CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`212690Orig1s000
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`CLINICAL REVIEW(S)
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`Review and Evaluation of Clinical Data
`
`
`212690 (0001)
`NDA (Serial Number)
`Jazz Pharmaceuticals, Inc.
`Sponsor:
`JZP-258*
`Drug:
`Narcolepsy
`Proposed Indication:
`New Drug Application
`Material Submitted:
`1/21/20
`Correspondence Date:
`1/21/20
`Date Received By Reviewer:
`7/21/20
`Date Review Completed
`Ranjit B. Mani, M.D.
`Reviewer:
`*The original full name for this product is JZP-258 (calcium oxybate, potassium
`oxybate, magnesium oxybate, sodium oxybate), oral solution, 0.5 g/mL. Further,
`the brand name XYWAV (Xywav) has been assigned this product.
`
`TABLE OF CONTENTS
`
`
`
`Executive Summary ...................................................................................................2
`1. Background .........................................................................................................7
`2. Contents Of Submission ....................................................................................8
`3. Contents Of Review............................................................................................9
`4. Proposed Indication For JZP-258 ....................................................................10
`5. History Of Clinical Development Of JZP-258..................................................10
`6. Chemistry And Related Items ..........................................................................11
`7. Overview Of Clinical Studies Of JZP-258 .......................................................11
`8. Outline Of Main Clinical Efficacy Study (Study 15-006) .................................12
`9. 120-Day Safety Update ....................................................................................52
`10. Additional Clinical Studies Of JZP-258 .........................................................52
`11. Additional Safety Data Supporting Current Application ...............................64
`12. Review Of Proposed Prescribing Information And Related Documents ....64
`13. Risk Evaluation And Mitigation Strategy (REMS) ........................................65
`14. Summary Of Statistical Review.....................................................................66
`15. Summary Of Nonclinical Review...................................................................66
`16. Summary Of Clinical Pharmacology Review................................................67
`17. Summary Of Quality Assessment (Chemistry) Review ...............................67
`18. Summary Of Office Of Surveillance And Epidemiology Reviews ...............68
`19. Patient Labeling Review ................................................................................68
`
`Reference ID: 4642941
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
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`Page 2 of 72
`7/21/20
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`20. Summary Of Office Of Prescription Drug Promotion (OPDP) Reviews......69
`21. Controlled Substances Staff Review ............................................................69
`22. Pediatric Labeling Review .............................................................................70
`23. Financial Disclosure Information ...................................................................70
`24. Site Inspection Report ...................................................................................71
`25. Pediatric Waiver .............................................................................................71
`26. Overall Conclusion.........................................................................................72
`27. Recommendation...........................................................................................72
`
`
`
`
`Executive Summary
`
`Recommendation
`I recommend that JZP-258 be approved for the treatment of cataplexy and
`excessive daytime sleepiness in patients 7 years of age and older with
`narcolepsy.
`
`Proposed Indications
`This New Drug Application (NDA) seeks the approval of JZP-258 for the
`treatment of cataplexy and excessive daytime sleepiness in patients 7 years of
`age and older with narcolepsy.
`
`Background To Application
`JZP-258 is an aqueous oral solution of calcium oxybate, potassium oxybate,
`magnesium oxybate, and sodium oxybate, 0.5 g/mL (total salt concentration),
`equivalent to 0.413 g/mL of oxybate, the active moiety. JZP-258 has been
`developed as a lower-sodium alternative to Xyrem® (sodium oxybate oral solution
`[500 mg/mL]), which is notable for its high sodium content.
`
`Xyrem® is currently approved for the treatment of cataplexy or excessive daytime
`sleepiness in patients 7 years or older with narcolepsy. Xyrem® is available only
`through a Risk Evaluation and Mitigation Strategy (REMS).
`
`The proposed proprietary name for JZP-258 is XYWAV (Xywav).
`
`Clinical Studies Of JZP-258
`
`
`
`• A main clinical efficacy and safety study (Study 15-006).
`
`Reference ID: 4642941
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
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`Page 3 of 72
`7/21/20
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`• Two clinical pharmacology studies (Studies 13-010 and JZP258-010)
`
`• A study investigating the taste of JZP-258 (Study 15-00#
`
`
`All clinical studies of JZP-258 have been conducted in adults.
`
`Summary of Main Clinical Study Supporting This Application
`Study 15-006 is the main clinical study supporting this NDA. Key aspects of this
`study are summarized below.
