CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203858Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`
`
`Department of Health and Human Services
`
`Public Health Service
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Surveillance and Epidemiology
`
`Office of Medication Error Prevention and Risk Management
`
`Risk Evaluation and Mitigation Strategy (REMS) Review Addendum
`
`Date:
`
`12/21/2012
`
`Reviewer(s):
`
`
`
`Team Leader:
`
`
`
`Drug Name(s):
`
`
`Therapeutic Class:
`
`Dosage and Route:
`
`
`
`Amarilys Vega, M.D., M.P.H, Medical Officer
`Division of Risk Management (DRISK)
`
`Cynthia LaCivita, Pharm.D., Team Leader
`DRISK
`
`Lomitapide (Juxtapid™)
`
`Cholesterol-lowering agent
`
`Starting dose is 5 mg once daily, titrated up to 60 mg as
`tolerated, oral administration
`
`Application Type/Number: NDA 203858
`
`
`Supplement # and Date
`Received:
`
`Email submissions dated December 20 and 21, 2012
`
`Applicant/sponsor:
`
`Aegerion Pharmaceuticals, Inc.
`
`2012-603
`
`OSE RCM #:
`
`
`*** This document contains proprietary and confidential information that should not be
`released to the public. ***
`
`
`
`Reference ID: 3236194
`
`1
`
`

`

`
`
`1
`
`INTRODUCTION
`
`This review documents DRISK’s evaluation of the amended lomitapide REMS submitted by
`Aegerion via email on December 20 and 21, 2012.
`
`2 MATERIALS REVIEWED
`
`2.1 Materials submitted by Aegerion
`
` REMS document
`
` Prescriber Training Module
`
` Prescriber Enrollment Form
`
` Prescription Authorization Form
`
` Dear Healthcare Provider letter
`
` Dear Professional Association letter
`
` REMS Webpages
`
` REMS Supporting document
`
`
`3 DISCUSSION AND RECOMMENDATIONS
`
`DRISK reviewed and provided comments on the revised lomitapide REMS submitted by
`Aegerion via email on December 20 in response to the Agency’s comments included in DRISK
`review addendum from December 19, 2012. Additional comments were sent to Aegerion on
`December 21, 2012 followed by a teleconference between Aegerion, the Division of Metabolism
`and Endocrinology Products (DMEP), and DRISK.
`
`On December 21, 2012 Aegerion submitted via email an amended version of all REMS
`documents addressing comments from FDA.
`
`DRISK finds the revised lomitapide REMS and REMS Supporting Document acceptable and
`recommends approval (see attachments).
`
`
`
`Reference ID: 3236194
`
`2
`
`

`

`Initial REMS Approval: 12/2012
`
`
`
`
`
`
`
`
`
`
`
`
`
`NDA 203858
`JUXTAPID (lomitapide) capsules
`Drug Class: Microsomal Triglyceride Transfer Protein Inhibitor (MTP-I)
`Aegerion Pharmaceuticals, Inc. (Aegerion)
`101 Main Street Suite 1850
`Cambridge, MA 02142
`Telephone: 617-500-7795
`
`
`
`
`
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS)
`
`Reference ID: 3236194
`
`68 Pages have been Withheld in Full as Duplicate REMS Documents (found
`elsewhere in this Approval Package) immediately following this page.
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMARILYS VEGA
`12/21/2012
`
`CYNTHIA L LACIVITA
`12/21/2012
`concur
`
`Reference ID: 3236194
`
`

