Development of a Novel Calcium Channel Therapeutic for the Treatment of Asthma - Vivreon Biosciences, LLC
4940 Carroll Canyon Rd., Ste. 110
San Diego, CA 92121
milton@vivreonbiosciences.com
NHLBI PA-21-259
Project Summary
Severe asthma is a potentially lethal disease that is not fully controlled by anti-inflammatory small molecule or
biologic therapies. Recent evidence indicates that severe asthma patients exhibit substantial airway remodeling
(AR) where the epithelial, goblet and smooth muscle cells adopt atypical phenotypes that lead to airway
restriction with airway tissue thickening and fibrosis, smooth muscle mass expansion (SMR), mucus
accumulation and airway hyper reactivity to irritants. These tissue remodeling changes are not responsive to
standard of care anti-inflammatory (small molecule or biologic) or airway relaxing agents. SMR masses are
responsive to ablation by bronchial thermoplasty and clinical improvements are documented suggesting that
reducing SMR is a novel means to control severe asthma. Recent studies indicate that the Ca2+ release-activated
Ca2+ (CRAC) channel is a critical driver of SMR and that inhibition of CRAC could control SMR. Vivreon
Biosciences is pursuing a novel approach to deliver a novel and potent CRAC modulator development candidate
locally to the airways to obtain maximal tissue distribution and efficacy to control SMR. Other orally delivered,
systemically active CRAC blockers showed efficacy in models of asthma by inhibiting the inflammatory mediators
of the disease. Vivreon will surpass these early successes via intranasal delivery to achieve maximal local
delivery to the tissue to reduce both SMR and local inflammation.
The CRAC pathway regulates many genes through activation of NFAT and NF-B transcriptional activity. These
attributes make the CRAC channel a suitable target for development of a drug that can suppress SMR and
inflammation that drives severe asthma. Vivreon’s experimental therapeutic exhibits sub nanomolar potency at
CRAC and a favorable safety profile (no CYP inhibition, acceptable off-target activity profile, no evidence of
cardiac ion channel inhibition) upon oral dosing. In this SBIR Phase 1 project we will confirm in vitro activity
against airway smooth muscle cell and leukocyte production of proinflammatory mediators. In Aim 2 we will
confirm achievement of lung tissue levels that exceed CRAC IC50 values following intranasal administration. We
will also monitor plasma exposure in this experiment to appreciate the potential for systemic activity with this
dosing regimen. In Aim 3 we will quantify the efficacy and dose response of our CRAC modulator delivered by
the intranasal route (confirmed in Aim 2) on the SMR process and smooth muscle mass, as well as inflammatory
processes, in a model of asthma. Successful completion of these Aims will position the program to advance
further into IND-enabling studies such as formulation and inhaler delivery optimization, advanced toxicology
testing, chemistry scale up and dose-range finding with Phase II SBIR funding and other external support.
