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

`

`
`
`Tertiary Pharmacology/Toxicology Review
`
`From: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and
`Toxicology, OND IO
`NDA: 203858
`Agency receipt date: February 29, 2012
`Drug: lomitapide
`Sponsor: Aegerion Pharmaceuticals Inc.
`Indication: homozygous familial hypercholesterolemia (HoFH) as an adjunct to
`diet and other lipid-lowering treatments
`
`Reviewing Division: Division of Metabolism and Endocrinology Products
`
`Introductory Comments: The pharm/tox reviewer and supervisor concluded
`that the nonclinical data support approval of lomitapide for the indication listed
`above.
`
`Lomitapide is a microsomal triglyceride transfer protein inhibitor. This is a new
`pharmacologic class.
`
`Lomitapide produced embryofetal death and fetal malformations in rats. Some
`effects were observed even at clinically relevant doses. Malformations were also
`noted in ferrets in a dose range-finding study. Adverse fetal effects were not
`observed in rabbits although the highest dose tested was only 3 times the clinical
`exposure. The sponsor and the primary and secondary pharm/tox reviewers
`recommended that the drug be contraindicated in pregnancy.
`
`Lomitapide was tested in a two-year oral gavage carcinogenicity study in rats and
`a two-year dietary study in mice. These studies were reviewed by the division
`and the Executive Carcinogenicity Assessment Committee. The Committee
`found the mouse study to be acceptable in spite of high mortality. A drug-related
`increase in animals with hepatocellular adenomas, carcinomas, and combined
`adenomas or carcinomas was observed in male mice at ≥1.5 mg/kg/day and in
`female mice at ≥7.5 mg/kg/day. In addition, the combined incidence of animals
`with adenomas or carcinomas in the small intestine was observed at ≥15
`mg/kg/day in both male and female mice. The Committee also found the rat
`study to be acceptable and no drug-related neoplasms were observed at doses
`producing up to approximately 6-8 fold the human exposure.
`
`Given the nature of the indication, lomitapide might be used in pediatric patients.
`The pharm/tox reviewer and supervisor believe that the possible impact of
`lomitapide on the neurological development of young children has not been
`adequately assessed in animals. This concern arises from the critical role played
`by lipids in neuron development. In addition, lomitapide alters fat-soluble vitamin
`absorption. The impact of lomitapide on vitamin malabsorption has also not been
`assessed in young animals. The reviewer and supervisor have recommended
`that a Postmarketing Requirement for a juvenile rat study with and without
`
`
`
`Reference ID: 3227461
`
`1
`
`

`

`
`
`vitamin and fatty acid supplementation be considered to help address the impact
`lomitapide may have on learning and memory in pediatric patients. The division
`is recommending that this be completed prior to trials in pediatric patients.
`
`
`Conclusions:
`I agree with the division pharm/tox conclusion that lomitapide can be approved
`from the pharm/tox perspective. I agree that lomitapide appears to carry risk for
`developing fetuses and, therefore, contraindication in pregnancy seems
`appropriate. I also agree that a Postmarketing Requirement for a juvenile animal
`study should be considered to help address the outstanding uncertainty around
`the impact of lomitapide on neurological development of young children.
`
`
`
`Reference ID: 3227461
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PAUL C BROWN
`12/07/2012
`
`Reference ID: 3227461
`
`

