CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
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`APPLICATION NUMBER:
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`212690Orig1s000
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`STATISTICAL REVIEW(S)
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
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`S T A T I S T I C A L R E V I E W A N D E VA L U A T I O N
`CLINICAL STUDIES
`
`NDA/BLA #:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`
`NDA 212,690
`JZP-258
`Narcolepsy
`Jazz Pharmaceuticals
`Date of Submission: January 21, 2020
`PDUFA Date: July 21, 2020
`Review Priority:
`Priority Review
`Biometrics Division:
`Division I
`Statistical Reviewer:
`Sharon Yan, PhD
`Concurring Reviewers: Kun Jin, PhD, Team Leader
`Jim Hung, PhD, Director
`Neurology I
`Ranjit Mani, MD, Clinical Reviewer and Team Leader
`Eric Bastings, MD, Director
`Vandna Kishore, PharmD
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`Medical Division:
`Clinical Team:
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`Project Manager:
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`Reference ID: 4629746
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`Table of Contents
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`1 EXECUTIVE SUMMARY .................................................................................................... 5
`2
`INTRODUCTION .................................................................................................................. 5
`2.1 OVERVIEW .......................................................................................................................... 5
`2.2 DATA SOURCES .................................................................................................................. 6
`3 STATISTICAL EVALUATION ........................................................................................... 6
`3.1 DATA AND ANALYSIS QUALITY .......................................................................................... 6
`3.2 EVALUATION OF EFFICACY ................................................................................................. 6
`3.2.1 Evaluation of Efficacy for Protocol RPC01-301 ........................................................ 6
`3.2.1.1
`Study Design ...................................................................................................................................................... 6
`3.2.1.2
`Study Endpoints ................................................................................................................................................. 8
`3.2.1.3
`Statistical Methodologies ................................................................................................................................... 9
`3.2.1.3.1 Analyses of the Primary Endpoints .............................................................................................................. 9
`3.2.1.3.2 Analysis of Secondary Endpoints ............................................................................................................... 10
`3.2.1.3.3 Handling of Missing Data ........................................................................................................................... 10
`3.2.1.3.4 Multiplicity Consideration .......................................................................................................................... 10
`3.2.1.4
`Study Patients ................................................................................................................................................... 10
`3.2.1.4.1 Patient Disposition ...................................................................................................................................... 10
`3.2.1.4.2 Patient Demographics ................................................................................................................................. 11
`3.2.1.4.3 Patient Baseline Disease Characteristics .................................................................................................... 12
`3.2.1.5
`Efficacy Results ............................................................................................................................................... 13
`3.2.1.5.1 Primary Endpoint – Cataplexy Attacks ....................................................................................................... 13
`3.2.1.5.2 Secondary Endpoints – Excessive Daytime Sleepiness (ESS) .................................................................... 13
`3.3 EVALUATION OF SAFETY .................................................................................................. 14
`4 FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ............................................... 14
`4.1 GENDER, RACE, AGE, AND GEOGRAPHIC REGION ............................................................ 14
`4.2 OTHER SPECIAL/SUBGROUP POPULATIONS ....................................................................... 16
`5 SUMMARY AND CONCLUSIONS................................................................................... 16
`5.1 STATISTICAL ISSUES ......................................................................................................... 16
`5.2 COLLECTIVE EVIDENCE .................................................................................................... 16
`5.3 CONCLUSIONS AND RECOMMENDATIONS ......................................................................... 17
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`LIST OF TABLES
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`Table 1 List of All Studies Included in This Review...................................................................... 6
`Table 2 Demographic Characteristics of Efficacy Population ...................................................... 12
`Table 3 Disease History (Efficacy Population) ............................................................................ 12
`Table 4 Analysis of Change in Average Weekly Number of Cataplexy Attacks (Efficacy
`Population) .................................................................................................................................... 13
`Table 5 Change in ESS Score from the End of Stable-Dose Period to End of Double-Blind
`Withdrawal Period - Efficacy Population ..................................................................................... 14
`Table 6 Analysis of Average Weekly Cataplexy Attacks by Subgroups of Sex, Age Group and
`Region (Efficacy Population) ....................................................................................................... 15
`Table 7 Average Weekly Cataplexy Attacks by Pre-randomization Group ................................. 16
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`Reference ID: 4629746
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`LIST OF FIGURES
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`Figure 1 Study Diagram for Main Study (source: Figure 1 of Protocol) ........................................ 8
`Figure 2 Disposition of Subjects (Source: CSR) .......................................................................... 11
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`1 EXECUTIVE SUMMARY
`
`This NDA application for ZEPOSIA™ (ozanimod) is seeking approval for the following
`indications:
`
`
`JZP-258 is being developed to provide the same treatment benefits as Xyrem (i.e., treatment
`of cataplexy or EDS in patients 7 years of age and older with narcolepsy) with 92% less
`sodium.
