`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`203858Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`NDA 203-858
`
`(Lomitapide mesylate) Capsules
`
`Aegerion Pharmaceuticals
`
`Xavier Ysern, PhD
`
`ONDQA/ DNDQA III/ Branch VII
`
`Reference ID: 3224834
`
`NDA 203-858 CMC Review # 3 Page 1 of 12
`
`

`

`'"E'X
`
`CHEMISTRY REVIEW
`
`'"fi'fi
`
`Table of Contents
`
`Table of Contents.........................................................................................................................................................2
`
`Chemistry Review Data Sheet ....................................................................................................................................3
`
`The Executive Summary .............................................................................................................................................6
`
`1. Recommendations .................................................................................................................................................. 6
`
`A. Recommendation and Conclusion on Approvability....................................................................................... 6
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management
`Steps, if Approvable ........................................................................................................................................ 6
`
`II. Summary of Chemistry Assessments ..................................................................................................................... 6
`
`A. Description of the Drug Product(s) and Drug Substance(s).............................................................................. 6
`
`B. Description of How the Drug Product is Intended to be Used .......................................................................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................................ 8
`
`III. Administrative ........................................................................................................................................................ 8
`
`A. Reviewer’s Signature ........................................................................................................................................ 8
`
`B. Endorsement Block ........................................................................................................................................... 8
`
`C. CC Block .......................................................................................................................................................... 8
`
`ChemistryAssessment.........9
`
`1. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ...................................... 9
`
`S
`
`P
`
`DRUG SUBSTANCE [Lomitapide Mesylate] ............................................................................................... 9
`
`DRUG PRODUCT [Lomitapide Capsules] ......................................................................................................
`
`A APPENDICES ............................................................................................................ [See CMC Review # 1]
`
`R REGIONAL INFORMATION................................................................................... [See CMC Review # 2]
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ................................................................. 9
`
`A. Labeling & Package Insert...............................................................................................................................9
`
`B. Environmental Assessment or Claim of Categorical Exclusion ........................... [See CMC Review # 1]
`
`HI. List of Deficiencies To Be Communicated (None)
`
`Reference ID: 3224834
`
`NDA 203-858 CMC Review # 3 Page 2 of 12
`
`

`

`'“fl‘v
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`f?!"
`
`1. NDA 203-585
`
`2. REVIEW #2
`
`3
`
`3. REVIEW DATE:
`
`03-Dec-2012
`
`4. REVIEWER:
`
`Xavier Ysern, PhD
`
`5. PREVIOUS DOCUNIENTS:
`
`Previous Documents
`—
`
`Original
`M‘9
`Amendment Request for Proprietary Name Review
`0')(4)
`Amendment Request for Proprietary Name Review
`Amendment Response to 08-May-2012 Quality Information Request Seq. 0012
`Amendment Response to 27-Jun-2012 Quality Information Request Seq. 0015
`Amendment Response to 27-Jun-2012 Quality Information Request (2, 6 & 7) Seq. 0018
`Amendment Request for Proprietary Name Review
`0) (0 Seq. 0021
`Amendment Response to 19-Jul-2012 Quality Information Request Seq. 0023
`Amendment Response to 06-Sep-2012 Quality Information Request Seq. 0028
`
`D___e_n_t_
`Date
`
`29-Feb-2012
`01-Mar-2012
`30-May-2012
`19-Jun-2012
`02-Jul-2012
`23-Jul-2012
`08-Aug-2012
`3 1-Aug-2012
`28-Sep-2012
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission( 5) Reviewed
`Original Amendment Request for Proprietary Name Review (Juxtapid'm) Seq. 0032
`
`Document Date
`27-Nov-2012
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Representative:
`
`Telephone:
`
`Aegerion Pharmaceuticals
`101 Main St., Suite 1850
`Cambridge, MA 02142
`Martha J.Carter
`Chief Regulatory Officer and Senior Vice President
`617-500-7795
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`.
`a) Propnetary Name:
`
`b) Non-Proprietary Name (USAN):
`c) Chem. Type/Submission Priority (ONDC only):
`
`(5)“)
`(proposed tradenames)
`('9 ‘9 not acceptable (29-May-2012)
`
`"’"":03-Aug-2012)
`
`('9 (4’ (not acceptable)
`JuxtapidTM (under review)
`Lomitapide Mesylate
`
`Type l-New Molecular Entity
`Chem. Type:
`Submission Priority: Standard
`
`Reference ID: 3224834
`
`NDA 203-858 CMC Review # 3 Page 3 of 12
`
`