`

`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`Food and Drug Administration
`
`
`
`
`
`
`
`Memorandum
`
`
`
`
`
`
`Date: November 13, 2012
`From: Karen Davis-Bruno PhD; Pharmacology Supervisor; DMEP
`Subject: Supervisory Pharmacology/Toxicology Memo
` To: NDA 203-858
`
`Reference is made to the Pharmacology/Toxicology Review of NDA 203-858 which
`recommends approval, which I am in agreement with.
`
`Lomitapide inhibits microsomal triglyceride transfer protein (MTP) an intracellular
`protein that regulates lipid transfer between membranes in the lumen of the endoplasmic
`reticulum. MTP inhibition prevents ApoB-lipoprotein (LDL-C) assembly in various
`tissues including hepatocytes and enterocytes reducing the production of lipid containing
`particles into the systemic circulation. This mechanism differs from currently approved
`lipid lower drugs which act by increasing the clearance of LDL-C systemically.
`
`Toxicology: Repeat dose toxicity studies were performed in rats, dogs and mice. The
`most significant effect was lipid accumulation in the liver, small intestine, and lungs.
`This was observed at comparable human therapeutic exposures and is consistent with the
`pharmacology of the drug. While reversibility of the lipid accumulation was
`demonstrated with discontinuation of drug treatment in rats, fat accumulation remains
`with long-term treatment and involves a potential risk of hepatotoxicity and perhaps liver
`carcinogenicity. In addition to lipid accumulation, hepatocellular lipid vacuolation is
`seen minimal-marked severity in the 6 month rat at 2 mg/kg/day (≥2X human AUC @
`MRHD=60 mg) in addition to multifocal subacute inflammation in all females at this
`dose. Hepatic lipid accumulation is seen in dogs treated for 6 months at doses ≥1
`mg/kg/day (17X human AUC @ 60 mg) and minimal vacuolization. Increases in liver
`enzymes (ALT, AST, ALP) were observed in drug treated rats (3-fold increase over
`controls) and dogs (7-fold mean increase and up to 25-fold individually). Patients with
`abetalipoproteinemia have elevated transaminases so this is not an unexpected finding.
`
`Increased incidences of multifocal minimal-moderate liver fibrosis and cystic
`degeneration (males; minimal-moderate) were observed with treatment ≥ 93 weeks in
`rats. The fibrosis was considered random and did not involve the majority of the liver.
`The sponsor attributes the hepatic related histopathology in the rat to greater hepatic drug
`and metabolite levels than the dog despite higher plasma exposures. This may account
`for the larger spectrum of hepatic related histopathology.
`
`Tissue levels of lomitapide and metabolites were assessed in the 6-month rat and dog
`toxicity studies. Although dog had higher plasma exposure at half the rat dose the rat
`liver and lung tissue had higher exposure to lomitapide. The elevated tissues levels may
`
`
`
`Reference ID: 3215803
`
`1
`
`

`

`explain the dose-related incidence and severity of findings in the rat compared to the dog.
`
`6-Month Toxicity
`
`Liver (ng/g)
`
`Lung (ng/g)
`
`Plasma AUC
`(ng*h/ml)
`M
`Lomitapide Dose
`117
`Rat (2 mg/kg/d)
`13
`M1
`331
`M3
`430
`Dog (1mg/kg/d)
`523
`M1
`289
`M3
`BLQ=below limit of quantitation < 90 ng/g
`
`Multifocal hemorrhages and increased APTT and PT were observed in rats at 20
`mg/kg/day (>20X human AUC@ 60 mg). This was attributed to vitamin K deficiency
`due to inhibition of fat soluble vitamin absorption. The increased mortality associated
`with multifocal hemorrhages was reduced by weekly vitamin supplementation in
`conjunction with lompitapide dosing. Poikilocytosis and/or anisocytosis and decreased
`RBC parameters were observed in rats and dogs not associated with hemorrhage and in
`animals receiving vitamin supplementation. The initial 6-month rat toxicity study
`identified the vitamin K deficiency and therefore in subsequent 6-month rat and dog
`toxicity studies and rodent carcinogenicity studies, groups with and without vitamin
`supplementation were included. Fat soluble vitamin supplementation was not considered
`to impact the 6-month dog toxicity study and therefore the 12-month dog toxicity study
`did not have vitamin supplementation. None of the developmental/reproductive toxicity
`studies used vitamin supplementation.
`
`Testicular tubular degeneration was observed in the 6-month dog toxicity study at 10
`mg/kg/day (200X human AUC @ 60 mg) but not present at 5 mg/kg/day (>50X human
`AUC @ 60 mg) in a 12-month dog toxicity study. This observation was not observed in
`the rat. Based on the exposure at which this finding is observed it is unlikely to have
`clinical relevance in a therapeutic setting.
`
`Lipid Accumulation in Tissues: Lipid accumulation was not restricted to the liver. The
`small intestine (absorptive epithelial cells) had lipid vacuolization (minimal to severe) in
`the rat and dog (minimal to moderate). Pulmonary histiocytosis was observed in mice
`(minimal), rats (minimal-marked; with foamy macrophages in the alveolar space), and
`dog (≥0.01 mg/kg/d at 6 months; at 12 months dogs given ≥0.05 mg/kg/d had pleural
`fibrosis at exposures less than human therapeutic exposure). Initial toxicology studies
`considered the pulmonary histiocytosis in rodents to be indicative of phospholipidosis.
`The basis of this diagnosis was ultrastructural transmission electron microscopy (TEM)
`evaluations of lungs from four lompitapide treated rats given 2 or 20 mg/kg/d (≥2X
`human AUC @ 60 mg human dose) which exhibited the characteristic concentric
`lamellar structures of phospholipidosis1. Aegerion performed further evaluations by
`
`F
`584
`53
`1165
`685
`
`M
`817
`BLQ
`17
`286
`228
`BLQ
`
`F
`12579
`BLQ
`153
`686
`148
`43
`
`M
`782
`BLQ
`BLQ
`741
`242
`59
`
`F
`7873
`23
`40
`206
`282
`BLQ
`
`
`1 Nonoyama 2008, J Toxicol Pathol ; Reasor 2006 Expert Opin Drug Safety
`
`
`
`Reference ID: 3215803
`
`2
`
`

