CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`210913Orig1s000
`
`CLINICAL PHARMACOLOGY
`REVIEW(S)
`
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`

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`Office of Clinical Pharmacology Review
`
`NDA Number
`Link to EDR
`Submission Date
`Submission Type
`Product Name
`Dosage Form and Strength
`Proposed Dose/Regimen
`
`Proposed Indication
`Applicant
`OCP Division
`Associated IND
`OCP Review Team
`
`212640
`\\CDSESUB1\evsprod\NDA212640\0001
`1/31/2019
`Original NDA – 505 (b)(2)
`Exservan® (Riluzole)
`Oral soluble film, 50 mg
`50 mg twice daily
`To be taken at least 1 hour before or 2 hours after a meal
`Treatment of Amyotrophic Lateral Sclerosis (ALS)
`Aquestive Therapeutics
`Division of Clinical Pharmacology I
`130939
`Gopichand Gottipati Ph.D., Sreedharan Sabarinath Ph.D.
`
`
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`Reference ID: 4514252Reference ID: 4525554
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`Table of Contents
`
`1.
`2.
`3.
`4.
`5.
`
`Executive Summary ................................................................................................................3
`Recommendation ...................................................................................................................3
`Background and Regulatory History .......................................................................................4
`Summary of Pivotal Relative BA/BE and Food Effect Study....................................................6
`Bioanalytical Method Validation ..........................................................................................15
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`1. Executive Summary
`Aquestive Therapeutics submitted an original New Drug Application (NDA 212640) for
`EXSERVAN® for the treatment of Amyotrophic Lateral Sclerosis (ALS) via 505(b)(2) regulatory
`pathway. The proposed product is 50 mg oral soluble film. The listed drug is riluzole oral tablet
`(RILUTEK®) approved in the US in 1996.
`This application relies on a pivotal relative bioavailability and food effect study (162020)
`conducted in healthy subjects to demonstrate a pharmacokinetic (PK) bridge between the
`proposed product (EXSERVAN® oral soluble film 50 mg) and the listed drug (RILUTEK® oral tablet
`50 mg). In this single-dose study, the proposed product was administered without water and
`listed drug was administered with water, both under fasting conditions. The exposure metrics
`AUC and Cmax met bioequivalence criteria, therefore EXSERVAN® is bioequivalent to RILUTEK®.
`RILUTEK® has a food effect (administration of high fat meal decreased AUC by 20% and Cmax by
`45% respectively), and therefore, it is required to administer RILUTEK® at least one hour before
`or two hours after a meal1. EXSERVAN® also had similar food effect. Administration of high-fat
`meal with EXSERVAN® decreased AUC by 15% and Cmax by 45% respectively. Therefore,
`EXSERVAN® should also be administered one hour before or two hours after a meal, like the listed
`drug. The relative bioavailability and food effect study conducted by the applicant provides an
`adequate scientific bridge for this 505(b)(2) application. Therefore, EXSERVAN® can rely on
`RILUTEK® and borrow information from its approved label.
`The Office of Study Integrity and Surveillance (OSIS) was consulted for clinical and analytical site
`inspections for the pivotal relative bioavailability study 162020. OSIS conducted inspection for
`the clinical site and found the data are reliable to support a regulatory decision (DARRTS
`10/04/2019) and analytical site was previously inspected (DARRTS 04/29/2019). The NDA also
`included a pilot phase 1 PK study (1897) evaluating BA/BE and organoleptic effect.
`
`2. Recommendation
`The Office of Clinical Pharmacology (OCP) has reviewed the information submitted in the NDA
`and recommends approval based on the bioequivalence demonstrated between 50 mg
`EXSERVAN® oral soluble film and listed drug RILUTEK® oral tablet 50 mg.
`Since EXSERVAN® has food effects similar to that with the listed drug, EXSERVAN® should be
`taken at least one hour before or two hours after a meal, similar to the listed drug.
`
`1 USPI of Rilutek 50 mg tablets: https://www.accessdata.fda.gov/drugsatfda docs/label/2016/020599s017lbl.pdf
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`3. Background and Regulatory History
`The applicant is seeking approval for EXSERVAN® via 505(b)(2) pathway and are relying on FDA’s
`findings of safety and efficacy of riluzole in addition to the results from the pivotal PK bridging
`study.
`The original clinical development plan (summarized in Table 1 & Table 2) included two phase 1
`studies: one pilot BA/BE organoleptic study (1897), and one pivotal relative bioavailability and
`food effect study (162020); and two phase 2 studies in subjects with ALS: swallowing study
`17MO1R-0012 and the long Term (LT) safety study 17MO1R-0016.
