Background Interstitial lung disease (ILD) is a common and serious complication of systemic sclerosis (SSc). Pirfenidone, a novel antifibrotic agent, has been shown to be safe and effective in the treatment of idiopathic pulmonary fibrosis (IPF).
Objectives The LOTUSS study was designed to assess the safety and tolerability of pirfenidone in patients with SSc-ILD.
Methods This is an open-label, 16-week study. Patients were randomized to a 2- or 4-week titration of pirfenidone to the target dose of 2403 mg/day. Eligibility required a diagnosis of SSc ≤7 years from first non-Raynaud's symptom, HRCT-confirmed ILD, FVC ≥50% and DLco ≥40%, absence of clinically significant pulmonary hypertension or severe GERD. Stable background treatment with mycophenolate mofetil (MMF) or oral cyclophosphamide was permitted. Safety assessments included collection of treatment emergent adverse events (TEAEs), vital signs, ECGs and laboratory tests. Though the study was not designed or powered to evaluate efficacy, FVC % predicted, DLco % predicted, modified Rodnan skin score (mRSS), Mahler BDI/TDI, and UCLA SCTC GIT 2.0 were recorded at baseline and 4 months.
Results Of the 63 patients enrolled, the mean (SD) age was 50.6 (12.3) years; the majority were female (82.5%) and white (76.2%). The mean (SD) SSc duration was 38.3 (26.0) months. Forty patients (63.5%) were on MMF and the rest (36.5%) were not receiving any immunosuppressants. The mean (SD) mRSS, %FVC and %DLco at baseline were 11.4 (9.6), 76.0 (14.2) and 59.7 (16.5), respectively. The frequency and type of TEAEs were similar for both titration groups. The safety results are summarized below. No clinically significant changes in vital signs, ECGs, or laboratory tests were observed. At week 16 (end of treatment), the median change from baseline in %FVC was -0.5% (range -42% to 12%); 10 patients (16.7%) had an increase ≥5% whereas 5 (8.3%) had a decrease >5% at week 16. Median change from baseline in %DLco was +1.5% (range -24.0% to 40.0%); 19 subjects (31.7%) had an increase ≥5% vs. 10 (16.7%) had a decrease >5% at week 16. Minor changes (mean ± SD) were observed in Mahler TDI (1.0±3.41) and mRSS (-0.4±3.71). No change was noted in the GI symptoms on UCLA SCTC GIT 2.0; the change was not clinically meaningful from baseline to week 16 (mean ± SD) in the UCLA Reflux scores (0.0330±0.29).
Conclusions In the 16-week, open label trial of pirfenidone in SSc-ILD, pirfenidone was generally well-tolerated in SSc-ILD patients, despite pre-existing co-morbidities, including underlying GI disease, and concomitant use of MMF. The observed AEs were expected and consistent with those previously seen with pirfenidone treatment in IPF trials. The data support further investigation of pirfenidone in SSc-ILD.
Disclosure of Interest D. Khanna Grant/research support from: Actelion, Astra-Zeneca, EMD Serono, Bristol Myers Squibb, Bayer, InterMune, Consultant for: Takeda, Sanofi-Aventis/Genzyme, EMD Serono, InterMune, Glaxo SmithKline, Genentech/ Roche, Bristol Myers Squibb, Actelion, Astra-Zeneca, Bayer, Biogen Idec, C. Albera Consultant for: InterMune, A. Fischer Grant/research support from: InterMune, J. Seibold Consultant for: InterMune, G. Raghu: None declared, N. Khalidi: None declared, L. Chung Grant/research support from: InterMune, E. Schiopu Grant/research support from: InterMune, D. Chen Shareholder of: InterMune, Genentech/Roche, Employee of: Genentech, E. Gorina Shareholder of: InterMune, Genentech/Roche, Employee of: Genentech