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

Talbot 4 Aug 2005 1

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.


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


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


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


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


As Antibiotic Discovery Stagnates ...A Public Health Crisis BrewsBAD BUGS, NO DRUGS

IDSA

July 2004


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


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)


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


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



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



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


Other Problem BugsOther Problem Bugs

Pseudomonas aeruginosaESBL-producing gram-negative bacilliCommunity-acquired S. aureusVancomycin-resistant enterococciAspergillus spp.Multi-drug resistant TB


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)


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)


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”


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?


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


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


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


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


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…..


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


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


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


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

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

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