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

Lead Research Organisation: University of Sunderland
Department Name: Sch of Pharmacy & Pharmaceutical Sci


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.

Technical Summary

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.

Planned Impact

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.


10 25 50
Description Funding for equipment : Oral Chroma Breath Analyser (and associated computer)
Amount £7,378 (GBP)
Organisation Cystinosis Research Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2020 
End 01/2020
Description Covance - pre-clinical studies 
Organisation Covance Clinical and Periapproval Services Limited
Country United Kingdom 
Sector Private 
PI Contribution The University team have provided liasion between the custom synthesis supplier (Lianhetech) and Covance; the team have also been involved in all decision making prior to Covance undertaking pre-clinical studies as indicated below.
Collaborator Contribution Covance have been contracted to undertake pre-clinical trials in safety and toxicology for CF10. Only limited work has, to date, been undertaken as we await bulk supply of CF10 from Lianhetech. From a small initial supply of CF10, Covance have undertaken the following studies: (i) two fasted dog pharmacokinetic studies, each in 3 animals; (ii) one rat multi-dose toxicology study in 8 animals. These studies have informed decisions for the direction of further pre-clinical studies on delivery of bulk supply of CF10 (this is anticipated in March/April 2020).
Impact To date, we only have preliminary pre-clinical trial data and this is being used to inform further study.
Start Year 2019
Description Lianhetech - Custom Synthesis 
Organisation Lianhetech
Country China 
Sector Private 
PI Contribution The University team has provided academic support to the process development (as outlined below) being undertaken by Lianhetech.
Collaborator Contribution Lianhetech are (under commercial contract) undertaking the development scale-up and subsequent custom synthesis of CF10. This synthesis will provide the relevant quantity of material (up to 10kg) of appropriate analytical standard for use in pre-clinical animal studies being undertaken by Covance. Lianhetech have taken the original laboratory synthesis developed by Professor Anderson and co-workers and explored the sythetic route to ensure that the synthesis is robust, scalable and provides material in reproducible quantity and quality; this is with a view to providing material for pre-clinical work but also to ensure that the synthetic approach is appropriate for manufacturing purposes. As such, Lianhetech have investigated raw material supply, quality and sustainability, variations to the synthetic route to ensure scalability, reaction efficiency and reproducibility and approaches to final material quality control and assurrance.
Impact Patent Application (1902018.9) was filed on 14/2/19. This was followed by Patent Cooperation Treaty application (PCT/GB2020/050347) was filed on 14/2/20. These applications cover the laboratory and large scale synthesis of CF10 and follow on from the initail publication associated with this work (L. Frost et al., Eur. J. Med. Chem., 2016, 109, 206-215).
Start Year 2019
Title Laboratory scale and scale-up synthesis of CF10 (g-glutamyl prodrug of cysteamine) 
Description The patent application relates to synthetic protocols for the five-step synthesis of CF10, a g-glutamyl prodrug of cysteamine from commercially available raw materials on both a laboratory and larger scale CF10 = 4-{[2-(S)-(acetylsulfanyl)ethyl]carbamoyl}-1-ethoxy-1-oxobutan-2-aminium chloride and associated free base form. 
IP Reference Patent Application 1902018.9 (filed 149/2019) and subsequent PCT application PCT/GB2020/050347 (filed 14/2/2020) 
Protection Patent application published
Year Protection Granted
Licensed No
Impact Lianhetech were involved in the development of the scale-up protocol component of the patent application - they are currently using this methodology to provide a bulk synthesis of CF10; this will be delivered to Covance to support proof-of-concept pre-clinical safety and toxicology studies.
Description Cystinosis Foundation UK 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact The project team have close links with Cystinosis Foundation UK (CFUK) (and wider cystinosis community) and meet on a regular basis with the trustees of the charity. (The CF10 prodrug of cysteamine is envisaged as a novel delivery technology to meet the medical needs of cystinosis patients by improving cysteamine pharmacokinetics and reduce the adverse side-effects of conventional cysteamine therapy including unpleasant taste/smell, nausea/vomitting, GI disturbance, noxious breath/sweat, high and repeated dosing).)
CFUK were the original charitable funders of the work to originally develop CF10 at the University of Sunderland prior to receiving MRC fuding for scale-up syntheis and pre-clinical testing.
We continue to keep them fully informed on the progress of work with outcomes and this provides impetus for them to drive forward in their charitable fundraining work.
As a result of the most recent update, CFUK agreed to fund purchase of a breath analyser (specifically for exhaled hydrogen sulphide, methanethiol and dimethyl sulphide). As part of continued support to the project, CFUK have begun fund-raising efforts to support the purchase of a handheld confocal microscope designed to measure cystine levels in body tissue.
Year(s) Of Engagement Activity 2020