`

`TEM in a 3 month study with rats given 4 mg/kg/d as well as during the carcinogenicity
`study where mice were given 45 mg/kg/d (79X human AUC @ 60 mg). The results of
`the later evaluations suggested that phospholipidosis was not present due to the absence
`of intra-lysosomal concentric lamellar inclusions. The histiocytosis noted under light
`microscopy was considered reflective of excessive accumulation of neutral lipids in the
`cytoplasm of alveolar macrophages.
`
`Increased incidences of foamy alveolar macrophages (histiocytes) were observed in the
`lungs of lomitapide treated rodents. In mice, histiocytes were observed in alveolar spaces
`at ≥5X maximum clinical exposures after 3 months. Pulmonary histopathology
`performed during the mouse 2-year carcinogenicity study revealed increased incidences
`of alveolar spicules and lymphocyte infiltration at ≥22X maximum clinical exposures.
`While histiocytosis was not noted by light microscopy, a low incidence was observed
`when examined by electron microscopy. In rats multifocal histiocytes accumulation was
`observed in the alveoli and subpleural tissues at less than clinical therapeutic exposure
`after 3 months of treatment. Dose related histiocytosis characterized by multifocal
`aggregates of large foamy macrophages within alveoli with or without subacute
`inflammation, necrotic debris, cholesterol-like clefts and/or type II alveolar cell
`proliferation were observed in rats following 6 months of treatment at exposures less than
`the clinical therapeutic exposure. EM evaluations of this lung tissue characterized the
`histiocytosis as focal aggregates containing residual/lamellar inclusion bodies, lipid
`droplets and phagolysosomes varying in size, shape and electron density. Some
`occasional, adjacent type II cells were enlarged with lipid droplets and lamellar inclusion
`bodies. A second 6-month rat study confirmed the observation of pulmonary
`phospholipidosis. Special staining indicated the presence of phospholipids and neutral
`lipids in the macrophages and adjacent type II alveolar cells. Histiocytosis appeared to
`be recoverable following a 6 months drug free period. These studies were performed
`early in development and subsequent studies with different pathologists did not confirm
`the pulmonary phospholipidosis which is characterized by the excessive accumulation of
`concentric lamellar inclusions in the lysosomes of macrophages or other pulmonary cells.
`
`In the rat 2-year carcinogenicity study increased incidence of alveolar spicules,
`lymphocyte infiltration with macrophage accumulation and thickened alveolar speta with
`macrophage infiltrates were observed at less than therapeutic exposures. An increase in
`septal cell mineralization was noted for male rats given lomitapide at 2X therapeutic
`exposure. Pleural/subpleural fibrosis was observed in female rats at this same exposure
`level. Although concentric lamellar inclusions were seen in rats they rarely observed in
`lysosomes and were present in cells from both control and lomitapide treated animals.
`No evidence of chronic interstitial inflammation in the alveolar wall adjacent to
`vacuolated macrophages was observed. Subsequent pathology examinations from longer
`duration studies (2-year carcinogenicity) showed some lipid accumulation but the
`findings were inconsistent with classical phospholipidosis. In dogs treated for one year, a
`low incidence of minimal to mild pleural fibrosis was observed at ≥3X therapeutic
`exposure. A slight increase in minimal focal mineraliaiton and mild chronic-active
`inflammation was observed in males and minimal to mild alveolar edema was seen in
`females in the absence of histiocytosis at >55X therapeutic exposures. Lung histiocytosis
`
`
`
`Reference ID: 3215803
`
`3
`
`

