CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
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`APPLICATION NUMBER:
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`
`210875Orig1s000
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`
`PRODUCT QUALITY REVIEW(S)
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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`_____________________________________________________________________________________________________________________
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` Memorandum
`
` DATE: May 8, 2020
`
` FROM: Martha R. Heimann, Ph.D., CMC Lead, Office of New Drug Products/DNDP I
`
` NDA: 210875
`
` SUBJECT: Approval Recommendation for NDA 210875
`
`
`This memorandum conveys the final Office of Pharmaceutical Quality (OPQ) recommendation
`
` for the resubmission of NDA 210875, KYNMOBI (apomorphine) sublingual film.
`
` NDA 210875 was originally submitted on 3/28/2019 under 505(b)(2), and relied, in part, on the
`
`Agency’s previous finding of safety for the drug/device combination product APOKYN
`
`
` (apomorphine injection)/APOKYN Pen. During the first review cycle, the OPQ review team
` recommended approval from a product quality perspective.1 Subsequently, Biopharmaceutics
`
`
`
` deficiencies were identified due to bridging issues raised by the CDER 505(b)(2) committee.
` Specifically, the applicant used a foreign drug/device combination product, the APO-go Pen, as a
`
`
` comparator in clinical studies, rather than APOKYN, the US listed drug (LD) and a scientific
`bridge between APOKYN and the foreign product was required. There were insufficient in vitro
`and device performance data to establish a bridge between the US and foreign products.
`
`
` Therefore, the OPQ recommendation was changed to Complete Response (CR). 2
`
`
` In the CR Letter dated 01/29/2019, the Agency recommended that the applicant submit the final
`
`
` study report for a completed comparative bioavailability (BA) study (CTH-203). In Study
`CTH-203, the single-dose pharmacokinetics (PK) properties of apomorphine from the sublingual
`
`
` film were compared to both APO-go and APOKYN in Parkinson’s disease patients. Thus, the
` study was considered critical to support scientific bridging to the APOKYN.
`
`
` The applicant resubmitted the NDA on 11/21/2019 with the final report for Study CTH-203. The
`
`
`Office of Clinical Pharmacology (OCP) review team has reviewed the study and determined that
`
` it is acceptable to support reliance on FDA’s findings of safety for APOKYN. As the applicant
`
` has established a PK bridge, there is no need for in vitro bridging.
`
`The 11/21/2019 resubmission did not provide for any CMC changes and all manufacturing and
`
` testing facilities associated with the application are currently acceptable. There are no
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` outstanding issues precluding approval.
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`1 Memorandum from Wendy Wilson-Lee, Ph.D., Branch Chief and Application Technical Lead dated 1/22/1019.
`
`http://panorama.fda.gov/PanoramaDocMgmt/webhooks/viewdownload?id=090026f881e81978
`
` 2 Memorandum from Wendy Wilson-Lee, Ph.D., Branch Chief and Application Technical Lead dated 1/29/1019.
` http://panorama.fda.gov/PanoramaDocMgmt/webhooks/viewdownload?id=090026f881ec9c52
`
`
` www.fda.gov
`
`
`
`Reference ID: 4605660Reference ID: 4613103
`
`

`

`Martha
`Heimann
`
`Digitally signed by Martha Heimann
`Date: 5/08/2020 01:59:17PM
`GUID: 504f845f00000ed260627d268a8cdc9d
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`
`
`Reference ID: 4605660
`Reference ID: 4613103
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`
`

