Here is the Cubist Executive Summary which was distributed at the panel meeting held yesterday.
NDA 21-572/ S-008 Cubicin8 (daptomycin for injection) Sponsor's Background Package January 31, 2006 EXECUTfVES ARY ') Inftoduction / Infections due to Staphylococcus aureus, particularly those due to methicillin-resistant S. au reus (MRSA), constitute a growing public health threat because of the increasing incidence of these infections in hospitals and in the community, and the increase in associated morbidity and mortality. Infective endocarditis (IE) is the most serious manifestation of S. aureus infection and may occur in patients with structurally normal heart
( valves after a clinically inapparent bacteremia. Recently reported mortality rates associated
) with S. au reus bacteremia and endocarditis are between 11 % and 43% in patients receiving / .../ conventional therapy, and no decrease in mortality rates has been seen for more than ' 15 years. The problem is compounded by the emergence of community-acquired MRSA
(CA-MRSA) infections, particularly because these can occur in patients not suspected of having MRSA. Recent cases of patients presenting with rapid-onset sepsis, purpura fulminans. toxic shock, and death have been reported. Currently, limited options are available for patients with S. aureus bacteremia, who often require a prolonged course of intravenous (Lv.) therapy. Standard of care consists of empiric therapy with vancomycin, with switch to antistaphylococcal semisynthetic penicillin (SSP) for methicillin-susceptible S. au reus (MSSA) infections. Vancomycin requires twice-daily dosing and plasma concentration monitoring, while SSPs require dosing up to 6 times a day. For both of these agents. there is a risk of missed doses leading to a potential for decreased therapeutic effect. and there are challenges for outpatient therapy. Tolerability issues include a history of penicillin allergy in up to 20% of patients. sodium load associated with i. v. antistaphylococcal penicillins. and infusion-related hypersensitivity reactions with vancomycin. Both agents are potentially nephrotoxic. as is gentamicin, which is recommended at low dose as part of initial combination therapy for S. au reus bacteremia. Because of the increasing prevalence of MRSA and the limitations of the currently available therapeutic options. patients are often treated with vancomycin, an agent that is, at best, weakly bactericidal and often bacteriostatic, particularly against stationary phase bacteria, characteristic of those in biofilm-associated vegetations. The properties of the ideal agent for the treatment of S. au reus bacteremia include bactericidal activity in both exponentially growing and stationary phase bacteria, potency against both MRSA and MSSA, proven efficacy in S. au reus infections. tolerability for long-term therapy, and suitability for outpatient administration. There is no current Food and Drug Administration (FDA) guidance document that defines the requirements for a registration study to support an indication of S. aureus bacteremia or endocarditis. The last-approved drug for endocarditis was imipencm in 1985 and was based on the experience of 11 patients with endocarditis in 3 studies. Cubist Pharmaceuticals, Inc. Page 2
y NDA 21-572 f S-008 Cubicin8 (daptomycin for injection) Sponsor's Backgronnd Package Jan 31t 2006 Cubicin@ (daptomycin for injection) was approved in the United States in September 2003, in Israel in July 2004, in Argentina in July 2005. and in the European UnioIlluJanuarv 2006 for the treatment of complicated skin infections, including infections caused by methicillin susceptible and methicillin-resistant S. aureus. The approved dose is 4 mglkg administered intravenously once daily. Daptomycin has many characteristics of the ideal agent for the treatment of systemic S. aureus infections. including rapid bactericidal activity; in vitro potency against both MRSA and MSSA; proven efficacy in complicated skin infections, including those caused by MRSA; efficacy demonstrated in animal models of S. aureus endocarditis at exposures similar to the human 6 mglkg daily dose; and once-daily dosing. In 2002, Cubist Pharmaceuticals, Inc., in collaboration with experts in S. aureus infections and with ongoing dialogue with the FDA, embarked on a landmark study to demonstrate the efficacy and safety of daptomycin in this seriously ill and growing patient population that urgently needs additional therapeutic options. This Briefing Package summarizes data provided by Cubist to the FDA in a supplemental New Drug Application (sNDA) submitted on September 26, 2005, for the following proposed supplemental indication supported by data from the pivotal Study DAP- IE-O 1-02. Proposed Supplemental Indication and