Development of Drugs for Resistant Pathogens

Francis P. Tally M.D.Cubist Pharmaceuticals, Inc.

Synthetic Molecules Natural Products• Sulfonamides• Trimethoprim• Quinolones• Nitroimidazoles• Nitrofurans• Oxazolidinones

• 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

Antimicrobials Developed

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 PathogensPreclinical 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 PathogensProblems 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 USACubist SECURE surveillance study, 50 Centers

Pathogen N Primary resistance (%) MDR* % ( 3 drugs)

S. aureus 1,018 OX – 30.0% Ery – 46.3% CIP – 32.5% GEN – 7.9%

27.1%

S. pneumoniae 1,163 PEN – 16.1% ERY – 31.8% SXT – 30.8%

14.7%

E. faecalis 2,092 AMP – 0% VAN – 1.9% CIP – 36.3% Q-D – 91.1%

2.6%

E. faecium 368 AMP – 81.8% VAN – 59.5% CIP – 82.3%

58.4%

*multi-drug resistance

Penicillinase-Producing Staphylococcus aureus

0102030405060708090

100

1940 1945 1950 1955 1960 1965 1970 1975(Year)

Prev

alen

ce (%

)

HospitalCommunity

H. Chambers (personal communication)

Nosocomial Methicillin-Resistant Staphylococcus aureus (MRSA) Infections

0

10

20

30

40

50

1989 1990 1991 1992 1993 1994 1995 1996 1997(Year)

Prev

alen

ce (%

)

ICUNon-ICU

Fridkin et al. Clin Chest Med.1999;20:303.

Methicillin-Resistant Staphylococcus aureus: SFGH

0

10

20

30

40

50

60

1993 1994 1995 1996 1997 1998 1999(Year)

Prev

alen

ce (%

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< 72 h> 72 h

Charlebois et al. EPI Center Data.

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 3 (seniors, rugby team, wrestlers)

1991-95 35% 10 0 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 PathogensNosocomial Enterococci Infections Resistant to Vancomycin*

0

5

10

15

20

25

1989 1990 1991 1992 1993 1994 1995 1996 1997Year

% R

esis

tanc

eICUNon-ICU

*NNIS 1989-1997.Fridkin SK, Gaynes RP. Clinics in Chest Medicine. 1999.

Antibacterial Drugs in Development

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 PathogensDrug 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 PathogensDrug 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

0

2

4

6

8

10

12

Met

ric

Ton

s

'84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96

(Year)

Kirst. AAC. 1998;42:1303.

ICU MRSA rate > 30%

VISA reported

Development of Drugs for Resistant PathogensOpinion

• 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 PathogensOpinion• 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 PathogensCubist 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 PathogensWhat 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 PathogensWhat 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, well-designed 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 PathogensWhat 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