# Presentation: 743059

## Development of Drugs for Resistant OrganismsPresentation to FDA Anti-Infective Drugs Advisory CommitteeMarch 5, 2003

- Francis P. Tally M.D.
- Executive Vice President, Scientific Affairs and Chief Scientific Officer
- Cubist Pharmaceuticals, Inc.

## 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 for oral switch
- Penetration of the drug to site of infection
- Safety
- balance risk/benefit with infection
- mild, reversible, easily monitored safety profile

## Identifying RPs of PH Importance -       Characteristics – FDA – Dr. Ed Cox – 2002

- Organism of sufficient prevalence
- Organism of sufficient virulence
- Data to show resistance affects outcomes
- Is the drug commonly used to treat infections due to the organism?
- Insufficient therapeutic alternatives
- Is the organism resistant to multiple drug classes?
- Resistance affects therapeutic decision making
- Drug is an essential treatment to prevent spread of a disease in the population (e.g. TB, STDs)

## Antimicrobial Resistance in Nosocomial Pathogens – Dr. David Ross, 1999

| 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 |

## Antimicrobial Resistance in Community Pathogens

- Penicillin-resistant *Streptococcus pneumoniae*
- Methicillin-resistant *Staphylococcus aureus*
- Vancomycin-resistant *Staphylococcus aureus***
- Multidrug-resistant Salmonella
- Penicillin/Quinolone-resistant *N. gonorrhea*
- Macrolide-resistant *Streptococcus pyogenes*
**List needs to be reviewed periodically.**

## Drug Resistance in the USACubist SECURE surveillance study, 50 Centers

- *multi-drug resistance

## Penicillinase-Producing Staphylococcus aureus

- H. Chambers (personal communication)

## Vancomycin Use in the US

- Kirst. *AAC*. 1998;42:1303.

- ICU MRSA rate > 30%

- VISA reported

- MRSA > 5%

## MRSA as a Community-Acquired Pathogen

- Community-acquired infections with MRSA have been reported in US, Australia, New Zealand, UK, Finland, and Canada recently.
- MRSA organisms are fully virulent and have caused fatal infections in children.
- Prevalence of community-acquired MRSA varies, as high as 21% in Finland and 55% in an American-Indian community.
- Community-acquired MRSA are usually not multiply drug-resistant.
- In a recent study of 32 community-acquired MRSA isolate in US, 31 were shown to produce the superantigens enterotoxin B or C which likely contribute to their virulence.

- MMWR 51:565, 2002
- Fridkin SK, CID 32:108, 2001
- Hussain FM et al. JID 186:661, 2002
- Moise-Border PA et al.  ICAAC Abstract C1-1059, 2002
- Sakoulas G et al.  ICAAC Abstract C1-1058, 2002

## Vancomycin-Resistant S. aureus (VRSA) from USA – 2002

**June 2002:**  VRSA (vancomycin MIC ≥ 128 μg/ml) isolated from dialysis catheter exit site of 40 year old diabetic patient in Michigan with end-stage renal disease.  Organism also resistant to oxacillin and contained *mecA* gene (MRSA).  Foot ulcer contained VRSA and VR *E. faecalis.  VanA* genes identified in both * E. faecalis *& VRSA.
**Sept. 2002:**  VRSA (Vanco MIC 32 μg/ml) isolated from patient in Pennsylvania with chronic foot ulcer and possible osteomyelitis.  Organism was resistant to oxacillin (MRSA) and vancomycin and contained *mecA* and * vanA *genes.
- Organisms not genotypically related.

