Calista Therapeutics has invented Calcaftor, a first-in-class peptide drug that can treat all Cystic Fibrosis (CF) patients. Calcaftor is validated in the gold standard pre-clinical model of CF using F508 -CFTR lung tissue harvested from CF transplant patients. Results from this model demonstrated a >25 hour duration of action that enables once daily inhaled nebulizer dosing and an efficacy that is predictive of clinical effect. CF is a common inherited disease that causes thick mucus in the lungs, digestive tract and other tissues. CF life expectancy is just 37.4 years and currently there is no approved treatment for the majority of CF patients. CF is a major unmet medical need. Calcaftor acts by inhibiting a CFTR trafficking protein CAL that promotes loss of CFTR from the epithelial membrane and premature lysosomal digestion. This Phase I SBIR will undertake critical proof of concept studies into the safety and pharmacokinetic distribution of Calcaftor following pulmonary instillation and intravenous injection and precisely addresses the NIH mission to identify "therapeutic approaches to modulating the transport defect in cystic fibrosis and to stabilize mutant CFTR and enhance its targeting and integration into the cell membrane". World-class experts in CF and drug development combined with an outstanding environment ensure successful execution of project aims.
Aim 1. Bioanalytical Method Development. Deliverable 1. LC-MS method allowing Calcaftor detection to 10ng/ml or below in body fluids and tissues. Milestone 1. Decision to proceed to Aim 2 toxicity and PK studies.
Aim 2 : Exploratory Toxicology and PK of Calcaftor in rats.
Aim 2. 1: Single ascending dose PK and toxicity of IT and IV Calcaftor. Deliverable 2.1: Determine MTD, half-life and PK parameters in IT and IV dosing that enable 10?M dosing and target organ concentration. Identification of PK data and PK modeling that informs Aim 2.2 repeat dosing regimen and amount. Milestone 2.1: Decision to proceed to repeat dose studies.
Aim 2. 2: 5-Day Repeated Dose Toxicity Study of IT Calcaftor. Deliverable 2.2: Determination of no observed adverse effect level of 5 day IT dosing. Milestone 2.2: Decision to proceed to IND enabling studies.
Aim 2. 3: Comparative 10-day PK studies of Calcaftor: IT instillation. Deliverable 2.3: IT PK profile reaching and sustaining effective lung, systemic and CF target organ Cssmax, without toxicity. IT dose-to-dose reproducibility, accumulation, and modeling PK data from daily repeat dosing. Milestone 2.2: NOAEL and MTD from 10-day repeat dosage study with daily dosing. Decision to solicit a Pre-IND meeting with FDA and proceed with full IND studies to enable clinical testing. This project will provide critica pre-clinical enablement of the dose form, toxicology, analytical methods, and pharmacokinetics to inform, enable, and justify the preclinical progression of the current lead compound to IND-enabling studies in CF. Our development plan delineates NDA approval 5 years after this Phase I SBIR.
Calcaftor is a novel drug treatment for the majority Cystic Fibrosis patients. This project describes pre-clinical proof-of-concept research characterizing safety and pharmacokinetic distribution following pulmonary and systemic administration. Cystic Fibrosis is the most common genetic disorder in white people, resulting in an average age of death of 37.4 years. Successful treatment would prevent the early deaths and disablement of thousands of patients and restore then to full health.