`

`
`
`
`
`Department of Health and Human Services
`
`Public Health Service
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Surveillance and Epidemiology
`
`Office of Medication Error Prevention and Risk Management
`
`Risk Evaluation and Mitigation Strategy (REMS) Review Addendum
`
`Date:
`
`12/19/2012
`
`Reviewer(s):
`
`
`
`
`
`Team Leader:
`
`
`Division Director
`
`
`Amarilys Vega, M.D., M.P.H, Medical Officer
`Division of Risk Management (DRISK)
`
`Kate Heinrich Oswell, MA,
`Health Communications Analyst (DRISK)
`
`Cynthia LaCivita, Pharm.D., Team Leader
`DRISK
`
`Claudia Manzo, Pharm.D, Director
`DRISK
`
`Drug Name(s):
`
`Lomitapide
`
`Therapeutic Class:
`Dosage and Route:
`
`Cholesterol-lowering agent
`Starting dose is 5 mg once daily, titrated up to 60 mg as
`tolerated, oral administration
`
`Application Type/Number: NDA 203858
`
`Supplement # and Date
`Received:
`
`0032 (amendment), received November 20, 2012 (Seq.no.
`0031)
`
`0034 (amendment), received December 05, 2012 (Seq.no.
`0033)
`
`Applicant/sponsor:
`
`Aegerion Pharmaceuticals, Inc.
`
`2012-603
`
`OSE RCM #:
`
`
`*** This document contains proprietary and confidential information that should not be
`released to the public. ***
`
`
`
`Reference ID: 3234283
`
`1
`
`

`

`
`
`1
`
`INTRODUCTION
`
`This review, an addendum to DRISK review dated November 11, 2012, documents DRISK’s
`review and comments on the revised Lomitapide REMS documents submitted by Aegerion on
`November 20, 2012 and December 5, 2012.
`
` 2
`
` MATERIALS REVIEWED
`
`2.1 Regulatory History
`
` November 28, 2012 – The Division of Metabolism and Endocrinology Products (DMEP) and
`DRISK reconsidered the language in the goal statement, specifically, the underlined text in the
`following goal statement:
`
`“…To limit access to therapy with lomitapide to patients with a clinical or
`laboratory diagnosis consistent with HoFH.”
`
`The proposed revised text for the goal statement is:
`
`“…To limit access to therapy with TRADENAME to patients with a
` consistent with homozygous familial
`hypercholesterolemia (HoFH).”
`Rationale – There is no consensus on clinical or diagnostic criteria for HoFH. 1 The use of the
`terms “clinical diagnosis”
` of HoFH is more consistent with the patient
`selection process followed by prescribers in clinical practice.
`
`
`
` December 4, 2012 – DRISK informed Aegerion that there was no need for the
`Prescriber’s Guide (originally submitted by Aegerion as one of the prescriber
`training materials).
`
`Rationale – The Training Slides Module will serve the same purpose. However,
`DMEP and DRISK agree that an abridged, one-page version of the Prescriber’s
`Guide may remain as part of the REMS and could be inserted as the last page of the
`training module with instructions to the prescriber to print as a reference.
`
`
`
` December 17, 2012 – Office of Regulatory Policy (ORP) recommended removal of
`the following text from the goal statement the goal statement:
`
`“…To educate prescribers about the approved indication for use of
`lomitapide”
`
`Rationale – There is not regulatory precedent for a REMS goal requiring prescriber education
`about the approved indication. DMEP and DRISK concurred with this recommendation.
`
`
`
`1 Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment.
`Atherosclerosis. 2012 Aug;223(2):262-8.
`
`
`
`
`Reference ID: 3234283
`
`2
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`2.2 Materials submitted by Aegerion
`
` November 20, 2012 submission from Aegerion:
`
`1) Proposed REMS with Appendices (Prescriber Enrollment Form,
` Proposed Prescription Authorization Form)
`
`
`
`2) Proposed REMS Supporting Document
`
` December 5, 2012 submission from Aegerion:
`
`1) Proposed REMS Web pages
`
`2) Proposed Dear Healthcare Provider (HCP) Letter
`
`3) Proposed Dear Professional Society Letter
`
`4) Proposed REMS Training Slides Module
`
`
`3 RECOMMENDATIONS
`
`DRISK recommends that DMEP send Aegerion the revisions to the REMS materials included in
`section 4 below.
`
` 4
`
` COMMENTS TO THE SPONSOR
`
`FDA reviewed the REMS documents submitted on November 20, 2012 and December 5, 2012
`and provides the following recommendations:
`
`1) REMS Document – see appended document with comments and tracked changes.
`
`a. Prescriber Enrollment Form
`
`b. Prescription Authorization Form
`
`c.
`
` – removed from the REMS
`
`d. Dear Healthcare Provider (HCP) Letter
`
`e. Dear Professional Society Letter
`
`f.
`
`– removed from the REMS
`
`g. REMS Training Slides Module
`
`h. Prescriber’s Guide – There is no need for the Prescriber’s Guide because the Training
`Slides Module (i.e., Prescriber Training Module) will serve the same purpose. However,
`DRISK agrees that an abridged, one-page version of the Prescriber’s Guide may remain
`as part of the REMS and could be inserted as the last page of the training module with
`instructions to the prescriber to print as a reference.
`
`i. REMS Web pages – see appended document with comments and tracked changes.
`
`2) REMS Supporting Document – please align REMS Supporting Document with revised
`REMS Document.
`
`
`
`Reference ID: 3234283
`
`3
`
`(b) (4)
`
`(b) (4)
`
`86 Pages of Draft Labeling have been Withheld in Full as b4 (CCI/TS)
`immediately following this page.
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMARILYS VEGA
`12/19/2012
`
`CLAUDIA B MANZO
`12/19/2012
`concur
`
`Reference ID: 3234283
`
`