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`Reference ID: 4605660Reference ID: 4613103
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`CHAPTER VI: BIOPHARMACEUTICS
`
`
`
` IQA NDA Assessment Guide Reference
`
`
`
` NDA Number
`
` 210875
`
`
` Drug Product Name/ Strength KYNMOBI™ (apomorphine hydrochloride)
`
`
`Sublingual Film, 10 mg, 15 mg, 20 mg, 25
`
` mg, and 30 mg
`
` Sublingual
` Sunovion Pharmaceuticals Inc.
`
` DN1
`
`
`
`
`
` Route of Administration
`
` Applicant Name
` Therapeutic Classification/
`
` OND Division
` RLD/RS Number
`
` Proposed Indication
`
`
`
` NDA 021264
`
`Acute, intermittent treatment of OFF
`episodes associated with Parkinson’s
`disease
`
`
`
`
`
`
`
` Submission Date
`
` Primary Reviewer
`
` Secondary Reviewer
`
`
`
` 11/21/2019 (Resubmission)
`
`
` Leah W. Falade, Ph.D.
`
` Ta-Chen Wu, Ph.D.
`
`
`
`
`Executive Summary
`
`
`
`
` The current resubmission contains the Applicant’s responses to the Complete
`
` Response (CR) Letter dated 01/29/2019, including the final study report for the
`
`
`
` completed Study CTH-203. Study CTH-203 is a comparative bioavailability
`
`
` (BA) study conducted to examine the single-dose pharmacokinetics (PK)
`
`
`
` properties of apomorphine from the proposed sublingual film (APL-130277)
`
`
` and 2 different formulations of subcutaneous apomorphine (APO-go and
`
` APOKYN®) in PD patients and to provide scientific bridging to the US Listed
`
` Drug (LD) APOKYN® subcutaneous injection.
`
`
`
`
` As noted in Biopharmaceutics review (dated 01/25/2019) for the original NDA,
`
`the complete study report of Study CTH-203 is critical to establish the PK
`
` bridge between the US LD product and the active comparator/EU drug product
` and is vital to Biopharmaceutics Reviewer’s bridging evaluation of the device
`
`components of the US and the EU reference products. The formulation of the
`test product used in Study CTH-203 has the same formulation, same
`manufacturing process, and API supplier as the to-be-marketed formulation,
`
` which warrants no additional formulation bridging.
`
` As concluded by the Office of Clinical Pharmacology (OCP) review team, the
`
`
`
` sublingual film (highest 30 mg dose) has lower bioavailability (i.e.,17% for
`
`
`OPQ-XOPQ-TEM-0001v06
`
`
`
` Effective Date: February 1, 2019
` Page 1
`
`
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`(b) (4)
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` AUC∞ and 12% for Cmax) for apomorphine compared to maximum dose of
`
`
`
`
`
` APOKYN subcutaneous injection. Therefore, it is acceptable for the applicant
` to rely on FDA’s findings of safety for APOKYN.
`
`
`
` Recommendation:
`
` NDA 210875 (Resubmission) is recommended for approval, considering the
`
`
`
` successful bridging of the device components PK-based scientific bridging to
` the US Listed Drug (LD) APOKYN® and for the device components (US and
`
`
`
` EU reference products).
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`Reference ID: 4605660Reference ID: 4613103
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`OPQ-XOPQ-TEM-0001v06
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` Page 2
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` Effective Date: February 1, 2019
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`

`

`Leah
`Falade
`
`Ta-Chen
`Wu
`
`Digitally signed by Leah Falade
`Date: 5/01/2020 08:40:42AM
`GUID: 508da6fd000284bfbc66b95729dcea7e
`
`Digitally signed by Ta-Chen Wu
`Date: 5/01/2020 09:12:41AM
`GUID: 508da6df000269e151ff37cd8f4e13a1
`
`
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`Reference ID: 4605660Reference ID: 4613103
`
`

`

`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/
`------------------------------------------------------------
`
`MARTHA R HEIMANN
`05/08/2020 02:33:08 PM
`
`
`
`Reference ID: 4605660Reference ID: 4613103
`
`

`

`
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`
`
`CENTER FOR EVALUATION OF DRUGS
`
`______________________________________________________________________________________________________________________________
`
` Memorandum
`
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` DATE: January 29, 2019
`
`
` TO: Division of Neurology Drug Products
`
`
`
` FROM: Wendy I. Wilson-Lee, Ph.D.
` Branch Chief
`
`
`
`
` SUBJECT: Change in approval recommendation for Kynmobi (apomorphine hydrochloride)
`
` Sublingual Film
`
` APPLICATION/DRUG: NDA 210875
`
` The Office of Pharmaceutical Quality initially recommended a complete response action for NDA
`
`210875 on December 20, 2018 based on insufficient information provided to qualify the
`
`drug product degradant
` at the proposed No More Than (NMT)
` mcg/film limit. Based
`
`on the new finding that the proposed limit for drug product degradant
` is qualified for safety,
`
`
` OPQ recommended approval of NDA 210875 for Kynmobi (apomorphine hydrochloride) Sublingual
` Film on January 22, 2019.
`
`
`
` After the January 22, 2019 recommendation revision, the CDER 505(b)(2) committee met to discuss the
`
`bridging strategy supporting approval. The outcome of this meeting resulted in a revision of the
`
` Biopharmaceutics recommendation to complete response due to the lack of a final report for the clinical
`pharmacokinetics study essential to establish the bridge between the US listed drug product and the
` active comparator, European Union drug product used in another critical relative bioavailability study.
`
`A new biopharmaceutics review was filed on January 25, 2019 which supersedes the original
`
` biopharmaceutics filed on December 20, 2018.
`
`Based on this new finding, OPQ recommends a COMPLETE
`
`RESPONSE action for NDA 210875.
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` www.fda.gov
`
`
`Reference ID: 4613103
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

