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` CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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` APPLICATION NUMBER:
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` 210557Orig1s000
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`MULTI-DISCIPLINE REVIEW
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`
` Summary Review
` Office Director
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` Division Diretcor
`
` CDTL Review
`Clinical Review
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`
` Non-Clinical Review
`Statistical Review
`
` Clinical Pharmacology Review
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`

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`Food and Drug Administration (FDA)
`
`Center for Drug Evaluation and Research (CDER)
`
`Office of New Drugs (OND)
`
`Office of Drug Evaluation (ODE) III
`
`Division of Bone, Reproductive, and Urologic Products (DBRUP)
`
`Clinical Memorandum
`
`
`June 25, 2019
`
`
`NDA 210557
`
`Christina Chang, M.D., M.P.H. – Clinical Team Leader, DBRUP
`
`
`To:
`
`From:
`
`Through:
`
`Audrey Gassman, M.D., – Deputy Division Director, DBRUP
`
`
`
`
`This memorandum serves to amend information contained Section 1.3 in the June 21, 2019
`Summary Review for Vyleesi.
`
`Vyleesi is a drug-device combination product containing the active ingredient bremelanotide
`(BMT), a synthetic heptapeptide and melanocortin receptor (MCR) agonist, in a prefilled
`syringe. Vyleesi was approved on June 21, 2019 for the treatment of premenopausal women with
`acquired, general hypoactive sexual desire disorder (HSDD).
`In the Summary Review finalized on June 21, 2019, a table in Section 1.3 (titled Patient
`Experience Data) was inadvertently truncated. The complete table is shown below.
`
`1
`
`
`Reference ID: 4454113
`
`

`

`1.3.
`
`Patient Experience Data
`
`Patient Experience Data Relevant to this Application (check all that apply)
`The patient experience data that were submitted as part of the Section of review where
`x
`application include:
`discussed, ifapplicable
`Section 8.1.1 Study
`x Clinical outcome assessment (COA) data, such as
`Endpoints
`
`0
`
`Patient reported outcome (PRO)
`x
`0 Observer repo1ted outcome (ObsRO)
`Clinician repo1ted outcome (ClinRO)
`Perfonnance outcome (PerfO)
`
`0
`0 Qualitative studies (e.g., individual patient/caregiver
`
`interviews, focus group interviews, expe1t interviews, Delphi
`
`Panel, etc.)
`
`x Patient-focused diug development or other stakeholder
`
`meeting summa1y reports1
`0 Observational survey studies designed to capture patient
`
`experience data
`
`0 Natural histo1y studies
`
`Patient preference studies (e.g., submitted studies or scientific
`
`publications)
`
`0 Other: (Please specify):
`
`
`0
`
`Section 8.1.1 Study
`Endpoints
`
`0
`
`Patient experience data that were not submitted in the application, but were considered
`in this review:
`o ~ Input info1med from paiticipation in meetings with patient
`
`~ stakeholders
`
`...........................................................................................................................................................
`
`o ~ Patient-focused diug development or other stakeholder meeting
`
`~ ..~~.~"Y...~:~P.9.~!~.................................................................................................................
`
`o ~ Observational survey studies designed to capture patient
`
`~ ..~.~P..~~-i~E.'?.~.9.:~~~....................................................................................................................
`
`~ Other: (Please specify):
`
`0
`
`0
`
`Patient experience data was not submitted as part of this application.