`
`
`The efficacy of JZP-258 is based on a single pivotal phase 3 study 15-006, which is a double-
`blind, placebo-controlled, randomized-withdrawal study.
`
`Study 15-006 demonstrated the clinical efficacy of JZP-258 in the treatment of cataplexy in
`patients with narcolepsy. Subjects randomized to placebo during the double-blind randomized
`withdrawal period experienced a significant increase (i.e., worsening) in the weekly number of
`cataplexy attacks compared with subjects randomized to continue treatment with JZP-258. The
`median change in the weekly cataplexy attacks was 2.35 for the placebo group compared with
`0.00 change for the JZP-258 group with a p-value < 0.0001.
`
`Subjects randomized to placebo during the double-blind randomized withdrawal period
`experienced a significant increase in Epworth Sleepiness Scale (ESS) score (i.e., worsening of
`excessive daytime sleepiness) compared with subjects randomized to continue treatment with
`JZP-258. The median change from the end of the stable dose period to the end of the double-
`blind withdrawal period in the ESS score was 2.0 for the placebo group compared with 0.0
`change for the JZP-258 group with a p-value < 0.0001.
`
`
` 2
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` INTRODUCTION
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`
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`2.1 Overview
`
`JZP-258 was being developed for the treatment of cataplexy and excessive daytime sleepiness
`(EDS) in patients with narcolepsy 7 years of age and older.
`
`Currently, Xyrem (sodium oxybate) oral solution is the only FDA approved therapy for the
`treatment of cataplexy and excessive daytime sleepiness (EDS) in patients with narcolepsy 7
`years of age and older. JZP-258, developed by Jazz Pharmaceuticals, has the same active moiety
`as Xyrem with substantially lower sodium content compared with approved dosage of Xyrem.
`By formulating oxybate with a mixture of cations (calcium, potassium, magnesium, and sodium),
`Jazz developed JZP-258 to have 92% less sodium than Xyrem: 87 to 131 mg versus 1100 to
`1638 mg in the anticipated dose range of 6 to 9 g nightly, to provide narcolepsy patients with the
`safety benefit of reduced sodium content and similar efficacy as Xyrem.
`
`Study 15-006 was designed as a 2-part study consisting of a Main Study (a double-blind,
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`placebo-controlled, randomized-withdrawal, multicenter study of the efficacy and safety of
`JZP-258) followed by an optional 24-week open-label extension (OLE) study.
`
`The primary endpoint of Study 15-006 was the change in the average weekly number of
`cataplexy attacks from the 2 weeks of the Stable Dose Period (SDP) to the 2 weeks of the
`Double-blind randomized-withdrawal period (DB RWP). The key secondary endpoint was the
`change in the ESS score from the end of the SDP to the end of the DB RWP.
`
`The following table presents a summary of the studies included in this review.
`
`Table 1 List of All Studies Included in This Review
`Phase and Design Treatment
`
`Period
`12-week open-label
`optimization, 2-week
`stable dose, 2-week
`randomized
`withdrawal
`
`Comparator
`
`Placebo
`
` # of Subjects
`randomized
`65 to placebo;
`69 to JZP-258
`
`Study
`Population
`Patients with
`cataplexy and
`EDS
`
`Study 15-006 Phase 3, double-
`blind, placebo-
`controlled,
`randomized-
`withdrawal trial
`Source: Reviewer’s summary
`
`
`2.2 Data Sources
`
`Original submission 1/21/2020: \\CDSESUB1\evsprod\NDA212690\0001
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`
` 3
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` STATISTICAL EVALUATION
`
`
`
`3.1 Data and Analysis Quality
`
`No notable issues were identified in the submission of data and study documents.
