Esbriet (pirfenidone) is an oral treatment for idiopathic pulmonary fibrosis (IPF) that was originally developed by Intermune, which later merged with Roche. Esbriet is currently being investigated and marketed by Genentech, a Roche company.
How does Esbriet work?
IPF is an irreversible and potentially lethal respiratory disease caused by a progressive decline in the ability of the lungs to absorb oxygen because of tissue scarring or fibrosis. IPF is characterized by shortness of breath because of the significant destruction of healthy lung tissue, mostly caused by inflammation in response to primary infections or excess secretion of collagen by lung-associated fibroblasts.
Although its mechanism of action is unclear, Esbriet is known to decrease inflammation by reducing the synthesis of a pro-inflammatory molecule called transforming growth factor-beta (TGF-β). This reduces excessive collagen production and secretion of other inflammatory mediators such as TNF-α and IL-1β.
Esbriet in clinical trials
Several clinical trials have shown that Esbriet is safe and well-tolerated, and significantly reduces the decline in respiratory function, and enhances the survival of IPF patients.
Long-term safety data were comprehensively analyzed from five clinical trials, including three multinational Phase 3 trials: CAPACITY-004 (NCT00287729), CAPACITY-006 (NCT00287716) and ASCEND (NCT01366209); and two open-label studies called PIPF-012 (NCT00080223) and RECAP (NCT00662038).
These included a large and well-defined group of 1,299 patients with IPF who were followed prospectively for up to 10 years. The data were published in the BMJ Open Respiratory Research journal and showed that long-term treatment with Esbriet was safe and well-tolerated.
The first two Phase 3 trials (CAPACITY-004 and CAPACITY-006) were conducted for 72 weeks in 110 centers in Australia, Europe, and North America to determine the safety and efficacy of Esbriet in adult patients with IPF.
In the CAPACITY-004 study, 435 IPF patients were randomly assigned in a 2:1:2 ratio to receive a high-dose of Esbriet (2,403 mg per day), a low-dose Esbriet (1,197 mg a day), or a placebo for 72 weeks. In the CAPACITY-006 study, 435 IPF patients were randomly assigned in a 1:1 ratio to receive a high-dose of Esbriet (2,403 mg per day) or a placebo for 72 weeks. Changes in forced vital capacity (FVC — a measure of lung function) were measured at week 72 as the primary endpoint to determine deterioration in lung function.
The results of these two trials were published in The Lancet. In the CAPACITY-004 study, the high-dose of Esbriet significantly reduced the decline in FVC at week 72 compared with the placebo control. During 72 weeks, 35 out of 174 patients treated with high-dose Esbriet showed a 10% or greater decline in FVC compared with 60 of the 174 patients in the placebo group. The change in FVC in the low-dose Esbriet group was between the high-dose Esbriet and placebo groups, thereby showing a dose-dependent response.
In the CAPACITY-006 study, there were no significant differences in the change in FVC between the high-dose Esbriet and placebo groups at week 72. The Esbriet treatment group showed consistent improvement compared with the placebo until week 48 and upon analysis of all study time points.
During these studies, fewer deaths related to IPF occurred in the high-dose Esbriet group (12 patients or 3%) compared with the placebo group (25 patients or 7%). This suggested that high-dose Esbriet treatment increased the progression-free survival of IPF patients.
Since the two trials produced different results, another Phase 3, randomized, double-blind, placebo-controlled trial, called ASCEND, was conducted to confirm the effect of Esbriet on disease progression in IPF patients.
In this study, 555 IPF patients were randomly assigned to receive either oral Esbriet at a dose of 2,403 mg per day or a placebo for 52 weeks. The primary endpoint was the change in FVC or death at week 52. The secondary endpoints included a decline in the six-minute walk test (6MWT), progression-free survival, dyspnea (shortness of breath), and death from any cause including IPF.
The results of the ASCEND study were published in The New England Journal of Medicine. They showed a 47.9% reduction in the number of patients with a 10% or more decline in FVC in the Esbriet group compared with the placebo group. The Esbriet group also showed a relative increase of 132.5% in the proportion of patients with no decline in FVC compared with the placebo group. Treatment with Esbriet significantly reduced the decline in the 6MWT and improved progression-free survival. There were no significant differences between the two groups in dyspnea scores or in rates of death from any cause including IPF. However, when the survival data were pooled for all three trials (CAPACITY-004, CAPACITY-006, and ASCEND), treatment with Esbriet was clearly found to increase the progression-free survival rate.
The two open-label trials (PIPF-012 and RECAP) exclusively studied the long-term safety of Esbriet.
The PIPF-012 trial enrolled 83 patients (81 with PF and two with other types of PF) between August 2003 and September 2006. The results were reported in the Pulmonary Therapy journal. Patients were exposed to a daily mean dose of 2,400 mg of Esbriet for a duration of three years. Nearly 98.8% of the patients reported at least one treatment-emergent adverse event (TEAE).
The most common TEAEs were nausea, IPF progression, fatigue, shortness of breath, upper respiratory tract infection, and cough. Serious TEAEs were reported in 49 patients, of which the most frequent were IPF progression and pneumonia. The most common TEAEs for discontinuing treatment were IPF progression and nausea. During this study, 21 patients died. Sixteen of the deaths were related to IPF.
In the RECAP trial, 1,058 out of 1,338 patients who participated in the three Phase 3 trials were studied from September 2008 to June 2015. The results of RECAP were reported in the journal Respiration. The mean Esbriet exposure was 122 weeks with a mean daily dose of 2,091.1 mg.
The safety data from this study were consistent with previous findings obtained from the three Phase 3 trials. The most common cause for the 231 deaths that occurred was IPF. FVC declined by 9.6% in 180 weeks for patients who enrolled in this trial from the CAPACITY trials. Median on-treatment survival from the first dose of Esbriet was 77.2 months. The TEAEs that led to discontinuation of treatment were related to IPF, pneumonia, respiratory failure, rash, and nausea.
Esbriet is administered orally and is recommended to be taken after food (usually three times daily) to reduce nausea and dizziness. It is mostly metabolized in the liver and excreted in the urine within 24 hours.
Mild side effects include nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, indigestion, dizziness, vomiting, decreased or loss of appetite, gastro-esophageal reflux disease, sinusitis, insomnia, weight loss, and joint pain.
Esbriet also causes photosensitivity and hence patients should limit sun exposure or use broad-spectrum sunscreen.
Patients with severe liver problems, end-stage kidney disease, those who require dialysis, or who are taking fluvoxamine (a medication used to treat depression and obsessive-compulsive disorder) are not advised to take Esbriet. Pregnant women need to consult with their doctors before taking the treatment.
Last updated: Nov. 8, 2019
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