Agenda
Below is the agenda for 2010′s 7th Anti-infectives Partnering and Deal-making Summit. To view the agenda for 2011′s 8th Anti-infectives Partnering and Deal-making summit information, which is taking place on November 7-8, 2011 in Boston, MA, please click here.
Day 1 – Thursday, October 7, 2010
7:00 Registration & Breakfast
7:55 Welcome and Opening Remarks
| Session I - Recent Advances in Anti-Infectives Development – Anti-bacterial Moderator: Mike Dudley, Mpex Pharmaceuticals, Inc. |
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[FEATURED PRESENTATION] 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 MRSA. In recent years, however drug development has expanded beyond MRSA to include Clostridium difficile infection (CDI) and gram-negative infections (GNIs). Drug developers seeking commercial success in the markets for MRSA, CDI, and GNIs market will face stiff competition from established therapies, heightened regulatory scrutiny, and more stringent reimbursement policies. Key questions Answered in this presentation: |
8:35 Identifying and Progressing Novel Antibacterial Compounds Through the Discovery Pipeline
Brian Noonan, Senior Director, Director of Bioscience, Astrazeneca
Diseases caused by drug-resistant bacteria are a major threat to human health across the globe. From drug resistant tuberculosis to MRSA, the available arsenal of effective therapies continues to diminish. Across the pharmaceutical industry, anti-bacterial drug discovery efforts have struggled to indentify novel compounds that address the rising threat of resistance and the discovery and development of novel antibacterial agents with activity against a spectrum of resistant pathogens has proven to be extremely challenging. This presentation will aim to highlight the key scientific challenges faced by the industry and discuss potential solutions.
• An overview of the key discovery challenges for the industry
• How lead generation can identify new antibacterial scaffolds
• In vivo models and efficacy predictions for novel agents
• New approaches to partnering
9:00 TP-434: A Novel, Gram-Negative Antibiotic in Clinical Development
Joyce Sutcliffe, Ph.D., Senior Vice President, Biology, Tetraphase Pharmaceuticals
Infections caused by multidrug-resistant (MDR) gram-negative bacterial pathogens cause great morbidity and mortality worldwide, with a recent study concluding that the spread of resistant pathogens has resulted in higher healthcare and societal costs of $13.5 billion dollars annually in the US. TP-434, a novel fluorocycline, was discovered using a break-through chemistry platform that forms the basis of Tetraphase’s proprietary product engine. TP-434 shows potent activity against a broad range of MDR aerobic and anaerobic gram-negative and gram-positive pathogens both in vitro and in vivo in a variety of murine infection models challenged with MRSA, Streptococcus pneumoniae, S. pyogenes or MDR gram-negative bacteria. In a successfully completed Phase 1 trial, TP-434 achieved clinically relevant and dose-proportional exposures with no serious side effects. With its excellent plasma exposure, volume of distribution, and 40-hour half-life, TP-434 has great potential as a once-daily treatment for serious bacterial infections, especially those caused by MDR gram-negative pathogens. TP-434 will advance in 2H2010 into a Phase 2 trial to explore its potential as a treatment for complicated intra-abdominal infections.
Participants will benefit by learning about:
• The seriousness of the public health threat imposed by increasingly drug-resistant gram-negative bacteria
• A powerful new hospital antibiotic that will address major unmet medical need
• The unique technology platform that was used to create TP-434 and that continues to serve as a prolific product engine.
• What can be achieved by a small team using the right kind of technology platform
9:25 Pleuromutilin Antibiotics: A New Class Delivering in Man
Rodger Novak, M.D., Chief Operating Officer, Nabriva Therapeutics
Despite a continuing rise in antibiotic resistance among key pathogens, both in hospitals and communities, there is a dearth of new antibiotics in the late stages of drug development. In the last 40 years only three compounds from new classes have been approved by the FDA for systemic treatment. These three molecules (linezolid, daptomycin and tigecyline) now generate $ 2 billion annual sales. Pleuromutilins were discovered as natural-product antibiotics in 1950, but other than the approval of the topical antibiotic retapamulin in 2007 have not been successfully applied to man. Nabriva Therapeutics is a spin-off from Sandoz/Novartis and not only “inherited” more than 30 years of experience in pleuromutilin synthetic chemistry but is also the owner of all IP and product rights of about 1500 pleuromutilins. Over the last 4 years Nabriva has advanced three pleuromutilin compounds into clinical development. These pleuromutilins combine potent antibacterial activity against most relevant pathogens involved in both skin and respiratory tract infections with favorable pharmaceutical properties. In May this year a phase II trial in acute bacterial skin and skin structure infections (ABSSSI) with intravenous BC-3781 was started in the US. This is the first ever patient study with a systemic pleuromutilin. It will be an important proof of concept for an exciting new class of antibiotics. The phase II study builds on Nabriva’s extensive preclinical and phase I data which have demonstrated that BC-3781 can achieve therapeutically relevant blood and tissue levels in man with excellent tolerability when administered by either oral or intravenous routes.
