CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICATION NUMBER:
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`210875Orig1s000
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`CLINICAL PHARMACOLOGY AND
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`BIOPHARMACEUTICS REVIEW(S)
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` Office of Clinical Pharmacology Review
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` NDA Number
` Link to EDR
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` Submission Date
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` Submission Type
` Proprietary Name
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` Dosage Form and Strength
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` Proposed Dose/Regimen
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` Proposed Indication
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` Applicant
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` OCP Division
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` Associated IND
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` OCP Review Team
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`Reference ID: 4601419Reference ID: 4613103
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` 210875
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` \\cdsesub1\evsprod\nda210875\0044
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` 11/21/2019
`
` NDA resubmission
`
` To be determined
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` Sublingual (SL) film
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` 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg
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` The proposed dose range for APL-130277 is 10 mg
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`
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` mg. Dose titration should be initiated with 10 mg dose
` when patients are in an “OFF” state. Continue dose
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` titration until an effective and tolerable dose is achieved.
` Do not administer more than 5 doses per day.
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` For the acute, intermittent treatment of “OFF” episodes
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` associated with Parkinson’s disease
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` Sunovion Pharmaceuticals, Inc.
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` Division of Neuropsychiatric Pharmacology
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` 110955
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` Mariam Ahmed Ph.D., Sreedharan Sabarinath Ph.D. and
` Mehul Mehta, Ph.D.
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` 1
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`Table of Contents
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`Executive Summary................................................................................................................. 3
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`1.
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`1.1 Recommendation.................................................................................................................. 3
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`1.2 Post-Marketing Requirements and Commitments............................................................... 4
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`2. Background and Regulatory History ....................................................................................... 5
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`Summary of Pivotal Relative Bioavailability Study: CTH-203 ................................................. 5
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`3.
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`Summary of Metabolite Exposures from Study CTH-203..................................................... 14
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`4.
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`5. Bioanalytical Method Validation .......................................................................................... 14
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`6.
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`7.
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`Summary of OSIS inspection for Study CTH-203 .................................................................. 15
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`In Vitro Studies...................................................................................................................... 15
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`Reference ID: 4601419Reference ID: 4613103
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`2
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`1. Executive Summary
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`This is a resubmission to address the deficiencies outlined in the complete response letter (CRL)
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`to the original NDA 210875 (CRL dated 29 January 2019) for apomorphine sublingual (SL) film
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`(APL-130277). The CRL identified three major sources of deficiencies: human factors, clinical
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`pharmacology and biopharmaceutics, and safety.
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`To address the clinical pharmacology and biopharmaceutics deficiency identified in the CRL, the
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`division requested the applicant (Sunovion Pharmaceuticals, Inc.) to complete and provide the
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`final report of Study CTH-203 to support the scientific appropriateness of reliance on FDA’s
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`finding of nonclinical safety and applicable clinical pharmacology information for the listed drug,
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`APOKYN® (apomorphine hydrochloride injection). In addition, the CRL included additional
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`comments and recommendations which were not approvability issues. These included
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`recommendations to conduct in vitro studies to evaluate the drug-drug interaction (DDI)
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`potential of two major metabolites of apomorphine from the proposed SL product (APL-130277):
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`apomorphine glucuronide and norapomorphine glucuronide.
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`In this resubmission, the applicant included the complete study report of the relative
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`bioavailability study (CTH-203) and in vitro DDI studies for apomorphine glucuronide. Study
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`CTH-203 was conducted to assess the comparative PK of apomorphine from APL-130277,
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`APOKYN (relied-upon listed drug) and APO-go (European product) in a 3-way crossover design
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`in patients with Parkinson’s Disease (PD).
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`The primary focus of this review is to assess the acceptability of the bridge between APL­
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`130277 and the listed drug. Although the applicant initially proposed
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`up to 30 mg
`for APL-130277, the clinical review team is recommending approval of doses
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`. This review also evaluates the in vitro DDI
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`results for apomorphine glucuronide.
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`1.1 Recommendation
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`The Office of Clinical Pharmacology (OCP) has reviewed the information submitted in the NDA
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`and recommends approval.
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`The SL route has lower bioavailability for apomorphine compared to subcutaneous (S.C.)
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`injection. The bioavailability for APL-130277 relative to APOKYN is about 17% for AUCinf and 12%
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`for Cmax. The doses of APL-130277 were adjusted for the difference in bioavailability of
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`apomorphine for the proposed SL route of administration. The recommended dose range of the
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`proposed SL product APL-130277 is 10-30 mg, while APOKYN’s approved dose range is 2-6 mg.
