Gaucher's disease is a genetic disorder in which individuals fail to produce the enzyme glucocerebrosidase (GCase) that breaks down the glycolipid glucocerebroside within lysosomes. In the enzyme's absence, lipids build up in the bone marrow, lungs, spleen, liver and the brain. Standard care for Gaucher's type I consists of replacing the missing enzyme with a recombinant human version. New York-based Pfizer's Elelyso (taliglucerase alfa) (Nat. Biotechnol. 30, 472, 2012), Dublin-based Shire's Vpriv (velaglucerase alpha) and Genzyme's own Cerezyme (imiglucerase) replace glucocerebrosidase. The three enzyme replacement therapies on the market “all work through the same mechanism,” says Seng Cheng, head of R&D for rare diseases at Genzyme: they replenish cells with recombinant enzyme to clear the glucosylceramide build up in lysosomes. “Cerdelga is different,” he says.
Cerdelga is a ceramide analog that works by blocking the enzyme β-glucosylceramide synthase, slowing production of glucocerebroside, the substance that builds up in patients' lysosomes. Patients with Gaucher's disease type I disease retain residual GCase enzyme activity. This is why “Cerdelga aims to slow down formation of the lipid to help rebalance cells' ability to clear it,” says Cheng. Cerdelga's mechanism is similar to Allschwil, Switzerland–based Actelion's oral Zavesca (miglustat). But because of its side effects, which include nerve and gastrointestinal damage, and inferior efficacy, Zavesca is limited to adult patients for whom enzyme replacement therapy is not an option.
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