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

`

` CLINICAL PHARMACOLOGY REVIEW
`MEMORANDUM
`(Addendum to the original review dated November 5, 2012)
`203-858; N-000, N-012, N-014, N-015, N-024, N-029
`February 29, 2012
`To be determined
`Lomitapide mesylate
`S.W. Johnny Lau, R.Ph., Ph.D.
`Immo Zadezensky, Ph.D.
`Chandrahas Sahajwalla, Ph.D.
`Clinical Pharmacology 2
`Metabolism and Endocrinology Products
`Aegerion Pharmaceuticals
`Oral immediate release capsule: 5, 10, and 20 mg
`50,820
`Treatment of homozygous familial hypercholesterolemia
`
`
`
`
`
`NDA
`Submission Date
`Brand Name
`Generic Name
`Reviewer
`Team Leader
`Division Director
`OCP Division
`OND Division
`Sponsor
`Formulation; Strength
`Relevant IND
`Indication
`
`
`
`
`Background
`
`Refer to Clinical Pharmacology review dated November 5, 2012 in DARRTS for the Clinical Pharmacology
`information of lomitapide. The purpose of this addendum is to summarize the Clinical Pharmacology related post
`marketing study requirement.
`
`Phase IV Requirements
`Severe Renal Impairment Study
`Lomitapide is mainly cleared via metabolism from the body. For drugs that are mainly metabolized, a study in all
`categories of renal impairment such as mild, moderate, severe, and end-stage renal disease (ESRD) for these drugs
`is generally not conducted but a Reduced Pharmacokinetic Study Design in ESRD patients not yet on dialysis as
`the “worst case” is acceptable. Data shows that the exposure increase of a drug that is mainly cleared via nonrenal
`route is higher in patients with severe renal impairment than ESRD patients receiving chronic hemodialysis (Zhang et
`al. J Clin Pharmacol 2012;52:79S-90S).
`
`The sponsor conducted the renal impairment study (AEGR-733-021) in patients with ESRD receiving
`hemodialysis treatment, such patients may not represent the “worst case” of renal impairment, since the clearance
`of lomitapide may have been altered as the chronic and predose hemodialysis may remove uremic inhibitors that
`are important for lomitapide metabolism and transporters (Nolin et al. Clin Pharmacol Ther 2008;83:898-903; Dreisbach & Lertora Expert
`Opin Drug Metab Toxicol 2008;4:1065-74). Thus, patients with severe renal impairment may represent the “worst case” of renal
`impairment.
`
`In Study AEGR-733-021, lomitapide AUC0-inf and Cmax of ESRD patients receiving hemodialysis treatment
`increased 40% and 50%, respectively, as compared to those of healthy participants. The potential lomitapide
`exposure increase in patients with severe renal impairment as compared to ESRD patients receiving hemodialysis
`may pose a safety concern since the use of lomitapide was associated with elevated transaminases even at low
`
`
`
`Reference ID: 3214360
`
`1
`
`

`

`doses, such as 2.5 mg lomitapide daily (FDA Briefing Document for the Lomitapide Advisory Committee Briefing Document, Pages 56 – 57). The
`exposure of a lomitapide metabolite, M1, is also significantly increased in ESRD patients receiving hemodialysis
`but the extent of M1 increase in severe renal impairment is unknown for toxicological assessment.
`
`Since the clearance of lomitapide decreased in patients with ESRD receiving hemodialysis (assuming no change in
`oral bioavailability) and such decrease is not generally expected of a drug mainly cleared via metabolism, we are
`requesting the Postmarketing Requirement. The sponsor should conduct a comparative study between patients
`with severe renal impairment and healthy volunteers with normal renal function to assess the effect of extreme
`renal impairment on lomitapide and M1’s exposures as a Postmarketing Requirement. The results of this study
`will help guide the dosing of lomitapide in the renally impaired patients with homozygous familial
`hypercholesterolemia.
`
`
`
`
`Reference ID: 3214360
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SZE W LAU
`11/08/2012
`
`IMMO ZADEZENSKY
`11/09/2012
`
`CHANDRAHAS G SAHAJWALLA
`11/09/2012
`
`Reference ID: 3214360
`
`

