Understanding Gaucher (pronounced Go-shay)
Gaucher disease, is a rare genetically inherited disorder, that affects fewer than 200,000 people in the United States at any given time. It is an autosomal recessive disorder caused by mutations in the GBA gene. Gaucher patients lack the normal form of the glucocerebrosidase, or GCD enzyme that breaks down specific fat molecules, resulting in the accumulation of fat in liver, spleen and bone marrow. With an incidence of about 1 in 20,000 live births, the market for Gaucher drugs is huge due to severity of the symptoms and the chronic nature of the disease.
Having said thus, let's dwell deeper into the Gaucher disease drug development saga involving Genzyme Corp. (GENZ); Israeli biotech firm Protalix Biotherapeutics Ltd. (PLX) and UK-based biopharmaceutical company Shire plc (SHPGY,SHP.L).
All was well for Cambridge, Massachusetts-based Genzyme, which made billions of dollars through sale of its Gaucher disease drug, Cerezyme and Fabrazyme, a Fabry disease drug, until May 2009. Genzyme generated total revenues of $4.60 billion, of which its blockbuster Gaucher drug, Cerezyme fetched $1.23 billion, while Fabrazyme booked revenues of $494.26 million, in fiscal 2008.
However, for the fiscal 2009 the drugmaker's revenues declined to $4.51 billion, with a sharp plunge in revenues of Cerezyme and Fabrazyme to $793.02 million and $429.69 million, respectively. The reason: temporarily closure of Genzyme's Allston facility in June, 2009 due to viral contamination. Allston plant's key product were Cerezyme and Fabrazyme. In the fourth quarter of fiscal 2009 alone, Cerezyme and Fabrazyme revenues dropped 66% and 54%, respectively.
Genzyme's Cerezyme is the only FDA approved indication for Gaucher disease. Cerezyme is an intravenous, freeze-dried medicine containing imiglucerase. In September 2009, the company shipped Cerezyme only to two patient populations: patients with Gaucher disease type 1 who are 18 years of age or younger, and patients with Gaucher disease types 2 and 3. According to reports, worldwide about 8,000 people use these drugs and production problems at Genzyme plant have resulted in a shortfall of the drugs -- Cerezyme and Fabrazyme.
Due to urgent unmet need for Gaucher drug, the U.S. Food and Drug Administration or FDA granted "Treatment Protocol" to Protalix and Shire.
Protalix
Protalix makes Plant Cell Expressed Recombinant Glucocerebrosidase, or prGCD - taliglucerase alfa, or Uplyso, an enzyme replacement therapy for Gaucher disease, based on plant cell expressed version of the GCD enzyme, developed through a protein expression system. According to the company, unlike Cerezyme, which is a mammalian cell expressed version of GCD enzyme, Uplyso is a plant cell expressed version and therefore does not carry the risk of infection by human or other animal viruses.
Protalix' Uplyso enjoys orphan product status, fast track designation and is developed under a Special Protocol Assessment, granted by the FDA. The drug is already available to Gaucher disease patients in the U.S. and other countries under an Expanded Access Program approved by the FDA.
In December 2009, Pfizer Inc. (PFE) entered into an agreement to develop and commercialize taliglucerase alfa. Pfizer acquired exclusive worldwide licensing and commercialization rights while Protalix retains the exclusive commercialization rights in Israel. The agreement entailed Protalix an upfront payment of $60 million and additional regulatory milestone payments of up to $55 million, from Pfizer.
Protalix completed its NDA filing for taliglucerase alfa in December, with the FDA. In January 2010, Protalix's taliglucerase alfa received positive opinion from the Committee for Orphan Medicinal Products, or COMP of the European Medicines Agency, or EMEA and recommendation for orphan drug designation in the EU.
Only recently, the FDA requested for additional details on the NDA, primarily related to manufacturing process. However, no additional Clinical or Preclinical information was requested. Protalix expects to submit the requested data regarding chemistry, manufacturing and controls to the FDA during the second quarter of 2010.
Protalix's projects under pipeline are therapeutic protein candidates for the treatment of Fabry disease, an acetylcholinesterase enzyme- based therapy for biodefense and intoxication treatments and an additional undisclosed therapeutic protein.
Shire
The other major beneficiary of production problems at Genzyme is Shire. Velaglucerase alfa is an enzyme replacement therapy in the human cell line, to treat Gaucher. The enzyme produced has the exact human amino acid sequence and has a human glycosylation pattern. Velaglucerase alfa is currently under FDA's review, with a PDUFA date on February 28.
