Protalix Biotherapeutics has had a tough time landing its first product on the market. Since the small Israeli company filed for approval for Uplyso (taliglucerase alfa) with the US Food and Drug Administration (FDA) two years ago, the agency has twice requested additional data about the manufacturing and long-term clinical benefits of the drug, a recombinant enzyme developed in partnership with the US pharma giant Pfizer to replace the defective protein found in people with Gaucher's disease. After responding to the agency's concerns, Protalix had expected a final decision on Uplyso by February. But, last month, the company announced that that date had been pushed back to the start of May as the FDA mulls over more late-breaking clinical information.

The clock is ticking. The market for Gaucher's drugs is relatively small to begin with, as fewer than 10,000 people, mostly of Ashkenazi Jewish descent, are affected by the lysosomal storage disorder worldwide. Plus, it's become an increasingly crowded space: Cerezyme (imiglucerase), a similar enzyme replacement therapy from the US biotech company Genzyme, currently dominates the market, with global sales of around $720 million in 2010, although shortages have recently plagued its distribution; and, in February 2010, another player—Ireland's Shire—entered the field with VPRIV (velaglucerase alfa), which netted $143 million in its first year alone.

But both drugs suffer from a common shortcoming: they are produced in hamster cells, an expensive system for manufacturing biologics. In contrast, Protalix's product, which has shown comparable safety and efficacy to its competitors, is made in cheap and easy-to-grow carrot cells—a fact that analysts think could give the Johnny-come-lately drug a unique selling point.

“The average Cerezyme treatment per patient per year is around $280,000,” says Ritu Baral, a research analyst with the Canadian investment bank Canaccord Genuity. “With this plant platform, we might be talking less than half the production cost.” Protalix and Pfizer haven't pinned down a final price for Uplyso. But Baral estimates that the biweekly medicine will hit the market at around $200,000 for a year's worth of treatment. “This cost difference,” she says, “will be a compelling reason to use the drug.”

Cincinnati Children's Hospital's Gregory Grabowski, a Gaucher's specialist who has consulted for both Genzyme and Shire, echoes Baral's sentiments. “From a medical standpoint, there doesn't seem to be a major reason to switch from the existing drugs to this one,” he says. “But if all other things are equal, the cost of the drug may be a driving force.”

Where novel Gaucher's drugs are needed, Grabowski says, is to treat advanced symptoms of more severe forms of the disease, not its underlying cause. But, looking beyond this single rare disorder, David Aviezer, president and chief executive of Protalix, says that Uplyso—as the first human biologic made using a plant cell-based technology—could be a game changer for the entire biotechnology industry.

“This will be a first-of-its-kind drug,” Aviezer says. “It will be a proof of concept for this new production platform, using plant cells as an expression system for making recombinant proteins.”

Planting a seed

Since the 1978 discovery that human insulin could be produced in the bacterium Escherichia coli, all biologics and vaccines have relied on living mammalian, avian and bacterial cells as a means of mass production. Alternative manufacturing platforms have been proposed to capture the $100-billion-a-year global biologics market, ranging from goats to yeast (see Nat. Med. 16, 146–149, 2010). But the closest to fruition are plant-based systems.

Aviezer says that the benefits of plant-derived proteins include cheaper manufacturing, owing to the ability to grow plant cells outside of expensive fermentation vats, as well as protection against the kinds of infections that have plagued Genzyme since a virus struck its Allston, Massachusetts plant in June 2009, leading to global shortages of Cerezyme and one other product. “Our system has a built-in firewall against mammalian viruses,” Aviezer says. On 1 December, Protalix announced that the Irish Medicines Board (on behalf of the European Medicines Agency) had joined the FDA and its regulatory counterpoints in Brazil and Israel in green-lighting the company's manufacturing facility—a necessary step ahead of a potential drug approval for Uplyso.

According to Andy Sheldon, president and chief executive of Medicago, a Canadian company that is growing virus-like particles in tobacco leaves that are being tested as vaccines against influenza, another big advantage of plant-based manufacturing is the speed of production. “Vaccine production can be initiated within less than three weeks from the identification of the genetic sequences from a pandemic or seasonal influenza strain,” he says.

Currently, the only plant-derived biological product approved in the world is a veterinary vaccine used to protect chickens from Newcastle disease virus that is grown in tobacco cell culture by US-based Dow AgroSciences. But many plant-based drugs for human use could hit the shelves in the near future, including an insulin produced in genetically engineered safflower cells by Canada's SemBioSys, a hepatitis C drug made in modified duckweed cells by US-based Biolex Therapeutics and a handful of vaccines manufactured in tobacco (see 'Down on the pharm').

“Hopefully,” says Aviezer, “this will be just the tip of the iceberg in terms of the capabilities of this new technology using plant cells.”

Table 1 Down on the pharm: Plant-based biologics and vaccines in clinical development.
Full size table