[PDF Agenda]     Day 1 Day 2   Day 1 - Monday, September 22, 2008     7:00 Registration & Breakfast     7:55 Welcome and Opening Remarks   Roger Echols, Consultant, Infectious Disease Drug Development Consulting (ID3C)     Session I - Novel Approaches to Problematic Pathogens, Part I – Community-Acquired Infections Moderator: Roger Echols, Infectious Disease Drug Development Consulting (ID3C)       8:00 Overview of the Antibacterial Market for Hospital Acquired Infections and Future Areas of Opportunity   Danielle Drayton, Ph.D., Therapeutic Area Director, Infectious Diseases & DecisionBase, Decision Resources       Hospital-acquired infections (HAIs) represent a high-value, high-unmet-need segment of the antibacterial market. This space is characterized by an expanding population of at-risk patients and growing prevalence and diversity of antibiotic-resistant pathogens. Over the last two decades, drug development for HAIs has focused on gram-positive pathogens, namely methicillin-resistant Staphylococcus aureus (MRSA). As a result, the pipeline is saturated with agents targeting gram-positive infections. Drug developers seeking commercial success in the HAI market will face stiff competition from established therapies, heightened regulatory scrutiny, and more stringent reimbursement policies. Key questions Answered in this presentation: • What are the most important trends and drivers for antibacterial drug development for HAIs over the next ten years? • What are the most promising near-term and long-term candidates in the pipeline? • Where are the high growth segments and opportunities in the HAI market and who is best positioned to capitalize upon them?       8:30 Diarylquinoline, Targeting ATP Synthase, as Novel Antimycobacterial Drugs   Anil Koul, Ph.D., Department of Antimicrobial Research, Tibotec, Johnson & Johnson       Diarylquinoline (TMC207), a new antibiotic, for treatment of mycobacterial infections • The diarylquinoline (TMC207) is a promising candidate in clinical development for the treatment of tuberculosis. • We established by genetic mutants, biochemical assays, compound linked affinity binding studies and BIAcore assays that the oligomeric subunit c (AtpE), a component of ATP synthase, is the target of R207910. The researchers pin-point that subunit-c, which is involved in proton translocation across ATP synthase, is the real binding site of compound. Binding to subunit –c likely leads to inhibition of proton transport which is coupled to ATP synthesis. Thus the compounds shut the energy supplies of the bacteria leading to cellular power breakdown. • We show the efficacy of this compounds on dormant/latent mycobacterial infections and establish clinical POC in Phase IIa trails. • Thus targeting ATP synthase or energy metabolism is a new, promising approach for antibacterial drug discovery.       9:00 NXL103, A Novel Oral Streptogramin for the Treatment of Resistant Gram Positive Infections   Carole Sable, Chief Medical Officer, Novexel SA       Resistance in Gram positive pathogens, most notably methicillin resistance in S. aureus, continues to increase in prevalence and spread into the community. A number of new agents with activity against MRSA have been approved or are in late stage development. However, most have only intravenous formulations. Linezolid is available as an oral formulation but has limitations. A safe and effective oral agent from a novel class would be a welcome new therapeutic alternative. NXL103 is a novel streptogramin comprised of two components (PI and PII). It is bactericidal and has potent in vitro activity against S. aureus (including CA-MRSA), S. pneumoniae, group A streptococci, H. influenzae, M. catarrhalis and atypical pathogens with MIC90s < 1 µg/mL. NXL103 has been evaluated in several Phase I studies in healthy subjects. The most common adverse events were nausea and vomiting, but no serious or severe adverse events were reported. The half life supports twice daily dosing. NXL103 is metabolized primarily through CYP3A4. Enrollment in a Phase II study of mild to moderate community acquired pneumonia (CAP) was recently completed. This was a double blind, randomized, multicenter comparative study of 2 doses of NXL103 vs. amoxicillin in 300 adult patients. Data are expected later this year. If developed successfully, NXL103 may be an alternative treatment for skin and skin structure infections and CAP, including those due to resistant Gram positive pathogens. Benefits: • Resistant infections are increasing in prevalence and spreading to the community • Limited oral options: NXL103 novel oral streptogramin may address this need • Review of key regulatory issues for study design for community acquired infections       9:30 Emerging Resistance among Community Gram Negative Bacilli   John P. Quinn, Senior Advisor, Antibacterials, Pfizer       Although extended-spectrum beta-lactamases (ESBLs) have been problematic in nosocomial enterics for 20 years, it is only in the past few years that they have emerged in community settings. Several investigators in Europe and Canada have reported CTX –type ESBLs in community E coli. In the UK in 2007, ~ 20 % of blood isolates of E coli harbored such enzymes. In January 2008 an international collaborative group described transcontinental spread of a specific clonal group, MLST-131, harboring CTX-M 15. In addition to beta-lactam resistance, these organisms are typically cross resistant to unrelated classes including TMP-SMX, quinolones, and aminoglycosides. In addition, they have enhanced virulence properties which facilitate invasive disease. At Cook County Hospital in Chicago, a public institution caring for the poor, the prevalence of an ESBL phenotype among community E coli rose from 0 % in 2002 to 4 % in 2007, while ESBL rates in Klebsiella were unchanged. These organisms were primarily from urine although a variety of other sites were noted including the blood. Molecular analysis revealed that these were MLST 131 clonal group isolates carrying CTX M 15. Preliminary chart review revealed that 10 of the first 12 patients had risk factors such as recent hospitalization and/or antibiotic therapy. The emergence of clones of ESBL producing, hypervirulent E coli in the community is disturbing, particularly in light of the concomitant rise in quinolone resistance in this species. This will drive the use of more expensive alternatives, such as carbapenems.       