Companies Seeking Solutions To Emerging Drug Resistance

PHASE III NEARS: Cubist Pharmaceuticals has a promising antibiotic--daptomycin--that the company hopes to have in Phase III clinical trials in late 1998 or early 1999. Bacteria are back. Following the discovery and introduction into medicine of penicillin in 1941, intense research in microbiology produced a potent armament of antibiotics that all but eliminated a variety of infectious diseases. With this success, many large pharmaceutical companies scaled back research and development of new compounds. But in the last decade, physicians and epidemiologists have seen resistance to antibiotics surge. Along with some pharmaceutical companies, small biotechnology firms now lead the drive against drug- resistant bacteria. Data collected by the Synercid Microbiology Assessment of Resistance Trends (SMART)--a surveillance project run by the State University of New York (SUNY) at Buffalo and the University of Iowa College of Medicine--show increasing drug resistance in the United States. More than 31 percent of 17,000 bacterial isolates of Streptococcus pneumoniae obtained from patients at U.S. hospitals were intermediately or completely resistant to penicillin, according to SMART reports. The rate of methicillin-resistant Staphylococcus aureus (MRSA) also has steadily increased to nearly 30 percent nationwide. "Increasing resistance to antibiotics alone is a major reason for concern in health care," warns Jerome J. Schentag, a professor of pharmacy at SUNY-Buffalo and director of the clinical pharmacokinetics laboratory at Buffalo's Millard Fillmore Hospital. Schentag also is director of the Resistance Web, a new Internet site (http://resistanceweb.mfhs.edu) that provides data on the use of antibiotics and the prevalence of drug-resistant strains in U.S. hospitals. "What perhaps is most alarming is that we're seeing resistant strains once found only in hospitals now appearing in the community," Schentag adds. For example, a team of University of Chicago Children's Hospital researchers reported that MRSA now infects children outside of hospital settings and without any identifiable risk factors for the disease (B.C. Herold et al., JAMA-Journal of the American Medical Association, 279:593-8, 1998). AMBI Inc. 771 Old Saw Mill River Rd. Tarrytown, N.Y. 10591 (914) 347-5767 * Fax: (914) 347-6370 Cubist Pharmaceuticals Inc. 24 Emily St. Cambridge, Mass. 02139 (617) 578-1999 * Fax: (617) 576-0271 http://www.cubist.com Demeter Biotechnologies Ltd. 905 W. Main St. Suite 20B Durham, N.C. 27701 (919) 682-7181 ekstromrd@aol.com IntraBiotics Pharmaceuticals Inc. 1245 Terra Bella Ave. Mountain View, Calif. 94043 (650) 526-6800 * Fax: (650) 969-0663 Rhône-Poulenc Rorer Inc. 500 Arcola Rd. P.O. Box 1200 Collegeville, Pa. 19426-0107 (610) 454-8000 http://www.rp-rorer.com RiboGene Inc. 26118 Research Rd. Hayward, Calif. 94545 (510) 731-1773 * Fax: (510) 731-1775 XOMA Corp. 2910 Seventh St. Berkeley, Calif. 94710 (800) BIO-XOMA * Fax: (510) 644-0471 http://www.xoma.com Potential markets for new therapies for drug- resistant bacteria are huge. The Centers for Disease Control and Prevention etimates that antibacterials are the third-largest pharmaceutical market, with annual sales totaling $6 billion in the U.S. and $23 billion worldwide. Va comycin alone generates about $250 million in sales worldwide. MRSA, which accounts for 108,000 of 270,000 cases of hospital-acquired Staphylococcus aureus (SA) infections in the U.S., could produce sales of more than $20 million, according to estimates by Tarrytown, N.Y.-based AMBI Inc., a biotechnology firm developing two promising strategies against drug-resistant infections. The savings that could result from breakthroughs in treatment for drug-resistant bacteria are similarly impressive. A Duke University study presented last September at the Interscience Conference on Antimicrobial Agents and Chemotherapy in Toronto found that drug-resistant infections acquired in hospitals nearly triple the cost and duration of a hospital stay from $9,661 to more than $27,000 and from four days to 12 days. In the 1980s and early 1990s, many large pharmaceutical companies cut back or eliminated antibiotics research and development. They believed that infectious disease caused by bacteria finally had been conquered and that markets for new drugs were limited, recalls Jean-Francois Desnottes, pharmacological director for antibacterial research and development at