`
`3.2 Evaluation of Efficacy
`
`
`3.2.1 Evaluation of Efficacy for Protocol RPC01-301
`
`3.2.1.1 Study Design
`
`
`The Main Study (the efficacy part) of Study 15-006 was a double-blind, placebo-controlled,
`multicenter, randomized-withdrawal study of the efficacy and safety of JZP-258.
`
`The Main Study consisted of 4 study periods as described below and in Figure 1.
`
`The Screening Period lasted up to 30 days and subjects were allowed to be rescreened.
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`Optimized Treatment and Titration Period (OL OTTP): During the 12-week OL OTTP,
`eligible subjects were transitioned to JZP-258 treatment based on their pretreatment status as
`follows:
`• Pre-randomization Group 1 (subjects receiving a stable dose of Xyrem only for at least 2
`months prior to screening): Subjects were switched from Xyrem to JZP-258 (gram for
`gram) and remained on this JZP-258 dose for a minimum of 2 weeks. If needed, the dose
`of JZP-258 could be titrated during the subsequent 8 weeks to a stable, tolerable, and
`effective dose.
`• Pre-randomization Group 2 (subjects receiving a stable dose of Xyrem and an additional
`anticataplectic for at least 2 months prior to screening): Subjects were switched from
`Xyrem to JZP-258 (gram for gram) and remained on this JZP-258 dose for a minimum of
`2 weeks. Following this 2-week period, subjects were tapered off the additional
`anticataplectic over a minimum period of 2 weeks and up to 8 weeks. If needed, the dose
`of JZP-258 could be further titrated to a stable, tolerable, and effective dose during this 8-
`week period.
`• Pre-randomization Group 3 (subjects receiving a non-Xyrem anticataplectic and not
`Xyrem at screening): Subjects were titrated to a tolerable dose of JZP-258 over a
`minimum of 2 weeks at the start of this period. After initial JZP-258 titration, subjects
`were tapered off other anticataplectics over a minimum of 2 weeks and up to 8 weeks. If
`needed, the dose of JZP-258 could be further titrated to a stable, tolerable, and effective
`dose during this 8-week period.
`• Pre-randomization Group 4 (subjects not receiving treatment with an anticataplectic at
`screening): Subjects were initiated and titrated with JZP-258 over a minimum of 2 weeks
`and up to 8 weeks to achieve a stable, tolerable, and effective dose during this period.
`
`
`All subjects were to be treated with JZP-258 alone for the final 2 weeks of this 12-week period.
`
`Open-Label Stable Dose Period (OL SDP): Subjects had to be titrated or converted to a
`tolerable and effective dose of JZP-258 alone for at least 2 weeks prior to entering the 2-week
`Stable Dose Period. During the 2-week SDP, subjects were to remain on the stable JZP-258 dose,
`unchanged, for 2 weeks. The baseline number of weekly cataplectic attacks and baseline EDS
`scores, as well as other secondary endpoints, were evaluated during this period.
`
`Double-Blind Randomized-Withdrawal Period (DB RWP): Subjects were then eligible to
`enter the Double-blind Randomized-withdrawal Period (DB RWP) if the dose of JZP-258
`remained unchanged during the SDP and, in the judgment of the investigator, no clinically
`significant worsening in narcolepsy symptoms or clinically significant adverse events (AEs) due
`to JZP-258 treatment had occurred and subjects completed daily dosing and cataplexy diaries in
`the SDP.
`
`Subjects eligible to enter the DB RWP were randomized 1:1 to receive 1 of the following 2
`treatments during the 2-week DB RWP:
`• JZP-258: JZP-258 was continued as a double-blind treatment at the stable dose taken in
`the prior 2 weeks.
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`• JZP-258 placebo: Placebo was initiated as a double-blind treatment at a volume
`equivalent to the JZP-258 dose taken in the prior 2 weeks.
`
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`Randomization was stratified based on each subject’s pre-randomization group, as defined
`above.
`
`The study enrolled male and female subjects between 18 and 70 years of age who had a primary
`diagnosis of narcolepsy with cataplexy and had a history of having at least 14 cataplexy attacks
`in a typical 2-week period and clinically significant symptoms of excessive daytime sleepiness
`(EDS) prior to any narcolepsy treatment.
