Serum surfactant protein D as a predictive biomarker for the efficacy of pirfenidone in patients with idiopathic pulmona
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RESEARCH
Serum surfactant protein D as a predictive biomarker for the efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis: a post‑hoc analysis of the phase 3 trial in Japan Kimiyuki Ikeda1, Hirofumi Chiba1*, Hirotaka Nishikiori1, Arata Azuma2, Yasuhiro Kondoh3, Takashi Ogura4, Yoshio Taguchi5, Masahito Ebina6, Hiroki Sakaguchi7, Shogo Miyazawa7, Moritaka Suga8, Yukihiko Sugiyama9, Toshihiro Nukiwa10, Shoji Kudoh11 and Hiroki Takahashi1Pirfenidone Clinical Study Group in Japan
Abstract Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease course. The recent advancement of antifibrotic therapy has increased the need for reliable and specific biomarkers. This study aimed to assess alveolar epithelial biomarkers as predictors for the efficacy of the antifibrotic drug pirfenidone. Methods: We conducted a post-hoc analysis of the prospective, multicenter, randomized, placebo-controlled, phase 3 trial of pirfenidone in Japan (total, n = 267; pirfenidone, n = 163; placebo, n = 104). Logistic regression analysis was performed to extract parameters that predicted disease progression, defined by a ≥ 10% relative decline in vital capacity (VC) from baseline and/or death, at week 52. For assessment of serum surfactant protein (SP)-D, SP-A and Krebs von den Lungen (KL)-6, all patients were dichotomized by the median concentration of each biomarker at baseline to the high and low biomarker subgroups. Associations of these concentrations were examined with changes in VC at each time point from baseline up to week 52, along with progression-free survival (PFS). Additionally, the effect of pirfenidone treatment on serial longitudinal concentrations of these biomarkers were evaluated. Results: In the multivariate logistic regression analysis, body mass index (BMI), %VC and SP-D in the pirfenidone group, and BMI and %VC in the placebo group were indicated as predictors of disease progression. Pirfenidone treatment reduced the decline in VC with statistical significance in the low SP-D and low SP-A subgroups over most of the treatment period, and also prolonged PFS in the low SP-D and low KL-6 subgroups. Furthermore, SP-D levels over time course were reduced in the pirfenidone group from as early as week 8 until the 52-week treatment period compared with the placebo group. Conclusions: Serum SP-D was the most consistent biomarker for the efficacy of pirfenidone in the cohort trial of IPF. Serial measurements of SP-D might have a potential for application as a pharmacodynamic biomarker. Trial registration The clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13, 2005 (registration No. JapicCTI-050121; http://Clinicaltrials.jp)
*Correspondence: [email protected] 1 Department of Respiratory Medicine and Allergology, School of Medicine, Sapporo Medical University, South 1, West 16, Sapporo 060‑8543, Japan Full list of author information is available at the end of the article © The Author(s) 2020. Th
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