CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`212690Orig1s000
`
`CLINICAL PHARMACOLOGY
`REVIEW(S)
`
`
`
`
`
`
`

`

`Office of Clinical Pharmacology
`Integrated Clinical Pharmacology Review
`
`NDA Number
`Link to EDR
`Submission Date
`Submission Type
`Brand Name
`Generic Name
`Dosage Form and Strength
`Proposed Indication
`
`Proposed Dose/regimen
`
`Applicant
`Associated IND
`OCP Review Team
`
`OCP Final Signatory
`
`212690 Sequence Number 0001
`\\CDSESUB1\evsprod\NDA212690\212690.enx
`01/21/2020
`505(b)(1) Application – Priority review
`XYWAV™
`JZP-258
`Solution (0.5 g/ml), for oral administration
`Treatment of cataplexy or excessive daytime sleepiness
`(EDS) in patients 7 years of age and older with narcolepsy
`Adults:
`Initiate dosage at 4.5 g per night orally divided into two
`equal doses taken 2.5 to 4 hours apart
`Titrate to effect in increments of 1.5 g per night at
`
`weekly intervals (0.75 g at bedtime and 0.75 g
`taken 2.5 to 4 hours later).
` Recommended dosage range: 6 to 9 g per night
`orally.
`Pediatric patients (7 years of age and older)
`The recommended starting dosage, titration regimen and
`maximum total nightly dosage are based on body weight
`Jazz Pharmaceuticals Ireland Limited.
`49641
`Gopichand Gottipati Ph.D., Atul Bhattaram, Ph.D.,
`Sreedharan Sabarinath, Ph.D.
`Mehul Mehta, Ph.D.
`
`Reference ID: 4634681
`
`

`

`Table of Contents
`
`1
`
`2
`
`Table of Contents.................................................................................................................2
`List of Abbreviations ...........................................................................................................3
`Executive Summary.............................................................................................................4
`1.1
`Recommendations....................................................................................................4
`1.2
`Post-marketing Requirements..................................................................................7
`Summary of Clinical Pharmacology Assessment................................................................7
`2.1
`The Pharmacology and Clinical Pharmacokinetics .................................................7
`2.2
`Dosing and Therapeutic Individualization...............................................................9
`2.2.1
`General dosing.........................................................................................9
`2.2.2
`Therapeutic individualization..................................................................9
`2.2.3
`Outstanding Issues...................................................................................9
`2.2.4
`Summary of Labeling Recommendations ...............................................9
`3 Comprehensive Clinical Pharmacology Review ...............................................................10
`3.1
`Overview of the Product and Regulatory Background ..........................................10
`3.2
`General Pharmacological and Pharmacokinetic Characteristics............................11
`3.3
`Clinical Pharmacology Questions..........................................................................12
`3.3.1
`To what extent does the available clinical pharmacology information
`provide pivotal or supportive evidence of effectiveness? .....................12
`Is the proposed dosing regimen appropriate for the general population
`for which the indication is being sought?..............................................13
`Is an alternative dosing regimen and management strategy required
`for subpopulations based on intrinsic/extrinsic factors? .......................14
`Are there clinically relevant food-drug or drug-drug interactions and
`what is the appropriate management strategy?......................................14
`Is the to-be-marketed formulation the same as the clinical trial
`formulation, and if not, are there bioequivalence data to support
`approval of the to-be-marketed formulation?........................................19
`4 APPENDICES ...................................................................................................................20
`4.1
`Summary of Bioanalytical Method Validation ......................................................20
`4.2
`Pharmacometrics Assessment: Population PK Analyses.......................................21
`4.2.1
`Applicant’s Population PK analysis:.....................................................21
`4.2.2
`Applicant’s Exposure-Efficacy Analyses..............................................28
`4.2.3
`Reviewer’s Exposure-Response Analyses: ...........................................34
`
`3.3.2
`
`3.3.3
`
`3.3.4
`
`3.3.5
`
`Reference ID: 4634681
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`2
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`