`

`was observed across dose groups but not in a dose-related incidence in the dogs treated
`for 6 months at high lomitapide exposures (>100X therapeutic exposure). Chronic
`inflammation and edema were observed across dose levels at an incidence and severity
`similar to controls. This suggests that the finding may have been an incidental
`background finding in dog.
`
`EM evaluation of lung tissue from mice treated for 2 years indicated that excessive lipid
`accumulation in macrophages occurred in the absence of concurrent epithelial
`degeneration or inflammatory changes in the alveolar wall. The sponsor did evaluate
`the function of rat macrophages isolated by bronchioalveolar lavage after 3 months of
`treatment. The results showed that the isolated macrophages had similar phagocytic
`and respiratory burst activity as control macrophages, although it is felt that the design
`of the study could have been improved to obtain more definitive results.
`
`Genotoxicity testing in a bacterial mutagenicity (Ames) assay, chromosomal aberration
`study in human lymphocytes and oral rat micronucleus assay were negative,
`demonstrating that lomitapide does not interact with DNA or pose a genotoxic risk.
`
`Carcinogenicity was assessed in a 2-year mouse bioassay by dietary administration at 0.3,
`1.5, 7.5, 15 or 45 mg/kg/day. Survival issues resulted in some mice being on study
`without being dosed from week 90 to study termination. Female dose groups were
`sacrified at week 99, mid dose males on week 101 and high dose males on week 101.
`Despite the high mortality ECAC considered the study to be acceptable. Drug related
`neoplasms included: hepatocellular adenomas, carcinomas and combined adenomas or
`carcinomas in males at ≥1.5 mg/kg/day (2X human AUC @ 60 mg) and in females at
`≥7.5 mg/kg/day (9X human AUC@60 mg); combined incidence of mice with adenomas
`or carcinomas in the small intestine of males and females at ≥15 mg/kg/day (>20X
`human AUC @ 60 mg).
`
` A
`
` 2-year bioassay was conducted in rats which were given 0.25, 1.7, 7.5 mg/kg/day in
`males or 0.03, 0.35, 2 mg/kg/day in females by oral gavage. The low dose females were
`sacrificed week 94 and remaining female dose groups by week 97. All the male dose
`groups were sacrificed during week 98. ECAC considered the study suboptimal and
`cautioned that the vehicle (75% PEG-400) may have affected the incidence of pancreatic
`acinar neoplasms. However drug-related neoplasms were not observed at 6-8X human
`AUC @ 60 mg.
`
`Reproductive/Developmental Toxicity: Embryonic death and major fetal malformations
`were noted in rats at drug exposures that are approximately 10-fold higher than the
`anticipated clinical exposure. Some malformations and developmental delays were also
`noted in rats at clinically relevant exposures. Effects in rats appeared to occur in the
`absence of overt maternal toxicity as decrements in maternal body weight were only
`observed at the high dose (10-fold clinical exposure) and were likely due to embryonic
`death and decreased fetal weights that occurred at the high dose. Similar findings were
`not observed in rabbits at clinically relevant doses; however, higher doses (> 3-fold
`clinical exposure) were not tested. Treatment with AEGR-733 was associated with
`
`
`
`Reference ID: 3215803
`
`4
`
`

