General Information

Procysbi is specifically indicated for the management of nephropathic cystinosis in adults and children ages 6 years and older.

Procysbi is supplied as a delayed-release capsule and can be administered either orally or via a feeding tube. It should be taken at least 2 hours after and at least 30 min before eating. Starting Dose: Procysbi therapy should be initiated promptly once the diagnosis is confirmed. Cysteamine-naïve patients should be started on 1/6 to 1/4 of the maintenance dose of Procysbi. The dose should be raised gradually over 4 to 6 weeks to help reduce the risk of side-effects. WBC cystine level and/or cysteamine concentration measurements, taken ½ hour after dose administration, are recommended for new patients after the maintenance dose is achieved. Maintenance Dose: The recommended maintenance dose is 1.3 gram/m2/day, in two divided doses given every 12 hours. The dose can be increased up to 1.95 grams/m2/day if the white blood cell cystine level remains higher than the target WBC cystine level and/or the target cysteamine concentration has not been achieved.

Clinical Results

FDA Approval
The FDA approval of Procysbi was based on the following trials. Trial 1 (RP103-01) was a single center, single-dose, open-label, non-randomized, 2-period, immediate-release cysteamine bitartrate vs. Pocysbi pilot study in 9 (8 pediatric and 1 adult) patients with nephropathic cystinosis ages 6 years to 24 years. The trial reported highly variable inter-patient bioavailability with both immediate-release cysteamine and Procysbi. The trial suggested that, when WBC cystine trough levels are used as a measurement of cellular cystine depletion, delayed-release cysteamine (Procysbi) administered every 12 hours (Q12H) is as effective as immediate-release cysteamine bitartrate administered every 6 hours (Q6H).
Trials 2, 5 and 6 (RP103-02, RP103-05, and RP103-06 respectively) were PK studies conducted in healthy volunteers. Trial 3 (RP103-03), the pivotal trial for Procysbi, was a phase III multicenter (US and EU) randomized, crossover, immediate-release cysteamine bitartrate vs. Procysbi trial in 43 (40 pediatric and 3 adult) patients with nephropathic cystinosis. Patient age ranged from 6 to 26 years. Prior to randomization, patients were to be on a stable dose of immediate-release cysteamine bitartrate administered Q6H. Procysbi dose adjustments of up to ~100% of the total daily dose of immediate-release cysteamine bitartrate were allowed by trial criteria. The average total daily dose of Procysbi for patients completing the clinical trial was ~91 % of the average total daily dose of immediate-release cysteamine bitartrate for patients at trial entry. Trial 3 demonstrated that at steady-state Procysbi (cysteamine bitartrate) delayed-release capsules administered Q12H was non-inferior to immediate release cysteamine bitartrate administered Q6H with respect to the depletion of WBC cystine levels. Forty out of forty-one patients completing Trial 3 are continuing treatment with Procysbi in an ongoing, open-label extension trial, i.e. Trial 4 (RP103 04), for total treatment duration of 24 months. Twenty additional patients (14 pediatric patients, ages 1 to 6 years, and 6 (4 adult and 2 pediatric) renal transplant patients) have also been enrolled in Trial 4. An interim analysis was performed after all enrolled patients from Trial 3 had been treated with Pocysbi for at least 12 months (n=33) and up to 19 months (n=3). The analysis indicated that patients switched from immediate-release cysteamine to a treatment regimen of Procysbi maintained a WBC level < 1 nmol/½ cystine/mg protein for up to 19 months at a total daily dose equal to their total daily dose of immediate release cysteamine at entry in Trial 3. During extended treatment there has been on average no worsening of the kidney function, as expressed by the estimated glomerular filtration rate (eGFR).

Mechanism of Action

Procysbi (cysteamine bitartrate) ) delayed-release capsules is a cystine depleting agent which lowers the cystine content of cells in patients with nephropathic cystinosis, an inherited defect of lysosomal transport. Cysteamine is an aminothiol that participates within lysosomes in a thiol-disulfide interchange reaction converting cystine into cysteine and cysteinecysteamine mixed disulfide, both of which can exit the lysosome in patients with cystinosis.

Literature References

Langman CB, Greenbaum LA, Sarwal M, Grimm P, Niaudet P, Deschênes G, Cornelissen E, Morin D, Cochat P, Matossian D, Gaillard S, Bagger MJ, Rioux P A randomized controlled crossover trial with delayed-release cysteamine bitartrate in nephropathic cystinosis: effectiveness on white blood cell cystine levels and comparison of safety. Clinical journal of the American Society of Nephrology 2012 Jul;7(7):1112-20