Velaglucerase alfa enjoys Priority Review designation and the FDA has also approved Treatment Protocol. In November 2009, Shire submitted a MAA to the European Medicines Agency for velaglucerase alfa, following its United States and Canada application.
Shire's pipeline includes Replagal (agalsidase alfa), a human-cell-line-derived form of enzyme alpha-galactosidase A manufactured in a human cell line by gene activation, to treat Fabry disease. Replagal, if approved would compete against Genzyme's Fabrazyme.
Fabry disease, affecting nearly 8,000 to 10,000 people worldwide, is a lysosomal storage disorder caused by inherited genetic mutations in the GLA gene, which results in deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A). This deficiency leads to lysosomal accumulation of globotriaosylceramide, or GL-3, interfering with the body's ability to break down a specific fatty substance. Lifespan of male Fabry patients is reduced by 20 years, while that of females shrink by 15 years, with symptoms including pain, kidney failure and increased risk of heart attack and stroke.
Replagal is available to U.S. patients since December 2009 under an FDA-approved Treatment Protocol filed at the request of FDA. Post Shire's submission of BLA in December, the FDA requested additional human pharmacokinetic data to confirm comparability between product that was manufactured in roller bottles, and that which is manufactured in bioreactors. Hence, Shire at the suggestion of the FDA, withdrew its BLA filed in December, only to request and receive a Fast Track designation. Shire also plans to initiate the rolling submission of the Replagal BLA, and submit the requested pharmacokinetic data around mid-year.
Another player, Amicus Therapeutics (FOLD) reported additional positive preliminary data from an ongoing Phase II extension study of its investigational drug Amigal, or migalastat Hcl, for Fabry disease, earlier this month. Amigal has orphan drug status in both the U.S and EU, granted by the FDA and the EMEA.
Genzyme
For fiscal 2010, Genzyme forecasts revenue from Fabrazyme between $360 million and $380 million, while Cerezyme revenues are expected between $980 million and $1.03 billion. Genzyme's lower Fabrazyme revenue guidance is driven by low productivity of the manufacturing process since the re-start of production, from December 1, 2009. In 2010, Genzyme expects capital expenditures be nearly $600 million, aimed at infrastructure improvements, including but not restricted to a new facility in Framingham, Massachusetts, for Fabrazyme and Cerezyme.
Genzyme anticipates acceleration of revenues and earnings in the second half of 2010, counting on approval of Lumizyme by FDA, which has an action date in June; its ability to increase manufacturing productivity for Fabrazyme and ability to maintain a substantial portion of the market for Cerezyme.
Genzyme is in the process of developing eliglustat tartrate, formerly Genz-112638, a novel investigational oral therapy for patients with Gaucher disease type 1. With positive results in phase 2 studies, it has begun enrollment in two global, multi-center, phase 3 trials for eliglustat tartrate. If successful, the therapy has the potential to transform the treatment experience for Gaucher patients by providing a daily oral capsule option instead of bi-weekly infusions lasting several hours or more.
Earlier this week, Genzyme faced with a new predicament, as activist investor Carl Icahn, just a after announcing his plans to nominate himself for the board of directors of Genzyme, said he aims to "fix the ailing biotech company." He plans to nominate Alexander Denner, Richard Mulligan and Steven Burakoff. Of these, Denner and Mulligan, reportedly, also worked together on the board of troubled biotech group ImClone Systems, which was later acquired by Eli Lilly & Co. (LLY).
Conclusion
Although, Protalix's efficacy or safety issues are undisputed and the fact that manufacturing issues can be fixed, it still has a long way to go. Genzyme's Cerezyme is bound to benefit from Protalix's delayed submission, as it's already fast recovering from the viral contamination woes, which, ironically, triggered FDA to seek new treatment options, in the first place. Shire currently seems to have an upper hand, however, uncertainty over FDA's decision persists. Once again, drug approval timing would determine who would amass larger part of the profit pie.
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June 12, 2026 17:14 ET Major central bank action was the focus this week in economic news. The European Central Bank became the first major central bank to move in response to the rising inflationary pressures in the backdrop of the conflict in the Middle East. In North America, the U.S. inflation and trade data as well as Canada’s central bank decision gained attention. The Chinese trade data was the main news in Asia.