The Dwindling Pipeline of Anti-Infectives Or….“Bad Bugs, No Drugs” George H. Talbot MD
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Transcript of The Dwindling Pipeline of Anti-Infectives Or….“Bad Bugs, No Drugs” George H. Talbot MD
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The Dwindling Pipeline of The Dwindling Pipeline of Anti-InfectivesAnti-Infectives
Or….“Bad Bugs, No Drugs”Or….“Bad Bugs, No Drugs”
George H. Talbot MD
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Presentation ObjectivesPresentation Objectives
Discuss the decrease in antibacterial R&D efforts by major pharmaceutical companies
Discuss IDSA initiatives & other possible solutions
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Why is IDSA Concerned?Why is IDSA Concerned?
And why we all should be…And why we all should be…
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William H. Stewart 1967William H. Stewart 1967Declared victory against the threat of infectious diseases and suggested that our nation turn its resources to the more important threat of chronic diseases….
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Important Concepts Regarding Important Concepts Regarding Infectious DiseasesInfectious Diseases
Infectious diseases: #3 cause of death, USWorldwide: #2 cause of deathHospital-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
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Emerging Infectious DiseasesEmerging Infectious Diseases
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Review of Antimicrobial Review of Antimicrobial Drug DevelopmentDrug Development
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Methods of StudyMethods 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 BookAnnual reports reviewed
– 15 largest pharmaceutical companies – 7 largest biotech companies
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Results of AnalysisResults of Analysis
New antibacterials approvals declined vs 1996Antibacterials decreasing as % of new drugs411 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
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02468
1012141618
1983-1987 1988-1992 1993-1997 1998-2002
*R2 = 0.99
Antibacterial ApprovalsAntibacterial Approvals
*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.
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Systemic Antibacterial AgentsSystemic Antibacterial Agents Approved Since 1998Approved Since 1998
ANTIBACTERIALQuinupristin/dalfopristinMoxifloxacinGatifloxacinLinezolidCefditoren pivoxilErtapenemGemifloxacinDaptomycinTelithromycinTigecycline
YEAR 1999 1999 1999 2000 2001 2001 2003 2003 2004 2005
NOVEL MOA No No No Yes No No No Yes No No
Spellberg et al, CID May 1 2004
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Antimicrobial AvailabilityAntimicrobial Availability Task Force 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
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AATF MembershipAATF Membership 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
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Defining the Problem:Defining the Problem:“Bad Bugs, No Drugs”“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
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As Antibiotic Discovery Stagnates ...A Public Health Crisis BrewsBAD BUGS, NO DRUGS
IDSA
July 2004
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What has AATF Learned?What has AATF Learned?OverviewOverview
Complex problem, multi-factorial etiology Potential solutions are apparentProgress requires long-term commitment &
the active collaboration of essential partners
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The ProblemThe 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)
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The ProblemThe 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.)
Talbot 4 Aug 2005 19FDA Critical Path 2004
Talbot 4 Aug 2005 20FDA Critical Path 2004
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Example:Example: Acinetobacter Acinetobacter spp. spp.The Pipeline is ThinThe 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
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Example:Example: Acinetobacter Acinetobacter spp. spp.The Pipeline is ThinThe 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
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Example:Example: Acinetobacter Acinetobacter spp. spp.The Pipeline is ThinThe 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
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Other Problem BugsOther Problem Bugs
Pseudomonas aeruginosaESBL-producing gram-negative bacilliCommunity-acquired S. aureusVancomycin-resistant enterococciAspergillus spp.Multi-drug resistant TB
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What Has AATF Learned?What Has AATF Learned? Issues for PharmaIssues 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)
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What Has AATF Learned?What Has AATF Learned? Issues for PharmaIssues 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)
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What Has AATF Learned?What Has AATF Learned? Issues for “Big” PharmaIssues 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”
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What Has AATF Learned?What Has AATF Learned?Issues for “Small” PharmaIssues 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?
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What Has AATF Learned?What Has AATF Learned?Clinical Trials of Anti-infectivesClinical Trials of Anti-infectives
Increasing standards for demonstration of efficacy and safety
Increasingly complex patients in trialsSignificantly increased costs of trialsConfidentiality issuesDifficult to find resistant pathogens
Reducing the # and size of clinical trials would alter the equation favorably
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What has AATF Learned?What has AATF Learned?Issues for FDAIssues 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
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PotentialPotential Solutions SolutionsLegislativeLegislative
For investments in priority antibacterialsIncentives 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
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PotentialPotential Solutions SolutionsLegislativeLegislative
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
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Legislative UpdateLegislative Update
Senate: S3 introduced by Senator FristHouse: Rep Cubin introduced billAddress bioterrorism, but also naturally
occurring infectious diseasesContain many elements of IDSA’s
recommendationsWe’ll see…..
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PotentialPotential Solutions SolutionsRegulatory adjustmentsRegulatory adjustments
Publish updated guidelines– Periodic, timely, review and revision
Encourage novel clinical trial designs to gather information on drug efficacy against resistant pathogens
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PotentialPotential Solutions SolutionsRegulatory adjustmentsRegulatory adjustments
And, relevant to today’s discussion:
Define surrogate endpoints, PK/PD parameters, & preclinical data that could reduce # and size of clinical studies
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ConclusionsConclusionsThe antibacterial pipeline is at risk,
especially for some key pathogensEtiology is multi-factorial: no single,
“easy” solutionSome hopeful signs for the future, but…Solutions needed!Appropriate use of surrogate markers could
help
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AcknowledgementsAcknowledgementsPotential 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