`

`
`
`Risk Evaluation and Mitigation Strategy (REMS) Memorandum
`
`U.S. FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF DRUG EVALUATION II
`DIVISION METABOLISM AND ENDOCRINOLOGY PRODUCTS
`
`
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`
`NDA/BLA #s:
`Products:
`APPLICANT:
`FROM:
`DATE:
`
`
`Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require
`the submission of a risk evaluation and mitigation strategy (REMS) if FDA determines that such
`a strategy is necessary to ensure that the benefits of the drug outweigh the risks
`[section 505-1(a)]. Section 505-1(a)(1) provides the following factors:
`
`
`203858
`Juxtapid (lomitapide) 5 mg, 10 mg, and 20 mg
`Aegerion Pharmaceuticals, Inc.
`Amy G. Egan, M.D., M.P.H.
`November 16, 2012
`
`
`
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`(A) The estimated size of the population likely to use the drug involved;
`(B) The seriousness of the disease or condition that is to be treated with the drug;
`(C) The expected benefit of the drug with respect to such disease or condition;
`(D) The expected or actual duration of treatment with the drug;
`(E) The seriousness of any known or potential adverse events that may be related to the
`drug and the background incidence of such events in the population likely to use the
`drug;
`(F) Whether the drug is a new molecular entity (NME).
`
`After consultations between the Office of New Drugs and the Office of Surveillance and
`Epidemiology, we have determined that a REMS that includes elements to assure safe use is
`necessary for Juxtapid (lomitapide) to ensure that the benefits of the drug outweigh the potential
`risk of hepatotoxicity. In reaching this determination, we considered the following:
`
`A. The estimated number of patients in the United States with homozygous familial
`hypercholesterolemia is approximately 300, based on a prevalence of 1 in 1 million persons.
`This estimate is based on a 1993 article in Lancet entitled “Mutations of low-density-
`lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart
`disease in homozygous familial hypercholesterolaemia.”1
`
`
`B. Homozygous familial hypercholesterolemia (HoFH) is a life-threatening genetic disease
`characterized by marked elevations in LDL-C, tendon xanthomas, and premature coronary
`atherosclerosis. HoFH patients frequently suffer major adverse cardiovascular events such as
`heart attack and stroke in adolescence and early adulthood. This aggressive and premature
`
`1Moorjani, S., M. Roy, et al. (1993). "Mutations of low-density-lipoprotein-receptor gene, variation in plasma
`cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia." Lancet
`341(8856): 1303-1306.
`
`
`
`Reference ID: 3235092
`
`