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`Wendy
`Wilson- Lee
`
`Digitally signed by Wendy Wilson- Lee
`Date: 1/29/2019 08:48:53AM
`GUID: 50816dbc000085595ca3284bbca465a8
`
`Reference ID: 4613103
`
`
`

`

`
` QUALITY ASSESSMENT
`
`
`BIOPHARMACEUTICS
`
`
`
`THIS REVIEW SUPERSEDES THE REVIEW FILED ON 12/20/2018.
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` Product Background:
`
`
` NDA: 210875; Fast Track Designation; Priority review requested
`
`
`
`
`
`
`
`Drug Product Name / Strength: KYNMOBI® (apomorphine hydrochloride)
`
`
` Film / 10, 15, 20, 25, and 30 mg
`
`
`
`
`
`
` Route of Administration: For sublingual administration
`
` Proposed Indication: Acute, intermittent treatment of “OFF” episodes associated with
`
`
`
` Parkinson’s disease
`
`
`
`
` under the tongue, up to 5 times daily (Start with 10
` Proposed Dosage: 10 mg
`
`
` mg, then (if tolerated) titrate to an effective dose.) Doses of 10 mg to 30 mg are
`administered as a single film.
`
` Up to 5 times daily as needed for management of OFF
` episodes; Doses should be at least 2 hours apart
`
`
`
` Maximum Daily Dose:
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` Applicant Name: Sunovion Pharmaceuticals Inc.
`
`
`
`
`
` Primary Reviewer: Gerlie Gieser, Ph.D.
` Secondary Reviewer: Ta-Chen Wu, Ph.D.
`
`
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`
`
` Review Recommendation:
`
` From the Biopharmaceutics perspective, NDA 210875 is not recommended for
`
`
`
`
`
`
` APPROVAL at this time, mainly due to an outstanding deficiency related to the lack of
` a final report for a clinical PK study essential to establish the bridge between the US
`
`
`
`
` Listed Drug product and the active comparator/European (EU) drug product used in
`
`
`
`
`
` another critical relative BA study.
`
`Review Summary:
`
` film
`This 505(b)(2) NDA for KYNMOBI® (apomorphine hydrochloride)
`
`
` (formerly known as APL-130277) for sublingual administration relies for approval, in
` part, on the nonclinical, clinical safety, and clinical pharmacology information of
`
`
`
` APOKYN® subcutaneous injection [NDA 21-264].
`
`
` Dosage Form Nomenclature
` The proposed drug product intended for sublingual administration is a film strip
`
`consisting of
`
`
`
`
`
`
`
`
` the proposed drug product, from
`
` the Biopharmaceutics perspective, it is more appropriate to refer to the proposed drug
`
`OPQ-XOPQ-TEM-0001v04
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`
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`Reference ID: 4613103
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` Page 1 of 12
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` Effective Date: 14 February 2017
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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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`(b) (4)
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`(b) (4)
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` QUALITY ASSESSMENT
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` product as a “sublingual film” or “film for sublingual administration”
`
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` .
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` Dissolution Method and Acceptance Criterion
`
`
`
` Based on the data generated from additional FDA requested studies, the dissolution
`
`
`
` method and acceptance criterion (as tabulated below) are approved for the routine QC of
` all five proposed commercial strengths of apomorphine sublingual film at batch release
`
`
` and during stability testing.
`
`
` USP
`
` Apparatus
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`5 (paddle
`
` over disk)
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` Speed
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` Medium
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` Volume
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` Acceptance criterion
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` 75 rpm
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` 20mM BIS-TRIS HCl
`
` pH 6.4 buffer,
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` 37 ± 0.5°C
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`
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` 500 mL NLT % (Q) of the label
`
` claim dissolved in 10 min
`
`
` Biowaiver/Bridging to the Proposed To-Be-Marketed Drug Product
`
`
`All proposed commercial strengths of the to-be-marketed drug product were evaluated
`
` in the pivotal clinical trials/studies. Additionally, the proposed to-be-marketed drug
`product has the same formulation and manufacturing process as those used in the pivotal
`
` clinical trials/studies and the registration stability studies. Therefore, bridging data to
` and a biowaiver request(s) for the proposed commercial drug product are not needed.
`
`
`
`
`
`
`
`
` 505(b)(2) Bridging Strategy to the Listed Drug Product - INCOMPLETE
` Overall, the provided in vivo PK (and supporting in vitro) data would have been
`
`
`sufficient to establish the bridge between the proposed apomorphine sublingual film and
` the Listed Drug product (APOKYN® for subcutaneous administration), thereby
`
`
`
`
`
` allowing the Applicant of this 505(b)(2) NDA to rely, in part, on the nonclinical and
` clinical systemic safety and clinical pharmacology information for APOKYN. However,
`
`
`
` the final clinical study report for one of the essential studies was not submitted thereby
`
`
`
` precluding the thorough evaluation of the comparative PK data by the Office of Clinical
`
` Pharmacology (OCP) Reviewers. Thus, the adequacy of the said in vivo PK study vital
`
`
` to this Biopharmaceutics Reviewer’s bridging evaluation of the device components of
`
`
` the US and the EU reference products cannot be concluded by OCP at this time. Note
`
`
`
` that the efficacy and local safety of the proposed drug product (administered
` sublingually at an adjusted dose in order to match systemic exposures to the
`
`
`
`
` subcutaneously administered Listed Drug product) were investigated versus placebo in a
` pivotal Phase 3 trial(s) conducted by the Applicant. For details, refer to “REVIEWER
`
`
` NOTE” on page 10 of this review.
`
`OPQ-XOPQ-TEM-0001v04
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`Reference ID: 4613103
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` Page 2 of 12
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` Effective Date: 14 February 2017
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`(b) (4)
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`(b) (4)
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`(b)
`(4)
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` QUALITY ASSESSMENT
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`
`
` List of Submissions reviewed:
`
`
` SDN-1, 3/29/2018, Original NDA
`
`
`
` SDN-7, 5/25/2018 [Part I Response to 5/17/2018 Biopharmaceutics Information
`
`
`
`
` Request (IR)]
` SDN-12, 6/15/2018 (Part II Response to 5/17/2018 Biopharmaceutics IR)
`
`
` SDN-18, 7/27/2018 (Part I Response to 7/12/2018 Biopharmaceutics IR)
` SDN-28, 9/18/2018 (Part II Response to 7/12/2018 Biopharmaceutics IR)
`
`
` SDN-35, 11/27/2018 (Response to 11/15/2018 Biopharmaceutics IR)
`
`
` SDN-38, 12/13/2018 (Response to11/29/2018 Biopharmaceutics IR)
` SDN-39, 12/19/2018 (Response to 12/17/2018 Biopharmaceutics IR)
`
`
` Concise Description of Outstanding Issues Remaining:
`
`
`
` Adequate bridging of the US Listed Drug and the EU reference drug products (pending
` final study report for CTH-203 for OCP review)
`
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` BCS Designation
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`
` Reviewer’s Assessment: NOT APPLICABLE
`
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`OPQ-XOPQ-TEM-0001v04
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`
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`Reference ID: 4613103
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` Page 3 of 12
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` Effective Date: 14 February 2017
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`(b) (4)
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`(b) (4)
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`

