CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-572
`
`Medical Review(s)
`
`

`

`|
`
`CLINICAL REVIEW
`Integrated Review of Safety and Efficacy
`
`Clinical Review
`
`NBA 21-572
`
`I
`
`Cubicin (daptornycin for injection)
`
`Original New Drug Application for marketing approval for treatment of
`complicated skin and skin structure infections (cSSSI) due to Gram-
`positive bacteria including Staphylococcus aureus (methicillin-resistant
`and susceptible strains), Streptococcus pyogenes, Enterococcusfaécalis
`(vaneomycin-susceptible strains), Streptococcus agalactiae,
`. Streptococcus dysgalactiae subsp. equisz'milis
`‘4'
`’—
`
`-
`
`Sponsor: Cubist Pharmaceuticals, Inc.
`Lexington, MA 02421
`
`Clinical Reviewers:
`
`Sumathi Nambiar, M.D.
`
`Susan Thompson, MD.
`
`Date of Submission: December 19, 2002
`
`Date Assigned:
`
`December 19, 2002 ,
`
`Date Review Begun: December 19, 2002
`
`Date Review to Supervisor: August 31, 2002
`
`PDUFA Deadline:
`
`September 19, 2002
`
`_~.‘.,
`
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`CLINICAL REVIEW
`lntegrated Review of Safety and Efficacy
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`'
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`I
`
`Integrated Review ofSafety and Efficacy
`This document is the integrated review of safety and efficacy for NDA 21—572.
`Appendices describing the individual protocols, safety and efficacy, and a detailed
`analysis of CPK are appended to this review.
`
`1.
`
`Recommendations
`
`A.
`
`Recommendation on Approvability
`
`CubicinTM (daptomycin for injection; Cubist Pharmaceuticals) is the lead
`investigational antibiotic in a new class of drugs knovm as cyclic
`lipopeptides. Based on evidence from two randomized, active-controlled
`clinical trials submitted by the sponsor, there is adequate efficacy and
`safety data to recommend approval of daptomycin 4 mg/kg/day
`intravenously for 7—14 days, in patients 18-85 years of age, with
`complicated skin and skin structure infections (cSSSl) due to Gram-
`positive bacteria including Staphylococcus aureus (methicillin-resistant
`and susceptible strains), Streptococcus pyogenes, Enterococcusfaecalis
`(vancomycin—susceptible strains), Streptococcus agalactiae, and
`Streptococcus dj'sgalactiae. In combined cSSSl studies, a total of 534
`patients were treated with daptomycin. The safety database comprised data
`on 602 daptomycin-treated patients in Phase 1 studies, 349 daptomycin-
`treated patients in Phase II studies, and 989 patients in Phase Ill studies.
`
`The two clinical studies conducted by Cubist in cSSSl were similar in trial
`design, but differed in certain baseline patient characteristics, such as
`underlying diabetes and peripheral vascular disease. Such differences in
`baseline characteristics may have had a significant effect on wound
`healing. Observed success rates were in fact quite different in the two
`studies. In both trials, daptomycin was demonstrated to be non-inferior to
`the comparator (vancomycin/semi-synthetic penicillins, including
`nafcillin, oxacillin, cloxacillin, or flucloxacillin), using a non-inferiority
`margin of 10%. Concomitant aztreonam or metronidazole could be used
`for Gram-negative/anaerobic coverage respectively. Concomitant surgical
`procedures such as debridement were also permitted during the study.
`
`Sufficient numbers of patients with complicated skin and skin structure
`infections such as major abscesses, infected ulcers, wound infections, and
`cellulitis were included in the studies to justify inclusion in the label. Data
`were inadequate to include patients with infected diabetic ulcers. The
`number of patients enrolled with infected diabetic ulcers was small, errors
`in classification of diabetic ulcers occurred, and the clinical success rates
`observed inthese limited data were low.
`_~_....