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`Based on Study CTH-203, the exposures of apomorphine from the recommended highest dose of
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`APL-130277 (30 mg) are lower for APL-130277 compared to the maximum dose of APOKYN.
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`Reference ID: 4601419Reference ID: 4613103
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` 3
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`Therefore, it is acceptable for the applicant to rely on FDA’s finding of non-clinical safety and
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`clinical pharmacology for APOKYN. The clinical safety and efficacy data for APL-130277 is
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`available from their own clinical development program.
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`1.2 Post-Marketing Requirements and Commitments
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`The applicant should submit in vitro studies that evaluate the DDI potential for the major
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`metabolite norapomorphine glucuronide, as listed in the original clinical pharmacology review
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`for NDA 210875 in DARRTS dated 12/29/2018.
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`Reference ID: 4601419Reference ID: 4613103
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`4
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`2. Background and Regulatory History
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`The applicant submitted the original NDA application on 29 March 2018 for APL-130277
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`(Sequence 0001). On 29 January 2019 the agency issued a Complete Response Letter (CRL) in
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`which three main deficiencies that prevented approval were identified. These deficiencies
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`were:
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`• Human Factors (HF): The HF study submitted in the original application did not provide
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`adequate data to demonstrate that the proposed mitigations are effective and do not
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`introduce new use-related risks. Furthermore, the HF study did not evaluate the final
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`intend-to-market user interface, specifically the proposed
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`packaging.
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`• Clinical Pharmacology and Biopharmaceutics: In order to justify the relevance of
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`comparative data with APL-130277 and APO-go® (apomorphine hydrochloride injection)
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`to support the scientific appropriateness of reliance on FDA’s finding of safety for
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`APOKYN® (apomorphine hydrochloride injection) the Division requested that Sunovion
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`complete and provide the final report for Study CTH-203.
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`• Safety: Division requested further characterization of oral adverse events (AEs)
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`associated with APL-130277 which was to also include an evaluation of oral adverse
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`events by an expert. The Division also requested that Sunovion provide a safety update
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`in accordance with 21 CFR 314.50(d)(5)(vi)(b).
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`The CRL also included additional comments and recommendations which did not constitute
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`approvability issues. The office of clinical pharmacology recommended conducting in vitro
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`studies to evaluate the DDI potential of two major metabolites from APL-130277: apomorphine
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`glucuronide and norapomorphine glucuronide. These metabolites exposures significantly
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`increased due to the change of administration route from S.C. to SL.
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`3. Summary of Pivotal Relative Bioavailability Study: CTH-203
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`Title: A Comparative Bioavailability Study to Evaluate the Single Dose Pharmacokinetic
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`Properties of APL-130277 with Two Different Formulations of Subcutaneous Apomorphine in a
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`Randomized, 3-Period Crossover Design in Subjects with Parkinson’s Disease Complicated by
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`Motor Fluctuations (“OFF” Episodes)
`Primary Objectives:
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`To evaluate the PK and comparative bioavailability of a single dose of APL-130277 SL
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`film with S.C. APO-go and S.C. APOKYN in subjects with PD complicated by motor fluctuations
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`(OFF Episodes).
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`Reference ID: 4601419Reference ID: 4613103
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`5
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`(b) (4)
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` Secondary Objectives: To evaluate the safety and tolerability of the study drugs.
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` Reviewer’s comment:
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` Although the study had 3 treatment arms (APL-130277, APOKYN and APO-go), the focus of this
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` review is on the relative bioavailability of APL-130277 SL film compared to the US listed drug,
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` APOKYN.
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`Methodology:
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`• This was as an open-label, randomized, 3-way, 6-sequece crossover study. Subjects were
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`to receive all 3 treatment arms (APL-130277 SL, S.C. APO-go and S.C. APOKYN) with a
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`minimum 1-day wash-out between each visit (excluding the Screening Visit).
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`• The dose of APOKYN was based on the subject’s prescribed dose at the time of
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`screening.
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`PK Sampling:
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`Blood samples from each subject were drawn prior to drug administration (pre-dose) and 0.25,
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`0.5, 0.75, 1, 1.5, 3, and 6 hours after dosing in each study period.