`In the pre-NDA meeting (dated March 2018), the adequacy of revised clinical development plan
`and overall submission package for EXSERVAN® was discussed. Upon review of adverse events
`reported in clinical study report for 162020, apart from oral hypoesthesia and erythema, the
`agency noted that no other concerning findings of oral cavity irritation were found. Therefore,
`the agency waived the conduct of study 17MO1R-0016 to assess chronic oral cavity irritation. The
`swallowing study 17MO1R-0012 was terminated early based on agreement with the agency.
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`Table 1 Summary of Phase 1 Studies in Clinical Development Plan
`
`Source: Investigational Brochurev2.0: Table – 4 on Page 19
`Table 2: Summary of Phase 2 Studies in Clinical Development Plan
`
`Source: Synopses of Individual Studies Table on Page 4
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`4. Summary of Pivotal Relative BA/BE and Food Effect Study
`Title: A pivotal, open-label, randomized, single dose, five-period, replicate crossover,
`comparative bioavailability study of EXSERVAN® 50 mg Oral Soluble Film (OSF) and RILUTEK® 50
`mg tablet in healthy male and female volunteers under fasting conditions with evaluation of food
`effect.
`Primary Objectives:
`
`
`
`
`
`To evaluate the comparative bioavailability of riluzole from EXSERVAN® administered
`orally as 1 x 50 mg OSF without water under fasting conditions versus RILUTEK® 1 x 50 mg
`tablets administered orally with 240 ml of water under fasting conditions in healthy non-
`smoking volunteers.
`To evaluate the food effect on the PK of ROSF, administered as 1 x 50 mg without water
`following a standardized high-fat meal.
`
`Treatment Administration:
`Test and reference products are summarized in Table 3 below.
`Table 3 Summary of treatments and instructions for administration
`
`Treatment
`
`Treatment A
`
`Treatment B
`
`Treatment C
`
`Product Administered
`
`EXSERVAN®
`oral soluble film
`
`RILUTEK® EXSERVAN®
`
`oral tablets
`oral soluble film
`
`Dose/Strength
`
`50 mg
`
`50 mg
`
`50 mg
`
`Route of administration
`
`Oral, with 240 mL of
`water
`
`Oral, without water,
`within 30 min of
`ingestion
`of
`standardized high-
`fat meal.
`Similar
`instructions
`as treatment A.
`
`Oral, without water,
`fasting conditions.
`Film was placed
`directly on the top
`of tongue, subject
`was asked to rub the
`film gently with the
`tongue against the
`roof of the mouth to
`promote melting
`and disappearance
`of the film
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`Methodology:
`Part I of the study compared the PK of the test and reference product in a replicate crossover
`design, each subject repeated treatments A and B for the assessment of BE under fasting
`conditions (Periods 1 – 4).
`Each subject then received treatment C under fed conditions (standardized high-fat meal) (Period
`5)
`
`Part II of the study evaluated the food effect on PK of riluzole with the test product.
`Subjects who met the eligibility criteria were randomly assigned equally into one of the 2
`treatment sequences with the medications: EXSERVAN® 50 mg under fasting conditions without
`water (Treatment A), RILUTEK® 50 mg tablet with 240 mL of water under fasting conditions
`(Treatment B) for part I of the study and EXSERVAN® 50 mg under fed conditions (standardized
`high-fat meal) without water for part II of the study. There was a washout period of a minimum
`of 7 days between each period.
`
`PK Sampling:
`Blood samples from each subject were drawn into blood collection tubes (3 mL) containing K2
`EDTA prior to drug administration (pre-dose) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24,
`36, 48, 72, 96, and 120 hours after dosing in each study period.
`
`Number of Subjects (Planned and Analyzed)
`A total of 135 healthy subjects were screened for the study, and 45 subjects were enrolled. Of
`these 45 subjects, 32, 31, 30, 30 and 30 subjects were enrolled in Periods 1, 2, 3, 4 and 5
`respectively (Table 4). All subjects who received at least one dose of study medication comprised
`of safety population (N=32). Of these, 30 subjects completed all treatment periods, 2 subjects
`discontinued from the study.
`
`Reviewer Comments
`The study design, treatment assignment, washout period (7 days, given the half-life of 12 hours),
`PK sampling scheme and sample size are acceptable
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`Table 4 Subject disposition characteristics
`
`Source: Clinical study report (162020) Table 10.1-1, Page 57
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`Main Criteria for Inclusion and Exclusion
`The key inclusion criteria are healthy, male or female subjects, non-smokers (for at least 6 months
`prior to first drug administration), 18 to 64 years of age (inclusive) with a body mass index (BMI)
`within 18.5 – 29.9 kg/m2 (inclusive).