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`Integrated Review of Safety and Efficacy
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`i
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`The safety profile of daptomycin is derived from 1755 subjects exposed to
`daptomycin in clinical studies conducted by Cubist and Lilly; limited 120-
`day safety data are available for an additional 52 patients enrolled in
`ongoing studies, most of whom received a higher dose of daptomycin at 6
`mg/kg IV given once daily. Overall, the MedDRA system organ class
`(SOC) with the greatest percentages of reported adverse events was
`gastrointestinal disorders, most frequently nausea, constipation, diarrhea,
`and vomiting. The rates of overall adverse events, deaths, serious adverse
`events (SAEs) other than death, and adverse events (AEs) leading to
`discontinuation were similar in both treatment groups. Preclinical studies
`had predicted that the primary target of daptomycin toxicity was skeletal
`muscle. This prediction was confirmed in Phase 1 studies by the observed
`elevation of CPK with muscle-related symptoms in 2/5 subjects given 4
`mg/kg IV quh and 2/4 subjects administered daptomycin at 4 mg/kg lV
`q24h. In Phase III cSSSl trials, elevations in serum CPK were reported as
`clinical adverse events in 15/534 (2.8%) daptomycin-treated patients,
`compared to 10/58 (1.8%) comparator-treated patients. Symptoms
`consistent with muscle injury were observed in 1/534 (0.2%) of
`daptomycin- treated patients.
`
`B.
`
`Recommendation on Phase 4 Studies and/or Risk Management Steps
`
`The Agency and Cubist have agreed that Cubist will conduct two Phase 4
`studies.
`-
`
`. The first study will consist ofa safety and efficacy study in patients
`with cSSSI. This study is scheduled to start in the first quarter of 2004
`and has an estimated 18-month study duration. The study will be open-
`label, randomized, multicenter, non-comparative study. The patient
`population for this study will consist of 72 patients with renal
`insufficiency in the following categories: Clcr 30-50 mL/min an Clcr
`<30 mL/min. Patients in the latter category may be on hemodialysis,
`continuous ambulatory peritoneal dialysis, or may not be maintained
`on dialysis. Pharmacokinetic data will also be collected in this study.
`E.
`
`I
`
`II.
`
`Summary of Clinical Findings
`
`A.
`
`Brief Overview of Clinical Program
`Daptomycin [Cubicin®] is a cyclic lipopeptide antibiotic that is
`administeretl‘j‘ntravenously.
`_-._.‘.,.
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`Integrated Review of Safety and Efficacy
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`Phase I and II studies
`
`The Cubist Phase 1 studies enrolled 240 subjects who received daptomycin.
`The Cubist human pharmacology studies included single- and repeat-dose
`phannacokjnetic studies in normal healthy subjects and in special
`populations. Repeat-dose studies were conducted in healthy subjects and in
`subjects with various degrees of renal impairment, including end~stage
`renal disease (ESRD). Single-dose studies were conducted in subjects with
`moderate hepatic impairment (Child-Pugh Classification B), in geriatric
`subjects, and in obese subjects, and in healthy‘subjects. Drug interaction
`studies with aztreonam, probenecid, warfarin, and simvastatin were
`conducted in healthy subjects. Studies on daptomycin protein binding were
`conducted in healthy subjects and in subjects with various degrees of renal
`impairment, including ESRD. A placebo-controlled study was conducted to
`examine the effect of daptomycin given to healthy subjects at 6 mg/kg
`q24h for 14 days on cardiac repolarization (QT interval) and peripheral
`nerve conduction. Cubist also studied the penetration of daptomycin into
`inflammatory exudate from cantharides-induced skin blisters. In vitro
`studies were conducted to assess the influence of daptomycin on induction
`or inhibition of cytochrome P450 enzymes in human hepatocytes.
`
`The Lilly Phase 1 studies enrolled 362 subjects who received daptomycin.
`These human pharmacology studies included single- and multiple-dose
`safety and phannacokinetic studies in healthy subjects. Multiple-dose
`studies examined various doses and regimens up to 4 mg/kg q 12h x 14
`days. Also included are in vivo protein binding studies; a metabolism and
`excretion study using radiolabeled daptomycin, a study in subjects with
`various degrees of renal impairment and drug interaction studies with
`tobramycin and amikacin.
