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The Dwindling Pipeline of Anti-Infectives Or….“Bad Bugs, No Drugs” George H. Talbot MD

The Dwindling Pipeline of Anti-Infectives Or….“Bad Bugs, No Drugs” George H. Talbot MD. Presentation Objectives. Discuss the decrease in antibacterial R&D efforts by major pharmaceutical companies Discuss IDSA initiatives & other possible solutions.

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The Dwindling Pipeline of Anti-Infectives Or….“Bad Bugs, No Drugs” George H. Talbot MD

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  1. The Dwindling Pipeline of Anti-Infectives Or….“Bad Bugs, No Drugs” George H. Talbot MD

  2. Presentation Objectives • Discuss the decrease in antibacterial R&D efforts by major pharmaceutical companies • Discuss IDSA initiatives & other possible solutions

  3. Why is IDSA Concerned?And why we all should be…

  4. William H. Stewart 1967 Declared victory against the threat of infectious diseases and suggested that our nation turn its resources to the more important threat of chronic diseases….

  5. Important Concepts Regarding Infectious Diseases • Infectious diseases: #3 cause of death, US • Worldwide: #2 cause of death • Hospital-acquired infections: 2 million per year in the U.S. (90,000 deaths) • More deaths from sepsis than myocardial infarctions in U.S. Thx to J. Edwards for selected slides

  6. Emerging Infectious Diseases

  7. Review of Antimicrobial Drug Development

  8. Methods of Study • FDA databases for new drug applications (NDAs) reviewed • New antibiotics defined as “new molecular entities to treat bacterial infections” • Cross-referenced with FDA Orange Book • Annual reports reviewed • 15 largest pharmaceutical companies • 7 largest biotech companies

  9. Results of Analysis • New antibacterials approvals declined vs 1996 • Antibacterials decreasing as % of new drugs • 411 NDAs approved from 1998 to 2002 • 6 antibacterials • During same period, 2 antifungal & 2 anti-parasitic agents approved • 12 new anti-virals: half for HIV

  10. Antibacterial Approvals *R2 = 0.99 *P=0.007 by linear regression. New antibacterial agent  new molecular entity (NME) with antimicrobial properties, administered for systemic infection; topical agents and immunomodulators excluded.

  11. ANTIBACTERIAL Quinupristin/dalfopristin Moxifloxacin Gatifloxacin Linezolid Cefditoren pivoxil Ertapenem Gemifloxacin Daptomycin Telithromycin Tigecycline YEAR 1999 1999 1999 2000 2001 2001 2003 2003 2004 2005 Systemic Antibacterial AgentsApproved Since 1998 NOVEL MOA No No No Yes No No No Yes No No Spellberg et al, CID May 1 2004

  12. Antimicrobial Availability Task Force AATF’s Charge Develop novel public policy to ensure a sustainable supply of safe and effective antimicrobial drugs to protect the public health

  13. John G. Bartlett, MD John S. Bradley, MD                            John E. Edwards, Jr., MD David N. Gilbert, MD W. Michael Scheld, MD George H. Talbot, MD FDA Advisor: John Powers, MD IDSA Staff Liaison: Robert J. Guidos, JD AATF Membership

  14. Defining the Problem:“Bad Bugs, No Drugs” • Input sought from major stakeholders: • IDSA’s membership base of 7,500 physicians, researchers, and health care providers • FDA • CDC, NIAID, HHS • Senior pharmaceutical executives • Venture capital companies • Legislators

  15. As Antibiotic Discovery Stagnates ...A Public Health Crisis BrewsBAD BUGS, NO DRUGS IDSA July 2004

  16. What has AATF Learned?Overview • Complex problem, multi-factorial etiology • Potential solutions are apparent • Progress requires long-term commitment & the active collaboration of essential partners

  17. The Problem “Drug options for treatment of infections are becoming increasingly limited, largely as a result of growing antimicrobial resistance. Many generic but essential antibiotics are in short supply, and the development of new antibiotics has been severely curtailed…. Only 4 large pharmaceutical companies with antibiotic research programs remained in existence in 2002….” (IOM Report: Microbial Threats to Health, 2003)

  18. The Problem “Product development in areas crucial to public health goals, such as antibiotics, has slowed significantly during the past decade.” (U.S. Food and Drug Administration. Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. March 2004.)

