Gaucher’s Disease Treatment Option Rides on Carrot Cells’ Biologic Power

Elelyso, derived from plant-cell technology, avoids many of the problems encountered when mammalian cells are used to create drugs

Many of our readers can remember their parents telling them to “eat your carrots because they are good for you.” That advice has taken on a totally different meaning with the May 1 FDA approval of taliglucerase alfa (Elelyso) for long-term enzyme replacement therapy for adults with a confirmed diagnosis of Type 1 Gaucher’s disease. As it happens, this enzyme, a direct competitor to Genzyme’s Cerezyme, is derived from carrot cells.

In a dramatic scientific breakthrough, a small Israeli company, Protalix Biotherapeutics, working with Pfizer, has developed a plant-cell-based recombinant protein production technology using carrot cells cultured in a disposable bioreactor system. There are no farm-based whole plants used in the manufacturing process, just plant cells in culture.

The company claims its technology is safer than the mammalian cell-based technology that is used in the production of most other complex biologically derived drugs, in particular because it does not rely on any mammalian products and it poses no risk of mammalian viral transmission.

Protalix also says that its plant-cell-based technology results in proteins that retain the same three-dimensional structures as proteins created in traditional yeast, bacteria, and mammalian bioreactor systems.

Gaucher’s disease

Gaucher’s disease, named after Philippe Gaucher, a French doctor who described this disease in 1882, is a genetic disorder generally classified as a lysosomal storage disease. It occurs in approximately 1 in 50,000 live births.

The disease is caused by an autosomal recessive genetic defect leading to a deficiency of the enzyme glucocerebrosidase. Glucocerebrosidase is a protein consisting of 497 amino acids that catalyses the breakdown of glucosylceramide, a constituent of red and white cell membranes.

Macrophages attempting to clear these cells are unable to eliminate the waste product glucosylceramide, which in turn accumulates, causing large fluffy-looking cells called Gaucher cells.

About 1 in 100 people in the United States are carriers. In Ashkenazi Jews, the carrier rate is nearly 9 percent, resulting in an incidence of 1 in 450 live births. There are about 80 known mutations of this gene, situated on chromosome number 21.

The disease expresses itself in three main types:

  • Type 1, the most common, is also called the non-neuropathic type. In the Ashkenazi population, this type has an occurrence rate of 100 times the rate in the general population. Type I is typically diagnosed in a person’s late 20s and results in a mildly decreased life expectancy.
  • Type 2 occurs in young children and is characterized by neurological problems; most die by age 3.
  • Type 3 occurs in Swedish patients who develop the disease in their second decade, with most succumbing by age 30.

The primary physical findings are painless hepatomegaly and splenomegaly. The normal spleen is 50-200 ml (roughly 2-7 ounces). With Gaucher’s disease, the spleen can grow to as large as three liters. The clinical trial used “Multiples of Normal Spleen Volume” as the inclusion criterion as well as the endpoint.

Genzyme’s product, imiglucerase (an analogue of human glucocerebrosidase), approved in 1994, has been the mainstay of therapy for Gaucher’s patients for 17 years. Genzyme announced several product shortages because of manufacturing problems over the past several years. Shire Pharmaceuticals developed an alternative therapy, velaglucerase alfa, a recombinant product identical to the naturally occurring glucocerebrosidase. It was approved by the FDA in 2010.


Elelyso, administered by intravenous infusion every two weeks, was approved based on two clinical trials, Study 1 and Study 2.

Study 1 looked at 31 treatment-naïve adult enzyme-replacement subjects. It was a nine-month, multicenter, double blind, randomized study and involved patients with type 1 Gaucher’s disease with splenomegaly (>8× normal size) and thrombocytopenia <120,000/mm3. In addition to the baseline patient requirements of splenomegaly and thrombocytopenia, 16 of the 31 had enlarged livers and 10 had anemia at baseline.

The patients were randomized to receive Elelyso at a dose of either 30 units/kg (15 subjects) or 60 units/kg (16 subjects). No placebo was given in the study. Results were significant.

Study 2 looked at 25 patients with type 1 Gaucher’s disease switching from Cerezyme to Elelyso. Identical doses of Cerezyme and Elelyso were administered during the nine-month, multicenter, open-label, single-arm study. Organ volumes and hematologic values remained stable through nine months.

The drug was approved with an initial dose of 60 units/kg with dose adjustments to be made based on achievement and maintenance of individual patient goals. Adverse events included allergic and infusion reactions, and although most of these were mild and did not require intervention, anaphylaxis has been reported. IgG antidrug antibodies have also been reported; their relevance is unclear, although the company noted that no association was demonstrated between neutralizing antibody assay results and therapeutic response.

This company claims that plant-cell-based plastic-bag bioreactor technology offers significantly lower upfront capital and production costs, is scalable, maintains protein assembly and post-translational modifications including glycosylation, and can be used for enzymes, cytokines, hormones, and monoclonal antibodies.

The Protalix strategy also involves the development of biosimilars and novel biologics. The pipeline includes a biosimilar of a leading anti-TNF drug as well as an enzyme replacement therapy for other lysosomal storage diseases.

Protalix is also attempting to develop a plant-cell-based, orally administered version of the glucocerebrosidase enzyme for Gaucher’s disease. The company says that the cellulose of the plant cells can prevent degradation of the protein until it is absorbed unchanged by the small intestine.

The development of Elelyso offers another alternative for patients with Gaucher’s disease. It will also be especially attractive to managed care companies. Pfizer plans to market it at a 25 percent discount to the competitors. This may mean a $50,000 per year savings, not a minor issue for a disease that needs to be treated for decades.

This competitive pricing strategy is likely to flow to all future products, ensuring that plant-based technology will be part of Tomorrow’s Medicine!

MD, is the immediate past president of the National Association of Managed Care Physicians. He has 24 years of managed care experience at the payer or health plan level. Contact him at
The author is a director in the value-based health department at Genentech. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow’s Medicine are the author’s alone.

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