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`Reviewer’s Comment:
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`Given that the Tmax for APOKYN occurs between 10 minutes and 1 hours, this sampling scheme
`may miss the true Cmax for APOKYN. This is not considered a major issue as it in fact would result
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`in an over estimation (i.e. conservative estimate) of the relative bioavailability for Cmax with APL­
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` 130277.
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` Number of Subjects (Planned and Analyzed):
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` Planned: 12; Screened: 8; Enrolled: 8; Completed: 7.
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` All 8 enrolled subjects were included in the Safety and PK Populations. There were data from 8
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` subjects included in the PK analysis for APL-130277 and APO-go and data from 7 subjects in the
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` analysis for APOKYN. Subject
` was excluded from the summary statistics for all analytes
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` in Period 1 (APOKYN) because all plasma concentrations for this subject were below the limit of
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` quantification (BLQ). This was likely due to a malfunction of the APOKYN delivery system (either
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` due to user error or malfunctioning device). Therefore, quantifiable PK data is only available from
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` 6 subjects who received both APL-130277 and APOKYN in both periods.
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`Reviewer’s Comment:
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`The study design, treatment assignment, washout period (1 day, given that apomorphine half-life
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`is ~2 hours), sample size and PK sampling scheme are acceptable (see previous comment
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`regarding the PK sampling scheme).
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`Reference ID: 4601419Reference ID: 4613103
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`6
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`(b) (6)
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`

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` Test Products and Dose:
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` APL-130277 dosing was based on the subject’s current prescribed dose of APOKYN, as shown in
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` Table 1.
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` Table 1: Doses of APOKYN® and Corresponding Dose of APL-130277 and Number of Subjects at
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` each Dose Level.
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` APL-130277 Dose
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` APOKYN Current Dose
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` 15 (N=0)
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` 2 (N=0)
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` 3 (N=3)a
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` 20 (N=3)
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` 25 (N=2)
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` 4 (N=2)
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` 5 (N=2)b
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` 30 (N=3)
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` a Although 3 subjects in the 3 mg dose levels received APOKYN dose, subject
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` was
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` excluded from the summary statistics for all analytes in Period 1 (APOKYN) because all plasma
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` concentrations for this subject were below the limit of quantification (BLQ). This was likely due
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` to a malfunction of the APOKYN delivery system (either due to user error or malfunctioning
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` device). Therefore, data from 2 subjects are available for this dose level for APOKYN. b Subject
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` terminated early and did not receive 5 mg APOKYN.
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`Source: CTH-203 study report, Table 10, Page 42.
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`Main Criteria for Inclusion and Exclusion:
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`The key inclusion criteria were male or female ≥ 18 years of age with clinical diagnosis of
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`idiopathic PD, consistent with United Kingdom Brain Bank Criteria (excluding the “more than 1
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`affected relative” criterion). The subjects were required to have clinically meaningful response
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`to levodopa with well-defined OFF episodes, as determined by the Investigator and be receiving
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`APOKYN of ≤ 5 mg per dose for at least 4 weeks before the Screening Visit. The subjects were to
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`be receiving stable doses of levodopa/carbidopa (immediate or sustained release) administered
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`at least 4 times per day or RYTARY™ administered 3 times per day, for at least 4 weeks before
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`the Screening Visit. Adjunctive PD medication regimens must have been maintained at a stable
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`dose for at least 4 weeks prior to the Screening Visit with the exception that MAO-B inhibitors
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`must have been maintained at a stable level for at least 8 weeks prior to the Screening Visit.
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`Subjects were to have Stage III or less on the modified Hoehn and Yahr scale in the ON state and
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`a Mini-Mental State Examination score > 23. There were to be no planned medication change(s)
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`or surgical intervention anticipated during the study and the subjects must have experienced a
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`well-defined OFF episode in the morning if they did not take their morning PD medications on
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`schedule and must have been willing to delay morning doses on the 3 study dosing days.
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`Subjects were excluded from participation in the study if they had atypical or secondary
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`treatment with continuous S.C. apomorphine
`infusion, or
`parkinsonism; previous
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`Reference ID: 4601419Reference ID: 4613103
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`7
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`(b) (6)
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`(b) (6)
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` DUODOPA/DUOPA; or had contraindications to APO-go or APOKYN or hypersensitivity to
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` apomorphine hydrochloride or any macrolide antibiotic or any of the ingredients of APO-go or
` APOKYN (notably sodium metabisulfite).