10:00 Refreshment Break and Networking       10:30 Application of Pharmacokinetics/Pharmacodynamics in the Clinical Development of Ceftobiprole, a Broad Spectrum Cephalosporin with Anti-MRSA Activity   Bindu Murthy, Pharm.D., Associate Director, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb       Ceftobiprole, a beta-lactam, is the first of a new generation of broad-spectrum cephalosporins in late-stage development with activity against methicillin-resistant Staphylococcus aureus (MRSA) in addition to broad-spectrum bactericidal activity against other Gram-positive and Gram-negative pathogens. Phase III trials in patients with complicated skin and skin structure infections are complete and trials are ongoing in patients with nosocomial and community-acquired pneumonia. During the course of anti-infective drug development, pharmacokinetic/pharmacodynamic (PK/PD) relationships are an important tool used for dose selection, in order to target certain pathogens and effectively treat various types of infections. This workshop addresses how these relationships were used to optimize dose selection for ceftobiprole, and the impact of these decisions on clinical outcomes. The objectives of the seminar are as follows: • Describe techniques used to evaluate PK/PD relationships for anti-infective compounds • Review clinical development program for ceftobiprole • Describe how results were used for dose selection for Phase 3 trials • Discuss the results of the Phase 3 clinical trials in patients with complicated skin and skin structure infections     Session I - Novel Approaches to Problematic Pathogens, Part II – Hospital-Acquired Infections Moderator: Barry Eisenstein, Cubist Pharmaceuticals       [FEATURED PRESENTATION]   11:00 Telavancin: A Novel Lipoglycopeptide Gram-Positive Antibiotic   Sharath Hegde, Ph.D., Vice President, Pharmacology, Theravance, Inc.     Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), are a major cause of serious nosocomial infections. Vancomycin, a glycopeptide that was introduced more than 50 years ago, still serves as the cornerstone in the treatment of drug-resistant Gram-positive infections. However, there are significant concerns over increases in rates of resistance to this agent among Enterococcus species and Staphylococcus aureus. Furthermore, the slowly bactericidal nature of vancomycin may be, in part, responsible for reported clinical failures when using this drug. The growing awareness of the limitations of vancomycin has served as an impetus for the development of newer agents. Telavancin (TLV) is an investigational lipoglycopeptide antibiotic that has broad-spectrum activity against Gram-positive bacteria, including MRSA and strains with reduced susceptibility to vancomycin. Telavancin's multifunctional mechanism of action, including inhibition of peptidoglycan synthesis and disruption of membrane potential, account for this enhanced activity as well as rapid bactericidal properties. TLV is a once-daily dosed antibiotic, and its pharmacodynamically-linked parameter is AUC/MIC. Several preclinical studies have demonstrated that telavancin is efficacious in animal models of soft-tissue (thigh) and deep-seated (endocarditis, bacteremia, pneumonia, meningitis and osteomyeletis) infections. Telavancin has been shown to be efficacious in Phase 3 clinical studies in patients with complicated skin and skin-structure infections (cSSSI) and hospital acquired pneumonia (HAP). Telavancin appears to be a promising agent for the treatment of serious infections caused by Gram-positive pathogens, including drug-resistant pathogens.           11:30 Virulence of Antibiotic-Resistant Pseudomonas Aeruginosa: Implications for Novel Therapeutics   Annie Wong-Beringer, Pharm.D., Associate Professor of Pharmacy, University of Southern California, School of Pharmacy       1. Pseudomonas aeruginosa is recognized by the Infectious Diseases Society of America as one of 6 drug-resistant microbes that poses an immediate threat to public health due to its leading role in causing hospital acquired infections, rapid emergence of multidrug-resistance and a relative lack of new antibacterial agents being developed in the pipeline. 2. Fluoroquinolone antibiotics are the most frequently prescribed antibiotics to adults in the U.S. 3. Development of Pseudomonas resistance towards the fluoroquinolones tripled in parallel to its widespread use. 4. Infections caused by fluoroquinolone-resistant Pseudomonas are associated with more prolonged illness and higher mortality compared to those caused by susceptible strains. 5. Fluoroquinolone-resistant Pseudomonas strains appear to be virulent than susceptible strains – they are more cytotoxic to human lung epithelial cells in vitro mediated by toxins secreted via the type III secretion system, a major virulence determinant of Pseudomonas aeruginosa during acute infections.       12:00 A Pseudomonas Antimicrobial with a Novel Mechanism of Action   Mark Alfenito, Head of Technology Licensing, KaloBios Pharmaceuticals, Inc.       Pseudomonas aeruginosa is growing increasingly resistant to antibiotics. Because new antibiotics are generally derivatives of established classes, Pseudomonas has pre-existing machinery to inactivate or to mutate around many of these second generation drugs. Dramatically new mechanisms of action are needed. We have developed a human, PEGylated Fab’ fragment directed against the Type III Secretion System of Pseudomonas that shows potent in vitro and in vivo activity on all Type III secreting strains of P. aeruginosa tested. Clinical trials are on going in cystic fibrosis and in mechanically ventilated patients. Most recent data will be shown.       12:30 Lunch       1:30 Modification of b-Lactam Antibiotics to Overcome Bacterial Resistance   Malcolm Page, Head, Discovery Biology, Basilea Pharmaceutica International Ltd.       