`

`malformations in ferrets at doses that are below the proposed clinical dose; however,
`these effects occurred in conjunction with signs of maternal toxicity (significant body
`weight loss and decreased food consumption). Based on the findings in rats and ferrets,
`the risk of embryonic death and/or teratogenicity at clinical exposures is possible unless
`additional information currently under review suggests a species specific explanation for
`the developmental findings observed. Therefore, pregnant women should not take
`lomitapide and women should take precautions so that they do not become pregnant
`while taking lomitapide. Women who become pregnant while taking lomitapide should
`consider discontinuation of lomitapide based on their risk:benefit with their physcician.
`Additional safety information will be needed prior to consideration of any pediatric
`dosing.
`
`The indicated patient population having homozygous familial hypercholesterolemia
`(HoFH) will likely have concomitant lipid lowering medications such as statins
`administered as well as lomitapide based on their presumed high cardiovascular risk.
`Statin are contraindicated in pregnancy based on the clinical risk:benefit with similar
`reproductive toxicity profiles in animals to lomitapide. This contraindication is managed
`by product labeling for statins and can be similarly managed with lomitapide.
`
`
`Lomitapide Reprotox Summary prepared by Tim Hummer PhD
`Type of
`Study
`Study
`Number
`Fertility and
`early
`embryonic
`development
`#733PC0001
`
`Species/Strain
`Rat/
`Sprague-
`Dawley
`(25/group)
`
`Dosing
`Duration
`15 days
`before
`mating
`through
`GD7;
`necropsy
`on GD13
`
`Dose Level
`(mg/kg/d)
`0.04
`0.2
`1
`(NOAEL)
`
`Exposure
`Margin*
`<1X
`~1X
`~3X
`
`Key Findings
`No treatment-related effects.
`No treatment-related effects.
`No treatment related effects
`on maternal body weight,
`food consumption, fertility
`indices, number of corpora
`lutea, implantation sites, or
`viable embryos.
`(maximum tolerated dose
`was not used as the high
`dose for this study. 4
`mg/kg/d would have been
`better)
`No treatment-related effects.
`
`• Slight decrease in fetal
`body weights.
`• The following fetal
`malformations were
`observed:
`o Abdomen: umbilical
`hernia, gastroschisis
`o Tail: short, stubbed,
`bent, or absent
`o Heart: alterations in
`size and/or shape
`
`5
`
`Embryo-fetal
`development
`#96039
`
`Rat/
`Sprague-
`Dawley
`(22/group)
`
`GD6
`through
`GD15;
`necropsy
`on GD20
`
`0.04
`(NOAEL)
`0.4
`
`<1X
`
`~2X
`
`
`
`Reference ID: 3215803
`
`

`

`4
`
`~10X
`
`Embryo-fetal
`development
`
`Rabbit/ New
`Zealand white
`
`GD6
`through
`
`0.1
`1
`
`0.03X†
`0.3X†
`
`
`
`Reference ID: 3215803
`
`o Limbs: malrotation
`o Anus: imperforate
`• The following fetal
`variations were observed:
`o Delays in
`ossification of the
`crainial, vertebral,
`and pelvic bones
`• Decreased maternal body
`weight gain, especially
`between GD16 and
`GD20, likely due to
`decreased litter size.
`• Increased maternal spleen
`weights.
`• Post-implantation loss of
`~50% due primarily to
`early resorptions.
`• Decreased mean fetal
`body weights.
`• The following fetal
`malformations were
`observed:
`o Abdomen: umbilical
`hernia, gastroschisis
`o Tail: short, stubbed,
`bent, kinked, curled,
`filamentous
`o Heart: alterations in
`size and/or shape
`o Limbs/paws:
`malrotation,
`shortening
`o Anus: imperforate
`o Brain: exencephaly,
`hydrocephaly,
`cerebral hernia,
`misshaped cerebral
`hemispheres
`• The following fetal
`variations were observed:
`o Delays in
`ossification of the
`crainial, vertebral,
`pelvic, sternal, and
`metacarpal bones
`o Variations in
`development of
`brain: slight dilation
`of the lateral and/or
`third ventricles
`o Skin: friable
`
`
`No treatment-related effects.
`• Maternal body weight
`
`6
`
`