`
`Study Design
`Protocol 15-006 had the following main features:
`
`
`• The primary objective of the study was to evaluate the efficacy of JZP-258
`in the treatment of cataplexy in patients with narcolepsy. A key secondary
`objective was to evaluate the efficacy of JZP-258 in the treatment of
`excessive daytime sleepiness in patients with narcolepsy.
`
`• This was a double-blind, placebo-controlled, randomized withdrawal
`multicenter study of the efficacy and safety of JZP-258. Patients enrolled
`in the study included those whose prior treatment status was in any of the
`following categories:
`
`1. Treatment with a stable dose of Xyrem® alone for at least 2 months prior
`to screening.
`2. Treatment with a stable dose of Xyrem® and an unapproved anti-
`cataplectic for at least 2 months prior to screening.
`3. Treatment with an unapproved anti-cataplectic, but no treatment with
`Xyrem®.
`4. No prior treatment with Xyrem® or an unapproved anti-cataplectic.
`
`• The study consisted of the following consecutive periods: screening; open-
`label titration and treatment optimization (of variable duration up to a
`maximum of 12 weeks, depending on prior treatment status); open-label
`stable dose treatment (2 weeks); double-blind randomized withdrawal (2
`weeks); and safety follow-up (2 weeks). All study patients (i.e., patients in
`all 4 entry categories) were to be titrated (during the variable-duration
`open-label titration period) to a dose of JZP-258 that was deemed both
`effective and tolerable and was maintained for at least 2 weeks prior to
`entering the two-week open-label stable-dose period.
`
`• A total of about 185 patients were planned to be enrolled in the study, of
`whom about 130 patients were expected to enter the double-blind
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`Reference ID: 4642941
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`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
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`Page 4 of 72
`7/21/20
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`withdrawal period during which they were to be randomly assigned 1:1 to
`either continuing the same dose of JZP-258 taken during the stable dose
`period or to placebo.
`
`• The main inclusion criteria for this study were as follows: men and women,
`aged 18 to 70 years; a primary diagnosis of narcolepsy with cataplexy that
`met the ICSD–3 criteria or DSM-5 criteria; a history of having at least 14
`cataplexy attacks in a typical two-week period and clinically significant
`symptoms of excessive daytime sleepiness prior to any narcolepsy
`treatment; treatment status prior to study entry consisting of one of the
`aforementioned 4 categories; if currently treated with Xyrem, must have
`had documented improvement documented clinical improvement of
`cataplexy and excessive daytime sleepiness; and if treated with a
`stimulant for narcolepsy must have been at an unchanged dose for at
`least 2 months prior to dosing or must not have been treated at all with a
`stimulant.
`
`• The primary efficacy parameter was the change in weekly number of
`cataplexy attacks from the 2-week stable-dose period to the 2-week
`double-blind treatment period. The key secondary efficacy parameter was
`the change in Epworth Sleepiness Scale score from the end of the 2-week
`stable-dose period to the end of the 2-week double-blind randomized-
`withdrawal treatment period. A number of other efficacy endpoints were
`also under evaluation in this study, including the Patient Global Impression
`of Change for narcolepsy overall; the Clinical Global Impression of
`Change for narcolepsy overall; the change in quality of life based on the
`Short Form-36 score; and EuroQol 5 Dimensions Self-Report
`Questionnaire.
`
`• Safety measures were to include adverse events, vital signs, weight,
`physical examinations, 12-lead electrocardiograms, safety laboratory tests
`(hematology, clinical chemistry, and urinalysis), and the Columbia-Suicide
`Severity Rating Scale (for assessing suicidality).
`
`• The final analysis of the primary efficacy parameter and key secondary
`efficacy parameters was to employ a fixed sequential testing strategy in
`which the initial step was to involve a comparison of JZP-258 with placebo
`for the primary efficacy parameter; if the initial comparison was statistically
`significant (currently p ≤ 0.05), the treatment groups would then be
`compared on the key secondary efficacy parameter at the same level of
`statistical significance (currently p ≤ 0.05). An analysis of covariance
`model was to be used at both steps.
`
`• The main study was to be followed by an open-label extension study
`(phase) lasting 24 weeks.
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`Reference ID: 4642941
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`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
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`Page 5 of 72
`7/21/20
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`Study Results
`Study 15-006 was conducted in a manner consistent with the study protocol.