Benefits of the presentation:
General introduction to pleuromutilins as a new class of systemic anti-bacterials in humans
Key aspects of in vitro and in vivo pharmacology properties
Presentation of clinical data around the intravenous/oral program of BC-3781
9:50 Networking & Refreshment Break
10:20 Beta-Lactams for Bad Bugs
Laurenz Kellenberger, Ph.D., Chief Scientific Officer, Basilea Pharmaceutica International
Antibiotics have substantially reduced the threat posed by bacterial disease but intensive, and sometimes inappropriate, use over more than sixty years has led to the development of resistance towards these agents. Resistance levels among Gram-positive and Gram-negative bacteria give cause for concern in many parts of the world. Beta-lactams have proved to be one of the most successful classes of antibiotics. Continual innovation around the beta-lactam core structure has given rise to new generations of this class that are able to overcome the problems caused by bacterial resistance. The latest additions to this group include agents with activity against MRSA as well as agents covering MDR Gram-negative bacteria.
The presentation will
-Summarize the resistance mechanisms against beta-lactams
-Highlight the opportunities and challenges in the discovery and development of new beta-lactams
-Give an update on compounds from Basilea’s pipeline that are active against multi-drug resistant pathogens
10:45 Clostridium Difficile: A New Scourge in Challenging Times. What Treatment Options Are in Development?
Glenn S. Tillotson, Ph.D., FRSM, FCCP, Head of Medical Affairs, Viropharma
The recent announcement that Clostridium difficile is the most frequent cause of hospital-associated infections in the USA should be a significant incentive to develop new therapeutic options. Clearly the current choices of management are not ideal or we would not be witnessing such a surge in incidence of this pathogen. The current disease has evolved from 1995 in that the prevalent strain today has increased virulence and can spread rapidly in hospitals. Now individuals with few or no risk factors can acquire the disease. This is due mainly to the NAP1 or BI epidemic strain which is now found in almost all US states as well as many European countries and Canada where it was first recognized. Therapies for C difficile infection (CDI) include metronidazole and oral vancomycin however recurrence is seen especially with the former agent. With these failures comes the spread of this sporulating pathogen in environments such as hospitals and nursing homes although the organism is being reported in more community settings and from a wider range of patients than previously reported. In an attempt to contain and better treat these life threatening infections new approaches are being developed these include fidaxomicin, a toxoid vaccine, a monoclonal antibody and a novel biotherapeutic involving a new strain of C difficile. Other antibacterials are being developed including a lipopolypeptide derivative from Cubist among several new and exciting agents. The changing landscape of CDI will be discussed including the regulatory and clinical hurdles to the introduction of new therapeutics for CDI.
11:10 A Novel Compound to Combat MDR Gram Negatives
John Quinn, Senior Advisor, Antibacterial, Pfizer
11:35 AFN–1252 Anti-Staphylococcal Program
Barry Hafkin, Chief Financial Officer, Affinium Pharmaceuticals
The antibiotic era of modern medicine has taught us all many lessons:
• common infections capable of producing profound morbidity and mortality can be effectively treated with antibiotics
• treatment has resulted in longer and better lives for millions
• the longer we use these treatments and the prevalence of antibiotic use the faster we lose them
• there is little hope that the emergence of antibiotic resistance in key pathogens can be stopped
• the need for innovation in the prevention and cure of infections will never stop
One approach is the development of narrower, selective spectrum antibiotics that target only key pathogens that frequently cause serious disease.
Key issues to be addressed
- constant ecologic pressures toward resistance development
- strategies commonly used to reduce resistance development
- suggestions for additional approaches through the development of selective spectrum antibiotics
- the clinical development of AFN-1252 – a selective spectrum anti-staphylococcal antibiotic
12:00 The Global Need for New Antibiotics – International Actions and Implications for Antibacterial Drug Development
Ursula Theuretzbacher, Ph.D., Principal, Center for Anti-Infective Agents (CEFAIA)
The pandemic of multi-drug resistant pathogens and their continuing spread is beyond dispute. Driven by concern regarding this rapidly worsening global health crisis and the confounding lack of robust drug pipelines, several multinational campaigns have initiated broad discussion and put action plans in place. In an impressive show of international interest, the ECDC, EMEA, WHO, and the US government, as well as the IDSA and several other large non-profit organizations, are addressing the global problem by bringing attention and focus to the problematic and systemic paucity of new antibiotics to combat drug-resistant bacteria.
• What are the predictions for future resistance development trends?
• How would the action plans influence the antibacterial R&D business?
• What are the challenges and opportunities arising from international action plans?
12:25 Lunch
| Session II – Recent Developments in Anti-infectives Discoveries – Anti-viral Moderator: Roger Echols, Infectious Disease Drug Development Consulting, LLC |
1:50 Development of Anti-virals to Treat and Prevent Respiratory Viral Diseases
Jane Ryan, Ph.D., Vice President, Product Development, Biota
Biota is a leading anti-infective drug development company, based in Melbourne, Australia. Biota’s initial success was the discovery of zanamivir, the first-in-class neuraminidase inhibitor for the treatment and prevention of influenza. Zanamivir is licensed to GlaxoSmithKline and marketed as Relenza™. Relenza is used to treat seasonal influenza and is currently being stockpiled by various governments for defence against pandemic influenza.
The Company’s research pipeline includes, small molecule anti-infective programs focused on diseases of significant medical need, such as influenza, rhinovirus, hepatitis C, respiratory syncytial virus, human cytomegalovirus and new classes of antibiotics to treat hospital-acquired and community-acquired infections.
