BioWorld Today Correspondent

LONDON - Shire plc is now poised to challenge the blockbuster status of Genzyme's Cerezyme, after reporting positive Phase III data and receiving approval of the treatment protocol, enabling it to start the rolling application of its enzyme replacement for Gaucher's disease under the FDA's fast-track process.

The company announced positive results for the product, velaglucerase alfa, in a multicenter, randomized, double-blind, two-dose study in 25 patients with type I Gaucher's disease. It is the first of three Phase III studies to report. The primary endpoint was reached, with patients showing a clinically relevant increase in mean hemoglobin concentration after 12 months' treatment. There also were significant improvements in platelet and spleen sizes.

At the same time, the FDA approved the treatment protocol - submitted at its request - allowing velaglucerase alfa to be prescribed in advance of its approval.

That leaves Basingstoke, UK-based Shire poised with Protalix BioTherapeutics Inc., of Carmiel, Israel, to meet an expected shortfall in supplies of the Gaucher's disease treatment Cerezyme, caused by the temporary closure of Genzyme Corp's Allston Landing facility in Cambridge, Mass. At the end of last week, Genzyme said the FDA is due to re-inspect the manufacturing facility after a warning letter in February, and the more recent production halt after a virus was found to have infected the hamster cell lines in which Cerezyme is generated.

The production shutdown will rob Cerezyme of some of its blockbuster status. The drug had sales of $1.2 billion in 2008, but the closure cut $13 million off sales in the second quarter of this year, and Genzyme has lowered 2009 revenue guidance down from between $1.25 billion and $1.275 billion, to $750 million to $1 billion.

After the complete shutdown and cleaning of the Allston Landing facility, the first Cerezyme off the restarted production line will not be released for patient use until November or December. Current inventories are not large enough to meet demand.

Shares of Genzyme (NASDAQ:GENZ) dropped $1.51 Monday, closing at $50.38.

Sylvie Gregoire, president of Shire's Human Genetic Therapies arm, said the progress with velaglucerase alfa was pleasing from both a clinical and regulatory perspective. "We will continue to work diligently with the FDA and other regulatory agencies to make [it] available as soon as possible."

Shire certainly has moved quickly. The rolling submission was initiated July 30, three weeks after it received fast-track designation, and will be completed before the end of September.

When the problems with Cerezyme manufacturing became known at the start of July, Shire was invited by the FDA to file a treatment protocol. Its approval means velaglucerase alfa now will be available free of charge in the lead up to registration, which is expected in 2010. Although Shire will not receive any revenues, that will allow physicians to gain experience in the use of the product.

Commenting on the results of the Phase III trial, lead investigator Atul Mehta, clinical director of the Lysosomal Storage Disorders Unit at the Royal Free Hospital in London, said velaglucerase alfa appears to be "an excellent choice" for treating Type I Gaucher's disease. "The prospect of having another treatment option available to help patients achieve therapeutic goals is very important." In total 100 patients in 24 sites in 10 countries are enrolled in the Phase III program. The product is expected to get approval in Europe in 2010.

Beyond the challenge to Cerezyme's blockbuster status, the FDA's approval of velaglucerase alfa also could signal the beginning of a shift away from the production of human enzymes in bacterial, yeast or mammalian recombinant cell lines.

Velaglucerase alfa is manufactured in a human cell line using Shire's gene activation technology. That draws on the fact that every human cell contains the full complement of DNA, even though much of it is inactive. Every cell for example, contains the DNA coding for insulin, but the enzyme is generated only in the pancreas. The gene activation technology selectively switches genes on.

That results in velaglucerase not only having the exact human amino acid sequence as the native enzyme, but also carrying the human glycosylation pattern. While it is not clear, as yet, if that results in a better clinical outcome, Shire said it enables it to sidestep the miasma of intellectual property rights encumbering recombinant protein production and results in lower production costs.

For its part, Protalix avoids this IP forest by producing its enzyme replacement product in plants.