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` Criteria for Evaluation:
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` Main Criteria for Relative Bioavailability Assessment:
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` The PK parameters calculated were: maximum observed plasma concentration (Cmax); observed
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`time of the maximum concentration (Tmax); terminal-phase half-life (t½); area under the
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`concentration-time curve from time zero to the last measurable plasma concentration-time
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`curve (AUClast); area under the concentration-time curve from time zero extrapolated to infinity
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`(AUCinf). Relative bioavailability between the test and reference products was also evaluated.
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`Reviewer’s Comment:
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`While the approved dose range for APOKYN is 2 to 6 mg, the applicant limited the inclusion criteria
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`to subjects receiving doses between 2-5 mg and limited the dosing of APL-130277 to 30 mg. This
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`could be due to the difficulty in recruiting subjects stabilized on the highest dose of APOKYN 6 mg.
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` APL-130277, the clinical
`Although the applicant
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`up to 30 mg
`review team is recommending approval of doses
`. Therefore, this review will focus on the acceptability of the PK bridge
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`between the highest recommended dose of APL-130277 (30 mg) and the highest approved dose
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`of APOKYN (6 mg). The PK bridging between APL-130277 and the listed drug will be considered
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`acceptable if apomorphine exposure from the 30 mg dose of APL-130277 is less than or equal to
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`that from the maximum approved dose of APOKYN.
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`Results:
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`Relative Bioavailability Assessment:
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`Table 1 shows the number of dose groups/levels studied and the number of subjects at each dose
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`level per treatment group. The applicant reported the individual subject plasma apomorphine
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`concentration-time data. The plot for the apomorphine plasma concentrations over the sampling
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`period are presented in Figure 1 below for each individual (N=6) who received both APL-130277
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`and APOKYN®. The descriptive statistics for the dose normalized PK parameters of APL-130277
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`(N=8) and APOKYN (N=6) as well as the least square mean ratios (i.e. relative bioavailability) of
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`APL-130277 to APOKYN® are shown in Table 2 below.
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`Reference ID: 4601419Reference ID: 4613103
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`8
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`(b) (4)
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`(b) (4)
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`(b) (4)
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` Figure 1: Plasma Concentration Time Profile for Apomorphine for Each Subject who Received
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` Both APL-130277 and APOKYN® (N=6, plasma profiles for each subject by treatment).
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`Reference ID: 4601419
`Reference ID: 4613103
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` 9
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`(b) (6)
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` Source: Reviewer’s analysis
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`Reference ID: 4601419
`Reference ID: 4613103
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` 10
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`(b) (6)
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`(b) (6)
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`

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` Reviewer’s Comment:
`
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` Note that the first scheduled PK sampling is at 15 minutes post dose in this study. The first point
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` of the plasma concentration time curve is the highest concentration for APOKYN in 4 patients,
` suggesting that true Cmax may have been missed because of insufficient early sampling times in
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`those subjects. This happened for APL-130277 in only one subject (Subject ID:
`). Thus,
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`there may be some under estimation of Cmax for APOKYN and the relative bioavailability
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`estimation for the Cmax of APL-130227 relative to APOKYN would be considered conservative.
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`Table 2: Summary of Dose Normalized Pharmacokinetic Parameters for Apomorphine
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`Following APL-130277™ and APOKYN® Treatment - PK Population
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` PK Parameter
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` APL-130277
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` (N=8)
` LSM (90% CI)
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` 0.28 (0.191, 0.413)
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` APOKYN
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` (N=6)
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` LSM (90% CI)
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` 2.29 (1.46, 3.59)
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` LSM Ratio
` (APL-130277 vs APOKYN
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` (90% CI)
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` 12.3 (7.5, 20.3)
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` 0.50 (0.34, 0.73)
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` 2.91 (1.97, 4.30)
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` Cmax/Dose
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`(ng/mL)/(mg)
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` AUClast /Dose
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`(h*ng/mL)/(mg)
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` AUCinf /Dose
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`(h*ng/mL)/(mg)
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` AUC: area under concentration-time curve; Cmax: maximum concentration; CI: confidence interval;
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` LSM: least square means.
