MICA: Pre-clinical studies on a novel prodrug delivery technology for cystinosis.

The rare genetic disease cystinosis affects approximately 1 in 200,000 births. It is characterized by accumulation of a waste product, cystine, in all cells and, if untreated, cystine crystals form, causing permanent organ damage and kidney failure, often death, by ten years of age. Cystinosis is currently treated with capsules of Cystagon or Procysbi, both of which contain the active agent cysteamine, which removes cystine and therefore delays disease progression. However, there are several problems with these medicines that lead to a large proportion of cystinosis patients missing doses: it has an intensely unpleasant taste and smell, which often cause nausea and vomiting during and after taking the capsules, and it can cause painful irritation, and even ulcer formation, in the gastrointestinal tract. Furthermore, most of the cysteamine is wasted when it is broken down by the body, converting some into unpleasant smells, which cause halitosis (bad breath) and pungent body odour. To maintain the correct levels of cysteamine in the blood, four daily doses of Cystagon are required, usually midnight, 6am, noon and 6pm - up to 24 capsules each day. To prevent the accumulation of cystine and organ damage, it is important that patients adhere strictly to the six hourly intake of Cystagon, despite disruption to sleep. The sustained release form Procysbi is taken twice per day, but is required in a similar high dose due to metabolic wastage, does not reduce the production of smelly metabolites and still causes stomach pains. Patients have to take several additional medicines every day to treat other symptoms; even small children can have four to six sets of medicine to take four times a day. Cystinosis patients have indicated that a medicine with less smell and taste, that doesn't cause stomach pains, is not required four times a day, and causes no halitosis and body odour would help them to maintain the dosage regimen.
We have developed a new technology to deliver an inactive form of cysteamine, CF10, directly to cells. It is activated on the cell surface to release cysteamine that can pass immediately into cells, avoiding the problem of wastage due to metabolism. This should lead to smaller and less frequent doses, causing fewer side effects. A reduction in halitosis is also anticipated, as there will be less cysteamine in the blood and so less production of smelly products by metabolism. CF10 was also designed to have an improved taste and smell and to cause less gastric irritation.
A wide range of experiments have been carried out and the results support progression of CF10 into pre-clinical development studies. If successful, these studies would support an application to the UK regulatory government agency MHRA for clinical trials approval for CF10.

This project seeks to evaluate the safety of cysteamine prodrug CF10 in an appropriate model and obtain sufficient pre-clinical data to support an MHRA application for clinical trials approval.
We have designed CF10 to address the unmet clinical need for a better treatment for cystinosis, a rare autosomal recessive disease characterized by raised intracellular levels of cystine. Untreated, cystine crystals accumulate in the lysosomes of all cells, leading to permanent organ damage and usually death by ten years of age. It is treated with oral cysteamine (as the bitartrate salt Cystagon or the sustained release bitartrate form Procysbi), which reduces lysosomal cystine levels and delays disease progression. However, both of these medicines cause problems that adversely affect compliance.
CF10 was designed to address the problems of cysteamine administration, aiming for: minimal taste and smell; low gastric irritation; good oral bioavailability; evasion of 1st pass metabolism, requiring fewer and lower doses; and, release of cysteamine systemically on the surface of cells for its rapid uptake. The preliminary evidence supports progression of the prodrug CF10 into pre-clinical studies.
In this project, GMP certified CF10 will be tested for genotoxicity and its toxicity evaluated in a suitable model, providing safety and toxicokinetic data to guide dosing for a 1st in man clinical trial. Concurrently, a liquid formulation of CF10 suitable for paediatric clinical trials will be developed.
The results will support applications for funding and regulatory approval to progress CF10 to a 1st in man clinical trial, alongside more detailed pre-clinical studies in preparation for the second phase of clinical trials. Clinical cystinosis experts are involved in the design of clinical trials and industrial support brings commercial expertise to the development of CF10.

The benefit from this project has worldwide impact. The main beneficiaries are cystinosis patients and their families and carers. Clinicians and other healthcare professionals with responsibility for the care of cystinosis patients, the NHS and other healthcare systems worldwide, academic researchers and future industrial partners will also benefit.
Patients will benefit from a medicine that: has little taste and smell, reducing the issue of nausea and vomiting; causes minimal gastric irritation, minimising the incidence of gastric pain and possible ulceration after oral administration; is subject to low first pass metabolism, particularly with respect to the production of noxious smelling metabolites; requires a reduced dose, leading to fewer side effects; requires less frequent dosing, causing less sleep disturbance; has greater efficacy, reducing the number of capsules needed daily and at each medication time; provides improved quality of life for patients and their families and carers; facilitates compliance with medication requirements, making it easier for patients to stay well for longer, improving the prognosis and increasing the time before kidney transplantation becomes necessary, reducing the adverse effects of surgery and subsequent lifelong immunosuppressant requirements on patients' lives.
The NHS and other healthcare systems across the world will benefit from a treatment that encourages better compliance and therefore improves patient health and independence, while reducing the need for hospitalisation, decreasing NHS and other healthcare costs.
Academic researchers will gain from the new knowledge provided by this approach to active agent delivery and reduction of side effects.
Future industrial partners will benefit from marketing a new treatment that has been developed at low cost, funded by alternative sources, allowing the minimum market cost to be agreed, which will facilitate its uptake worldwide. The 10 years exclusivity of EU marketing, afforded to an orphan drug after orphan marketing authorisation is achieved, offers similar benefits to a patent protected drug, making this an interesting and worthwhile acquisition.