`
`
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`Figure 1 Study Diagram for Main Study (source: Figure 1 of Protocol)
`
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`3.2.1.2 Study Endpoints
`
`
`Primary Endpoint
`
`The primary efficacy endpoint was the change in average weekly number of cataplexy attacks
`from the 2 weeks of the open-label SDP to the 2 weeks of the DB RWP.
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`Subjects were to complete a daily Cataplexy Frequency Diary each night prior to bedtime.
`Subjects were to record the number of cataplexy attacks that they had each day from the
`beginning of OTTP through the end of the DB RWP. Subjects were to complete the Cataplexy
`Frequency Diary on at least 10 out of the 14 days in the SDP occurring prior to the start of the
`DB RWP, or they were to be discontinued from the study.
`
`Key Secondary Endpoint
`
`The key secondary efficacy endpoint was the change in Epworth Sleepiness Scale (ESS) score
`from the end of the OL SDP to the end of the DB RWP.
`
`ESS was a self-administered questionnaire with 8 questions asking the subject how likely they
`would be to doze off or fall asleep in different situations. Responses ranged from 0=would never
`doze to 3=high chance of dozing. Subjects were asked to complete the ESS regarding the level of
`sleepiness they experienced over the past 7 days at end of the SDP and at the end of the DB
`RWP or Early Termination from the DB RWP. The ESS total score was the sum of the 8 item-
`scores and ranged between 0 and 24. Higher scores indicated greater daytime sleepiness.
`
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`3.2.1.3 Statistical Methodologies
`
`
`The efficacy population (EFF) was to contain all randomized subjects who had received at least
`one dose of DB study drug and had at least one set of post-randomization efficacy data.
`
`3.2.1.3.1 Analyses of the Primary Endpoints
`
`For subjects with at least one day of cataplexy attack data, the average weekly number of
`cataplexy attacks over each of the two weeks of the OL SDP was to be calculated as follows:
`
`
`
`
`
`Average weekly number of cataplexy attacks over each of the two weeks of the DB RWP was to
`be calculated similarly.
`
`For the primary efficacy endpoint, an analysis of covariance (ANCOVA) was to be performed
`using the PROC GLM SAS procedure. The model was to include the change in average weekly
`number of cataplexy attacks from the two weeks of the OL SDP to the two weeks of the DB
`RWP as the dependent variable; the treatment group and Pre-randomization Group (Refer to
`Section 3.2.1.1) as fixed effects as well as the average weekly number of cataplexy attacks over
`the 2 weeks of the OL SDP as a covariate.
`
`The normality assumption of the ANCOVA model was to be examined by residual analysis
`using the Shapiro-Wilk test at a 0.05 significance level. If the normality assumption was
`considered violated, a non-parametric ANCOVA with the covariate and response variables
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`replaced by their ranks was to be used as the primary efficacy analysis. P-values was to be
`presented from the rank based ANCOVA. Location shift between the change in the average
`weekly number of cataplexy attacks between the two treatment groups and asymptotic 95%
`confidence intervals was to be presented using the Hodges-Lehman estimator (Hodges and
`Lehman 1962).
`
`
`3.2.1.3.2 Analysis of Secondary Endpoints
`
`The ESS total score was to be analyzed similarly to the primary efficacy endpoint.
`
`
`3.2.1.3.3 Handling of Missing Data
`
`For subjects without post-randomization daily cataplexy attack data, the average weekly number
`of cataplexy attacks from the OL SDP was to be carried forward using a baseline observation
`carry forward (BOCF) approach.
`
`For ESS total score, if three or more item scores were missing at a specific time point, the ESS
`total score was to be set to missing. If one or two ESS item scores were missing at a specific time
`point, the mean of the remaining seven or six non-missing ESS item scores at that time point was
`be used to impute the missing ESS item scores. The ESS total score was to be then calculated as
`the sum of the observed and imputed item scores.
`
`For subjects without post-randomization ESS data, the result form the OL SDP was to be carried
`forward using a BOCF approach.
`
`
`3.2.1.3.4 Multiplicity Consideration
`
`The primary endpoint was to be tested first at a 2-sided significance level of 0.05. If the primary
`endpoint reached statistical significance, the key secondary endpoint was to be tested at the 2-
`sided significance level of 0.05; otherwise the key secondary endpoint was not to be tested.