`

`List of Abbreviations
`
`AE
`AUC
`AUCinf
`AUClast
`CI
`Cmax
`FDA
`LLOQ
`NDA
`PK
`Tmax
`USPI
`
`Adverse event
`Area under the concentration-time curve
`AUC from time 0 to extrapolated to infinity
`AUC from time 0 to last measurable concentration
`Confidence intervals
`Maximum (peak) drug concentration
`Food and drug administration
`Lower limit of quantification
`New Drug Application
`Pharmacokinetics
`Time of maximum (peak) drug concentration
`United States package insert
`
`Reference ID: 4634681
`
`3
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`

`

`Executive Summary
`1
`Jazz Pharmaceuticals Ireland Limited submitted this original 505(b)(1) New Drug Application
`(NDA 212690) seeking approval for XYWAV™ (JZP-258) for the treatment of cataplexy or
`excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. JZP-258
`is a 0.5 g/mL aqueous solution of mixture of calcium, potassium, magnesium, and sodium salts
`of oxybate; equivalent to 0.413 g/mL oxybate. Xyrem® (sodium oxybate) oral solution (also
`marketed by the same applicant) was approved by the Food and Drug Administration (FDA) for
`the treatment of cataplexy in narcolepsy (07/17/2002) and excessive daytime sleepiness
`(11/18/2005) in adults, and subsequently in pediatric patients 7 years and above for both
`indications (10/26/2018).
`The proposed adult JZP-258 dosing recommendations are to initiate JZP-258 at 4.5 g per night
`orally in two equally divided doses taken 2.5 to 4 hours apart, and titrate to effect in increments
`of 1.5 g per night at weekly intervals (0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later), not
`exceeding total nightly dose of 9 g. The proposed JZP-258 pediatric dosing recommendations for
`initiation, titration regimen and maximum total nightly dosage are based on body weight. These
`recommendations are identical to those included in US package insert (USPI) for Xyrem®1.
`The application package includes two relative bioavailability/bioequivalence studies, 13-010 and
`JZP258-101, in healthy subjects comparing JZP-258 with Xyrem® and a phase 3 double-blind,
`placebo-controlled randomized withdrawal study (15-006) in adult patients with narcolepsy. In
`addition, population PK and exposure-response analyses were included in this submission. This
`NDA relies on the approved product Xyrem (also from the same applicant) for dosing
`recommendations for intrinsic and extrinsic factors.
`The primary focus of this review is to evaluate the dosing recommendations for JZP-258 with
`regards to food-intake.
`
`Recommendations
`1.1
`The Office of Clinical Pharmacology (OCP) recommends the approval of JZP-258 for the treatment
`of cataplexy or excessive daytime sleepiness (EDS) in adult and pediatric populations at doses
`listed below.
`
` The first dose of JZP-258 should be
`administered at least 2 hours after meals, just as it is recommended in the USPI for Xyrem.
`Key review issues with specific recommendations and comments are summarized below.
`
`1 USPI for Xyrem accessed at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021196s030lbl.pdf
`
`Reference ID: 4634681
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`

`

`Review Issues
`
`Evidence of
`effectiveness:
`
`General dosing
`instructions:
`
`Recommendations and Comments
`randomized-withdrawal,
`One double-blind, placebo-controlled,
`multicenter, phase 3 study (15-006) in patients with narcolepsy
`provided the primary evidence of effectiveness.
`In this study patients were titrated to an optimal dose (administered as
`two equally divided nightly doses) of
`JZP-258 based on
`tolerability/efficacy over a 12-week open-label period and continued
`this stable dose for 2 weeks. Subsequently, they were randomized to
`either continue the stable dose or to placebo over a 2 week double-
`blind withdrawal period. Please refer to the clinical and biometrics
`reviews for more information.
`The total nightly dose of JZP-258 is divided into two equal doses,
`
`and the patients should not take the second dose until 2.5 to 4
`hours after the first dose.
`The total nightly dose of JZP-258 is gradually titrated based on
`efficacy and tolerability
`
`
`
`The recommended adult XYWAV dose regimen (g = grams)
`If a Patient’s Total
`Take at Bedtime:
`Take 2.5 to 4
`Nightly Dose Is:
`Hours Later:
`
`4.5 g per night
`6 g per night
`7.5 g per night
`9 g per night
`
`2.25 g
`3 g
`3.75 g
`4.5 g
`
`2.25 g
`3 g
`3.75 g
`4.5 g
`
`The first dose of JZP-258 should be taken at least 2 hours after meals.
`A food-effect study indicated that oxybate PK is impacted by
`concomitant administration of JZP-258 with food. Additionally, the
`patients enrolled in pivotal phase 3 study were instructed to take JZP-
`258 at least 2 hours after meals, which is also consistent with the
`recommendation in USPI for Xyrem. Lastly, reviewer’s independent
`population PK and exposure-efficacy analyses indicated that there
`could be a potential for loss of efficacy by 30-40% in cataplexy
`frequency and 10-20% in Epworth Sleepiness Scale when JZP-258 is
`taken with food.
`
`Reference ID: 4634681
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`