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` Source: CTH-203 Clinical Study Report, Table 12 and 14, Page 51 and 60
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`Reviewer’s Comments and Additional Analyses:
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`• Given that the study was conducted in PD patients who were already stabilized on
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` APOKYN®, these patients were on different dose levels. The patients were then
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` randomized to a dose of APL-130277 that would provide comparable exposure for
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` apomorphine following APOKYN® dosing. Given the limited number of subjects in each
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` dose level, it was not possible to naively pool the data from all individuals and assess the
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` central tendency (i.e. geometric mean) and variability (i.e. 90% confidence interval) of
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` aporphine exposures following APL-130277 and APOKYN® administration. Therefore, the
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` sponsor chose to calculate the dose normalized ratios for Cmax and AUC assuming dose
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` proportionality for APL-130277 and APOKYN®. According to this assumption, the relative
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` 17.2 (13.1, 22.5)
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`0.52 (0.36, 0.76)
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`2.97 (2.02, 4.39)
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`17.6 (13.7, 22.5)
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`Reference ID: 4601419Reference ID: 4613103
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`11
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`(b) (6)
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`

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`bioavailability of the proposed SL formulation was approximately 17% (AUC) and 12%
`
`
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`(Cmax) compared to APOKYN®. While APOKYN® has linear PK over the approved dose range
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`of 2-6 mg (Ref. APOKYN USPI), APL-130277 has less than dose proportional PK over the
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`
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`range of 10-35 mg (Study CTH-201, please refer to the original clinical pharmacology
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`
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`
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`review). Therefore, the relative bioavailability estimate reported here may be an over
`
`
`estimation and may be considered as a conservative estimate.
`
`• The review team aimed to understand if the exposure from the highest recommended dose
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`of APL-130227 (30 mg) is covered by the exposure from APOKYN® highest approved dose
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`(6 mg). Since there is limited number of subjects at this dose level (N=2 subjects
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`administered both SL and S.C. products), the review team used superposition rule to
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`predict apomorphine exposure following the highest recommended dose administration
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`
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`for the APL-130277 and the highest approved dose for the APOKYN® for all patients
`
`
`in this study
`administered both SL and S.C. products
`(N=6). This assumes
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`linear/proportional PK for APL-130277. Figure 2 presents the mean (±SE) apomorphine
`plasma concentrations over the sampling period for the highest studied dose for both
`
`products in Study CTH-203.
`
`• The least square mean for apomorphine exposure following the highest recommended
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`
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`dose for APL-130277 (30 mg) and APOKYN (6 mg) using the superposition rule is presented
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`in Table 3. The recommended highest dose of APL-130277 (30 mg) has ~40 and 10% lower
`Cmax and AUCinf respectively as compared to the highest approved dose of APOKYN® (6
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`
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`mg).
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`12
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`Reference ID: 4601419Reference ID: 4613103
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`

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` Figure 2: Mean (±SE) Apomorphine Dose Normalized Plasma Concentration for Subjects
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` Received Both APL-130277 (Normalized to 30 mg) and APOKYN® (Normalized to 5 mg)
` predicted using superposition principle, assuming linear/proportional PK for both
`
`
` products(N=6).
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`Source: Reviewer’s analysis.
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`Table 3: Summary of Predicted Exposures for APL-130277 and APOKYN highest
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`Recommended Dose for Subjects Treated with Both Products in Study CTH-203 (N=6).
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` PK Parameter
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` Cmax (ng/mL)
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`AUCinf (h*ng/mL)
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` APL-130277
`LSM (30 mg)
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` 8.76
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` 16.04
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` APOKYN
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` LSM (6 mg)
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` 14.05
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` 18.21
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` LSM Ratio
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`(APL-130277/APOKYN)
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` 0.6
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` 0.9
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` AUC: area under concentration-time curve; Cmax: maximum concentration; CI: confidence interval;
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` LSM: least square means.
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` Source: Reviewer’s analysis
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`Reference ID: 4601419Reference ID: 4613103
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`13
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`Conclusion:
`
`Study CTH-203 was conducted to assess the comparative PK of apomorphine from APL-130277,
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`APOKYN (relied-upon listed drug), and APO-go (European product) in a 3-way crossover design.
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`Based on this study, the SL route has lower bioavailability for apomorphine compared to
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`subcutaneous injection. The doses of APL-130277 were adjusted for the difference in
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`bioavailability of apomorphine for the proposed SL route of administration; the dose range of
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`the proposed SL product APL-130277 is 10-30 mg, while APOKYN’s dose range is 2-6 mg. Based
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`on Study CTH-203, the exposures of apomorphine from the highest dose of APL-130277 (30 mg)
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`are approximately 40% and 10% lower Cmax and AUCinf, respectively, for APL-130277 compared
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`to APOKYN. Therefore, it is acceptable for the applicant to rely on FDA’s finding of non-clinical
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`safety and applicable clinical pharmacology for APOKYN. The clinical safety and efficacy data for
`APL-130277 is from their own clinical development program.
