Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, New Drug Application NDA /S-008 Cubicin® (daptomycin for injection) Microbiology: Increased Daptomycin MICs During Therapy Peter Coderre, PhD, MBA CDER, DAIOP Anti-Infective Drugs Advisory Committee Meeting Rockville, Maryland March 6, 2006 Microbiology: Increased Daptomycin MICs During Therapy Peter Coderre, PhD, MBA CDER, DAIOP Anti-Infective Drugs Advisory Committee Meeting Rockville, Maryland March 6, 2006

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, Increased Daptomycin MICs Increasing daptomycin MICs documented in vitro, in vivo, in the literature and during this clinical trial Currently: S. aureus isolates with a MIC ≤ 1  g/ml are considered susceptible to daptomycin Breakpoints for intermediate and resistant isolates have yet to be established Increasing daptomycin MICs documented in vitro, in vivo, in the literature and during this clinical trial Currently: S. aureus isolates with a MIC ≤ 1  g/ml are considered susceptible to daptomycin Breakpoints for intermediate and resistant isolates have yet to be established

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, Increased Daptomycin MICs What are the implications of increasing daptomycin MICs during treatment with daptomycin for infective endocarditis and bacteremia? In patients with persistent or relapsing bacteremia, S. aureus demonstrated increasing daptomycin MICs ( ≥ 1  g/ml) during or after therapy with the drug. What are the implications of increasing daptomycin MICs during treatment with daptomycin for infective endocarditis and bacteremia? In patients with persistent or relapsing bacteremia, S. aureus demonstrated increasing daptomycin MICs ( ≥ 1  g/ml) during or after therapy with the drug.

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, Changes in MICs for Relapsing or Persistent Bacteremia Patients # MIC >1 > 2 stepsMRSAMSSA daptomycin arm (N=20) 9/20 (45.0%) 12/20 (60.0%)* 11/20 (55.0%)* comparator arm (N=10) 1/10 (10.0%) 0/10 (0%) 8/10 (80.0%) 2/10 (20.0%) 3 patients had both MSSA and MRSA # FDA Analysis

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, Distribution of Terminal MICs for Daptomycin Treated Patients (ITT) by Clinical Outcome MIC (  g/ml) clinical success (N=53) 1 (1.9%) 36 (67.9%) 14 (26.4%) 2 (3.8%) 0 (0%) clinical failure (N=59) 1 (1.7%) 34 (57.6%) 15 (25.4%) 3 (5.1%) 5 (8.5%) 1 (1.7%) total (N=112) 2 (1.8%) 70 (62.5%) 29 (25.9%) 5 (4.4%) 5 (4.5%) 1 (0.9%)

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, Clinical Failures in Daptomycin Arm with Increased Daptomycin MICs Case #Final DiagnosisOrganismBaselineHighMIC Step MIC Increase complicated bacteremiaMRSA complicated RIEMSSA complicated bacteremiaBoth left IEBoth left IEMRSA complicated bacteremiaMRSA left IEMRSA left IEMRSA0.2512

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, Frequency of Increased MICs and Non- Susceptibility/Resistance to Daptomycin or Vancomycin in Patients during Therapy^ N, % ↑ N, % developed Dapto MICVanco MICDapto NS Vanco R IEAC successes daptomycin (N=53)17 (32.1%)*12 (22.6%)*0 (0%)* comparator (N=48)11 (22.9%)13 (27.1%)1 (2.1%)0 (0%) IEAC failures daptomycin (N=67)23 (34.3%)16 (24.2%)*6 (9.0%)0 (0.0%)* comparator (N=65)12 (18.5%)*17 (26.2%)*0 (0.0%)** *determination of MICs not done for one patient; **determination of MICs not done for two patients; *** one or more dilution increase; ^ contains non-evaluable patients as failures

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, Overview of Isolates with Treatment Associated Decreases in Daptomycin Susceptibility Following Commercial Availability Isolate/NSourceDaptomycin MIC (  g/ml) S.aureusblood0.251 S.aureus*0.254 S.aureus--5blood0.54 S.aureus**0.54 S.aureusblood12--4 S.aureus0.58 MRSA E. faeciumurine/blood432 E. faeciumblood4> 32 VRE***blood4 VRE***8

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, Recent Literature Reporting Clinical Failures with Daptomycin Treatment OrganismConditionSourceDoseHighestReference (mg/kg) MIC (  g/ml) MRSAbacteremiablood42Mangili et al., 2005 MRSAosteomyelitisblood64Hayden et al., 2005 MRSAbacteremiablood84Skiest, 2006 MRSAbacteremiablood64Marty et al., 2006 E. faeciumbacteremiablood6>32Sabol et al., 2005 E. faeciumfeverbloodnone4Lesho et al., 2006 E. faecalis (VRE)bacteremiablood*16Munoz-Price, et al., 2005 E. faecalis (VRE)febrile neutropeniablood?? Long et al., 2005 *400 mg q48h