`Summary of Review Issues and OCP Recommendations
`Table 1-1
`Review Issues
`Recommendations and Comments
`Recommended initial XYWAV dosage for patients 7 years of age and older*
`
`Initial Dosage
`
`Take at
`Bedtime:
`
`Patient
`Weight
`
`<20 kg**
`
`Maximum Recommended
`Dosage
`Take at
`Bedtime:
`
`Take 2.5 to 4
`Hours Later:
`
`Maximum Weekly
`Dosage Increase
`Take at
`Take 2.5 to
`Take 2.5 to
`Bedtime:
`4 Hours
`4 Hours
`Later:
`Later:
`There is insufficient information to provide specific dosing recommendations for
`patients who weigh less than 20 kg.
`≤1 g
`≤1 g
`0.5 g
`
`General dosing
`instructions:
`
`0.5 g
`
`3 g
`
`3 g
`
`20 kg to
`<30 kg
`30 kg to
`<45 kg
`4.5 g
`4.5 g
`0.75 g
`0.75 g
`≤2.25 g
`≤2.25 g
`45 kg
`* For patients who sleep more than 8 hours per night, the first dose of XYWAV may be given at bedtime or after an initial period
`of sleep.
`**If XYWAV is used in patients 7 years of age and older who weigh less than 20 kg, a lower starting dosage, lower maximum
`weekly dosage increases, and lower total maximum nightly dosage should be considered.
`Note: Unequal dosages may be required for some patients to achieve optimal treatment.
`
`≤1.5 g
`
`≤1.5 g
`
`0.5 g
`
`0.5 g
`
`3.75 g
`
`3.75 g
`
`Reference ID: 4634681
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`