Beta-lactam antibiotics are the among the most frequently used drugs to treat bacterial infections. Resistance has inevitably become widespread and may involve multiple mechanisms. In Gram-positive bacteria the principle mechanisms are penicillinases and target proteins (penicillin-binding proteins, PBPs) that are either intrinisically non-susceptible (e.g. in methicillin-resistant staphylococci, MRSA), or have been mutated to become resistant (e.g. in penicillin-resistant Streptococcus pneumoniae, PRSP), to inhibition by b-lactams. Among the Gram-negative bacteria one finds a plethora of b-lactamases that may be combined with modified influx or efflux across the outer membrane to provide effective protection against the antibiotics. Altered pennicillin-binding proteins are less common, although they have been implicated in resistance in some species (e.g. H. influenzae). Successive generations of b-lactam antibiotics have been developed to obtain stability towards penicillinases and the broad spectrum b-lactamases. More recently, novel cephalosporins and carbapenems that are able to overcome the PBP-mediated resistance in MRSA and PRSP have entered development and a number of experimental approaches to tackling the more complex resistance of Gram-negative bacteria have been described. The mechanism of action of anti-MRSA b-lactams and experimental anti-Gram-negative b-lactams will be reviewed.       2:00 Aminoglycosides for the 21st Century: Aspects of Design and Development   Jon B. Bruss, M.D., Chief Medical Officer, Achaogen, Inc.       Aminoglycosides are a well known class with an established record of efficacy and safety, particularly against Gram-negative bacterial pathogens. They were first administered to humans over 50 years ago when streptomycin was introduced for the treatment of tuberculosis. Over the ensuing decades, several other compounds in the class were subsequently developed and approved, including gentamicin, tobramycin, and amikacin, all of which continue to share a role in treating Gram-negative bacteria. Today, Gram-negative pathogens are rapidly acquiring multiple drug resistance factors, including ESBLs, metallo-β lactamases, Klebsiella pneumoniae Carbapenemases, DNA gyrase mutations, and AMEs, that threaten to render all known classes of antibiotics ineffective. As a result, there is renewed interest in novel approaches to older classes with known Gram-negative efficacy that address these resistance mechanisms. In addition to diminishing efficacy due to resistance, the older aminoglycosides continue to face concerns about safety, particularly when the compounds are dosed according to current label recommendations. The primary adverse reactions associated with the class is nephrotoxicity and to a lesser extent ototoxicity. Advances in our understanding of the pharmacokinetics as well as the pathophysiology of aminoglycoside-associated toxicity have provided a basis for maximizing the bactericidal efficacy while ameliorating the toxicities. Newer members of the class that overcome the resistance mechanisms expressed by Gram-negative pathogens can be optimally developed to meet a significant unmet medical need. This lecture will present the historical landscape for aminoglycoside class and present new opportunities for developing new members of the class that overcome resistance mechanisms, maximize efficacy, and manage potential toxicity.       2:30 Oritavancin, a Potent Lipo-Glycopeptide with Unusual Pharmacokinetic Properties that May Allow Single or Infrequent Dosing Schedules   Thomas Parr, Ph.D., Chief Scientific Officer, Targanta       Oritavancin is a novel semi-synthetic lipoglycopeptide antibiotic with potent bactericidal activity against a broad spectrum of gram-positive bacteria. The product candidate has been tested in over 2,400 subjects and has completed two Phase 3 studies for the treatment of complicated skin and skin structure infection (cSSSI) in which the primary endpoints were met. In addition, oritavancin completed two Phase 2 trials for the treatment of bacteremia, also with successful outcomes. The U.S. NDA and European Union MAA submissions for the first indication have been made with the U.S. PDUFA date is December 8, 2008. Targanta believes oritavancin's properties may give it distinct advantages over currently marketed therapies. The molecule is rapidly bactericidal with strong in vitro potency. In clinical studies to date there was a lower incidence of adverse events vs. the comparators. Favorable pharmacokinetics may also enable less than once a day dosing. Targanta has concluded enrollment in a Phase 2 single/infrequent dosing study of oritavancin in the treatment cSSSI. In this trial (“SIMPLIFI”) a single dose for cure, vs. two dose therapy is being compared to the once a day for 3-7 days therapy that was successful in Phase 3 studies. Oritavancin is also being examined preclinically for the treatment of Clostridium difficile colitis and inhalation anthrax. If ultimately approved for commercialization, Targanta believes that oritavancin could provide physicians with an efficacious and novel antibiotic for the treatment of serious gram-positive infections while providing significant pharmacoeconomic benefits by reducing the need for patient monitoring and shortening hospital stays.       3:00 Addressing the Challenge of Gram-Negative Resistance   Nafsika Georgopapadakou, Ph.D., Vice President, Research, NovaBay Pharmaceuticals       Gram-negative bacteria cause a variety of nosocomial and community-acquired infections. Their resistance to an increasing number of commonly used antibiotics – b-lactams, quinolones, aminoglycosides, tetracyclines, sulfonamides – referred to as multiresistance, represents an unmet medical need with enormous clinical implications. In fact four gram-negative organisms – Escherichia coli, Klebsiella sp., Acinetobacter baumanii and Pseudomonas aeruginosa – are on the IDSA target pathogen list. Alarmingly, there are no novel systemic agents in development for multidrug-resistant gram-negative bacteria. Under these circumstances, old antibiotics such as polymyxins – colistin E and polymyxin B – have re-emerged as options of last-resort for the systemic therapy of many infections. Infection control and prophylaxis have also assumed center stage. With multi-resistance nearing pan-resistance, a sensible approach is to treat topical infections in vulnerable patients aggressively with non-antibiotics, reserving the few antibiotics still effective for systemic gram-negative infections. A longer-term approach is to re-initiate drug discovery efforts for new classes of antibacterials less likely to be affected by existing resistance mechanisms.       