`

`'T‘E'X
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`'7'?
`
`9. LEGAL BASIS FOR SUBNIISSION:
`
`505(b)(1)
`Orphan Drug (Designation request 07-2459, granted for
`treatment of homozygous familial hypercholesterolemia on
`23-Oct-2007)
`
`10.
`
`ll.
`
`12.
`
`PHARMACOL. CATEGORY:
`
`Microsomal triglyceride transfer protein (MI'P) inhibitor.
`Lipid altering agent.
`[Indicationz Treat homozygous familial hypercholesterolemia (HoFH)
`as an adjunct to diet and other lipid-lowering treatments]
`
`DOSAGE FORM:
`
`[Hard Gelatin] Capsules
`
`STRENGTH/POTENCY:
`
`5, 10, and 20 mg
`
`13.
`
`ROUTE 0F ADMJNISTRATION:
`
`Oral
`
`14.
`
`Rx/OTC DISPENSED:
`
`Rx
`
`15.
`
`16.
`
`SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`Not a SPOTS product
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT:
`
`Lomitapide Mesylate
`
`Chemical Structure:
`
`Molecular Formula: C39H37F6N302 - CH4038
`
`Molecular Weight: 789.8 amu (693.7 + 96.1)
`
`Chemical Name:
`
`N-(2,2,2-trifluoroethyl)-9-[4—[4-[[[4'-(n'ifluoromethyl)[ 1 , 1 '-biphenyl]-2-yl]carbonyl]amino]- 1 -
`piperidinyl]butyl]-9H-fluorene—9-carboxamide, methanesulfonate salt
`
`Reference ID: 3224834
`
`NDA 203-858 CMC Review # 3 Page 4 of 12
`
`

`

`
`
`Chemistry Review Data Sheet
`
`1 7. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`Date Review
`
`
`
`Com u leted
`LOA date
`--—
`
`Item Referenced
`
`2
`
`Adequate
`
`Adequate
`
`08—Feb—2012
`
`08—Feb—2012
`
`
`
`
`
`
`
`
` Action codes for DMF Table:
`l — DMF Reviewed
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type I DMF
`3 — Reviewed previously and no revision since last review 4 — Suficient information in application
`5 — Authority to reference not gamed
`6 — DMF not available
`7 — Other (explain under "Comments")
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application therefore the DNIF did not need to be reviewed)
`B. Other Documents:
`
`Lomita tide Me late Ca - sules 77.775
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`50.820
`
`AEGR-733 onnerl EMS-201038
`
`18. STATUS:
`
`RECOMMENDATION21|
`
`EEl
`CONSULTS
`
`.>
`Biometrics
`EES
`Acc table
`Pharm/Tox
`Acc table
`Bioharm
`Acc table
`
`02-Dec-2012 Office of Co u liance
`
`26-Oct-2012
`
`Dr. Elsbeth Chikhale
`
`ZP’
`
`Proposed proprietary tradenames
`under review
`Revalidation b A ° enc laboratories is not recommended
`
`0’) (0 and JuxtapidTM
`
`Acce table
`
`Part of CMC review # 1
`
`DMEPA
`
`Methods Validation
`OPDRA
`>
`
`E M
`
`icrobiolo 3
`
`Reference ID: 3224834
`
`NDA 203—858 CMC Review # 3 Page 5 of 12
`
`