`

`
`
`cardiovascular disease often requires interventions such as coronary bypass surgery, coronary
`stenting, carotid endarterectomy, and aortic valve replacement.
`
`
`C. When added to background lipid-lowering therapy, Juxtapid (lomitapide) led to mean
`decrease in LDL-C of 40%. This level of reduction was maintained at 56 weeks (-44%)
`despite a decrease in background lipid-lowering therapy in some patients. In addition, eight
`(35%) of the 23 patients who completed the efficacy period were able to achieve an LDL-C
`level <100 mg/dL at week 26, with one patient achieving an LDL-C level <70 mg/dL.
`
`
`D. The expected duration of treatment is lifelong.
`
`E. Juxtapid (lomitapide) can cause elevations in transaminases. In the Juxtapid (lomitapide)
`clinical trial, 34% of patients treated with Juxtapid (lomitapide) had at least one elevation in
`alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times upper limit of
`normal (ULN). Juxtapid (lomitapide) also increases hepatic fat, with or without concomitant
`increases in transaminases. The median absolute increase in hepatic fat was 6% after both 26
`and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance
`spectroscopy. Although hepatic failure has not been observed with Juxtapid (lomitapide),
`hepatic steatosis is a risk factor for steatohepatitis, which can progress over several years to
`advanced liver disease and cirrhosis. Given the small size and relatively short duration of
`Juxtapid (lomitapide) exposure in the pivotal trial, it is not surprising that these potential
`adverse effects have not yet been observed. In addition to the most serious risk of
`hepatotoxicity, Juxtapid (lomitapide) has been associated with a pre-clinical signal for
`teratogenicity. Due to its mechanism of action in the small intestine Juxtapid (lomitapide)
`may reduce the absorption of fat-soluble nutrients (fat-soluble vitamins, β-carotene, and
`essential fatty acids). Juxtapid (lomitapide) has also been associated with gastrointestinal
`adverse reactions, including diarrhea, nausea, dyspepsia, and vomiting.
`
`
`F. Juxtapid (lomitapide) is a new molecular entity.
`
`The elements of the REMS will be elements to assure safe use, including that healthcare
`professionals who prescribe Juxtapid (lomitapide) are specially certified (ETASU A),
`pharmacies that dispense Juxtapid (lomitapide) are specially certified (ETASU B), and Juxtapid
`(lomitapide) will be dispensed to patients with evidence or other documentation of safe-use
`conditions (ETASU D), an implementation system, and a timetable for submission of
`assessments of the REMS.
`
`
`
`Reference ID: 3235092
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMY G EGAN
`12/20/2012
`
`Reference ID: 3235092
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`Final Risk Evaluation and Mitigation Strategy (REMS) Review
`
`
`
`Date:
`
`Reviewer(s):
`
`
`
`11/08/2012
`
`Amarilys Vega, M.D., M.P.H, Medical Officer
`Division of Risk Management (DRISK)
`
`Kate Heinrich Oswell, MA,
`Health Communications Analyst (DRISK)
`
`
`Team Leader:
`
`Division Director
`
`Drug Name(s):
`Therapeutic Class:
`Dosage and Route:
`
`Cynthia LaCivita, Pharm.D., Team Leader
`DRISK
`Claudia Manzo, Pharm.D, Director
`DRISK
`Lomitapide
`Cholesterol-lowering agent
`Starting dose is 5 mg once daily, titrated up to 60 mg as
`tolerated, oral administration
`Application Type/Number: 203858
`Applicant/sponsor:
`Aegerion Pharmaceuticals, Inc.
`OSE RCM #:
`2012-603 and 2012-1935
`
`
`
`
`
`
`
`
`
`
`
`*** This document contains proprietary and confidential information that should not be
`released to the public. ***
`
`Reference ID: 3214570
`
`