This presentation will focus on the development antivirals for treatment and prevention of influenza, rhinovirus and respiratory syncytial virus infections. Included will be a discussion of the development of a second generation influenza anti-viral; laninamivir which is co owned with Daiichi Sankyo. Daiichi- Sankyo has developed laninamivir for the Japanese market.
2:20 Latest Developments in Direct Antiviral Therapy for Hepatitis C and Implications for Partnering
Casey Logan, Vice President, Corporate Development & Strategic Planning, Anadys Pharmaceuticals
• There is a great deal of new innovation in the treatment of Hepatitis C virus (HCV), particularly small molecule direct antiviral therapies
• These new therapies (still in clinical development) have the potential to substantially improve and alter the treatment of HCV
• The most current thinking is that combinations of these direct antiviral agents will be the most effective way to treat HCV patients in the future
• Those that are trying to build (or maintain) a presence in HCV are doing so through a combination of internal drug discovery and development efforts as well as through in-licensing
• This talk will address (from a small company perspective) how this future treatment paradigm affects the company’s overall drug development and licensing strategy – how far to develop on one’s own, ideal time to partner, who to partner with, etc.
2:45 TBR-652: The Next Generation of Therapy for HIV
Robert Jacks, MS, MBA, Business Development Advisor, Tobira Therapeutics
Tobira Therapeutics, Inc is a private, venture capital financed company focused on driving the next generation of HIV therapy by developing breakthrough drugs and utilizing innovative clinical trial designs. Tobira’s lead candidate, TBR-652, a potent, oral, CCR5/CCR2 antagonist, recently completed a successful phase 2a proof-of-concept trial, the results of which were presented at CROI in February 2010.
TBR-652 will drive the next generation of HIV therapy because it offers patient health benefits separate from, and in addition to, long-term viral suppression, all as a safe, well tolerated, low dose QD agent.
There is increasing recognition that chronic inflammation caused by low grade HIV infection, even in patients whose virus is fully suppressed by anti-retroviral drugs, is causing an increased rate of morbidity and mortality from cardiovascular disease, metabolic disease, and non AIDS related cancers. In fact, recent studies reveal that more HIV+ persons in the western world now die of non-AIDS related causes than of AIDS related causes1. The anti-inflammatory benefits of CCR2 inhibition, as demonstrated in TBR-652’s phase 2a clinical trial, provide additional long-term health benefits to patients beyond those achieved by suppressing viral replication to non-detectable levels. Tobira is currently planning for phase 2b clinical studies to begin in early 2011.
Attendees will:
• Learn about TBR-652, a late stage HIV drug candidate with a best-in-field profile
• Learn about the paradigm changing CCR2 anti-inflammatory properties of TBR-652
3:10 Is Late Better than Never? Shifting Unmet Needs and Time-sensitive Opportunities in the HCV Market
Alexandra Makarova, M.D., Ph.D., Analyst, Infectious Diseases, Decision Resources
Currently, the Hepatitis C (HCV) market is characterized by a low diagnosis rate, very few treatment options, and an increasing number of patients who have failed prior treatment (nonresponders). Improved efficacy (especially in prior nonresponders) and safety are the most important unmet needs in today’s HCV field. However, the long-anticipated launch of HCV-specific direct antiviral agents (DAAs) will change the HCV treatment algorithm and significantly improve the efficacy of HCV therapy. As a result, the distribution of HCV patient subpopulations as well as the competitive landscape will change rapidly in the near future thereby creating novel expectations from emerging HCV therapies. Moreover, opportunities for novel HCV drugs will be time-limited due to the low incidence of the disease, the curable nature of the disease, and ageing of the HCV-infected cohort. To ensure success of their drugs, developers of early-stage HCV therapies must evaluate upcoming changes in patient subpopulations and evolving opportunities in the HCV market.
The presentation will:
–review the HCV market and future shifts in treatment regimens
–address effects of the launch of HCV-specific direct antiviral agents on unmet needs
–discuss current and future dynamics of HCV patient subpopulations
–discuss opportunities for drugs entering the HCV market at different stages of the market’s maturation
3:35 The Emergence of Durable Broad Spectrum Antivirals
Michael Goldblatt, Vice President,President and CEO, Functional Genetics
The emergence of drug resistant viruses, compounded by the specificity of antiviral therapeutics, has created persistent treatment problems that have historically fractured the antiviral market. The development of broad spectrum antivirals, which minimize the potential for the development of drug resistance, to treat or prevent many different viral diseases holds the promise to reanneal the antiviral market. This new class of durable antivirals arises from emerging knowledge of highly conserved host cellular machinery whose functions are hijacked by many viruses as an essential part of their life cycle. These changes in host target function provide an opportunity to safely selectively target and destroy virus infected cells, without harming normal cells.
One such example is the targeting of host cellular TSG101 which is fundamental for, and shared by, many different enveloped virus families. This feature facilitates the targeting of unrelated virus types by a single therapeutic while minimizing the likelihood that drug resistant variants will arise. The market opportunities for this approach include the treatment or prevention of entire constellations of viruses including seasonal infections of the lung and sexually-transmitted diseases regardless of genetic or geographic origin and independent of established drug resistance.