`

`Review Issues
`Dosing in patient
`subgroups (intrinsic
`and extrinsic factors)
`Bridge between the
`“to-be-marketed”
`and clinical trial
`formulations
`
`Recommendations and Comments
`The dosing in patient subgroups based on intrinsic and extrinsic factors
`are identical to the recommendations provided in USPI for Xyrem.
`Please refer to the USPI of Xyrem for details.
`
`The commercial and clinical trial formulations are the same and
`therefore, no PK bridging studies were required.
`
`Post-marketing Requirements
`
`1.2
`None.
`
`Summary of Clinical Pharmacology Assessment
`2
`The Pharmacology and Clinical Pharmacokinetics
`2.1
`The information listed below is mostly based on the clinical pharmacology information provided
`in the USPI for Xyrem, except for the absorption section, which presents information relevant to
`JZP-258 from the relative bioavailability/food-effect studies.
`Mechanism of Action:
`Oxybate is a CNS depressant. The exact mechanism of action of JZP-258 in the treatment of
`narcolepsy is unknown. JZP-258 is a mixture of calcium oxybate, potassium oxybate, magnesium
`oxybate, and sodium oxybate (gamma hydroxybutyrate). Gamma-Hydroxy Butyrate (GHB)2 is an
`endogenous compound and metabolite of the neurotransmitter GABA. It is hypothesized that
`the therapeutic effects of JZP-258 on cataplexy and excessive daytime sleepiness are mediated
`through GABAB actions during sleep at noradrenergic and dopaminergic neurons, as well as at
`thalamocortical neurons.
`
`2 GHB and oxybate have been used interchangeably in this review
`
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`
`
`Absorption
`Following oral administration of JZP-258 in healthy adults in fasted state, the average
`
`Tmax for GHB was about 1.3 hours.
`Following oral administration of JZP-258, the plasma levels of GHB increased more than
`dose-proportionally, with Cmax increasing approximately 2-fold and AUC increasing
`2.9-fold as the dose was doubled from 2.25 g to 4.5 g. Single doses greater than 4.5 g have
`not been studied.
` Administration with food decreases exposures of GHB. Concomitant administration of
`JZP-258 with a standardized high fat meal resulted in a mean reduction in Cmax and AUC0-
`inf of GHB by 33% and 16% respectively, while mean Tmax was unaffected. Concomitant
`administration of Xyrem with a standardized high fat meal resulted in a mean reduction
`in Cmax and AUC0-inf of GHB by 44% and 19% respectively, and 0.36 hours delay in mean
`Tmax.
`Distribution
`GHB is a hydrophilic compound with an apparent volume of distribution averaging 190 mL/kg to
`384 mL/kg. At GHB concentrations ranging from 3 mcg/mL to 300 mcg/mL, less than 1% is bound
`to plasma proteins.
`Metabolism and Excretion
`Animal studies indicate that metabolism is the major elimination pathway for GHB, producing
`carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-
`oxidation. No active metabolites have been identified.
`The clearance of GHB is almost entirely by biotransformation to carbon dioxide, which is then
`eliminated by expiration. On average, less than 5% of unchanged drug appears in human urine
`within 6 to 8 hours after dosing. Fecal excretion is negligible. GHB has a mean terminal
`elimination half-life of 0.66 hours.
`Specific Populations
` Renal elimination is a minor pathway for GHB clearance. No dose adjustments are
`required based on renal function impairment.
`The recommended starting dosage in patients with hepatic impairment is one-half of the
`original dosage per night administered orally, divided into two doses.
` Dosing in pediatric subjects ≥ 7 years is based on body weight.
`
`
`
`Reference ID: 4634681
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`

`Dosing and Therapeutic Individualization
`2.2
`General dosing
`2.2.1
`The adult dosing recommendations for JZP-258 are consistent with instructions provided to
`patients enrolled in the phase 3 study as noted in Table 1-1 above. The pediatric dosing
`recommendations in patients ≥ 7 years are based on bodyweight such that the exposures match
`the adult exposures and based on extrapolating efficacy of JZP-258 from adults. These pediatric
`dosing recommendations are consistent with those included in USPI for Xyrem.
`
`Therapeutic individualization
`2.2.2
`No clinical studies were conducted by the applicant to inform therapeutic individualization for
`JZP-258. Differences in the salt forms with the equivalent oxybate concentrations are not
`expected to result in changes in the impact of intrinsic/extrinsic factors relative to that following
`oral administration Xyrem®. Please refer to the recommendations included in the USPI for
`Xyrem®3 for additional details.
`
`Outstanding Issues
`
`2.2.3
`None.
`
`Summary of Labeling Recommendations
`2.2.4
`The Office of Clinical Pharmacology review team accepts the labeling concepts proposed by the
`applicant
` The
`review team recommends that the first dose of JZP-258 should be administered at least 2 hours
`after meals. Please refer section 3.3.4 for additional details.
`
`3 USPI for Xyrem accessed at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021196s030lbl.pdf
`
`Reference ID: 4634681
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`