Dose . Daptomycin is indicated for the treatment of patients with S. aureus bacteremia, including those with known or suspected endocarditis, caused by methicillin-susceptible and methicillin-resistant su'ains. . The proposed daptomycin dose is 6 mgfkg administered as a 30-minute i.v. infusion once per day for a minimum duration of 2 to 6 weeks, depending on the clinical condition. Major Findings The pivotal Study DAP-IE-OI-02 was designed as an open-label, randomized (1:1), prospective, non-inferiority trial to evaluate monotherapy with daptomycin i.v. (6 mgfkg once daily) compared with conventional combination i.v. therapy (SSP 2 g q4h [nafcillin, oxacillin, c1oxaciUin, or fIucloxacillin] or vancomycin 1 g q 12h, both with initial low-dose gentamicin). . A total of 236 patients were treated in the study, the largest randomized trial conducted to date in patients with bacteremia. with or without endocarditis. due to S. aureus. . The baseline characteristics of the patient population and underlying risk factors were similar to those in several large recently reported epidemiologic studies in patients with S. aureus endocarditis. The population was hospitalized and severely ill (75% with systemic inflammatory response syndrome [SIRS]); 38% had infections caused by MRSA. Approximately one-quarter of the patients were 65 years of age or older. The study met its primary endpoint, success documented 6 weeks following the end of therapy (test-of-cure [TOC] evaluation) determined by an independent Adjudication
Cubist Pharmaceuticals, Inc. Page 3
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./ r NDA 21-572/8-008 Cubicin411 (daptomycin for injection) Sponsor's Background Package January 31, 2006 Committee expert in the evaluation of S. aureus infections who were blinded to study drug therapy. . Results were robust, meeting the primary efficacy endpoint in the co-primary intent-to treat (ITT) and per protocol (PP) populations. . In the ITT population, 44.2% of daptomycin-treated patients had a successful outcome 6 weeks post-treatment compared with 41.7% of comparator-treated patients. . In the PP population, 54.4% of daptomycin-treated patients bad a successful outcome
6 weeks post-treatment compared with 53.3% of comparator-treated patients. . The greatest difference in success rates was observed in patients in the ITT population with infections caused by MRSA, with 44.4% and 31.8% of patients in the daptomycin and comparator groups, respectively, experiencing success 6 weeks post-treatment. Success rates were similar between the treatment groups for patients with infections caused by MSSA (44.6% and 48.6% in the daptomycin and comparator groups, respectively). . Daptomycin efficacy was demonstrated across pre-specified diagnostic strata: . In patients with known or suspected S. aureus IE at baseline (DefInite or Possible IE according to the Modified Duke Criteria), who accounted for 77% of the population, success rates at 6 weeks post-treatment were 45.6% and 40.7% in the daptomycin and comparator groups, respectively; and . In patients retrospectively categorized with S. aureus complicated bacteremia or right-sided IE (RIE), who accounted for 66% of the population, success rates at
6 weeks post-treatment were 43.0% and 39.0% in the daptomycin and comparator groups, respectively. Each study Investigator also determined response to treatment. Investigator-assessed success rates at the 6-week post-treatment time point were similar between the treatment groups: . In the ITT population, 53.3% of daptomycin-treated patients had a successful outcome
6 weeks post-treatment compared with 50.4% of comparator-treated patients. . In the PP population, 63.3% of daptomycin-treated patients had a successful outcome
6 weeks post-treatment compared with 58.3% of comparator-treated patients. Overall success rates were higher at the end-of-therapy (EOT) visit relative to those reported at TOC and were comparable between the treatment groups. The overall lower success rates at TOC were related to reasons other than relapse of S. aureus infection, and included receipt of potentially effective non-study antibiotics and lack of documented blood cultures. . Adjudication Committee-reported success rates at EOT were 61.7% and 60.9% in the daptomycin and comparator groups, respectively. . Investigator-reported success rates at EOT were 64.2% and 64.3% in the daptomycin and comparator groups, respectively. '" Cubist Pharmaceuticals, Inc. Page 4
