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On April 30, 2013, Raptor Pharmaceuticals' (NASDAQ:RPTP) cysteamine bitartrate delayed release (RP103, Procysbi™) will be up for approval for the treatment of nephropathic cystinosis. RP103 is a reformulation of cysteamine bitartrate (Cystagon®) which allows dosing every 12 hours as opposed to every six hours with Cystagon. Why is this change in regimen important?

Cystinosis: disease background and treatment

Nephropathic cystinosis is an inherited (autosomal recessive) lysosomal storage disorder caused by defective transport of the amino acid cystine out of lysosomes. The stored cystine is poorly soluble and crystallizes within the lysosomes of many cell types, leading to widespread tissue and organ damage. In North America, the incidence of infantile nephropathic cystinosis is 1 case per 100,000-200,000 live births; an estimated 400 individuals in the United States have cystinosis. Approximately 15 new cases of cystinosis are diagnosed each year in the United States.

In the past, the treatment of cystinosis was limited to treating metabolic acidosis and, often, replacing electrolytes lost in the urine; later during the course of the disease, chronic kidney disease was treated. Today, the wide availability of an effective drug, cysteamine, and kidney replacement therapy with transplantation has dramatically improved the outlook for patients and altered management strategies.

Cysteamine bitartrate (Cystagon) was approved by the FDA in August 1994; the sole distributor of this drug in the United States is CVS Procare. It is used as a cystine-depleting agent in cystinosis. Cysteamine and its prodrug analog, phosphocysteamine, are very beneficial to patients with cystinosis, especially when started early in life. Diagnosis of cystinosis as early as possible is important because efficacy of cysteamine or phosphocysteamine treatment clearly relates to age at which the drugs are started.

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 non-adherence. RP103 is an enteric coated microbead formulation of cysteamine bitartrate, being developed to deliver cysteamine in a twice daily formulation.

RP103 clinical development

A Phase III 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 non-inferior to Cystagon for maintenance of white blood cell [WBC] cystine at levels associated with optimal outcomes in the disease. A schematic of the clinical trial is presented here:


(Click to enlarge)

Forty-three patients were randomized. In the per protocol population (n=38), the mean peak value of white blood cell cystine level was 0.62±0.05 nmol 1/2 cystine/mg protein after 12 hours under RP103 and 0.54±0.05 nmol 1/2 cystine/mg protein after 6 hours under Cystagon, a difference of 0.08±0.04 nmol 1/2 cystine/mg protein (95.8% confidence interval, 0-0.16). It is encouraging to note that in the intent to treat population the trend is toward an improvement in WBC cystine levels (0.70 vs. 0.97). Per protocol patients had to have a stable dose of Cystagon sufficient to maintain their white blood cell cystine level at ≤ 1.0 nmol/half-cystine/mg protein and some patients had difficulty achieving good control on Cystagon.

What are the known weaknesses of the Phase III? The trial was not blinded, which can be a source of bias, and was of short duration for a lifelong therapy. Also, there were three-fold more gastrointestinal [GI] side effects in the RP103 arm compared with Cystagon. These side effects were poorly characterized in the publication.

Some of these concerns were addressed in the follow-on (extension) study. It is encouraging that 40/41 patients opted to participate in this study. This study lasted up to 20 months and showed that optimal WBC cystine levels could be achieved using twice daily RP103, with preservation of renal function. From the study onset to the study end, patients demonstrated significant improvement in quality of life, and in particular in social performance. Most patients (31/40) were able to not use antacids for the duration of the study, perhaps offering some reassurance on the frequency of GI side effects noted in the Phase 3.

Why RP103 is likely to be approved

From the Phase III data, the pharmacology of RP103 supports twice daily dosing and RP103 appears to be as effective as Cystagon for the maintenance of WBC cystine levels. The follow-on study confirms the efficacy of RP103 and offers some reassurance on safety. On this basis it is likely that RP103 will be approved, though a delay related to manufacturing [CMC] is always possible with a new formulation.

Source: Procysbi (Raptor Pharmaceuticals): A Long Acting Cysteine For The Treatment Of Cystinosis