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, Surveillance Data SpeciesStudy/ Year N Daptomycin MIC Distribution n (%) MIC (  g/ml) ≤ MSSA (18.9%)1165 (72.7%)131 (8.2%)1 (0.1%)0 (0%) (5.4%)1140 (73.7%)319 (20.6%)3 (0.2%)2 (0.1%) (7.9%)2371 (81.9%)285 (9.9%)8 (0.3%)1 (<0.1%) (2.1%)1891 (57.6%)1297 (39.5%)25 (0.8%)1 (<0.1%) MRSA (7.9%)396 (61.9%)187 (29.3%)5 (0.8%)0 (0%) (1.9%)655 (60.9%)388 (36.1%)13 (1.2%)0 (0%) (2.7%)963 (65.6%)452 (30.8%)13 (0.9%)0 (0%) (0.5%)878 (44.4%)1047 (52.9%)40 (2.0%)1 (<0.1%) Source: Table , NDA SN008

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, S. aureus MIC Distributions: (2004: n = 317; 2005: n = 359) 0.9%3.3% < 1 (  g/ml) > 1 (  g/ml) MIC Group % of Total 99.1%96.7% Source: Focus Technologies

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, In Vivo Evidence Sponsor data from rabbits, mice, rats for bacteremia, endocarditis, fibrin clot, etc. In rabbit model, daptomycin more efficacious than vancomycin, however, diminished susceptibility developed during therapy —due to selection by sub-inhibitory concentrations of daptomycin in vegetations Silverman et al. (2001): extensive clinical use required to establish if resistance will be a major clinical problem Sponsor data from rabbits, mice, rats for bacteremia, endocarditis, fibrin clot, etc. In rabbit model, daptomycin more efficacious than vancomycin, however, diminished susceptibility developed during therapy —due to selection by sub-inhibitory concentrations of daptomycin in vegetations Silverman et al. (2001): extensive clinical use required to establish if resistance will be a major clinical problem

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, In Vitro Evidence Spontaneous mutations rare; no known transferable elements Liebowitz et al. (1988): stable resistant organisms after multiple passages in increasing [daptomycin] and after chemical mutagenesis— isolates 16X higher than parental isolates Kaatz et al. (1990): Dapto R mutants were Van S, Amp S but cross-resistance to Nisin Spontaneous mutations rare; no known transferable elements Liebowitz et al. (1988): stable resistant organisms after multiple passages in increasing [daptomycin] and after chemical mutagenesis— isolates 16X higher than parental isolates Kaatz et al. (1990): Dapto R mutants were Van S, Amp S but cross-resistance to Nisin

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, In Vivo Evidence--Biofilms Evidence for pathogenesis of biofilms in IE is strong 60% of daptomycin penetrates vegetation but 90% is protein bound; therefore, expect < 60% penetration Vegetations manifest biofilm-like antibiotic resistance that cannot be completely explained by poor penetration of antimicrobials Composition of the valve biofilm has direct bearing on clinical outcomes Results demonstrate association between biofilm composition and clinical manifestations—IE can be manipulated by targeting biofilm development Evidence for pathogenesis of biofilms in IE is strong 60% of daptomycin penetrates vegetation but 90% is protein bound; therefore, expect < 60% penetration Vegetations manifest biofilm-like antibiotic resistance that cannot be completely explained by poor penetration of antimicrobials Composition of the valve biofilm has direct bearing on clinical outcomes Results demonstrate association between biofilm composition and clinical manifestations—IE can be manipulated by targeting biofilm development

Center for Drug Evaluation and Research Anti-Infective Drug Advisory Committee March 6, SummarySummary On therapy (endocarditis): increasing daptomycin MICs particularly among persisting or relapsing bacteremia On therapy (all-comers): increasing daptomycin MICs among clinical failures Surveillance data: increasing daptomycin MICs over time; more reports in literature (2005-6) showing daptomycin resistance In vivo: rabbit model, daptomycin more efficacious than vancomycin but diminished daptomycin susceptibility during therapy In vitro: bacteria develop resistance at sub-inhibitory concentrations; cross-resistance to nisin, but not vancomycin or ampicillin; biofilms—subinhibitory concentrations? On therapy (endocarditis): increasing daptomycin MICs particularly among persisting or relapsing bacteremia On therapy (all-comers): increasing daptomycin MICs among clinical failures Surveillance data: increasing daptomycin MICs over time; more reports in literature (2005-6) showing daptomycin resistance In vivo: rabbit model, daptomycin more efficacious than vancomycin but diminished daptomycin susceptibility during therapy In vitro: bacteria develop resistance at sub-inhibitory concentrations; cross-resistance to nisin, but not vancomycin or ampicillin; biofilms—subinhibitory concentrations?