`

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` QUALITY ASSESSMENT
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` Disintegration in lieu of Dissolution Testing of the Sublingual film
`
`
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`
`
` Reviewer’s Assessment: NOT ACCEPTABLE
`
`
`
`OPQ-XOPQ-TEM-0001v04
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`
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`Reference ID: 4613103
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`
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` Page 4 of 12
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` Effective Date: 14 February 2017
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`(b) (4)
`
`1 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

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` QUALITY ASSESSMENT
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` Dissolution Method and Acceptance Criterion
`
`
` Reviewer’s Assessment: DISSOLUTION TESTING RECOMMENDED USING
`
`
` OPTIMIZED METHOD AND ACCEPTANCE CRITERION
`
` Dissolution Method
`
`Dissolution Method 01512 (as tabulated below) was used during pharmaceutical
`
`OPQ-XOPQ-TEM-0001v04
`
`
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`Reference ID: 4613103
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` Page 6 of 12
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` Effective Date: 14 February 2017
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`(b) (4)
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`(b) (4)
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`2 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
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`

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` QUALITY ASSESSMENT
`
`
`
`
` Bridging of Apomorphine Sublingual Film Formulations
`
`
`
` Reviewer’s Assessment: NOT NEEDED
`
`
`
`OPQ-XOPQ-TEM-0001v04
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`
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`Reference ID: 4613103
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` Page 9 of 12
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` Effective Date: 14 February 2017
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`(b) (4)
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`(b) (4)
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`

