Phase 1 clinical trial of the cysteamine prodrug CF10 for the treatment of cystinosis

A Phase 1 clinical trial of CF10 ((S)-ethyl 5-((2-(acetylthio)ethyl)amino)-2-amino-5-oxopentanoate hydrochloride) will be performed. CF10 is a cysteamine prodrug for the treatment of nephropathic cystinosis (hereafter cystinosis). Cysteamine (mercaptamine) is the only approved therapy for the management of cystinosis, an inherited recessive lysosomal storage disease. However, side-effects (gastrointestinal toxicity, halitosis and body odour problems) and poor pharmacokinetics (2g/day or greater with dosing every 6 hours) make adherence to cysteamine treatment very challenging. Due in large part to poor adherence, most cystinosis patients develop severe Fanconi syndrome and progress to end stage kidney failure (ESKD) requiring dialysis or transplant between the age of 10 and 20, followed by widespread multi-system endocrine and muscle disease. CF10 has been designed to avoid gastrointestinal toxicity, enhance oral bioavailability, limit systemic cysteamine concentrations and metabolism to methanethiol and dimethyl sulphide, and hence halitosis/poor body odour, whilst maintaining high tissue cysteamine delivery. Overall, CF10 will improve cystinosis therapy adherence and hence outcomes. The project has three components: 1. Synthesis of the CF10 active pharmaceutical ingredient (API) to Good Manufacturing Practice (GMP) standards by a contract research organisation (CRO). 2. Manufacture of CF10 capsules, also to GMP standards, by a CRO. 3. A Phase 1 clinical trial of CF10 to Good Clinical Practice (GCP) standards with associated data management and comprehensive pharmacokinetic and pharmacodynamic studies. The Phase 1 trial will comprise two components: a Phase 1a dose-finding study to define the dose of CF10 that produces depletion of the established biomarker cystine to less than 1 nmol ½ cystine/mg protein after 7 days treatment, and describe any associated toxicities, and a Phase 1b study to confirm safety and maintained cystine depletion when CF10 is administered once daily for 28 days at the dose identified in the Phase 1a trial. The project will define the CF10 dose that causes depletion of cystine to below the clinically accepted target of 1 nmol ½ cystine/mg protein and establish the safety of this dose when given daily for 28 days. This dose of CF10 will subsequently be used in Phase 2 trials to establish the efficacy of CF10 in the management of cystinosis. The research team has the required expertise to deliver the project in collaboration with Cystinosis Foundation UK and CROs; namely expertise in synthetic and process chemistry (AM), pharmaceutical science and pharmacy (AM), drug discovery and development (HN/SB), early phase clinical trials (SB/HN/GL/VH), rare disease trial methodology and trial statistics (VH), clinical cystinosis research and management (GL/SW) and clinical cystinosis biomarkers - cystine analyses (AG). The contractors selected (High Force Research, Newcastle Specials and CEMAS) have the accreditation needed to perform the work to the required standard (GMP/GCLP/GCP). Patient treatment and sample collection will be undertaken at the Birmingham NHS England designated national cystinosis hub and conducted in the NIHR/Wellcome Trust Clinical Research Facility, which is based across University Hospitals Birmingham and Birmingham Women’s and Children’s Hospital. Data monitoring and management will be performed by the accredited University of Birmingham Cancer Research UK Clinical Trials Unit.