`

`#96032
`
`(20/group)
`
`GD20;
`necropsy
`on GD29
`
`10
`(NOAEL)
`
`3X†
`
`
`Embryo-fetal
`development
`(range-
`finding study)
`#97008
`
`Ferret
`(6/group)
`
`1.6
`(NOAEL not
`identified)
`
`0.3X†
`
`GD12
`through
`GD28;
`necropsy
`on GD35
`
`4
`
`0.8X†
`
`
`
`Reference ID: 3215803
`
`gain was 65% less than
`controls during the
`treatment period.
`• No treatment-related
`effects on number of
`implantation sites,
`resorptions, number of
`viable fetuses, litter size,
`male/female ratio, fetal
`body weights, or fetal
`alterations.
`• Maternal body weight
`gain was 76% less than
`controls during the
`treatment period.
`• No apparent treatment-
`related effects on number
`of implantation sites,
`resorptions, number of
`viable fetuses, litter size,
`male/female ratio, fetal
`body weights, or fetal
`alterations.
`
`• Profound body weight
`loss between GD12 and
`GD29 - 15% loss from
`GD12 weight, which
`correlated with decreased
`food consumption.
`• Mean fetal body weights
`were slightly lower than
`controls.
`• The following fetal
`malformations were
`observed at a low
`incidence (1-4 fetuses and
`1-2 litters per finding:
`o Limbs/paws: rotated
`medially, digits
`absent or fused
`o Head: cleft palate,
`red eyes, open eye
`lids, low set ears
`o Kinked tail
`o Body: umbilical
`hernia
`• Profound body weight
`loss between GD12 and
`GD29 - 18% loss from
`GD12 weight, which
`correlated with decreased
`food consumption.
`• Increased vomiting
`• Slight increase in
`
`7
`
`

`

`resorptions, resulting in
`slight decrease in number
`of live fetuses/litter.
`• The following fetal
`malformations were
`observed at a low
`incidence, except for
`limbs rotated medially
`and umbilical hernia (5-9
`fetuses and 3-4 litters):
`o Limbs/paws: rotated
`medially or short,
`digits absent or fused
`o Head: red eyes, open
`eye lids
`o Body: umbilical
`hernia
`
`
`• Profound body weight
`loss between GD12 and
`GD29 - 21% loss from
`GD12 weight, which
`correlated with decreased
`food consumption.
`• Increased vomiting
`• Increased resorptions,
`resulting in decreased
`number of live
`fetuses/litter.
`• Mean fetal body weights
`were lower than control.
`• The following fetal
`malformations were
`observed at a low
`incidence, except for
`limbs rotated medially
`and umbilical hernia (11-
`16 fetuses and 4-5 litters):
`o Limbs/paws: rotated
`medially or
`shortened, digits
`absent
`o Head: red eyes, open
`eye lids, low set ears
`o Kinked tail
`o Body: umbilical
`hernia
`
`
`• Profound body weight
`loss between GD12 and
`GD29 - 24% loss from
`GD12 weight, which
`correlated with decreased
`food consumption.
`• Increased vomiting
`
`10
`
`2X†
`
`25
`
`5X†
`
`
`
`Reference ID: 3215803
`
`8
`
`

