A disease progression model of longitudinal lung function decline in idiopathic pulmonary fibrosis patients
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ORIGINAL PAPER
A disease progression model of longitudinal lung function decline in idiopathic pulmonary fibrosis patients Youwei Bi1 • Dinko Rekic´1,3 • Miya O. Paterniti2 • Jianmeng Chen1 • Anshu Marathe1,4 • Badrul A. Chowdhury2,5 Banu A. Karimi-Shah2 • Yaning Wang1
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Received: 14 May 2020 / Accepted: 1 September 2020 Ó This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2020
Abstract Pirfenidone and nintedanib are the first two FDA-approved therapies for treatment of idiopathic pulmonary fibrosis (IPF). The clinical programs for pirfenidone and nintedanib included 1132 patients in the placebo arms and 1691 patients in the treatment arms across 6 trials. We developed a disease progression model to characterize the observed variability in lung function decline, measured as percent predicted forced vital capacity (%p-FVC), and its decrease in decline after treatment. The non-linear longitudinal change in %p-FVC was best described by a Weibull function. The median decreased decline in %p-FVC after treatment was estimated to be 1.50% (95% CI [1.12, 1.79]) and 1.96% (95% CI [1.47, 2.36]) at week 26 and week 52, respectively. Smoking status, weight, %p-FVC, %p-DLco and oxygen use at baseline were identified as significant covariates affecting decline in %p-FVC. The decreased decline in %p-FVC were observed among all subgroups of interest, of which the effects were larger at 1 year compared to 6 months. Based on the disease progression model smoking status and oxygen use at baseline may affect the treatment effect size. At week 52, the decreased decline in %p-FVC for current smokers and patients with oxygen use at baseline were 1.56 (90% CI [1.02, 1.99]) and 2.32 (90% CI [1.74, 2.86]), respectively. These prognostic factors may be used to enrich studies with patients who are more likely to respond to treatment, by demonstrating a lesser decline in lung function, and therefore provide the potential to allow for IPF studies with smaller study populations or shorter durations. Keywords Interstitial lung disease Nintendanib Pirfenidone Disease progression Pulmonary function tests Enrichment strategies
Introduction Youwei Bi and Dinko Rekic´ have contributed equally.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10928-020-09718-9) contains supplementary material, which is available to authorized users. Anshu Marathe, Dinko Rekic´ and Badrul A. Chowdhury: denotes authors performed this work when in the US FDA.
Idiopathic pulmonary fibrosis (IPF) is a deadly, chronic disease of unknown etiology that is characterized by scarring of lung tissue, leading to a progressive decline in lung function over time. Median survival time has been estimated to be 3 years from time of diagnosis and approximately 40,000 patients die each year in the U.S. [1]. Prior to the approval of pirfenidone [2] and nintedanib [3]
& Yaning Wang [email protected]
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Present Address: AstraZeneca, Cambridge, UK
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Present