`Cubist conducted two Phase II studies; a third study was discontinued due
`to slow enrollment. DAP-BAC-9803, is an open-label, Phase II, dose—
`ranging trial in subjects with culture-confirmed Gram-positive bacteremia
`or presumed bacteremia. The study compared three doses of daptomycin
`(4 mg/kg q24h, 6 mg/kg q24h, or 3 mg/kg q12h with a 6 mg/kg loading
`dose) with standard therapy (vancomycin 1 g every 12 hours or nafcillin or
`oxacillin 4-12 g daily in equally divided doses) and enrollment was 3:1
`daptomycin:comparator. The second Phase II study, DAP—RRC-9804, is an
`open-label, non-comparative, multicenter study utilizing three dose
`regimens of daptomycin in hospitalized subjects with bacteremia (4 mg/kg
`q24h, 6 mg/kg q24h, 3 mg/kg q12h following a 6 mg/kg loading dose),
`complicated skin and skin structure infections (c5881) (4 mg/kg q24h),
`lower respiratory Uact infections (LRTI) (6 mg/kg q24h), intra—abdominal
`infections (1A1) (6 mg/kg q24h), or complicated urinary tract infections
`(UTI) (4 mg/kg q24h potentially adjusted according to MIC level) caused
`by Gram-positive pathogens that were resistant to vancomycin or whose
`infection wasghemise refractory to currently available therapy or for
`whom' currently available therapy was contraindicated. Study DAP-RRC-
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`Integrated Review of Safety and Efficacy
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`1
`
`9804 was terminated due to slow enrollment. Study DAP-00—03 was an
`open-label, microbiologist-blinded, Phase III study comparing daptomycin
`at a dosage of4 mg/kg q24h with ciprofloxacin 400 mg in subjects with
`complicated urinary tract infections caused primarily by Gram-positive
`pathogens. Due to slow enrollment, this trial was temiinated.
`
`Three Phase II studies were conducted by Lilly during the years 1987 -
`1990. Study BBB-MC-AVAE/B8B-EW-AVAG is described below, as it
`was submitted with the NDA as supportive of the cSSSl indication. The
`second Phase 11 study, B8B-MC-AVAM, was a randomized, open-label
`study in which subjects with endocarditis and bacteremia were given
`daptomycin (loading dose-of6 mg/kg followed by 3 mg/kg q 12h) for up
`to 42 days; phamtacodynamic data was collected in this study. The third
`Phase II study, BSB-EW-AVAH, was an open label, uncontrolled study to '
`evaluate the efficacy of daptomycin in subjects with Gram-positive skin
`and skin structure infections. This study was temtinated after only 4 of the
`planned 50 subjects were enrolled due to adverse events..
`
`One controlled study, B8B-MC-AVAE/AVAG conducted by Lilly, was
`submitted as a supportive study. The dose of daptomycin used in this
`study was 2 mg/kg q 24 hours for a total duration of five days. As the
`dosing regimen of daptomycin used in this study is different from that
`used in the two Phase 11] cSSSl clinical trials, results of this study are not
`included in the overall efficacy analyses and will not be discussed in this
`revrew.
`
`Phase III studies
`
`Complicated skin and skin structure infections
`Results of two Phase II] studies, DAP-SST-980] and DAP-SST-990l ,
`
`were included in this NDA to support the indication of complicated skin
`and skin structure infections. The safety and efficacy of daptomycin was
`compared to that of vancomycin or a semi-synthetic penicillin (cloxacillin,
`flucloxacillin, oxacillin, or nafcillin) for the treatment of hospitalized
`patients with complicated skin and skin structure infections due to Gram-
`positive bacteria. The two studies were similar in design and conduct to a
`great extent. Both studies were randomized, active-controlled, and
`investigator-blinded. Study 9801 was conducted at 68 study sites, 63 in the
`United States and 5 in South Africa. Study 9901 was conducted at 67
`study sites including Europe, South Africa, Australia, and Israel.
`
`In the two pivotal studies, patients with complicated skin and skin
`structure infections including ulcers (diabetic and non-diabetic), wound
`infections, and major abscesses were randomized on a 1:1 basis to receive
`7-14 days treatment with daptomycin 4 mg/kg intravenously as a single
`daily dose orLacomparator agent. The comparator drug could be either
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`Integrated Review of Safety and Efficacy
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`vancomycin or a semi-synthetic penicillin. Investigators could select the
`semi-synthetic penicillin based on local availability and treatment practice.
`Randomization was stratified based on the presence or absence of an
`infected diabetic ulcer as the primary site of infection. Adjunctive
`treatment with aztreonam or metronidazole could be given for Gram~
`negative or anaerobic organisms, respectively. Ancillary surgical
`treatment (e.g., debridement) was pemtitted.
`
`In study 9801, a total of 547 patients were randomized and 530 received at
`least one dose of study medication. In study 9901, a total of 571 patients
`were randomized and 562 received at least one dose of study medication.
