Phase 3 Study of Cysteamine Bitartrate Delayed-release (RP103) Compared to Cystagon® in Patients With Cystinosis

• To assess the safety and tolerability of RP103 compared to Cystagon® [ Time Frame: 4 weeks after the last subject has completed the study ] [ Designated as safety issue: Yes ]
• To assess the steady state pharmacokinetics and pharmacodynamics of RP103 compared to Cystagon®. [ Time Frame: 4 weeks after the last subject has completed the study ] [ Designated as safety issue: No ]

• To assess the safety and tolerability of RP103 compared to Cystagon® [ Time Frame: 27-37 days (duration of study) ] [ Designated as safety issue: Yes ]
• To assess the steady state pharmacokinetics and pharmacodynamics of RP103 compared to Cystagon®. [ Time Frame: Periodically over a 3 day window for each drug ] [ Designated as safety issue: No ]
• To compare the incidence of concomitant gastric acid reduction therapies [e.g., proton pump inhibitors (PPI)] between Cystagon® and RP103. [ Time Frame: 27-37 days (duration of study) ] [ Designated as safety issue: Yes ]

Cystinosis is an inherited disease that if untreated, results in kidney failure as early as the first decade of life. The current marketed therapy is Cystagon® (cysteamine bitartrate) which must be taken every six hours for the rest of the patient's life to prevent complications of cystinosis. RP103 is a formulation of cysteamine bitartrate that is being studied to see if it may be able to be given less frequently, once every 12 hours, and have similar results to four times a day Cystagon®.

This is a multi-center, open-label, randomized, cross-over study to determine whether steady-state, twice a day treatment with Cysteamine Bitartrate Delayed-release Capsules(RP103) results in comparable depletion of white blood cell (WBC) cystine levels compared to the existing four times a day cysteamine treatment. It will involve up to 20 clinic visits plus intermittent home use of the RP103. Most of these clinic visits occur in clusters of 3-4 consecutive days. Eligible patients will be offered enrollment into a long-term follow up study.

• Drug: Cystagon® (Cysteamine Bitartrate)

  Run-in Period (Weeks 1, 2, 3) and Period 1 (Weeks 4, 5, 6) or Period 2 (Weeks 7, 8, 9); Immediate crossover to opposite treatment than taken during Period 1:

  Every 6H, supplied in 150 and 50mg capsules/Duration of Treatment: 3 weeks each period used

• Drug: Cysteamine Bitartrate Delayed-release Capsules (RP103)

  Period 1 (Weeks 4, 5, 6) or Period 2 (Weeks 7, 8, 9); Immediate crossover to opposite treatment than taken during Period 1:

  Every 12H, supplied in 75 and 25mg capsules/Duration of Treatment: 3 weeks

• Experimental: RP103 Q12H
  Intervention: Drug: Cysteamine Bitartrate Delayed-release Capsules (RP103)
• Active Comparator: Cystagon® Q6H
  Intervention: Drug: Cystagon® (Cysteamine Bitartrate)

• Dohil R, Fidler M, Barshop BA, Gangoiti J, Deutsch R, Martin M, Schneider JA. Understanding intestinal cysteamine bitartrate absorption. J Pediatr. 2006 Jun;148(6):764-9.
• Fidler MC, Barshop BA, Gangoiti JA, Deutsch R, Martin M, Schneider JA, Dohil R. Pharmacokinetics of cysteamine bitartrate following gastrointestinal infusion. Br J Clin Pharmacol. 2007 Jan;63(1):36-40.
• 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 Jan;21(1):110-3. Epub 2005 Oct 27.

Inclusion Criteria:

• Male and female subjects must have nephropathic cystinosis.
• Subjects must be on a stable dose of Cystagon® sufficient to maintain their white blood cell (WBC) cystine level at ≤ 1.0 nmol/half-cystine/mg protein.
• Subjects must be able to swallow their typically administered Cystagon® capsule with the capsule intact.
• Within the last 6 months, no clinically significant change in liver function [i.e., ALT, AST, total bilirubin] and renal function [i.e., estimated GFR] at Screening as determined by the Investigator.
• Subjects with an estimated GFR (corrected for body surface area) > 30 mL/min/1.73m2.
• Sexually active female subjects of childbearing potential (i.e., not surgically sterile [tubal ligation, hysterectomy, or bilateral oophorectomy] or at least 2 years naturally postmenopausal) must agree to utilize the same acceptable form of contraception from Screening through completion of the study.
• Subjects must be willing and able to comply with the study restrictions and requirements.
• Subjects or their or their parent or guardian must provide written informed consent and assent (where applicable) prior to participation in the study.

Exclusion Criteria:

• Subject's age < 6 years old or subject's weight < 21 kg.
• Subjects with a known history, currently of the following conditions or other health issues that make it, in the opinion of the investigator, unsafe for them to participate: inflammatory bowel disease (if currently active) or have had prior resection of small intestine; Heart disease (e.g., myocardial infarction, heart failure, arrhythmias or poorly controlled hypertension) 90 days prior to Screening; Active bleeding disorder 90 days prior to Screening; Malignant disease within the last 2 years.
• Patients with a hemoglobin level < 10 g/dL at Screening or a level that, in the opinion of the investigator, makes it unsafe for the subject to participate.
• Subjects receiving any form of cysteamine medication through a gastric tube.
• Subjects who are receiving maintenance dialysis or who have had a kidney transplant.
• Subjects who are on an active kidney transplant list or who are planning to receive a kidney transplant within 3 months of Screening.
• Subjects with known hypersensitivity to cysteamine or penicillamine.
• Female subjects who are nursing, planning a pregnancy, known or suspected to be pregnant, or have a positive serum pregnancy screen.
• Subjects who have a made a blood donation within 30 days of Screening.
• Subjects who, in the opinion of the Investigator, are not able or willing to comply with the protocol.