NDA 21-572/8-008 Cubicioe (daptomycin for injection) Sponsor's Background Package January 31, 2006 . These EOT results were consistent with response rates reported in recent S. aureus bacteremia and endocarditis studies (>60%). The secondary efficacy endpoint of the study, time to clearance of S. aureus bacteremia in the ITI population, was not significantly different between the treatment groups. . Median times to clearance of S. aureus bacteremia were 5 and 4 days in the daptomycin and comparator groups, respectively. For patients with infections caused by MSSA, median times to clearance were 4 and 3 days, respectively, and for patients with infections caused by MRSA, 8 and 9 days, respectively. Patients in the daptomycin group were more likely to be reported by the Adjudication Committee as failures due to persisting/relapsing S. aureus infection and/or clinical failure (19.2% in the daptomycin group and 13.0% in the comparator group), and patients in the comparator group were more likely to be reported as failures due to premature discontinuation due to adverse events (6.7% and 14.8%, respectively). . Most patients who failed treatment with daptomycin, vancomycin, or SSPs due to persisting or relapsing S. Qureus infections had deep-seated infections and did not or could not receive necessary surgical intervention, including, for example, valve replacement surgery for left-sided IE (LIE), drainage of abscesses, removal of prosthetic devices, and debridement of septic arthritis. . No association was found between plasma daptomycin or vancomycin levels and microbiologic failure. . Six daptomycin patients with persisting or relapsing S. Qureus had treatment-emergent decreases in susceptibility of S. Qureus to daptomycin (daptomycin minimum inhibitory concentration [MIC] increase to 2 J.LglmL [5 patients] or 4 J.Lg/mL [1 patient]). . One vancomycin patient with persisting or relapsing S. Qureus had a treatment-emergent S. Qureus with a rise in vancomycin MIC to 2 J.Lg/mL isolated on study. . The most common treatment-limiting adverse events reported as the reason for failure were rash (2 patients), increased creatine phosphokinase (CPK) (2 patients), and gastrointestinal events (2 patients) in the daptomycin group and hypersensitivity-type events (6 patients) and renal toxicities (5 patients) in the comparator group. There was no difference in overall survival between the treatment groups (p=O.976; log-rank statistic). As of last follow-up, 85% of daptomycin-treated patients and 84% of comparatortreated patients were alive. Treatment with daptomycin was well tolerated in a seriously ill patient population with S. Qureus bacteremia and endocarditis, and the safety profIle was similar to the known safety profile of daptomycin at 4 mglkg. . Similar overall rates of adverse events and serious adverse events were reported in daptomycin and comparator patients. . The most commonly reported events in the daptomycin group were gastrointestinal in nature. The incidence of these events was similar or higher in the comparator group.
I Cubist Pharmaceuticals, Inc. Page 5
- ..-- J y' NDA 21-572/ S-008 Cubicine (daptomycin for injection) Sponsor's Background Package January 31, 2006 . Elevations in CPK were observed more often in the daptomycin group, with 3 daptomycin patients discontinuing for elevated CPK. . More renal toxicity adverse events and abnormal laboratory fmdings were observed in the comparator group, irrespective of comparator agent, with 5 comparator patients discontinuing for renal toxicity. Conclusions Daptomycin administered Lv. at 6 mglkg once daily is an effective alternative to standard of care in the treatment of patients with S. aureus bacteremia with known or suspected endocarditis and has several advantages over current therapy, including: . rapid bactericidal activity . activity in stationary phase bacteria, typical of bioftlm-associated vegetations . proven efficacy in S. aureus bacteremia with known or suspected endocarditis, including infections caused by MRSA and MSSA . demonstrated tolerability for long-term therapy . convenient once-daily administration, allowing for outpatient therapy In an era of limited therapeutic options and in the face of an emerging public health threat, daptomycin 6 mglkg once daily provides a much-needed treatment option for patients with S. au reus bacteremia with known or suspected endocarditis.
This being my first post on this board allow me to introduce myself.When my wife was found to be sensitive to vancomycin her ID Doc put her on Daptomycin. This was two years ago. With this real world introduction to dapto I became an investor and have been closely tracking developments ever since. My office is but 2 miles from FDA so it was easy for me to attend yesterdays meeting, Be glad to try and answer any questions.
The best summary of the meeting was given by Dr. Cory from Dike Medical Center. He also served as the chair of the independent analysis team looking at trial data. he said very loudly
Bad Bug-----No Drug
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