`
`Community-acquired pneumonia
`Cubist conducted two controlled clinical trials, DAP-CAP-OO-OS and
`DAP-CAP-00~O8, of essentially identical design to evaluate daptomycin in
`the treatment of moderate to severe community~acquired pneumonia
`(CAP) due to S. pneumoniae, including penicillin-resistant strains. Each
`study was a randomized, multicenter, multinational, double~blinded,
`parallel group, active-treatment controlled trial using a dosage of 4 mg/kg
`q24h. The comparator in each trial was ceftriaxone 2 g q24h. At the
`discretion of the investigator, adjunctive treatment with aztreonam could
`be given for suspected Gram-negative organisms. Therapy was to be
`administered 5 to 14 days, followed by Test-of-Cure and Post—Study visits
`conducted 7 to 14 and 21 to 28 days, respectively, after the last dose of
`study drug. Men and women who were 18 years of age or older and had
`pneumonia which required hospitalization and intravenous therapy for at
`least 5 days were eligible for the study. The infection must have been
`known or suspected to be due, at least in part, to Gram-positive bacteria.
`Subjects previously treated with potentially effective anti-infective agents
`for >24 hours (or one dosing day) within 72 hours of enrollment were
`excluded. Protocol DAP-CAP-OO-OS enrolled patients in the US, Europe,
`Canada, Australia, South America, and New Zealand. Study DAP-CAP-
`00-05 enrolled 355 patients in the daptomycin arm and 359 in the
`comparator arm and was completed in October 2000.
`
`Staghylococcus aureus infective endocarditis
`In study BSB—MC-AVAM, the clinical efficacy of daptomycin 3 mg/kg
`q12 hours as treatment of S. aureus infective endocarditis was lower that
`that of comparator (usually nafcillin/gentamicin). The Applicant
`. postulated that this lower efficacy rate in the treatment of S. aureus
`endocarditis was due to low daptomycin peaks and troughs with q 12 hour
`dosing, and proposed a new trial DAP-IE-Ol-OZ in infective endocarditis
`using daptomycin 6 mg/kg q 24 hours. Since patients with left-sided
`endocarditis might experience more severe consequences in terms of
`morbidity or mortality should daptomycin be inferior to comparator, given
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`I
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`the intrinsically more fulminant course of left-sided infective endocarditis,
`the Agency agreed to the proposed trial in patients with right-sided
`endocarditis only. A Data Management Committee will be convened
`following completion of the first 30 subjects (15 per aim) to review the
`safety and efficacy in these 30 subjects prior to enrollment of patients with
`left-sided endocarditis. This analysis as well as preliminary
`phannacokinetic data will be submitted to the Agency.
`
`B.
`
`Efficacy
`DAP-SST-9801 and DAP-SST-9901: Complicated skin and skin
`structure infections
`
`Cubist has provided sufficient data to support granting the indication of
`complicated skin and skin structure infections. Intravenous daptomycin 4
`mg/kg/day as a single dose was demonstrated to be non-inferior to
`comparator (semi-synthetic penicillins or vancomycin). The 95%
`confidence intervals around the difference in clinical cure rates
`
`demonstrated that the two treatment regimens were equivalent using a
`non-inferion'ty margin of 10%.
`
`Patients 18 years of age and older with complicated skin and skin structure
`infections including wound infections, major abscess, cellulitis, or infected
`ulcer (diabetic and non-diabetic) were enrolled in the studies. Patients with
`bacteremia, osteomyelitis, patients on hemodialysis or peritoneal dialysis,
`those receiving HMG-CoA reductase inhibitors, and those with creatinine
`clearance < 30 ml/rnin were excluded.
`'
`
`The primary efficacy endpoint was sponsor—defined clinical outcome at
`the test of cure (TOC) visit, 6-20 days after the end of therapy. The
`sponsor defined clinical outcome took into account the length of therapy
`in addition to the investigator’s clinical response. The patient must have
`received 2 4 calendar days of study medication to be classified as a cure or
`> 2 days to‘ be classified as a failure. Investigator response of either
`improved/cure at the TOC visit was considered a clinical success.
`
`Study 9801 was conducted at sites in the United States and South Africa,
`while study 9901 was conducted entirely outside the Unites States, mainly
`in South Africa and Europe. Both studies were similar in design, but
`differed significantly in patient baseline characteristics that potentially
`impact the overall cure rates. Patients in study 9801 tended to be sicker,
`with more co-morbid conditions, required concomitant antibiotics for
`Gram-negative/anaerobic coverage more commonly, and needed
`concomitant surgical procedures more often. Patients in study 9901 were
`less sick, had fewer complicating medical illnesses, and the need for
`concomitant antibiotics for Gram-negative/anaerobic coverage or
`concomitantls‘urgical procedures was also less frequent. Efficacy estimates
`
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`Integrated Review of Safety and Efficacy
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`differed significantly in the two studies in both the daptomycin and
`comparator arms. Results of the two studies will thus be presented
`separately rather than in an integrated manner.