`
`201 patients were enrolled in the study. They consisted of: 52 patients who were
`receiving Xyrem only; 23 patients were receiving a combination of Xyrem and
`another (unapproved) anti-cataplectic drug; 36 patients were on a non-Xyrem
`(unapproved) anti-cataplectic drug; and 90 patients were drug-naïve at study
`entry. All 201 patients entered the main study in the optimized treatment and
`titration period (12 weeks). 155 patients completed that period, of whom 149
`patients entered the stable-dose period (2 weeks). 144 out of 149 patients
`completed the stable-dose period.
`
`136 out of 144 patients who completed the stable-dose period were then
`randomized, entering the randomized, double-blind, placebo-controlled,
`withdrawal period (2 weeks). At the beginning of that period, 69 patients were
`randomized to JZP-258 and 67 patients were randomized to placebo; all 69
`patients randomized to JZP-258 and all 59 patients randomized to placebo
`completed the study.
`
`The primary efficacy analysis (based on an analysis of covariance) indicated that
`the mean change from baseline over the two-week randomized withdrawal period
`in the weekly number of cataplexy attacks was 11.46 for the placebo group and
`0.12 for the group that continued to take JZP-258 (this change was an increase
`in cataplexy frequency). This difference was statistically significant (p < 0.0001).
`Statistically significant treatment differences favoring JZP-258 over placebo were
`seen on the key secondary efficacy parameter analyzed in the prespecified
`sequence: the change from baseline in modified Epworth Sleepiness Scale score
`was 3.0 in the placebo group and 0.0 in the group that continued to take JZP-258
`(p < 0.0001).
`
`74 patients then entered the open-label extension study; 67 patients completed
`that part of the study.
`
`The adverse event profile of JZP-258 as seen in this study was not substantially
`different from that seen with Xyrem. The other safety outcomes did not reveal
`any data of concern.
`
`Additional Clinical Studies Of JZP-258
`The additional clinical studies conducted with JZP-258 included:
`
`
`• Two clinical pharmacology studies.
`
` Study 13-010, a randomized, open-label cross-over study in healthy
`subjects, primarily intended to compare the relative bioavailability
`
`
`
`Reference ID: 4642941
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
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`Page 6 of 72
`7/21/20
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`
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`and bioequivalence of JZP-258 with Xyrem under fasting and fed
`conditions.
`
` Study JZP258-101, a randomized open-label crossover study
`intended to compare the relative bioavailability and bioequivalence
`of JZP-258 with Xyrem under fasting conditions.
`
`• A randomized, double-blind, placebo-controlled crossover study in healthy
`subjects evaluating the taste of JZP-258 (Study 15-003)
`
`
`The safety profile of JZP-258, as seen in this study, was not substantially
`different from that seen with sodium oxybate alone (i.e., with Xyrem®).
`
`Pharmacokinetic and other data from the first two of the above studies are
`summarized later in this review; importantly, neither Study 13-010 nor Study
`JZP258-101 provided evidence that JZP-258 is bioequivalent to Xyrem.
`
`Proposed Labeling And Risk Evaluation And Mitigation Strategy (REMS)
`This subject is addressed later in the body of this review.
`
`Conclusion
`Substantial evidence of the efficacy of JZP-258 for the treatment of cataplexy
`and excessive daytime sleepiness in narcolepsy is provided by single efficacy
`Study 15-006, with confirmatory evidence coming from the prior finding of
`efficacy of Xyrem (sodium oxybate, i.e., containing the same active moiety) for
`the same indication as that proposed for JZP-258.
`
`The safety profile of JZP-258 is acceptable, and not substantially different from
`that seen with Xyrem.
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`Reference ID: 4642941
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`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
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`Page 7 of 72
`7/21/20
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`
`1. Background
`This New Drug Application (NDA) seeks the approval of JZP-258 for the
`treatment of cataplexy and excessive daytime sleepiness in patients 7 years of
`age and older with narcolepsy.
`
`This New Drug Application has been submitted under the Section 505(b)(1)
`pathway.
`
`The full name for this product, as stated in the cover letter for this submission, is
`as follows: JZP-258 (calcium oxybate, potassium oxybate, magnesium oxybate,
`sodium oxybate), oral solution, 0.5 g/mL. The proposed trade name for this
`product is XYWAV™, which is also referred to as “”Xywav” in this review.