The presentation will cover how this new class of targets is identified, their mechanisms of action, constellation of activity and potential for broad spectrum vaccine development for viral infection.
4:00 Networking and Refreshment Break
| Session III – Investment Opportunities in the Anti-Infectives Space Moderator: Glenn S. Tillotson, Viropharma |
4:30 Development of a Completely Novel Antibiotic Class: PMX-30063 Small Molecule Mimetic of Host Defense Proteins
Nicholas Landekic, President & CEO, PolyMedix
The rapid rise of drug-resistant bacteria is one of the most serious unmet medical needs facing the world, and a significant commercial opportunity. 70% of infections in the U.S. are now drug resistant. 14.2 million people are treated for MRSA infections annually in the U.S., a 700% increase over 4 years, and cost the U.S. healthcare system over $10 billion. With bacterial resistance a risk for any biochemical antibiotic, there is an urgent and tremendous need for a fundamentally new approach.
Using a proprietary computational drug design technology, created by National Academy of Science members Drs. William DeGrado and Michael Klein, PolyMedix has developed a novel class of antibiotic drugs: small synthetic molecules that mimic the activity of host defense proteins, and imitate natural human immunity. With a completely different mechanism of action from other antibiotics – direct disruption of bacterial cell membranes – these unique compounds function in a way which makes bacterial resistance unlikely to develop. The first compound in clinical testing is PMX-30063, being developed for the broad treatment of Staphylococcus (MRSA) infections. Single and multi-dose Phase 1 clinical studies have been completed, with results showing it was possible to safely administer PMX-30063 without any serious side effects at doses which exceeded those associated with full efficacy in animal models of infection, and with full bactericidal activity in human blood.
PolyMedix has created 12 distinct chemical classes of defensin-mimetics, with over 200 next-generation lead compounds identified to date. These compounds are active against and being developed for Gram-negative infections, tuberculosis, malaria, fungal infections, and biowarfare pathogens.
4:55 A New Approach to HIV Treatment: Targeting the T-Cell
Dennis Molnar, Vice President, Corporate Development, Paratek Pharmaceuticals
When looking for improved treatment strategies for AIDS, targeting T-Cell activation (which is required for HIV viral proliferation) is an exciting new approach that may preserve immune system functionality while allowing dramatic reductions in viral load. Could this strategy even contribute to one day curing AIDS?
Paratek has developed novel small molecules that inhibit activation of T-Cells. These same compounds reduce HIV viral load when tested in vitro. Paratek will introduce its program to conference attendees. Attendees may expect to learn about this approach to HIV treatment and where the Paratek program may fit in this paradigm.
| [KEYNOTE PRESENTATION] 5:20 Infectious Diseases: No Need to Treat If You Can Prevent Stuart B. Levy, M.D., Professor, Molecular Biology & Microbiology and Medicine; Director, Center for Adaptation Genetics and Drug Resistance, Tufts University; President, Alliance for the Prudent Use of Antibiotics; Chief Scientific Officer and Co-Founder, Paratek Pharmaceuticals
Antibiotic resistance continues to plague public health globally. The emergence of multidrug resistance in bacteria has made the situation more grave, since even the first- and second-line antibiotics do not work against these organisms. Alternative approaches are therefore sought. In an effort to avoid resistance and develop a means to control infection, Paratek has focused attention on the Multiple Adaptational Response (MarA) protein in E. coli and its paralogs in other bacteria. This member of the AraC family of regulators is uniquely poised as a target for therapy, since it controls infection and often antibiotic resistance in bacteria. In work performed at Paratek, three animal models have demonstrated efficacy of this approach: E. coli in pyelonephritis, Yersinia pseudotuberculosis pneumonia (as a surrogate for Yersinia pestis), and acute pneumonia caused by Pseudomonas aeruginosa. In all models, infection was prevented or greatly attenuated by treatment. The principal anti-virulence agents are chemical derivatives of benzimidazoles, which have no antibacterial activity. Given that the target of these drugs is the DNA-binding domain of Mar proteins, any mutations which affect the binding to the drug would likely interfere with its DNA-binding capacity, and consequently, prevent its ability to activate genes associated with infection and resistance. These new agents prevent acute and fatal disease dramatically, and so demonstrate the efficacy of this approach. Anti-virulence drugs hold promise for patients at high-risk for infection, such as entering the ICU, being placed on a ventilator, recovering from surgery, and confronting travelers’ diarrhea. Besides being less likely to select for resistance during therapy, the drug, when released into the environment, would not affect bacterial growth and so would not lead to environmental propagation of drug-resistant strains. |
5:55 NAEJA: Over Two Decades of Anti-Infective Discovery
Sameeh Salama, Senior Director, Business Development, NAEJA Pharmaceutical
For over two decades, anti-infective drug discovery has taken centre stage at NAEJA. The initial discovery of Tazobactam by NAEJA’s team, led by the late Dr. Ronald Micetich, triggered a long list of antibacterial and antifungal discoveries including a diverse string of various β-lactam molecules, quinolones, oxazolidinones and azole antifungal agents to name a few. This is in addition to a long list of natural product discoveries. NAEJA’s track record in the area is well documented through the many published patents and publications (for a list follow this link: http://www.naeja.com/#/publications_0)
Recognizing the value of this experience, NAEJA began to offer its expertise in the design, synthesis, and biological profiling of antibacterial and antifungal agents to clients worldwide. Details of such expertise and infrastructure will be the subject of this short presentation.