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`4. Summary of Metabolite Exposures from Study CTH-203
`
`The applicant measured apomorphine sulfate and norapomorphine in Study CTH-203 following
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`both SL and S.C. route of administrations. Administration of APL-130277 led to increased
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`exposure of apomorphine sulfate compared to administration of APOKYN. The geometric mean
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`Cmax and AUClast values were roughly 3-fold higher after APL-130277 compared to APOKYN. On
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`the other hand, norapomorphine was not detectable in any subject following the administration
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`of both SL and S.C. products.
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`Reviewer’s Comments:
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`The observations for these two metabolites from Study CTH-203 are in agreement with previous
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`studies that were reviewed in the original submission. Please refer to the original OCP review in
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`DARRTS dated 12/29/2018 for details.
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`5. Bioanalytical Method Validation
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`Plasma concentrations of apomorphine and two of its metabolites (norapomorphine and
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`apomorphine sulfate) were determined utilizing a validated liquid chromatography-tandem
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`mass spectrometry (LC-MS/MS) method with a linearity range of 0.02 to 20 ng/mL for
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`apomorphine; 10 to 1000 ng/mL for apomorphine-sulfate; and 0.50 to 20 for norapomorphine
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`(Method Validation Report APL-MV-03). This method was reviewed previously was found to be
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`acceptable.
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`Additionally, in this resubmission, the applicant submitted detailed plasma apomorphine,
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`norapomorphine and apomorphine sulfate concentration results and assay performance (see
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`Report APL-SA-203). In this analytical report a total of 183 human plasma samples from 8
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`completed patients have been analyzed for apomorphine, norapomorphine and apomorphine­
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`sulfate concentrations using the validated LC-MS/MS method. Incurred sample reanalysis (ISR)
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`Reference ID: 4601419Reference ID: 4613103
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`14
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` reproducibility was performed for 46 samples for all three analytes. The ISR met the acceptance
` criteria with overall acceptance of % for apomorphine ISR samples that had the repeat and
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`original results within 20% of each other. All sample analyses were completed within the
`established frozen sample storage stability period of 517 days at ≤-60oC (APL-MV-03­
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`Addendeum-2).
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`6. Summary of OSIS inspection for Study CTH-203
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`The Office of Clinical Pharmacology consulted the Office of Study Integrity and Surveillance (OSIS)
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`to inspect the analytical and the clinical sites for Study CTH-203. The three clinical sites for this
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`study were inspected, and the final inspection classification is No Action Indicated (NAI). For more
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`information please refer to the review by Dr. Xingfang Li (available in DARRTS dated 03/20/2020).
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`OSIS concluded that no inspection is warranted for the analytical site as the same site was
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`inspected recently under
`with an inspection classification of Voluntary Action
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`Indicated (VAI)
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`. However, OSIS stated that the observations
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`did not impact the reliability of other studies conducted at the site and recommended that other
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`studies conducted using similar methods of analysis (LC-MS/MS) be accepted for Agency review.
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`For more information, please refer to the review by Dr. James J Lumalcuri (available in DARRTS
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`dated 02/20/2020).
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`7. In Vitro Studies
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`Due to the change in the route of administrations, apomorphine SL administration results in 3
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`inactive metabolites: apomorphine
`sulfate, apomorphine glucuronide and
`major
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`norapomorphine glucuronide (Study CTH-200). In the original submission, the applicant
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`submitted the in vitro DDI potential for apomorphine sulfate. In this resubmission, the in vitro
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`DDI studies for apomorphine glucuronide were included and are reviewed below. The applicant
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`should also conduct in vitro DDI studies for norapomorphine glucuronide post-marketing.
`
`Apomorphine glucuronide
`
`
`The applicant evaluated the potential of apomorphine glucuronide to inhibit human
`
`cytochrome P450 (CYP) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5
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`catalytic activity in pooled human liver microsomes over a concentrations range of 0.06 - 60 μM
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`using human liver microsomes (HLM) (Document No. 277-512A). The maximum direct inhibition
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` by apomorphine glucuronide was observed for CYP3A4 (20%). Therefore, the IC50 of
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` apomorphine glucuronide associated with inhibition of major transporters is greater than 60
`
` μM. Likewise, no significant time-dependent and co-factor-dependent loss of initial product
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` formation was observed for any CYP enzyme indicating absence of any time-dependent
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` inhibition.