`

`
`
`
`
`NDA
`Submission Dates
`
`Brand Name
`Generic Name
`Reviewer
`Team Leader
`OCP Division
`OND Division
`Sponsor
`Formulation; Strength
`Relevant IND
`Indication
`
`
`
` CLINICAL PHARMACOLOGY REVIEW
`203-858; N-000, N-012, N-014, N-015, N-024, N-029
`February 29, 2012, June 18, 2012, June 27, 2012, July 2,
`2012, September 7, 2012, October 1, 2012
`To be determined
`Lomitapide mesylate
`S.W. Johnny Lau, R.Ph., Ph.D.
`Immo Zadezensky, Ph.D.
`Clinical Pharmacology 2
`Metabolism and Endocrinology Products
`Aegerion Pharmaceuticals
`Oral immediate release capsule: 5, 10, and 20 mg
`50,820
`Treatment of homozygous familial hypercholesterolemia
`
`
`
`
`
`
`
`
`
`Table of Contents
` Executive Summary
`
`
`
`
`
`
`1.1 Recommendations
`
`
`
`
`
`
`
`
`
`1.2 Post Marketing Requirement
`1.3 Summary of Important Clinical Pharmacology Findings
` Question Based Review
`
`
`2.1 General Attributes
`2.2 General Clinical Pharmacology
`2.3 Intrinsic Factors
`
`
`2.4 Extrinsic Factors
`
`
`2.5 General Biopharmaceutics
`
`2.6 Bioanalytical
`
`
`
`
`
`
`
`
`
`
`3 Labeling Recommendations
`
`
` Appendix
`4.1 Proposed Labeling
`
`
`
`
`1 Executive Summary
`Lomitapide mesylate is a new molecular entity and is the first in the class of microsomal triglyceride transfer
`protein inhibitor. The sponsor seeks approval for NDA 203-858 with the once daily oral administration of a 5,
`10, 20,
` mg lomitapide dose as an adjunct therapy to a low-fat diet and other lipid-lowering drugs with
`or without low density lipoprotein apheresis to treat homozygous familial hypercholesterolemia. The Office of
`Orphan Products Development granted the orphan-drug designation for lomitapide to treat homozygous familial
`hypercholesterolemia on October 23, 2007 (designation request number 07-2359).
`
`
`1.1 Recommendations
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 2 (OCP/DCP2) has reviewed NDA
`203-858’s Clinical Pharmacology data, and finds it acceptable.
`
`- 1 -
`
` 1
`
` 2
`
` 4
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`Reference ID: 3212881
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`Page
`1
`2
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`31
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`51
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`61
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`(b) (4)
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`
`1.2 Post Marketing Requirement
`Severe Renal Impairment Study
`The draft renal impairment guidance
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM204959.pdf) recommends the Reduced
`Pharmacokinetic Design to be conducted in patients with end-stage renal disease (ESRD) not yet on dialysis to
`assess the “worst case” of renal impairment effect on drug pharmacokinetics. However, the sponsor conducted
`the renal impairment study (AEGR-733-021) in patients with ESRD receiving hemodialysis treatment, such
`patients may not represent the “worst case” of renal impairment since the chronic and predose hemodialysis
`may remove uremic inhibitors that are important for lomitapide metabolism and transporters (Nolin et al. Clin Pharmacol
`Ther 2008;83:898-903; Dreisbach & Lertora Expert Opin Drug Metab Toxicol 2008;4:1065-74). The sponsor should conduct a comparative
`study between patients with severe renal impairment and healthy volunteers with normal renal function to
`assess the effect of extreme renal impairment on lomitapide and M1 metabolite’s exposures as a Postmarketing
`Requirement.
`
`1.3 Summary of Important Clinical Pharmacology Findings
`Pharmacokinetics (PK)
`Absorption
`Upon oral administration of a single 60 mg dose (3 x 20 mg) of lomitapide, the lomitapide Cmax, AUC0-inf, and
`tmax are 1.2 ng/mL, 65 nghr/mL, and 6 hours, respectively, in healthy volunteers. Mean lomitapide absolute
`oral bioavailability is 7.1% between an oral 50 mg lomitapide capsule of an early formulation and intravenous
`30 mg lomitapide solution. Of the same 50 mg lomitapide capsule, a high fat meal increases lomitapide Cmax
`and AUC 77% and 58%, respectively, as compared to fasting, whereas a low fat meal increases lomitapide Cmax
`and AUC 70% and 52%, respectively, as compared to fasting. Lomitapide PK is approximately dose-
`proportional for oral single doses from 10 – 100 mg.
`
`Distribution
`The mean lomitapide volume of distribution at steady state is 985 – 1292 L. Lomitapide is 99.8% plasma
`protein bound. Lomitapide is not a P-gp substrate. Lomitapide inhibits P-gp but does not inhibit BCRP.
`
`Metabolism
`Liver extensively metabolizes lomitapide. The metabolic pathways include oxidation, oxidative N-dealkylation,
`glucuronide conjugation, and piperidine ring opening. Cytochrome P450 (CYP) 3A4 metabolizes lomitapide to
`its major metabolites, M1 and M3, as detected in plasma. CYPs 1A2, 2B6, 2C8, and 2C19 may metabolize
`lomitapide to a small extent to M1. M1 and M3 do not have the microsomal triglyceride transfer protein
`inhibition activity. Lomitapide does not induce CYPs 1A2, 3A4, and 2B6. Lomitapide is a weak in vivo
`CYP3A inhibitor. Lomitapide does not inhibit CYPs 1A2, 2B6, 2C9, 2C19, 2D6, and 2E1. M1 and M3 do not
`induce CYPs 1A2, 3A4, and 2B6. M1 and M3 do not inhibit CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1,
`and 3A4.
`
`Excretion
`In a mass-balance study, a mean of 59.5% and 33.4% of the dose was excreted in the urine and feces,
`respectively. In another mass-balance study, a mean of 52.9% and 35.1% of the dose was excreted in the urine
`and feces, respectively. M1 is the major urinary metabolite. Lomitapide is the major component in the feces.
`The mean lomitapide terminal half-life is 39.7 hours.
`
`Dose-Response Relationships
`Per Pharmacometrics, a dose-response analysis for effectiveness (% change from baseline in LDL-C) in Phase 3
`study was not performed because doses were escalated from 5 mg to an individually determined maximum
`tolerated dose up to 60 mg. Per Pharmacometrics, a dose-response analysis for safety in Phase 3 study was not
`
`
`
`Reference ID: 3212881
`
`- 2 -
`
`

