Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

Jamie N Justice, Anoop M Nambiar, Tamar Tchkonia, Nathan K LeBrasseur, Rodolfo Pascual, Shahrukh K Hashmi, Larissa Prata, Michal M Masternak, Stephen B Kritchevsky, Nicolas Musi, James L Kirkland, Jamie N Justice, Anoop M Nambiar, Tamar Tchkonia, Nathan K LeBrasseur, Rodolfo Pascual, Shahrukh K Hashmi, Larissa Prata, Michal M Masternak, Stephen B Kritchevsky, Nicolas Musi, James L Kirkland

Abstract

Background: Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.

Methods: A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored.

Findings: Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50).

Interpretation: Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases. ClinicalTrials.gov identifier: NCT02874989 (posted 2016-2018).

Keywords: Aging; Cellular senescence; Clinical trial; Idiopathic pulmonary fibrosis; Interstitial lung disease; Senolytics; Translation.

Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
CONSORT flow diagram. Patient allocation in single-arm open label pilot study conducted at Wake Forest School of Medicine (WFSM) and University of Texas Health Science Center San Antonio (UTHSCSA) shown in CONSORT flowchart.
Fig. 2
Fig. 2
Three weeks of intermittent DQ dosing and assessment schedule. Dasatinib (100 mg per day) and Quercetin (1250 mg per day) were self-administered by participants for three consecutive days per week on three consecutive weeks according to the dosing schedule shown (dosing days 1–3, 8–10, and 15–17). Study coordinators called participant to confirm adherence and administer safety and symptom questionnaires approximately 24 h after the last dose of each week.

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