Safety of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF): Integrated analysis of cumulative data from 5 clinical trials

Rationale: IPF is a chronic, progressive disease that requires long-term treatment. To evaluate the clinical safety of pirfenidone (PFD) in IPF, we performed a comprehensive integrated analysis of safety data from 5 clinical trials.

Methods: All patients treated with PFD 2403 mg/d in the Phase 3 multinational studies (Ph.3: 004, 006, and 016) and all patients receiving at least one dose of PFD in the ongoing open-label studies (002 and 012) comprised the integrated population. Interim data cut was on January 15, 2014. Cumulative safety outcomes in the pooled PFD 2403 mg/d and placebo (PBO) groups in Ph. 3 are presented for comparison.

Results: 1299 patients were included in the integrated population. The cumulative total exposure to PFD was 3160 person exposure years (PEY). The median duration of exposure was 1.7 years (1 week-9.9 years); 545 (42%) patients received PFD for ≥2 years and 325 (25%) for ≥4 years. The majority (75.8%) received a mean daily dose of ≥1800 mg. Consistent with prior observations, gastrointestinal and skin-related events were the most common treatment emergent adverse events (Table 1); these were almost always mild to moderate in severity, reversible with dose modification, and rarely led to treatment discontinuation. Respiratory adverse events were more common in the integrated population than in the pooled PFD and PBO groups in Ph. 3 -a finding expected in a population with a progressive respiratory disease followed over a long period. Aminotransferase (ALT or AST) elevations (> 3 x ULN) occurred in 40/1299 (3.0%) patients in the integrated population, compared with 23/623 (3.7%) patients treated with PFD in Ph. 3.

Tab. 1: Treatment emergent adverse events in the integrated population compared with the pooled pirfenidone 2403 mg/d and placebo groups in the Phase 3 trials*

	Integrated Population (N = 1299)†	Phase 3 Multinational Trials‡
		Pirfenidone (N = 623)	Placebo (N = 624)
Median (range) duration of exposure, yr	1.7 (> 0, 9.9)	1.0 (> 0, 2.3)	1.0 (> 0, 2.3)
Treatment emergent adverse event. %
Nausea	37.6	36.1	15.5
Cough	35.1	27.8	29.2
Dyspnea	30.9	16.9	20.2
Upper respiratory tract infection	30.6	26.8	25.3
Idiopathic pulmonary fibrosis	29.3	13.0	19.9
Fatigue	28.2	26.0	19.1
Diarrhea	28.1	25.8	20.4
Rash	25.0	30.3	10.3
Bronchitis	23.8	14.1	15.4
Headache	21.6	22.0	19.2
Nasopharyngitis	21.3	16.7	17.9
Dizziness	21.2	18.0	11.4
Dyspepsia	18.4	18.5	6.9
Vomiting	15.9	13.3	6.3
Weight decreased	15.6	10.1	5.4
Back pain	15.4	10.4	10.4
Anorexia	15.2	13.0	5.0
*Occurring in s 15% of patients in the cumulative clinical database †Includes 2 patients in Study 002 with a diagnosis of "pulmonary fibrosis" ‡CAPACITY (studies 004 and 006) and ASCEND (study 016)

Conclusions: A comprehensive integrated analysis of safety outcomes in a large and well-defined cohort of 1299 patients with IPF who were treated with pirfenidone for up to 9.9 years demonstrated that pirfenidone is safe and generally well tolerated, further supporting the long-term clinical safety of pirfenidone in IPF.