`
`Sponsor-defined and FDA-defined populations differed in certain respects.
`Hence, re-analyses were performed using FDA~defmed populations.
`In study 9801, the sponsor discontinued 13 patients from the study after
`they were randomized, and had received at least one dose of study
`medication; 12 of these patients had osteomyelitis, and one had an infected
`foreign body that was not removed. These patients were excluded from the
`sponsor-defined 111‘ population. All patients who are randomized and
`receive at least one dose bf study medication should be included in the
`ITT population and hence they were included in the FDA-defined lTT
`population. The sponsor did not reject any patients in study 9901.
`
`The sponsor-defined clinically evaluable (CE) population and the FDA-
`defrned CE population differed in two respects.
`I
`Patients who had received > 2 days of study medication, and had a
`missing test-of-cure (TOC) visit were classified as evaluable failures
`by the sponsor, and as non-evaluable in the FDA analyses.
`I All patients who received concomitant antibiotics for > 2 days for
`reasons other than lack of efficacy were excluded by the sponsor. All
`patients who received concomitant antibiotics from day 2- TOC visit
`irrespective of the duration of such treatment were excluded from the
`FDA-defined CE population.
`
`In the FDA analyses, 95% confidence intervals (Cl) around the difference
`in success rates (daptomycin-comparator) were calculated, while the
`sponsor calculated the 95% CI for difference in success rates between
`comparator and daptomycin. Hence, using a non-inferiority margin of IO
`%, non-inferiority is established if the value of the lower bound of the
`95% CI is less than 10 % in the FDA analyses and a valire of the upper
`bound of the 95% Cl is less than 10 % in the Sponsor’s analyses.
`
`The primary efficacy populations were the Intent To Treat (ITT) and
`Clinically Evaluable (CE) populations. Clinical success rates using the
`sponsor defined clinical outcome for the ITT and CE populations for both
`studies are presented below.
`
`Studv 9801
`
`In study 980] , success rates in the ITT and CE p0pulations (Tables I, 2)
`were similar in the two treatment arms in analyses performed by the
`sponsor. Daptomycin was demonstrated to be non-inferior to the
`comparator using a non-inferiority margin of 10 %. This was evidenced by
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`Integrated Review of Safety and Efficacy
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`the upper bound of the 95% Cl around the difference in success rates
`being less than- 10 % and the 95 % Cl including the value of zero.
`
`Sponsor’s Results
`Table l: Sponsor-defined clinical outcome (Population: lTT)
`
`Daptomycin
`N = 256
`
`Cure
`
` Clinical Response
`
`
`
`
`
`
`
`Failure
`
`
`33 13%
`Unable to evaluate
`Source: Table 14.2.1.1, final study report
`‘95% confidence interval around the difference in success rates (comparator~
`daptomycin)
`
`95% Cl'
`
`N = 261
`
`Comparator
`
`
`
`39 (15%
`
`
`Table 2: Sponsor-defined clinical outcome (Population: CE)
`
`95% C1‘
`
`Clinical Response
`
`Cure
`Clinical imrovement
`
`N = 223
`167 75%
`
`
`
`N=222
`166 75%
`
`66 30%
`
`Comparator
`
`
`
`
`
`
`Source: Sponsor table 11-7, final study report
`‘95% confidence interval around the difference in success rates (comparator-
`daptomycin)
`
`FDA Results
`
`In study 9801 , success rates in the HT and CE populations (Tables 3, 4)
`were similar in the two treatment arms in analyses performed by the FDA.
`Daptomycin was demonstrated to be non-inferior to the comparator using
`a non-inferiority margin of 10 %. This was evidenced by the lower bound
`of the 95% C1 around the difference in success rates being less than 10 %
`and the 95% C1 including the value of zero. Results of the FDA analyses
`were similar to those obtained by the sponsor.
