Lysosomal storage diseases market.

Dear Sir

Yaron Werber¹ presented an interesting overview of the market of drugs to treat lysosomal storage diseases (LSDs). However, we would like to correct the misrepresentation of the drug Zavesca as provided by the author. Zavesca is the first oral drug for the treatment of type 1 Gaucher disease with a new mechanism of action known as substrate-reduction therapy (SRT). In this respect, Table 1 of Werber's article is misleading, as Zavesca should not be listed as enzyme-replacement therapy (ERT).

The goal of SRT is to restore the balance between production and degradation of glucosylceramide. Glucosylceramide is the substrate of glucocerebrosidase, an enzyme that is partially deficient in Gaucher disease, leading to the toxic accumulation of glucosylceramide in tissues. Restoring balance is achieved with Zavesca by reducing the rate of glucosylceramide biosynthesis, such that glucosylceramide levels are lowered, allowing its further degradation by the residual glucocerebrosidase activity².

Importantly, Zavesca is the only SRT that has been studied in patients with LSDs, in particular Gaucher patients. Three registration studies, in a total of 80 patients with type 1 Gaucher disease, have been conducted with Zavesca (US Package Insert 31 July 2003). The benefit/risk ratio of Zavesca treatment has been carefully evaluated by the EMEA and the US FDA, leading to its approval in the Europe Union and in the United States, for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom ERT is not a therapeutic option. Zavesca is also approved in Israel. It is therefore inappropriate to quote the drug as “toxic”¹.

Further, Werber stated that Cerezyme will continue be to the “mainstay” in Gaucher disease. Although this might be true for type 1 Gaucher disease, the utility of the enzyme in the type 2 and type 3 neuronopathic forms of this disease remains unproven, because of its inability to effectively cross the blood-brain barrier, and hence to achieve therapeutic levels in the central nervous system (CNS). Conversely, the small molecule Zavesca is likely to achieve therapeutic concentrations in the CNS and, importantly, its mode of action would give the drug potential utility in several other LSDs, unlike ERT, for which one unique enzyme has to be developed for each specific disease.

Werber's article suggests that a small molecule P4 analogue has shown preclinical activity in animal models of Tay-Sachs and Sandhoff diseases. To our knowledge there is no publication currently available on this compound in such preclinical studies, not to mention studies in patients, and it is therefore difficult to justify that “GENZ-112638 is many times more potent than Zavesca and displays a more attractive therapeutic index”¹. The only SRT molecules reported so far in animal models of LSDs are miglustat (the active ingredient of Zavesca) and its epimer NB-DGJ³. Using these two compounds, Platt et al.³ and Zervas et al.⁴ have demonstrated that inhibition of glucosylceramide synthase was also effective in correcting the pathophysiology in mouse models of Tay–Sachs, Sandhoff and Niemann–Pick C disease. More specifically, these compounds were able to reduce the accumulation of GSLs in the CNS and visceral tissues; delay the onset of the inflammatory process and disease pathogenesis; delay the onset of neuromotor symptoms; and increase life expectancy. These data imply that the drug achieved therapeutic levels in the CNS. On this basis, three new Zavesca clinical trials have been initiated in type 3 Gaucher disease, late-onset Tay–Sachs and Niemann–Pick type C. These Phase II–III studies should have been included in Table 2 of Werber's article.

In conclusion, Zavesca is now available in the European Union, the United States and Israel. Although ERT is a safe and effective treatment, an oral small SRT molecule such as Zavesca does provide a new treatment option to patients afflicted with type 1 Gaucher disease. Ongoing studies will determine the efficacy and tolerability of SRT in the treatment of other rare LSDs with high unmet medical needs, including those with neurological alterations.