`

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` QUALITY ASSESSMENT
`
`
` REVIEWER NOTE:
`
`
` The Applicant provided in vivo relative bioavailability data comparing the proposed to­
`
`
`
`
`
` be-marketed drug product (Apomorphine Sublingual Film) to two reference products,
` i.e., the Listed Drug, APOKYN® and the European approved product, Apo-go®
`
`
`
`
`
`
` subcutaneous (s.c.) injections (CTH-203). The interim PK study report states “The two
`s.c. formulations were nearly identical to each other with a bioavailability relative to
`
`
`
` each other of over % when APO-go was compared to APOKYN. Compared to the
` s.c. regimens, apomorphine sublingual film relative bioavailability was approximately
`
`
`
` %.” Additional relative BA data are available to compare the proposed sublingual
` film to Apo-go® (CTH-200). Note that during the IND stage, FDA recommended that
`
`
`
`
` the PK study report of Study CTH-203 be also included in the NDA to confirm the
` “sameness” of APOKYN and APO-go. Note that in an internal meeting held on
`
`
`
` 1/25/2019 among representatives of the Division of Biopharmaceutics, the Office of
` Clinical Pharmacology (OCP), and the 505(b)(2) Committee, it was concluded that the
`
`
`
` final clinical study report of PK Study CTH-203 had to be submitted because it is a
`
`study essential to supporting the bridge between the US and EU reference products
`(APOKYN and Apo-go, respectively), and ultimately, the bridge between the US
`Listed Drug product and the proposed sublingual film product (APOKYN and
`
` KYNMOBI, respectively). Note also that previously, the Clinical Pharmacology
` Reviewer (Dr. Mariam Ahmed) confirmed the adequacy of the comparative in vivo PK
`
`
`
`
` data generated in relative BA Study CTH-200.
`
`
`
`
`
`
`
`
` To support the “sameness” of the Listed Drug product to the PK comparator used in an
` earlier relative BA study CTH-200 (APOKYN® Autopen 10 mg/mL Solution for
`
`
`
`
`
`
` Injection and Apo-go® PEN 10 mg/mL Solution for Injection, respectively),
`
`
`
`
` comparative in vitro data (pH, assay, appearance, impurities) were provided for the test
`
`
`
` and reference injectable solution drug products. This Reviewer confirms that the drug
`
`
`
` components of these two drug-device combination products are comparable in terms of
`
`
`
` physicochemical properties; see Table 8 of Report SCAR-0878. Additionally, the
`
` Applicant pointed out that although APOKYN multi-dose cartridge (but not Apo-go)
`
`
`
`
` contains the preservative, benzyl alcohol 5 mg/mL, a version of APOKYN (solution in
`
`
`
` ampoule) without this preservative was once approved under the same US Prescribing
`
`
`
` Information; Tables 1 and 2 of the Report show that with the exception of the presence
`
`
`
` of benzyl alcohol in APOKYN Autopen, the compositions of the two injectable
` solutions (APOKYN and Apo-go) are the same. However, this Reviewer notes that the
`
`
`
`
`
`
`
`
`
`
`
` Effective Date: 14 February 2017
`
`
`
`OPQ-XOPQ-TEM-0001v04
`
`
`
`Reference ID: 4613103
`
`
`
` Page 10 of 12
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`(b) (4)
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`(b)
`(4)
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`(b)
`(4)
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`

