Cambridge Healthtech Institute’s Fourth Annual

Targeting Gram-Negative Pathogens

October 19-20, 2017 | Omni Parker House | Boston, MA

Multidrug-resistant Gram-negative bacteria are one of the main challenges for the healthcare system and public health in general. Gram-negative bacteria have specific scientific problems such as low permeability of the outer membrane that must be overcome, complicated and multiple resistance mechanisms, etc. The Targeting Gram Negative Pathogens conference will be taking place October 19-20 in Boston as a part of the Fourth Annual Re-Entering Antibacterial Discovery and Development Summit. It will be preceded by the more general Antibacterial Discovery and Development on October 18-19.

Final Agenda

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Thursday, October 19

10:30 am Registration

PLENARY SESSION:
MONEY, COLLABORATION, POLICY

11:00 Chairperson’s Remarks

Melissa Stundick, Ph.D., Head of Strategic Alliances, Spero Therapeutics

11:15 Series of Brief Presentations  

Driving Re-Investment in Antibiotics: Update from Europe’s DRIVE-AB

Kevin Outterson, Professor of Law, Boston University & Executive Director, CARB-X

DRIVE-AB has spent three years evaluating economic incentives to rekindle antibiotic R&D (www.drive-ab.eu), funded by the European Union with matching contributions from EFPIA companies. Final results and recommendations from DRIVE-AB will be presented.

Venture Capitalists: What Are Investors Looking For?

Vikas Goyal, Associate, SR One

CARB-X: What Does It Mean to be Powered by CARB-X?

Tyler Merkeley, CARB-X Co-Founder, BARDA’s CARB-X Program Manager, U.S. Department of Health and Human Services (HHS), Biomedical Advanced Research and Development Authority (BARDA)

CARB-X is a global innovation fund to support antibacterial product development supported by the Biomedical Advanced Research and Development Authority (BARDA), National Institute of Allergy and Infectious Diseases and Wellcome Trust, the UK-based global charitable foundation dedicated to improving health. Co-founder, Tyler Merkeley, will share BARDA’s continued vision for CARB-X as the “Global Innovation Fund” to address antibiotic resistant infections, highlight the Powered by CARB-X portfolio, and discuss future partnerships and funding opportunities.

Update on Pathways & Policies to Facilitate Antibiotic Development

Nicole Mahoney, Director, Global Policy, Merck

Antibiotic resistance continues to be a focus for policy makers determined to ensure the continued availability of effective treatments for patients with serious infections. This talk will provide an update on recent discussions with an emphasis on regulatory developments.

12:15 pm PANEL DISCUSSION:Non-Scientific Solutions to Advance Antimicrobial Pipeline 

Moderator:
Melissa Stundick, Ph.D., Head of Strategic Alliances, Spero Therapeutics
Panelists: Speakers of the Session

1:00 Enjoy Lunch on Your Own

BREAKING OPEN BARRIERS

2:00 Chairperson’s Opening Remarks

Helen Zgurskaya, Ph.D., Professor, Chemistry and Biochemistry, University of Oklahoma

2:05 Antimicrobial Resistance in Gram-Negative Pathogens: Extent of the Problem and Clinical Impact

David C. Hooper, M.D., Chief, Infection Control Unit, Massachusetts General Hospital

Human Gram-negative pathogens have an extensive set of tools that they have deployed to resist antibiotic therapies. Multi-drug resistance has increased, and Gram-negative bacillary infections constitute two of the three urgent resistance threats and seven of the 12 serious threats that the CDC estimates are responsible overall for over 2,000,000 illnesses and 23,000 deaths annually. The prevalence of resistance directly affects choice of antimicrobials for empiric therapy of serious infections and with fewer active agents funnels selection pressures toward newer agents. The occurrence of infections for which few or no active agents are available highlights the urgency of the problem and the importance of careful management of current antimicrobials through stewardship programs to reduce selection pressure and of infection control practices to reduce transmission of resistant pathogens.

2:45 Predictive Guidelines for Compound Accumulation in Gram-Negative Bacteria

Paul J. Hergenrother, Ph.D., Kenneth L. Rinehart Jr. Endowed Chair in Natural Products, Chemistry Department of Chemistry, University of Illinois

The inability of most compounds to penetrate and accumulate in gram-negative bacteria has been a major obstacle to the discovery of new broad-spectrum antibiotics. We assessed the ability of ~200 diverse compounds to accumulate in E. coli, and through computational analysis of the results we have developed predictive guidelines for compound accumulation in gram-negative pathogens. The use of these guidelines to convert gram-positive-only drugs to broad-spectrum antibiotics will be discussed.

