In July FDA asked Shire and Protalix BioTherapeutics to submit treatment protocols for their Gaucher disease therapies in the wake of Genzyme’s Allston Landing plant closing. The company halted production after it detected a virus that impaired growth of producer cells in one of the site’s six bioreactors. Genzyme’s Gaucher drug, Cerezyme, was affected by the plant shutdown with third quarter sales dropping by 69.7% to $93.6 million.
The closing thus gave Shire and Protalix an opening to accelerate clinical testing and commercialization of their recombinant protein drug candidates, velaglucerase alfa and taliglucerase alfa (Uplyso), respectively. Both Shire and Protalix have reported positive results from Phase III trials in the last couple of months.
Protalix’ shares rose nearly 9% on the Phase III data news; the company said it expects to complete its NDA at the end of this year and could have the drug on the market by mid-2010. FDA has granted priority review to Shire’s drug, and the PDUFA date has been set as February 28, 2010.
Analysts expect serious competition for Genzyme, should both new drugs win marketing approval. “We see Shire and Protalix as real competitors in the space and remain skeptical that Genzyme will be able to win back all of its patients once its manufacturing issues are resolved,” notes JP Morgan analyst Geoffrey Meacham.
These recent events bring into focus the problems with systems used for recombinant therapeutic protein production. Perhaps as a result, there seems to be a renewed interest in plant-based methods.
More than 370 therapeutic proteins are currently in development, according to BIO. Current mammalian cell production capacity is thus experiencing serious stress.
Traditional cell culture methods require significant capital and labor investment; cell culture facilities cost about $250 million to $450 million to build, take from three to five years to build, and must be individually approved and certified by the FDA prior to full-scale operation. Additionally, animal cells generally require costly and complex media to sustain the cells and the addition of growth factors and animal-based products that may themselves introduce contaminants into culture systems.
Genzyme’s Cerezyme is produced by recombinant CHO cells, and Shire’s drug is produced in an undisclosed human cell line. Cerezyme requires postproduction chemical modification to humanize the glycosylation pattern. Shire's technology, on the other hand, activates expression of glucocerebrosidase in a cell line in which it is not normally expressed.
This produces a protein with the same human amino acid sequence as the native human enzyme and with the human glycosylation pattern, according to the company. Glycosylation patterns affect the biological properties of therapeutic proteins including their activity. They are thus closely monitored during therapeutic protein production, as a change in pattern may provide an early indication of a problem.
Scientists have long noted the benefits of plant cell culture in achieving human-like protein production. Like bacteria, plant cells can be grown in relatively simple synthetic media. Additionally, since they are eukaryotes like mammalian cells, they can execute post-translational modifications that occur in human cells. They don’t harbor human pathogens, and they don’t produce endotoxins. The use of plant cells and plant tissue culture, however, has historically been held back by certain limitations, chief among them getting expression levels that make plant-production commercially viable.
Protalix claims that its plant cell-based manufacturing for therapeutic proteins produces potentially less expensive products that are therapeutically equivalent or superior to the existing mammalian cell-produced treatments. Instead of using stainless steel tanks, Protalix grows recombinant carrot cells expressing the human protein in disposable 800-L bags. This cuts down on cleaning costs as well as expensive plumbing.
In particular, the company notes that its proteins don’t require post-translational modification because plant cells produce glycosylation patterns more closely resembling human proteins. The plant cell-produced proteins do not, thus far, show increased immunogenicity. The company says that data from its clinical trials showed that the half-life of Uplyso is significantly longer than that of Cerezyme when measured and compared to publicly available data on Cerezyme.
Uplyso is Protalix’ lead product, and the plant-produced replacement enzyme was well tolerated, with 6% of patients in the trial developing antibodies to the protein during the study. The nine-month, double-blind, parallel-group study randomized patients to receive either 60 units/kg or 30 units/kg of Uplyso administered intravenously once every two weeks, with a total of 31 patients enrolling in the trial. The trial met its primary endpoint, a mean reduction in spleen volume among treated patients after nine months compared with baseline, at both doses.
Protalix has three other plant cell-produced enzymes in its preclinical pipeline: PRX-12, a galactosidase enzyme-replacement therapy for Fabry disease; pr-antiTNF, a biosimilar version of Enbrel; and acetylcholinesterase to treat nerve-gas and pesticide poisoning.
Restricted Competition Among Plant-Based Manufacturers
Biolex Therapeutics develops therapeutic proteins in its LEX system in Lemna, a small aquatic plant about 0.5 cm in diameter. Lemna is especially suited to recombinant protein expression because it is clonal, and the original transformant can be converted to a stable production line within six months, according to COO, David Spencer, Ph.D.
Tiny but powerful, Lemna doubles its biomass in 36 hours, allowing rapid scale-up to a multiton format. Grown in disposable plastic bags in medium consisting of water and inorganic salts, the plant does not require any animal-derived products to support growth.
Biolex’ lead product, Locteron, combines BLX-883, a recombinant interferon alpha produced in the LEX system, with controlled-release drug-delivery technology developed by OctoPlus. Lemna secretes BLX-883 into the plant-culture medium, greatly facilitating its purification.
Dr. Spencer says that unlike mammalian cell culture or with products produced in transgenic animals, “We don’t have to deal with pre- and postviral inactivation zones in our production facilities, nor do we require a viral inactivation process since the plants don’t contain animal viruses.”
Biolex completed enrollment for a Phase IIb study of Locteron in chronic hepatitis C patients in June and will meet with the FDA early in 2010. The company is also working on BLX-155, a full-length recombinant human plasmin being developed as a clotting agent, and BLX-301, a humanized anti-CD20 mAb in development. Both are produced on the LEX system.
While neither Protalix nor Biolex have much competition right now, Dr. Spencer says, “I think we need more entrants into the plant field.” Both Biolex’ and Protalix’ plant-cell culture technology circumvent the issue of foreign genes in food crops and the patent disputes around bacterial and mammalian protein-expression systems. At the moment, however, neither company has much competition in the plant-cell production business.
Protein-expression economics and investor enthusiasm, though, might change all that. Signs of this are already popping up with Biolex closing a $60 million Series D financing in October 2008. Additionally, Cannacord Adams reiterated its Buy rating on Protalix on November 10, saying “We think Uplyso data gives good proof of concept to Protalix’ plant-based protein-expression platform, which could be the basis of additional clinical programs and partnerships.”
Protalix located in Karmiel, Israel, has also garnered several pharma suitors like current partner Teva Pharmaceutical and Pfizer. Protalix CEO, David Aviezer, said that he has no plans to sell the company unless an exceptional offer is tendered.