Super Bugs

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Cynthia Borda

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Bacteria have proven to be resourceful organisms. They are so resourceful that the widespread use of antibiotics in recent years has enabled bacteria to adapt and develop resistance to currently marketed treatments. Antibiotics stop infection and the spread of infection, yet they also eventually decrease in effective ness because of mutations of the pathogen. In fact, more than 70% of the bacteria that cause hospital acquired infections are resistant to at least one of the antibiotics most commonly used to treat them, according to the National Institute of Allergy and Infectious Diseases. Drug resistant infections have become a serious health concern. MRSA, or methicillinresistant Staphylococcus aureus, caused more than 94,000 lifethreatening infections and almost 19,000 deaths in the United States in 2005, according to the Centers for Dis ease Control and Prevention (CDC). The proportion of drugresistant infections has been growing. According to CDC data, MRSA infections accounted for 2% of the total number of staph infections in 1974; in 1995 the rate was 22%; and in 2004 it was 63%. “There is a continued expansion and pro gression of resistant pathogens that common empiric treatments no longer cover,” says Barry Eisenstein, M.D., senior VP of scientific affairs at Cubist Pharmaceuticals Inc. “Some of these pathogens, for example, MRSA, have emerged in the community, which means emergency departments are now treating infections with drugs that no longer work against these pathogens. This leads to increased treatment failures, including death.” MARKET IMPACT Worldwide, the antiinfec tive market is expected to grow to more than $45 billion by 2012, according to research by Arrowhead Publishers. This growth will be driven by the uptake of newer antibacterial agents such as glycopep tides and carbapenems, which demonstrate resistance to MRSA and vancomycinresistant Enterococcus (VRE). According to the Arrowhead report, phar maceutical companies will continue to develop new generations of antibacterial agents — cephalosporins, macrolides, and quinolones. In addition, a number of new drug classes, such as dihydrofolate reductase inhibitors (DHFR), are under evaluation for their effectiveness in multidrug resistant organisms. Kalorama Information researchers estimate that the market will grow 2.5% from 2006 to 2011. Sales will likely increase by almost $3 billion to $25.5 billion in 2011. In 2006, antibacterial drugs accounted for an estimated $22.6 billion in revenue, accord