3:25 Building an Understanding of Porin-Permeation in Gram-Negative Pathogens

Ruben Tommasi, Ph.D., CSO, Entasis

To address the knowledge gap in understanding Gram-negative permeation, we developed a sensitive and specific whole-cell approach in Escherichia coli called titrable outer membrane permeability assay system (TOMAS). We used TOMAS to characterize the structure porin-permeation relationships of a set of novel carbapenem analogues through the Pseudomonas aeruginosa porin OprD. Our results suggest that small structural modifications, especially the number and nature of charges and hydrogen bonding groups and their position, have dramatic effects on the ability of these molecules to permeate into cells through OprD. 

4:05 Refreshment Break in the Exhibit Hall with Poster Viewing

4:35 Disrupting the Gram-Negative Outer Membrane

Lee Swem Ph.D., Senior Vice President, CSO, Achaogen

The outer-membrane is a formidable barrier that protects gram-negative bacteria from antibacterial assault. We are focused on identifying compounds that compromise the integrity of the gram-negative outer-membrane. Specifically, we are developing potent small molecule inhibitors of the essential LPS biosynthetic protein, LpxC. In addition, we have developed a rare antibody discovery platform to identify antibodies that inhibit the essential functions of proteins found in the outer-membrane, necessary for its biogenesis.

5:05 Permeability Barriers of Gram-Negative Pathogens and Approaches to Bypass Them

Helen Zgurskaya, Ph.D., Professor, Chemistry and Biochemistry, University of Oklahoma

Gram-negative bacteria are intrinsically resistant to many antibiotics. The problem is broadly recognized and tackled at fundamental and applied levels. The major obstacle in discovery and development of antibiotics effective against such pathogens is the low permeability barrier of Gram-negative pathogens. This presentation will discuss ongoing efforts to understand molecular bases of this barrier and specific strategies to break it in order to achieve potent activities against difficult Gram-negative bacteria.

5:35 Close of Day

5:45 Dinner Short Course Registration*

*(Separate Registration required)

6:00 Dinner Short Course

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Friday, October 20

8:00 am Interactive Breakout Discussion Groups with Continental Breakfast

This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Continental breakfast is available for all participants. Details on the topics and moderators are available on the conference website.

Topic: Compound Permeability in Gram Negative Bacteria

Moderator: Folkert Reck, Ph.D., Senior Investigator, Global Discovery Chemistry, Novartis Institutes for BioMedical Research

• Property space for permeability through porins and lipid bilayers
• Self-promoted uptake/ membrane disruption – Opportunities and Challenges
• Active transport approach – Opportunities and Challenges
• Property space for minimizing impact by efflux –new insights

Topic:Antibacterial Biologics

Moderator: Patricia A. Bradford, Ph.D., Antimicrobial Development Specialists, LLC

• Which type of biologics (monoclonal antibodies, phages, antimicrobial peptides) have the best chance to break the disillusionment (due to past failures) and disbelief in antibacterial biologics
• What is the most attractive clinical target: prophylaxis, preemptive therapy of high-risk individuals, or combination with / potentiation of existing antibiotic therapies?
• What are the major hurdles for pathogen-specific approaches (regulatory, commercial, etc)?

Topic:Small Molecules for Gram-Negatives

Moderator: Peter Smith, Ph.D., Scientist, Infectious Disease at Genentech

• Overcoming lack of treatments for MDR Gram Negatives
• Where will new scaffolds come from?
• Discussion of platforms for screening

THERAPEUTIC APPROACHES

8:55 Chairperson’s Remarks

Todd A. Black, Ph.D., Executive Director, Infectious Diseases, Basic Research, Merck Research Laboratories

9:05 Filling in the Gaps in the MDR Gram-Negative Pipeline

Todd A. Black, Ph.D., Executive Director, Infectious Diseases, Basic Research, Merck Research Laboratories

Antibiotic-resistant Gram-negative bacteria are increasing in prevalence. Some strains are now resistant to all classes of antibiotics, including polymyxins. The discovery of new classes of agents that are effective against Gram-negative pathogens have thus far proven to be an insurmountable challenge despite years of intensive efforts. The recent development of compounds that address specific subsets of resistance mechanisms have thus far been the only effective response. However, this approach provides only incremental improvements in strain coverage and presents challenges identifying the right patients and strategies to ensure appropriate use to reduce rapid development of resistance.

9:35 TP-6076, A Novel Fluorocycline Antibiotic with Potent Activity against Carbapenem-Resistant Gram-Negative Isolates

Jacques Dumas, Ph.D., CSO, Tetraphase Pharmaceuticals, Inc.

Tetraphase (NASDAQ:TTPH), a clinical-stage biopharmaceutical company, is currently developing TP-6076 as a novel, synthetic, fluorocycline antibiotic. TP-6076 is derived from Tetraphase’s proprietary chemistry technology platform and shows high potency against clinically important Gram-negative pathogens, including carbapenem-resistant Acinetobacter baumannii and Enterobacteriaceae. TP-6076 is in Phase I clinical trials, with the goal of addressing serious and life-threatening bacterial infections, including those caused by pathogens otherwise resistant to current treatment options. In this talk, we review the synthesis, in vitro and  in vivo activity of TP-6076, as well as the human data available to date. The ongoing development of TP-6076 will be supported by the CARB-X initiative.