`Comprehensive Clinical Pharmacology Review
`3
`Overview of the Product and Regulatory Background
`3.1
`JZP-258 is a mixed salt formulation consisting of calcium, potassium, magnesium, and sodium
`salts of oxybate; equivalent to 0.413 g/mL oxybate. In late 2013, the applicant discussed their
`plans to pursue development of a low sodium alternative to Xyrem® oral solution (which is also
`a product of the same applicant) with the agency and proposed to conduct a Phase 1 relative
`bioavailability (BA)/bioequivalence (BE) and food effect study (13-010). The Agency agreed to
`waive the requirement to conduct a Phase 3 study to demonstrate safety/efficacy of JZP-258
`contingent upon establishing BE between their product and Xyrem® oral solution.
`In late 2015, at the end-of-phase 2 meeting, the applicant noted that the relative BA/BE study
`13-010 (in which both the products were administered with 240 ml of water) met the BE criteria
`for AUC0-inf but not for Cmax (geometric mean ratio of JZP-258 to Xyrem: 74.2% [90% confidence
`interval: 67.8% – 81.2%]) under fasting conditions. The applicant also noted a similar outcome in
`another relative BA/BE study JZP258-101 (in which both the products were administered with 60
`ml of water, which is the recommended volume per the package insert for Xyrem®): met the BE
`criteria for AUC0-inf but not for Cmax (geometric mean ratio of JZP-258 to Xyrem: 77.0% [90%
`confidence interval 71.9% - 82.6%]) under fasting conditions. At this meeting, there was a
`discussion between the applicant and the agency on the need for a phase 3 study, and an
`agreement was reached that no additional clinical pharmacology, or safety data are needed.
`In late 2019, at the pre-NDA meeting, the agency agreed to the applicant’s proposal to use data
`from relative BA/BE study 13-010 (which include dose levels 2.25 g and 4.5) and population PK
`analyses to describe the dose-proportionality of JZP-258 in adults and pediatric subjects.
`Furthermore, the agency agreed that a pediatric efficacy study will be waived if the efficacy
`findings of JZP-258 in adults are similar to those of Xyrem®. The efficacy of JZP-258 can then be
`extrapolated to pediatric population and have the same dosage recommendations as Xyrem® in
`pediatric patients ≥ 7 years.
`
`Reference ID: 4634681
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`

`General Pharmacological and Pharmacokinetic Characteristics
`3.2
`Please refer to the general clinical pharmacology information included in the USPI for Xyrem®4
`for additional details on distribution, metabolism and excretion of GHB.
`
`Table 3-1
`Pharmacology
`
`Summary of Pharmacological and Pharmacokinetic Characteristics
`
`is an endogenous
`[GHB])
`(gamma-hydroxybutyrate
`Mechanism of Action Oxybate
`compound and metabolite of the neurotransmitter gamma-amino
`butyric acid (GABA). GHB is known to act as a Central Nervous System
`(CNS) depressant and is hypothesized to exerts its effects at
`noradrenergic, dopaminergic neurons and thalamocortical neurons,
`mediated through GABAB actions during sleep.
`
`QT prolongation
`
`No QTc studies were conducted
`
`General Information
`
`Healthy volunteers vs.
`patients
`
`Dose proportionality
`
`Accumulation
`
`Absorption
`
`Tmax
`
`Bioavailability
`
`PK data was not collected in the pivotal phase 3 study (JZP-258-101)
`for JZP-258. Oxybate PK is not expected to be different between
`healthy volunteers and patients.
`
`Following oral administration of JZP-258, the plasma levels of GHB
`increased more than dose-proportionally, with Cmax increasing 2-
`fold and AUC increasing 2.9-fold as the dose was doubled from 2.25
`g to 4.5 g.
`
`Minimal accumulation is expected with the recommended dosing
`regimen.
`
`The average time to peak plasma GHB concentrations was about 1.3
`hours
`
`An absolute bioavailability study was not conducted with JZP-258.
`Following oral administration of Xyrem, the absolute bioavailability is
`about 88%. The absolute bioavailability of oxybate is not expected to
`be very different between JZP-258 and Xyrem.
`
`4 USPI for Xyrem accessed at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021196s030lbl.pdf
`
`Reference ID: 4634681
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`