`

`performed because doses were escalated from 5 mg to an individually determined maximum tolerated dose up
`to 60 mg.
`
`QT Prolongation
`A thorough QT study does not detect the single doses of 75 and 200 mg lomitapide as well as single dose of 75
`mg lomitapide and 200 mg ketoconazole twice daily have significant QT prolongation effect.
`
`Pharmacogenomics
`This submission does not contain any pharmacogenomic data.
`
`Intrinsic Factors
`
`When compared with matching healthy volunteers, moderate hepatically impaired patients’ lomitapide AUCo_inf
`and Cmax increased 164% and 361%, respectively, whereas mild hepatically impaired patients’ lomitapide
`AUCo_,-,.f and Cmax increased 47% and 4%, respectively. When compared with matching healthy volunteers,
`moderate hepatically impaired patients’ M1 AUCO_inf and Cum increased 39% and 27%, respectively, whereas
`mild hepatically impaired patients’ M1 AUCo_inf and cum; increased 22% and 17%, respectively. When
`compared with matching healthy volunteers, moderate hepatically impaired patients’ M3 AUCO_jnf and Cmax
`decreased 19% and 4%, respectively, whereas mild hepatically impaired patients’ M3 AUCO_inf and Cmax
`decreased 25% and 4%, respectively. These observations are consistent that metabolism of lomitapide
`decreases as liver disease worsens. Per these data, lomitapide should be contraindicated from use in patients
`with moderate and severe hepatic impairment. The dose for patients with mild hepatic impairment should not
`exceed 40 mg lomitapide.
`
`When compared with matching healthy volunteers, lomitapide AUCMnf and Cm of patients with end stage
`renal disease (ESRD) receiving hemodialysis increased 40% and 50%, respectively, whereas M3 exposure of
`ESRD patients on hemodialysis is comparable to that of healthy volunteers. However, Ml AUCO_inf and Cm of
`ESRD patients on hemodialysis increased about 200% and 108%, respectively, as compared to those of healthy
`volunteers. The 200% increase in M1 exposure does not appear to pose safety issue. The dose for patients with
`ESRD receiving dialysis treatment should not exceed 40 mg lomitapide.
`Pupuldliml Dcwripliun
`PK
`Fold Chang: and 90% CI
`Rccmnlmmluliun
`
`Hepatic Impairment
`Mndcralc
`
`Mild
`
`Renal Impairment
`End Stage on Hemodialysis
`
`Cmau
`AUC
`
`Cmax
`
`AUC
`
`szn‘
`AUC
`
`Extrinsic Factors
`
`l—+—l
`l-—-O-—l
`
`Cunlraiimliculiun fur sewn: auul mmlcrulc Ilcpulic impalinucnl
`
`l—H
`
`-H
`
`l—O—l
`l—O—l
`fiéfié—
`0
`2
`4
`6
`8
`
`Change relative to reference
`
`Maximum dose < 40 mg from 60 mg
`
`Maximum (lose < 40 mg from 60 mg
`
`Best Available Copy
`
`Effect of other drug on lomitapide exposure
`In the presence of ketoconazole, lomitapide Cmax and AUCjnf increased 1382% and 2625%, respectively.
`Therefore, concomitant administration of lomitapide with strong CYP3A inhibitors should be contraindicated.
`Concomitant use of moderate CYP3A inhibitors with lomitapide should be avoided. When concomitantly used
`with weak CYP3A inhibitors, lomitapide dosage should not exceed 30 mg daily since lomitapide exposure
`approximately doubled in the presence of oral contraceptives (weak CYP3A inhibitors) via cross-study
`comparison. OCP encouraged the sponsor to model the effect of weak and moderate CYP3A inhibitors on
`lomitapide exposure in the pre-NDA meeting. However, the sponsor did not submit such modeling data in
`NDA 203-858.
`
`Reference ID: 3212881
`
`