BY CYNTHIA BORDA

BUGS SUPER SUPER Antibiotics have saved millions of lives and increased the quality of life of people throughout the world. Now, new bacteria that are resistant to drugs threaten the advances made in the last half century. Never before has the pharmaceutical pipeline been more important. MEDICINES IN DEVELOPMENT FOR INFECTIOUS DISEASES Vaccines Antibiotics/Antibacterials Antivirals Antifungals Antiinfectives Antiparasitics Antimalarials Other B Sales of antibacterials will likely increase by almost $3 BILLIONTO $25.5 BILLION IN 2011. Kalorama Information 146 83 75 25 10 9 6 35 Source:Pharmaceutical Research and Manufacturers of America,Washington,D.C. For more information, visit phrma.org. 34 F e b r u a r y 2008 PharmaVOICE 0208issue FINAL 1/18/08 5:35 PM Page 34 ing to Kalorama. This is, however, a decline of 1.8% from 2004. According to Kalorama Analyst Melissa Elder, the decline is due to a shift in sales from branded products to generic products resulting from recent patent expirations. “The penicillins and cephalosporins have been negatively impacted in this market, and they are having a difficult time remaining on top,” Ms. Elder says. “Newer products, which show less resistance, have taken their place with physicians. Few branded products in this segment currently hold much weight. Products such as Augmentin and Zosyn remain the only brands to have a significant market share. And Aug mentin sales continue to slide because of generic competition, while sales of Zosyn remain steady.” Product sales in the quinolone and miscel laneous segments were responsible for the high est growth and will continue to play a key role in fueling the market, according to the Kalo rama report. INFECTIOUS DISEASE PIPELINE The Pharmaceutical Research and Manufac turers Association’s 2007 Infectious Disease Report states that there are 146 vaccines to pre vent diseases from staph infections to pneumo coccal infections; 83 antibiotics; and 75 antivi rals for treating such viruses as hepatitis, herpes, and influenza in clinical trials or awaiting approval from the Food and Drug Administra tion. Despite what appears to be a substantial cadre of new products in the pipeline, a Phar macor report from January 2007 finds the late stage antibacterial pipeline is not keeping up with the increasing need for novel agents to tar get drugresistant bacteria. The Pharmacor report finds that the late stage pipeline is skewed toward products tar geting the crowded market of resistant Gram positive infections, but the true commercial opportunity may lie in novel classes in earlier stages of development. “The cost of development has hampered research and development efforts into antimi crobials, prompting large companies to seek out contract research services, an industry that is growing at exceptional rates,” Ms. Elder says. “More complex products have been shown to require larger amounts of investment.” According to Decision Resources analysts, developing new drug classes remains a chal lenge in antibacterial R&D. In the past decade, only two entirely new antibacterial classes have been introduced to the market: oxazolidinones and lipopeptides. Although companies have found some suc cess with spinoffs of existing classes, such as the ketolides and glycylcy clines, experts emphasize that agents with entirely novel mechanisms of action are needed. “One of the most com plex issues for smaller companies is that the reg ulatory environment is becoming murkier and more challenging,” says Susan Froshauer, Ph.D., president and CEO of Rib X Pharmaceuticals Inc. “We have serious valuecreation goals and bud get drivers from our investors and, therefore, need to operate with defined timelines. An uncertain regulatory environment slows down progress. I suspect that the regulatory environ ment will stabilize as more discussion unfolds during advisory meetings in the months ahead, but in the meantime, trial design discussions with the regulatory agency can take some time.” Despite the barriers, there are a few products showing promise. Astellas Pharma US and Theravance Inc. received an FDA approvable letter in October 2007 for Arbelic (telavancin) for use in treating complicated skin and skin structure infections (cSSSIs) caused by Gram positive bacteria, including MRSA. Arbelic also is in Phase III development for the treatment of hospitalacquired pneumonia, including patients with ventilatorassociated pneumonia caused by Grampositive bacteria. Another lipoglycopeptide in the pipeline is oritavancin, which is being developed by Tar ganta Therapeutics Corp. Phase II and III trials have shown promise against MRSA and van comycinresistant pathogens, such as enterococ ci and staphylococci. There are two nextgeneration cephalosporins being investigated. Ceftobiprole is being developed through a collaboration between Basilea Pharmaceutica and Johnson & Johnson Pharmaceutical Research & Develop ment. It is a broadspectrum cephalosporin that has demonstrated positive results in two Phase III trials in cSSSIs. Basilea also is conducting Phase III clinical BACTERIAL infections DR.BARRY EISENSTEIN Cubist Pharmaceuticals There is now the diversion of resistant pathogens that common empiric treatments no longer cover. THE END RESULT IS AN INCREASE IN MORTALITY. rimary to the defenses of bacteria are their complexouter structures:the”capsule,”the”cell wall,”and the “cytoplasmic membrane.”It is these structures that first protect the bacteria from foreign compounds, like antibiotics. In general, bacteria become resistant to antibiotics by using three major strategies. The first is to prevent the drug from reaching its target. Some bacteria accomplish this by having a “doublemembrane” layer to retard the entry of the compound into the cell. Other bacteria simply expel the drugs from inside the cell using pumps located in the membrane. The second strategy bacteria employ to become drug resistant is to produce enzymes that physically alter the antibiotic so that it can no longer