`Food Effect
`
`Both JZP-258 and Xyrem reported a reduction in exposure when
`administered with
`food. When
`JZP-258 was administered
`immediately after a standardized high fat meal, mean oxybate
`exposures Cmax and AUC0-inf decreased by 33%, and 16% respectively
`and no change was noted in the average Tmax. When Xyrem was
`administered immediately after a standardized high fat meal, mean
`oxybate exposures Cmax and AUC0-inf decreased by 44%, and 19%
`respectively and the average Tmax was delayed by 0.36 hours.
`In the phase 3 clinical efficacy/safety study (15-006), the subjects
`were instructed to take the first dose of JZP-258 at least 2 hours after
`meals. This instruction is consistent with the recommendations
`included in the USPI for Xyrem.
`
`3.3
`3.3.1
`
`Clinical Pharmacology Questions
`To what extent does the available clinical pharmacology information
`provide pivotal or supportive evidence of effectiveness?
`The evidence of effectiveness of JZP-258 for the treatment of the treatment of cataplexy or
`excessive daytime sleepiness (EDS) in patients with narcolepsy was demonstrated in one phase
`3 clinical study (15-006).
`Study 15-006 was a double-blind, placebo-controlled, randomized-withdrawal, multicenter study
`(NCT03030599) in adult patients with narcolepsy. It consisted of 2 parts – part 1 consisted of a
`12-week open-label optimized treatment and titration period followed by a 2 week stable dose
`period (SDP) and finally a 2 week double-blind randomized-withdrawal period (DB RWP);
`followed by part 2, an optional 24-week open-label extension period. The study enrolled 201
`subjects, 18 – 70 years of age, with narcolepsy with cataplexy, and a baseline history of at least
`14 cataplexy attacks in a typical two week period prior to any treatment for narcolepsy symptoms.
`Of the 201 subjects, 134 were randomized 1:1, either to continue treatment with JZP-258 or to
`placebo in the 2 week DB RWP. PK data were not collected in this study. The subjects were
`instructed to take the first dose of JZP-258 at least 2 hours after meals. This instruction is
`consistent with the recommendations in the USPI for Xyrem.
`Twice-nightly doses of JZP-258 were administered in 99% (68/69) of patients and one patient
`received JZP-258 thrice-nightly. The total nightly dose of JZP-258 was administered in two equally
`divided doses in 90% (62/69) of patients. Unequal doses were administered in seven patients
`treated with JZP-258.
`The primary efficacy endpoint was the change in frequency of cataplexy attacks from the 2 weeks
`of the SDP to the 2 weeks of the DB RWP. The key secondary endpoint was the change in the
`
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`

`Epworth Sleepiness Scale (ESS) score as a measure of reduction in EDS from the end of the SDP
`to the end of the DB RWP. The results for study 15-006 met the pre-specified statistical criteria
`for both the primary and secondary efficacy endpoints and are summarized in Table 2 below.
`Please refer to statistical review by Drs. Xiaorong Yan and Kun Jin and clinical review by Dr. Ranjit
`Mani for additional details.
`JZP-258 was not studied in a pediatric clinical trial. As noted in Section 3.1 above, the agency
`agreed to extrapolating efficacy/safety from adults to pediatric subjects ≥ 7 years, and that the
`same recommendations in USPI of Xyrem® in the pediatric subjects are recommended for JZP-
`258. This was based on similar efficacy in adults observed for Xywav and Xyrem using same
`dosage and regimen.
`
`Table 2 Mean Number of Weekly Cataplexy Attacks and Epworth Sleepiness Scale (ESS)
`Average Weekly Number of
`ESS SCORE
`Cataplexy Attacks
`
`Placebo
`XYWAV
`Placebo
`(N = 65)
`(N = 69)
`(N = 65)
`Baseline (2 Weeks of the Stable Dose Period)
`
`XYWAV
`(N = 69)
`
`8.9 (16.8)
`7.2 (14.4)
`Mean (SD)
`Change from Baseline (2 Weeks of the Stable
`Dose Period) to the 2 Weeks of the DB RWP
`
`13.6 (5.3)
`12.6 (5.5)
`Change from End of Stable Dose Period
`to End of DB RWP
`
`Mean (SD)
`
`11.5 (24.8)
`
`0.1 (5.8)
`
`3.0 (4.7)
`
`0.0 (2.9)
`
`p-value
`
`<0.0001
`
`< 0.0001
`
`DB RWP = Double-blind Randomized-withdrawal Period; SD = standard deviation
`
`Source: Adapted based on Summary of Clinical Overview.
`
`3.3.2
`
`Is the proposed dosing regimen appropriate for the general population for
`which the indication is being sought?
`The proposed dosage recommendations for initiation, titration and maximum recommended
`daily dosages are acceptable in adult and pediatric populations. The adult regimen is identical to
`those evaluated in their pivotal phase 3 study where they demonstrated efficacy/safety by
`meeting the pre-specified statistical criteria for both primary and secondary efficacy endpoints.
`The review team recommends administering the first dose of JZP-258 at least 2 hours after meals,
`just as studied in phase 3. Please refer to Section 3.3.4 for more information.
`
`Reference ID: 4634681
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`

