of atrial fibrillation, which occurred in 0.6 percent of patients in the combined pirfenidone and placebo groups in the Phase 3 trials, the frequency of each of these events was higher in the placebo group compared to the pirfenidone group in the Phase 3 trials.
No elevated risk of increased liver toxicity following prolonged exposure to pirfenidone could be observed. Serious liver-related adverse events occurred in 1 percent in the pirfenidone-treated patients across all studies, compared to 1 percent and 0.2 percent in the combined pirfenidone and placebo groups in the Phase 3 trials.
Combining data from the five clinical trials, the study reported that 17.9 percent of patients died during the study. However, death occurred more frequently in the placebo group (5.9 per PEY) than in the pirfenidone group (3.7 per PEY).
Given the present data, the authors suggested that long-term treatment with pirfenidone is safe and generally well-tolerated.