  19. FDA Critical Path 2004

  20. FDA Critical Path 2004

  21. Example: Acinetobacter spp.The Pipeline is Thin • Nosocomial & community-acquired pathogen, incidence increasing • National Nosocomial Infection Survey: 1-1.5% of nosocomial bloodstream infections and 3% of hospital-acquired pneumonias • For HAP caused by Acinetobacter spp., mortality rates in the US range from 19-54% • War-related infections now problematic

  22. Example: Acinetobacter spp.The Pipeline is Thin • Increasing resistance: aminoglycoside-modifying enzymes, ESBLs, carbapenemases, changes in outer membrane proteins and PBPs. • Many isolates now resistant to aminoglycosides, cephalosporins, chloramphenicol, & FQs. • Beta-lactam/ beta-lactamase inhibitor combinations & carbapenems retain useful activity. • Colistin most reliably active

  23. Example: Acinetobacter spp.The Pipeline is Thin • Tigecycline recently approved by FDA for cSSSI and cIAI indications • Active in vitro vs. Acinetobacter spp. • Clinical utility for this pathogen not defined • AATF has not been able to identify any other drugs in pipeline with potent activity vs this pathogen

  24. Other Problem Bugs • Pseudomonas aeruginosa • ESBL-producing gram-negative bacilli • Community-acquired S. aureus • Vancomycin-resistant enterococci • Aspergillus spp. • Multi-drug resistant TB

  25. What Has AATF Learned?Issues for Pharma “When it comes to annual sales potential, antibiotics don’t measure up. .. a musculoskeletal drug is worth about $1.15 billion, a neuroscience treatment … $720 million, & a medicine for resistant Gram-positive cocci … only $100 million.” (Sellers, LJ. Pharmaceutical Executive. Dec 2003)

  26. What Has AATF Learned?Issues for Pharma “U.S. demographics shifting toward an increasingly older population will lure even more investors and companies to the chronic diseases market. As generics compete with existing products, companies face additional pressure to develop new blockbusters...” (Health Care Industry Market Update: Pharmaceuticals, CMS, Jan 10, 2003)

  27. What Has AATF Learned?Issues for “Big” Pharma • “Big” Pharma sees better return from the treatment of chronic diseases. • In contrast, antibacterial therapies are: • Short course, used for acute illnesses • Not embraced by the marketplace (cost, resistance, “satisfied” market) • Rarely “blockbusters” • Prone to becoming “auto-obsolete”

  28. What Has AATF Learned?Issues for “Small” Pharma • “Small” Pharma is more engaged • Financial return better matched to size • Market opportunity is more clear • Regulatory uncertainty: a lesser concern? • Focus • For some, in-licensed compounds only • Others, robust Discovery efforts Will it be enough?

  29. What Has AATF Learned?Clinical Trials of Anti-infectives • Increasing standards for demonstration of efficacy and safety • Increasingly complex patients in trials • Significantly increased costs of trials • Confidentiality issues • Difficult to find resistant pathogens Reducing the # and size of clinical trials would alter the equation favorably

  30. What has AATF Learned?Issues for FDA • FDA understands the problem • Wishes to partner in finding solutions • Regulatory uncertainty, when present, further clouds the development process (FDA’s 2004 “Critical Path” report) • Maintaining scientific rigor • Limited flexibility per statutory constraints • e.g., waiver of user fees not possible

  31. Potential SolutionsLegislative For investments in priority antibacterials • Incentives successful elsewhere to spur R&D • e.g., focused R& D tax credits • Supplemental IP protections • e.g., wild-card patent exclusivity • Mechanisms to attract smaller companies • e.g., waiver of user fees for supplemental NDAs

  32. Potential SolutionsLegislative • Commission to Prioritize Antimicrobial Discovery (CPAD) • Independent, to be est. by Congress • Broad representation from stakeholders • Charges • Identify priority pathogens • Decide which antibiotics should receive the benefits of legislated incentives

  33. Legislative Update • Senate: S3 introduced by Senator Frist • House: Rep Cubin introduced bill • Address bioterrorism, but also naturally occurring infectious diseases • Contain many elements of IDSA’s recommendations • We’ll see…..

  34. Potential SolutionsRegulatory adjustments • Publish updated guidelines • Periodic, timely, review and revision • Encourage novel clinical trial designs to gather information on drug efficacy against resistant pathogens

  35. Potential SolutionsRegulatory adjustments And, relevant to today’s discussion: • Define surrogate endpoints, PK/PD parameters, & preclinical data that could reduce # and size of clinical studies

  36. Conclusions • The antibacterial pipeline is at risk, especially for some key pathogens • Etiology is multi-factorial: no single, “easy” solution • Some hopeful signs for the future, but… • Solutions needed! • Appropriate use of surrogate markers could help

  37. Acknowledgements • Potential Conflicts: • No external financial support for AATF effort • AATF members provide consultative services to industry • Thanks to: • AATF members • IDSA staff, esp. R. Guidos & D. Olson • The many people with whom we have spoken

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