`
`
`3.2.1.4 Study Patients
`
`3.2.1.4.1 Patient Disposition
`
` A
`
` total of 225 subjects were screened and of these, 201 subjects entered the OL OTTP and
`received at least 1 dose of study drug.
`
`Subjects were treated with JZP-258 without other anticataplectic for at least the final 2 weeks of
`this 12-week OTTP. A total of 149 subjects overall achieved a tolerable and efficacious dose of
`JZP-258 and entered the OL SDP.
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`After completing the OL SDP, 136 subjects were randomized, but two subjects were randomized
`in en or and did not receive any dose of study drng in the DB RWP. Therefore, 134 subjects
`received at least 1 dose of study chu g in the DB RWP (69 subjects in the JZP-258 group and 65
`subjects in the placebo group), which comprised of Efficacy Population.
`
`Overall, a total of 5 subjects discontinued from the SDP, 8 subjects completed the SDP but were
`not randomized, 2 subjects who were randomized in the DB RWP in enor and did not receive a
`dose of double-blind study ch11g, and 6 subjects discontinued from the DB RWP.
`
`A summaiy of patient disposition is presented in Figure 3.
`
`Prt-rHdomizltion
`Group ([nroU..i
`Su.\jec.ts)
`
`Xyr<m Only
`N • 52
`
`Xyrtm + Othtt
`Anticataplectic
`". 2J
`
`t\on· X}Ttm
`.l\.nt1eataplecUc
`
`1'----~-~-~·(_;,_d _ _,t;1.__-Sct_•_;;i_!_~_"'_"_;i_,
`"= 36 [;;J~
`
`~---~-----~---
`OL OITP (1: ... tks)
`N" = 20 1
`
`Completed Poriod: N•!Sl
`CittcluditlJ 6 ntljecu'&'hocompJm4t.-Jt didoo1 e:a.m
`tM St.hie Dow Pawd~ lo tl. £d.lowui.i prctccd
`~ti«!. [3],A£ f ll Ueko! ~!!°'!Cs:y [ll ot
`Otbeu...oa(l]t
`
`Did Xot Complete Period.: N = 5
`
`Reasons for diseonti:nu:auon:
`Protocol deviation
`.'\!
`Lo i t to follow-up
`
`:'\l = l
`N - 1
`:-: = I
`
`Stahl• Dost Poriod (l .. u lu)
`N • 149
`
`Completed Period: N • l.U
`Ccoc.luditli S r:ft,jecu '11.ocomsilu!t b':t v;-ttt ttot rr.dcmi..::etd':le to the
`foll.O"OMJ:proo:oJ~~ [ S), AE(ll1K1lQOrrp.:i21X't11ti1bt1lldy
`~ ( l], orW1thclnwt.lbystll,i-!<t(l J)
`
`DB RWP (2 wulu)
`:<I = 136 (rudoalied)'
`
`Did Not Complete Period:: N = '6
`Rusons fM dLSconttnuation:
`AE
`Prorocol de\'Ution
`Withdrawal by suti,ect
`Koncompliance ......mi study drug
`lnvutig.uor d~sion
`Lost to fotlow-up
`Sponsor decision
`Lack of efficacy
`01h...
`
`:-<=IS
`'N = S
`~ • 6
`~ • 4
`~ • 3
`~ • 3
`N • 2
`~ • l
`:-< · I
`
`Did Not Com.pl~te Period: N • 6
`
`IZP-2SS N = 69
`
`Completed Period: N = 69
`
`Reasons for discontitlwtion:
`Placebo ~ •61
`'---~--i:====::::::::.__j AE
`l.atk of df.cacy
`Completed Penod: ~ = 5-9
`Wrthdrawal by sub)ecc
`
`!\ ot mttting OLE. N • 5~
`
`Oiseontinucd tarl>• from. tbis period: N•6
`
`OLr (24 Yittks)
`~ • ? 4 ('27 OLC ~nrr:r, 4 7 OLI roUon.r )
`
`Completed Period: l'\ • 19
`St:iD on.going:; ~ • 49
`
`R~asonsfor discontinw.tion:
`AE
`lost to foDow-0p
`Lack of t fficacy
`01he<
`
`AE = adve1se event; DB RWP = Double-blind Rllndonllzed-mtbdrawal Penod; OLE= Open-label ExteuSJon; OL OTTP =open-label Optimized Treatment and T1lration Penod
`For OLE re-entry sutijects. there. was a variable gap between complel!on of Main Study and re-enlly for OLE due lo availability of approved Protocol Amendment 4.