`The key exclusion criteria were presence of mouth jewelry, dentures, braces, piercings, or
`irritation in the mouth or tongue, that in the opinion of the investigator, would likely interfere
`with successful completion of dosing, known history of clinically significant medical history,
`concurrent diseases, use of any central nervous system depressants or cytochrome P450 enzyme-
`modifying drugs (inhibitors, inducers) in the previous 30 days before the first drug administration
`and subjects having difficulty with swallowing intact tablets or keeping oral soluble films in the
`mouth until dissolution.
`
`Criteria for Evaluation
`Criteria for Relative Bioavailability Assessment
`Data from first 4 fasting periods were included in this analysis. The analysis method
`recommended in FDA draft guidance on progesterone2 was adapted to reflect the multi-group
`nature of the study. Briefly, within-subject coefficient of variation was first calculated for the
`reference product (CVWR). Based on a cut-off value of 30% for CVWR (equivalent to the within-
`subject standard deviation [SWR] <0.294), the following decision criteria for BE assessment were
`used:
`
` Average BE: If CVWR < 30% for the primary parameter (AUC0-t, AUC0-inf, and Cmax), the point
`estimates and 90% confidence interval (C.I) for the Test-to-Reference geometric mean ratio
`(A/B) were calculated. If the 90% C.I. for the ratio based on least-square means from the
`analysis of variance (ANOVA) of ln-transformed parameter(s) is(/are) within 80.00 to 125.00
`%, then the test product was concluded to be BE to the reference product for that
`parameter(s).
`Scaled-Average BE: If CVWR ≥ 30% for the primary parameter (AUC0-t, AUC0-inf, and Cmax), then:
`o The point estimate of the Test-to-Reference should be within 80.00 to 125.00 %, and
`o The 95% upper confidence bound for the scaled average BE criterion should be equal
`to or less than zero (≤ 0),
`Then the test product was concluded to be BE to the reference product for that
`parameter(s).
`
`
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`2 FDA Draft Guidance on Progesterone, Recommended Apr. 2010, Revised Feb 2011. Available online at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorInformation/Guidances/UCM209294.pdf
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`Criteria for Determination of Food-Effect
`The ratio and 90% C.I. for Fed-Fasted ratio (C/A) were calculated and if the 90% C.I. for the ratio
`based on the least square means from ANOVA of ln-transformed for AUC0-t, AUC0-inf, and Cmax are
`within 80.00 to 125.00%, then it was concluded that there was no food-effect.
`The primary PK endpoints were observed Cmax and AUC0-inf, both derived using non-compartment
`methods. Other parameters included: AUC0-t and Tmax.
`
`Reviewer Comments:
`The inclusion/exclusion criteria and the criteria for assessing BE (including the decision criteria of
`using average BE or scaled-average BE method based on CVWR cut-off of 30%3) and food-effect
`are acceptable.
`
`Results
`Part I: Bioequivalence Assessment in Fasted State: Test (A) versus Reference (B)
`The plot for the mean (±SD) riluzole plasma concentrations over the sampling period are
`presented in Figure 1 below and the descriptive statistics for PK parameters of the reference
`product, including CVWR are shown in Table 5. The CVWR values were > 30% for Cmax alone and
`< 30% for AUC0-inf and AUC0-t. Therefore, average BE criteria for AUC0-inf and AUC0-t: 90% C.I. for
`the geometric mean ratio of Test-to-Reference (A/B) were within 80 – 125%; and average scaled-
`BE criteria were used for Cmax as described above: the point estimate for Test-to-Reference were
`be within 80 – 125%, and the 95% upper confidence bound was less than zero (-0.0123). These
`results are shown in Table 6 below
`
`3 Davit BM, Chen ML, Conner DP, Haidar SH, Kim S, Lee CH, Lionberger RA, Makhlouf FT, Nwakama PE, Patel DT,
`Schuirmann DJ. Implementation of a reference-scaled average bioequivalence approach for highly variable generic
`drug products by the US Food and Drug Administration. The AAPS journal. 2012 Dec 1;14(4):915-24.
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`Figure 1 Mean (±SD) Riluzole Plasma Concentration (Treatments A and B)
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`Source: Clinical study report (162020) Figure 11.4.2.3-1, Page 67
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`Table 5 Summary of Pharmacokinetic Parameters for Riluzole Following RILUTEK® 50 mg
`Treatment - PK Population
`
`Source: Clinical study report (162020) Table 11.4.2.3-2, Page 69
`
`Table 6 Ratio of A/B, Confidence Intervals and BE Analysis for PK Parameters – PK Population
`
`Source: Clinical study report (162020) Table 11.4.2.3-4, Page 71
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`Reviewer Comments
`The reviewer was able to replicate the analyses conducted by the applicant. The results indicate
`that the test and reference products show similar rate and extent of riluzole absorption after
`single dose administration under fasting conditions.