`
`JZP-258 is described in the cover letter to this submission as “an aqueous oral
`solution of calcium oxybate, potassium oxybate, magnesium oxybate, and
`sodium oxybate, 0.5 g/mL, equivalent to 0.413 g/mL of oxybate, the active
`moiety.”
`
`JZP-258 has been developed as a lower-sodium alternative to Xyrem (sodium
`oxybate oral solution [500 mg/mL]; see below), which is notable for its high
`sodium content. Sodium oxybate is another name for the sodium salt of gamma
`hydroxybutyrate.
`
`The sodium content of the maximum total nightly dose of Xyrem® is 9 grams,
`which has a sodium content of 1638 mg. The WARNINGS AND PRECAUTIONS
`section of the current product label for Xyrem® states that the high salt content of
`that product should be considered in patients sensitive to a high salt intake (such
`as those with heart failure, hypertension, or renal impairment). On the other
`hand, the sodium content of the maximum dose of JZP-258 is 131 mg.
`
`Xyrem (sodium oxybate oral solution [500 mg/mL]) is currently approved in this
`country for the treatment of cataplexy and excessive daytime in narcolepsy.
`Xyrem was originally approved by the Agency on July 17, 2002, for the treatment
`of cataplexy in narcolepsy, under NDA 21196. A supplemental NDA (an efficacy
`supplement; S-005) proposing an expansion of the originally approved claim was
`approved on November 18, 2005; the approved expanded indication was (and
`still is) as follows: “The treatment of excessive daytime sleepiness and cataplexy
`in patients with narcolepsy.” Xyrem was originally approved under the Subpart H
`(21 CFR 314.520) regulations, which have remained applicable to this product.
`Xyrem was originally approved for marketing under a restricted distribution
`program. A formal Risk Evaluation and Mitigation Strategy (REMS) for Xyrem
`was approved on February 27, 2015. Most recently, the Agency expanded the
`approved use of Xyrem to the treatment of cataplexy or excessive daytime
`sleepiness in pediatric patients 7 years of age and older on October 26, 2018.
`
`Reference ID: 4642941
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
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`Page 8 of 72
`7/21/20
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`Xyrem has been designated as a Schedule III controlled substance under the
`Federal Controlled Substances Act. The sponsor has proposed that in
`accordance with 65 FR 13235 and 21 CFR 1308.13 Schedule III (c) (6), JZP-258
`should also be placed into Schedule III upon Agency approval of that product.
`
`This NDA for JZP-258 refers to NDA 21196 for Xyrem, for which Jazz
`Pharmaceuticals is also the sponsor and license holder; a Letter of Authorization
`from Jazz Pharmaceuticals, permitting the Agency to reference NDA 21196 for
`Xyrem accompanies the current application.
`
`The submission of this application was preceded by the submission (under IND
`49641, Serial Number 351), on October 21, 2019, of a notification of the
`sponsor’s intention to redeem a priority review voucher (PRV) (Rare Pediatric
`Disease PRV BLA 125610). That voucher, which was granted at the time of
`approval of Biologics Licensing Application 12561, was purchased from Spark
`Therapeutics. This application was therefore granted Priority Review status.
`
`Oxybate (gamma-hydroxybutyrate) is the active moiety in JZP-258 and in
`Xyrem®. Oxybate has been granted Orphan Drug Designation (#94-858) for the
`treatment of narcolepsy by the Agency on November 7, 1994.
`
`In this review, the names “JZP-258” and “Xywav” have been used
`interchangeably.
`
`Please note that this single review is intended to encompass all the
`following: primary clinical review; and team leader and cross-disciplinary
`team leader summary.
`
`2. Contents Of Submission
`This NDA submission has two main components.
`
`
`• The original sNDA submission of January 21, 2020, which has been
`provided in standard electronic Common Technical Document format. This
`component has five main sections, enumerated and headed as follows:
`
`Module 1: Regional.
`Module 2: Common Technical Document summaries.
`Module 3. Quality.
`Module 4. Nonclinical study reports.
`Module 5. Clinical study reports.
`
`• A 120-Day Clinical Safety Update submitted on April 16, 2020, which has
`also been provided in standard electronic Common Technical Document
`
`
`
`
`
`Reference ID: 4642941
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
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`Page 9 of 72
`7/21/20
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`format. This component thus has three main sections, enumerated and
`headed as follows:
`
`
`
`Module 1: Regional.