6:00 Networking Reception
Day 2 – Friday, October 8, 2010
7:30 Continental Breakfast
| Session IV – Scientific & Regulatory Updates Moderator: Glenn S. Tillotson, Viropharma |
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[FEATURED PRESENTATION] Serious and life-threatening fungal infections have advanced in step with modern medical procedures which have increased the number of patients with compromised defenses against these organisms. Although invasive fungal infection is still a major cause of mortality in such patients, discovery and development of new and more effective therapies has proved to be challenging and few new agents are currently in the pipeline. The eukaryotic nature of fungal pathogens brings inherent challenges in terms of target selection and selectivity; however, there are also potential benefits to be gained from application of spin-offs from human biology programs and discovery technologies. Conversely, a number of important drugs were first discovered as antifungal compounds. There are also significant potential synergies with research into neglected diseases caused by other eukaryotic pathogens such as trypanosomes which are gaining increasing attention as a global health threat. The presentation will review current and novel approaches to new antifungal therapies, focusing on: • The key future needs and opportunities for new antifungal agents |
8:35 A Review of Recent Federal Actions that Impact Antimicrobial Drug Research, Development and Use and the Infectious Diseases Society of America’s (IDSA) Recent Efforts and Successes
Robert Guidos, Vice President, Public Policy & Govt. Relations, Infectious Diseases Society of America (IDSA)
For the past decade, IDSA has raised concerns about the imbalance between the dwindling antibiotic pipeline and the significant and concomitant need for new antibiotics to treat an increasing number of drug-resistant infections. In 2004, concluding that immediate government action was essential, IDSA published its report “Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates a Public Health Crisis Brews.” In response to the expanding crisis, IDSA recently launched the 10 x ’20 initiative to create a sustainable antibiotic R&D enterprise that in the short-term can produce 10 new safe and effective antibiotics by 2020. The antibiotics we seek are those that can treat the most serious and life-threatening pathogens against which most approved antibiotics are not effective. IDSA is working with Congress and key federal agencies to identify and enact mechanisms to strengthen antibiotic and related diagnostic R&D, antimicrobial resistance surveillance, research, and prevention and control, and better antimicrobial stewardship.
Attendees will learn about:
-legislative developments that could impact antibiotic R&D and resistance
-recent and upcoming FDA/NIAID/IDSA joint ventures
-other federal activities that could impact upon this critical area of drug development, research and use
9:00 Understanding the Regulatory Hurdles for Anti-bacterial Drug Development in the Post-Ketek World
Roger Echols, M.D., Principal, Infectious Disease Drug Development Consulting, LLC
Antibiotics (antimicrobials) were once considered “safe bets” in the world of clinical development based on the predictability of therapeutic success. Safety was the greatest unknown in phase 3 and beyond. The regulatory approval of Ketek (telithromycin) in 2003 followed the conduct of a 24,000 patient safety study. Two years later published reports of severe hepatic toxicity led to a re-examination of the benefit risk of Ketek in which the benefit (efficacy) was questioned based on the validity of non-inferiority study design.
Since 2005 only one new antibacterial drug has been approved by the FDA (telvavancin in 2009). At least 7 other original NDAs have been either withdrawn or denied for a variety of reasons: faropenem, garenoxacin, dalbavancin, cethromycin, iclaprim, ceftobiprole, oritavancin. New draft clinical trial guidelines have been issued for CABP (community acquired pneumonia), ABS (acute sinusitis) and ABOM (acute otitis media). Some indications for which NI margins cannot be justified on the basis of historical data will require superiority trials, including placebo controlled.
The presentation will provide up-to-date information on phase 3 clinical trial requirements which:
Identify study population definitions
Identify clinical outcome measures
Provide sample size estimates
Discuss regulatory risk
9:25 [Oral Presentations from Outstanding Abstracts]
Squarylated Homoserine Lactone SHL: A Class of Non-halogenated Potent Quorum Sensing Inhibitors for Biofilm Formation
Yan-Yeung Luk, Department of Chemistry, Syracuse University
Quorum sensing QS is a process by which microbials secrete and sense small chems. called auto inducers to monitor their local population densities and to carry out large physiological and communal response. In most bacteria, as the threshold cell density is reached, chemical signals bind to their cognate receptor proteins and trigger the expression of target genes that cause biofilm formation or lead to an expression of virulence factors, which is a major source for infectious diseases. Controlling quorum sensing thus is a promising approach for controlling bacterial populations and for preventing infectious diseases. Here, we report an efficient synthesis of a new library of non-toxic nonhalogenated small molecules based on a squaramide moiety. Evaluation of these squaramide on biofilm formation has revealed a potent set of quorum sensing inhibitors. These squaramides offer new structures to tackle infectious bacterial-related diseases and will provide insights to understand bacterial pathogenesis.