Rhône-Poulenc Rorer (RPR) in Paris. RPR, however, hopes to soon win U.S. Food and Drug Administration (FDA) approval for its antibiotic combination Synercid (quinupristin/dalfopristin). Taken alone, quinupristin and dalfopristin are moderately active against bacterial infections. Together, they are 16 times more potent against protein synthesis, which is essential for bacterial proliferation. Recent trials by SMART show that the antibiotic combination is active against more than 90 percent of vancomycin-resistant Enterococci faecium in clinical bacterial isolates. In comparison, antibiotics such as ampicillin, oxacillin, cefazolin, and erythromcyin are virtually inactive against resistant strains of Enterococci faecium. By binding to ribosomes, Synercid prevents the replication of invading bacteria. Because the compound is bactericidal, researchers are hopeful that resistance will not develop anytime soon. "Unlike traditional antibiotics, Synercid does not merely slow the growth of bacteria; the drug is lethal to them," Desnottes explains. "Looking far into the future, you can never rule out the development of Synercid-resistant strains of bacteria. Evolution is on their side. However, by rapidly killing bacteria, you reduce the potential for selection pressure to give rise to resistant strains." Other pharmaceutical giants have joined the race to develop antibiotics that work against drug-resistant bacteria. Currently in Phase II clinical trials, oxazolidinones are the first new class of antibiotics in 15 years from Bridgewater, N.J.-based Pharmacia and Upjohn Inc. Recent studies by the company show the antibiotics are active against MRSA and a variety of drug-resistant Streptococcus pneumonia (SP) (C.W. Ford et al., Antimicrobial Agents and Chemotherapy, 40:1508-13, 1996). Researchers at Pharmacia and Upjohn believe that oxazolidinones inhibit growth by binding to ribosomal subunits on bacteria. Cubist Pharmaceuticals Inc., based in Cambridge, Mass., has a promising new antibiotic--daptomycin--that could face off against Synercid in the marketplace. Daptomycin is a lipopeptide that binds to lipoteichoic acid in Gram-positive bacteria. In vitro, the compound is active against all Gram- positive bacteria, including MRSA, PRSP, and vancomycin-resistant strains of Staphylococus aureus. Late in 1998 or early in 1999, Cubist expects to begin Phase III clinical trials of daptomycin in patients with skin and soft tissue infections and urinary infections. Unlike Synercid, which must be administered via a central venous catheter, daptomycin can be given via a peripheral venous catheter, explains Susan K. Whoriskey, director of scientific licensing at Cubist. FUTILE RESISTANCE: Cubist's Scott Rockledge says bacterial resistance to daptomycin has been on the edge of being measurable. While the eventual development of drug resistance always worries researchers, it has not been a major concern for scientists working on daptomycin. "I would be a fool to pretend that this issue has not crossed our minds," Scott Rockledge, CEO of Cubist, acknowledges. "The history of antibiotics shows that you can never in principle rule out the possibility of drug resistance developing. But our studies show that this is a minimal concern for daptomycin. In fact, resistance was on the edge of even being measurable." In vitro studies by Cubist indicate that less than 1 in 10 billion bacteria is resistant to daptomycin. Interest by pharmaceutical companies in renewing antibiotic research has sparked alliances with biotech firms specializing in mapping the genomes of organisms and screening for potential drug targets. Microcide Pharmaceuticals Inc., headquartered in Mountain View, Calif., is collaborating with New York-based Pfizer Inc. in using bacterial genomics to discover novel classes of antibiotics. RiboGene Inc., based in Hayward, Calif., also has teamed up with pharmaceutical companies to identify promising targets and compounds. In partnership with Dainippon Pharmaceutical Co., based in Osaka, Japan, RiboGene developed a screening system to identify compounds that cause the accumulation of guanosine tetraphosphate, which triggers bacterial adaptive responses in conditions of stress. The company also has developed a screening system for the discovery of deformylase inhibitors. Formyl is a residue produced by newly synthesized proteins in bacteria and must be removed by deformylase enzymes so that the proteins can become functional. "Mammalian cells do not