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WALL STREET BIOBEAT Biobusiness Biopharmas Drive Antibiotic Development Gail Dutton At a time when the need for antibiotics is high, pharmaceutical companies are abandoning antibiotics development in favor of larger, more predictable markets. That has been the situation for the past few years, and it isn't changing, according to Aaron S. Kesselheim, M.D., J.D., associate physician at Brigham and Women's Hospital, and assistant professor of medicine at Harvard Medical School. Yet, with the incidence of antibiotic resistance growing, there is an acute need for new, more effective targets. The Infectious Diseases Society of America (IDSA) reports that only two new antibiotics for gram-negative bacterial infections have been approved since 2009, and fewer than 10 As the incidence of antibiotic resistance continues to grow, a number of small to mediumsized biofirms are focusing on developing new products to treat this global health problem. Zmeel Photography/iStockphoto are in Phase II/III development. Of those, only a handful are active against bacteria that produce metallo-b-lactamases, which are important determinants of resistance. Market research company Global Information, Inc. (GII) estimates the cost of hospital-acquired infections alone at $32.5 billion for the United States, the European Union, Canada, Australia, and Japan—–about $25 for every person living in those regions. Of the 109 antibiotics that it identifed in the pipeline last winter, approximately 70% were in the Phase I or preclinical stage, and only 9 candidates (roughly 8%) were in Phase III. GII identifed 66 companies involved in antibiotics research. Of those, 86% were small to medium-sized enterprises. Policy Changes "Drug resistance is an important issue in drug development and makes antibiotic drugs relatively unusual. If antibiotics are not used properly after approval, resistance can develop quickly," said Dr. Kesselheim. He wrote in 2010, and still maintains, that the goals of public health agencies and pharmaceutical manufacturers are "woefully misaligned," and that "current incentives for antibiotic development are inadequate." Three years ago, Dr. Kesselheim proposed a reimbursement system of grants and prizes in which payments were based upon meeting goals of antibiotic conservation. Not surprisingly, he pointed out, it has not been adopted. "Current proposals still mostly fall into the realm of providing more patent exclusivity or reducing barriers to entry." Of more immediate note, the U.S. Department of Health and Human Services (HHS) signaled a policy change in May when it awarded funds to GlaxoSmithKline in a way that allows the company to shift funds around its antibiotic programs. This is the frst time HHS has taken a portfolio approach to its grants and contracts. With this fexibility, GlaxoSmithKline has the incentive to develop the most promising antibiotic candidates rather than those that are funded, thus allowing progress in a way that acknowledges the fuctuations of scientifc advances and failures. This also allows compounds to be investigated as treatments for conventional and biothreat pathogens. Regulators are beginning to consider ways to address antibiotic resistance. "We're seeing policy and regulatory changes to encourage development of new antibiotics for resistant bacteria on both sides of the Atlantic," noted Michael Bonney, CEO of Cubist Pharmaceuticals. For example, the Generating Antibiotic Incentives Now (GAIN) Act was signed into law in July 2012, and the FDA has issued guidance documents on complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs), among others, that are considered signifcant. In June, U.S. Senator Diane Feinstein (DCA) introduced the Preventing Antibiotic Resistance Act (S. 1256). The bill limits the non-routine use of important antimicrobials in animal production in an attempt to reduce the antibiotics found in the natural environment and in foods, and thereby slow the proliferation of drug-resistant bacteria. It was referred to the Senate Committee on Health, Education, Labor, and Pensions, and is similar to H.R.1150 in the U.S. NEWS Products & Services > Instrumentation supplier Rigaku has acquired Emerald Bio's crystallization reagent and consumable business, including Emerald Bio's Wizard™ screen kits. In addition, both companies have agreed to work together to develop integrated solutions in protein science, supporting their customers' workflow needs. > Fluidigm and Olink Bioscience will co-market the combination of their respective products—Fluidigm's BioMarkTM HD System and Olink Bioscience's Proseek® Multiplex technology. The companies intend to help researchers uncover biomarkers by giving them