Transcript Development of Drugs for Resistant Pathogens Francis P. Tally M.D. Cubist Pharmaceuticals, Inc.

Development of Drugs for
Resistant Pathogens
Francis P. Tally M.D.
Cubist Pharmaceuticals, Inc.
Development of Drugs for
Resistant Pathogens
Antimicrobials Developed
Synthetic Molecules
•
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Sulfonamides
Trimethoprim
Quinolones
Nitroimidazoles
Nitrofurans
Oxazolidinones
Natural Products
• ß-lactams
– Penicillins
– Cephalosporins
– Carbapenems
– ß-lactamase
inhibitors
• Tetracyclines
• Chloramphenicol
• Aminoglyosides
• Glycopeptides
•
•
•
•
•
•
•
Lincosamides
Macrolides
Streptogramins
Polymyxins
Rifampicins
Lipopeptides
Mupirocin
Development of Drugs for
Resistant Pathogens
Characteristics to Justify Development
• Microbiological Superiority
– Inhibit resistant organisms
• Pharmacological Advantage
– Frequency of dosing
– Ease of administration
• Safety Advantage
Development of Drugs for
Resistant Pathogens
Preclinical IND Criteria
• Potency
– therapeutic potency vs. drug resistant pathogens
– novel MOA, cidality, low induction of resistance
• Efficacy
– Competitive efficacy vs. key pathogens in salient models
• Pharmacokinetics
– IV required for serious infections
– Oral bioavailability desired to facilitate registration study
• Safety
– balance risk/benefit with infection
– mild, reversible, easily monitored safety profile
Development of Drugs for
Resistant Pathogens
Problems With IV Only Drugs
• Serious Infections – limited Subjects for
enrollment – cSST, pneumonia
intraabdominal infections
• Selection of Comparative Agent (Stop
Biocreep)
• Inpatient Hospital Requirement vs. Home
IV Therapy
• Criteria for oral switch – small delta
magnifies the challenges to perform
adequate studies
Antimicrobial Resistance in
Nosocomial Pathogens
Drug/Pathogen
Resistance (%)
Vancomycin/enterococci
24.7
Methicillin/S. aureus
53.5
Methicillin/CNS
88.2
3rd Ceph/E. coli
3.9
3rd Ceph/K. pneumoniae
10.4
Imipenem/P. aeruginosa
16.4
Quinolone/P. aeruginosa
23.0
3rd Ceph/P. aeruginosa
20.6
3rd Ceph/Enterobacter spp.
33.1
Drug Resistance in the USA
Cubist SECURE surveillance study, 50 Centers
Pathogen
N
S. aureus
1,018
S. pneumoniae 1,163
E. faecalis
E. faecium
2,092
368
Primary resistance (%)
MDR* % ( 3 drugs)
OX – 30.0%
Ery – 46.3%
CIP – 32.5%
GEN – 7.9%
27.1%
PEN – 16.1%
ERY – 31.8%
SXT – 30.8%
14.7%
AMP – 0%
VAN – 1.9%
CIP – 36.3%
Q-D – 91.1%
2.6%
AMP – 81.8%
VAN – 59.5%
CIP – 82.3%
58.4%
*multi-drug resistance
Prevalence (%)
Penicillinase-Producing
Staphylococcus aureus
100
90
80
70
60
50
40
30
20
10
0
Hospital
Community
1940
1945
1950
1955
1960
(Year)
H. Chambers (personal communication)
1965
1970
1975
Nosocomial Methicillin-Resistant Staphylococcus
aureus (MRSA) Infections
Prevalence (%)
50
40
30
20
ICU
Non-ICU
10
0
1989
1990
1991
1992
1993
(Year)
Fridkin et al. Clin Chest Med.1999;20:303.
1994
1995
1996
1997
Methicillin-Resistant
Staphylococcus aureus: SFGH
Prevalence (%)
60
50
40
30
20
< 72 h
> 72 h
10
0
1993
1994
1995
1996
(Year)
Charlebois et al. EPI Center Data.
1997
1998
1999
MRSA in Bay Area Communities
% Carriage
% With MRSA
Western addition
25
16
Tenderloin
20
21
Mission
34
35
Bayview
23
12
Oakland
18
12
Richmond
20
6
H. Chambers (personal communication)
Reports of Community-Acquired
MRSA
Hosp. rate Studies
Children
Others
1996-99
54%
29
8
1991-95
35%
10
0
3 (seniors,
rugby team,
wrestlers)
0
1986-90
20%
5
1
0
1981-85
5%
5
0
4 (addicts)
1976-80
< 5%
0
0
Nosocomial
H. Chambers (personal communication)
Resistant Pathogens
Nosocomial Enterococci Infections
Resistant to Vancomycin*
ICU
Non-ICU
25
% Resistance
20
15
10
5
0
1989 1990 1991 1992 1993 1994 1995 1996 1997
Year
*NNIS 1989-1997.
Fridkin SK, Gaynes RP. Clinics in Chest Medicine. 1999.
