CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203858Orig1s000
`
`SUMMARY REVIEW
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`NDA 203858/S000 (lomitapide)
`Summary Basis for Regulatory Action
`
`
`
`1. Introduction and Background
`This memo summarizes the basis for the regulatory action for lomitapide. This oral drug is
`being proposed for the orphan indication of the treatment of homozygous familial
`hypercholesteremia (HoFH). In-depth review and analyses of specific issues can be found in
`the primary reviews of the respective disciplines. This memo contains my summary,
`assessments, and conclusions concerning the major issues identified during the review of this
`application.
`
`Lomitapide is a first-in-class small molecule inhibitor of the microsomal triglyceride protein
`(MTP) that transfers lipids to apolipoprotein B to form the apo B-containing lipoprotein
`complex. Inhibition of MTP prevents the assembly and secretion of apo B-containing
`lipoproteins, which include VLDL-C (the precursor of LDL-C), and chylomicrons from the
`liver and intestine, respectively.
`
`Homozygous familial hypercholesteremia (HoFH) results from loss of function mutations in
`both alleles of the LDL receptor (LDL-R). These mutations render the LDL-Rs absent or non-
`functional leading to reduced clearance of LDL particles from circulation, resulting in marked
`elevation in plasma LDL-C levels. Untreated LDL-C levels in individuals with HoFH usually
`range from 500 to 1000 mg/dL. If left untreated, HoFH patients die prematurely from
`accelerated atherosclerotic cardiovascular disease by the second or third decade of life. In the
`U.S., the prevalence of HoFH is approximately 1 per million persons.
`
`Treatment options for HoFH are limited in number and in scope. High potency HMG-CoA
`reductase inhibitors (statins), with or without a cholesterol absorption inhibitor, and LDL
`apheresis are the mainstay of therapy (see Table 1). Statin therapy depends on functional
`LDL-Rs for most of its lipid lowering effects and, therefore, has limited efficacy in HoFH.
`Similar to dialysis, LDL apheresis is an extracorporal procedure that selectively removes apo-
`B containing lipoproteins (VLDL-C, LDL-C, lipoprotein (a), and triglycerides). The
`procedure, however, needs to be performed on a chronic, repetitive basis of every one to two
`weeks, and there are currently only 35 apheresis centers in the U.S. Liver transplantation has
`been employed rarely as a last resort.
`
`Table 1: Non-surgical therapies for HoFH
`Therapy
`Mechanism of action
`
`LDC-C lowering response in
`HoFH
`
`< 10 – 25%
`< 10%
`
`LDLR activity
`HMG-CoA reductase inhibitors
`LDLR activity, inhibits
`Cholesterol absorption
`cholesterol absorption
`inhibitors
`~30 – 40%1
`LDL-C removal
`LDL-apheresis*
`*Response based on time averaged LDL-C levels; acutely, apheresis lowers LDL-C by 50-75%
`
`Drug therapy in combination with LDL apheresis can typically reduce LDL-C by 45% to
`55%.2 Because HoFH patients have such elevated LDL-C levels at baseline (> 500 mg/dL),
`
`1 Pfohl M, Naoumova RP, Klass C, Knisel W, Jakober B, Risler T, Thompson GR. Acute and chronic effects on cholesterol
`biosynthesis of LDL-apheresis with or without concomitant HMG-CoA reductase inhibitor therapy. J Lipid Res. 1994;35(11):1946.
`2 Gilbert R. Thompson, M. Barbir, D. Davies, et al. Efficacy criteria and cholesterol targets for LDL apheresis. Atherosclerosis 208
`(2010) 317–321.
`
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`NDA 203858/S000 (lomitapide)
`Summary Basis for Regulatory Action
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`combining multiple treatment modalities still fails to provide adequate control of LDL-C, and
`HoFH patients remain at high-risk for serious adverse cardiovascular events and premature
`death. There is a clear need for additional therapies to help HoFH patients either approach or
`reach LDL-C treatment goals.
`
`This NDA submission supports the use of lomitapide at a starting daily dose of 5 mg titrated to
`a maximum of 60 mg, based on safety and tolerability, as an adjunct to diet and lipid lowering
`therapies to reduce LDL-C in HoFH patients.
`
`2. Recommendations of Review Disciplines regarding Approvability
`This section summarizes key recommendations from the review disciplines.
`
`CMC: In his review signed on October 18, 2012, the primary reviewer (Xavier Ysern)
`recommended approval of lomitapide from a CMC perspective.
`
`Biopharmaceutics (ONDQA): In her review signed October 26, 2012, the primary reviewer
`(Elsbeth Chikhale) recommended approval of lomitapide from a biopharmaceutics perspective.