`
`1 FDA Patient-Focused Drug Development Public Meeting and Scientific Workshop on Female Sexual Dysfunction
`held on October 26 and 27, 2014, respectively. https://www.federalregister.gov/documents/2014/09/26/2014­
`22983/patient-focused-drug-development-public-meeting-and-scientific-workshop-on-female-sexual-dysfunction
`
`2
`
`Reference ID 4454113
`
`

`

`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/
`------------------------------------------------------------
`
`CHRISTINA Y CHANG
`06/25/2019 03:40:37 PM
`Amendment to Section 1.3 of UniReview
`
`AUDREY L GASSMAN
`06/25/2019 03:42:11 PM
`
`Reference ID: 4454113
`
`

`

`E DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ^ƚĂŶĚĂƌĚ ϮϭϬϱϱϳ
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`
`Eͬ> DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ
`ƉƉůŝĐĂƚŝŽŶ dLJƉĞ E
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`ŝǀŝƐŝŽŶͬKĨĨŝĐĞ ZhW
`ZĞǀŝĞǁ ŽŵƉůĞƚŝŽŶ ĂƚĞ
`:ƵŶĞ Ϯϭ͕ ϮϬϭϵ
`ƐƚĂďůŝƐŚĞĚ EĂŵĞ ƌĞŵĞůĂŶŽƚŝĚĞ
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`ŽĚĞ ŶĂŵĞ
`ƉƉůŝĐĂŶƚ D' WŚĂƌŵĂĐĞƵƚŝĐĂůƐ͕ /ŶĐ͘
`&ŽƌŵƵůĂƚŝŽŶ;ƐͿ ^ƵďĐƵƚĂŶĞŽƵƐ ŝŶũĞĐƚŝŽŶ
`ŽƐŝŶŐ ZĞŐŝŵĞŶ KŶĞ ŝŶũĞĐƚŝŽŶ͕ ĂƐ ŶĞĞĚĞĚ͕ ŶŽƚ ƚŽ ĞdžĐĞĞĚ ŵŽƌĞ ƚŚĂŶ ŽŶĞ ĚŽƐĞ ŝŶ
`Ă ϮϰͲŚŽƵƌ ƉĞƌŝŽĚ ĂŶĚ ŶŽƚ ƚŽ ĞdžĐĞĞĚ ϴ ĚŽƐĞƐ ƉĞƌ ŵŽŶƚŚ
`dƌĞĂƚŵĞŶƚ ŽĨ ƉƌĞŵĞŶŽƉĂƵƐĂů ǁŽŵĞŶ ǁŝƚŚ ĂĐƋƵŝƌĞĚ͕
`ŐĞŶĞƌĂůŝnjĞĚ ŚLJƉŽĂĐƚŝǀĞ ƐĞdžƵĂů ĚĞƐŝƌĞ ĚŝƐŽƌĚĞƌ ;,^Ϳ ĂƐ
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`Žƌ ŝŶƚĞƌƉĞƌƐŽŶĂů ĚŝĨĨŝĐƵůƚLJ
`ƉƉƌŽǀĂů
`
`ƉƉůŝĐĂŶƚ WƌŽƉŽƐĞĚ
`/ŶĚŝĐĂƚŝŽŶ;ƐͿͬWŽƉƵůĂƚŝŽŶ;ƐͿ
`
`ZĞĐŽŵŵĞŶĚĂƚŝŽŶ ŽŶ
`ZĞŐƵůĂƚŽƌLJ ĐƚŝŽŶ
`ZĞĐŽŵŵĞŶĚĞĚ
`/ŶĚŝĐĂƚŝŽŶ;ƐͿͬWŽƉƵůĂƚŝŽŶ;ƐͿ
`;ŝĨ ĂƉƉůŝĐĂďůĞͿ
`
`WƌĞŵĞŶŽƉĂƵƐĂů ǁŽŵĞŶ ǁŝƚŚ ĂĐƋƵŝƌĞĚ͕ ŐĞŶĞƌĂůŝnjĞĚ ,^
`
`Reference ID: 4452816
`
`ϭ
`
`

`

`E DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ^ƚĂŶĚĂƌĚ ϮϭϬϱϱϳ
`NDA Multi-Disciplinary Review and Evaluation Standard 210557
`sLJůĞĞƐŝͬďƌĞŵĞůĂŶŽƚŝĚĞ
`Vyleesi/bremelanotide
`
`dĂďůĞ ŽĨ ŽŶƚĞŶƚƐ
`
`Table of Contents
`
`Ϯ
`2
`
`ϰ
`4
`
`dĂďůĞ ŽĨ dĂďůĞƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰ
`Table of Tables ................................................................................................................................ 4
`dĂďůĞ ŽĨ &ŝŐƵƌĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϳ
`Table of Figures ............................................................................................................................... 7
`ZĞǀŝĞǁĞƌƐ ŽĨ DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϵ
`Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 9
`ĚĚŝƚŝŽŶĂů ZĞǀŝĞǁĞƌƐ ŽĨ ƉƉůŝĐĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϵ
`Additional Reviewers of Application ............................................................................................... 9
`ZĞǀŝĞǁĞƌ ^ŝŐŶĂƚƵƌĞƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϭ
`Reviewer Signatures ..................................................................................................................... 11
`'ůŽƐƐĂƌLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϰ
`Glossary ......................................................................................................................................... 14
`ϭ
`džĞĐƵƚŝǀĞ ^ƵŵŵĂƌLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϳ
`1
`Executive Summary ............................................................................................................... 17
`ϭ͘ϭ͘ WƌŽĚƵĐƚ /ŶƚƌŽĚƵĐƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϳ
`1.1.
`Product Introduction ...................................................................................................... 17
`ϭ͘Ϯ͘ ĞŶĞĨŝƚͲZŝƐŬ ƐƐĞƐƐŵĞŶƚ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϴ
`1.2.
`Benefit-Risk Assessment ................................................................................................ 18
`ϭ͘ϯ͘ WĂƚŝĞŶƚ džƉĞƌŝĞŶĐĞ ĂƚĂ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϲ
`1.3.