Antibacterial Drugs in
Development
Drug
Class
Target
Mechanism
Route
Potential Class
Adverse Events
Linezolid
(Approved)
Oxazolidinone
Ribosome A Site
Static
Oral/IV
Marrow Suppression
Quinupristin /
dalfopristin
(Approved)
Streptogramin
Ribosome
Static
IV
Musculoskeletal Pain,
Phlebitis
Oritavancin
(Phase 2/3)
Glycopeptide
Cell Wall
D-Ala D-Lac
Cidal
IV
Hypersensitivity
Daptomycin
(Phase 3)
Lipopeptide
Cell Membrane
Cidal
IV
Skeletal Muscle
Tigecycline
(Phase 2/3)
Tetracycline
Ribosome
Static
IV
GI Intolerance
Development of New Chemical
Entity
• Efficacy – type of infection
– Mild - UTI, Otitis Media
– Serious – pneumonia, intraabdominal infections
– Severe – meningitis, endocarditis
• Two well-controlled trials with appropriate
“delta” are required
• Safety - over 1,000 patients required will
result in study of 2,500-3,000 patients
• Cost of each patient enrolled $30,182 in
Cubist studies in 2002
Development of Drugs for
Resistant Pathogens
• Cost of Clinical Studies with per patient
cost of $30,182:
Number of
Patients
Total Cost
2500
$75,455,000
3500
$105,637,700
5000
$150,910,000
Action Item 82
• Streamline the regulatory process to bring
AR products to market efficiently while
assuring safety and efficacy
• Subpart E
– Surrogate endpoints – not appropriate in bacterial
infections – resistant pathogen is endpoint
– Potential surrogate is susceptible pathogen
– Animal model surrogates are only guides to the
clinical study
Action Item 82
• AR for life threatening infections focus
development – selected infections
– MRSA – incidence high enough in U.S. clinical
studies
» cSST
» BE/bacteremia
» Nosocomial pneumonia
– VRE – incidence low in different infections drives
need to obtain microbiology claim
» cUTI
» Wound
» Bacteremia - in ICU, transplant and
immunocompromised patients
Action Item 80
• To promote development and appropriate
use of priority AR products
• Restrictive labeling to antibiotic resistant
organism
– MRSA - empiric therapy worth developing
– VRE - niche product not worth developing
• Products with safety issues and activity vs.
resistant pathogens will be restricted
based on the physicians creed to do no
harm
Development of Drugs for
Resistant Pathogens
Drug Categories
• Broad range of indications requires large
clinical program with two well controlled
and sized studies to support claims. Two
potential sources:
– New classes of drugs
– Analog of an approved drug with novel activity
versus resistant pathogens
• Conclusion: Both types need full
development to determine appropriate use
– Adequate dose to retard resistance development
– Appropriate indications for use
Development of Drugs for
Resistant Pathogens
Drug Categories
• Narrow range e.g. gram positive for serious
infections requires IV
• New agents vs. old agents approved
previously for susceptible pathogens.
• Learn from vancomycin use tracts with
increasing frequency of MRSA
Vancomycin Use in the US
VISA reported
12
Metric Tons
10
ICU MRSA rate > 30%
8
6
4
2
0
'84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96
(Year)
Kirst. AAC. 1998;42:1303.
Development of Drugs for
Resistant Pathogens
Opinion
• What is the “problem” in focused drug
development for Antimicrobial Resistant
Organisms?
– Very limited drugs in pipeline
– The promise that genomic sequencing of
pathogens and combinatory chemistry would yield
new antimicrobial drugs has failed
– To realize the potential of genomics in
antimicrobial development will require substantial
funding for new approaches
Development of Drugs for
Resistant Pathogens
Opinion
• What is the “problem” in focused drug
development for Antimicrobial Resistant
Organisms? (continued)
– FDA clearly indicate the number of patients with
resistant infections required in efficacy trials
» Is it absolute number or
» A percentage of the dominant pathogen e.g.
MRSA/MSSE; VRE/Enterococci
– Cost to prove clinical efficacy and safety of known
novel compound ~$75M-$150M
– To restrict novel new drugs for antibiotic resistant
isolates only would limit market return to levels
that would not justify development
Development of Drugs for
Resistant Pathogens
Cubist Path with IV Only Narrow Spectrum Drug
• Efficacy – selected indication with high
incidence of Gram positive pathogens
– cSST – Staphylococcus aureus, MRSA
– CAP – Streptococcus pneumoniae
– Bacterial endocarditis – S. aureus
– cUTI – Enterococci, VRE
• Safety – new classes of drugs
– Two well-controlled trials for each indication
• Special antibiotic resistant pathogens
– MRSA – efficacy proven in selected indications
– VRE – design pathogen-based clinical trial
Development of Drugs for
Resistant Pathogens
What is the answer? – Frank Tally
• Antimicrobial resistance is a complex issue
without simple solutions
• Reserving novel new antimicrobial agents
for antimicrobial resistant pathogens will
– Limit the economic return
– Result in decreased research in both big pharma
and biotech sectors
– Doesn’t solve the problem
Development of Drugs for
Resistant Pathogens
What is the answer? – Frank Tally
• To justify the high investment to develop
novel drugs, the drug’s use should be
determined based upon the safety and
effectiveness of the agent in focused, welldesigned clinical studies
• Industry and Regulatory Agencies should
have frequent dialog in the design of
clinical studies to develop novel agents for
antimicrobial resistant pathogens
Development of Drugs for
Resistant Pathogens
What is the answer? – Frank Tally
• In order to restrict a safe novel
antimicrobial agent to the shelf for only
antimicrobial resistant pathogens, the
government would have to develop a large
funded program similar to the efforts for
AIDS and cancer