`

`
`
`CONTENTS
`
`1
`
`4
`5
`
`INTRODUCTION....................................................................................................... 1
`1.1
`Background......................................................................................................... 1
`1.2
`Regulatory History.............................................................................................. 2
`2 MATERIALS REVIEWED ........................................................................................ 3
`2.1
`Data and Information Sources ............................................................................ 3
`3 RESULTS OF REVIEW............................................................................................. 3
`3.1
`Clinical Development Program........................................................................... 3
`3.2
`Sponsor’s Initial REMS Proposal ....................................................................... 4
`3.2.1 Goals ................................................................................................................... 5
`3.2.2 REMS Elements.................................................................................................. 5
`3.2.3 REMS Assessment Activities ............................................................................. 7
`3.3
`Other Risk Management Activities Proposed by the Sponsor............................ 8
`FDA’S ASSESSMENT OF NEED FOR A REMS..................................................... 9
`SPONSOR’S REVISED REMS PROPOSAL .......................................................... 10
`5.1
`Revised Goals ................................................................................................... 10
`5.2
`Revised REMS Elements.................................................................................. 10
`5.3
`Revised REMS Assessment.............................................................................. 11
`6 ADVISORY COMMITTEE PANEL RECOMMENDATIONS.............................. 11
`7
`FDA’S PROPOSED REMS ...................................................................................... 11
`7.1
`Goals ................................................................................................................. 11
`7.2
`REMS Elements................................................................................................ 12
`7.2.1 Elements to Assure Safe Use ............................................................................ 12
`7.2.2
`Implementation System .................................................................................... 15
`7.2.3 Timetable for Submission of Assessments ....................................................... 15
`7.3
`REMS Assessment Plan.................................................................................... 16
`7.4
`REMS Elements Proposed by the Sponsor but Excluded by FDA................... 16
`8 DISCUSSION ........................................................................................................... 17
`9 CONCLUSIONS....................................................................................................... 18
`10 RECOMMENDATIONS FOR DMEP ..................................................................... 18
`11 COMMENTS FOR THE SPONSOR........................................................................ 18
`ATTACHMENTS............................................................................................................. 22
`Proposed Lomitapide REMS Prescription Authorization Form ........................... 22
`•
`•
`Examples of Revised Dear Healthcare Provider /Professional Association Letters
`
`22
`
`Reference ID: 3214570
`
` 2
`
`

`

` 1
`
`
`INTRODUCTION
`This review documents DRISK’s evaluation of the proposed Risk Evaluation and
`Mitigation Strategy (REMS) for lomitapide. Aegerion Pharmaceuticals is seeking
`approval of lomitapide 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 triglycerides in
`patients with homozygous familial hypercholesterolemia (HoFH).
`
`1.1 BACKGROUND
`Familial Hypercholesterolemia.1 Familial Hypercholesterolemia (FH) is an autosomal
`codominant disorder caused by a large number (>1000) of mutations in the Low-density
`Lipoprotein (LDL) receptor gene and characterized by elevated plasma levels of LDL-
`Cholesterol (LDL-C) with normal triglycerides, tendon xanthomas, and premature
`coronary atherosclerosis. The elevated levels of LDL-C in FH are due to an increase in
`the production of LDL from Intermediate-density Lipoprotein (IDL) and a delayed
`removal of LDL from the blood. Patients with HoFH have mutations in both LDL
`receptor alleles and have much higher LDL-C levels than those with Heterozygous
`Familial Hypercholesterolemia (HeFH) who have only one mutant allele. Patients with
`HoFH are categorized in two groups based on the amount of LDL receptor activity
`measured in their skin fibroblasts: receptor-negative (<2% of normal LDL receptor
`activity) and receptor-defective (2–25% of normal LDL receptor activity). Most patients
`with HoFH are diagnosed in childhood and present with cutaneous xanthomas (hands,
`wrists, elbows, knees, heels, or buttocks), have total cholesterol levels of >500 mg/dL
`(can be >1000 mg/dL), and have accelerated atherosclerosis. Receptor-negative patients
`rarely survive beyond the second decade unless treated; receptor-defective patients have a
`better prognosis but develop atherosclerotic vascular disease by age 30 or sooner.
`Treatment for patients with HoFH includes a low fat diet, lipid lowering agents and LDL
`apheresis. Unfortunately, patients with HoFH are minimally responsive to available lipid
`lowering drugs and, even with maximal pharmacologic doses of these drugs, generally have
`LDL-C levels >300 mg/dL.
`
`Lomitapide. Lomitapide is an oral microsomal triglyceride transfer protein (MTP)
`inhibitor. MTP is an intracellular lipid-transfer protein responsible for transferring
`triglycerides onto apolipoprotein B (apo-B) during the formation of very-low density
`lipoprotein (VLDL) in the liver and chylomicrons in the intestine. VLDL is the precursor
`of LDL. Through its potent inhibition of MTP, lomitapide therapy results in a reduction
`in synthesis and transport of apo-B containing lipoprotein and circulating LDL-C. The
`proposed dosing regimen is to escalate from 5 mg daily to 60 mg daily, as tolerated,
`during a 14-week period.
`
`
`
`1 Rader D.J., Hobbs H.H. (2012). Chapter 356. Disorders of Lipoprotein Metabolism. In D.L. Longo, A.S.
`Fauci, D.L. Kasper, S.L. Hauser, J.L. Jameson, J. Loscalzo (Eds), Harrison's Principles of Internal
`Medicine, 18e. Retrieved October 22, 2012 from
`http://www.accessmedicine.com/content.aspx?aID=9143689 .
`
`Reference ID: 3214570
`
`