`

` QUALITY ASSESSMENT
`
`
`
` Applicant was not able to provide comparative in vitro data with respect to the
`
`
`
` functional performance characteristics (e.g., activation force, volume dispensed,
`
`
`
` dispensing time, extended needle length, leakage rate) of the device components of
`
`
`
`
`
`
` these two drug-device combination products. Thus, it was deemed necessary to rely
`
`
`
`
`
` mainly on in vivo comparative PK data from Study CTH-203 to establish “sameness”
`
`
`
` of these two drug-device combination products, i.e., Listed Drug, APOKYN® Auto-
`
`
`
` pen (multi-dose cartridge, formulation with benzyl alcohol) versus Apo-go PEN (multi­
`
` dose cartridge, formulation without benzyl alcohol). Of note, Study CTH-203 was
`
`designed to also provide a direct PK comparison of the proposed apomorphine
`
`
` sublingual film versus APOKYN (the Listed Drug product).
`
`For this 505(b)(2) NDA, the Applicant declared reliance, in part, on APOKYN’s
` nonclinical toxicology/PK and clinical PK (metabolism, drug interactions) information.
`
`Provided the final PK study report findings of CTH-203 is deemed acceptable/adequate
`by OCP, in this Reviewer’s opinion, it is justified to rely on the FDA’s findings of
`
`
` nonclinical and clinical systemic toxicology/safety for subcutaneously administered
` APOKYN, based on the following information: (1) Based on the (interim) comparative
`
`
`
`clinical PK findings of relative BA Study CTH-203, the systemic bioavailability of
`
`
` apomorphine from the sublingual film is approximately % relative to that following
`subcutaneous administration of the same dose of the reference product, APOKYN, and
`
`
` the systemic bioavailabilities of APOKYN and Apo-go are similar (
` . (2) Thus,
` as confirmed by Dr. Ahmed, based on the comparative PK findings of CTH-200 and
`
`
`
` CTH-203, the sublingual administration of the recommended starting dose of 10 mg
` apomorphine film will provide apomorphine systemic exposures that are similar to
`
`
`
`
` those achieved following subcutaneous administration of the recommended starting (2
` mg apomorphine) dose of Apo-go or APOKYN. Refer also to the Medical Review for
`
`
`
`
` the evaluation of the findings of Phase 3 clinical trials that evaluated the efficacy
`and/or (long-term) local safety of the proposed sublingual film, using a starting dose of
`
` 10 mg. Refer also to DMEPA’s review of the human factors study. (3) Per the Clinical
`
`
`
` Pharmacology Reviewer, although the resulting plasma exposures (as AUC0-inf) to the
`
`
`
`
`
`
`
`
` major metabolite, apomorphine sulfate are expected to be substantially higher from the
` sublingual film as compared to the subcutaneously administered reference products
`
`
`
`
` based on the in vitro
`
`
` transporter substrate/inhibitor and metabolic inhibition/induction studies conducted by
`
`
` the Applicant, the potential for apomorphine sulfate and apomorphine associated drug
`
`
`
`
` interactions are unlikely. Additionally, Dr. Ahmed confirmed that it is appropriate to
`
` determine relative bioavailability of the proposed and the reference drug products
`
`
` based on apomorphine (rather than apomorphine sulfate) concentrations because none
`
`
` of the three major metabolites are pharmacologically and toxicologically active.
`
`
`
`
`
`
` Therefore, such in vitro metabolism and drug interaction information provides
`
`additional support to the conclusion that the systemic safety of apomorphine sublingual
`
`film and APOKYN
`
` is expected to be similar.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Effective Date: 14 February 2017
`
`
`
`OPQ-XOPQ-TEM-0001v04
`
`
`
`Reference ID: 4613103
`
`
`
` Page 11 of 12
`
`
`
`
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
` Biowaiver Request
`
` QUALITY ASSESSMENT
`
`
`
`
` Reviewer’s Assessment: NOT NEEDED
`
`
`
` A biowaiver request was not submitted (and is no longer deemed necessary) because
`the Applicant included all five proposed commercial strengths of the final, to-be­
`
` marketed apomorphine sublingual film in the clinical efficacy/safety trials.
`
`
`
`
`
`
`
`
`
`
`
` List of Deficiencies:
`
`
`
` Submission of the final study report for CTH-203 (for OCP review)
`
`
`
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v04
`
`
`
`Reference ID: 4613103
`
`
`
` Page 12 of 12
`
`
`
`
`
`
`
` Effective Date: 14 February 2017
`
`
`
`(b) (4)
`
`

`

`
`
`
`
`
`CENTER FOR EVALUATION OF DRUGS
`
`______________________________________________________________________________________________________________________________
`
` Memorandum
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` DATE: January 22, 2019
`
`
` TO: Division of Neurology Drug Products
`
`
`
` FROM: Wendy I. Wilson-Lee, Ph.D.
` Branch Chief
`
`
`
`
` SUBJECT: Change in approval recommendation for Kynmobi (apomorphine hydrochloride)
`
` Sublingual Film
`
` APPLICATION/DRUG: NDA 210875
`
` The Office of Pharmaceutical Quality initially recommended a complete response action for NDA
`
`
` drug product degradant
`210875 based on insufficient information provided to qualify the
`
`
`
`
`at the proposed No More Than (NMT)
` mcg/film limit.
` includes a
`structural alert for mutagenicity. Several rounds of information requests were sent to the applicant
`
`
` requesting additional information to support qualification or reduction of the specification limit to NMT
` mcg/film to comply with the NMT mcg/day limit for mutagenic impurities. In response to
`
`
`
`
` these information requests, the applicant did not revise the specification limit and reiterated the
` mcg/film limit. Hence, OPQ
`
`previously submitted justification for the proposed NMT
`
` recommended a complete response action on December 20, 2018.
`
` Since the initial recommendation, OPQ has continued to work with the nonclinical and clinical teams on
` The initial mcg/day limit for
`
`
` the qualification of
`was based on the
`
`
` assumption of lifetime exposure (i.e. > 10 years). Additional clarity on the anticipated duration of
`
` human use was provided by the clinical team, indicating that the expected use of this product is less than
`
` 10 years for most patients. Based on an anticipated duration of human use of < 10 years, the acceptable
`
`
`
`
` total daily intake for potentially mutagenic impurities increases to NMT mcg/day (ICH
`
` mcg/film, the total daily intake would be
`. At the currently proposed limit of NMT
`
` mcg/day (2 films per dose x 5 doses per day = 10 films per day). This total daily intake is well within
`
`
` the limit established for duration of treatments < 10 years.
`
`
` is qualified for
`Based on the new finding that the proposed limit for drug product degradant
`
`
` safety, OPQ recommends approval of NDA 210875 for Kynmobi (apomorphine hydrochloride)
` Sublingual Film. All deficiencies have been adequately addressed in this review cycle. There are no
`
`
` outstanding issues precluding approval.
`
`
`
`
`
`
`
`
`
`
`
`
` www.fda.gov
`
`
`Reference ID: 4613103
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Wendy
`Wilson- Lee
`
`Digitally signed by Wendy Wilson- Lee
`Date: 1/22/2019 09:50:37AM
`GUID: 50816dbc000085595ca3284bbca465a8
`
`Reference ID: 4613103
`
`
`