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`Table 3: Sponsor-defined clinical outcome (Population: lTT)
`
`
`
`1 Clinical Response
`
`i
`
`
`. Clinical Success
`
`Clinical Failure
`
`1 Difference in Success Rate 2
`! Da-tomvcin vs. Com-arator
`
`
`
`
`(N=264
`
`'=266
`
`
`
`
`1.6%, 95% CL: —7.1%, 10.3% .J
`
`
`
`
`Table 4: Sponsor-defined clinicalloutcome (Population: CE) ‘
`
`
`m“m
`i
`. '=208
`‘=206
`
`'_-_
`48 23%
`
`Difference in Success Rate:
`
`Datomvcin vs. Comarator
`
`~0.7%, 95% Cl: -9.4%, 7.9%
`
`
`
`
`
`Studv 9901
`
`S onsor’s Results
`
`In study 9901 , success rates in the ITI‘ and CE populations (Tables 5, 6)
`were similar in the two treatment arms in analyses performed by the
`sponsor. Daptomycin was demonstrated to be non-inferior to the
`comparator using a non~inferiority margin of 10 %. This was evidenced by
`the upper bound of the 95% C1 around the difference in success rates
`being less than 10 % and the 95 % CI including the value of zero.
`
`Table 5:'Sponsor-defincd clinical outcome (Population: ITT)
`
`linical Success
`
`
`
`Clinical 1m rovement
`linical Failure
`
`N = 270
`218 81%)
`103 38%)
`115 43%)
`52 (19%
`28 (10%
`
`
`
`
`
`
`Unable to Evaluate
`Source: Table 14.2.1.1, final study report
`‘95% confidence interval around the difference in success rates (comparator-
`daptomycin)
`
`N= 292
`237 81%
`123 (42%
`114 39%)
`55 (19%
`27 (9%
`28 10%
`
`
`
`
`
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`Table 6: Sponsor-defined clinical outcome (Population: CE)
`
`Clinical Response
`
`linical SUCCESS
`
`Clinical lm-rovemem
`
`
`
`N = 245
`
`N = 262
`
`95% Cl*
`
`4-3. 6-5
`
`
`
`27 (l0%
`27 10%)
`
`
`
`
`
`linical Failure
`
`
`
`
`28 (11%
`28(n%)
`Source. Sponsor table ll -,7 final study report
`'95% confidenceinten al around the differencein success rates (comparator-
`daptomycin)
`
`FDA Results
`
`In study 9901 , success rates in the UT and CE populations (Tables 7, 8)
`were similar in the two treatment arms in analyses performed by the FDA.
`Daptomycin was demonstrated to be non-inferior to the comparator using
`a non-inferiority margin of 10 %. This was evidenced by the lower bound
`of the 95% Cl around the difference in success rates being less than 10 %
`and the 95 % Cl including the value of zero. Results of the FDA analyses
`were similar to those obtained by the sponsor.
`
`—'-a
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`Table 7: Sponsor-defined clinical outcome (Population: ITT)
`
`i
`
`Clinical Success
`
`-
`
`‘=270
`
`(N=292
`
`
`
`
`
`
`
`
`Difference in Success Rate:
`Datomvcin vs. Com-arator
`
`
`
`
`
`-0.1%, 95% CL: -7.0%, 6.8%
`
`Table 8: Sponsor-defined clinical outcome (Population: CE)
`
` ‘_ Clinical Response
`
`
`? Clinical Success
`Clinical Failure
`
`
`! Difference in Success Rate:
`
`' Da-tomvcin vs. Com-arator
`
`
`‘=250
`‘=238
`
`226 90%
`214 (90%
`24(10%
`24 10%)
`
`-0.5%, 95% CL: -6.2%, 5.2%
`
`
`-
`
`Efficacy Summary:
`Based on the results of these two randomized, active-controlled, Phase III
`clinical trials there is sufficient evidence to support the efficacy of
`intravenous daptomycin in the treatment of complicated skin and skin
`structure infections. Intravenous daptomycin 4 mg/kg/day as a single daily
`dose for 7-14 days was demonstrated to be non-inferior to comparator
`drug (semi-synthetic penicillin or vancomycin). The 95% confidence
`intervals around the difference in clinical cure rates demonstrated that the
`
`two treatment regimens were equivalent using a non—inferiority margin of
`10%.
`
`Demographic Characteristics
`
`The number of male patients enrolled in both studies was slightly higher
`(~5 5%) than that of female patients (~45%). Distribution of patients by
`gender was comparable between the two treatment arms.
`
`The protocol Specified age groups to be enrolled in the two cSSSI studies
`were patients from 18-85 years of age, except in South Africa, where the
`upper age limit for enrollment was 65 years. A few patients < 18 years/
`>85 years-were also enrolled. Overall, patients in study 9801 were slightly
`older, with a mean age ~55 years versus ~48 years in study 9901. The
`majority of patients in both studies were between 40-64 years of age. In
`both studies, distribution of patients by age group was comparable in the
`two treatment arms.
