IDL-2965: A Selective, highly-potent, oral Integrin antagonist for IPF

Introduction: IPF is a fatal orphan fibrotic lung disease for which next generation treatments are urgently needed. RGD-binding integrins are an attractive therapeutic target involved in TGF-b activation, fibroblast migration, and myofibroblast survival. IDL-2965 is a selective, orally available, small molecule integrin antagonist being developed for IPF and other serious fibrotic diseases. Aims: Preclinical characterization of the potency, selectivity, pharmacokinetics, safety, and antifibrotic activity of IDL-2965. Methods: A robust drug discovery campaign identified integrin antagonists with strong antifibrotic activity and favorable PK. IDL-2965 emerged from these screens and was characterized for potency, selectivity, and antifibrotic efficacy, as well as for safety in a formal toxicology program. Results: Cell-based potency of IDL-2965 was 1.5, 1.4 and 0.4 nM against human αvβ1, αvβ3 and αvβ6, respectively. Oral administration in rat and nonhuman primate provided a t1/2 ≈ 8 hrs. Once-daily oral therapeutic dosing reduced fibrosis in multiple models across organ systems with minimal effective doses ranging from 0.4-3 mg/kg. In a bleomycin model of pulmonary fibrosis, therapeutic dosing of 0.4 mg/kg significantly reduced fibrosis and combination studies with pirfenidone suggest compatibility with current standard of care. 28-day GLP safety studies suggest a large therapeutic index. Conclusions: IDL-2965 is a selective integrin antagonist with significant antifibrotic effect at low, once-daily, oral doses and a favorable safety profile in formal toxicology and safety pharmacology studies. Based on these results a clinical study examining IDL-2965 in healthy subjects and IPF patients will commence in 2019.