3:30 Refreshment Break and Networking       4:00 Structure-Based Drug Design Targeting Infectious Disease   Francois Franceschi, Sr. Director of Ribosome Targeting and Technology, Rib-X Pharmaceuticals, Inc.       We have designed and elaborated three completely novel series of compounds that show significant microbiological activity against serious Gram-negative pathogens, including multidrug resistant Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter baumanii, Klebsiella pneumoniae and Escherichia coli. These new antibacterials target one of two binding sites on the bacterial 50S ribosomal subunit. For each series, good binders were “tuned” for molecular features that allow them to access Gram-negative membranes and to avoid efflux pumps. Because they are completely novel scaffolds, they offer promise for therapy in an area were multidrug resistance has grown rapidly. The same structure-based design approach afforded our most advanced program, which features an enhanced oxazolidinone, RX-1741. This compound is progressing through two human Phase 2 clinical trials as an oral/IV agent to treat serious hospital Gram-positive infections, including both Vancomycin- and Zyvox-resistant enterococci as well as MRSA. We will share in this talk the structural foundations we laid in our oxazolidinone program for targeting the bacterial 50S ribosomal subunit as well as the computational models and molecular properties we perceived and used prospectively to drive towards a particular antibacterial spectrum. Building on this, we will describe our de novo design approach to novel Gram-negative agents.       4:30 Ygiene™ Hospital Grade Antimicrobial – Raising the Bar and Setting New Standards of Performance   Andrew Kielbania, Chief Scientist, BioNeutral Laboratories       While many of the presentations at this GTCbio conference deal with eliminating the infections already contracted by individuals caused by health threatening microorganisms, BioNeutral’s presentation deals with the upfront problem of controlling and eradicating these harmful microorganisms in order to prevent microorganisms from causing illnesses and infections, especially hospital acquired infections. The performance characteristics of Ygiene™ Hospital Grade Disinfectant provide utility against a broad spectrum of microorganisms. The technology platform which underpins Ygiene™ is very robust and can be used to easily customize products for specific end uses ranging from disinfectants to sterilants to antimicrobials for Military and Homeland Security uses. The water based characteristics of Ygiene™ provide multiple modes by which Ygiene can be applied, further enhancing its utility. Many regard water disinfectants as simple systems, in reality they are very complex. The incorporation of actives into water and maintaining them in water along with long term stability is a major challenge. However, the biggest challenge, and one often overlooked, is the delivery of actives through water to the specific targeted site. This ability of Ygiene™ to deliver actives to the microorganism results in its broad spectrum efficacy against both vegetative and spore forms of harmful microorganisms including the biofilms which can harbor these microorganisms. The various testing protocols and superior findings will be presented. A majority of the testing and these results have been verified by Dr. Philip Tierno, Head of Microbiology at the Langone Medical Center at NYU. In addition to superior antimicrobial efficacy, Ygiene™ Hospital Grade Disinfectant is not corrosive to many metals including ferrous metals. This will result in orders of magnitude lower impact on surfaces being treated. Currently, many of today’s disinfectants erode and eventually destroy the treated article resulting in costly replacement. Because of the multiple modes of action, the rapid and total kill observed with Ygiene™ against microorganisms, including those that are antibiotic resistant and spores such as Clostridium difficile, we believe Ygiene™ will have a huge positive impact on both the cost and the saving of lives from hospital acquired infections.     Session II - Contingency Plans for Biological Weapons and Disease Outbreaks Moderator: Roger Echols, Infectious Disease Drug Development Consulting (ID3C)       5:00 Structural and Functional Studies of the Non-structural Protein 3 from the SARS Coronavirus by Nuclear Magnetic Resonance Spectroscopy   Pedro Serrano-Navarro, Ph.D., Research Associate, Department of Molecular Biology, The Scripps Research Institute       The SARS coronavirus (SARS-CoV) is the infectious agent responsible for the severe acute respiratory syndrome (SARS) which affected thousands of people worldwide in 2003, and which is considered the first pandemic of the 21st century. Although control strategies such as the isolation of individuals diagnosed with SARS or feared exposed to the virus could contain this outbreak, no vaccine or treatment is as yet available against this pathology. As a response to the lack of therapeutic targets, the Functional and Structural Proteomics of the SARS-CoV (FSPS) initiative is working on the structural characterization of several SARS-CoV proteins, as a basis for further functional studies and pharmacological intervention. In this context, we present here the progress on the study of nsp3, the largest of the SARS-CoV non-structural proteins, which was predicted to comprise seven functional domains by phylogenetic and bioinformatics analysis. The further structural and functional characterization of individual globular domains of nsp3 by Nuclear Magnetic Resonance (NMR) spectroscopy and X-ray crystallography revealed a much more detailed picture of the protein. We have shown that the number of nsp3 domains is much larger than previously estimated, and that these domains exhibit several different activities, such as deubiquitination, proteolysis and nucleic acid binding. Further NMR studies provided detailed information on the interaction between single-stranded RNA and several nsp3 domains, for which the residues involved in RNA binding have been identified. These results represent a starting point for the design of new drug candidates against the SARS-CoV.       [FEATURED PRESENTATION]   5:30 Controlling Infectious Diseases: Progress and Challenges in Addressing Known and Unknown Threats   Rita Helfand, M.D., Associate Director, Epidemiologic Science, National Center for Preparedness, Detection, and Control of Infectious Diseases, Centers for Disease Control and Prevention       Despite major advances in their prevention and treatment, infectious diseases continue to pose significant threats to public health, remaining leading causes of death worldwide especially for children. Today’s highly globalized world has given microbes ready access to new geographic areas and populations, and generated a host of newly recognized diseases and unexpected challenges. Examples include continued outbreaks of avian influenza and threats of a pandemic, the resurgence of tuberculosis, domestic outbreaks of vaccine preventable diseases due to imported cases, and issues affecting food safety. Antimicrobial resistance also remains a growing concern, complicating healthcare and treatment efforts. In addition to these naturally occurring events, potential bioterrorist threats continue to demand increased vigilance. Experiences with recent domestic and global infectious disease outbreaks have uncovered strengths and weaknesses in public health preparedness and provided important lessons for improving our ability to respond to infectious disease threats. These lessons include the importance of national, state, and local preparedness planning and training, enhanced surveillance measures, and improved collaborations among the clinical, research, public health, and veterinary sectors. Ensuring strong collaborative activities across multiple levels and disciplines will expand our ability to monitor infectious diseases, enable earlier recognition and prompt response to unusual signs, symptoms, or laboratory results that could signal a potential outbreak, and improve the focus and outcome of infectious disease control efforts.       6:00 Networking Reception and Poster Session     Day 2 - Tuesday, September 23, 2008   Top of Page 7:30 Continental Breakfast       [KEYNOTE PRESENTATION]   8:00 Getting Congress to Understand the Need for Antibiotic Development   Barry Eisenstein, Senior VP, Scientific Affairs, Cubist Pharmaceuticals; Clinical Professor of Medicine, Harvard Medical School       In contrast to the discovery and development of other therapeutic areas, antimicrobials, and specifically anti-bacterial agents, have unique biological, regulatory, and economic challenges, which have produced a dry pipeline. As they are used almost exclusively for acute conditions, sales and marketing requires many more new patient interactions for the same return on investment. As infectious agents are unique in both mutating to resistance, a property shared with cancer cells, and also transferring horizontally to new patients (not seen with cancer cells), antimicrobials have a limited life and are depreciating assets. As a consequence, physicians tend to reserve the newest (and sometimes the best) antimicrobial agents for the sickest patients and sometimes only as rescue agents when other drugs have failed. This approach, along with others like rapidly narrowing the anti-bacterial spectrum once susceptibilities are determined, is known as “antibiotic stewardship”, and is actively taught and modeled in teaching institutions. Although aiding the “demand side” on antibiotic resistance, this approach further suppresses economic incentives to discover and develop new agents, leading to a problem on the “supply side”. An additional challenge is the regulatory uncertainly brought about by the need to demonstrate efficacy and safety compared with placebo under conditions where placebo controlled trials are unethical. The alternative approach of using “non-inferiority” studies for registration is fraught with regulatory concerns about how potent and efficacious the “old” comparator agent ever was or now remains. Paradoxically, these old agents, though held in questionable repute by regulatory agencies, are held up as “standard of care” by practitioners, who are often using old labeling standards for determination of antibiotic resistance (i.e., “breakpoint”) and for spectrum of indications. The example of vancomycin, which was approved before the modern criteria for efficacy were established, will be discussed. Taken together, these challenges require new statutory approaches. Recent testimony before the HELP committee of the Senate will be discussed, which focuses on some of the potential economic incentives that can be applied to reignite the vigor of antibiotic discovery and development that used to exist and that led to the medical miracle of the last century.     Session III - The Changing Landscape of Antibacterial Development - Politics vs. Commerce Moderator: Mike Dudley, MPEX Pharmaceuticals       8:45 The Changing Regulatory Climate for Anti-infectives in the Post-Ketek World   Roger Echols, Consultant, Infectious Disease Drug Development Consulting (ID3C)       FDA regulatory process for approval of anti-infectives drugs has undergone a major shift in requirements to demonstrate efficacy. Non-inferiority clinical trials are no longer acceptable for many treatment indications, and for those where non-inferiority (NI) trials remain acceptable, the justification of the NI margin promises to make future studies larger, and riskier. ICH documents E-9 and E-10 identify the criteria by which a non-inferiority margin can be justified. The requirement of historical placebo controlled data demonstrating the treatment benefit (M1) of active therapy vs. no treatment do not exist because antibiotics became standards of care prior to the conduct of randomized clinical trials. In treatment indications where historical evidence supports a large treatment benefit for mortality, a NI margin (M2) can be constructed. Recent FDA Advisory Committee meetings have examined this process for community acquired pneumonia (CAP) and nosocomial pneumonia (NP). For indications which are not life-threatening, NI margins cannot be justified and therefore to demonstrate efficacy superiority studies are needed. Recent FDA Guidances for acute bacterial otitis media and acute bacterial sinusitis include non-traditional outcome measures such as time-to-response or patient reported outcomes (PROs) analyses rather than physician’s assessment. There remains considerable uncertainty for other indications, for example complicated skin infections, for which there are several pending NDAs. One additional impact of the Ketek saga is the concern about data integrity which has resulted in extending PDUFA timelines and cancellation of Advisory Committee meetings. The implications of these changes at FDA and their impact on future anti-infective drug development will be discussed.       