CAMBRIDGE, Mass., May 30 /PRNewswire/ -- Genzyme General (Nasdaq: GENZ - news) today reported research and pre-clinical data demonstrating the potency and specificity of its lead small-molecule substrate inhibition compound, Genz- 78132 (D-threo-et-P4), compared with first-generation compounds under investigation elsewhere. The data were presented at the 2nd International Conference on Prospects in the Treatment of Rare Diseases, held in Trieste, Italy, by Seng H. Cheng, Ph.D., Genzyme's vice president for genetic diseases science.
Genzyme is developing Genz-78132 for its potential to treat a number of lysosomal storage diseases, including Gaucher disease and Fabry disease, which each are caused by a deficiency of a specific enzyme responsible for the breakdown of glycolipids in cells. Glyoclipids that are normally broken down into smaller building blocks instead accumulate inside cells, disrupting their function and leading to a range of devastating and potentially fatal symptoms. Genz-78132 is designed to address this underlying cellular disorder by inhibiting the synthesis of glycolipids.
Two classes of small molecules have been studied for their ability to inhibit glucosylceramide synthase, a key enzyme in the glycosphingolipid synthesis pathway: ceramide-based analogs, including Genz-78132, and sugar- based analogs belonging to the deoxynojirimycin (DNJ) family. In a series of pre-clinical studies, Genzyme researchers evaluated the specificity, potency, and toxicity of Genz-78132 in comparison with three sugar analogs: N-butyl- deoxynojirimycin (NB-DNJ); N-butyl-deoxygalactonojirimycin (NB-DGJ); and N-(5- adamantane-1-yl-methoxypentyl)-DNJ (AMP-DNJ).
Genz-78132 was found to be 100 to 5,000 times more potent in vitro for substrate inhibition than the sugar analogs, as measured by inhibition of the expression of cell surface ganglioside GM1, an indicator of glycosphingolipid synthesis. This far greater potency is important as it may allow the administration of smaller quantities of a drug to achieve the desired therapeutic effect, while minimizing the potential for toxic side effects.
Genz-78132 was at least 20 times more potent in vivo than AMP-DNJ, the most potent sugar analog, at inhibiting the re-accumulation of the substrate globotriaosylceramide (GL-3) in liver tissues in a Fabry mouse model following a single infusion of alpha-galactosidase. The Fabry mouse is a well-recognized disease model for the study of lysosomal storage disorders. In the same model, no difference in the inhibition of the re-accumulation of GL-3 was observed in mice that received NB-DNJ administered at a 100-fold greater dose than Genz-78132 and control mice.
Specificity differences toward glycolipid enzymes in vitro were also identified. While Genz-78132 is designed to inhibit the action of glucosylceramide synthase exclusively, the sugar analogs are far less specific, acting on many additional enzymes. Compared with the sugar analogs, Genz-78132 was shown to be highly specific for inhibition of glucosylceramide synthase. It was the only compound studied that did not inhibit the activity of the enzymes glucocerebrosidase or alpha-galactosidase A, enzymes that are affected in Gaucher and Fabry disease respectively. Genzyme believes that the high specificity of Genz-78132 will likely result in the absence of the associated adverse side effects that have been observed in the non-specific sugar analogs.
Genz-78132 was well tolerated at the doses studied in both in vitro and in vivo experiments. Cell viability in vitro was maintained at 100 percent at high doses, suggesting an acceptable toxicity profile. With the sugar analogs in vitro cell death was observed at much lower doses, suggesting a more narrow therapeutic window.
In Genzyme's pre-clinical studies, the potency and efficacy of oral delivery of Genz-78132 was confirmed, as measured by a significant decrease of glucosylceramide levels in the liver, kidneys, and spleen of normal mice after three days of treatment.
``These studies form the core of our comprehensive pre-clinical plan to evaluate the toxicity and potency profile of this compound before the initiation of human clinical trials,'' said Dr. Cheng. ``We are committed to exploring a range of potential therapies, including substrate inhibition compounds, in our ongoing search for next-generation treatments for patients with lysosomal storage disorders. The data we reported highlight why we believe that Genz-78132 is the best candidate with which to evaluate a substrate inhibition approach to treating these diseases. In pre-clinical studies, the compound has a substantially greater therapeutic index than the first-generation sugar analogs, which have shown limited efficacy and significant toxicity.''
Genzyme General has a comprehensive program to develop and market therapies for lysosomal storage disorders utilizing a wide range of technologies and therapeutic approaches to treating this family of genetic diseases. Genzyme's lead product in this area is Cerezyme® (imiglucerase for injection) enzyme replacement therapy for Type 1 Gaucher disease, which has had a profound effect in restoring the health of over 3000 patients worldwide.
``The standard established by Cerezyme is a high hurdle to overcome,'' said Dr. Cheng. ``However, these results are consistent with our goal to bring to Gaucher patients a more convenient therapy without sacrificing the safety and efficacy currently available with Cerezyme. Although these data are promising, it remains to be determined what role, if any, substrate inhibition agents may play in improving the treatment of lysosomal storage disorders.''
In its search for next-generation products for lysosomal storage disorders such as Gaucher disease, Genzyme has been actively researching small-molecule drug treatments -- which are orally available, increasing patient convenience. Small-molecule drugs also have the potential to address the central nervous system effects of lysosomal storage disorders because they may be capable of crossing the blood-brain barrier, which protein therapies cannot do. Genzyme has its own internal small-molecule drug discovery program, and also continually evaluates compounds under development elsewhere for potential licensing opportunities. Genz-78132 is one of a class of compounds licensed by Genzyme that were developed by James Shayman, M.D., and Norman Radin, Ph.D., of the University of Michigan. AMP-DNJ is a compound developed by Hans Aerts, Ph.D., of the Amsterdam Medical Center. Genzyme has ongoing active research collaborations with Dr. Shayman and Dr. Aerts... |
