A Randomized Controlled Crossover Trial with Delayed-Release Cysteamine Bitartrate in Nephropathic Cystinosis

Abstract

SummaryBackground and objectives Immediate-release cysteamine bitartrate (Cystagon; Mylan Pharmaceuticals, Canonsburg, PA) may prevent or delay kidney transplantation and other serious outcomes in patients with cystinosis, but has never been subjected to a prospective clinical trial. Cystagon efficacy requires strict lifelong dosing every 6 hours. Such a dosing schedule and Cystagon-associated side effects are often cited by patients as reasons for nonadherence. Design, setting, participants, & measurementsThis open-label, randomized, controlled, crossover trial was powered to show that a new delayed-release formulation of cysteamine bitartrate, RP103, taken every 12 hours, was noninferior to Cystagon for maintenance of white blood cell (WBC) cystine at levels associated with optimal outcomes in the disease.Results Forty-three patients were randomized. Using a mixed-effects statistical analysis model, the least-squares mean peak value of WBC cystine level was 0.6260.05 nmol 1/2 cystine/mg protein after 12 hours under RP103 and 0.5460.05 nmol 1/2 cystine/mg protein after 6 hours under Cystagon, a difference of 0.0860.04 nmol 1/2 cystine/mg protein (95.8% confidence interval, 0-0.16). The average steady-state total daily dose of RP103 was 82% of the incoming steady-state total daily dose of Cystagon. There were three-fold more gastrointestinal side effects compared with using Cystagon.Conclusions A new delayed-release Q12H formulation of cysteamine bitartrate is not inferior to the Q6H formulation (Cystagon) in maintaining low WBC cystine levels in patients with cystinosis but at a lower total daily dose.

Orphan drug policies and use in pediatric nephrology

“…This preparation requires administration every 6 h and has considerable gastrointestinal side effects [31]. A delayed-release preparation (Procysbi) given every 12 h within enteric-coated spheres reduced the side effects and improved quality of life, and thereby compliance to administration regimens [32].…”

Failure to Thrive with Polyuria

“…For this, topical cysteamine is used to dissolve the corneal cystine crystals [1,4,5], and must be used frequently throughout the day, often resulting in poor compliance. As expected, poor compliance with both oral cysteamine and topical cysteamine has a detrimental effect, with more rapidly progressive renal insufficiency and poor growth [1,7].…”

“…Cystinosis is a rare autosomal recessive disorder caused by mutations in the CTNS gene (17p13.2) [1][2][3][4][5][6][7]. It is a lysosomal storage disorder whereby there is a defect in the membrane transport protein, cystinosin, causing systemic accumulation of cystine crystals and is the most common cause of inherited renal Fanconi syndrome in children [1,3,4,5].…”

Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases

“…Although all these scientific reports seem to support the hypothesis of a direct role of transglutaminase activity in the pathogenesis of the polyglutamine diseases, cystamine is also found to act in the HD-transgenic mice by mechanisms other than the inhibition of TGs, such as the inhibition of caspases [80] , suggesting that this compound can have an additive effect in the therapy of HD. Currently, cysteamine is already in phase I studies in humans with HD [81] , but several side effects, such as nausea, motor impairment and dosing schedule have been reported as reasons for non-adherence during phase II studies in human patients affected by cystinosis [82,83] . Another critical problem in the use of TG inhibitors in treating neurological diseases relates to the fact that, as previously reported, the human brain contains at least four TGs, including TG1, 2, 3 [22] and TG6 [84] , and a strong non-selective inhibitor of TGs might also inhibit plasma Factor XIIIa, causing a bleeding disorder.…”