RP103 (DR Cysteamine) for Nephropathic Cystinosis

Nephropathic cystinosis is a rare lysosomal storage disease that may affect as many as 2,000 people worldwide. The disease is usually diagnosed in early childhood.

Cysteamine therapy may be effective at preventing or delaying kidney transplants in nephropathic cystinosis patients (Gahl 2007, Levtchenko 2006, Markello 1993, Kleta, Bernadini 2004). However, patient adherence is challenging due to frequent dosing and gastrointestinal side effects (Levtchenko 2006, Kleta, Bernardini 2004, Kleta, Gahl 2004, Cystagon Package Insert).

RP103 is an enteric coated microbead formulation of cysteamine bitartrate, being developed to efficiently deliver cysteamine in a well tolerated twice daily formulation. (Dohil 2006).

Current Status

In March 2012, Raptor applied for marketing approval in the U.S. and E.U. of RP103 for the potential treatment of nephropathic cystinosis. Based on standard regulatory review timelines, Raptor anticipates decisions from EMA and FDA in the first calendar quarter of 2013.

Clinical Trial Summary

Overview

In July 2011, Raptor announced that its Phase 3 clinical trial of RP103 for the treatment of nephropathic cystinosis met its primary endpoint of non-inferiority compared to Cystagon®, the currently marketed immediate-release cysteamine bitartrate. Additionally, RP103 achieved the endpoint at a lower average dose and a lower dosing frequency (q12h) than Cystagon® (q6h). The pivotal Phase 3 clinical trial was an outpatient study designed to compare the pharmacodynamics, pharmacokinetics, safety, and tolerability of RP103 versus Cystagon® in cystinosis patients. The study was conducted at eight clinical research centers in the US and Europe.

Study Participants

Of 41 patients who completed the Phase 3 protocol, 38 were included in the evaluable data set; three were not fully compliant with the protocol. The age range of participants was 6-26 years, with 87% of patients below 16 years of age.

Summary of Results

On average, the peak white blood cell (WBC) cystine level measured in patients treated with Cystagon® was 0.54 ± 0.05 nmol of half cystine/mg protein. By comparison, the average peak WBC cystine level measured in patients treated with RP103 was 0.62 ± 0.05 nmol of half cystine/mg protein. The mean difference was 0.08 nmol of half cystine/mg protein, with a 95.8% confidence interval of 0.00-0.16 (one sided p=0.021).

Achieving Clinical Trial Endpoint

As stipulated in the Statistical Analysis Plan with the FDA, meeting the non-inferiority endpoint of the clinical trial required that the upper end of the confidence interval around the mean difference of WBC cystine levels did not exceed an absolute value of 0.3. In this study, the upper end of the confidence interval was 0.16, thus the clinical trial met the primary non-inferiority clinical trial endpoint.

Average daily dose and dosing frequency

RP103 achieved the endpoint at a lower average daily dose compared to Cystagon® and at a lower dosing frequency (q12h vs. q6h). Patients enrolled in the study were required to be “well controlled” under the existing Cystagon® therapy. The starting dose of RP103 for patients in the Phase 3 clinical trial was initially set at 70% of their established dose of Cystagon®. The protocol allowed for a single RP103 dose increase of 25%, based on intermediate WBC cystine results to reflect the current standard of care in establishing appropriate dosing of Cystagon® in cystinosis patients. Approximately one-third of patients remained at 70% of their starting Cystagon® dose throughout the clinical trial. The remaining two-thirds of the patients had their RP103 dose increased. On average, the total daily steady-state dose of RP103 in patients in the Phase 3 clinical trial was 82% of their established starting dose of Cystagon®.

Ongoing Extension Study

Raptor is conducting an ongoing safety extension study in which patients who completed the Phase 3 clinical trial may elect to continue on RP103 treatment and be monitored for WBC cystine levels and safety parameters. Upon completion of the Phase 3 clinical trial, 38 out of the 41 patients elected to continue into the extension study.

Raptor has expanded its extension study to include patients ineligible to participate in the Phase 3 clinical trial, specifically, patients under six years old and patients who have undergone kidney transplants. Raptor currently has 13 patients under six years old and 5 patients with kidney transplants enrolled in the extension study.

Related Clinical Trial

In a related clinical trial, Raptor demonstrated bioequivalence between RP103 administered as either whole capsules or as capsule contents sprinkled onto applesauce. As a significant number of cystinosis patients are too young to take whole capsules, the results of this clinical trial have enabled Raptor to expand enrollment in the extension study to include patients who are too young to swallow whole capsules and were ineligible for the pivotal Phase 3 clinical trial protocol.

Learn more about Raptor's other clinical programs:

• RP103 for Huntington's Disease
• RP104 for Non-alcoholic Steatohepatitis (NASH)
• Convivia™ for ALDH2 Deficiency
• Tezampanel for Thrombotic Disorder

Raptor Applies for Marketing Approval of RP103 for the Potential Treatment of Nephropathic Cystinosis in the U.S. and E.U.

In March 2012, Raptor received validation of its Marketing Authorization Application from the European Medicines Agency for RP103 cysteamine bitartrate delayed-release capsules (DR Cysteamine) for the potential treatment of nephropathic cystinosis. Raptor also submitted its New Drug Application with the U.S. Food and Drug Administration.

Raptor’s Phase 3 Clinical Trial Meets Primary Endpoint

Raptor’s Phase 3 clinical trial of RP103 (Delayed-Release or DR Cysteamine) for the treatment of nephropathic cystinosis met the primary endpoint of non-inferiority compared to the currently marketed immediate-release cysteamine bitartrate – at lower average daily dose and lower dosing frequency.

Raptor intends to file for marketing approval of RP103 in the U.S. and E.U. in 2012.

RP103 Receives EMA Orphan Medicinal Product Designation

The European Medicines Agency granted Orphan Medicinal Product Designation for RP103 for the potential treatment of nephropathic cystinosis, giving Raptor 10 years of market exclusivity in the E.U. once the drug is approved.