the ability to interrogate 96 samples across 92 proteins in a single run from one microliter of sample in less than a day. > A co-marketing agreement between EMD Millipore, the life science division of Merck KGaA, and groninger calls for EMD Millipore to be groninger's partner of 16 | choice for single-use technology and for groninger to be EMD Millipore's partner of choice for filling equipment. Together, the companies intend to help biopharmaceutical manufacturers to handle challenges such as smaller lot sizes and highly potent ingredients while ensuring the safety of filling operations. > Genisphere has licensed its 3DNA® dendrimer signal-amplification technology to Chembio Diagnostics. Chembio plans to use the technology to expand the detection limits of its Dual Path Platform (DPP ®) point-of-care diagnostic tests. Chembio is particularly interested in improving the performance of its lateral flow assays. > Sanguine BioSciences has entered a distribution partnership with AMS Biotechnology to make its products and services available to researchers in Europe. Instead of working through treatment-focused hospital personnel, September 1, 2013 | GENengnews.com | Genetic Engineering & Biotechnology News researchers will have the option of working with Sanguine, which collects and de-indentifies biospecimen, medical history, and other data from patients diagnosed with severe and chronic diseases for use in biomarker research. The company's patient-engagement methods have led to a 95% retention rate, which may facilitate follow-up draws for longitudinal studies. > Harlan Contract Research Services (CRS) Cytotest Cell Research has been named one of the first laboratories selected for inclusion in the European Union Network of Laboratories for the Validation of Alternative Methods (EU-NETVAL). Harlan CRS will help develop documents, procedures, and tools to broaden the application of nonanimal tests, thereby assisting EU-NETVAL, which supports the work of the European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM). n House of Representatives. Innovative Approaches The bulk of the work in antibiotics is being done by small biotech companies, according to IDSA. At newly formed Enbiotix, J. Ruben Morones-Ramirez, Ph.D., professor at Universidad Autónoma de Nuevo León, James J. Collins, Ph.D., and other scientists are showing that the addition of silver to standard antibiotics targeting gram-negative bacteria improves their effcacy between 100- and 1,000-fold. "This is the frst work to biochemically and genetically decipher the mechanisms by which silver treatment led to cell death," said Dr. Morones-Ramirez. Lab work shows that this approach enhances existing antibiotics, broadens the spectrum of vancomycin, and helps resensitize resistant bacterial strains. "We've been approached by some pharmaceutical companies, such as Cubist Pharmaceuticals and Pfzer, that are interested in our work. We believe the technology of adding silver to antibiotic therapies will be explored much further and has a very nice shot at being successfully implemented as a therapeutic in approximately fve years," continued Dr. Morones-Ramirez. The next stage of the company's work will be to explore silver toxicity in higher organisms (that is, sheep) to move quickly into human trials. Dr. Morones-Ramirez's university laboratory is exploring nanotechnology as well as synthetic and systems biology to develop intelligent delivery systems and to design therapeutics that decrease toxicity and possible side effects from the antibiotics, silver, and their combinations to enable faster commercialization. "We look for these therapeutics to be target-specifc, have a controlled release, and stay in the body until the infection is gone," explained Dr. Morones-Ramirez Cubist Pharmaceuticals, since its founding in 1992, has focused on the acute care hospital environment and maintained a strong interest in antibiotics. "Antibacterials will be an important part of our future," said Bonney. "Gram-negative bacteria account for 80% more days of therapy than the methicillin-resistant Staphylococcus aureus (MRSA) market, so this is an area of real, unmet medical need and one that we are focused on at Cubist. Two of our Phase III antibiotics have been declared as Qualifed Infectious Disease Products, gaining an extension of Hatch– Waxman exclusivity." Currently ceftolozane/tazobactam (CXA201) is undergoing Phase III trials for cUTIs and cIAIs. Cubist also is planning a Phase III program for ceftolozane/tazobactam in hospital-acquired/ventilator-associated bacterial pneumonia. That drug targets gramnegative bacteria. "Pseudomonas aeruginosa is high on that [gram-negative target] list," according to Bonney. The FDA granted fast-track status