`

`Inlerncling Dmg
`
`PK
`
`Fold (‘Imnge and 90% Cl
`
`Recommcmlal inn
`
`Ketoconazole
`
`2(X) mg BID
`
`Cmax
`
`l—O—l
`
`Conlraimlicalc kcloconazolc coadminislralion
`
`AUC
`
`I—o—I
`
`
`15
`20
`25
`30
`
`Change relalive to reference
`
`Best Available Copy
`
`Effect of lomitapide on other drugs’ exposure
`The following highlights the significant ding-drug interaction. See the remainder in the chart below. The
`dosing regimen under the affected drug is the lomitapide dosing regimen.
`
`Both simvastatin Cmax and AUanf doubled in the presence of lomitapide. The approved maximum daily
`simvastatin dose has been lowered to 40 mg. However, the approved maximum daily simvastatin dose is 80 mg
`for patients who have been taking 80 mg simvastatin for 1 year without evidence of muscle toxicity. With
`concomitant use of lomitapide, the maximum daily simvastatin dose should not exceed 20 mg and should not
`exceed 40 mg for patients who have been taking 80 mg simvastatin for 1 year without evidence of muscle
`
`tox1c1ty.
`
`Achclml Dnlg
`
`PK
`
`Fnkl Change and 00%. (‘l
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`
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`Simvastatin
`
`[0 mg QD
`Atorvastatin
`
`60 In}; Q0
`Atorvastahn
`
`1 mg
`Rosuvulalin
`60 mg QD
`Rosuvastatin
`
`10 mg QD
`Ezetimibe
`
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`
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`S—warfarin
`60 mg QD
`
`AUC
`Cmax
`
`AUC
`CIna.\
`
`m
`
`W
`
`AUC
`Cmax
`
`W
`‘
`AUC
`Cmax %
`.
`
`AUL'
`Cmax W
`
`AUC
`Cmax
`"MIX
`C
`AUC
`
`max
`C
`AUC
`
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`Am}?
`
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`AUL
`
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`
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`
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`
`mv
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`i“ Q
`
`mix
`INRI
`IN AUC
`
`Reference ID: 3212881
`
`

`

`
`Lomitapide mesylate shows pH-dependent solubility. However, acid-reducing agents such as proton pump
`inhibitor may have minimal effect on lomitapide exposure since the highest lomitapide mesylate dose of 60 mg
`will be soluble in 250 mL of water from pH 1.3 – 6.
`
`Biopharmaceutics
`Lomitapide mesylate’s Biopharmaceutics Classification System class status is unkown.
`
`Formulation
`The clinically-tested formulations (5 and 20 mg lomitapide capsules) are identical to the to-be-marketed
`formulations.
`
`
`
`________________________
`S.W. Johnny Lau, R.Ph., Ph.D.
`OCP/DCP2
`
`
`
`FT signed by, Immo Zadezensky, Ph.D., Team Leader 11/ /12
`
`
`An Office Level Clinical Pharmacology Briefing for NDA 203-858 was conducted on October 19, 2012; participants included K.
`Burkhart, D. Abernethy, S. Doddapaneni, Y. Xu, A. Mushtaq, G. Ngo, K. Estes, M. Pacanowski, K. Reynolds, D. Bashaw, Y. Ren, S.
`Chung, C. Sahajwalla, I. Zadezensky, and J. Lau in person; E. Chikale, J. Vaidyanathan, and L. Zhang via Adobe Connect.
`
`
`
`Reference ID: 3212881
`
`- 5 -
`
`

`

`2 Question-Based Review
`This review will frequently refer to the drafi Guidance for Industry Drug Interaction Studies — Study Design,
`Data Analysis, Implications for Dosing, and Labeling Recommendations
`(h ://www.fda. ov/downloa
`Guidanc
`lianceRe
`a
`Information/Guidances/UCM292362. df . This review refers such guidance
`as the draft drug interaction guidance for simplicity.
`
`2.1 General Attributes
`
`2.1.1 What are lomitapide mesylate’s key physicochemical properties?
`Figure 1. Lomitapide mesylate‘s molecular structure. Source: M3.2.S.1.2
`
`
`
`Lomitapide mesylate has a molecular weight of 789.8 amu, empirical formula of C39H37F6N302 ° CH403S
`(molecular weight of the lomitapide moiety is 693.8 amu), and is freely soluble in methanol, acetone, and
`ethanol; soluble in methylene chloride, 2-butanol, and acetonitrile; sparingly soluble in l-octanol and 2-
`propanol; slightly soluble in ethyl acetate; and insoluble in heptane. Lomitapide mesylate has the following pH
`solubility profile as shown in Figure 2.
`
`Figure 2. Lomitapide mesylate‘s pH solubility profile. Source: Data from M3.2.S.3.l page 28 of 51.
`
`Lomitapide Mesylate pH Solubility Profile
`
`mglml
`
`AqueousSolubility,
`
`Lomitapide has a pKa value of about 8.2. The apparent l-octanol:water distribution coefficient of lomitapide is
`45.7 — 27.4 for pH 3.07 — 4.21, respectively, with a maximum value of 169 at pH 5.48 and decreasing to 66.8 at
`pH 6.46. Lomitapide is achiral.
`
`Reference ID: 321 2881
`
`