`

`.
`
`;
`
`.
`
`CHEMISTRY REVIEW
`
`_
`
`; 5
`
`Executive Summary Section
`
`The Chemistry Review for NBA 203—858
`
`111: Executive Salim
`
`1. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`From CMC point of view this application is recommended for APPROVAL. All paiding issues have been
`satisfactorilyresolved.
`
`Basedonfltestabflitydatasubnfified,anexphyof24monthsfordmgpmduct
`child
`in- high-dmsity polyethylene (HDPE) bottles sealed with an induction seal and closed Willi a
`resistant (CR) twist-OH closure is granted lmda' the recommended storage conditions: Store at 25 “C (77 "F);
`excursions permitted to 15-30 ”C (59-86 “F) [see USP Controlled Room Temperature]. Protect from moisture.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`None.
`
`11. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug thstance(s)
`
`Drug Substance Lomitapide Mesylate
`
`Lomitapide mesylate drug substance is a white to 05-white powder. It is very soluble in methanol, acetone,
`and ethanol. Solubilityis reducedin other
`solvents and it is insolublein heptane. Aqueous solubilityis
`greatestatapproximatelypHS.5-4withasolubilitylimitof3.7mg/mL. Itismodeiatelyhygroscopic,themaxinmm
`water adsoipfionisapproximatelys %at95 %relative hiimidity(RH).
`
`arecommerciallyavailable. Theinten
`omltapi
`is
`
`
`thatcouldbepresentin
`BMS,flieoriginalmam1facturer, hadidentifiedSrelated
`
`havebeenobservedin
`thelomitapidedrugsubstanceWOftheseSOnIyZ
`
`
`lonfihpidedmgsubshncepmfiwedat_(conmudflmm1fachna.1hehighestlevek observedin
`manufactureddrugbatcheslnvebeenapproximately
`
`'tieshavebeen
`'
`-. TheseZ'
`
`
`
`
`ifications.
`
`
`NDA203-858 (MCReview#3 PageGole
`
`Reference ID: 3224834
`
`

`

`fl-AFH
`him ,
`
`CEHENIISTRY REVIEW
`
`Executive Summary Section
`
`“DA.“
`
`t m: ‘
`
`not been qualified but is limited by specification to— in accordance with the thresholds
`described in ICH Q3A given a maximum daily dose of S 2 g/day.
`
`microorganisms). The total amount of impurities cannot exceed
`
`
`
`
`The ac
`
`tance criterion for the h sical form is “XRPD attem con-e
`
`ds to
`
`Drug Product
`
`The formulation and manufacturing process for lomitapide capsules was developed by Bristol-Myers
`Squibb (BMS), the company that initially developed lomitapide. The qualitative composition of the formulation has
`not changed during the course of development and the quantitative composition has changed only to accommodate
`changes in the strength of the dose. Three strengths, 5 mg, 10 mg and 20 mg, are proposed for commercialization.
`Different strength capsules, all Size 1 hard gelatin capsule, are distinguished by the color of the capsule and the
`imprinting.
`
`The manufacturin
`
`rocess for the
`
`
`
`IAdl'ugisconsideredliighlysolublewliuitl'ieliigiestdosestrengIhG-IDSMSsolublei11250mLou’lessofaqueousmediaovel’tllepl-Iiangeofl
`to 7.5 (Biopharmacaun‘cs Classification 5315mm ). The HDS value for lomitapide is 20 mg. and the solubility of either Form of lomitapide for that
`range ofpH is higierthan 0.08 mg/mL (20/250 mg/mL).
`
`Reference ID: 3224834
`
`NDA 203-858 CMC Review # 3 Page 7 of 12
`
`