9:30 Controlling Bacterial Biofilms and Persister Cells Using Novel Brominated Furanones
Dacheng Ren, Department of Biomedical and Chemical Engineering, Syracuse University
Biofilms are highly hydrated structures comprised of a polysaccharide matrix secreted by the bound bacterial cells. Such sessile communities are ubiquitous in natural, engineering, and medical environments and biofilm cells are up to 1000 times more tolerant to antibiotics than their planktonic counterparts. In addition, it is well known that a small percentage of cells in a bacterial population normally less than 1% can form dormant persister cells that are tolerant to almost all antibiotics. Persister formation increases significantly in biofilms and both biofilms and persister cells are thought to be the leading causes of chronic infections. Such intrinsic tolerance also facilitates the development of multidrug resistance through acquired mechanisms. Increasing evidence has shown that a bacterial cell-cell signaling system, known as quorum sensing, controls bacterial virulence, biofilm development and persister formation. Thus, therapies targeting quorum sensing have potential to effectively control chronic infections. Recently, we synthesized several new brominated furanones and demonstrated that they are strong inhibitors of bacterial quorum sensing and biofilm formation. Furthermore, E-4-bromo-5-bromomethylene-3-methylfuran-25H-one was found to increase the susceptibility of Pseudomonas aeruginosa persister cells to ciprofloxacin more than 100 fold compared to the untreated control. The activities of these compounds and their potential applications will be discussed.
9:35 High Extracellular Levels of Cefpirome in Healthy and Infected Lung Tissue of Patients
Christian Joukhadar, M.D., Managing Director & Chief Operating Officer, J&P Medical Research
Cefpirome, a fourth generation intravenous cephalosporin antibiotic, is widely prescribed for the empiric therapy of severe bacterial infections in critically ill patients in intensive care, oncology and transplantation units in distinct member states of the European Union and Asia. The objective of the present investigation was to measure the extracellular concentrations of cefpirome in healthy and infected lung tissue of septic patients by use of the innovative microdialysis method. We provide strong evidence that cefpirome achieves antimicrobially effective concentrations in plasma, healthy and infected lung over the entire dosing interval of up to 12 h after intravenous administration of 30 mg/kg total body weight. transplantation units in distinct member states of the European Union and Asia.
9:40 HuCAL Platinum Antibodies in Infectious Diseases
Anne Assmus, Specialist Business Development, MorphoSys AG
The growing problem of multi-drug resistant pathogens, the emergence of new pathogens, the need for treatment that is effective in immunocompromised patients and the ongoing battle against nosocomial infections make the field of infectious diseases a highly attractive area for the development of antibody-based therapeutics.
MorphoSys is therefore currently actively engaging in exploring this field with its 15 years of antibody-drug development know-how and its best-in-class antibody technology, HuCAL Platinum.
The size of the HuCAL Platinum library with ~45 billion different members results in affinities in the two-digit picomolar range already in the first round of selection. Phage display allows for selection of antibodies against any kind of disease causing agent or molecule. Especially the high number of antibodies with long stable HCDR3 regions makes HuCAL Platinum the optimal toolbox for drug development in infectious diseases, because long HCDR3 regions have proven to be essential to target difficult-to-reach epitopes close to the membrane of the pathogen.
In our lead project targeting Staphylococcus aureus infections, MorphoSys is applying the HuCAL Platinum technology to, in our view, some of the most promising targets currently on the market through a collaboration with the company Absynth, UK. Absynth’s genomics-based approach allows identification of previously overlooked targets, such as bacterial components which are crucial to the organism, conserved across different bacterial strains and accessible for antibodies. Antibodies against these targets inhibit the growth of S. aureus and recruit the human immune system to eliminate bacteria via phagocytosis.
9:45 TD-1792, Theravance’s First-in-Class Glycopeptide-Cephalosporin (Gp-Ceph) Heterodimer Antibiotic for Serious Gram-positive Infections
Clint Rogers, Director, Business Development, Theravance
TD-1792 is an extremely potent, rapidly bactericidal agent with a novel mechanism that offers broad activity against Gram-positive pathogens and a low potential for the emergence of resistance.
TD-1792 has successfully completed a Phase 2 study vs. vancomycin in 200 patients with complicated skin and skin structure infections (cSSSI). This study demonstrated TD-1792 to be at least as effective as vancomycin against vancomycin-susceptible pathogens and potentially more effective against MRSA. Importantly, TD-1792 also demonstrated the potential for a better safety profile than vancomycin, including a lower potential for renal toxicity.
TD-1792 has also demonstrated excellent lung penetration in a bronchoalveolar lavage (BAL) study in human subjects. In addition, TD-1792 has shown potent efficacy in multiple animal models of infection, including thigh, pneumonia, bacteremia, and endocarditis. Taken together, these results support moving forward with Phase 3 studies in nosocomial pneumonia, cSSSI, and bacteremia/endocarditis.