`

`1.2 REGULATORY HISTORY
`Following are pertinent milestones in the regulatory history of lomitapide:
`• June18, 1996 – IND 50820 submitted by Bristol-Myers Squibb.
`• August 21, 2002 – IND 50820 transferred to Daniel Rader, MD, University of
`Pennsylvania (study for the treatment of HoFH).
`• January 27, 2006 – The Office of Orphan Products Development Grant 1R01
`FD003098-01 awarded for MTP Inhibitor for Familial Hypercholesterolemia, Marina
`Cuchel, MD, PhD was the principal investigator.
`• April 13, 2007 – IND 50820 transferred to Aegerion for development of lomitapide
`for moderate hypercholesterolemia, which included severe refractory
`hypercholesterolemia.
`• May 16, 2007 – IND 77775 submitted by Daniel Rader, MD, University of
`Pennsylvania, for HoFH.
`• October 23, 2007 – Orphan drug designation for the treatment of HoFH.
`• February 28, 2008 – IND 77775 transferred to Aegerion from Dr. Rader to facilitate
`conducting multi-site trials.
`• May 17, 2010 – End of Phase 2 (EOP2) meeting with FDA. FDA expressed concern
`about potential off-label use and the sponsor agreed to the need of implementation of
`post-approval supply constraints.
`• March 03, 2011 – Orphan drug designation for the treatment of familial
`chylomicronemia.
`• June 15, 2011 – The Agency confirmed that a single, pivotal phase 3 study lacking a
`placebo control arm would not preclude filing or approval of the lomitapide NDA for
`the HoFH population and that the available exposure data from the single pivotal
`phase 3 study are sufficient to support an NDA for HoFH. FDA noted that including
`a “functional HoFH” definition of average fasting LDL > 300 mg/dL on maximally
`tolerated lipid-lowering therapy closely resembles the severe refractory HeFH
`population, which would shift the risk:benefit ratio. FDA encouraged the sponsor to
`provide detailed plans of how distribution would be restricted to the HoFH population
`studied in the Phase 3 trial, including how documentation of HoFH status would be
`collected and confirmed, how distribution would be accomplished, and how the
`system would be monitored for compliance.
`• February 29, 2012 – Submission of NDA 203858 for the use of lomitapide 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 triglycerides in patients with
`HoFH.
`• October 17, 2012 – Advisory Committee meeting voted 13:2 in favor of the approval
`of lomitapide (with a restrictive REMS) for the treatment of HoFH.
`
`
`
`Reference ID: 3214570
`
` 2
`
`