`

`2.1.2 What is the formulation for the to-be-marketed oral lomitapide mesylate?
`Tables 1 — 3 show the to-be-marketed formulations for 5. 10. and 20 mg 10mitapide mesylate capsules.
`Table 1. Conmosition of the 5 mg lomitaBide cagsule formulation. Source: M3.2.P.l
`COMPONENT
`FUNCTION
`GRADE
`BMS CAPSULE AEGERION
`FOR‘MULA
`CAPSULE
`CLINICAL
`FORLIULA
`
`AEGERION
`CAPSULE
`COLILIERCIAL
`FOR)!ULA
`
`Lomitapide
`mesylatel
`Pregelatinised
`starch
`
`Microcrystallin
`e cellulose
`Lactosez;
`Sodium starch
`
`glycolate
`
`Colloidal
`silicon dioxide
`
`Active
`ingredient
`0') (4)
`
`In house
`
`NF. Ph.Eur.
`
`NF. Ph.Eur.
`
`NF. Ph.Eur.
`NF. Ph.Eur.
`
`“M"
`
`USP. Ph.Eur.
`
`5.69 mg (5.00
`mg free base)
`
`5.69 mg (5.00
`mg fi‘ee base)
`
`5.69 mg (5.00
`mg free base)
`(b) (4)
`
`(I!) (4)
`
`m“)
`
`NF. Ph.Eur.
`
`Magnesium
`stearate
`Total amount 100.00 mg 250.00 mg 100.00 mg
`
`
`
`
`
`
`
`Table 2. Con-leasition of the 10 mg lomitaeide cazsule formulation. Source: M3.2.P.l
`COLIPONENT
`FUNCTION
`GRADE
`BMS CAPSULE AEGERION
`FORRIULAI
`CAPSULE
`CLINICAL
`FORNICLAz
`
`Lomitapide
`mesylatez
`
`Active
`ingredient
`
`In house
`
`Pregelatinised
`starch
`
`Microcrystallin
`e cellulose
`
`Lactose4,s
`Sodium starch
`
`glycolate
`
`Colloidal
`silicon dioxide
`
`(”(4)
`
`NF. Ph.Eur.
`
`NF. Ph.Eur.
`
`NF. Ph.Eur.
`NF. Ph.Eur.
`
`W"
`
`USP. Ph.Eur.
`
`-—
`
`-—
`
`-—
`
`--
`---
`
`-—
`
`-—
`
`—-
`
`-—
`
`--
`---
`
`AEGERION
`CAPSULE
`CONDIERCIAL
`FORLIULA
`
`1 1.39 mg
`(10.00 mg free
`base)
`
`(m4)
`
`(5N4)
`
`"M"
`
`Magnesium
`stearate
`
`Total amount
`-—
`-—
`200.00 mg
`
`NF. Ph.Eur.
`
`-—
`
`---
`
`Reference ID: 3212881
`
`_ 7 _
`
`