9:15 The Changing Landscape of Anti-Bacterial Development Commercial Implications   Gary Patou, Managing Director, MPM Capital       There have been a number of recent regulatory changes in the criteria for approval of certain antibacterial indications. It is unlikely that new antibiotics being developed will have as broad a range of indications as prior products have enjoyed. This will reduce the commercial opportunity or these agents. The commercial opportunities and challenges posed by these regulatory changes and changes in the pharmaceutical landscape will be discussed.       9:45 Leveraging Strengths of Pharma and Academia to Accelerate Drug Discovery for Disease of the Developing World   Adam R. Renslo, Ph.D., Associate Director, Small Molecule Discovery Center, University of California, San Francisco       Cysteine proteases play important roles in the pathogenesis of many parasitic diseases. A number of these proteases are now recognized as promising drug targets in major diseases of the developing world such as trypanosomiasis, schistosomiasis, and malaria. Notably, inhibition of a homologous class of mammalian proteases (cathepsins) is under active investigation in the pharmaceutical industry as a novel approach to treat osteoporosis and rheumatoid arthritis. In this presentation we summarize our efforts to leverage an institutional strength in parasite biology with chemical and pharmacological insights (and actual compounds) gleaned from cathepsin inhibitor programs in the pharmaceutical industry. By procuring and screening cathepsin inhibitors from industry partners, we have quickly identified lead compounds that potently inhibit parasitic proteases and kill parasites in culture. Both vinylsulfone and nitrile-based inhibitors identified in this way have subsequently been shown to be efficacious in animal models of trypanosomiasis. Most recently, we have applied medicinal chemistry to improve the pharmacokinetic properties of these inhibitors and to address potential liabilities such as lysosomotropism and hepatotoxicity. Both our general approach and our most recent studies will be discussed. Benefits (topics discussed): •  Survey the landscape of academic drug discovery efforts in parasitic disease. •  Discuss SAR of antiparasitic cysteine protease inhibitors • Discuss how the pharmaceutical industry can help advance the antiparasitic drug discovery efforts of academic and non-profit organizations.       10:15 Refreshment Break and Networking       [Oral Presentations from Submitted Abstracts]   10:45 The Biodefense Industry: Infrastructure, Funding and Medical Countermeasure Development   Benjamin Krantz, Student, Tufts University School of Medicine       Since 9/11, the anthrax attacks, the SARS outbreak, and the threat of avian flu, the US government has attempted to motivate the bio-pharmaceutical industry to develop biodefense countermeasures. The aim of this report is to: describe the infrastructure and funding of the industry identify the various approaches to medical countermeasure development and determine whether they have been successful. Information gathered from government documents, press releases, company websites, databases and scholarly articles reveal that, despite an appropriation of $3.4 B between 2004-2008 for bioterror countermeasures, only $1.5 B has been spent despite a proposal of $7.1 B for pandemic flu, only $5.6 B had been appropriated between 2005-2007. A few priority countermeasures have been adopted for smallpox, anthrax, botulinum and avian flu, but most specific threats still lack countermeasures, and flexible defenses are all but non-existent. Biotechs have been the predominant companies engaged in biodefense, sponsoring some 70% of the products, with pharmaceutical firms essentially making up the rest. Of these companies, 76% have fewer than 100 employees, and 76% are also US-based. European companies account for 18.5% of the biodefense industry. Factors that account for the heavy biotech involvement include the niche sector size, major pharma''s aversion to government involvement, the lack of established infrastructure, market uncertainty and equity-free funding. These biotechs have employed a variety of business models, from small scale versions of traditional pharmaceutical companies, to developing technology for licensing. Products and platforms are varied as well, but are focused broadly on two market needs - fixed defenses e.g., immunoglobulins and vaccines for specific diseases and flexible defenses e.g., broad-spectrum antibiotics or adjuvants/immunostimulants adaptable to a panoply of noxious agents. In conclusion, the biodefense arena is characterized by copious, but confusing legislation, insufficient and indeterminate infrastructure, uncertain and unfocused funding, as well as untested business models. The US government has not been able to attract big pharma in a big way, but has left small biotechs to battle the Goliath of pandemic disease preparedness. However, engaging all the players, both the reluctant, but resource-rich, as well as the eager, but easily exhausted, to do what they do best may yet win the day.       10:55 Seattle Structural Genomics Center for Infectious Disease   Alex Burgin, COO, Decode Biostructures       The Seattle Structural Genomics Center for Infectious Disease SSGCID is a consortium of four institutions SBRI, deCODE biostructures, UW, and Pacific Northwest National Laboratory funded by NIAID to determine the structure of ~400 protein targets from NIAID Category A-C, as well as emerging and re-emerging infectious disease organisms over a period of five years. Accomplishment of this goal will be achieved by employing a high-throughput gene-to-structure pipeline