`
`- In study 9801, over 60 % of patients were Caucasian, ~ 20% were blacks
`and the remaifid'er were Asian/others. In study 9901 ~50% of patients were
`
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`Integrated Review of Safety and Efficacy
`
`Caucasian, over a third were blacks and the remainder were Asian/others.
`In both studies, distribution of patients by race was comparablem the two
`treatment arm's.
`
`The demographic characteristics of patients in study 9801 and 9901 are
`summarized in Tables 9 and 10 respectively.
`
`Studv 9801
`
`Table 9: Demographic characteristics (Population: ITT)
`
`CharacteristicDaptomycin
`. ‘=264
`
`Comparator
`‘=266
`
`
`
`PNalue
`
`
`
`
`
`
`Range (Min, Max)
`(18,91)
`(18, 94)
`§
`
`MeaniSD\
`55.2il7.6
`55.5.il77
`‘0.8455
`’
`
`
`
`
`Distribution
`
`
`
`
`
`173 (65.5%)
`183 (68.8%)
`0.4233
`< 65 years
`
`
`
`83 (31.2%)
`i
`91 (34.5%)
`
`
`
`Gender
`
`
`Male
`148 (55.6%)
`143 (54.2%)
`Female
`
`m 45.8%)
`118 44.4%
`
`
`
`
`
`167 (62. 8%)
`0.5366
`177 (67.1%)
`
`
`60 (22.6%)
`50 (18.9%)
`
`
`37(14.0%)
`39(14 7%
`
`’Weight (kg)
`
`Range (Min, Max)
`Mean+SD
`
`0.7334
`
`‘08417
`
`
`
`i
`
`‘
`‘
`‘
`
`
`
`(36 274)
`87.6+33.5
`
`(44,193)
`87.0+27.7
`
`* Usingt--;test others using chi--square test
`
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`Integrated Review of Safety and Efficacy
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`Study 9901
`
`Table 10: Demographic characteristics (Population: lTT)
`
`Characteristic
`
`
`
`
`Range (Min, Max)
`(18, 87)
`(17, 85)
`‘0.6284
`
`
`Mean: SD
`47.9: 17.2
`48.6: 16.7
`
`
`
`1 Distribution
`
`
`' < 65 years
`216 (80.0%)
`236 (80. 8%)
`0. 8062
`
`> 65 years
`.
`54 (20.0%)
`56 (19.2%)
`
`
`
`
`
`
`
`
`
`146 (50. 0%)
`91 (31 .2)%
`55(l8.8%
`
`(40,130)
`727+17.4
`
`'0.6244
`
`.
`
`i
`
`150 (55. 6%)
`120 (44.4%)
`
`160 (54.8%)
`132 (45.2%).
`
`0.8562
`
`136 (50.4%)
`95 (35.2%)
`39(l4.4%)
`
`
`
`
`
`Weight (kg)
`
`Range (Min, Max)
`
`
`MeaniSD
`
`* Using t-test; others using chi——square test
`
`(40 165)
`73.5+198
`
`Efficacy
`
`Study 9801
`In study 9801, clinical success rates were slightly higher in females in
`both treatment arms. In the daptomycin arm, success rates were lower in
`patients 2 65 years of age. In the comparator arm, success rates were
`comparable in the two age group categories. In study 9801, higher success
`rates were seen in black patients compared to Caucasian and others.
`Clinical success rates by demographic characteristics in the ITT
`population in study 9801 are presented in table 15.‘
`
`Table 15: FDA efficacy analyses by demographic characteristics
`(Population: ITT)
`
`g Subgroup
`
`Daptomycin_ Comparator
`‘=26‘4
`'=266
`
`95% Cl
`
`(-21 .8%, 27.9%)
`
`119/173 (69%)
`46/91 (50.5%)
`
`112/183 (61%
`50/83 (60%)
`
`(29%, 18.)0%
`(25. 6%,6 2%)
`
`86/143 (60%)
`79/121(65%)
`
`87/148(59%)_
`75/118(64%)
`
`(-10.6%,l3.3%)
`(-11.2%, 14.7%)
`
`101/177 (57%)
`42/50 (84%)
`"22/37 (59.5%)
`
`93/167 (56%)
`47/60 (78%)
`22/39 (56%)
`
`(9.7%, 12.4%)
`(40.7%, 22.1%)
`
`Page 14
`
`1
`
`P-Va
`
`Comparator
`. "=292
`
`
`
`Daptomycin
`"=270
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`

`CLINICAL REVIEW
`
`Integrated Review of Safety and Efficacy
`
`Study 9901
`
`In study 9901, slightly higher success rates were seen in females in the
`comparator arm, and in males in the daptomycin arm. Success rates were
`lower in patients 2 65 years of age in both arms. However, the reduction in
`success rates in patients 2 65 years was more pronounced in the
`daptomycin arm. Higher success rates were seen in patients of black/other
`races compared to Caucasian. Clinical success rates by demographic
`characteristics in the HT population in study 9801 are presented in table
`16.