formylate proteins and therefore do not need deformylase activity," explains Laura Lehman, vice president of research at RiboGene. "So inhibitors of this process naturally would show great promise as selective antibacterial agents." Investigators and corporate leaders in the field of antimicrobials say the emergence of drug-resistant bacteria has reinvigorated research in microbiology. Opportunity in this discipline all but vanished in the 1980s and early 1990s. "The 1970s were a golden age of antibiotic development," Whoriskey relates. "Then the big pharmaceuticals assumed they finally licked infectious disease and ended many research programs." Whoriskey says many large pharmaceutical firms have taken the emergence of drug resistance as a cue to get back into antibiotic development. For example, Medford, Mass.-based ArQule Inc. and Madison, N.J.-based Schering-Plough Corp. are working with genetics firms to identify antimicrobial targets and compounds. "Drug resistance has made pharmaceutical companies and biotech firms take notice of the need and enormous market for new antibiotic compounds," she explains. "I think we will be seeing a boom in this area of research." NATURAL CANDIDATE: Because it is derived from proteins found in human white blood cells, XOMA's rBPI21 has regulatory advantages over other novel treatments for infectious disease. Even with renewed interest from large pharmaceutical companies, Patrick Scannon, chief scientific and medical officer at XOMA, notes that biotech firms still have the upper hand in research and development of novel antibiotics. "Biotechnology has traditionally assumed the task of discovering new mechanisms of action against disease," he declares. "So it is not surprising that biotech firms have taken the lead in the fight against drug-resistant infections." Companies such as Cubist offer a variety of research opportunities. In the last three years, Cubist has seen its staff grow from 40 to 72 employees, of whom 60 are engaged primarily in research. Whoriskey says the company employs researchers in a wide range of disciplines, including microbiology, organic and inorganic chemistry, and informatics. "This variety reflects our interdisciplinary approach to discovery and development," she says. RESTORED STRENGTH: XOMA's Neuprex has been shown to enhance the performance of antibiotics against tough drug-resistant bacteria. Some biotech firms have looked to the body's own defenses against infection for strategies against drug-resistant bacteria. One of these companies is XOMA Corp., based in Berkeley, Calif. Taking inspiration from the body's own defenses against infection, XOMA has developed rBPI21, a compound known as Neuprex. The compound is derived from bacterial/permeability increasing protein (BPI), which is found in human white blood cells and plays a crucial role in the body's host-defense systems against infection. Studies by XOMA show that the compound--whether taken alone or as an antibiotic adjuvant--is effective against a variety of tough infections that often afflict patients with cystic fibrosis (CF). In vitro studies led by Lewis Lambert, director of medical microbiology at XOMA, indicate that rBPI21 enhances the activity of 13 antibiotics commonly used to treat respiratory infections in CF patients. Taken alone, rBPI21 was bactericidal against drug-resistant strains of Pseudomonas aeruginosa isolated from CF patients. BPI was discovered in 1978 by Peter Elsbach and Jerrold Weiss, both professors of microbiology at New York University (J. Weiss et al., Journal of Biological Chemistry, 253:2664-72, 1978). They found that natural host defenses against bacteria rely on three crucial activities--the regulation of specialized cells and proteins that block bacterial proliferation, the clearance of toxic microbial material, and the down-regulation of the host's inflammatory responses that are often toxic when uncontrolled. BPI plays a critical role in all three activities. For example, BPI kills or weakens proliferation by increasing permeability of cell membranes. BPI also appears to be highly effective at suppressing toxic inflammatory responses to infection. From a regulatory point of view, rBPI21 has advantages over other novel treatments for infectious disease. "BPI is a native protein in humans and plays an important role in natural resistance," Lambert explains. "With Neuprex, we are not really introducing a foreign compound to the body." Therefore, FDA may be more