We have a new orphan drug on the market thanks to last week’s FDA approval of Cerdelga, a small-molecule therapeutic developed by Sanofi for treatment of Gaucher’s disease. This rare genetic disorder is thought to affect around 6,000 in the United States. Regular WEEKLY readers know we like to highlight new drug approvals. After all, there are only 25 to 40 of them a year on average.

Cerdelga is a drug 25 years in the making. What started as research at the University of Michigan in 1989 turned into a licensing and development deal with Genzyme in 2000 (now part of Sanofi). Over the last15 years, the drug was tested in clinical trials on over 400 patients in 29 countries, leading to the FDA’s approval and orphan drug distinction last week.

Gaucher’s is an inherited disease caused by a recessive mutation in a gene located on chromosome 1. It leads to the accumulation of glucocerebroside, a fatty substance essential in nerve cells, resulting in chronic fatigue and easily fractured bones in the most common form of the disease, type 1. To date, the standard of care has been regular infusions with recombinant versions of the enzyme made in biomanufacturing facilities.

The new oral treatment, Cerdelga, is a small molecule inhibitor of the enzyme that produces the glucocerebrosides in the first place—glucosylceramide synthase. If the enzyme is not produced, it will not need to be broken down.

Cerdelga is not the first oral treatment for Gaucher’s. Zavesca (Oxford GlycoSciences and Actelion) was approved in 2003 as an oral treatment for use in patients who had only mild or moderate Gaucher’s, or could not tolerate infusion therapy. With its better safety and efficacy profile, Cerdelga has been approved as a first-line treatment—an idea that can be easily swallowed.


We all have two copies of each gene—one that we inherited from our mother and the other from our father. In order to develop Gaucher’s and other autosomal recessive disorders, one must inherit two copies of the gene causing the disease. Someone who has one copy of the gene but does not have disease symptoms can still pass that gene on to their children, hence the term “carriers.”

  • If the disease gene is dominant in both parents, all of their children will develop Gaucher’s.
  • If the disease gene is dominant in one parent and the other parent is a carrier, there is a 50% chance that their child will develop Gaucher’s and a 50% chance the child will be a carrier.
  • If the disease gene is dominant in one parent and the other parent is unaffected, all of their children will be carriers and will not develop Gaucher’s.
  • If both parents are carriers there is a 25% chance that their child will develop Gaucher’s, a 50% chance that their child will carry the gene recessively, and a 25% chance that they will be unaffected.
  • If one parent is a carrier and the other parent unaffected, there is a 50% chance that their child will be a carrier and a 50% chance that their child will be unaffected.


How does lipid accumulation cause such serious problems in Gaucher’s patients? Simply put, it interferes with the normal functioning of the organs in which it accumulates. For example, lipid accumulation in bone marrow interferes with the production of the platelet cells required for successful blood clotting, leading to bleeding and bruising. The production of the oxygen-carrying red blood cells is also impacted, leading to chronic fatigue and anemia.


Zavesca, an earlier oral treatment for Gaucher’s, was originally developed as an alpha-glucosidase inhibitor when it was discovered that it also inhibited glucosylceramide synthase. Today, alpha-glucosidase inhibitors are used for the treatment of type 2 diabetes, and work by preventing the digestion of carbohydrates, thus reducing their impact on blood sugar levels. There is some preclinical evidence that a more specific glucosylceramide synthase inhibitor, such as Cerdelga, may also be effective at controlling blood glucose levels in type 2 diabetics.


For patients who do not generate enough of a needed enzyme, the standard treatment is enzyme replacement therapy: provide them with the enzyme they need from an outside source.

Substrate reduction therapy obviates the need for the enzyme by reducing the amount of substrate—the molecule upon which the enzyme acts.

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