Post hoc pooled analyses of open-label and randomized controlled trials of senolytics dasatinib and quercetin in Idiopathic Pulmonary Fibrosis

Background: IPF is characterized by premature and progressive cellular senescence(definition) (CS). Our two first-in-human pilot studies (open-label and randomized placebo-controlled (RCT)) of the senolytic combination of dasatinib and quercetin (D+Q) had identical designs, regimens and outcomes and thus pooled for these analyses. This study also investigated two markers of senescent burden – GPNMB (seno-antigen) and alpha-klotho (associated with preclinical senescent cell accumulation). Aims and objectives: Assess safety, functional changes and senolytic efficacy after 3 weeks of D+Q Methods: The participants had confirmed IPF with clinical stability for a year. The treatment regimen was 3 days per week of quercetin 1250mg and dasatinib 100mg daily for 3 weeks. Adverse events and adherence assessments were performed during treatment. Pulmonary and physical function assessments as well as alpha-klotho and GPNMB were done at baseline and 1 to 2 weeks after treatment. Results: 20 participants (14 from open-label and 6 from RCT) received D+Q, and 6 in the RCT received placebo. The post hoc analysis did not have significant differences in frailty, physical function, or pulmonary function between D+Q and placebo groups but did suggest an improvement in SPPB with D+Q that did not reach significance. GPNMB consistently decreased with D+Q (p=0.0008), and urinary alpha-klotho increased (p=0.04). Pooled analysis of IPF patients treated with D+Q did not show significant improvement in frailty nor physical or pulmonary function versus placebo. Senescent biomarkers support senolytic efficacy of D+Q. Given the reported safety, future RCTs of D+Q in IPF are needed.