`

`
`
`Executive Summary Section
`
`Proposed drug product specifications include Description (visual), Identification (I-H’LC and MS), Assay
`(HPLC), Purity (HPLC), Dissolution (Apparatus 2), Dosage Uniformity (usp<905>),
`W"
`and Microbial testing (USP<61> and <62>). The same I-IPLC method, method QM3255, employed for both assay
`and impurity determinations in the drug substance, is used for the drug product. The pmity acceptance criteria
`requires that the
`W" Impurity to be
`“M" any unidentified impurity
`“"0 and the total
`impurities not to exceed @(4)
`
`The stability of lomitapide drug product has been established by placing 3 primary lots of 5 mg capsules
`and 4 primary lots of 20 mg capsules into long-term and accelerated stability studies. The proposed commercial drug
`product configuration will differ from the primary stability lots in capsule color (removal of a colorant in the case of
`the 20 mg capsule drug product) and the addition of imprinting on the capsule for identification. To bridge these
`differences between the primary stability lots and proposed commercial configuration a comparison stability study
`was carried out. The results of the 3-month bridging stability study are comparable to the results for the primary
`stability lots and indicate that the changes have had no impact on the stability of lomitapide drug product.
`
`The stability of the 10 mg strength for lomitapide drug product, is bracketed by the data from the 5 mg and 20
`mg primary stability lots. Based on the 24-month stability results at 25 °C/60 % RH for the 5 mg and 20 mg
`lomitapide capsule drug product. the Applicant proposes a 24-month expiry dating for the 5, 10, and 20 mg
`commercial drug product. The stability data fully supports the proposed 24-months expiry dating.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Lomitapide Capsules are indicated as an adjunct to a low-fat diet and other lipid-lowering drugs with or
`without LDL apheresis to reduce low-density lipoprotein cholesterol,
`total cholesterol. apolipoprotein B and
`triglycerides in patients with homozygous familial hypercholesterolemia. The drug product is intended to be
`administered orally once daily at bedtime. with a glass of water and without food.
`
`Prior to initiating treatment the patients should follow a low-fat diet supplying less than 20 % of energy
`from fat, and should continue this diet during treatment. The recommended starting dose is 5 mg. After 2 weeks the
`dose may be increased. based on acceptable safety and tolerability, to 10 mg and then, at a minimum of 4-week
`intervals, to 20 mg, 40 mg, and the maximum recommended dose of 60 mg.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`Adequate information has been submitted to allow a satisfactory evaluation of the quality of both drug
`substance (DS) and drug product (DP). DS and DP manufactured and packaged in accordance with the procedures
`and recommendations given in the original submission and pertinent amendments were shown, judged by
`compliance to their proposed specifications. to assure their quality throughout shelf live.
`
`III. Administrative
`
`A, Reviewcr’s Signature
`Xavier Ysern, PhD
`
`B. Endorsement Block
`
`Chemist, ONDQA/ DNDQA 1]]! Branch VII
`
`Date: 03-De-2012
`
`Ali Al-Hakim, PhD
`
`Branch Chief. ONDQA/ DNDQA 1]]! Branch VII
`
`Date: 03-Dec-2012
`
`C. CC Block
`
`Kati Johnson
`
`Regulatory PM/ODEH/DMEP
`
`4 pages have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`Reference ID: 3224834
`
`NDA 203—858 CMC Review # 3 Page 8 of 12
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`XAVIER J YSERN
`12/03/2012
`
`ALI H AL HAKIM
`12/03/2012
`
`Reference ID: 3224834
`
`

`

`
`
`NDA 203-858
`
`(Lomitapide mesylate) Capsules
`
`Aegerion Pharmaceuticals
`
`Xavier Ysern, PhD
`
`ONDQA/ DNDQA III/ Branch VII
`
`Reference ID: 3205314
`
`NDA 203-858 CMC Review # 2 Page 1 of 25
`
`