`Patient Experience Data ................................................................................................. 26
`dŚĞƌĂƉĞƵƚŝĐ ŽŶƚĞdžƚ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϳ
`Therapeutic Context .............................................................................................................. 27
`Ϯ͘ϭ͘ ŶĂůLJƐŝƐ ŽĨ ŽŶĚŝƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϳ
`2.1. Analysis of Condition ...................................................................................................... 27
`Ϯ͘Ϯ͘ ŶĂůLJƐŝƐ ŽĨ ƵƌƌĞŶƚ dƌĞĂƚŵĞŶƚ KƉƚŝŽŶƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϳ
`2.2. Analysis of Current Treatment Options ......................................................................... 27
`ϯ ZĞŐƵůĂƚŽƌLJ ĂĐŬŐƌŽƵŶĚ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϵ
`Regulatory Background ......................................................................................................... 29
`3
`ϯ͘ϭ͘ h͘^͘ ZĞŐƵůĂƚŽƌLJ ĐƚŝŽŶƐ ĂŶĚ DĂƌŬĞƚŝŶŐ ,ŝƐƚŽƌLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϵ
`3.1. US. Regulatory Actions and Marketing History ............................................................. 29
`ϯ͘Ϯ͘ ^ƵŵŵĂƌLJ ŽĨ WƌĞƐƵďŵŝƐƐŝŽŶͬ^ƵďŵŝƐƐŝŽŶ ZĞŐƵůĂƚŽƌLJ ĐƚŝǀŝƚLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϵ
`3.2.
`Summary of Presubmission/Submission Regulatory Activity ........................................ 29
`^ŝŐŶŝĨŝĐĂŶƚ /ƐƐƵĞƐ &ƌŽŵ KƚŚĞƌ ZĞǀŝĞǁ ŝƐĐŝƉůŝŶĞƐ WĞƌƚŝŶĞŶƚ ƚŽ ůŝŶŝĐĂů ŽŶĐůƵƐŝŽŶƐ ŽŶ
`Significant Issues From Other Review Disciplines Pertinent to Clinical Conclusions on
`ĨĨŝĐĂĐLJ ĂŶĚ ^ĂĨĞƚLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϲ
`Efficacy and Safety ................................................................................................................. 36
`ϰ͘ϭ͘ KĨĨŝĐĞ ŽĨ ^ĐŝĞŶƚŝĨŝĐ /ŶǀĞƐƚŝŐĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϲ
`4.1. Office of Scientific Investigations ................................................................................... 36
`ϰ͘Ϯ͘ WƌŽĚƵĐƚ YƵĂůŝƚLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϲ
`4.2.
`Product Quality .............................................................................................................. 36
`ϰ͘ϯ͘ ůŝŶŝĐĂů DŝĐƌŽďŝŽůŽŐLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϳ
`4.3.
`Clinical Microbiology ...................................................................................................... 37
`ϰ͘ϰ͘ ĞǀŝĐĞƐ ĂŶĚ ŽŵƉĂŶŝŽŶ ŝĂŐŶŽƐƚŝĐ /ƐƐƵĞƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϴ
`4.4. Devices and Companion Diagnostic Issues .................................................................... 38
`ϱ EŽŶĐůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJͬdŽdžŝĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϵ
`Nonclinical Pharmacology/Toxicology................................................................................... 39
`5
`ϱ͘ϭ͘ džĞĐƵƚŝǀĞ ^ƵŵŵĂƌLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϵ
`5.1.
`Executive Summary ........................................................................................................ 39
`ϱ͘Ϯ͘ ZĞĨĞƌĞŶĐĞĚ EƐ͕ >Ɛ͕ D&Ɛ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϲ
`5.2. Referenced NDAs, BLAs, DMFs ....................................................................................... 46
`ϱ͘ϯ͘ WŚĂƌŵĂĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϳ
`5.3.
