Therapeutic correction of deltaF508-CFTR cystic fibrosis by a novel PDZ12 drug.

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DESCRIPTION (provided by applicant): Calista Therapeutics has discovered a first-in-class, proprietary PDZ1-2 lead drug, AT010, that is being optimized and developed as an inhaled daily therapy for cystic fibrosis (CF). CF is a deadly inherited genetic disorder that disrupts chloride channel function, resulting in the buildup of sticky mucus in patient's lungs and other organs.CF patients have a life expectancy of 37 years and need intensive therapeutic interventions for chronic co-morbidities and symptoms. Critically, there are no approved disease-modifying treatments for 96% of CF patients, resulting in a very high unmet clinical need. Preliminary AT010 results already show proof of efficacy in the restoration of the chloride channel in human CF bronchial epithelium. In addition, AT010 can be delivered through CF mucus following topical apical dosing. PDZ1-2 is a well-validated therapeutic target in CF that influences both the CF chloride channels trafficking and anchoring at the cell membrane, and its activation. The high level of restoration we have already observed with AT010 is established to be predictive of clinical efficacy. The novel and distinct PDZ1-2 mechanism of action in CF also suggests it will have a beneficial additive effect with other CF drugs. We have built a world-class team of CF and drug development experts and our results demonstrate technical competence and the environment to successfully achieve the project's aims: Aim 1. Synthesis of an optimized clinical lead AT010-derived peptide library: AT010 analogs designed to have stability, efficacy, low cost of manufacture, simple predicted CMC, non-immunogenicity, bioavailability, mucus penetration and target specificity will be synthesized in sufficient quantity and purity for Aim 2. Aim 2. Stability and efficacy testing of candidate compounds in human CF models. Aim 2.1: We will test and percentage rank the library for stability in human CF epithelial lining fluid. Peptides wil be eliminated from further development only if they show low solubility or a half-life <30 minutes because this will lead to unacceptable bioavailability. Aim 2.2: We will assess efficacy of the peptide drug library using CF patient tissues and samples and gold standard pre-clinical models that provide the best predictive power for clinical success: (1) Restoration of human delta-F508-CFTR chloride current >10%, (2) Restoration of normal airway surface liquid (ASL) height and (3) Unimpaired diffusion through CF mucus. This will provide a percentage ranked peptide drug library for CF-relevant in vitro stability and efficacy endpoints that will identify clinical lead nd back-up peptide drugs ready for toxicity assessments. Milestone 2: Upon completion we will solicit a Pre-IND meeting to allow rapid lead drug progression to IND studies and clinical trials. An expert team, substantially validated target, proprietary novel drug class (AT010), compelling preliminary data and an outstanding environment combine to ensure successful commercialization. Calista therapeutics has planned IND enabling studies and clinical trials that project completion of Phase1 and 2a trials in Year 4 post-grant award with a pivotal Phase 2b/3 trial prior to New Drug Application for approval.