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Transcript Talbot-ISAP-post

The Dwindling Pipeline of
Anti-Infectives
Or….“Bad Bugs, No Drugs”
George H. Talbot MD
Talbot 4 Aug 2005
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Presentation 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?
And why we all should be…
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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….
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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.
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Thx to J. Edwards for selected slides
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Emerging Infectious Diseases
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Review of Antimicrobial
Drug Development
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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
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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 antiparasitic agents approved
 12 new anti-virals: half for HIV
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Antibacterial Approvals
18
16
14
12
10
8
6
4
2
0
*R2 = 0.99
1983-1987
1988-1992
1993-1997
1998-2002
*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 Agents
Approved Since 1998
ANTIBACTERIAL
Quinupristin/dalfopristin
Moxifloxacin
Gatifloxacin
Linezolid
Cefditoren pivoxil
Ertapenem
Gemifloxacin
Daptomycin
Telithromycin
Tigecycline
YEAR
1999
1999
1999
2000
2001
2001
2003
2003
2004
2005
NOVEL MOA
No
No
No
Yes
No
No
No
Yes
No
No
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Spellberg et al, CID May 1 2004
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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
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AATF Membership

John G. Bartlett, MD

John S. Bradley, MD

David N. Gilbert, MD

W. Michael Scheld, MD

George H. Talbot, MD
FDA Advisor:
 John Powers, MD
 John E. Edwards, Jr., MD
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IDSA Staff Liaison:
 Robert J. Guidos, JD
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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
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As Antibiotic Discovery Stagnates ...
A Public Health Crisis Brews
BAD BUGS, NO DRUGS
IDSA
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July 2004
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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
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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)
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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.)
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FDA Critical Path 2004
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FDA Critical Path 2004
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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
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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
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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
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Other Problem Bugs

Pseudomonas aeruginosa
 ESBL-producing gram-negative bacilli
 Community-acquired S. aureus
 Vancomycin-resistant enterococci
 Aspergillus spp.
 Multi-drug resistant TB
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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 Grampositive cocci … only $100 million.”
(Sellers, LJ. Pharmaceutical Executive.
Dec 2003)
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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)
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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”
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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?
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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
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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
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Potential Solutions
Legislative
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
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Potential Solutions
Legislative

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 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…..
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Potential Solutions
Regulatory 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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Potential Solutions
Regulatory 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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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
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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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