involving a multi-pronged serial escalation approach to protein expression in bacterial, wheat-germ cell-free translation, baculovirus and mammalian systems followed by structure solution using X-ray crystallography and NMR spectroscopy. Pro-active engagement of the infectious disease research and drug therapy communities in the target selection process will help ensure that the resulting protein structures provide a blueprint for structure-based drug design of new therapeutics to combat infectious diseases. This goal will be facilitated by the annual selection of a small number of high-impact targets for a fragment-based drug lead discovery campaign within SSGCID. SSGCID is also committed to providing structural genomics service to the research community and publicly disseminating all structure information and material resources generated as part of the NIAID contract. This presentation will focus on organizational aspects of the project, pipeline structure and review of interesting PDB depositions.       11:05 Cyclic Lipodepsopeptides as Promising Lead Structures for New Antibiotics Discovery   Predrag Cudic, Professor, Chemistry & Biochemistry, Florida Atlantic University       Natural products are important source of pharmacologically active compounds or lead structures for the development of novel synthetically derived drugs. Among them cyclic lipodepsipeptides represent very attractive class of compounds for the development of new therapeutics since they exhibit a diverse spectrum of biological activities. In particular, they have shown the greatest therapeutic potential as antimicrobial agents. Cyclic lipodepsipeptide daptomycin Cubicin® was approved in 2003 for the treatment of skin infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. However, cyclic lipodepsipeptide exploitation as lead compounds for the development of new antimicrobial therapeutics strongly depends on gaining unlimited synthetic access to this class of natural products and their analogs. Katanosin B and fusaricidin A are interesting members of cyclic lipodepsipeptide family that exhibit promising antimicrobial activity against various kinds of fungi and Gram-positive bacteria. In order to obtain larger quantities of these two antibiotics and their analogs, we have developed a rapid and efficient solid-phase synthesis fully compatible with the standard Fmoc-chemistry. Our synthetic strategy comprises resin attachment of the first amino acid via side chain, stepwise Fmoc solid-phase synthesis of a linear precursor peptide, lipid tail attachment followed by the last amino acid coupling via ester bond and on resin head to tail macrolactamization. Synthesized cyclic lipodepsipeptides showed promising activity against Gram-positive pathogens including methicillin-resistant S. aureus and vancomicyn-resistant E. faecium. In addition, Ala-scan analogs of these two cyclic lipodepsipeptides revealed importance of the lipid tail, ester bond and aminoacids side chains for their antibacterial activity.     Session IV - Future of Infectious Disease Therapeutics Moderator: Roger Echols, Infectious Disease Drug Development Consulting (ID3C)       11:15 Target-Based Drug Discovery Applied to Anti-Bacterials   Jacques Dumas, Associate Director, Infection Chemistry, AstraZeneca R&D       The emergence of antibacterial resistance has become a major challenge in intensive care. For example, MRSA infections alone caused nearly 19,000 deaths in the US in 2005. Established compound classes (quinolones, beta-lactams, macrolides, glycopeptides, aminoglycosides) have been widely exploited in the past thirty years to overcome resistance. Nevertheless, the best way to address resistance on the long term is to focus on novel targets. AstraZeneca's antibacterial Discovery Research group in R&D Boston covers all disciplines from target identification to late-stage optimization, and works exclusively on new compound classes. In this talk, we will discuss the specific challenges of target validation, lead generation, and lead optimization in the antibacterial field, and how these compare with the ones encountered in other therapeutic areas.       11:45 MP-376 (Levofloxacin Inhalation Solution) for Management of Chronic Respiratory Infections in Cystic Fibrosis and COPD   Mike Dudley, Senior Vice President, Research and Development, MPEX Pharmaceuticals       Chronic bacterial infection in cystic fibrosis and COPD is associated with long term decline in pulmonary function and resultant morbidities. Aerosol delivery of tobramycin has shown benefit in chronic Pseudomonas infections in cystic fibrosis (CF) patients; however, drug resistance and inconvenient administration schedules have necessitated a need for new agents. In patients with severe COPD, chronic bacterial infection in the lung results in inflammation and a pulmonary tract at risk for periodic exacerbations manifested by an acute decline in pulmonary function, shortness of breath, and inability to perform routine tasks. In both of these patient populations, exacerbations require treatment with systemic antibiotics. In CF, regular use of aerosol antibiotics is now recommended to preserve pulmonary function and reduce pulmonary exacerbations. Studies in patients treated with oral antibiotics for acute bacterial exacerbations in COPD show reduction in bacterial load is associated with prolonged exacerbation-free interval. MP-376 is a novel formulation of levofloxacin optimized for rapid and safe delivery by the aerosol route. Aerosol delivery provides high concentrations of drug at pulmonary sites of infections that are key for efficacy, even against pathogens considered “resistant” to traditional oral or IV routes of administration. A study with single daily aerosol dosing of MP-376 in infection models due to Pseudomonas aeruginosa showed superior bacterial killing compared to tobramycin and aztreonam. Studies in animal models of infection and Phase 1 studies in patients show that MP-376 provides high levofloxacin concentrations in pulmonary tissues that exceed accepted PK-PD exposure targets for efficacy and reduced resistance selection in the clinic. Phase 2 studies in maintenance treatment of chronic pulmonary infections are in progress. Benefits of this presentation: • Review of the pathogenesis of chronic pulmonary infections in CF and COPD • PK-PD considerations in aerosol antibiotic delivery • Advantages of aerosol antibiotic delivery • Review of current clinical trial results       12:15 Lunch       1:15 The Ribosome - Taking a New Look at an Old Target   Bruce A. Maguire, Ph.D., Principal Scientist, Pfizer, Inc.       