`

`'"E'X
`
`CHEMISTRY REVIEW
`
`'"fi'fi
`
`Table of Contents
`
`Table of Contents.........................................................................................................................................................2
`
`Chemistry Review Data Sheet ....................................................................................................................................3
`
`The Executive Summary .............................................................................................................................................6
`
`1. Recommendations .................................................................................................................................................. 6
`
`A. Recommendation and Conclusion on Approvability....................................................................................... 6
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management
`Steps, if Approvable ........................................................................................................................................ 6
`
`II. Summary of Chemistry Assessments ..................................................................................................................... 6
`
`A. Description of the Drug Product(s) and Drug Substance(s).............................................................................. 6
`
`B. Description of How the Drug Product is Intended to be Used .......................................................................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................................ 8
`
`III. Administrative ........................................................................................................................................................ 8
`
`A. Reviewer’s Signature ........................................................................................................................................ 8
`
`B. Endorsement Block ........................................................................................................................................... 8
`
`C. CC Block .......................................................................................................................................................... 8
`
`ChemistryAssessment.........9
`
`1. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ...................................... 9
`
`S
`
`P
`
`DRUG SUBSTANCE [Lomitapide Mesylate] ............................................................................................... 9
`
`DRUG PRODUCT [Lomitapide Capsules] .................................................................................................. 19
`
`A APPENDICES ............................................................................................................ [See CMC Review # l]
`
`R REGIONAL INFORMATION.....................................................................................................................20
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ............................................................... 21
`
`A. Labeling & Package Insert............................................................................................................................. 22
`
`B. Environmental Assessment or Claim of Categorical Exclusion ...................................... [See CMC Revie # 1]
`
`HI. List of Deficiencies To Be Communicated (None)
`
`Reference ID: 3205314
`
`NDA 203-858 CMC Review # 2 Page 2 of25
`
`

`

`'“E'X
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`f'fe"
`
`1. NDA 203-585
`
`2. REVIEW #2
`
`2
`
`3. REVIEW DATE:
`
`17-Oct-2012
`
`4. REVIEWER:
`
`Xavier Ysern, PhD
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission 5 Reviewed
`
`Original
`W(4)
`Amendment Request for Proprietary Name Review
`”(4)
`Amendment Request for Proprietary Name Review
`Amendment Response to 08-May-2012 Quafity Information Request Seq. 0012
`Amendment Response to 27-Jun-2012 Quality Information Request Seq. 0015
`Amendment Response to 27-Jun-2012 Quality Information Reguest (2, 6 & 7) Seq. 0018
`Amendment Request for Proprietary Name Review
`0‘"
`Seq. 0021
`Amendment Response to 19-Jul-2012 Quality Information Request Seq. 0023
`Amendment Response to 06-Sep-2012 Quality Information Request Seq. 0028
`
`Document Date
`
`29-Feb-2012
`01-Mar-2012
`30-May-2012
`19-Jun-2012
`02—Jul—2012
`23-Jul-2012
`08-Aug-2012
`31-Aug-2012
`28-Sep-2012
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Representative:
`
`Telephone:
`
`Aegen'on Pharmaceuticals
`101 Main St., Suite 1850
`Cambridge, MA 02142
`Martha J.Carter
`Chief Regulatory Officer and Senior Vice President
`617-500-7795
`
`8. DRUG PRODUCT NAL/fE/CODE/TYPE:
`
`a) Proprietary Name:
`
`b) Non-Proprietary Name (USAN):
`c) Chem. Type/Submission Priority (ONDC only):
`
`(m4) (proposed tradenames)
`(5X4) not acceptable (29-May-2012)
`(”(4) not acceptable,
`(5)“) (03-Aug-2012)
`0') (0 (under review)
`Lomitapide Mesylate
`
`Type l-New Molecular Entity
`Chem. Type:
`Submission Priority: Standard
`
`Reference ID: 3205314
`
`NDA 203-858 CMC Review # 2 Page 3 of25
`
`