`(b) (6) and ~were randomized in en-oc- a11d did not take Sllldy drug i11 the DB RWP.
`• SUbjects
`Source: Tables 14.1.1.l, 14.1.l.2, and Posthoc Table 14.1.l.IOO; Lisl!ng 16.2.1.l
`Figure 2 Disposition of Subjects (Source: CSR)
`
`3-2-1-4-2 Patient Demographics
`
`Demographic and baseline chai·acteristics ai·e sUlillnai·ized for the Efficacy Population in Table 2.
`Overall, baseline demographic chai·acteristics were generally balanced between treatment groups
`in the Efficacy Population.
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`Table 2 Demographic Characteristics of Efficacy Population
`JZP-258
`
`N=69
`
`Age (years)
`
` Mean (SD)
`37.2 (11.79)
` Median
`39.0
`Sex, n (%)
`
` Male
`26 (37.7)
` Female
`43 (62.3)
`Race, n (%)
`
` White
`64 (92.8)
` Other and Not Reported
`5 (7.2)
`Region, n (%)
`
` North America
`23 (33.3)
` Europe
`46 (66.7)
`Source: Table 7 of CSR
`
`
`Placebo
`N=65
`
`37.8 (12.69)
`35.0
`
`26 (40.0)
`39 (60.0)
`
`59 (90.8)
`6 (9.2)
`
`23 (35.4)
`42 (64.6)
`
`3.2.1.4.3 Patient Baseline Disease Characteristics
`
`Baseline disease characteristics were similar between treatment groups in the Efficacy
`Population. On average, subjects had been diagnosed with narcolepsy for 8.4 and 6.8 years in the
`JZP-258 and placebo groups, respectively (Table 3).
`
`Table 3 Disease History (Efficacy Population)
`
`
`Time since diagnosis (years)
` Mean (SD)
` Median
`Past symptoms prior to treatment, n (%)
` Cataplexy
` EDS
` Hypnagogic hallucinations
` Sleep paralysis
` Disrupted nighttime sleep
`Current symptoms of narcolepsy, n (%)
` Cataplexy
` EDS
` Hypnagogic hallucinations
` Sleep paralysis
` Disrupted nighttime sleep
`Source: Table 9 of CSR
`
`
`JZP-258
`N=69
`
`8.4 (8.46)
`5.6
`
`69 (100.0)
`69 (100.0)
`38 (55.1)
`41 (59.4)
`43 (62.3)
`
`66 (96.7)
`67 (97.1)
`27 (39.1)
`29 (42.0)
`40 (58.0)
`
`Placebo
`N=65
`
`6.8 (5.63)
`5.8
`
`65 (100.0)
`65 (100.0)
`42 (64.6)
`42 (64.6)
`44 (67.7)
`
`60 (92.3)
`63 (96.9)
`27 (41.5)
`23 (35.4)
`37 (56.9)
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`3.2.1.5 Efficacy Results
`
`
`
`3.2.1.5.1 Primary Endpoint – Cataplexy Attacks
`
`At baseline (2 weeks of the Stable Dose Period), the median average weekly number of
`cataplexy attacks was similar between the JZP-258 and placebo groups (1.08 and 1.00,
`respectively). During the DB RWP, the average weekly number of cataplexy attacks increased
`for subjects randomized to placebo with a median change of 2.35, while the median change was
`0.00 for subjects randomized to continue treatment of JZP-258. The comparison of the change
`from baseline between treatments was statistically significant (estimated median difference [JZP-
`258 – placebo]: -3.308; p < 0.0001).
`
`The normality assumption of the ANCOVA model was considered violated based on
`prespecified criteria and a nonparametric ANCOVA with ranks was used. The median difference
`between the treatment groups and 95% CI were estimated with the location shift by Hodges-
`Lehmann method. The results of the analysis of cataplexy attacks are summarized in Table 4.
