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insights LIFESCIENCELEADER.COM MARCH 2014 60 PHARMA BUSINESS signed to the history books, at least in the West," says Hardcastle. But now phages are attracting the attention of the West again as the fear of drug resistance rises. However, while there is animal data available from work in Western labs, the human data generat- ed by the old Eastern bloc countries isn't acceptable to the regulatory authorities, largely because of the manufacturing conditions under which the cocktails are manufactured and the lack of rigorous double-blind clinical trials. Phages have a number of advantages over antibiotics. They are dosed "live," and will continue to replicate and attack bacteria until the infection is cleared. In contrast with small molecules and vac- cines, which target one particular path- way or antigen, phages can be dosed as a cocktail attacking different targets on a specific bacterial pathogen of interest. This future-proofs the treatment against changes in targets on the bacteria's sur- face, thus reducing the risk of driving resistance to the phage treatment. Novolytics' lead product, NOV012, is an example of a phage in development against resistant bacteria. It's a topi- cal gel formulation of a bacteriophage cocktail targeted at methicillin-resistant Staphylococcus aureus (MRSA). The company has completed preclinical ani- mal toxicity tests of NOV012 with no adverse outcomes, along with in vitro studies showing equivalent or better efficacy against MRSA compared with Mupirocin. Novolytics is planning a Phase 1/2 clinical trial for the nasal decol- onization of MRSA as a prophylactic in carriers, and NOV012 also has potential as a therapeutic in wound care manage- ment. In mid-2013, Novolytics signed a manufacturing deal with Cobra Biologics to support GMP manufacturing, and is seeking further partnerships to drive development of both the therapeutics and diagnostics. AmpliPhi Biosciences, another biotech company focused on developing bacte- riophage-based antibacterial therapies to treat antibiotic-resistant infections, has a number of collaborations support- ing its research. Those include an R&D; agreement with the United States Army to develop phage therapeutics to treat Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa infections; a collaboration with Intrexon to develop phage-based therapies to target spe- cific antibiotic-resistant infections; and most recently, an agreement with the U.K.'s University of Leicester to license a number of phages with activity against Clostridium difficile. French company Pherecydes Pharma is developing phages targeted against E. coli, Pseudomonas, and Staphylococcus, and has seen efficacy in animal studies with no toxicity. The French government's defense procurement agency has invest- ed €0.9 million ($1.2 million) into the PHAGOBURN project to create a product to use on infected burns. Other projects are underway for respiratory, bone, and joint infections, and Pherecydes Pharma is seeking partners to support the clinical development of its phages and the associ- ated companion diagnostics. PRECISION MEDICINE DRIVEN BY PROTEINS Other approaches to antibacterial thera- py include nonviral therapeutics, which do not include genetic material and can- not replicate. One company taking this route is AvidBiotics, which is developing Avidocins (R-type bacteriocins). These are reengineered forms of bacterial defensive proteins that target surface molecules on the bacteria. They lock onto specific receptors on the bacteria's surface and physically punch holes in the cell enve- lope. AvidBiotics' molecules successfully treated E. coli O157-induced diarrhea in rabbits and Pseudomonas aeruginosa peritonitis in mice. "We are starting with Clostridium dif- ficile, the number one urgent threat to U.S. citizens, according to the CDC," says Jim Knighton, president and cofounder, AvidBiotics. "If we kill only Clostridium difficile, this could eliminate selective pressure for the spread of drug resis- tance and leave unharmed the insensitive members of the microbiota. Our approach could change the practice of medicine." According to Martin, around 3 percent to 11 percent of people going into the hospi- tal carry Clostridium difficile. When these people are treated with broad-spectrum antibiotics, which kill most if not all of the sensitive bacteria, the resistant forms of the bug can recolonize the gut, leading to C. difficile-related diarrhea, which kills around 14,000 people in the U.S. every year. THE CHALLENGES Obviously, precision medicine is better for everyone — patients, physicians, and payors. Specific agents like these bacte- riophages and nonphage proteins will need accurate and rapid diagnostics that can be deployed at the bedside or in the emergency room, and this creates anoth- er challenge, or perhaps another oppor- tunity, for the originator companies and potential partners. Another challenge for these new approaches, which is similar for any first-in-class project, is reedu- cating the stakeholders, including phy- sicians, payors, regulators, and health technology assessment bodies such as NICE (National Institute for Health and Clinical Excellence) in the U.K. If these challenges can be overcome, phages, antibacterial proteins, and other nonantibiotic therapeutics and prophy- lactics could provide a new way to tackle the old enemy of bacterial infection, mov- ing medicine on from the threat of the post-antibiotic era. l NONANTIBIOTICS SPUR BIOTECH-PHARMA COLLABORATIONS By S. Elvidge J O H N H A R D C A S T L E CEO of Novolytics The antibiotics industry is well estab lished, but over the last two to three decades the amount of research effort placed behind new antibiotics has tailed off. 0 3 1 4 _ P h a r m a _ B u s i n e s s _ A n t i b i o t i c . i n d d 4 0314_Pharma_Business_Antibiotic.indd 4 2 / 1 9 / 2 0 1 4 2 : 4 4 : 5 8 P M 2/19/2014 2:44:58 PM