`The pediatric dosing is based on matching exposures to adult exposures and extrapolating
`efficacy from adults. Additionally, as noted in section 3.3.1, the proposed dosage regimens are
`identical to those listed in the USPI for Xyrem® for both adult and pediatric populations.
`No new major safety concerns were observed in study 15-006 relative to those reported in the
`package insert of Xyrem®. Overall, in the safety database, the most commonly reported AEs in
`part-1 of study 15-006 included headache, nausea, dizziness, decreased appetite, parasomnia,
`diarrhea, hyperhidrosis, anxiety, and vomiting. Please refer to the clinical safety review by Dr.
`Ranjit Mani and for further details. In conclusion, we recommend the approval of the dosage
`regimens for JZP-258 in both adult and pediatric subjects ≥ 7 years.
`
`3.3.3
`
`Is an alternative dosing regimen and management strategy required for
`subpopulations based on intrinsic/extrinsic factors?
`The applicant did not conduct any studies in this current program to evaluate the impact of
`intrinsic/extrinsic factors. Differences in the salt forms with the same equivalent amount of
`oxybate are not expected to result in changes in the impact of intrinsic/extrinsic factors relative
`to
`that
`following oral administration Xyrem®. Therefore
`JZP-258 will have same
`recommendations for intrinsic and extrinsic factors as with Xyrem. Please refer to the
`recommendations included in the USPI for Xyrem®5 for additional details.
`
`3.3.4
`
`Are there clinically relevant food-drug or drug-drug interactions and what
`is the appropriate management strategy?
`Food-Drug Interactions
`Yes. In a food-effect study (JZP258-101), administration of JZP-258 with 60 ml water immediately
`after a high-fat meal resulted in a mean reduction in Cmax and AUC0-inf of GHB by 33% and 16%
`respectively and no change was noted in mean Tmax.
`
`5 USPI for Xyrem accessed at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021196s030lbl.pdf
`
`Reference ID: 4634681
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`14
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`(b) (4)
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`

`

` because of the following considerations:
`The review team disagrees
`1. Both JZP-258 and Xyrem showed reduction in exposure with food.
` the
`results from study JZP258-101 indicate that food-intake impacts the PK of oxybate following
`JZP-258 administration, though the magnitude of this impact of food-intake on oxybate PK
`following JZP-258 dosing was marginally lower compared to that following Xyrem dosing.
`2. The USPI of Xyrem instructs administration of the first dose at least 2 hours after meals. The
`subjects enrolled in the pivotal Phase 3 study 15-006, were instructed to take JZP-258 at
`least 2 hours after meals, that is similar to the recommendation per USPI for Xyrem.
`
`3.
`
`Reference ID: 4634681
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`15
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`4. The reviewer’s analyses (described below in brief and in detail in Section 4.2.3) under the
`‘worst-case’ scenario indicated that the magnitude of the impact of food-intake on potential
`loss of efficacy is larger than the applicant’s analyses.
`The reviewer’s independent analyses suggested that the estimate for potential loss of efficacy in
`TCAT is 30-40% and ESS scores is 10-20% due to decrease in Cmax following first dose of JZP-258
`when taken with food under the worst-case scenario noted above. These estimates are generally
`comparable to the estimates for potential loss of efficacy (20-40% for TCAT and 10-20% for ESS
`score) provided by the applicant under the worst-case scenario in response to information
`request (received 05/21/2020) [Please refer to Appendix 4.2 for additional details].
`
`Briefly, the reviewer noted that the popPK model characterized the observed data reasonably
`and therefore, it is considered acceptable. Next, plasma-concentration profiles based on
`bodyweight and food-intake status following 4.5 g in equally divided doses administered 4 hours
`apart: JZP-258 and Xyrem under fed and fasted conditions respectively. Subsequently, exposure-
`efficacy analyses were conducted using the popPK derived exposures, summarized by Cmax
`following the first dose and primary efficacy endpoints – TCAT and ESS score from parallel-group
`design studies OMC-GHB-02 and/or OMC-SXB-15 (please refer to appendix 4.2 for additional
`considerations regarding study designs and rationale for selecting these studies]. The results for
`reviewer’s analyses are shown below.
`
`Reference ID: 4634681
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`16
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`