`

`'T‘E'X
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`'7'?
`
`9. LEGAL BASIS FOR SUBNIISSION:
`
`505(b)(1)
`Orphan Drug (Designation request 07-2459, granted for
`treatment of homozygous familial hypercholesterolemia on
`23-Oct-2007)
`
`10.
`
`ll.
`
`12.
`
`PHARMACOL. CATEGORY:
`
`Microsomal triglyceride transfer protein (MI'P) inhibitor.
`Lipid altering agent.
`[Indicationz Treat homozygous familial hypercholesterolemia (HoFH)
`as an adjunct to diet and other lipid-lowering treatments]
`
`DOSAGE FORM:
`
`[Hard Gelatin] Capsules
`
`STRENGTH/POTENCY:
`
`5, 10, and 20 mg
`
`13.
`
`ROUTE 0F ADMJNISTRATION:
`
`Oral
`
`14.
`
`Rx/OTC DISPENSED:
`
`Rx
`
`15.
`
`16.
`
`SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`Not a SPOTS product
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT:
`
`Lomitapide Mesylate
`
`F‘CFa
`
`:ONHNC>:0:;’
`
`0 |
`
`|
`H3C—S—OH
`
`0
`
`Chemical Structure:
`
`MolecularFormula:C39H37F6N302-CH403$
`
`Molecular Weight: 789.8 amu (693.7 + 96.1)
`
`Chemical Name:
`
`N-(2,2,2-uifluoroethyl)-9-[4-[4-[[[4'-(trifluoromethyl)[ 1 , 1 '-biphenyl]-2-yl]carbonyl]amino]- l -
`piperidinyl]butyl]-9H-fluorene-9-carboxamide, methanesulfonate salt
`
`Reference ID: 3205314
`
`NDA 203-858 CMC Review # 2 Page 4 of25
`
`

`

`
`
`Chemistry Review Data Sheet
`
`1 7. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`Date Review
`
`
`
`Com u leted
`LOA date
`-_ 18.....2012
`
`Item Referenced
`
`2
`
`
`
`
`Adequate
`
`Adequate
`
`08—Feb—2012
`
`08—Feb—2012
`
`
`
`
`
`Action codes for DMF Table:
`l — DMF Reviewed
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type I DMF
`3 — Reviewed previously and no revision since last review 4 — Sumcient information in application
`5 — Authority to reference not gamed
`6 — DMF not available
`7 — Other (explain under "Comments")
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application therefore the DMF did not need to be reviewed)
`B. Other Documents:
`
`DESCRIPTION 50.820
`
`APPLICATION NUMBER
`
`77.775
`
`Lomitatide Me late Casules
`AEGR-733 onnerl EMS-201038
`
`18. STATUS:
`
`ONDC:
`DATE
`RECOMMENDATION
`CONSULTS
`
`Biometrics
`EES
`
`Microbioloa
`
`Bio - harm
`DMEPA
`Methods Validation
`
`'
`
`Dr. Elsbeth Chikhale
`
`OPDRA —
`EA
`
`Part of this review
`
`Reference ID: 3205314
`
`NDA 203—858 CMC Review # 2 Page 5 of25
`
`