`Pharmacology ................................................................................................................. 47
`ϱ͘ϯ͘ϭ͘ WƌŝŵĂƌLJ WŚĂƌŵĂĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϳ
`5.3.1. Primary Pharmacology ............................................................................................... 47
`ϱ͘ϯ͘Ϯ͘ ^ĞĐŽŶĚĂƌLJ WŚĂƌŵĂĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϮ
`5.3.2. Secondary Pharmacology ........................................................................................... 52
`ϱ͘ϯ͘ϯ͘ ^ĂĨĞƚLJ WŚĂƌŵĂĐŽůŽŐLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϯ
`5.3.3. Safety Pharmacology ................................................................................................. 53
`ϱ͘ϰ͘ DͬW<͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϵ
`5.4. ADM E/PK ........................................................................................................................ 59
`ϱ͘ϱ͘ 'ĞŶĞƌĂů dŽdžŝĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϲϳ
`5.5. General Toxicology ......................................................................................................... 67
`ϱ͘ϲ͘ 'ĞŶĞƚŝĐ dŽdžŝĐŽůŽŐLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϳϯ
`5.6. Genetic Toxicology ......................................................................................................... 73
`ϱ͘ϳ͘ ĂƌĐŝŶŽŐĞŶŝĐŝƚLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϳϱ
`5.7. Carcinogenicity ............................................................................................................... 75
`ϱ͘ϳ͘ϭ͘ <ĞLJ ^ƚƵĚLJ &ŝŶĚŝŶŐƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϳϱ
`5.7.1. Key Study Findings ..................................................................................................... 75
`ϱ͘ϳ͘Ϯ͘ ĚĞƋƵĂĐLJ ŽĨ ĂƌĐŝŶŽŐĞŶŝĐŝƚLJ ^ƚƵĚŝĞƐ͗͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϳϲ
`5.7.2. Adequacy of Carcinogenicity Studies: ........................................................................ 76
`ϱ͘ϴ͘ ZĞƉƌŽĚƵĐƚŝǀĞ ĂŶĚ ĞǀĞůŽƉŵĞŶƚĂů dŽdžŝĐŽůŽŐLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϳϲ
`5.8. Reproductive and Developmental Toxicology ............................................................... 76
`ϱ͘ϵ͘ KƚŚĞƌ dŽdžŝĐŽůŽŐLJ ^ƚƵĚŝĞƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴϯ
`5.9. Other Toxicology Studies ............................................................................................... 83
`ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴϱ
`Clinical Pharmacology ............................................................................................................ 85
`ϲ͘ϭ͘ džĞĐƵƚŝǀĞ ^ƵŵŵĂƌLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴϱ
`6.1.
`Executive Summary ........................................................................................................ 85
`ϲ͘Ϯ͘ ^ƵŵŵĂƌLJ ŽĨ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ ƐƐĞƐƐŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴϲ
`6.2.
`Summary of Clinical Pharmacology Assessment ............................................................ 86
`ϲ͘Ϯ͘ϭ͘ WŚĂƌŵĂĐŽůŽŐLJ ĂŶĚ ůŝŶŝĐĂů WŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴϲ
`6.2.1. Pharmacology and Clinical Pharmacokinetics ........................................................... 86
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`6
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`Reference ID: 4452816
`Reference ID: 4452816
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`E DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ^ƚĂŶĚĂƌĚ ϮϭϬϱϱϳ
`NDA Multi-Disciplinary Review and Evaluation Standard 210557
`sLJůĞĞƐŝͬďƌĞŵĞůĂŶŽƚŝĚĞ
`Vyleesi/bremelanotide
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`ϲ͘Ϯ͘Ϯ͘ 'ĞŶĞƌĂů ŽƐŝŶŐ ĂŶĚ dŚĞƌĂƉĞƵƚŝĐ /ŶĚŝǀŝĚƵĂůŝnjĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴϳ
`6.2.2. General Dosing and Therapeutic Individualization .................................................... 87
`ϲ͘ϯ͘ ŽŵƉƌĞŚĞŶƐŝǀĞ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ ZĞǀŝĞǁ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴϵ
`6.3. Comprehensive Clinical Pharmacology Review ............................................................. 89
`ϲ͘ϯ͘ϭ͘ 'ĞŶĞƌĂů WŚĂƌŵĂĐŽůŽŐLJ ĂŶĚ WŚĂƌŵĂĐŽŬŝŶĞƚŝĐ ŚĂƌĂĐƚĞƌŝƐƚŝĐƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴϵ
`6.3.1. General Pharmacology and Pharmacokinetic Characteristics ................................... 89
`ϲ͘ϯ͘Ϯ͘ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ YƵĞƐƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϵϬ
`6.3.2. Clinical Pharmacology Questions ............................................................................... 90
`^ŽƵƌĐĞƐ ŽĨ ůŝŶŝĐĂů ĂƚĂ ĂŶĚ ZĞǀŝĞǁ ^ƚƌĂƚĞŐLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϱ
`Sources of Clinical Data and Review Strategy ..................................................................... 105
`ϳ͘ϭ͘ dĂďůĞ ŽĨ ůŝŶŝĐĂů ^ƚƵĚŝĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϱ
`7.1.
`Table of Clinical Studies ................................................................................................ 105
`ϳ͘Ϯ͘ ZĞǀŝĞǁ ^ƚƌĂƚĞŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϴ
`7.2.
