Pirfenidone. First, do no harm

Idiopathic pulmonary fibrosis is a rare disorder due to progressive, widespread fibrotic damage of the lung parenchyma. It usually occurs after the age of 50, and its cause is unknown. Symptoms include progressive shortness of breath and nonproductive cough. The course of the disease is marked by exacerbations. Death from respiratory failure occurs about 2 to 5 years after diagnosis. There are currently no drugs that can control or slow the fibrotic process. Pirfenidone, an immunosuppressant, has been authorised in the European Union for the treatment of mild to moderate idiopathic pulmonary fibrosis. Clinical evaluation is based on two double-blind randomised placebo-controlled trials lasting 72 weeks in a total of 779 patients. Mortality, the frequency of exacerbations and the number of lung transplants did not differ significantly between the pirfenidone and placebo groups in either trial. Decline in forced vital capacity was smaller with pirfenidone than with placebo, but the difference was statistically significant in only one of the trials. The small difference in this surrogate endpoint is of questionable clinical relevance. 14.8% of the patients taking pirfenidone 2403 mg/day (maintenance dose according to the marketing authorisation) discontinued treatment because of adverse events, versus 8.6% of patients in the placebo groups. Serious adverse effects included 3 cases of bladder cancer in the pirfenidone groups versus 1 case in the placebo groups. Photosensitivity and skin rash, cardiac arrhythmias and coronary artery disease were more frequent with pirfenidone 2403 mg/day than with placebo. Abnormal transaminase elevation occurred in 4.1% of patients on pirfenidone 2403 mg/day versus 0.6% of patients on placebo. A few cases of acute renal failure were also observed. In practice, there is no evidence that pirfenidone improves quality of life in patients with mild to moderate idiopathic pulmonary fibrosis, or that it slows the progression of pulmonary fibrosis. The adverse effect profile is already burdensome. Pending real therapeutic advance, it is best to avoid pirfenidone altogether and to focus on symptomatic treatment.