`
`Part II: Food Effect Assessment
`The plot for the mean (±SD) riluzole plasma concentrations over the sampling period are
`presented for the test product without (treatment A) and with standardized high-fat meal
`(treatment C) in Figure 2 below
`Figure 2 Mean (±SD) Riluzole Plasma Concentration (Treatments A and C)
`
`Source: Clinical study report (162020) Figure 11.4.2.3-2, Page 72
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`The results for geometric mean ratios for fed/fasted with 90% CI are shown in Table 7 below:
`Cmax decreased by 45%, while AUC0-inf decreased by 15%.
`
`Table 7 Geometric Mean Ratio (C/A) and 90% Confidence Interval for PK parameters:
`PK Population
`
`Source: Clinical study report (162020) Table 11.4.2.3-6, Page 74
`
`Reviewer Comments
`The reviewer was able to replicate the analyses conducted by the applicant. The results indicate
`that the test product has a significant food effect: Cmax decreased by 45%, while AUC0-inf decreased
`by 15%. The magnitude of the food-effect is consistent with that observed with listed drug
`(RILUTEK® 50 mg tablet) – decrease of Cmax by 45% and AUC by 20%. The USPI for RILUTEK®
`includes a recommendation: should be taken at least 1 hour before or 2 hours after a meal.
`Therefore, an identical recommendation should be included in the USPI of EXSERVAN®.
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`5. Bioanalytical Method Validation
`A validated HPLC method using MS/MS detection was employed for determining the
`concentrations of riluzole in human plasma. The sample analysis was conducted in accordance
`with the FDA Guidance for the Industry, Bioanalytical Method Validation (May 2018) and EMA
`Guideline on Bioanalytical Method Validation. The validation method included the assessment of
`linearity, precision, accuracy, dilution and recovery, matrix effect, selectivity, carry-over and
`stability
`This method involved the extraction of riluzole and the internal standard riluzole-13C-15N2 from
`human EDTA K2 plasma using an automated protein precipitation procedure and LC-MS/MS
`determination according to method SOP
`10942.01. Samples were kept frozen at -20ºC prior
`to analysis and 0.05 mL of matrix was used for analysis. Bioanalytical methods and validation
`results are summarized in Table 8.
`
`Reviewer Comments
`The method was shown to be precise, accurate, sensitive, and selective over the validated range.
`Furthermore, the method was reliable and reproducible, and the analyte and the internal
`standard were stable under all conditions tested. Based on these results, the method was
`considered suitable for the analyses for riluzole in human plasma over the range of 0.50 to 500
`ng/mL.
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`Table 8 Summary of Bioanalytical Method and Validation Characteristics
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`Parameter
`
`Analyte
`
`Parent Drug
`
`Riluzole
`
`Internal Standard (IS)
`
`Riluzole-13C-15N2
`
`Limit of quantification (ng/ml)
`
`Lower Limit of Quantification (LLOQ): 0.5
`
`Average recovery of drug (%)
`
`Means: 87.72, 95.26, 92.71
`
`Average recovery of IS (%)
`
`Mean: 95.55
`
`Calibration curve range (ng/mL) and
`linearity (r2)
`
`0.5 to 500 ng/mL; Linearity: r² ≥ 0.9957
`
`QC concentrations (ng/mL)
`
`LLQC: 0.5, QC1: 1.5, QC2: 250 and QC3: 375
`
`Between-run accuracy and precision
`
`Biases: -2.03 to 4.38%; CV: 1.92 to 10.79%
`
`Within-run accuracy and precision
`
`Biases: -4.70 to 6.00%; CV: 0.82 to 7.15%
`
`Bench-top stability (hrs) (equivalent to
`short-term stability of analyte in matrix)
`
`24h 05min at room temperature;
`25h 07min at 4°C
`
`Stock stability (days) (equivalent to long-
`term stability of analyte or internal
`standard in solution)
`
`Processed stability (hrs) (equivalent to
`post-preparative stability)
`
`729 days at -20°C (low and high concentrations)
`
`95h 47min at room temperature
`
`Freeze-thaw stability (cycles)
`
`4 cycles at -20°C and -80°C
`
`(days)
`stability
`storage
`Long-term
`(equivalent to
`long-term stability of
`analyte in matrix)
`
`731 days at -20°C
`
`Selectivity
`
`No effect on the quantitation of the analyte
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`Signature Page 1 of 1
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`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
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`/s/
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`
`GOPICHAND GOTTIPATI
`10/31/2019 02:55:46 PM
`
`SREEDHARAN N SABARINATH
`10/31/2019 03:42:24 PM
`
`
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`Reference ID: 4514252Reference ID: 4525554
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