Orphan Technologies to develop CU treatment for life-threatening metabolic disorder

The University of Colorado has signed exclusive, worldwide licensing and collaboration agreements with rare-disease research-and-development firm Orphan Technologies Ltd. to develop an enzyme replacement therapy for Cystathionine Beta-Synthase (CBS) -deficient homocystinuria, a rare, inherited metabolic disease that is often fatal at a young age. The collaboration was initiated in 2010 and includes sponsored-research funding by OT to continue development of the treatment approach pioneered by Jan P. Kraus, a professor of pediatrics at the CU School of Medicine. Orphan Technologies plans to begin first-in-human trials in 2014.

CBS-deficient homocystinuria is a rare genetic disorder caused by low levels of active CBS enzyme. Individuals with this disease are unable to fully metabolize the amino acid methionine, which is found in nearly all foods. That leads to the accumulation of toxic levels of related metabolites (molecules that are the product of metabolism), and deficits in others.

Patients with homocystinuria suffer major multi-systemic disorder, including mental retardation, dislocation of the lens of the eye (leading to blindness if not treated), seizures, osteoporosis and stroke. Taken together, these lead to a significantly shorter life expectancy; almost one fourth of untreated patients die before the age of 30.

About 40 percent of patients with homocystinuria benefit from vitamin B6 supplementation. But for the rest, treatment is limited to a methionine-restricted (low protein) diet and supplementation with cystine, folate, and betaine (Cystadane) which partially restore metabolic balance; however, these treatment approaches do not repair the broken methionine metabolic cycle and don’t resolve all metabolic abnormalities, so patients still suffer from severe, life-threating symptoms.

Professor Kraus has devised an enzyme replacement therapy to correct the underlying cause of the disease. This approach has the potential to restore the normal metabolism of methionine, which could avoid the accumulation of toxic levels of metabolites, prevent the appearance or worsening of symptoms, normalize life expectancy, and eliminate the need for diet restrictions.

“Today the therapy for homocystinuria concentrates on lowering the concentration of a single metabolite, homocysteine, while metabolites further downstream are unaffected by the available treatment,” said Professor Kraus. “However, these downstream metabolites may be of considerable clinical significance, and our approach has the potential to restore all the affected metabolites to their normal level, and as such reduce or prevent symptoms and enable a return to a normal diet.”

CBS-deficient homocystinuria impacts at least 1 in 300,000 people worldwide (though prevalence may be higher due to under-diagnosis). It is designated by the U.S. Office of Rare Diseases Research (part of the National Institutes of Health) as a rare disease. Because of the smaller market, drugs to treat these ‘orphan diseases’ are eligible for special financial and clinical trial incentives (including fast-tracked FDA approval) and extended exclusivity periods in the U.S, Europe and other countries.

"We are excited to partner with CU and Professor Jan Kraus, a pioneer in the field of homocystinuria, in order to advance the development of a potential therapy for this tragic disease," said Josef Rosenberg, Director of Orphan Technologies. "Our collaboration is intended to accelerate the translation of fundamental advances in enzyme biochemistry at CU into the introduction of a new clinical therapy. Our alliance with CU constitutes another important step towards the reinforcement of Orphan's presence in the field of rare diseases worldwide."

David Poticha, a senior licensing manager at CU’s technology transfer office, said, “We are encouraged by the preclinical data for this technology and believe that it could bring hope for a patient population desperately in need of clinical alternatives. We are very pleased to be working with Orphan to develop this technology for those patients.”