RP104 (DR Cysteamine) for Non-alcoholic Steatohepatitis (NASH)

Non-alcoholic Steatohepatitis (NASH) is a progressive liver disease, with a 25% incidence in obese patients. Approximately 2%-5% of the U.S. population is afflicted with this disease, which can cause cirrhosis, liver failure and end-stage liver disease (NDDIC 2008, Hashimoto 2011, Targher 2010).

The incidence of NASH is increasing in the U.S. adolescent population (Te Sligte 2004, Papandreou 2007, Strauss 2000).

Currently there are no treatment options for NASH. The disease is managed with lifestyle changes such as diet, exercise and weight reduction.

Cysteamine is a precursor of the potent liver anti-oxidant glutathione (GSH) and increasing GSH has the potential to reverse NASH-related liver damage. Glutathione itself does not enter easily into cells, even when given in large amounts. However, glutathione precursors, such as cysteamine, enter into cells and have been shown to be effective in the treatment of certain conditions by preventing significant GSH depletion (Te Sligte 2004). Raptor is therefore investigating the use of RP103/RP104 for the potential treatment of NASH.

Development Status for RP103/RP104 for NASH

Phase 2b Clinical Trial

Raptor has executed a cooperative research and development agreement (CRADA) with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH) to conduct a Phase 2b clinical trial of RP103 in pediatric patients with NASH. Although RP103 is being used for the Phase 2b clinical trial, Raptor continues formulation studies of RP104, a delayed-release tablet form of RP103, for future NASH studies. The clinical trial is expected to begin in the second calendar quarter of 2012. The Cysteamine Bitartrate Delayed-Release for the Treatment of Non-alcoholic Fatty Liver Disease in Children (CyNCh) trial is expected to enroll a total of 160 pediatric participants at ten U.S. centers in the NIDDK-sponsored NASH Clinical Research Network (NASH CRN). Enrolled participants will range in age from 8 to 17 years and have biopsy-confirmed moderate to severe NAFLD. The primary objective of this randomized, multicenter, double-blind, placebo-controlled clinical trial is to evaluate whether 52 weeks of treatment with RP104 in children reverses damage caused by NASH as measured by changes in NAFLD Activity Score (NAS), a histological rating scale of disease activity. Secondary endpoints will include blood markers for liver health including alanine transaminase (ALT) and aspartate transaminase (AST), as well as safety and tolerability.

Phase 2a Clinical Trial

Raptor’s Phase 2a clinical trial of delayed-release cysteamine bitartrate (a prototype of Raptor’s RP103) showed a marked decline in alanine aminotransferase (ALT) levels during the treatment period with 7 of 11 juvenile patients achieving a greater than 50% reduction and 6 of 11 reduced to within normal range.

Aspartate aminotransferase (AST) levels were improved with patients averaging 41% reduction by the end of the treatment phase. The reduction in liver enzymes was largely sustained during the 6 month post-treatment monitoring phase. Other important liver function markers showed positive trends. Levels of cytokeratin 18, a potential marker of disease activity in Non-alcoholic Fatty Liver Disease, decreased by an average of 45%. Adiponectin levels increased by an average of 35% during the treatment period. Reduced adiponectin levels are thought to be a marker of the pathogenesis and progression of NASH.

The trial results are consistent with ALT and AST reductions seen in patients that achieve a 10% weight loss. Body Mass Index did not change significantly during both the treatment and post-treatment phases in Raptor's Phase 2a study.

Delayed-release cysteamine bitartrate demonstrated a strong, favorable safety profile, with mean gastrointestinal symptom scores of 1.1 at baseline and 0.7 after 6 months of treatment using a rating system in which the maximum score of 14 indicates most severe gastrointestinal symptoms.

Learn more about Raptor’s other clinical programs:

• RP103 for Nephropathic Cystinosis
• RP103 for Huntington's Disease
• Convivia™ for ALDH2 Deficiency
• Tezampanel for Thrombotic Disorder

Phase 2b Clinical Trial Collaboration

In collaboration with the NIH, Raptor is conducting a Phase 2b clinical trial of RP103 for the potential treatment of NASH, anticipated to start in the second calendar quarter of 2012.

Phase 2a Clinical Trial Completed

Results presented at the Digestive Disease Week 2010 Conference. Primary endpoints met.