`

`.
`
`;
`
`.
`
`CHEMISTRY REVIEW
`
`_
`
`; 5
`
`Executive Summary Section
`
`The Chemistry Review for NBA 203—858
`
`111: Executive Salim
`
`1. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`From CMC point ofview this application is rue-ended for APPROVAL. The recommendation from the
`OfficeisCompliancefortheacceptabilityoffllemamrfacturingsitesis stillpending.
`
`Basedonthestabilitydatawbmitted, anexpiryof24monthsf0tdrugpmduct
`child
`in- high-dmsity polyethylene (HDPE) bottles sealed with an induction seal and closed with a
`resistant (CR) twist-OH closure is granted lmda' the recommended storage conditions: Store at 25 “C (77 "F);
`excursions permitted to 15-30 ”C (59-86 “F) [see USP Controlled Room Temperature]. Protect from moisture.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`None.
`
`11. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Snbstance(s)
`
`Drug Substance Lomitapide Mesylate
`
`Ionfitapidemsylatednlgsllbstanceisawhitetoofi-Whitepmvder. Itisverysolubleinmethanol, acetone,
`and ethanol. SolubilityIS reducedin other
`solvents and it is insolublem heptane. Aqueous solubilityIS
`gl'eatestatapproxnnatelypH35-4mfl1asolublhtyhm1tof37mg/mL Itismoderatelyhygroscopic,themaxinmm
`water adsorptionis approximately 5 % at 95 %relative humidity (RH).
`
`
`
`are commercially available. The inten
`snze
`omltap
`ls
`
`
`
`'ties and l
`thatcouldbepresentin
`BMS,flleoriginalmamrfactmer,hadidentified5related'
`
`
`havebeenobservedin
`thelomitapidedrugsubstance.0fthese5,only2,
`lonlitapidedrugsubstancepmlhleedat-(connnercialmamficturer. Thehighestlevels observedin
`
`
`
`
`Reference ID: 3205314
`
`NDA203-858 (MCReviewiIZ PageGonS
`
`

`

`fl-AFH
`him ,
`
`CEHENIISTRY REVIEW
`
`Executive Summary Section
`
`“DA.“
`
`t m: ‘
`
`not been qualified but is limited by specification to— in accordance with the thresholds
`described in ICH Q3A given a maximum daily dose of S 2 g/day.
`
`microorganisms). The total amount of impurities cannot exceed
`
`
`
`
`The ac
`
`tance criterion for the h sical form is “XRPD attem con-e
`
`ds to
`
`Drug Product
`
`The formulation and manufacturing process for lomitapide capsules was developed by Bristol-Myers
`Squibb (BMS), the company that initially developed lomitapide. The qualitative composition of the formulation has
`not changed during the course of development and the quantitative composition has changed only to accommodate
`changes in the strength of the dose. Three strengths, 5 mg, 10 mg and 20 mg, are proposed for commercialization.
`Different strength capsules, all Size 1 hard gelatin capsule, are distinguished by the color of the capsule and the
`imprinting.
`
`The manufacturin
`
`rocess for the
`
`
`
`IAdl'ugisconsideredliighlysolublewliuitl'ieliigiestdosestrengIhG-IDSMSsolublei11250mLou’lessofaqueousmediaovel’tllepl-Iiangeofl
`to 7.5 (Biopharmacaun‘cs Classification 5315mm ). The HDS value for lomitapide is 20 mg. and the solubility of either Form of lomitapide for that
`range ofpH is higierthan 0.08 mg/mL (20/250 mg/mL).
`
`Reference ID: 3205314
`
`NDA 203-858 CMC Review # 2 Page 7 of25
`
`