`Review Strategy ............................................................................................................ 108
`^ƚĂƚŝƐƚŝĐĂů ĂŶĚ ůŝŶŝĐĂů ĂŶĚ ǀĂůƵĂƚŝŽŶ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϵ
`Statistical and Clinical and Evaluation ................................................................................. 109
`ϴ͘ϭ͘ ZĞǀŝĞǁ ŽĨ ZĞůĞǀĂŶƚ /ŶĚŝǀŝĚƵĂů dƌŝĂůƐ hƐĞĚ ƚŽ ^ƵƉƉŽƌƚ ĨĨŝĐĂĐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϵ
`8.1.
`Review of Relevant Individual Trials Used to Support Efficacy .................................... 109
`ϴ͘ϭ͘ϭ͘ dƌŝĂůƐ DdͲϯϬϭ ĂŶĚ DdͲϯϬϮ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϵ
`8.1.1. Trials BMT-301 and BMT-302 .................................................................................. 109
`ϴ͘ϭ͘Ϯ͘ ^ƚƵĚLJ ZĞƐƵůƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϮϳ
`8.1.2. Study Results ............................................................................................................ 127
`ϴ͘ϭ͘ϯ͘ ƐƐĞƐƐŵĞŶƚ ŽĨ ĨĨŝĐĂĐLJ ĐƌŽƐƐ dƌŝĂůƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϱϬ
`8.1.3. Assessment of Efficacy Across Trials ........................................................................ 150
`ϴ͘ϭ͘ϰ͘ /ŶƚĞŐƌĂƚĞĚ ƐƐĞƐƐŵĞŶƚ ŽĨ ĨĨĞĐƚŝǀĞŶĞƐƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϱϭ
`8.1.4.
`Integrated Assessment of Effectiveness .................................................................. 151
`ϴ͘Ϯ͘ ZĞǀŝĞǁ ŽĨ ^ĂĨĞƚLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϱϭ
`8.2.
`Review of Safety ........................................................................................................... 151
`ϴ͘Ϯ͘ϭ͘ ^ĂĨĞƚLJ ZĞǀŝĞǁ ƉƉƌŽĂĐŚ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϱϭ
`8.2.1. Safety Review Approach .......................................................................................... 151
`ϴ͘Ϯ͘Ϯ͘ ZĞǀŝĞǁ ŽĨ ƚŚĞ ^ĂĨĞƚLJ ĂƚĂďĂƐĞ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϱϯ
`8.2.2. Review of the Safety Data base ................................................................................ 153
`ϴ͘Ϯ͘ϯ͘ ĚĞƋƵĂĐLJ ŽĨ ƉƉůŝĐĂŶƚ͛Ɛ ůŝŶŝĐĂů ^ĂĨĞƚLJ ƐƐĞƐƐŵĞŶƚƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϱϱ
`8.2.3. Adequacy of Applicant’s Clinical Safety Assessments ............................................. 155
`ϴ͘Ϯ͘ϰ͘ ^ĂĨĞƚLJ ZĞƐƵůƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϱϴ
`8.2.4. Safety Results ........................................................................................................... 158
`ϴ͘Ϯ͘ϱ͘ ŶĂůLJƐŝƐ ŽĨ ^ƵďŵŝƐƐŝŽŶͲ^ƉĞĐŝĨŝĐ ^ĂĨĞƚLJ /ƐƐƵĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϳϲ
`8.2.5. Analysis of Submission-Specific Safety Issues .......................................................... 176
`ϴ͘Ϯ͘ϲ͘ ůŽŽĚ WƌĞƐƐƵƌĞ ůĞǀĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϳϳ
`8.2.6. Blood Pressure Elevations ........................................................................................ 177
`ϴ͘Ϯ͘ϳ͘ ,ĞƉĂƚŝĐ ĚǀĞƌƐĞ ǀĞŶƚƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϵϱ
`8.2.7. Hepatic Adverse Events ........................................................................................... 195
`ϴ͘Ϯ͘ϴ͘ ^ŬŝŶ ŝƐŽƌĚĞƌƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϬϬ
`8.2.8. Skin Disorders .......................................................................................................... 200