`

`• Increased resorptions,
`resulting in decreased
`number of live
`fetuses/litter.
`• Mean fetal body weights
`were lower than control.
`• The following fetal
`malformations were
`observed at a low
`incidence, except for
`limbs rotated medially
`and umbilical hernia (19
`fetuses and 5 litters):
`o Limbs/paws: rotated
`medially, digits
`fused
`o Head: cleft palate,
`cleft facial, red eyes,
`open eye lids, low
`set ears
`o Short tail
`o Body: umbilical
`hernia
`o Skull: depressed
`
`
`No treatment-related effects
`
`• Slightly lower maternal
`body weights, likely due
`to lower fetal body
`weights.
`• Fetal eye anomalies
`(missing eye,
`microphthalmia) at low
`incidence. 2 pups had
`dilation of the lateral
`ventricles of the brain
`• Lower maternal body
`weights, likely due to
`decreased litter size and
`lower fetal body weights.
`• Slightly increased
`gestation period
`• Decreased indices of live
`liter size/litter, number of
`live pups, viability index,
`lactation index, and fetal
`body weight.
`• Increased number of
`stillborn pups and pups
`dying on LDs 1-7.
`• Fetal eye anomalies
`(missing eye,
`
`9
`
`Peri- and
`post-natal
`development
`#AEGR-
`733PC0014
`
`Rat/
`Sprague-
`Dawley
`(25/group)
`
`GD7
`through
`LD20
`
`<1X
`
`~1X
`
`0.1
`(NOAEL for
`F1
`development)
`0.3
`(NOAEL for
`F0
`reproduction)
`
`~3X
`
`1
`(NOAEL for
`F0 maternal
`toxicity)
`
`
`
`Reference ID: 3215803
`
`

`

`microphthalmia) at low
`incidence. Increase in tail
`anomalies (bent, short,
`tail or tip of the tail
`missing or absent, purple,
`red and/or black), pale
`body, or a head mass.
`• 1 pup had dilation of the
`lateral ventricles of the
`brain and 1 pup and
`malformed forelimb.
`• F1 generation rats were
`not able to overcome the
`deficits in postpartum
`body weights (remained
`lower after weaning).
`• No statistically significant
`or biologically important
`differences occurred in
`watermaze performance
`of the F1 generation male
`and female rats regarding
`learning, short-term
`retention, long-term
`retention, or response
`inhibition.
`• There were no statistically
`or biologically important
`effects on the mating and
`fertility parameters
`evaluated in the F1
`generation male and
`female rats.
`• All fetal gross alterations
`of the F2 generation were
`considered unrelated to in
`utero maternal (F1)
`exposure.
`
`*Estimated based on exposure data for non-pregnant animals.
`†Based on body surface area extrapolation; exposure data not available for this species.
`GD = gestation day; LD = lactation day; NOAEL = no observed adverse effect level.
`
`
`Proposed Labeling:
`
`8.1
`
`Pregnancy
`
`Pregnancy Category X.
`
`Risk Summary
`
`
`
`Reference ID: 3215803
`
`10
`
`

`

`TRADENAME is contraindicated during pregnancy because TRADENAME may cause fetal harm when
`administered to a pregnant woman. Lomitapide was teratogenic in rats and ferrets at exposures estimated to
`be less than human therapeutic exposure at 60 mg (AUC<67 ng h/ml) when administered during
`organogenesis. There was no evidence of teratogenicity in rabbits at 3 times the maximum recommended
`human dose (MRHD) of 60 mg based on body surface area. Embryo-fetal lethality was observed in rabbits
`at 6-times the MRHD. If this drug is used during pregnancy, or if the patient becomes pregnant while
`taking this drug, the patient should be apprised of the potential hazard to a fetus.
`
`
`
`Reference ID: 3215803
`
`11
`
`(b) (4)
`
`

