As a privately owned company with no stock price to support, Biosynexus doesn't put out many press releases. When it does, though, the news is usually pretty big.
Last October, the Gaithersburg, Md.-based biotech firm made two announcements about the efficacy of the enzyme lysostaphin in eradicating Staphylococcalaureus--a stubborn bacteria also known as staph--both in the nose and on artificial surfaces.
In a Phase I/II study of BSYX-L210, Biosynexus' lysostaphin-based cream, S. aureus was completely eliminated from the noses of all volunteers, with no significant adverse effects. A separate study demonstrated lysostaphin's ability to kill S. aureus and S. aureus biofilms on artificial surfaces such as those found in pacemakers and artificial joints.
The positive results appear to validate the business model on which Biosynexus was founded in 1999--to commercialize protein-based products for the treatment of hospital-acquired infections. In particular, the firm is focused on staph, a bacteria that is becoming increasingly resistant to conventional antibiotics.
According to Biosynexus, staph is now the leading cause of infection in hospitals. S. aureus is found in the nasal passages of up to 30% of the general population and up to half of individuals with compromised immune systems. The bacteria is harmless to many people, but it is also the cause of a quarter of the 2 million hospital-acquired infections reported annually in the U.S.
Lysostaphin works by cleaving the pentaglycine bond unique to staph's cell wall. Jeff Fischer, Biosynexus' head of strategic business development, has a less scientific description of the enzyme's bacteria-killing prowess. "It sees the cell wall and cuts right through it," he says. "Experts have called it the most powerful antistaphylococcal, 40 times more potent than penicillin."
This unique ability has been known for some time. In the 1960s, the drug company Mead Johnson tried to develop a product based on a natural lysostaphin extracted from the bacteria Staphylococcus simulans. But according to Fischer, the firm had trouble obtaining a consistently pure and active product. Cheap β-lactam antibiotics effective against staph were hitting the market at the same time, so lysostaphin commercialization effort was halted.
Still, staph researchers continued to use lysostaphin in their studies, and by the 1980s they had developed recombinant organisms that express the enzyme. Biosynexus licensed one of these in August 2000 as part of its effort to develop staph-fighting drugs.
The company conducted early trials using small quantities of lysostaphin that were produced in a Good Laboratory Practices-certified lab and then purified in a current Good Manufacturing Practices (cGMP) facility. The initial clinical studies on material made via this hybrid approach were successful, Fischer says. "But to capture the U.S. market--and Europe and elsewhere--we wanted a partner to make it entirely GMP."
EARLY LAST YEAR, Fischer and colleagues surveyed the microbial fermentation market and narrowed the field down to three possible partners. They informed these candidates that Biosynexus was seeking a three-fold improvement in lysostaphin expression, from less than 300 mg per L with the hybrid approach to more than 1 g per L under cGMP conditions.
After a due diligence process and a review of proposals, the company chose Avecia last May. Fischer says his team was particularly sold by Avecia's promise to improve output of the enzyme by using in-house technology rather than a potentially expensive licensed expression system.
For Avecia, the contract was another win for its biologics business, which in December opened the first phase of a $100 million fermentation center in Billingham, England. Other key contracts include the arthritis treatment CDP 484, which is being developed by the U.K. biotech firm Celltech, and a recombinant blood-clotting agent for U.S.-based ZymoGenetics. And the Billingham center is working on filling a $71 million contract to supply a new recombinant anthrax vaccine to the U.S. government.
The lysostaphin that Biosynexus used in its Phase I and II clinical trials was derived from Lactococcus lactis. But according to Andy Topping, Avecia's early-phase project manager, this system was not an economically viable candidate for commercial supply of the drug. Avecia's solution was to clone the relevant gene that Biosynexus had obtained from S. simulans, insert it into Escherichia coli, and perfect a new expression system.
Azam Razzaq, the Avecia project leader on the Biosynexus contract, says his team also needed to develop a new downstream purification scheme capable of processing the higher amounts of cell mass generated by the E. coli system. And, of course, the new material would have to demonstrate comparable purity, homogeneity, and activity as that from L. lactis.
Topping says Avecia has succeeded in increasing lysostaphin yields to "significantly higher" than the 1 g per L target set by Biosynexus. A product that looked like it might need to be made in one of Avecia's new 5,000-L fermenters will instead fit into a few 100-L vessels--a nice cost savings for Biosynexus. Fischer believes his company will eventually require the bigger vessel anyway, particularly if it is successful in developing an injectable version of the drug.
At the moment, Razzaq's team is optimizing the lysostaphin purification. He expects to run it soon under non-cGMP conditions, obtaining material for equivalency tests, and then to begin cGMP production late in the summer. According to Fischer, this timeline fits with Biosynexus' plan to begin late-stage trials near the end of the year and to file a New Drug Application by the end of 2005 or early 2006.
Fischer says he and other Biosynexus executives liked Avecia's work enough that they may hire it for a second developmental product, which will need to go cGMP within the next 12 months. "With some of the companies we've worked with, what they said they could do and what they actually did often did not meet up," he says. "With Avecia, they did."
Topping believes the key to this kind of success is delivering people and attitude as much as equipment and technology. "I view an early-phase project as a people deal rather than a manufacturing deal," he says. "We try to get across that the people at Avecia feel ownership of the project. Because at the end of the day, it's people that will make or break it."