`ϴ͘Ϯ͘ϵ͘ ůŝŶŝĐĂů KƵƚĐŽŵĞ ƐƐĞƐƐŵĞŶƚ ŶĂůLJƐĞƐ /ŶĨŽƌŵŝŶŐ ^ĂĨĞƚLJͬdŽůĞƌĂďŝůŝƚLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϬϯ
`8.2.9. Clinical Outcome Assessment Analyses Informing Safety/Tolera bility ................... 203
`ϴ͘Ϯ͘ϭϬ͘ ^ĂĨĞƚLJ ŶĂůLJƐĞƐ ďLJ ĞŵŽŐƌĂƉŚŝĐ ^ƵďŐƌŽƵƉƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϬϯ
`8.2.10. Safety Analyses by Demographic Subgroups ........................................................... 203
`ϴ͘Ϯ͘ϭϭ͘ ^ƉĞĐŝĨŝĐ ^ĂĨĞƚLJ ^ƚƵĚŝĞƐͬůŝŶŝĐĂů dƌŝĂůƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϬϰ
`8.2.11. Specific Safety Studies/Clinical Trials ....................................................................... 204
`ϴ͘Ϯ͘ϭϮ͘ ĚĚŝƚŝŽŶĂů ^ĂĨĞƚLJ džƉůŽƌĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϭϳ
`8.2.12.Additional Safety Explorations ................................................................................. 217
`ϴ͘Ϯ͘ϭϯ͘ ^ĂĨĞƚLJ ŝŶ ƚŚĞ WŽƐƚŵĂƌŬĞƚ ^ĞƚƚŝŶŐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϮϯ
`8.2.13. Safety in the Postmarket Setting ............................................................................. 223
`ϴ͘Ϯ͘ϭϰ͘ /ŶƚĞŐƌĂƚĞĚ ƐƐĞƐƐŵĞŶƚ ŽĨ ^ĂĨĞƚLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϮϰ
`8.2.14. Integrated Assessment of Safety ............................................................................. 224
`ϴ͘ϯ͘ ^ƚĂƚŝƐƚŝĐĂů /ƐƐƵĞƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϮϲ
`8.3.
`Statistical Issues ........................................................................................................... 226
`ϴ͘ϰ͘ ŽŶĐůƵƐŝŽŶƐ ĂŶĚ ZĞĐŽŵŵĞŶĚĂƚŝŽŶƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϮϳ
`8.4. Conclusions and Recommendations ............................................................................ 227
`ϵ ĚǀŝƐŽƌLJ ŽŵŵŝƚƚĞĞ DĞĞƚŝŶŐ ĂŶĚ KƚŚĞƌ džƚĞƌŶĂů ŽŶƐƵůƚĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϮϴ
`Advisory Committee Meeting and Other External Consultations ....................................... 228
`9
`ϭϬ WĞĚŝĂƚƌŝĐƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϮϴ
`10 Pediatrics ............................................................................................................................. 228
`ϭϭ >ĂďĞůŝŶŐ ZĞĐŽŵŵĞŶĚĂƚŝŽŶƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϮϵ
`11 Labeling Recommendations ................................................................................................ 229
`ϭϭ͘ϭ͘ WƌĞƐĐƌŝƉƚŝŽŶ ƌƵŐ >ĂďĞůŝŶŐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϮϵ
`11.1. Prescription Drug Labeling ........................................................................................... 229
`ϭϮ ZŝƐŬ ǀĂůƵĂƚŝŽŶ ĂŶĚ DŝƚŝŐĂƚŝŽŶ ^ƚƌĂƚĞŐŝĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϯϬ
`12 Risk Evaluation and Mitigation Strategies ........................................................................... 230
`ϭϯ WŽƐƚŵĂƌŬĞƚŝŶŐ ZĞƋƵŝƌĞŵĞŶƚƐ ĂŶĚ ŽŵŵŝƚŵĞŶƚ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϯϬ
`13 Postmarketing Requirements and Commitment ................................................................ 230
`ϭϰ ƉƉĞŶĚŝĐĞƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϯϮ
`14 Appendices .......................................................................................................................... 232
`ϭϰ͘ϭ͘ ZĞĨĞƌĞŶĐĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϯϮ
