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)

Purpose: Alerts for bleeding events are included in the Japanese package inserts of some anti-influenza drugs, including baloxavir marboxil and oseltamivir. However, there are few reports on the incidence of bleeding events during treatment with antiinfluenza drugs. This large-scale quantitative assessment compared the incidence of bleeding events in influenza patients treated with baloxavir and other anti-influenza drugs and in untreated patients.Methods: This retrospective cohort study used a large-scale Japanese employmentbased health insurance claims database provided by JMDC Inc. and included outpatients diagnosed with influenza between October 1, 2018 and April 11, 2019. Bleeding events were identified by International Classification of Diseases 10th revision codes. Incidences were compared between patients treated with baloxavir or neuraminidase inhibitors and untreated patients.Odds ratios were calculated after exact matching to adjust for potential confounders.

Background Influenza affects approximately a billion people globally, including >10 million Japanese individuals every year. Baloxavir marboxil (baloxavir [BXM]; a selective cap-dependent endonuclease inhibitor) is approved for influenza treatment in Japan. We compared the incidence of intra-familial transmission of influenza between BXM and oseltamivir (OTV) treatments using a simulation model. Methods Using the JMDC claims database, we identified index case (ICs) as the first family member diagnosed with influenza during the 2018–2019 influenza season, and classified the families into BXM or OTV group per the drug dispensed to ICs. Using a novel influenza intra-familial infection model, we simulated the duration of influenza infection in ICs based on agent-specific virus shedding periods. Intra-familial infections were defined as non-IC family members infected during the agent-specific viral shedding period in ICs. The virus incubation periods in the non-IC family members were considered to exclude secondary infections from potentially external exposure. The primary endpoint was proportion of families with intra-familial infections. For between-group comparisons, we used a multivariate logistic regression model. Results The median proportion of families with intra-familial transmission was 9.57% and 19.35% in the BXM (N=84,672) and OTV (N=62,004) groups, respectively. The multivariate odds ratio of 1.73 (2.5th-97.5th percentiles, 1.68-1.77) indicated a substantially higher incidence of intra-familial infections in the OTV group versus the BXM group. Subgroup analyses by ICs’ age category, virus type, and month of onset revealed similar trends favoring BXM. Conclusion BXM treatment of ICs may contribute to a greater reduction in intra-familial influenza transmission than OTV treatment.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating fibrotic lung disease. 1 Patients with IPF often experience various symptoms as pulmonary function deteriorates, which are associated with an increase in the prescription of concomitant drugs. Most IPF patients are middle-aged to older adults with various comorbidities, leading to further increase in the use of concomitant drugs. 2 This polypharmacy results in complications related to the drug-drug interactions and increases in medical spending. 3 There is an urgent need to find ways to avoid polypharmacy in the management of IPF.Pirfenidone is an antifibrotic drug approved in multiple countries for the treatment of IPF. [4][5][6] In multinational phase III clinical trials, pirfenidone reduced disease progression as reflected by pulmonary function, exercise tolerance, and progression-free survival in patients with IPF. 4,5 Studies further demonstrated that pirfenidone reduces respiratory-related hospitalizations and objective cough. 7,8 Considering these findings, we posited that pirfenidone may reduce the prescription of antibiotics and antitussive drugs and contribute to the avoidance of polypharmacy. The aim of this study was to assess the potential effects of pirfenidone in delaying the prescription of concomitant drugs in patients with IPF. MethodsThis is a post hoc exploratory analysis of a phase III multicenter, randomized, double-blind, placebo-controlled trial, conducted with Japanese IPF patients to determine the efficacy and safety of pirfenidone over 52 weeks. 6 In this phase III clinical trial, 325 patients were screened at 73 centers in Japan, and 275 patients were randomized to one of the three groups: high-dose pirfenidone (1,800 mg/day), low-dose pirfenidone (1,200 mg/day), and placebo. Two hundred sixty-seven patients were deemed eligible for the full analysis set (high-dose pirfenidone, n ¼ 108; low-dose pirfenidone, n ¼ 55; placebo, n ¼ 104). Eight patients were excluded for lack of post-baseline data. The full analysis set population was used in this post hoc exploratory analysis. The clinical trial protocol was approved by the institutional review board at each center, and written informed consent was obtained from all participants. The diagnostic criteria of IPF in the trial was previously described. 6 This clinical trial was registered with the Japan Pharmaceutical Information Center on September 13, 2005 (JapicCTI-050121).

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