`

`Figure 1 Exposure-efficacy analyses conducted by the reviewer to evaluate the impact of
`food-intake on exposures and potential loss of efficacy in primary efficacy endpoints
`
`*Study 2 – OMC-GHB-02; and Study15 - OMC-SXB-15;
`Note: Red vertical line represents Cmax following first dose of 2.25 g of Xyrem in fasted state
`and green vertical line represents Cmax following first dose of 2.25 g of JZP-258 in fed state,
`both derived based on popPK model
`
`Reference ID: 4634681
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`17
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`

`The reviewer noted minor discrepancies with the applicant’s exposure-efficacy analyses (i.e.,
`slope of the relationships) and sent information requests (IR) to verify the applicant’s analyses.
`Based on the responses to IR, the applicant noted that the magnitude of the potential for loss in
`efficacy in cataplexy frequency by 22% and in ESS score by 12%, while the reviewer’s analyses
`indicated that these estimates were 27% and 13% for cataplexy frequency and ESS score
`respectively.
`Though the popPK model was considered reasonable in characterizing the general trends and
`variability in the observed data, there were minor inconsistencies in predicting the Cmax
`following the first dose as noted in tables below. Therefore, the reviewer also estimated the
`potential loss of efficacy in TCAT and ESS scores using the observed data in addition to the popPK
`derived metrics and the review team considered these values in providing the final
`recommendations.
`Table 3 Estimates for potential loss of efficacy in TCAT based on pooled data from studies
`OMC-GHB-02 and OMC-GHB-15
`Cmax following first dose: JZP-258
`Reviewer’s
`fed vs. Xyrem fasted [mcg/ml]
`Analyses
`
`Applicant’s
`Analyses
`
`Study
`
`PopPK model-
`derived
`
`JZP258-101
`
`78.5 vs. 111.6
`
`27%↓
`
`22%↓*
`
`62.3 vs. 120.2
`
`43%↓
`
`37%↓**
`
`* Estimate based on applicant’s response to IR received 05/21/2020; **Estimated by reviewer
`based on applicant’s response to information request.
`
`Table 4 Estimates for potential loss of efficacy in ESS based on data from study OMC-GHB-15
`Cmax following first dose: JZP-258
`Reviewer’s
`Applicant’s
`fed vs. Xyrem fasted [mcg/ml]
`Analyses
`Analyses
`
`Study
`
`PopPK model-
`derived
`
`JZP258-101
`
`78.5 vs. 111.6
`
`13%↓
`
`12%↓*
`
`62.3 vs. 120.2
`
`22%↓
`
`20%↓**
`
`* Estimate based on applicant’s response to IR received 05/21/2020; **Estimated by reviewer
`based on applicant’s response to information request.
`Please refer to section 4.2.3 for further details regarding methods and additional considerations.
`
`Reference ID: 4634681
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`18
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`3.3.5
`
`Is the to-be-marketed formulation the same as the clinical trial formulation,
`and if not, are there bioequivalence data to support approval of the to-be-
`marketed formulation?
`Yes, the dosage form and strength of the commercial to-be-marketed formulation (oral solution)
`is the same as the formulation used by the applicant in their pivotal phase 3 study (15-006).
`
`Reference ID: 4634681
`
`19
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`

`

`APPENDICES
`4
`Summary of Bioanalytical Method Validation
`4.1
`Plasma concentrations of oxybate were determined using a validated liquid chromatography (LC)
`– tandem mass spectrometry (MS/MS) detection method. The linearity range was 0.750 – 192
`μg/mL. The bioanalytical method study report is referenced from Study No. BJAZZ1602P1 and
`the assay performance characteristics for the relative BA/BE study JZP258-101 are summarized
`below:
`
`%CV = percent coefficient of variation