Raptor Pharmaceutical Corp. has signed 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 II b clinical trial, to evaluate the safety and potential efficacy of RP104, Raptor's proprietary delayed-release tablet formulation of cysteamine bitartrate, as a potential treatment of non-alcoholic steatohepatitis (NASH), an advanced form of non-alcoholic fatty liver disease (NAFLD), in children. The clinical trial is expected to begin in the first calendar quarter of 2012 with NIDDK and Raptor sharing the costs to conduct the clinical trial.

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 paediatric participants at ten US centres in the NIDDK-sponsored NASH Clinical Research Network (NASH CRN). Enrolled participants will range in age from 8 to17 years and have biopsy-confirmed moderate to severe NAFLD. The primary objective of this randomized, multi-centre, 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.

“NAFLD now affects millions of children in the United States,” said Jeffrey Schwimmer, MD, the director of the Fatty Liver Clinic at Rady Children's Hospital San Diego and the Principal Investigator for the NASH CRN Paediatric Clinical Centre at the University of California, San Diego (UC, San Diego). “In the absence of an effective therapy, we are increasingly seeing adolescents with advanced liver disease. Therefore we are excited about the opportunity to evaluate RP104 as a potential treatment for paediatric NAFLD in the NASH Clinical Research Network.”

Raptor estimates the total cost of the CyNCh trial to be in the range of $14-$16 million. Under the CRADA agreement, Raptor will fund a total of $6 million of the cost of the trial, in addition to providing clinical trial materials and drug manufacturing/quality support estimated at approximately $1 million. The remainder of the funding will come from NIDDK. Raptor holds worldwide, exclusive licenses from UC San Diego to patents relating to use of cysteamine in NAFLD and NASH. Under this CRADA collaboration, Raptor will retain exclusive development and commercial rights to the clinical data resulting from the CyNCh trial.

“This agreement is an important step in advancing our RP104 programme for NASH. In addition to the substantial funding, this collaboration enables us to work with an already established network of many of the leading NASH clinics in the US,” said Ted Daley, president of Raptor. “We believe that this will enable Raptor to commence and complete the phase II b clinical trial far sooner than if we were to conduct the clinical trial entirely on our own. We are excited to work with NIDDK and these top investigators to advance our programme.”

This planned CyNCh trial follows positive results of an open-label phase II a clinical trial which was conducted under a collaboration agreement between Raptor and UC San Diego at UC San Diego's General Clinical Research Centre. The phase II a clinical trial involved children with biopsy-confirmed diagnosis of moderate to severe NAFLD and baseline ALT and AST measurements at least twice that of normal levels. These patients received a prototype formulation of RP104 twice daily for six months, followed by a six-month post-treatment monitoring period. All patients showed marked decline in ALT and AST levels during the treatment period with 7 of 11 patients achieving a greater than 50 percent reduction and 6 of 11 patients with reductions to within normal range. The reductions in ALT and AST were largely sustained during the 6 month post-treatment phase. Other important liver function markers showed positive trends with cytokeratin levels decreasing by an average of 45 percent and adiponectin increasing by 35 percent during the treatment period.

Under its licenses with UC San Diego, Raptor is developing proprietary formulations of delayed-release (DR) cysteamine bitartrate for a number of therapeutic indications, including RP103 (DR cysteamine bitartrate microbeads in capsules) for the potential treatment of nephropathic cystinosis and Huntington's Disease, and RP104 for NASH. Cysteamine is a precursor of the potent liver anti-oxidant glutathione (GSH) and increasing GSH has the potential to reverse NASH-related liver damage. GSH itself does not enter easily into cells, even when given in large amounts. However, GSH 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.

NASH is a more aggressive form of NAFLD that affects 2 to 5 per cent of Americans. It occurs in patients who drink little or no alcohol, and is the most common cause of chronic liver disease in North America. Although most patients are asymptomatic and feel healthy in early phases of the disease, NASH causes decreased liver function and can lead to cirrhosis, liver failure and end-stage liver disease.