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A disease progression model of longitudinal lung function decline in idiopathic pulmonary fibrosis patients

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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.

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The views expressed in this paper are those of the authors and do not necessarily represent those of the FDA.

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Author notes

  1. Dinko Rekić

    Present address: AstraZeneca, Cambridge, UK

  2. Anshu Marathe

    Present address: Novartis, East Hanover, NJ, USA

  3. Badrul A. Chowdhury

    Present address: Savara Inc., Austin, TX, USA

  4. Youwei Bi and Dinko Rekić have contributed equally.

Authors and Affiliations

  1. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

    Youwei Bi, Dinko Rekić, Jianmeng Chen, Anshu Marathe & Yaning Wang

  2. Division of Pulmonary, Allergy, and Rheumatology Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

    Miya O. Paterniti, Badrul A. Chowdhury & Banu A. Karimi-Shah

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  1. Youwei Bi
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Contributions

DR, YB, MOP, JC, AM, BAC, BAK-S and YW wrote the manuscript, DiR and YB analyzed the data.

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Correspondence to Yaning Wang.

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Anshu Marathe, Dinko Rekić and Badrul A. Chowdhury: denotes authors performed this work when in the US FDA.

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Bi, Y., Rekić, D., Paterniti, M.O. et al. A disease progression model of longitudinal lung function decline in idiopathic pulmonary fibrosis patients. J Pharmacokinet Pharmacodyn 48, 55–67 (2021). https://doi.org/10.1007/s10928-020-09718-9

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  • DOI: https://doi.org/10.1007/s10928-020-09718-9

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