The study, “An Open-Label Study of the Long-Term Safety of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (RECAP),” was recently published in the journal Respiration.
Esbriet, an anti-fibrotic drug, was approved as a therapy for IPF in 2011 in the European Union. It was approved three years later in the U.S. Data from clinical trials show that Esbriet slows disease progression and reduces patient mortality when compared with placebo controls. A pooled analysis of three clinical trials showed that on average, Esbriet reduced IPF patients’ mortality from any cause by 48% within one year.
Esbriet treatment also improves other lung function characteristics without compromising patient safety, the study noted. It showed a safe and tolerable profile and manageable side effects throughout a number of clinical trials.
To evaluate the long-term safety of Esbriet, an international team of researchers sponsored by therapy developer Genentech launched the clinical trial RECAP (NCT00662038). This study enrolled patients who had participated in previous phase 3 clinical trials: CAPACITY 1 (NCT00287729), CAPACITY 2 (NCT00287716), or ASCEND (NCT01366209).
Patients were enrolled in RECAP within 10 days of completing the final visit of their qualifying trial. A total of 1,058 patients from the three previous trials joined RECAP.
RECAP’s primary objective was to assess Esbriet’s safety when administered in doses of 2,403 mg per day. Patients received 2,403 mg/day of Esbriet in equally divided doses three times a day with food. In the trial’s first 15 days, patients started with Esbriet at 801 mg/day followed by a maintenance dose of 2,403 mg/day.
Researchers investigated the safety of Esbriet by analyzing treatment-emergent adverse events and by performing laboratory tests and physical examinations throughout the trial. Specifically, lung function tests — including forced vital capacity (FVC), forced expiratory volume in 1 s, and diffusing capacity for carbon monoxide — were performed at baseline, at week 12, and then every 24 weeks.
The trial lasted more than five years, during which the majority of patients (98%) reported more than one adverse event. Because of these adverse reactions, a third of the patients – 33.8% – discontinued treatment. Discontinuation occurred most frequently during the first year and in patients who were just starting Esbriet treatment.
These numbers are in line with previous studies, first author Ulrich Costabel, senior consultant at Ruhrlandklinik, University Hospital in Essen, Germany, told Pulmonary Fibrosis News in an interview.
“Discontinuation rates due to drug adverse reactions were similar between the RECAP study and the phase 3 trials, indicating that prolonged exposure to the drug does not increase the risk of adverse reactions,” Costabel said.
Nausea (21.6%), diarrhea (12.3%), and rash (11.6%) were the most frequent adverse reactions observed in the RECAP study, a similar trend found in previous studies.
Of the 358 patients who discontinued treatment, the cause for 67.9% (243 patients) was unrelated to IPF progression. This suggests that there is a need for patients to be carefully monitored during the early treatment period to reduce the risk of discontinuation.
According to Costabel, “for treatment adherence, it is very important that patients be educated how to manage side effects, [for example, to] prevent/ameliorate phototoxicity by regular daily use of sunblock, or reduce nausea by splitting the intake of the 3 tablets over the full length of a meal. Other measures to keep patients on-drug include intermittent dose reduction or a ‘drug holiday’ and re-titration to the full dose over a longer period, [such as an] increase in dose every 2 to 3 weeks instead of every week.”
The frequency of adverse drug reactions associated with Esbriet was reported to be lower in the RECAP study than in previous phase 3 clinical trials – 74.3% versus 89.2% – which the team suggested could be attributed to a positive selection bias, meaning that those selected for the RECAP trial were “only patients who tolerated the drug fairly well and did not discontinue during the [previous] phase 3 trials,” Costabel said.
When asked if patients could adapt to the treatment over time, or in contrast, if the patient’s body could become resistant to Esbriet, Costabel noted that there is “no concern and no scientific evidence that patients may become resistant to pirfenidone or that the drug loses efficacy over time.”
Overall, the RECAP trial results “are consistent with the known safety profile of pirfenidone, with no new safety signals observed. These findings support the clinical use of pirfenidone in patients with IPF,” the team concluded in their study.
In an editorial about the study titled, “Pirfenidone in Idiopathic Pulmonary Fibrosis ‘RECAP-itulating Safety into the Real World,'” other researchers acknowledged the importance of RECAP’s findings, but highlighted that the trial recruited patients with mild to moderate disease severity only. As such, the study “may have missed a significant proportion of patients with more severe disease that could potentially be in greater need for therapeutic interventions.”
They also pointed to other possible selection bias, such as the fact that the majority of patients (90%) were Caucasians and only patients who completed a previous phase 3 clinical trial were recruited.
Nonetheless, they noted that “a recently published integrated analysis of 1,299 patients from 5 studies (including RECAP) that had been followed up for almost 10 years clearly demonstrated that prolonged exposure to pirfenidone is safe and well tolerated.” This supports the use of Esbriet in long-term treatment of IPF.
RECAP is one of the largest trials testing Esbrief’s safety in a large group of IPF patients. The trial has been referred to as the first study assessing the safety of an anti-fibrotic agent in a large group of patients in real-world clinical practice. However, Costabel emphasized that RECAP does not represent a real-world clinical setting.
“It is not correct to refer to RECAP as a study in the real-world setting. All RECAP patients were rolled over from the phase 3 CAPACITY and ASCEND trials, respectively, and therefore were carefully selected trial patients, not reflecting the broad spectrum of real-world patients. RECAP aimed to assess the long-term safety of pirfenidone, which is not the same as real-world safety,” Costabel said.