`
`Table 4 Analysis of Change in Average Weekly Number of Cataplexy Attacks (Efficacy Population)
`JZP-258
`Placebo
`Average of Weekly Number of
`N=69
`N=65
`Cataplexy Attacks
`Baseline (2 weeks of Stable Dose)
`
`
` Mean (SD)
`8.91 (16.83)
`7.16 (14.41)
` Median
`1.08
`1.00
` Min-Max
`0.00 – 82.25
`0.00 – 83.07
`2 weeks of DB RWP
`
`
` Mean (SD)
`9.03 (16.93)
`18.63 (32.75)
` Median
`2.15
`5.44
` Min-Max
`0.0 – 87.23
`0.0 – 157.00
`Change from Baseline
`
`
` Mean (SD)
`0.12 (5.77)
`11.46 (24.75)
` Median
`0.00
`2.35
` Min-Max
`-23.30 – 26.12
`-5.00 – 124.00
`Primary analysis (non-parametric)
` Median Difference: JZP-Placebo
` 95% CI
` p-value
`Source: Reviewer’s analysis
`Altogether, 6 patients withdrew from the DB RWP, all from the placebo group. For those 6
`patients, their average weekly number of cataplexy attacks was carried from baseline. This
`imputation assumes that their weekly cataplexy attacks were unchanged after withdrawal from
`the active treatment of JZP-258. Since there were no patients withdrew from patients randomized
`to continue JZP-258, such imputation is considered most conservative.
`
`
`
`
`-3.308
`(-6.044, -1.500)
`<0.0001
`
`3.2.1.5.2 Secondary Endpoints – Excessive Daytime Sleepiness (ESS)
`
`
`
`13
`
`Reference ID: 4629746
`
`

`

`At the end of the 2-week SDP, the median ESS score was 13.0 for the placebo group and 14.0 for
`the JZP-258 group. At the end of the DB RWP, the median ESS score for subjects randomized to
`placebo increased by 2.0, while the median change was 0.00 for subjects randomized to continue
`treatment of JZP-258. The comparison of the change from baseline between treatments was
`statistically significant (estimated median difference [JZP-258 – placebo]: -2.000; p < 0.0001)
`from the non-parametric ANCOVA with ranks. The results of the analysis of ESS scores are
`summarized in Table 5.
`
`Table 5 Change in ESS Score from the End of Stable-Dose Period to End of Double-Blind
`Withdrawal Period - Efficacy Population
`
`
`Baseline (End of Stable Dose)
` Mean (SD)
` Median
` Min, Max
`End of DB RWP
` Mean (SD)
` Median
` Min, Max
`Change from Baseline
` Mean (SD)
` Median
` Min, Max
`Primary analysis (non-parametric)
` Median Difference: JZP-Placebo
` 95% CI
` p-value
`Source: Reviewer’s analysis
`
`
`3.3 Evaluation of Safety
`
`Please refer to Evaluation of Safety by Dr. Ranjit Mani for evaluation of safety.
`
`
` 4
`
` FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`
`
`4.1 Gender, Race, Age, and Geographic Region
`
`Analyses of the primary endpoint on subpopulations of sex and age group were performed. Age
`was grouped by < 38 years and > 38 years, where 38 was the median age. Almost all patients
`were white and thus analysis by race was not performed.
`
`Patients in each of the individual European countries were in small numbers and therefore,
`countries were pooled into two regions of Europe and USA.
`
`
`
`
`Reference ID: 4629746
`
`14
`
`JZP-258
`N=69
`
`13.62 (5.25)
`14.0
`3 - 24
`
`13.64 (4.66)
`14.0
`4 - 24
`
`0.01 (2.90)
`0.0
`-9, 7
`
`Placebo
`N=65
`
`12.57 (5.46)
`13.0
`
`
`15.58 (4.88)
`16.0
`
`
`3.02 (4.68)
`2.0
`-6, 20
`
`
`-2.00
`(-4.00, -1.00)
`<0.0001
`
`

`

`Regardless of sex, age, or region, patients who were randomized to placebo had experienced an
`increase of at least 1 cataplexy attack in weekly median after withdrew from JZP-258, while
`patients who randomized to continue treatment with JZP-258 saw no change in their weekly
`number of cataplexy attacks. A summary of results is presented in Table 6.