`

`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`
`Recommendation: COMPLETE RESPONSE
`
`
`
`
`
`
`
`
`NDA 210875
`
`
`Review # 01
`
`
`
`
`
` Apomorphine Hydrochloride Sublingual Film
`
` 10 mg, 15 mg, 20 mg, 25 mg, 30 mg
`
` Sublingual
`
` Rx
` Sunovion Pharmaceuticals Inc.
`
` N/A
`
`
`
`
`
` Drug Name/Dosage Form
`
` Strength
`
` Route of Administration
` Rx/OTC Dispensed
`
`
` Applicant
` US agent, if applicable
`
`
`
`
`
`
`
`
`
`
`SUBMISSION(S)
`
` REVIEWED
`
` Original
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
`
`
`DOCUMENT
`
` DATE
`
` 29-MAR-2018
`
` 25-MAY-2018
`
` 13-JUN-2018
`
` 15-JUN-2018
`
` 15-JUN-2018
`
` 18-JUN-2018
`
` 12-JUL-2018
`
` 20-JUL-2018
`
` 27-JUL-2018
`
` 03-AUG-2018
`
`
`
`SUBMISSION(S)
`
` REVIEWED
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
` Amendment
`
`DOCUMENT
`
` DATE
`
` 13-AUG-2018
`
` 22-AUG-2018
`
` 18-SEP-2018
`
` 21-SEP-2018
`
` 30-OCT-2018
`
` 27-NOV-2018
`
` 30-NOV-2018
`
` 07-DEC-2018
`
` 13-DEC-2018
`
` 19-DEC-2018
`
`
`
` DISCIPLINE
`
`
` Drug Substance
`
` Drug Product
` Environmental
`
`
` Labeling
`
`
`
` Process
`
` Facility
`
` Biopharmaceutics
`
`
` Regulatory Business Process
` Manager
`
`Application Technical Lead
`
`
`
`
`
` Quality Review Team
`
`PRIMARY
`
` REVIEWER
`
` Ben Zhang
`
`SECONDARY
`
` REVIEWER
`
` Suong Tran
`
`
`
` Rao Kambhampati Wendy Wilson-Lee
`
`
`
`
`
` Yuesheng Ye
`
`
`
` Gerlie Geiser
`
`Nallaperumal
`
` Chidambaram
`
` Ruth Moore
`
` Ta-Chen Wu
`
`
`
` Dahlia Walters
`
`
`
` Wendy Wilson-Lee
`
`OPQ
` OFFICE
`
`
`ONDP
`
`
`
`
`
` OPF
`
`
`
` ONDP
`
`
`
` OPRO
`
`
`
` ONDP
`
`
`
`
` OPQ-XOPQ-TEM-0001v03 Page 1 of 9
`
`
`Reference ID: 4613103
`
`
`
` Effective Date: 18 Feb 2016
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` QUALITY ASSESSMENT
`
`
` Quality Review Data Sheet
`
`
`
`
`
`
`
`
` 1. RELATED/SUPPORTING DOCUMENTS
`
`
`
`
` A. DMFs:
`
` DMF
`
` #
`
`
`
` Type
`
`
`
` Holder
`
`
`
` Type II
`
` Item
`
` Referenced
`
`Apomorphine
`
` hydrochloride
`
`
`Status
`
`
` Date Review
`
` Completed
`
` Adequate 15-AUG-2018
`
`
`
`
` Comments
`
`
`
`
`
`
` B. Other Documents: IND, RLD, or sister applications
`
`
`
`
`
` DESCRIPTION
`
` Apomorphine Film
`
` APOKYN (apomorphine) Injection
`
`
`
`
`
` DOCUMENT APPLICATION NUMBER
`
`
`
`
` 110955
`
` 21264
`
` IND
`
`
` NDA
`
`
`
`2. CONSULTS
`
`
`
`
`
`
` None.
`
`
`
`
`
`
` OPQ-XOPQ-TEM-0001v03 Page 2 of 9
`
`
`Reference ID: 4613103
`
`
`
` Effective Date: 18 Feb 2016
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`
`
`Executive Summary
`
`
`
`
`
`
`
`
` I. Recommendations and Conclusion on Approvability
`
`
`
`
`
`
`
`
`
`
`
` OPQ recommends a COMPLETE RESPONSE for NDA 210875 due to inadequate
` controls for a mutagenic impurity in the drug product.
`
`
` Draft Complete Response Deficiency
`
` The proposed drug product limit for the orthoquinone degradant
`
`
`
`
`
`
` mcg/film) is not acceptable as it results in a daily intake of
` mcg/day for this potentially
` mutagenic impurity at the maximum recommended dose (2 films per dose X 5 doses per day
