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/PathogenResistance (%) Vancomycin/enterococci 24.7 Methicillin/S. aureus 53.5 Methicillin/CNS rd Ceph/E. coli rd Ceph/K. pneumoniae 10.4 Imipenem/P. aeruginosa 16.4 Quinolone/P. aeruginosa rd Ceph/P. aeruginosa rd 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 VancomycinLinezolid First clinical use USFDA approval First resistant enterococci First VISA/GISA1996NA First fully resistant S. aureus Moellering – January 2003

Rank Order of Nosocomial U.S.Bloodstream Infections and Mortality SCOPE Surveillance System CNS S.aureus* Enterococcus Candida n=3908 n=1928 n=1354 n=934 proportion of BSI (%) 0 proportion crude mortality crude mortality (%) Edmond et al CID 1999; 29: * ~50% resistant to Methicillin

Significance of Bacteremia Caused by Staphylococcus aureus (n=122) total cases recovered No. patients case fatality = 82% age strata Skinner & Keefer Arch Int. Med 1941; 68:

ICU BSI: Increased Mortality with Inadequate Antimicrobial Therapy Adequate Inadequate (n=345) (n=147) therapy 29% 62% Mortality (%) Ibrahim et al Chest 2000; 118:

Attributable Mortality: The Promise of Better Antimicrobial Therapy 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 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

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