`

`
`
`Executive Summary Section
`
`Proposed drug product specifications include Description (visual), Identification (I-H’LC and MS), Assay
`(HPLC), Purity (HPLC), Dissolution (Apparatus 2), Dosage Uniformity (usp<905>),
`W"
`and Microbial testing (USP<61> and <62>). The same I-IPLC method, method QM3255, employed for both assay
`and impurity determinations in the drug substance, is used for the drug product. The pmity acceptance criteria
`requires that the
`W" Impurity to be
`“M" any unidentified impurity
`“"0 and the total
`impurities not to exceed @(4)
`
`The stability of lomitapide drug product has been established by placing 3 primary lots of 5 mg capsules
`and 4 primary lots of 20 mg capsules into long-term and accelerated stability studies. The proposed commercial drug
`product configuration will differ from the primary stability lots in capsule color (removal of a colorant in the case of
`the 20 mg capsule drug product) and the addition of imprinting on the capsule for identification. To bridge these
`differences between the primary stability lots and proposed commercial configuration a comparison stability study
`was carried out. The results of the 3-month bridging stability study are comparable to the results for the primary
`stability lots and indicate that the changes have had no impact on the stability of lomitapide drug product.
`
`The stability of the 10 mg strength for lomitapide drug product, is bracketed by the data from the 5 mg and 20
`mg primary stability lots. Based on the 24-month stability results at 25 °C/60 % RH for the 5 mg and 20 mg
`lomitapide capsule drug product. the Applicant proposes a 24-month expiry dating for the 5, 10, and 20 mg
`commercial drug product. The stability data fully supports the proposed 24-months expiry dating.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Lomitapide Capsules are indicated as an adjunct to a low-fat diet and other lipid-lowering drugs with or
`without LDL apheresis to reduce low-density lipoprotein cholesterol,
`total cholesterol. apolipoprotein B and
`triglycerides in patients with homozygous familial hypercholesterolemia. The drug product is intended to be
`administered orally once daily at bedtime. with a glass of water and without food.
`
`Prior to initiating treatment the patients should follow a low-fat diet supplying less than 20 % of energy
`from fat, and should continue this diet during treatment. The recommended starting dose is 5 mg. After 2 weeks the
`dose may be increased. based on acceptable safety and tolerability, to 10 mg and then, at a minimum of 4-week
`intervals, to 20 mg, 40 mg, and the maximum recommended dose of 60 mg.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`Adequate information has been submitted to allow a satisfactory evaluation of the quality of both drug
`substance (DS) and drug product (DP). DS and DP manufactured and packaged in accordance with the procedures
`and recommendations given in the original submission and pertinent amendments were shown, judged by
`compliance to their proposed specifications. to assure their quality throughout shelf live.
`
`III. Administrative
`
`A, Reviewcr’s Signature
`Xavier Ysern, PhD
`
`B. Endorsement Block
`
`Chemist, ONDQA/ DNDQA 1]]! Branch VII
`
`Date: 17-Oct-2012
`
`Ali Al-Hakim, PhD
`
`Branch Chief. ONDQA/ DNDQA 1]]! Branch VH
`
`Date: 17-Oct-2012
`
`C. CC Block
`
`Kati Johnson
`
`Regulatory PM/ODEH/DMEP
`
`l7 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`Reference ID: 3205314
`
`NDA 203—858 CMC Review # 2 Page 8 of25
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`XAVIER J YSERN
`10/18/2012
`
`ALI H AL HAKIM
`10/18/2012
`
`Reference ID: 3205314
`
`

`

`
`
`NDA 203-858
`
`(Lomitapide mesylate) Capsules
`
`Aegerion Pharmaceuticals
`
`Xavier Ysern, PhD
`
`ONDQA/ DNDQA III/ Branch VII
`
`Reference ID: 31 92800
`
`NDA 203-858 CMC Review # l Page 1 of 136
`
`

`

`“”5“.
`
`CHEMISTRY REVIEW
`
`'"fi'fi
`
`Table of Contents
`
`Table of Contents .........................................................................................................................................................2
`
`Chemistry Review Data Sheet ....................................................................................................................................3
`
`The Executive Summary .............................................................................................................................................6
`
`1. Recommendations .................................................................................................................................................. 6
`
`A. Recommendation and Conclusion on Approvability....................................................................................... 6
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management
`Steps, if Approvable ........................................................................................................................................ 6
`
`II. Summary of Chemistry Assessments ..................................................................................................................... 6
`
`A. Description of the Drug Product(s) and Drug Substance(s).............................................................................. 6
`
`B. Description of How the Drug Product is Intended to be Used .......................................................................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................................ 8
`
`III. Administrative ........................................................................................................................................................ 8
`
`A. Reviewer’s Signature ........................................................................................................................................ 8
`
`B. Endorsement Block ........................................................................................................................................... 8
`
`C. CC Block .......................................................................................................................................................... 8
`
`ChemistryAssessment...........9
`
`1. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ...................................... 9
`
`S
`
`P
`
`DRUG SUBSTANCE [Lomitapide Mesylate] .............................................