`Module 5. Clinical study reports.
`
`
`Since the original submission of this sNDA, there have a number of additional
`communications such as, but not limited to, information requests and responses
`to those requests from the sponsor.
`
`3. Contents Of Review
`The contents of this submission have been reviewed under the following primary
`headings and in the same order as below.
`
`
`• History of clinical development of JZP-258.
`
`• Chemistry and related items.
`
`• Overview of clinical studies of JZP-258.
`
`• Outline of main clinical efficacy study of JZP-258 (15-006).
`
`• 120-Day Safety Update.
`
`• Additional clinical studies of JZP-258.
`
`• Additional safety data supporting current application.
`
`• Review of proposed Prescribing Information and related documents.
`
`• Risk Evaluation and Mitigation Strategy (REMS).
`
`• Summary of statistical review.
`
`• Summary of nonclinical review.
`
`• Summary of clinical pharmacology review.
`
`• Summary of quality assessment review.
`
`• Summary of Office of Surveillance and Epidemiology reviews.
`
`• Patient labeling review.
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`Reference ID: 4642941
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`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
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`Page 10 of 72
`7/21/20
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`• Summary of Office of Prescription Drug Promotion reviews.
`
`• Controlled Substances Staff review.
`
`• Pediatric labeling review.
`
`• Financial disclosure information.
`
`• Site inspection report.
`
`• Pediatric waiver.
`
`• Overall conclusion.
`
`• Recommendation.
`
`• An End-of-Phase 2/Pre-Phase 3 meeting for which the preliminary
`response document issued by the Agency on September 18, 2015,
`together with additional clarifications provided to the sponsor, was
`considered to be sufficient.
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`4. Proposed Indication For JZP-258
`The proposed indication for JZP-258 is the treatment of cataplexy and excessive
`daytime sleepiness in patients 7 years and older with narcolepsy.
`
`The above proposed indication is the same as that for which Xyrem is currently
`approved.
`
`5. History Of Clinical Development Of JZP-258
`JZP-258 has been developed under IND 49641, the same IND under which
`Xyrem was developed for the treatment of narcolepsy.
`
`The development of JZP-258 for the treatment of narcolepsy was first discussed
`with the Agency at a Type C face-to-face meeting on December 2013.
`Subsequently, there have been a number of further communications with the
`sponsor regarding this development program. These included, but were not
`limited to, the following:
`
`
`• A Pre-NDA meeting held on October 2, 2019.
`
`
`Please see the contents of the above communications regarding the
`development plan for JZP-258 for further details.
`
`Reference ID: 4642941
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
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`Page 11 of 72
`7/21/20
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`
`6. Chemistry And Related Items
`JZP-258 is an aqueous solution of calcium oxybate, potassium oxybate,
`magnesium oxybate, and sodium oxybate. This solution is intended for oral
`administration.
`
`As per the sponsor, the content of each of above salts in the JZP-258 oral
`solution is as follows.
`
`
`Content (per mL of JZP-258 oral solution)
`0.234 grams
`0.130 grams
`0.096 grams
`0.040 grams
`
`Salt
`Calcium oxybate
`Potassium oxybate
`Magnesium oxybate
`Sodium oxybate
`
`
`The pharmacologically-active moiety in both JZP-258 and Xyrem is oxybate (4-
`hydroxybutanoate or gamma-hydroxybutyrate [GHB]); GHB is, in turn, an
`endogenous compound and a metabolite of gamma-aminobutyric acid. JZP-258
`is thus NOT designated as a New Molecular Entity.
`
`According to the sponsor, the oral solution formulations of both JZP-258 and
`Xyrem contain the same concentration of active ingredient (0.5 g/mL) and the
`same concentration of active moiety, i.e., oxybate (0.413 g/mL).
`
`The mechanism of action of oxybate in the treatment of narcolepsy is unknown.
`The current submission states the following: “It is hypothesized that the
`therapeutic effects of Xyrem on cataplexy and EDS are mediated through
`GABAB actions during sleep at noradrenergic and dopaminergic neurons, as well
`as at thalamocortical neurons.” That statement is consistent with the text of the
`current Prescribing Information for Xyrem.
`
`As with Xyrem, the total nightly dose of JZP-258 is to be administered in two
`equal divided doses 2.5 to 4 hours apart, with an effective and tolerable dose
`being reached by titration. The recommended starting dose, titration regimen,
`and maximum total nightly dosage in children are to be based on body weight.
