Development of a Novel Calcium Channel Therapeutic for Dystrophinopathies

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd. Suite 110 San Diego, CA 92121 [email protected] Vivreon Biosciences – NIAMS PA-23-230 Project Summary Vivreon is an innovative life sciences company that is developing a novel small molecule Ca2+ channel therapeutic lead candidate to delay the progressive muscle weakening associated with dystrophinopathies,

including Duchenne muscular dystrophy (DMD). The lead modulates the Orai1 Ca2+ channel which has recently been validated as a drug target in preclinical models. To this end, Orai1 is upregulated in skeletal muscle of dystrophin mutants and skeletal muscle-specific knockout of Orai1 improves muscle force generation in

preclinical models of DMD. Orai1 upregulation in disease leads to cytotoxic Ca2+ overload as well as activation of the myofibrillar protease calpain. The subsequent skeletal muscle fibrosis and necrosis leads to chronic activation and recruitment of resident and peripheral leukocytes, including neutrophils and macrophages leading

to secondary pathological chronic inflammation. A role for Orai1 activity as an activator of nuclear factor of activated T cells (NFAT) and κB (NF-κB) transcription factors in these cells is well established. Therefore, the lead, with its excellent oral bioavailability, potency, and ability to abrogate multiple pathological processes, is a

strong candidate for reducing the progressive muscle weakening in DMD. This grant effort will further assess the suitability of the candidate drug’s properties and its efficacy in preserving muscle force generation in a DMD model. The candidate compound does not inhibit seven primary cytochrome P450 enzyme activities, demonstrates

promising preliminary pharmacokinetic properties, and possesses low nM potency against the Orai1 channel. In Aim 1 we will assess the toxicity profile of the therapeutic candidate to identify an appropriate dose for efficacy studies. In Aim 2 we will test the efficacy of the candidate for reducing eccentric contraction-induced muscle

damage using a well-validated in situ muscle force generation system in a model of DMD. Additional endpoints will include serum creatine kinase levels and histology to assess gross muscle structure, inflammatory infiltration and fibrosis. We will compare our candidate to another cytotoxic Ca2+ targeted small molecule therapeutic that

is currently in Phase 2 clincal trials for DMD. Our goal is a 50% improvement of muscle force production. Achieving these milestones will signal that the candidate therapeutic should be developed as a candidate for dystrophinopathy therapy.