`

`Table 3. Composition of the 20 mg lomitapide capsule formulation. Source: M3.2.P.1
`COMPONENT
`FUNCTION
`GRADE
`BMS
`AEGERION
`CAPSULE
`CAPSULE
`FORMULA1
`CLINICAL
`FORMULA
`22.77 mg
`(20.00 mg free
`base)
`
`Lomitapide
`mesylate2
`
`Active
`ingredient
`
`In house
`
`NF, Ph.Eur.
`
`AEGERION
`CAPSULE
`COMMERCIAL
`FORMULA
`22.77 mg
`(20.00 mg free
`base)
`
`---
`
`---
`
`Pregelatinised
`starch
`Microcrystalli
`ne cellulose
`Lactose3,4
`Sodium starch
`glycolate
`
`NF, Ph.Eur.
`
`NF, Ph.Eur.
`NF, Ph.Eur.
`
`---
`
`---
`---
`
`USP, Ph.Eur.
`
`NF, Ph.Eur.
`
`
`
`
`
`---
`
`---
`
`---
`
`200.00 mg
`
`200.00 mg
`
`
`
`Colloidal
`silicon dioxide
`Magnesium
`stearate
`Total amount
`
`The sponsor studied the 5 and 20 mg lomitapide capsules in the clinical efficacy and safety study. However,
`there is no comparable clinical dosage unit for the 10 mg lomitapide capsule. The 10 mg lomitapide capsule is
` to the 5 mg lomitapide. The sponsor seeks in vivo
`bioavailability study waiver for the 10 mg lomitapide capsule. The Office of New Drugs, Quality Assurance,
`Biopharmaceutics is responsible to review this waiver. Also, the sponsor does not intend to market the 50 mg
`lomitapide capsule (Table 4) and the sponsor did not study this strength of capsule in the clinical efficacy and
`safety study. However, the sponsor used the 50 mg lomitapide capsule to conduct the food-effect study
`(CV145-005), oral single-dose study (CV145-001), oral multiple-dose study (CV145-002), and absolute
`bioavailability study (CV145-003). The 50 mg lomitapide capsule’s formulation is
` the other 3 strengths of to-be-be-marketed lomitapide capsules.
`
`
`Table 4. Composition of the 50 mg lomitapide capsule formulation. Source: Sponsor’s July 2, 2012 response to information request
`INGREDIENT
`GRADE
`RATIONALE FOR USE
`AMOUNT (MG/CAPSULE
`56.926a
`Lomitapide mesylate
`Active ingredient
`Lactose,
`Microcrystalline cellulose
`Pregelatinized starch
`Sodium starch glycolate
`Colloidal silicon dioxide
`Magnesium stearate
`
`
`
`
`
`NF
`NF
`NF
`NF
`NF
`NF
`
`
`
`
`
`
`
`One
`capsule
`
`Total fill weight
`
`250.00
`
`- 8 -
`
`
`
`
`
`Reference ID: 3212881
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`2.1.3 How does lomitapide work to reduce blood cholesterol?
`Lomitapide is a microsomal transfer protein (MTP) inhibitor. MTP transfers triglyceride (TG) to nascent
`apolipoprotein B (apo B), aiding the formation of TG-rich lipoproteins, namely chylomicrons and very low
`density lipoprotein (VLDL) in enterocytes and hepatocytes, respectively. Thus, MTP inhibition would lead to
`decreases in chylomicrons and VLDL. Since LDL is formed from VLDL, MTP inhibitors would decrease
`plasma LDL-C concentrations (T.R. Joy. Pharmacol Ther 2012;135:31-43).
`
`2.1.4 What are the sponsor’s proposed indication and dosage regimen for lomitapide mesylate?
`Lomitapide is indicated as an adjunct to a low-fat diet and other lipid-lowering drugs with or without LDL
`apheresis to reduce LDL-C, total cholesterol, apo B, and TG in patients with homozygous familial
`hypercholesterolemia (HoFH).
`
`The proposed starting daily dose is 5 mg lomitapide. After 2 weeks, the daily dose may be increased, based on
`acceptable safety and tolerability to 10 mg lomitapide and then, at a minimum of 4-week intervals, to 20, 40,
`and 60 mg lomitapide (maximum proposed dose).
`
`2.2 General Clinical Pharmacology
`2.2.1 What is lomitapide’s clinical pharmacokinetic (PK) characteristics?
`Absorption
`Study CV145-003 is an ascending dose, parallel group, placebo-controlled study. Thirty two randomized
`healthy men received 0, 7.5, 15, 30, or 60 mg lomitapide as a 30-minute intravenous (IV) infusion after an
`overnight fast. After a washout of  7 days, those participants who received the 30 mg lomitapide IV infusion
`also orally (PO) received a 50 mg lomitapide capsule after an overnight fast. Serial plasma samples were
`collected for 72 hours postdose to determine lomitapide, M1, M2, and M3 concentrations via validated
`bioanalytical methods. M1, M2, and M3 are lomitapide metabolites; see the “Metabolism and Excretion”
`section below for details.
`
`Table 5. Mean (SD) lomitapide PK parameters upon IV and PO administration. Source: Study CV145-003’s report Table 11.1.3
`Treatment
`CL, mL/hr
`Cmax, ng/mL
`AUCinf,
`Vss, L
`t½, hr
`nghr/mL
`192.9 (20.2)
`422.6 (51.4)
`837.9 (72.4)
`1776.5 (200.9)
`
`96.7 (35.6)
`
`*CL/F
`
`Figure 3. Mean plasma lomitapide concentrations versus time profiles upon IV and PO administration. Source: Study CV145-003’s
`report Figure S.11.1.3
`
`
`
`Reference ID: 3212881
`
`- 9 -
`
`
`
`7.5 mg IV
`15 mg IV
`30 mg IV
`60 mg IV
`
`50 mg PO
`
`36.8 (11.2)
`71.4 (21.7)
`177.3 (65.1)
`350.7 (100.9)
`
`2.2 (0.8)
`
`1075.3 (120.8)
`1126.2 (131.0)
`1292.0 (744.5)
`985.1 (210.6)
`
`NA
`
`39269.6 (4574.9) 24.7 (6.1)
`35891.8 (3936.3) 29.5 (5.4)
`36039.6 (3407.2) 37.5 (21.5)
`34160.7 (4139.0) 24.8 (6.9)
`
`
`*573465.6
`43.6 (24.3)
`(188810.1)
`
`