`

`dedsimshofldbemdewhdhubdimonfinmmmhgmdiscmfimmfiedmg,hfinghoamumme
`
`importaneeoflhedmgtofllemother.
`
`8.4
`
`Pediatric Use
`
`Safetyandefl‘ecfivenesshavenotbeenesmblishedinpediauicpafients.
`
`8.8
`
`Females of Reproductive Potential
`
`TRADENAME may cause fetal harm [see Use in Specy‘ic Populations (8.1)]. Females who become
`
`pregnmtmningTRADENAMEflluapyshwldsmpmADENAMEimmediamlymdnofifymdr
`
`healfllcate provider.
`
`Pregnancy testing
`
`Females ofreproducfive potemial should have a negative pregnancy test before starting TRADENAME.
`
`Contraception
`
`Females ofreproductive potenfial should use efi'ective conflacepfion dining TRADENAME metapy.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutngeueeis, Impairment of Fertility
`
`
`
`Reference ID: 3215803
`
`12
`
`

`

`Lomitapide did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial
`Reverse Mutation (Ames) assay, an in vitro cytogenetics assay using primary human lymphocytes, and an
`oral micronucleus study in rats.
`
`Lomitapide had no effect on fertility in rats at doses up to 5 mg/kg/day at systemic exposures estimated to
`be 4-times (females) and 5-times (males) higher than in humans at 60 mg based on AUC.
`
`
`
`Nonclinical Support for Pediatric Use: Based on the
`severity of dyslipidemia in the HoFH population, it is
`likely that lomitapide will be used in the pediatric
`population. Based on the age of the dogs (6-months) at the
`initiation of the chronic dog toxicity study it is likely
`that the results of this study would be informative for an
`adolescent population. This is similar for the 7-8 week old
`rat at initiation of the chronic rodent toxicity studies.
`The pre- and post-natal developmental study assessed rats up
`to 20 days old which developmentally equivalent to a child
`(~3 yrs). In this study there were no biologically
`important differences in learning or memory (short or
`longterm). Only the 6-month toxicity and carcinogenicity
`studies utilized vitamin supplementation in conjunction with
`lomitapide. There is an informational gap for rats
`postnatal day 20-50 for assessment of learning and memory.
`Based on this consideration of a juvenile rat study ± fat
`soluble vitamin and essential fatty acid supplementation as
`a PMR can be considered to address concerns for
`malabsorption and any potential for learning and memory
`prior to lomitapide exposure in developing pediatrics • 5
`years old.
`
`
`
`
`
`
`Reference ID: 3215803
`
`13
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KAREN L DAVIS BRUNO
`11/13/2012
`Pharm/Tox Supervisory Memo
`
`Reference ID: 3215803
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Review number
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`Review Division:
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`203858
`1
`1
`28 February 2012
`29 February 2012
`Lomitapide (AEGR-733)
`Hypercholesterolemia
`Aegerion Pharmaceuticals, Inc.
`Metabolism and Endocrinology Products
`B. Timothy Hummer, PhD, DABT
`Karen Davis-Bruno, PhD
`Mary Parks, MD
`Kati Johnson
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203858 are owned by Aegerion Pharmaceuticals, Inc. or
`are data for which Aegerion Pharmaceuticals, Inc. has obtained a written right of
`reference. Any information or data necessary for approval of NDA 203858 that
`Aegerion Pharmaceuticals, Inc. does not own or have a written right to reference
`constitutes one of the following: (1) published literature, or (2) a prior FDA finding of
`safety or effectiveness for a listed drug, as reflected in the drug’s approved labeling.
`Any data or information described or referenced below from reviews or publicly
`available summaries of a previously approved application is for descriptive purposes
`only and is not relied upon for approval of NDA 203858.
`
`Reference ID: 3212681
`
`1
`
`

`

`Reviewer: B. Timothy Hummer, PhD, DABT
`
`
`NDA #203858
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 4
`1.1
`INTRODUCTION.................................................................................................... 4
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 4
`1.3 RECOMMENDATIONS............................................................................................ 6
`2 DRUG INFORMATION ............................................................................................ 8
`2.1 DRUG................................................................................................................. 8
`2.2 RELEVANT INDS.................................................................................................. 9
`2.3 DRUG FORMULATION ........................................................................................... 9
`2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 10
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 10
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ................................