First to market with an all-oral first-line therapy for adults with Gaucher disease type 1, the most common form, is the Genzyme unit of Paris-based Sanofi SA, which gained FDA marketing clearance for Cerdelga (eliglustat), giving patients an option to the infused enzyme replacement therapy (ERT) Cerezyme (imiglucerase), also developed by Genzyme.

"We invested more than 20 years in Cerezyme, and we have a phenomenal drug," said Simone Azevedo, vice president of the Gaucher portfolio for Genzyme, adding that 15 years went into Cerdelga. The FDA cleared Cerezyme in 1994. "Although [Cerdelga] is not a biologic, it still requires a lot of time and the same sort of approach that a biologic would require," especially given the rarity of the disease, which means longer enrollment periods. (See BioWorld Today, May 25, 1994.)

"Either [Cerdelga or Cerezyme] should work pretty well," though some patients will not be eligible for switching and the decision should be made after talking with doctors. Cerdelga is approved only for adults. There are childhood versions of type 1 as well as type 2 (the most severe form of Gaucher, with a very short life span), and type 3 (which brings neurological problems for the patients).

Genzyme expects to make Cerdelga available to patients within a month, providing a twice-daily treatment for Gaucher. The compound is likely to be priced in the same ballpark as Cerezyme, which goes for about $300,000 per year. Cerezyme is given every two weeks, and holds 70 percent of the worldwide market.

"We want to be as close [in price] as possible to Cerezyme," Azevedo told BioWorld Today, adding that giving patients the choice is "more important than driving the decision based on the cost of treatment."

Cerdelga blocks the buildup of fatty deposits that lead to Gaucher symptoms, rather than filling the enzyme shortfall, as Cerezyme does. Specifically, the glucosylceramide analogue partially inhibits the glucosylceramide synthase, and that causes the body to make less glucosylceramide, which is the substance that accumulates in Gaucher patients' cells and tissues.

Gaucher strikes fewer than 10,000 people around the world, and is less rare in Ashkenazi Jews. Although it typically does not affect the brain, type 1 leads to spleen and liver enlargement, anemia, excessive bleeding and bruising, bone disease and other problems.

Two phase III studies formed the basis for Cerdelga's approval by the FDA under priority review, along with four years of efficacy data from phase II experiments. The phase III trials enrolled patients new to therapy and those who switched from an approved replacement therapy. Subjects in both arms turned up improvements and are still on the extension parts of their studies.

Assimilating Cerdelga is mainly catalyzed by cytochrome P450 CYP2D6, so the drug is indicated for extensive, intermediate or poor metabolizers of CYP2D6, as determined by a lab test. Adults who metabolize quickly or at an undetermined rate are not eligible for the oral therapy, but they are considered a small number.

Protalix Biotherapeutics Inc., of Carmiel, Israel, which has Gaucher competitor Elelyso (taliglucerase alfa) on the market with New York-based Pfizer Inc., is working on an oral therapy, too, and began a phase II trial in June. Dublin-based Shire plc has a competitor in Vpriv (velaglucerase alfa). (See BioWorld Today, Dec. 2, 2009.)

"The whole world welcomes competition, as well as Genzyme welcomes competition," Azevedo said. "What Protalix is trying to do is actually a liquid formulation of the same drug that they already have as an enzyme replacement therapy," she said, calling the stage "too early to say how successful they will be, or if there will be room for one more oral therapy. It's an interesting question."

There's also Zavesca (miglustat), from Actelion Ltd., of Allschwil, Switzerland, approved as a second-line oral therapy for type 1 Gaucher, given to patients for whom ERT is unsuitable.

"It's not that [such patients] have something in addition to Gaucher," Azevedo said, but instead has to do with "their immune system or the way they react to the treatment. There are patients, for example, who might have needle fear, and those also could go into oral therapy."

Although a rare disease, Gaucher has drawn plenty of drug developers. "Believe it or not, in terms of the proportion, we probably have more products addressing Gaucher disease than different types of insulin" for diabetes, Azevedo said.