10:05 Coffee Break

10:35 LYS228, A Novel Monobactam to Treat Infections Caused by Multi-Drug Resistant Enterobacteriaceae

Folkert Reck, Senior Investigator II, Global Discovery Chemistry, Infectious Diseases, Novartis

We describe the optimization of novel monobactams leading to LYS228, currently in early clinical development. LYS228 is the first single agent -lactam that retains potency in the presence of all known classes of -lactamases, with potent activity against carbapenem-resistant enterobacteriacease, including serine-carbapenemase and metallo -lactamase producing strains.

11:05 Discovery of a Novel Class of Gram-Negative Antibiotics

Peter Smith, Ph.D., Scientist, Infectious Disease at Genentech

This presentation will feature a case study dedicated to discovery of novel class of small molecules for Gram-Negative pathogens.

11:35 The Use of Target-Based Screening to Discover Novel Antibiotic Scaffolds against Multi-Drug Resistant (MDR) Gram-Negative Pathogens

Moritz von Rechenberg, Ph.D., Group Leader, Protein Production, TDS, X-Chem Pharmaceuticals

Despite years of intensive efforts, the discovery of truly novel classes of agents that are effective against MDR pathogens have proven to be a challenge. By combining a multi-target screening campaign against a DNA-encoded library of over 200 billion compounds, focusing our synthetic efforts on compounds consistent with the property space of active Gram-negative antibiotics, and using a whole-cell screening assay (MIC) in multiple Gram-negative bacterial species to rapidly validate activity, we are discovering novel scaffolds that will lead to effective, new antibiotics.

12:05 pm Enjoy Lunch on Your Own

BIOLOGICS FOR GRAM NEGATIVES

1:30 Chairperson’s Remarks

Patricia A. Bradford, Ph.D., Antimicrobial Development Specialists, LLC

1:40 Fully Human Antibacterial Monoclonal Antibodies for the Treatment of Acute Pneumonia

Vu Truong, Ph.D., CEO, Aridis Pharmaceuticals Inc.

Anti-infective immunotherapy using human monoclonal antibody (mAb) is a promising approach that is being explored by an increasing number of researchers. We have a human mAb discovery platform that allows for rapid discovery and manufacture of fully human monoclonal antibodies from patients, and are developing several anti-bacterial antibodies as adjunctive immunotherapy to standard of care antibiotics. Clinical data on Aridis’ mAb programs and our future directions will be presented.

2:10 MEDI3902: An Alternative Treatment for MDR P. aeruginosa  

Bret Sellman, Ph.D., Director, Department of Infectious Diseases and Vaccines, MedImmune

Broad-spectrum antibiotic therapy has fueled the current antibiotic resistance epidemic. Taken together with the recent understanding of the adverse effects of antibiotic therapy on the healthy microbiome, pathogen specific therapies (i.e. monoclonal antibodies, mAbs) are being considered as alternatives to empiric broad-spectrum antibiotics for multidrug resistant pathogens such as Pseudomonas aeruginosa. In this presentation, I will discuss promising mAb-based methods for the prevention and treatment of serious P. aeruginosa infections.

2:40 CO-PRESENTATION: Antisense Approaches for Treating Multidrug-Resistant Pathogens

David Greenberg, M.D., Associate Professor of Infectious Diseases and Microbiology Internal Medicine, University of Texas Southwestern

Gunnar J. Hanson, Ph.D., Senior Director of Research Chemistry, Research Chemistry, Sarepta Therapeutics, Inc

The rapid rise in antibiotic resistance worldwide illustrates the need for new paradigms in antimicrobial development. We have developed novel species-specific gene-specific therapeutics utilizing antisense technologies (peptide-conjugated phosphorodiamidate morpholino oligomers; PPMOs). We have developed lead PPMOs in numerous drug-resistant gram-negative pathogens that demonstrate activity both in vitro and in in vivo infection models. We will review the different targeting strategies that are used with this platform technology.

3:10 Recombinant Lysins as Potent and Novel Anti-Infectives

Raymond Schuch, Ph.D., Vice President of Research, Microbiology, ContraFect Corporation

ContraFect is the leader in the discovery and development of lysins, an innovative approach to treat bacterial infections. Lysins are purified recombinant proteins that act on the cell wall of bacterial pathogens, resulting in lysis on contact and multi-log-fold killing.  CF-301, ContraFect’s most advanced product candidate, is a lysin with potent bactericidal activity against Staphylococcus aureus. ContraFect is also engineering lysins against Gram-negative pathogens including Pseudomonas aeruginosa

3:40 Q&A with the Speakers of the BIOLOGICS FOR GRAM NEGATIVES Session

4:00 Close of Conference

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