- MMWR 51:565, 2002
- MMWR 51:902, 2002

## Timeline for Development of Resistance to Vancomycin and Linezolid

|  | Vancomycin | Linezolid |
| --- | --- | --- |
| First clinical use | 1956 | 1997 |
| USFDA approval | 1958 | 2000 |
| First resistant enterococci | 1988 | 1998 |
| First VISA/GISA | 1996 | NA |
| First fully resistant S. aureus | 2002 | 2001 |

- Moellering – January 2003

## Rank Order of Nosocomial U.S.Bloodstream Infections and MortalitySCOPE Surveillance System

**40**

**30**

**20**

**10**

**CNS             *****S.aureus*       ***** Enterococcus*****     *****Candida**
**n=3908     n=1928           n=1354        n=934**

**proportion  of  BSI (%)**

**0**

**proportion**

**crude mortality**

**crude**
**mortality**
**    ****(%)**

**32****  ****21               16  25               11  32                 8  40**

- Edmond et al *CID*  1999; 29:239-44

*** ~50% resistant to Methicillin**

## Significance of Bacteremia Caused by Staphylococcus aureus (n=122)

**total cases**

**recovered**

**13**

**33**

**20**

**16**

**15**

**14**

**9**

**3**

**4**

**9**

**4        4**

**0         0**

**1**

**0**

**No. patients**

**case fatality = 82%**

**age strata**

- Skinner & Keefer
*Arch Int. Med *1941; 68: 851-75

## ICU BSI: Increased Mortality with Inadequate Antimicrobial Therapy

**Adequate   Inadequate**
**  ****(n=345)       (n=147)**
**          ****therapy**

**29%**

**62%**

**Mortality (%)**

- Ibrahim et al *Chest *2000; 118: 146-55

## Attributable Mortality: The Promise of Better Antimicrobial Therapy

**80**

**70**

**60**

**50**

**40**

**30**

**20**

**10**

**all-cause (crude) mortality -  percent-**

**Attributable mortality of resistance gene**

**Attributable mortality of infection**

**Mortality from underlying disease**

**infection**
**and**
**no Rx**

**infection **
**and Rx**

**infection **
**and **
**no Rx**

**resistance**
**gene**

**resistance**
**gene**

**infection**
**and Rx**

- effect of
- existing Rx

**1               2                 3               4                 5**

**  ****scenarios**

- effect of
- existing Rx

- Wenzel RP *JID* 1998; 178:917-9

## Development of Drugs for Resistant Pathogens

- What is the “problem” in 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 date
- To realize the potential of genomics in antimicrobial development will require substantial funding for new approaches

## Antibacterial Drugs in Development

## Antibacterial Drugs in Development

## Development of Drugs for Resistant Pathogens

- To promote development and appropriate use of therapies for antimicrobial resistant pathogens
- Restrictive labeling of drug to antibiotic resistant organism is a problem;
- MRSA - empiric therapy potentially positive ROI
- VRE - niche product potentially negative ROI
- Products with safety issues and activity vs. resistant pathogens will be restricted based on safety profile, IV-only drugs will be restricted to hospital and home IV use

## 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

## Development of Drugs for Resistant PathogensAction Points

- Serious infection e.g. meningitis and endocarditis:  _Microbiological endpoint_ is key – clearing cerebral spinal fluid or blood of pathogens
- Surrogate endpoints –
- Infection claim: Susceptible/resistance isolate: what number of resistant isolates are required
- Microbiological claim: what number of resistant isolates in overall population?  Current standard is only the resistant isolates are evaluated
- Requirements for two well-controlled studies for each indication – needs to be more carefully evaluated
- Use Target Package Insert FDA initiative to increase communication

## Incentives in Drug DevelopmentBiotech View

- Expanded access – charge fee to cover expenses
- Patent term extension (*c.f.* Hatch-Waxman)
- Funded consortiums – model on cancer and AIDS trials
- Government loans or Government guaranteed loans
- Program modeled after Fannie Mae or Freddie Mac
- Small business loans
- Repayable upon commercialization

## Incentives in Drug DevelopmentBiotech View

- Tax credit or deductions
- Valuable only for profitable companies
- Extend period for tax loss carry forwards
- Transferable tax losses
- Targeted Grants
- SBIR
- CRADAS – Fund Phase I & II trials need to streamline review process