TD-1792 has a unique combination of advantageous features that differentiate it from other antibiotics for treating serious Gram-positive infections:
- Unique multivalent mode of action, utilizing a novel chemical construct combining the features
of both a glycopeptide and a cephalosporin
- Multivalent MOA enables synergistic potency over individual components
- Exceptional potency vs. a broad spectrum of Gram-positive pathogens, including
MRSA,hVISA, VISA, LRSA, Dap-NSSA, and other resistant strains
- 15-100 fold greater potency than existing MRSA-targeted drugs
- Exceptional potency allows use of a significantly lower dose, providing expected
safety advantages relative to existing MRSA-targeted drugs
- Potent bactericidal activity at low multiples of the MIC
- Superior to vancomycin and linezolid
- Low potential for emergence of resistance
- Confirmed in single and multi-step resistance studies
- Lung penetration enables use in pneumonia
- Demonstrated in human bronchoalveolar lavage (BAL) study
- Potential for approval in multiple MRSA indications, including nosocomial pneumonia,
cSSSI, and bacteremia/endocarditis
9:55 Networking and Refreshment Break
| Session V - Recent Advances in Anti-Infectives Development – Anti-bacterial (continued) Moderator: Mike Dudley, Mpex Pharmaceuticals, Inc. |
10:25 AN3365: A Novel Boron Containing Antibacterial Agent in Clinical Development for Gram-negative Infections
Vincent Hernandez, Director, Medicinal Chemistry, Anacor Pharmaceuticals
The global rise of multi-drug resistant Gram-negative bacteria necessitates the introduction of truly novel therapeutic agents. We report the discovery of AN3365, a new aminomethylbenzoxaborole in Phase I clinical development for Gram-negative infections. AN3365 inhibits leucyl-tRNA synthetase (LeuRS) by the novel oxaborole tRNA trapping (OBORT) mechanism of action. AN3365 was found to be a potent compound with an IC50 value of 0.31 µM against E. coli LeuRS and with MIC ranges of 0.25-2 µg/mL against a wide variety of Gram-negative bacteria including Enterobacteriaceae and nonfermenting bacilli. The co-crystal structure of AN3365 with LeuRS-tRNALeu shows the boron of AN3365 forms an adduct with the terminal adenosine ribose of tRNA in the editing active site with additional interactions being made between the protein and the aminomethyl group. The tRNALeu is thus trapped on the enzyme leading to a block in protein synthesis. AN3665, in phase I clinical development, is a member of a novel class of boron-containing antibacterial protein synthesis inhibitors which inhibits leucyl-tRNA synthetase via a unique mechanism of action.
Benefits of the presentation include:
1. Introduction to boron-containing therapeutic agents
2. Discussion of leucyl-tRNA synthetase editing active site as a new antibacterial drug target
3. Description of the novel OBORT mechanism of action
4. Biological activity of AN3365 including MIC90 and in vivo efficacy data
10:50 Torezolid: The Next Generation
Karen Joy Shaw, Ph.D., Senior Vice President, Biology, Trius Therapeutics
11:15 Redefining the Paradigm for Aminoglycoside Therapeutics: Development of Best-in-Class Broad-Spectrum Parenteral and Inhaled Antibiotics for Serious Gram-Negative Infections
Michael Chaparian, Ph.D., President and CEO, SelectX Pharmaceuticals
SelectX has developed a powerful platform to enable the discovery of novel aminoglycoside therapeutics for a variety of indications. The platform completely modernizes aminoglycoside drug discovery through its close integration of state-of-the-art aminoglycoside medicinal, synthetic and analytical chemistry; molecular modeling and structural biology; genetic chemistry; proprietary biochemical and functional assays; and proprietary structure-activity and structure-toxicity relationships (SAR, STR).
The company’s most advanced program, development candidate SXP2523, is a next generation aminoglycoside antibiotic for serious, MDR gram-negative hospital-acquired infections (HAIs). SXP2523 features broad spectrum coverage and excellent potency against the most problematic gram-negative organisms including Pseudomonas, Klebsiella, Acinetobacter, and E. coli (MIC90s ≤ 2 µg/ml). SXP2523 has demonstrated excellent efficacy in animal models, as well as safety, resulting in a superior predicted therapeutic index compared to amikacin and other marketed aminoglycosides. Lastly, SXP2523 possesses a novel molecular structure designed to maintain stability toward the most relevant mechanisms of clinical resistance.
SelectX is also developing novel inhalable aminoglycosides for lung infections that have superior potency against the most problematic respiratory gram-negatives. These compounds are further differentiated from competing products by possessing mucolytic activity, enhanced biofilm penetration and/or anti-inflammatory activity. SXP2554, the company’s current lead, has excellent potency against resistant gram-negatives including Pseudomonas, Acinetobacter, Klebsiella and against community-acquired MRSA (MIC90s ≤ 2 µg/ml). Similar to other inhaled antibiotics, SXP2554 shows virtually no systemic exposure when delivered via inhalation and, like SXP2523 is designed to be “resistant to resistance”.
This presentation will provide the audience with:
• An introduction to the industry’s most advanced aminoglycoside drug discovery platform
• A discussion regarding key considerations guiding the development of next-generation aminoglycoside antibiotics
• A description of the biological activities and development status of the company’s best-in-class parenteral and inhaled aminoglycoside antibiotics, SXP2523 and SXP2554
11:40 Bad Bugs, Some Drugs
Timothy Keutzer, Senior Director, Project Management, Cubist
12:05 The New Era of Innovative Therapies: Monoclonal Antibodies for the Treatment of Severe Infections
Antonio Perez, M.D., Senior Medical Officer, Kenta Biotech
The need for the development of novel anti-infectives treatments is driven by the growing incidence of infections caused by common multi-drug resistance pathogens, which is accompanied by a dramatic increase of associated high morbidity and mortality, very high costs and consumption of resources. Unfortunately, new and long-lasting efficacious antibiotics rarely reach the market.
