Clinical trial of enzyme replacement therapy for the treatment of Gaucher disease

Transkaryotic Therapies, Inc. today announced that it has initiated a clinical trial to evaluate the safety and clinical activity of GA-GCB, its enzyme replacement therapy for the treatment of Gaucher disease.

The clinical trial will involve twelve patients with Type I Gaucher disease, who will receive treatment for nine months. TKT expects the trial will be completed in 2005. "This trial was designed to replicate key results of the study the FDA and other regulatory agencies relied upon in approving the first enzyme replacement therapy for Gaucher disease," said Paul M. Martha, M.D., Vice President, Clinical Affairs at TKT. "We are pleased to take this step toward offering patients with Gaucher disease an alternative enzyme replacement therapy product." GA-GCB is a human glucocerebrosidase product developed using TKT's proprietary gene activation technology and is the first potential competing enzyme replacement therapy for Gaucher disease to be tested in patients.

TKT intends to seek a partner for its GA-GCB product. Gaucher disease is caused by deficiency of the enzyme glucocerebrosidase, resulting in accumulation of a toxic substrate, specifically the glycolipid glucocerebroside.

Gaucher's disease also known as Gaucher disease is an inherited metabolic disorder in which harmful quantities of a fatty substance called glucocerebroside accumulate in the spleen, liver, lungs, bone marrow, and, in rare cases, the brain. It is the most common lysosomal storage disease. Gaucher's disease results from a deficiency of acid â-glucosidase, a lysosomal hydrolase, which is encoded on chromosome 1. The lack of this enzyme causes the progressive accumulation of undegraded glycolipid substrates, particularly glucosylceramide, in reticuloendothelial cells, and results in infiltration of the bone marrow, spleen, and liver.

Three clinical forms (phenotypes) of Gaucher's disease are recognized.

• Type 1, the adult, non-neuronopathic type, is by far the most common. Patients in this group usually bruise easily and experience fatigue due to anemia, low blood platelets, enlargement of the liver and spleen, weakening of the skeleton, and in some instances, lung and kidney impairment. There are no signs of brain involvement. The onset of clinical manifestations may be early in life, or delayed until adulthood.

• Type 2 is the infantile or acute neuronopathic type. In this form, liver and spleen enlargement are apparent by 3 months of age. In addition, there is extensive and progressive brain damage. These patients usually die by 2 years of age.

• Type 3 is the juvenile or Norrbotten form, in which liver and spleen enlargement is variable, and signs of brain involvement such as seizures gradually become apparent. All of these patients exhibit a deficiency of an enzyme called glucocerebrosidase that catalyzes the first step in the biodegradation of glucocerebroside. Except for the brain, glucocerebroside arises mainly from the biodegradation of old red and white blood cells. In the brain, glucocerebroside arises from the turnover of complex lipids during brain development and the formation of the myelin sheath of nerves.