`14.1. References .................................................................................................................... 232
`ϭϰ͘Ϯ͘ &ŝŶĂŶĐŝĂů ŝƐĐůŽƐƵƌĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϯϮ
`14.2. Financial Disclosure ...................................................................................................... 232
`ϭϰ͘ϯ͘ ŶĂůLJƐŝƐ ŽĨ Y ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϯϰ
`14.3. Analysis of EDQ ............................................................................................................ 234
`
`Reference ID: 4452816
`Reference ID: 4452816
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`ϯ
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`3
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`E DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ^ƚĂŶĚĂƌĚ ϮϭϬϱϱϳ
`NDA Multi-Disciplinary Review and Evaluation Standard 210557
`sLJůĞĞƐŝͬďƌĞŵĞůĂŶŽƚŝĚĞ
`Vyleesi/bremelanotide
`
`dĂďůĞ ŽĨ dĂďůĞƐ
`
`Table of Tables
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`dĂďůĞ ϭ͘ ZĞŐƵůĂƚŽƌLJ ,ŝƐƚŽƌLJ͗ DĂũŽƌ DŝůĞƐƚŽŶĞƐ ĂŶĚ ŽŵŵƵŶŝĐĂƚŝŽŶƐ /E ϲϰϭϭϵ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϵ
`Table 1. Regulatory History: Major Milestones and Communications IND 64119 ....................... 29
`dĂďůĞ Ϯ͘ DͬW< ZĞƐƵůƚƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϲϭ
`Table 2. ADM E/PK Results ............................................................................................................ 61
`dĂďůĞ ϯ͘ KďƐĞƌǀĂƚŝŽŶƐ ĂŶĚ ZĞƐƵůƚƐ &ƌŽŵ ^ƚƵĚLJ ϵϵϲͲϬϮϴ͗ ŚĂŶŐĞƐ &ƌŽŵ ŽŶƚƌŽů͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϲϴ
`Table 3. Observations and Results From Study 996-028: Changes From Control ........................ 68
`dĂďůĞ ϰ͘ KďƐĞƌǀĂƚŝŽŶƐ ĂŶĚ ZĞƐƵůƚƐ &ƌŽŵ ^ƚƵĚLJ ϵϵϲͲϬϬϯ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϳϬ
`Table 4. Observations and Results From Study 996-003 .............................................................. 70
`dĂďůĞ ϱ͘ ZĞƐƵůƚƐ͗ /ŶĐŝĚĞŶĐĞ ŽĨ LJƚŽƉůĂƐŵŝĐ sĂĐƵŽůĂƚŝŽŶ ŝŶ ĚƌĞŶĂů ŽƌƚĞdž ŝŶ Dd ^ƚƵĚŝĞƐ ϭϬϯͲ
`Table 5. Results: Incidence of Cytoplasmic Vacuolation in Adrenal Cortex in BMT Studies 103-
`ϬϬϰ ĂŶĚ ϭϬϯͲϬϬϰ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϳϮ
`004 and 103-004 .................................................................................................................... 72
`dĂďůĞ ϲ͘ KďƐĞƌǀĂƚŝŽŶƐ ĂŶĚ ZĞƐƵůƚƐ &ƌŽŵ ^ƚƵĚLJ ϵϵϲͲϬϮϲ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϳϳ
`Table 6. Observations and Results From Study 996-026 .............................................................. 77
`dĂďůĞ ϳ͘ KďƐĞƌǀĂƚŝŽŶƐ ĂŶĚ ZĞƐƵůƚƐ &ƌŽŵ ^ƚƵĚLJ ϵϵϲͲϬϯϯ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϳϵ
`Table 7. Observations and Results From Study 996-033 .............................................................. 79
`dĂďůĞ ϴ͘ KďƐĞƌǀĂƚŝŽŶƐ ĂŶĚ ZĞƐƵůƚƐ &ƌŽŵ ^ƚƵĚLJ ϵϵϲͲϬϯϮ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴϭ
`Table 8. Observations and Results From Study 996-032 .............................................................. 81
`dĂďůĞ ϵ͘ 'ĞŶĞƌĂů WŚĂƌŵĂĐŽůŽŐLJ ĂŶĚ WŚĂƌŵĂĐŽŬŝŶĞƚŝĐ ŚĂƌĂĐƚĞƌŝƐƚŝĐƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴϵ
`Table 9. General Pharmacology and Pharmacokinetic Characteristics ........................................ 89
`dĂďůĞ ϭϬ͘ ^ƵŵŵĂƌLJ ŽĨ WƌŝŵĂƌLJ ĨĨŝĐĂĐLJ ŶĚƉŽŝŶƚ ŝŶ ^ƚƵĚLJ WdͲϭϰϭͲϱϰ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϵϭ
`Table 10. Summary of Primary Efficacy Endpoint in Study PT-141-54 ......................................... 91
`dĂďůĞ ϭϭ͘ ^ŝŵƵůĂƚĞĚ >ĂƌŐĞƐƚ DĞĂŶ ^LJƐƚŽůŝĐ ůŽŽĚ WƌĞƐƐƵƌĞ ĂŶĚ ŝĂƐƚŽůŝĐ ůŽŽĚ WƌĞƐƐƵƌĞ
`Table 11. Simulated Largest Mean Systolic Blood Pressure and Diastolic Blood Pressure
`/ŶĐƌĞĂƐĞƐ ĨƚĞƌ ^ŝŶŐůĞ ^ ŽƐĞ ŽĨ Ϭ͘ϳϱ ŵŐ͕ ϭ͘Ϯϱ ŵŐ͕ ϭ͘ϳϱ ŵŐ͕ ĂŶĚ ϱ ŵŐ Dd͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϵϱ
`Increases After Single SC Dose of 0.75 mg, 1.25 mg, 1.75 mg, and 5 mg BMT ..................... 95
`dĂďůĞ ϭϮ͘ DĞĂŶ ц ^ W< WĂƌĂŵĞƚĞƌƐ ŽĨ Dd ŝŶ ^ƵďũĞĐƚƐ tŝƚŚ EŽƌŵĂů ZĞŶĂů &ƵŶĐƚŝŽŶ ĂŶĚ DŝůĚ͕
`Table 12. Mean i SD PK Parameters of BMT in Subjects With Normal Renal Function and Mild,
`DŽĚĞƌĂƚĞ͕ ĂŶĚ ^ĞǀĞƌĞ ZĞŶĂů /ŵƉĂŝƌŵĞŶƚ ŝŶ ^ƚƵĚLJ DdͲϭϭϱ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϵϴ
`Moderate, and Severe Renal Impairment in Study BMT-115 ............................................... 98
`dĂďůĞ ϭϯ͘ DĞĂŶ ц ^ W< WĂƌĂŵĞƚĞƌƐ ŽĨ Dd ŝŶ ^ƵďũĞĐƚƐ tŝƚŚ EŽƌŵĂů ,ĞƉĂƚŝĐ &ƵŶĐƚŝŽŶ ĂŶĚ DŝůĚ
`Table 13. Mean i SD PK Parameters of BMT in Subjects With Normal Hepatic Function and Mild
`Žƌ DŽĚĞƌĂƚĞ ,ĞƉĂƚŝĐ /ŵƉĂŝƌŵĞŶƚ ŝŶ ^ƚƵĚLJ DdͲϭϭϲ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϵϵ
`or Moderate Hepatic Impairment in Study BMT-116 ........................................................... 99
`dĂďůĞ ϭϰ͘ ^ƵŵŵĂƌLJ ŽĨ KďƐĞƌǀĞĚ ŵĂdž ;ŶŐͬŵ>Ϳ sĂůƵĞƐ ĨŽƌ Dd ϭ͘ϳϱͲŵŐ ŽƐĞ͕ dŚŝŐŚ ǀƐ͘
`Table 14. Summary of Observed Cmax (ng/mL) Values for BMT 1.75-mg Dose, Thigh vs.
`ďĚŽŵŝŶĂů /ŶũĞĐƚŝŽŶ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϬ
`Abdominal Injection ............................................................................................................ 100
`dĂďůĞ ϭϱ͘ ĨĨĞĐƚƐ ŽĨ Dd ϭ͘ϳϱ ŵŐ ^ ŽŶ dŵĂdž sĂůƵĞƐ ŽĨ KƌĂůůLJ ĚŵŝŶŝƐƚĞƌĞĚ DĞĚŝĐĂƚŝŽŶƐ ŝŶ Dd
`Table 15. Effects of BMT 1.75 mg SC on Tmax Values of Orally Administered Medications in BMT
`^ƚƵĚŝĞƐϭϬϭ͕ ϭϬϯ͕ ϭϬϰ͕ ϭϬϱ͕ ĂŶĚ ϭϭϴ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϭ
`Studielel, 103, 104, 105, and 118 .................................................................................... 101
`dĂďůĞ ϭϲ͘ ůŝŶŝĐĂů dƌŝĂůƐ ZĞůĞǀĂŶƚ ƚŽ E ϮϭϬϱϱϳ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϱ
`Table 16. Clinical Trials Relevant to NDA 210557 ....................................................................... 105
`dĂďůĞ ϭϳ͘ ŶĚƉŽŝŶƚ WŽƐŝƚŝŽŶ͕ ĞĨŝŶŝƚŝŽŶ͕ ĂŶĚ ƐƐĞƐƐŵĞŶƚ ^ĐŚĞĚƵůĞ ĨŽƌ Dd ^ƚƵĚŝĞƐ ϯϬϭ ĂŶĚ ϯϬϮ
`Table 17. Endpoint Position, Definition, and Assessment Schedule for BMT Studies 301 and 302
`͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϭϬ
`............................................................................................................................................. 110
`dĂďůĞ ϭϴ͘ ^ĐŚĞĚƵůĞ ŽĨ ǀĞŶƚƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϮϬ
`Table 18. Schedule of Events ...................................................................................................... 120
`dĂďůĞ ϭϵ͘ WĂƚŝĞŶƚ ŝƐƉŽƐŝƚŝŽŶ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϮϳ
`Table 19. Patient Disposition ...................................................................................................... 127
`dĂďůĞ ϮϬ͘ ZĞĂƐŽŶ ĨŽƌ dƌĞĂƚŵĞŶƚ ŝƐĐŽŶƚŝŶƵĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϮϳ
`Table 20. Reason for Treatment Discontinuation ....................................................................... 127
`dĂďůĞ Ϯϭ͘ /ŵƉŽƌƚĂŶƚ WƌŽƚŽĐŽů ĞǀŝĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