`
`= 10 films). The data and justification provided in the submission were not adequate to
` mcg/day intake given the likely chronic administration for this product. As such,
`
`
`
` support
`
`
`
` provide a revised drug product specification that reflects a control limit for
` that
` mcg/day intake based on the maximum recommended dose (i.e. 10 films).
`
`
` ensures a NMT
`
`
` Revise all relevant sections of the submission to reflect this change. Alternatively, provide
` additional justification, supported by data, to demonstrate that the proposed
`
` mcg/day
`
`
`
` intake of
`is safe.
`
`
`
`
`II.
`
`
`Summary of Quality Assessments
`
`
`
`
` A. Product Overview
`
`
`Proposed Indication(s) including
`
` Intended Patient Population
`
`
`
`
`
`
`
` Duration of Treatment
`
`
` Maximum Daily Dose
`
`
` Alternative Methods of
` Administration
`
`
`
`
`
`
`
`
`
`
` Treatment of acute, intermittent hypomobility
` “OFF” episodes associated with Parkinson’s
`
`
`
` Disease
`
`
` Chronic
`
`
`
` None
`
`
`
` The Applicant is seeking approval of Apomorphine Sublingual Film as an acute,
`
`
`
`
`
`
`
`
`
` intermittent treatment of “OFF” episodes associated with Parkinson’s disease
`
`
` The sublingual film dosage form is an alternative dosage form
`
`
`
`
`
`
`
` to the listed drug APOKYN (apomorphine) Injection for subcutaneous administration
`
`
`
` (NDA 21264, approved April 2004). The subcutaneous injection is the only FDA-
`
`
`
`
`
`
`
`
`
` approved apomorphine product. FDA granted Fast Track designation for the sublingual
`
`
`
`
`
`
`
`
`
` film dosage form (August 2016). FDA reached agreement with the Applicant regarding
`
`
`
` the initial pediatric study plan in August 2015 (intent to request full waiver based on
`
`
`
`
` disease). OPQ provided advice on the development program as part of the End of Phase
`
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v03
`
`
`
`
`Reference ID: 4613103
`
`
` Page 3 of 9
`
`
`
`
`
`
`
`
`
` Effective Date: 18 Feb 2016
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`
`
`
`
`
`
` 2 Meeting (March 2015; Topics – stability protocol, packaging integrity, excipient
` control strategy, impurity/degradant control strategy) and via an Advice Letter (April
`
`
`
`
` 2016; Topic – determination of product sameness).
`
`
`
`
`
`
`The drug product
`
`
`
` consisting of an active apomorphine HCl
`
`
`
`
` The apomorphine hydrochloride drug substance used in the product is
`
`
` manufactured to comply with the current USP monograph under
` DMF.
` The sublingual film is a blue, rectangular film with white imprints to distinguish the
`
`
`strength. The bulk master
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` B. Quality Assessment Overview
`
`
`
`
`The apomorphine hydrochloride drug substance used in the product is manufactured to
`
`comply with the current USP monograph under
` DMF
`. Batch
` analysis data for the three registration batches was provided in the NDA. The drug
`
`
`substance specification was provided in the NDA in response to an in