comfortable with XOMA's compound than with other drugs not based on a human protein. But Lambert adds, "Some researchers worry that if resistance would develop to BPI-derived compounds, then natural BPI would be eliminated as a defense mechanism in humans. However, we have not found this to be an issue because we have not seen resistance developing to rBPI21 even when we have attempted to induce it." SWEEPING ACTION: According to IntraBiotics' John Fiddes, the broad spectrum of activity of the company's protegrin analogs makes resistance unlikely. IntraBiotics Pharmaceuticals Inc., a biotech firm based in Mountain View, Calif., hopes it can harness the host defense system of pigs in the battle against drug-resistant bacteria. The company is developing synthetic versions of protegrins, which are naturally occurring antimicrobial peptides. They were discovered in pigs in 1994 by Robert I. Lehrer, a professor of medicine at the University of California, Los Angeles. In vitro, protegrin analogs developed by IntraBiotics show activity against a wide range of microorganisms, including fungi and drug-resistant bacteria. Recent studies show that IB-1, IntraBiotics' first protegrin-based compound, rapidly kills MRSA in vitro and improves mortality rates in MRSA and vancomycin-resistant Enterococci faecalis -injected animal models (D.A. Steinberg et al., Antimicrobial Agents and Chemotherapy, 41:1738-42, 1997). IB-367, another pro-tegrin in development at the company, is in Phase I clinical trials for the prevention of oral mucositis, a bacterial infection inside the mouth caused by chemotherapy and associated with difficult-to-treat complications. IntraBiotics also is developing analogs of protegrin for use in the treatment of multidrug-resistant respiratory infections in CF patients and drug-resistant systemic infections. "Preclinical trials indicate that protegrins show great promise in fighting drug-resistant organisms," reports John Fiddes, vice president for research and development at IntraBiotics. "We don't completely understand their mechanism of action. However, they do not appear to target specific enzymes of a pathogen. Instead, they seem to rapidly kill a broad spectrum of disease pathogens by destroying the cell membrane." He adds that "this is reason for hope because this mechanism of action and broad spectrum of activity mean that pathogens are unlikely to develop resistance to the compound." Demeter Biotechnologies Ltd. is one of the smallest biotech firms taking aim at drug-resistant bacteria. Based in Durham, N.C., Demeter employs only seven workers, three of whom are engaged primarily in research. Preclinical trials show that Demeter's peptidyl membrane interactive molecules (PMIMs) rapidly kill a number of drug- resistant bacteria, according to Demeter president Richard D. Ekstrom. In vitro, PMIMs were active against both MRSA and vancomycin-resistant Enterococci. Moreover, antibacterial activity was achieved using concentrations of peptidyl membrane interactive molecules 10 to 20 times below levels cytotoxic to liver cells. "Naturally, this result is encouraging because it is a common indicator of the safety of a drug for human consumption," Ekstrom says. PMIMs attack bacteria by attaching to the cell membrane, explains Jesse Jaynes, chief of research at Demeter. "The compound interacts with the cell surface and triggers an osmotic process," he says. "The cell then cannot maintain equilibrium and literally bursts. The development of bacterial resistance to PMIMs is not a major concern because the compound attacks the cell membrane, which may not be subject to selection pressures that bring on resistance." Demeter has taken a different approach to expanding research opportunity. The company has collaborated with more than 20 universities in exploring novel uses of PMIMs and continues to seek new research partners. Recent collaborators include San Diego-based Mycogen Corp., which will examine the use of PMIMs in making transgenic, disease-resistant crops. Researchers can expect efforts in the development of novel antibiotics to grow in the years to come, Ekstrom says. "In the past, multidrug resistance was not a major concern because effective alternative drugs were always available," he explains. "The emergence of VRSA sounded an alarm to researchers--pan-antibiotic resistance has become a possibility."

Companies Seeking Solutions To Emerging Drug Resistance

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