`

`The mean (SD) lomitapide absolute oral bioavailability is 7.1 (2.4) between PO 50 mg lomitapide and IV 30 mg
`lomitapide.
`
`Distribution
`Per Study CV145-003, the mean lomitapide volume of distribution at steady state is 985.1 – 1292.0 L.
`
`Study BMS-910060036 examined the in vitro binding of [14C]lomitapide in pooled human plasma. The spiked
`samples were dialyzed against Trizma NaCl buffer for 16 hours at 37C. The mean percent bound is 99.8% and
`is independent of the lomitapide concentrations over the range of 250 – 5000 ng/mL.
`
`Study AEGR-733PC0025 showed that the mean (SD) lomitapide apical to basolateral membrane permeability is
`8.57 (2.24) x 10-6, 20.5 (3.41) x 10-6, and 11.3 (8.90) x 10-6 cm/sec, respectively, for 1, 3.5, and 8 M
`lomitapide and the basolateral to apical membrane permeability is 11.9 (1.87) x 10-6, 7.5 (1.19) x 10-6, and 8.04
`(2.34) x 10-6 cm/sec, respectively, for 1, 3.5, and 8 M lomitapide in in vitro Caco-2 experimental cell systems.
`The mean (SD) digoxin apical to basolateral membrane permeability is 1.18 (0.08) x 10-6 cm/sec and the
`basolateral to apical membrane permeability is 17.0 (1.66) x 10-6 cm/sec; the bidirectional digoxin permeability
`(efflux ratio) is 14.4. Digoxin is a known P-gp substrate (positive control) and these observations suggest that
`the Caco-2 system functions as expected. The bidirectional lomitapide permeability (net efflux ratio) is 1.4, 0.4,
`and 0.7 for 1, 3.5, and 8 M lomitapide, respectively. Since the net efflux ratios for lomitapide are < 2,
`lomitapide is either a poor or non P-gp substrate per the decision tree in Figure A1 of the draft drug interaction
`guidance. When compared with digoxin’s net efflux ratio, lomitapide is a non-P-gp substrate. The sponsor
`also claimed that lomitapide is a high permeability compound; see further discussion in Question 2.5.1 below.
`
`Study AEGR-733PC0023 showed that the net efflux ratios of lomitapide decreases with increasing lomitapide
`concentration. Thus, lomitapide probably is a P-gp inhibitor. Study AEGR-733PC0023 showed that 6 g/mL
`lomitapide inhibited digoxin efflux mediated by P-gp expressed in Caco-2 cells in a concentration dependent
`manner. The lomitapide IC50 per the corrected efflux ratios of digoxin was 0.49 g/mL or 0.62 M. The
`lomitapide [I]1/IC50 value is 0.035 (17.3 ng/mL/0.49 g/mL; [I]1 = 17.3 ng/mL and is the Cmax upon single dose
`of 200 mg lomitapide oral administration). The guidance recommends lomitapide Cmax (1.23 ng/mL) upon
`single dose of 60 mg lomitapide (the highest dose). The lomitapide [I]1/IC50 value is 0.0025 (1.23 ng/mL/0.49
`g/mL). This reviewer erred on the side of being conservative to use the highest oral dose studied, 200 mg
`lomitapide. The lomitapide [I]2/IC50 value is 490.1 (molecular weight of lomitapide mesylate is 789.8; highest
`daily oral dose = 60 mg; [I]2 = 60000/789.8 Moles in 250 mL; IC50 is 0.62/(1000/250) Mole in 250 mL).
`Even though lomitapide’s [I]2/IC50 value is > 10, the draft drug interaction guidance recommends an in vivo
`drug interaction study between lomitapide and a P-gp substrate. Since lomitapide’s label will recommend that
`dose adjustment of P-gp substrate may be necessary when lomitapide is concomitantly administered with P-gp
`substrate, the sponsor may not need to conduct the in vivo interaction study between a P-gp substrate and
`lomitapide.
`
`Study AEGR-733PC0023 also examined the inhibition of BCRP function (cladribine bidirectional transport) by
`6 g/mL lomitapide in CPT-P1 cell monolayers with 10 M cladribine as the BCRP probe substrate. Ko143
`(10 M; positive control) reduced the cladribine efflux ratio from 12 to 0.9 (corrected efflux ratio [CER] from 11
`to 0) indicating the CPT-P1 cells had appropriate BCRP function. The efflux cladribine ratio (9.9) in the
`presence of 6 g/mL lomitapide was not significantly different from the control value of 12. Thus, lomitapide
`at 6 g/mL did not inhibit BCRP and IC50 determination may not be necessary.
`
`Study AEGR-733PC0023 also examined the in vitro inhibition of hepatic uptake transporters, OATP1B1 and
`OATP1B3 (transfected and vector control-transfected cells) as well as OCT1 (transfected and parental cells) by
`40 ng/mL lomitapide. It also examined the in vitro inhibition of renal uptake transporters, OAT1, OAT3, and
`OCT2 (all transfected and parental cells) by 40 ng/mL lomitapide. Lomitapide at 40 ng/mL did not inhibit
`
`- 10 -
`
`Reference ID: 3212881
`
`