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`Reference ID: 4601419Reference ID: 4613103
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`15
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`
`(b)
`(4)
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`(b) (4)
`
`(b) (4)
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`

`

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` The applicant studied the induction potential of apomorphine glucuronide with major CYP
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` enzymes (Document No. 277-513A). Induction was measured by catalytic activity and mRNA
`
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` expression assays selective for isoforms CYP1A2, CYP2B6, and CYP3A4 in cultured primary
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` human hepatocytes from 3 separate donors at apomorphine glucuronide concentrations range
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` of 0.06 - 60 μM. Apomorphine glucuronide caused no increases of CYP1A2, CYP2B6 and CYP3A4
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` mRNA or enzyme activity that were greater than 2.0-fold, and that were 20% or greater than
`
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` the positive control response for all three lots of hepatocytes.
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`The applicant conducted a study to investigate the interaction of apomorphine glucuronide
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`
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`
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`with human ABC (efflux) transporters: BCRP, BSEP, MDR1, MRP2, MRP3, MRP4, and human SLC
`(uptake) transporters: MATE1, MATE2-K, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2
`
`
`
`
` (Document No. 277-511A). According to this study, apomorphine glucuronide inhibited the
` BCRP and MRP3 mediated probe substrate accumulation at the applied concentrations with a
`
` maximum inhibition of 22% and 50% at 50 μM, respectively. Additionally, apomorphine
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` glucuronide inhibited the MATE1-, OAT1- and OAT3-mediated probe substrate accumulation by
` 28%, 22% and 40% at 50 μM, respectively. Apomorphine glucuronide did not influence the
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`
` BSEP, MDR1, MATE2-K, OATP1B1-, OATP1B3-, OCT1- and OCT2-mediated probe substrate
`
`
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` accumulation at concentrations up to 50 μM.
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`
` Reviewer’s Comments:
` • The mean Cmax (total) of apomorphine glucuronide observed after a single sublingual
`
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`dose of 35 mg is 182 ng/mL or 0.4 μM (N=5, Study CTH-301 reviewed in the original
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`submission). Given the half-life is approximately 3 hours for this metabolite, the
`projected Cmax of apomorphine glucuronide at steady state (assuming administration 5
`
`
`
` times daily every 2 hours) is ~1 μM). Given that the IC50 was greater than the maximum
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` concentration tested in vitro (i.e. >60 μM which is at least 60-fold higher than the
`
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`
` maximum concentration following the maximum recommended dose), the potential for
` apomorphine glucuronide to interfere with the metabolism of concomitant medications
`
`
`
`
` by CYP inhibition or induction is considered low.
` • Apomorphine glucuronide was not an in vitro inducer of CYP1A2, CYP2B6 and CYP3A4
`
`
`
` mRNA or enzyme activity at the concentrations tested in human hepatocytes. Therefore,
`
`
`
` the potential for apomorphine glucuronide to affect the metabolism of concomitant
` medications by CYP induction is considered low.
`
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`
`
` • The DDI potential due to inhibition of major transporters is considered minimal.
`
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`Reference ID: 4601419Reference ID: 4613103
`
`16
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`

`

`• The applicant also studied the potential for apomorphine glucuronide as a substrate for
`
`
`major transporters. However, this is not considered relevant as the metabolite is
`
`
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`pharmacologically inactive and of no toxicological concern.
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`Reference ID: 4601419
`Reference ID: 4613103
`
`
`17
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`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MARIAM A AHMED
`05/01/2020 05:56:10 AM
`
`SREEDHARAN N SABARINATH
`05/01/2020 08:08:26 AM
`
`MEHUL U MEHTA
`05/01/2020 08:47:49 AM
`
`
`
`Reference ID: 4601419Reference ID: 4613103
`
`

`

`Office of Clinical Pharmacology
`
`Review Addendum
`
`NDA Number
`210875
`
` Link to EDR
`\\cdsesub1\evsprod\nda210875\0001
`Submission Date
`03/29/2018
`Submission Type
`
` 505 (b)(2)
`Brand Name
`KYNMOBI™
`Generic Name
`Apomorphine hydrochloride sublingual film (APL-130277)
`Dosage Form and Strengths Subl