`
`7. Overview Of Clinical Studies Of JZP-258
`The following clinical studies of JZP-258 have been conducted.
`
`
`• Two clinical pharmacology studies.
`
` Study 13-010, a randomized, open-label cross-over study in healthy
`subjects, primarily intended to compare the relative bioavailability and
`bioequivalence of JZP-258 with Xyrem under fasting and fed conditions.
`
`
`
`
`
`Reference ID: 4642941
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
`
`Page 12 of 72
`7/21/20
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` Study JZP258-101, a randomized open-label crossover study intended to
`compare the relative bioavailability and bioequivalence of JZP-258 with
`Xyrem under fasting conditions.
`
`• A clinical efficacy and safety study.
`
`Study 15-006, a double-blind, placebo-controlled, randomized-withdrawal study
`in patients with narcolepsy.
`
`• A study evaluating the taste of JZP-258.
`
`
`
`
`
`
`
`
`
`Study 15-003, a randomized, double-blind, placebo-controlled crossover study in
`healthy subjects.
`
`
`Further details of these studies are in later sections of this review.
`
`An efficacy and safety study of JZP-258 (i.e., Study 15-006) was required by
`the Agency, as bioequivalence could not be established between JZP-258
`and Xyrem® for Cmax of oxybate in either Study 13-010 or Study JZP258-101
`under fasting conditions.
`
`8. Outline Of Main Clinical Efficacy Study (Study 15-006)
`This study was conducted in the following countries: Belgium, Croatia, Czech
`Republic, Finland, France, Germany, Holland, Poland, Spain, Switzerland, the
`United Kingdom, and the United States.
`
`8.1 Outline Of Study Protocol
`The sponsor conducted a single clinical efficacy study of JZP-258 after
`bioequivalence between JZP-258 and Xyrem could not be demonstrated on the
`Cmax of oxybate.
`
`The key elements of the final protocol for that efficacy study are summarized
`below. The version of Protocol 15-006 summarized below is that contained in
`Amendment #5, dated May 15, 2019.
`
`8.1.1 Title
`A Double-Blind, Placebo-Controlled, Randomized-Withdrawal Multicenter Study
`Of The Efficacy And Safety Of JZP-258 In Subjects With Narcolepsy With
`Cataplexy
`
`
`Reference ID: 4642941
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
`
`Page 13 of 72
`7/21/20
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`8.1.2 Objectives
`8.1.2.1 Primary Objective
`To evaluate the efficacy of JZP-258 in the treatment of cataplexy in subjects with
`narcolepsy.
`
`8.1.2.2 Key Secondary Objective
`To evaluate the efficacy of JZP-258 in the treatment of excessive daytime
`sleepiness in subjects with narcolepsy.
`
`8.1.2.3 Secondary Objective
`To evaluate the safety of JZP-258 in the treatment of subjects with narcolepsy.
`
`8.1.2.4 Exploratory Objective
`To characterize the conversion from other anti-cataplectic treatment regimens to
`JZP-258.
`
`8.1.3 Design, Dose, Sample Size, And Duration
`This (i.e., the main study) was to be a double-blind, placebo-controlled,
`randomized- withdrawal multicenter study of the efficacy and safety of JZP-258.
`
`Those enrolled in the study were to include those whose prior treatment status is
`in any of the following categories:
`
`
`• Treatment with stable dose of Xyrem alone (≤ 9 g/night) for at least 2 months
`prior to screening (Pre-Randomization Group 1).
`
`• Treatment with a stable dose of Xyrem (≤ 9 g/night) and an unapproved anti-
`cataplectic for at least 2 months prior to screening (Pre-Randomization Group 2).
`
`• Treatment with an unapproved anti-cataplectic, without Xyrem (Pre-
`Randomization Group 3).
`
`• No prior treatment with Xyrem or an unapproved anti-cataplectic (Pre-
`Randomization Group 4).
`
`
`All study patients (i.e., patients in all 4 entry categories above) were to eventually
`be titrated to a dose of JZP-258 that is deemed both effective and tolerable and
`is maintained for at least 2 weeks prior to entering the two-week open-label
`stable-dose period outlined in the schematic below.
