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

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)

Blood Krebs von den Lungen-6 levels predict treatment response to antifibrotic therapy in patients with idiopathic pulmonary fibrosis

“…Moreover, in this group, the short-term changes in KL-6 levels correlated with FVC changes over 6 months. Few recent studies have studied biomarkers for predicting treatment response in patients with IPF receiving antifibrotic agents [12,13]. Ikeda et al, in the post-hoc analysis of the phase 3 trial of pirfenidone in Japan, showed that baseline serum surfactant protein D level (OR, 1.003; 95% CI 1.000-1.006, p = 0.028) predicted DP (≥ 10% relative decline in FVC from baseline and/or death over 1 year after treatment) in the pirfenidone group (n = 163) in the multivariate logistic analysis adjusted for smoking, BMI, FVC and alveolar-arterial oxygen difference [12].…”

“…Few recent studies have studied biomarkers for predicting treatment response in patients with IPF receiving antifibrotic agents [12,13]. Ikeda et al, in the post-hoc analysis of the phase 3 trial of pirfenidone in Japan, showed that baseline serum surfactant protein D level (OR, 1.003; 95% CI 1.000-1.006, p = 0.028) predicted DP (≥ 10% relative decline in FVC from baseline and/or death over 1 year after treatment) in the pirfenidone group (n = 163) in the multivariate logistic analysis adjusted for smoking, BMI, FVC and alveolar-arterial oxygen difference [12]. Neighbors et al, in a post-hoc assessment of the CAPACITY (n = 184) and ASCEND (n = 229) trials, also investigated the association between the levels of various biomarkers (CCL13, CCL17, CCL18, CXCL13, CXCL14, COMP, interleukin 13, MMP3, MMP7, osteopontin, periostin, and YKL40) and absolute decline in FVC (%) over 12 months in patients with IPF treated with pirfenidone; however, they were unable to find biomarkers associated with the treatment response to antifibrotic agents [13].…”

“…Therefore, predicting the treatment response of antifibrotics may be useful for deciding appropriate treatment plans such as drug selection or lung transplantation. Predictive biomarkers have been evaluated for identification and assessment of disease progression (DP) in patients with IPF who were enrolled in phase 3 clinical trials of antifibrotic agents [12,13], and baseline surfactant protein D was the only biomarker predicting the response to antifibrotics [12]. However, it has not been confirmed whether the evaluation of this marker is useful in clinical settings.…”

Post-COVID-19 Pulmonary Fibrosis

“…De Lara et al obtained evidence that SP-A can downregulate DNA synthesis and inhibit the secretion of inflammatory mediators [44]. The cohort trial performed in Japan in 2020 has shown the efficacy of pirfenidone in IPF based on the reduction of serum concentration of SP-D, concluding that this biomarker might have a predictive and informative value [45].…”

Biomarkers in Progressive Fibrosing Interstitial Lung Disease: Optimizing Diagnosis, Prognosis, and Treatment Response

“…Assassi and colleagues recently developed a prediction model for response to cyclophosphamide and mycophenolate in SSc-ILD using interferon-induced serum proteins ( 172 ). Ikeda et al showed plasma SP-D concentration may predict favorable response to pirfenidone ( 173 ) in patients with IPF, though Neighbors and colleagues showed consistent pirfenidone treatment effect irrespective of plasma concentration for a panel of prospectively collected candidate biomarkers ( 126 ).…”