Nearly half of known antibiotics target the ribosome. Although its size and complexity have always presented special challenges, X-ray crystallography of antibiotic-ribosome complexes have revolutionized our understanding. New insights are emerging into how the ribosome functions and how antibiotics intervene in this process, suggesting new areas that have not yet been exploited. Benefits: • An overview of one of the most important and enduring antibacterial targets • What aspects of ribosome function are targeted by existing antibiotics? • What additional aspects could be targeted? • How is our understanding of antibiotic action evolving?       1:45 Selective Spectrum Therapies the Promise of Safer and Better Tolerated Treatments…   Barry Hafkin, Chief Medical Officer, Affinium Pharmaceuticals       The wide spread use of broad spectrum antibiotics in the treatment and prophylaxis of infections in human and veterinary medicine and the use of broad spectrum antibiotics in the production of foods has led to an ever increasing prevalence of drug resistant bacteria in the barn-yard , in our communities, and in our hospitals. This has lead to the ever increasing need for new safe and effective antibacterial therapies. The discovery and the early clinical development of a specific spectrum antibiotic, optimized to inhibit bacterial fatty acid metabolism in susceptible and resistant strains of Staphylococcus is described. The unique antibacterial spectrum, exquisite antibacterial potency against target pathogens, and the good preclinical and clinical safety profile will be reviewed. Benefits of the talk: - the disadvantage of overly broad antibacterial spectrum agents will be reviewed - the benefits of targeted antibacterial agents will be pointed out - the early clinical development of an antibiotic with a novel mechanism of action will be reviewed - novel approaches to addressing the unmet medical need for effective antibiotic treatment will be discussed       2:15 Advances in Diagnostics and their Impact on Narrow Spectrum Antibacterials   Andrew MacPherson, President and Co-Founder, Diagnostics Intelligence Group, Inc.       Diagnostic tests have historically been at the forefront of the clinical decision making process. However, the virulence of many new strains of bacterial infections has made the traditional culturing of patient specimens in central laboratories a virtual afterthought in the minds of many clinicians. Recently, new generations of diagnostic tests have been developed utilizing technologies which have compressed the timelines for typing and sub-typing of bacterial infections from days to mere hours. Continued expansion of the capabilities of diagnostic tests facilitates the timely and appropriate utilization of narrow spectrum antibacterials. Benefits: • Learn about the current state of diagnostics for bacterial infections • Assess the strengths and weaknesses of different diagnostic technologies • Find out how quickly new diagnostics are able to reach the market • Learn which new diagnostics are anticipated to reach the market in the next 2 years       [FEATURED PRESENTATION]   2:45 The Seemingly Never-ending Promise of Bacteriophage Therapy: Exploiting Smaller Fleas   Stanley Deresinski, Clinical Professor, Medicine-Med/Infectious Diseases, Stanford       Phage therapy has been in continuous use in Russia and parts of Eastern Europe since 1919, despite a lack of scientifically acceptable clinical trial data demonstrating its efficacy. Elsewhere, however, interest in potential phage therapy was largely abandoned after the introduction of antibiotics. The inevitable widespread emergence of antibacterial resistance has, however, engendered renewed interest in novel approaches, including phage therapy. Areas for use in addition to clinical therapeutics may include agriculture, animal husbandry, veterinary, aquaculture, waste water treatment, and food science. In 2006, IntraLytics received U.S. FDA approval for a preparation of 6 phages specific for Listeria monocytogenes for spray application on ready-to-eat meat and poultry preparations. Phage preparations are also approved in the U.S. for use as agricultural pesticides. Administration of phage may involve topical application (including aerosol), oral,and parenteral administration.. Since phage specifically replicate at the site of infection, small doses and single administrations may be sufficient. This replicative characteristic, together with the fact that most phage are rapidly cleared by the reticuloendothelial system, contribute to the unusual pharmacokinetic characteristics of phage, which do not resemble those of small molecules. The unusual pharmacokinetics may contribute to the regulatory uncertainty which is an important obstacle to the ultimate approval of systemic use of phage in humans. Another important regulatory obstacle is the need in some circumstances to overcome phage target specificity by their administration in combination. Potential barriers to the efficacy of phage therapy, such as whether intracellular location of bacteria or their growth in biofilm impede its activity, require further exploration. In addition, bacterial resistance to phage occurs at a frequency similar to that of resistance to many antibiotics. While lytic phage are themselves lethal to bacteria, the use of phage as a delivery system for drugs, toxins and antibody has also been explored. Phage may also prove to be effective carriers of peptide and DNA vaccines. Administration of phage lysin, which allows the phage to degrade bacterial peptidoglycan, has been effective in animal models of infection. In the preclinical setting, phage may prove useful in identifying bacterial targets of novel antimicrobials and also serve as a means of rapid precise etiologic diagnosis of bacterial infections, with simultaneous susceptibility testing.     3:15 Conference Concludes       Top of Page Day 2

 

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