`
`
`
`
`
`
`
`
`Reference ID: 4642941
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
`
`Page 14 of 72
`7/21/20
`
`
`Further details of the open-label titration period for each entry category are as
`follows.
`
`
`• Patients (Pre-Randomization Group 1) receiving only a stable dose of Xyrem at study
`entry were to be switched to JZP-258 on a gram for gram (total nightly dose) basis, and
`were to remain on that dose of JZP-258 for a minimum of 2 weeks. If necessary, that
`dose of JZP-258 was to be further titrated over an additional 8 weeks. Subjects were to
`be maintained on an unchanged, tolerable, and effective dose of JZP-258 for at least 2
`weeks prior to entering the stable dose period.
`
`
`
`• Patients (Pre-Randomization Group 2) receiving a stable dose of Xyrem at study entry
`together with an unapproved anti-cataplectic medication were to first be switched to JZP-
`258 on a gram for gram (total nightly dose) basis, and were to remain on that dose of
`JZP-258 for a minimum of 2 weeks. They were then to be tapered off the unapproved
`anti-cataplectic medication over a minimum of 2 weeks, and for up to 8 weeks. If
`necessary, the dose of JZP-258 could be further titrated to a stable, tolerable, and
`effective dose over that 8-week period. Subjects were to be maintained on an
`unchanged, tolerable, and effective dose of JZP-258 for at least 2 weeks prior to entering
`the stable dose period.
`
`• Patients (Pre-Randomization Group 3) receiving only an unapproved anti-cataplectic (and
`no Xyrem) at entry were to be first be titrated to a tolerable dose of JZP-258 over a
`minimum of 2 weeks at the start of that period. The dose of unapproved anti-cataplectic
`medication was then to be tapered off over a further 2 to 8 weeks. Next, if necessary, the
`dose of JZP-258 could be further titrated over a period of up to 8 weeks. Subjects were to
`be maintained on an unchanged, tolerable, and effective dose of JZP-258 for at least 2
`weeks prior to entering the stable dose period.
`
`
`
`
`
`
`
`Reference ID: 4642941
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
`
`Page 15 of 72
`7/21/20
`
`• Patients (Pre-Randomization Group 4) not receiving any anti-cataplectic medication at
`entry were to receive JZP-258 over a minimum of 2 weeks and up to 8 weeks to achieve
`a stable, tolerable, and effective dose during that period. Subjects were to be maintained
`on an unchanged, tolerable, and effective dose of JZP-258 for at least 2 weeks prior to
`entering the stable dose period.
`
`
`The open-label stable-dose period of 2 weeks was to be followed by a
`randomized withdrawal period also lasting 2 weeks: during that period, patients
`were to be randomized 1:1 to either continue to take the same dose of JZP-258
`or to receive placebo.
`
` A
`
` safety follow-up period of 2 weeks was to follow.
`
`
`The main study was to be followed by an open-label extension study (phase)
`lasting 24 weeks. Patients could enter the open-label phase of the study in two
`categories, as further described immediately below.
`
`
`• Rollover subjects: those who enter the open-label extension study directly
`from the main study, with Visit 16 being both the last day of the main study
`and first day of the open-label extension study.
`
`
`
`• Re-entry subjects: those enter the open-label extension study sometime
`after completion of the main study.
`
`
`The schematic for the open-label phase of the study is below.
`
`
`
`
`
`
`Reference ID: 4642941
`
`
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 212690 (0001), JZP-258*, Jazz Pharmaceuticals, Inc.
`
`
`
`Page 16 of 72
`7/21/20
`
`About 185 subjects were to be enrolled in the study. It was hoped that as a
`result, 130 patients (65 patients per group) would enter the double-blind
`randomized withdrawal period.
`
`8.1.4 Key Inclusion Criteria (For Main Study)
`• Male or female. Age 18 to 70 years.
`
` •
`
` •
`
` •
`
`
`
`
`
` •
`
` Primary diagnosis of narcolepsy with cataplexy that meets the International
`Classification of Sleep Disorders (ICSD) – 3 criteria or DSM-5 criteria.
`
` History of having at least 14 cataplexy attacks in a typical two-week period
`and clinically significant symptoms of excessive daytime sleepiness prior to
`any narcolepsy treatment.
`
` Treatment status prior to study entry consisting of one the following:
`
` Taking Xyrem® alone at unchanged doses (no greater than 9 g/night) for the
`treatment of cataplexy in narcolepsy for at least 2 months prior to