Substrate reduction therapy in lysosomal storage diseases: a clarification

Dear Sir

We read with interest 'From the Analyst's Couch: lysosomal storage diseases market' by Yaron Werber¹.

We disagree with the interpretation of the published studies about Zavesca (now approved worldwide for mild to moderate type 1 Gaucher disease, in patients unwilling or unable to take enzyme-replacement therapy).

• Zavesca is not “toxic” as stated (which implies it is a poison). Like all prescription drugs, it has side effects, but this is not preventing its use. Several patients have been on the drug for six years now with no serious adverse effects and are clinically improved.

• Efficacy has been reported in a peer-reviewed Lancet article². The drug was comparable to enzyme-replacement therapy if patients with the same severity of symptoms were compared³; “modest clinical benefit”, as reported by Werber¹, is therefore misleading.

• The Genzyme P4 compound is indeed more potent than Zavesca in tissue-culture studies. However, this has the potential to inhibit the pathway too efficiently, and reversibility on withdrawal of the drug is very slow. Partial inhibition of the glycosphingolipid biosynthetic pathway is the aim, not its complete inhibition/ablation. The therapeutic index of the P4 analogues is not superior to Zavesca, and a comparison of published in vitro data reveals that Zavesca has a fivefold greater therapeutic index⁴.

There are no data in the public domain on the P4 compound's effects in Tay–Sachs and Sandhoff disease (nor indeed on whether this compound crosses the blood–brain barrier) and so any reference to the potential use of this compound for treating the neuropathic disorders is impossible to assess. This is in contrast to the expanding off-label use of Zavesca for these disorders, which is based upon proven efficacy of this drug in multiple animal models (Tay–Sachs, Sandhoff and Niemann–Pick disease type C1) with CNS involvement^5,6,7.

Yours sincerely,