`

`2 MATERIALS REVIEWED
`
`2.1 DATA AND INFORMATION SOURCES
`• Lomitapide, Risk Management Plan, Aegerion, February 29, 2012.
`• Division of Metabolism and Endocrinology Products (DMEP), Advisory
`Committee meeting background document.
`• Aegerion, Advisory Committee meeting background document.
`• Patricia L. Bright, M.S.P.H., Ph.D., Epidemiologist, Division of
`Epidemiology 1 (DEPI 1), Office of Pharmacovigilance and Epidemiology
`(OPE), Office of Surveillance and Epidemiology (OSE): Lomitapide, Review
`of Sponsor’s Product Registry Proposal, October 2, 2012.
`
` 3
`
` RESULTS OF REVIEW
`
`3.1 CLINICAL DEVELOPMENT PROGRAM
`Lomitapide’s clinical development program included 15 phase 1 studies, 6 phase 2
`studies, and one phase 3 trial (26 weeks duration) with an extension (up to 56 weeks).
`Nine hundred fifteen subjects were exposed to lomitapide in the clinical development
`program. One of the phase 2 studies was a 16-week, single-arm, 6-subject proof-of-
`concept trial (HoFH Pilot study). The pivotal phase 3 trial included 29 patients with
`HoFH and the extension of the phase 3 study included 19 patients. The dosing regimen
`consisted of forced-titration of lomitapide as follows: daily dose of 5 mg for two weeks
`followed by dose increase to 10, 20, 40, and 60 mg at four weeks intervals as tolerated.
`The primary study endpoint was the decrease in mean LDL-C.
`
`Efficacy
`The evaluation of the efficacy and safety of lomitapide included a pivotal phase 3, single-
`arm trial including 29 patients with HoFH, a pivotal trial extension, and a pilot phase 2,
`single-arm, 16-week duration trial including 6 HoFH patients. Lomitapide’s clinical
`development program demonstrated LDL-C reduction in the HoFH population greater
`than that observed with potent statins. In the pivotal phase 3 trial, the mean LDL-C
`decreased was 40% (95% CI, 28% to 52%, p<0.001) during 26 weeks of treatment with
`lomitapide. Statistically significant reductions from baseline were observed in total
`cholesterol, apoB, non-HDL-C, triglycerides, and VLDL-C.
`
`Safety Concerns
`Potential Hepatotoxicity. Lomitapide therapy was associated with increased serum
`transaminases and increased hepatic fat. Thirty-four percent (10/29) of patients with
`HoFH treated with lomitapide had ALT ≥3x ULN at least once during the pivotal trial;
`however, none of these subjects had bilirubin levels outside of the normal range.
`Seventy-eight percent (18/23) subjects in the pivotal trial showed a maximum absolute
`increase in hepatic fat >5%; 13% or 3 patients had an absolute increase of greater than
`20%.
`
`Reference ID: 3214570
`
` 3
`
`

`

`Lomitapide-induced increase in hepatic fat appears to be reversible after short-term (16
`weeks) administration in the HoFH Pilot study. Five of the six subjects in the pilot study
`showed near-complete resolution of hepatosteatosis after discontinuation of lomitapide
`and a subsequent publication describing the results of this study indicate that, in the
`remaining subject, hepatic fat returned to baseline 14 weeks after stopping lomitapide.2
`Teratogenic Risk. Developmental toxicity studies in rats showed decrease in fetal body
`weight and malformations (abdomen, tail, heart, limbs, anus) at doses lower than human
`clinical exposure and fetal death, shortened limbs, and brain defects at doses 10-fold
`higher than the anticipated clinical exposure. Studies in ferrets showed embryonic death,
`decreased fetal body weight, and malformations (abdomen, tail, limbs, head) at less than
`clinical dose level. Studies in rabbits showed no effects on survival or development at
`doses up to three times higher than human clinical exposure. There were no pregnancy
`exposures in the clinical development program.
`
`3.2 SPONSOR’S INITIAL REMS PROPOSAL
`Pre-NDA REMS Discussions. In a 17 May 2010 EOP2 meeting with FDA, Aegerion
`noted that they would be pursuing submission of an NDA solely for the HoFH population
`due to financial constraints. The sponsor recognized the potential for unauthorized
`prescribing and was amenable to the implementation of post-approval supply constraints
`to ensure that the drug was available only to the HoFH population. In several meetings,
`DMEP expressed the position that the use of lomitapide outside the HoFH population
`would require additional clinical studies due to the shift in risk/benefit ratio.
`In the background materials for the 15 June 2011 pre-NDA meeting, Aegerion posed the
`following question: “Aegerion believes that a Risk Evaluation and Mitigation Strategy
`(REMS) program with Elements to Assure Safe Use will be important to ensure that drug
`use is confined to the specific population identified in the proposed label and, further, that
`risks are minimized in the marketed use of lomitapide. In this briefing package, we
`outline the elements of the proposed plan. Does the Agency agree . . .?”. The agency
`responded that there was insufficient information at the time to determine whether a
`REMS would be necessary and, if it would be necessary, what the required elements
`would be. Aegerion was advised to submit all planned materials with the NDA.
`Lomitapide was submitted with a proposed REMS addressing the risks of poten