Within new therapies to counteract such threats, monoclonal antibodies (mAbs) given as first line, in combination with antibiotics, may play a relevant role to treat the most deadly pathogens.
MAbs enhance the original mechanism of defense of natural antibodies, and are not expected to develop resistance mechanism from pathogens. They cannot only complement but to improve antibiotic therapy without interfering their mechanism of action, and are highly personalized for its specificity to target pathogens. MAbs have an excellent safety profile. MAbs have a significant longer serum half life, thus having longer span of antimicrobial activity and they can neutralize toxins and toxic effects of bacterial compounds even after the killing of the bacterial cells. MAbs can be developed in shorter times compared to standard antibiotics. Promising results have been achieved with a new fully human mAb, panobacumab, for the treatment of ventilator-associated pneumonia caused by Pseudomonas aeruginosa.
This presentation will:
• Position the advantages, properties and role of mAbs in infectious diseases
• Highlight mAbs opportunities for the treatment of infections caused by deadly pathogens
• Review recent clinical experience with Panobacumab
12:30 Lunch
| Session V - Recent Advances in Anti-Infectives Development – Anti-bacterial (continued) Moderator: Roger Echols, Infectious Disease Drug Development Consulting, LLC |
1:30 What’s Next for MRSA Drugs
Jarrod Longcor, Senior Director, Business Development, Rib-X Pharmaceuticals
Because of the focus over the recent past on MRSA drugs, many have wonder if the MRSA market is saturated and whether there is a market for new drugs in what is becoming a generic market. But with so many recent failures, new regulatory standards, new warning labels on existing products, and increasing rates of strains resistant to marketed products is there an opportunity for a differentiated product. Delafloxacin is a new class of quinolone with broad spectrum coverage including MRSA. The properties that differentiate delafloxacin from both quinolones and the other MRSA treatments will be discussed, including its in vitro potency, efficacy in preclinical models of infection, and how it will fit in the clinic.
1:55 Increasing Resistance in Gram-Negative Pathogens: Threat and Opportunity
Mike Dudley, Senior Vice President, Research & Development and Chief Scientific Officer, Mpex Pharmaceuticals, Inc.
| Session VI – Innovative Partnering & Licensing Strategies Moderator: Sameeh Salama, NAEJA Pharmaceutical |
2:20 Monetizing Your Inventions: Strategies For Maximizing License Revenue
Mike Fuller, Partner, Knobbe Martens Olson & Bear
Partnering and Deal-Making for anti-infectives revolve around strong intellectual property rights. This session will teach you how to properly obtain and license your inventions in order to maximize revenue. There are many ways to protect an invention, but only some ways are designed with licensing in mind. Patents not only protect your innovations from competitors, but also can be used as a shield from competitors. This session will discuss the proper strategies for patenting inventions, and also teach you how to avoid common pitfalls that lead to lower license revenue.
This session will cover:
- How to protect key inventions with patents
- Patent claim strategies that are geared towards maximizing license revenue
- Avoiding common pitfalls in protecting inventions
- Using intellectual property to as a sword and a shield
2:45 How to Increase the Overall Value of Your Anti-Infective Technology Portfolio
Paul A. Stewart, Director, Global Business Development, Eli Lilly and Company – Elanco Animal Health Division
Recent deal activity has confirmed that universities, biotech firms and even some large pharmaceutical companies can increase the overall value of their technology portfolio by first licensing animal health applications of that technology to one of the “brand name” global animal health players. Since animal health is only about 5% of the size of the human pharmaceutical business worldwide, licensing the animal health applications first (while still retaining human pharmaceutical rights for later sale or licensing) allows these organizations to validate to the external world that their technology has scientific merit (and even perhaps realize commercial value through earlier launch and revenues to the inventor) while still retaining the vast majority of the technology value. Of course, animal health uses can be an excellent backup plan – and in some instances, a better primary use – of certain anti-infective compounds, but a deliberate strategy to secure animal health partners might add to overall value of the technology.
BENEFITS:
1. Introduce conference participants to the global Animal Health industry and its various uses of anti-infective compounds.
2. Help participants understand that they might benefit from a deliberate strategy to license out animal health uses of their technology – while still retaining human pharmaceutical uses where the vast majority of the value remains with the originator / inventor.
3. Inform participants of the in-licensing process used by major animal health companies and how development and registration of animal health compounds differs from human ones.
3:10 Considerations for Developing a Compelling Partnering Value Proposition
Thomas Storey, Manager, External R&D Affairs, Amgen
Accessing external innovation is essential for realizing Amgen’s mission to serve patients. Licensing and acquisition opportunities are an attractive method of complementing internal research programs and ensuring Amgen develops medically important medicines. Toward this end, licensing and acquisition opportunities must be thoroughly vetted throughout the organization and top proposals presented to senior management for consideration. This presentation outlines the opportunity identification and evaluation process at Amgen and highlights elements of attractive licensing and acquisition opportunities. Topics covered include:
• Amgen’s mission and values
• Amgen’s sourcing and evaluation process
• How valuation concepts shape the value proposition of an opportunity
• The role of diligence in supporting the value proposition
3:35 Conference Concludes