`

`OATP1B1, OATP1B3, OCT1, OAT1, OAT3, and OCT2. The unbound Cmax/IC50s of lomitapide for OAT1,
`OAT3, and OCT2 will be at least 0.0009, which is 111 times less than the cutoff value of 0.1 as recommended
`by the draft drug interaction guidance (Figure A6). This reviewer calculated the unbound Cmax/IC50s of 0.0009
`as [0.002 X 17.3 ng/mL]/40 ng/mL (0.2% is the unbound fraction since lomitapide is 99.8% plasma protein
`bound). Thus, the sponsor does not need to determine the IC50s of lomitapide for OAT1, OAT3, and OCT2 in
`vitro. The draft drug interaction guidance does not provide recommendation to assess the potential of a
`investigational drug’s potential to inhibit OCT1.
`
`The total Cmax/IC50s of lomitapide for OATP1B1 and OATP1B3 will be at least 0.43. This reviewer calculated
`the total Cmax/IC50s of 0.43 as (17.3 ng/mL/40 ng/mL). The IC50s of lomitapide for OATP1B1 and OATP1B3
`will be > 40 ng/mL. Rosuvastatin Cmax and AUC0-t increased 4% and 32%, respectively, in the presence of
`lomitapide (see Section 2.4.2.4 below). CYPs 2C9 and 2C19 metabolize rosuvastatin (Neuvonen et al. Clin Pharmacol Ther
`2006;80:565-81). Rosuvastatin is a substrate of OATP1B1, OATP1B3, and BCRP but is not a substrate of P-gp.
`Lomitapide does not inhibit CYPs 2C9 and 2C19 (see Section 2.2.1’s Metabolism and Excretion). Lomitapide
`does not inhibit BCRP (see Section 2.2.1’s Distribution). The increase in rousuvastatin exposure may reflect
`the effect of lomitapide on OATP1B1 and OATP1B3, which are not extensive (32%). Thus, the sponsor may
`not need to determine the IC50 of lomitapide for OATP1B1 and OATP1B3.
`
`The sponsor did not assess the substrate statuses of lomitapide for BCRP, OATP1B1, OATP1B3, OCT1, OAT1,
`OAT3, and OCT2. The draft drug interaction guidance (page 48) recommends the routine evaluation of an
`investigational drug’s role in BCRP, OATP, OATs, and OCTs. However, lomitapide was not detectable in the
`urine (see Study AEGR-733-010’s discussion in the Metabolism and Excretion section below) and OATs and
`OCTs are primarily renal transporters. Thus, the sponsor may not need to study the substrate statuses of
`lomitapide for OCT1, OAT1, OAT3, and OCT2. The sponsor used the in vitro Caco-2 cells to determine the
`substrate status of P-gp (Study AEGR-733PC0025) and the bidirectional lomitapide permeability (net efflux
`ratio) is 1.4, 0.4, and 0.7 for 1, 3.5, and 8 M lomitapide, respectively. There is evidence that Caco-2 cell based
`bidirectional efflux ratio of  2 suggests that the drug is not an efflux transporter substrate such as P-gp and
`BCRP (Mease et al. J Pharm Sci 2012;101:1888-97). Thus, the sponsor may not need to study the substrate statuses of
`lomitapide for BCRP. Per the draft drug interaction guidance, atazanavir, cyclosporine, eltrombopag,
`gemfibrozil, lopinavir, rifampin, ritonavir, saquinavir, and tipranavir are in vivo OATP1B1 and OATP1B3
`inhibitors. Most of such inhibitors (atazanavir, cyclosporine [weak CYP3A inhibitor], lopinavir, ritonavir,
`saquinavir, and tipranavir [weak CYP3A inhibitor]) are also strong or moderate CYP3A inhibitors, which are
`contraindicated with concomitant use of lomitapide. Thus, the sponsor may no