DR Cysteamine for Cystinosis

Raptor's DR Cysteamine product candidate is a delayed-release oral formulation of cysteamine bitartrate. We are investigating DR Cysteamine as a potential improvement in the management of nephropathic cystinosis (cystinosis), a serious lysosomal storage disease. The disease is primarily diagnosed in early childhood.

Cysteamine therapy may be effective at preventing or delaying kidney transplants in cystinosis patients.1,2,3,4 However, patient compliance is challenging due to frequent dosing and gastrointestinal side effects.2,4,5,6

Raptor's DR Cysteamine for cystinosis was designed to potentially mitigate some of these difficulties. It is expected to be dosed twice daily, compared to the current every-six-hour dosing schedule. In addition, DR Cysteamine is designed to pass through the stomach and deliver the drug directly to the small intestine, where it may be more easily absorbed into the bloodstream and may result in fewer gastrointestinal side effects.7

Development Status for DR Cysteamine for Cystinosis

In June 2010, Raptor commenced a pivotal, Phase 3 clinical trial, designed as a multi-center, randomized, crossover, outpatient study of the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of every 12-hour DR Cysteamine compared to immediate-release cysteamine bitartrate in cystinosis patients.

The primary endpoint of the study is the steady-state white blood cell (WBC) cystine levels of patients taking DR Cysteamine compared to immediate-release cysteamine bitartrate. Secondary endpoints are the safety and tolerability of DR Cysteamine and the comparability of steady-state PK of DR Cysteamine and immediate-release cysteamine bitartrate in cystinosis patients.

The Phase 3 clinical trial will involve up to nine sites in North America and Europe and is expected to initially enroll up to 30 patients. Patients who complete the nine-week clinical trial will be offered enrollment into Raptor’s long-term follow-on study. Raptor anticipates that the Phase 3 clinical trial will be completed in December 2010.

In November 2009, Raptor completed its Phase 2b clinical trial of DR Cysteamine in cystinosis. DR Cysteamine demonstrated improved tolerability and the potential to reduce total daily dosage and administration frequency compared to immediate-release cysteamine bitartrate. Specific trial results that support this finding include:

  • Pharmacokinetic evaluation showed that DR Cysteamine had a terminal half-life more than three times longer than the terminal half-life of immediate-release cysteamine bitartrate capsules.
  • Twice-daily DR Cysteamine may achieve the same pharmacodynamic result while using a daily dose 30% lower than immediate-release cysteamine bitartrate capsules administered four times daily.

Raptor's Phase 2b clinical trial followed earlier clinical trials with an enteric-coated cysteamine prototype8 conducted by Ranjan Dohil, M.D., Associate Professor of Pediatrics at University of California, San Diego (UCSD) and funded by the Cystinosis Research Foundation (CRF). The CRF also supported Raptor's Phase 2b clinical trial.

The FDA and EMA have granted orphan drug designation for DR Cysteamine for the treatment of cystinosis.

Results Suggest A More Practical Assay for Cysteamine Bitartrate Dose Management

Recently published results from Raptor’s Phase 2b study of Cysteamine Bitartrate Delayed-Release Capsules (RP103) suggest pre-dose plasma cysteamine may be predictive enough for cysteamine bitartrate dose management. The results from the UCSD Phase 2b study of Raptor's DR Cysteamine (RP103) showed strong correlation between plasma cysteamine (pharmacokinetics) and white blood cell (WBC) cystine levels (pharmacodynamics) in the nine participating patients.

These data support the conclusion that pre-dose plasma cysteamine concentration is sufficiently predictive that it could be used to determine effective cysteamine bitartrate dosing necessary for the management of cystinosis patients. The plasma cysteamine concentration test is easier and more practical to run in most clinical settings than the highly specialized WBC cystine test.


Learn more about Raptor's other clinical programs:

References:

  1. Gahl WA, Balog JZ, Kleta R. Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Annals of Internal Medicine. 2007;147:242-250.
  2. Levtchenko EN, van Dael CM, de Graaf-Hess AC, Wilmer MJ, van den Heuvel LP, Monnens LA, Blom HJ. Strict cysteamine dose regimen is required to prevent nocturnal cystine accumulation in cystinosis. Pediatr Nephrol. 2006;21:110–113.
  3. Markello TC, Bernardini IM, Gahl WA. Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med. 1993;328:1157-1162.
  4. Kleta R, Bernadini IM, Ueda M, Varade WS, Phornphutkul C, Krasnewich D, Gahl WA. Long-term follow-up of well-treated nephropathic cystinosis patients. J Pediatr. 2004; 145:555-60.
  5. Kleta R, Gahl WA. Pharmacological treatment of nephropathic cystinosis with cysteamine. Expert Opin. Pharmacother. 2004;5(11):2255-2262.
  6. http://www.fda.gov/medwatch/SAFETY/2007/Jun_PI/Cystagon_PI.pdf
  7. Dohil R, Fidler M, Barshop BA, Martin M, Gangoiti J, Deutsch R, Schneider JA. Understanding intestinal cysteamine bitartrate absorption. J Pediatr. 2006;148:764-769.
  8. Dohil R, Fidler M, Gangoiti JA, Kaskel F, Schneider JA, Barshop BA. Twice-daily cysteamine bitartrate therapy for children wtih cystinosis. J Pediatr. 2010 Jan; 156(1):71-75.e1-3.