`
`’
`
`Table 16: FDA efficacy analyses by demographic characteristics
`(Population: lTT)
`,
`
`Daptomycin
`.‘=270
`
`Comparator
`'=292
`
`95% Cl.
`
`
`
`
`
`Subgroup
`
`
`
`194/236 (82.3%)
`181/216 (83.8%)
`
`
`(-5.8%, 9.0%)
`‘
`
`36/54 (66.7%)
`41/56 (73.2%)
`(25.5%, 12.4%)
`
`
`
`
`
`
`
`122/150 (81.3%)
`125/160 (78.1%)
`(-6.4%, 12.8%)
`95/120 (79.2%)
`110/132 (83.3%)
`(44.6%, 6.3%)
`
`
`
`
`
`
`
`
`
`107/136 (78.7%)
`111/146 (76.0%)
`(-7.8%, 13.1%)
`78/95 (82.1%)
`75/91 (82.4%)
`(-12.4%.11.7%)
`
`
`
`
`32/39 (82.1%)
`49/55 (89.1%)
`(—23.8%, 9.7%)
`
`
`
`
`
`§u_n_1_m_a_r1
`Success rates in patients 2 65 years of age were lower in the daptomycin
`arm in both studies. In the comparator arm, reduction in success rate in
`patients 2 65 years of age was seen only in study 9901. The reason for a
`more pronounced reduction in success in older patients treated with
`daptomycin is unclear. Success rates were higher in patients of black race
`in both studies. No specific gender differences in efficacy were noted in
`either study.
`
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`Integrated Review of Safety and Efficacy
`
`Safety
`
`The safety database comprised data on 602 daptomycin-treated patients in
`Phase I studies, 349 daptomycin-treated patients in Phase II studies, and
`989 patients in Phase III studies.
`
`Adverse events in Phase I studies
`
`A total of 240 subjects received daptomycin in the Phase I studies: 19
`human pharmacology studies were conducted by Lilly (9 single-dose
`Phase I in the US, 3 repeat-dose in the U.S., 3 single dose in Japan, and 4
`repeat dose in Japan). Cubist conducted 22 human pharmacology studies
`(7 single dose and 5 repeat dose). In Lilly-sponsored Phase I studies, 102
`subjects were administered single-dose daptomycin at doses ranging from
`5 mg to 6.0 mg/kg; Phase I repeat-dose studies assessed doses of 1 mg/kg
`q 24h in a total of 25 subjects. In the Cubist-sponsored Phase I studies
`there were 240 daptomycin-treated patients and 109 comparator treated
`patients. The greatest number of subjects in the Cubist-sponsored Phase I
`trials were exposed to daptomycin for less than or equal to one day, or to a
`single dose and received a dose of daptomycin <1 g. Eighty-six subjects
`received a total dose of daptomycin >4g in multiple dose studies.
`
`No deaths occurred in clinical pharmacology studies conducted by either
`sponsor. Three serious adverse events (SAEs) in daptomycin-treated
`subjects were reported in the Cubist-sponsored Phase 1 studies. Two
`subjects had gastrointestinal symptoms considered “probably related” to
`study drug, and one subject had Bell's palsy considered by the investigator
`to be unrelated to study drug. One subject in the Lilly-sponsored Phase I
`trials developed the SAE of anemia, described as unrelated to study drug.
`
`In the Cubist-sponsored clinical pharmacology studies, seven subjects
`discontinued study medication due to adverse events (ABS): 5 of 240
`(2.1%) in the daptomycin group and 2 of 109 (1.8%) in the comparator
`group. The most common reason for discontinuation was elevation of
`CPK, with three subjects in the daptomycin group and one in the
`comparator group being discontinued for this reason. The three subjects
`with elevation in CPK (maximum of 1940/ 1593/4490 with MM
`isoenzymes, all asymptomatic) were considered to have a drug-related AE;
`AEs of facial palsy and diarrhea were also considered drug related in the
`daptomycin group. In the comparator group 1/2 AEs was drug-related, a
`rash with pruritis. In the Lilly-sponsored Ph