Cudetaxestat (BLD-0409) CAS No.:1782070-21-6 promising drug that offers significant potential in the fight against IPF

Cudetaxestat (BLD-0409) is an oral small molecule targeting the enzyme autotaxin (ATX) by noncompetitve inhibition. ATX is a secreted enzyme that produces most of the lysophosphatidic acid (LPA). Increased ATX activity and excessive LPA production cause multiple adverse pathophysiologic phenomenon including myofibroblast activation. Activated myofibroblasts secrete extracellular matrix proteins which aggregate into fibrotic lesions. In preclinical studies, cudetaxestat demonstrated direct anti-fibrotic activity and differentiating biochemical characteristics.

Cudetaxestat was neither a substrate nor an inhibitor of P-gp at physiologically relevant concentrations. No significant change in plasma concentration of nintedanib was observed when cudetaxestat was co-administered in rats.

Cudetaxestat is a weak P-gp inhibitor when either quinidine or nintedanib is used as substrate.Cudetaxestat does not significantly alter nintedanib exposure when co-dosed in vivo in rats.

Introduction:Cudetaxestat is a differentiated, non-competitive small-molecule inhibitor of autotaxin being developed as daily oral treatment for idiopathic pulmonary fibrosis (IPF), systemic sclerosis-interstitial lung disease (SSc-ILD) and other fibrotic diseases.
Methods: A battery of preclinical in vitro and ex vivo biochemical assays, along with pharmacokinetic (PK) and pharmacology studies (mouse bleomycin model), were initially conducted to assess the potency and activity of cudetaxestat. Four Phase 1 studies with healthy volunteers (N=216) were then completed to evaluate safety/tolerability along with PK and pharmacodynamic (PD) activity. These include a double-blind, placebo-controlled SAD/MAD study [NCT04146805]; a relative bioavailability study [NCT04814472]; a CYP substrate interaction study [NCT04814498]; and a drug-drug interaction (DDI) with approved standard of care (SOC) therapies (nintedanib or pirfenidone) for IPF [NCT04939467]. Results: Cudetaxestat maintained potency against its target in vitro regardless of substrate concentration. It demonstrated significant anti-fibrotic activity in multiple in vivo preclinical models. Plasma LPA (C18:2) levels were measured in the SAD/MAD study and increasing doses resulted in more sustained LPA reduction across the 24-hour dosing intervals. When dosed concomitantly with either nintedanib or pirfenidone, the total exposure for each of these SOC therapeutics was not significantly altered. There were no drug-related serious adverse events (SAE’s) in any of the four Phase 1 human trials.

Conclusion: Cudetaxestat is a potential first-in-class, non-competitive (allosteric) autotaxin inhibitor with robust preclinical antifibrotic activity and good PK/PD correlations in Phase 1 clinical trials. This body of data provide a dose rationale for Phase 2 clinical development of cudetaxestat in IPF with or without SOC.