bind to its cellular target. The third strategy is to physically alter the cellular target (the ribosome) so that an antibi otic can no longer bind and inhibit its function. Bacteria can use any combination of these methods to resist the action of antibiotics, rendering them therapeutically ineffective. DNA mutations that allow bacteria to become antibiotic resistant occur as a natural con sequence of the bacteria duplicating their DNA.Such mutations typically occur infrequently, but because bacteria can reproduce every 20 minutes, mutations are much more common than in human cells. In addition to random mutation, bacteria are often able to exchange their DNA with one another thereby transferring resistance determinants to their antibioticsensitive neighbors. By employing these strategies,bacteria have virtually assured themselves of ways to develop resistance to the antibiotics in use today. Source:RibX Pharmaceuticals Inc., New Haven,Conn.For more information, visit ribx.com. UNDERSTANDING DRUG RESISTANCE P 35 PharmaVOICE F e b r u a r y 2 008 0208issue FINAL 1/18/08 5:35 PM Page 35 36 F e b r u a r y 2008 PharmaVOICE BACTERIAL infections studies of ceftobiprole for the treatment of hos pitalacquired pneumonia. Ceftobiprole is currently under review with the FDA, with the European Medicines Agen cy, and Health Canada for cSSSIs. Upon approval, the product will be marketed by OrthoMcNeil Inc. in the United States and JanssenCilag in Europe and Asia. Ceftaroline, which is being developed by Forest Laboratories, is another broadspectrum cepha losporin to receive FDA fasttrack review for cSSSIs caused by MRSA. Further in the pipeline are products from both RibX Pharma ceuticals and Cubist. “Our most advanced pro grams target MRSA, but we also are closely looking at multidrug resistant Gramnegative organisms as well,” RibX’s Dr. Froshauer says. “We have potent molecules that are tightly bound to the bacterial ribosome, and this suggests that higher levels of bacterial resis tance may be tolerated before a drug becomes resistant.” RibX’s technology platform is based on the highresolution crystal structure of the 50S sub unit (the large subunit) of the ribosome. One product is RX3341 (WQ3034 or ABT492), a quinolone antibiotic with broad spectrum activity against MRSA and other Grampositive pathogens resistant to other quinolones. RibX has an agreement with Japanbased Wakunaga Pharmaceutical Company to develop and commercialize the product worldwide. The product is about to enter Phase III studies in an IV formulation. RibX also has an agreement with Molec ular Biology of the Medical Research Coun cil of London to explore the high resolution crystal structure of the full 70S ribo some recently determined by MRC’s ribosome scientist. Cubist is conducting Phase II develop ment of Cubicin in highdose short duration and a Phase II comparative dose study in pros thetic joint infections. # PharmaVOICE welcomes comments about this article.Email us at feedback@pharmavoice.com. DR.SUSAN FROSHAUER RibX Pharmaceuticals THE MOSTCOMPLEX ISSUE FOR SMALLER COMPANIES DEVELOPING ANTIBACTERIALS IS THE REGULATORY ENVIRONMENT,which is becoming murkier and more challenging. BARRY I. EISENSTEIN,M.D.Senior VP, Scientific Affairs, Cubist Pharmaceuticals Inc., Lexington,Mass.; Cubist Pharmaceuticals is a biopharmaceutical company focused on developing and commercializing antiinfective therapies for the acutecare environment.For more information, visit cubist.com. MELISSA ELDER. Analyst, Kalorama Information,New York; Kalorama Information,a division of Market Research Group,publishes market research in medical markets, including the biotechnology,diagnostics, healthcare, medicaldevice,and pharmaceutical industries. For more information, visit kaloramainformation.com. SUSAN FROSHAUER,PH.D.President and CEO,RibX Pharmaceuticals Inc., New Haven,Conn.;RibX Pharmaceuticals is a productdriven, smallmolecule drug discovery and development company focused on the structurebased design of new classes of antibiotics. For more information, visit ribx.com. Experts on this topic MARKET DRIVERS The increasing prevalence and diversity of bacterial resistance to an antibiotic or class of antibiotics will fuel a continuous need for novel therapies that are unaffected byexisting resis tance mechanisms. The hospital Grampositive market is set to expand significantly. Generic vancomycin is the current patientshare leader for treating hospitalacquired infections (HAIs) caused by drug resistant Grampositive pathogens. Therapeutic antibodies (TAs) represent a new approach to the treatment of bacterial infec tions, including those caused by MRSA.Because TAs will command a significant price premi um and will be used in combination with antibiotic therapy, they will have an additive effect on the market. MARKET LIMITERS The patents of several key antibiotic products will expire over the next 10 years. Generic erosion of these products will be the most significant constraint on antibiotic sales. Despite the increasing incidence of communityacquired infections caused by drugresistant pathogens, U.S. managed care organizations will likely restrict the use of premiumpriced branded products in favor of equally safe and effective lowerpriced generics. In the hospital setting, formulary and infection control officials will limit the use of both advancedgeneration compounds from existing classes and innovative agents from novel drug classes.Agents from novel drug classes will face restricted use because infection control officials will want to limit the development of resistance and preserve their activity. Source:Decision Resources,Waltham,Mass.For more information, visit decisionresources.com. THE ANTIBACTERIAL MARKET The estimated number of people developing a serious MRSA infection in 2005 WAS 94,360. ABOUT 18,650 PEOPLE DIED during a hospital stay related to an MRSA infection. Centers for Disease Control 0208issue FINAL 1/18/08 5:35 PM Page 36

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