`
`Table 6 Analysis of Average Weekly Cataplexy Attacks by Subgroups of Sex, Age Group and
`Region (Efficacy Population)
`Median of Average of Weekly Number
`of Cataplexy Attacks
`Sex
` Male
` N
` Baseline
` Change
` Median Difference: JZP-Placebo
` (95% CI)
` Female
` N
` Baseline
` Change
` Median Difference: JZP-Placebo
` (95% CI)
`Age Group
` < 38 ears
` N
` Baseline
` Change
` Median Difference: JZP-Placebo
` (95% CI)
` > 38 years
` N
` Baseline
` Change
` Median Difference: JZP-Placebo
` (95% CI)
`Region
` USA
` N
` Baseline
` Change
` Median Difference: JZP-Placebo
` (95% CI)
` Europe
` N
` Baseline
` Change
` Median Difference: JZP-Placebo
` (95% CI)
`Source: Reviewer’s analysis
`
`
`
`Placebo
`N=65
`
`
`26
`0.68
`1.07
`
`39
`1.62
`2.55
`
`
`
`37
`1.40
`4.71
`
`
`
`28
`0.52
`1.56
`
`
`
`23
`1.00
`2.06
`
`
`
`42
`1.04
`2.37
`
`
`
`
`
`
`
`JZP-258
`N=69
`
`
`26
`1.12
`0.00
`-2.72
`(-5.44, 0.00)
`
`43
`1.08
`0.00
`-4.94
`(-8.12, -1.77)
`
`
`31
`1.08
`0.00
`-5.45
`(-9.22, -1.70)
`
`38
`1.88
`0.00
`-2.63
`(-4.85, -0.42)
`
`
`23
`1.00
`0.10
`-3.50
`(-7.00, 0.00)
`
`46
`2.75
`0.00
`-4.82
`(-7.85, -1.79)
`
`
`
`Reference ID: 4629746
`
`15
`
`

`

`4.2 Other Special/Subgroup Populations
`
`Efficacy of the primary endpoint by pre-randomization group was analyzed. Patients who were
`randomized to placebo group experienced an increase in cataplexy attacks after withdrew from
`JZP-258 treatment while patients who continued JZP treatment had generally no change in
`cataplexy attacks, independent of their pre-randomization status (Table 7).
`
`Table 7 Average Weekly Cataplexy Attacks by Pre-randomization Group
`Median of Average of Weekly Number
`JZP-258
`of Cataplexy Attacks
`N=69
`Pre-Randomization Group
`
` Naive
`
` N
`30
` Baseline
`1.62
` Change
`0.00
` Median Difference: JZP-Placebo
`-4.32
` (95% CI)
`(-7.85, -0.80)
` Non-Xyrem
`
` N
`11
` Baseline
`5.50
` Change
`0.0
` Median Difference: JZP-Placebo
`-15.24
` (95% CI)
`(-28.68, -1.80)
` Xyrem Only
`
` N
`22
` Baseline
`1.04
` Change
`0.00
` Median Difference: JZP-Placebo
`-1.75
` (95% CI)
`(-3.50, 0.00)
` Xyrem+Other
` N
` Baseline
` Change
` Median Difference: JZP-Placebo
` (95% CI)
`Source: Reviewer’s analysis
`
`Placebo
`N=65
`
`
`28
`0.95
`2.47
`
`
`
`10
`1.38
`6.29
`
`
`
`19
`1.00
`1.12
`
`
`
` 5
`
` SUMMARY AND CONCLUSIONS
`
`
`
`5.1 Statistical Issues
`
`No notable statistical issues were identified.
`
`
`5.2 Collective Evidence
`
`Collective evidence is not evaluated since this is a single study application.
`
`
`
`
`Reference ID: 4629746
`
`16
`
` 8
`
`
`1.06
`3.47
`
` 6
`
`
`13.50
`0.29
`-5.98
`(-13.13, 1.17)
`
`

`

`5.3 Conclusions and Recommendations
`
`Study 15-006 has provided sufficient evidence that JZP-258 is effective as compared with
`placebo in reducing the number of cataplexy attacks and daytime sleepiness, regardless of
`patient’s previous treatment for cataplexy attacks.
`
`
`
`
`Reference ID: 4629746
`
`17
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record