`A waiver for the requirement to conduct a BA/BE study for the 10 mg capsule strength was
`granted.
`
`Pharmacology Toxicology: In his review signed November 5, 2012, the primary reviewer
`(Brian [Tim] Hummer) recommended approval of lomitapide from a pharmacology-toxicology
`perspective. Safety concerns based on preclinical findings are discussed in Section 4 (Safety).
`The team recommended a juvenile toxicology study, as a postmarket requirement, to be
`conducted prior to evaluating lomitapide in pediatric HoFH patients.
`
`Clinical Pharmacology: In his review signed November 5, 2012, the primary reviewer (Sze
`[Johnny] Lau) recommended approval from a clinical pharmacology perspective.
`Recommended dosing modifications based on drug-drug interactions, food effect, and
`hepatic/renal impairment that will be incorporated into labeling are discussed in Section 4
`(Safety).
`
`Statistics: In her review signed November 30, 2012, the primary reviewer (Cynthia Liu)
`concluded that lomitapide was effective in reducing LDL-C and the pre-specified secondary
`lipid parameters and recommended approval from a statistical perspective.
`
`Clinical: In his review signed November 27, 2012, the primary reviewer (James Smith)
`recommended approval from a clinical perspective. Important clinical findings and
`assessments are discussed in Sections 3 (Efficacy) and 4 (Safety) below.
`
`I concur with the recommendation of approval from the review disciplines.
`
`3. Efficacy
`Efficacy of lomitapide in HoFH patients was demonstrated in one Phase 3 trial (HoFH-pivotal,
`29 HoFH patients); with supportive evidence from one Phase 2 study (HoFH-pilot, 6 HoFH
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`NDA 203858/S000 (lomitapide)
`Summary Basis for Regulatory Action
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`patients). The primary efficacy endpoint in both trials was the percent change from baseline to
`endpoint in directly measured serum LDL-C; each subject served as his or her own control.
`
`The surrogate endpoint of serum LDL-C has been an accepted primary efficacy measure in
`marketing applications for lipid-lowering therapies in the U.S. The relationship between
`reductions in LDL-C levels and decreased risk of adverse cardiovascular outcomes has been
`well established for statin therapy. Although there are no data correlating LDL-C reduction
`and improved cardiovascular outcomes for MTP inhibitors, there is no reason to believe that
`LDL-C would not be an acceptable efficacy endpoint for HoFH patients treated with
`lomitapide. Moreover, a definitive cardiovascular outcomes trial in HoFH patients would be
`infeasible because of the rarity of the disease, and LDL-C is the most appropriate surrogate
`measure available.
`
`The HoFH-pivotal trial was a multinational, open-label, single-arm trial in 29 HoFH patients
`on stable diet and maximally tolerated LDL lowering drugs, with or without apheresis, at
`baseline. Patients received lomitapide as add-on therapy at an individually defined maximum
`tolerated dose between 5 and 60 mg once daily for 78 weeks (weeks 0 to 26 was the efficacy
`phase, weeks 26 to 78 was the safety phase). Patients could enroll in the extension study
`(HoFH-extension) after completing the 78 weeks of treatment; the extension study is ongoing.
`
`The primary efficacy endpoint, % change in LDL-C levels from baseline to Week 26/end of
`treatment, was analyzed using paired t-test performed on the intent to treat population (all 29
`patients) with last-observation-carried-forward (LOCF) imputation of missing data. Primary
`efficacy results are shown in Table 2. It should be noted that the observed LDL-C reduction
`from lomitapide treatment was in addition to the lipid lowering effects of baseline therapies.
`Table 2: Primary Endpoint – Percent change in LDL-C from baseline to Week 26 (HoFH-
`pivotal)
`
`N = 29
`
`Baseline LDL-C
`(mg/dL)
`
`Relative
`Change from
`Baseline (%)
`
`-40 (32)
`-52 to -27
`-50
`-93, +21
`
`P*
`
`<0.001
`
`Absolute
`Week 26/ITT/LOCF
`Change from
`LDL-C
`Baseline
`(mg/dL)
`(mg/dL)
`
`
`
`
`Mean (SD)
`337 (114)
`191 (107)
`-147 (127)
`95% CI
`
`
`
`Median
`357
`169
`-107
`Min, Max
`152, 565
`28, 443
`-351, +49
`Source: Adapted from primary statistical review (Cynthia Liu), Table 2
`* P-value based on paired t-test for mean % change
`
`Maximum LDL-C reduction reached plateau at Week 18 and was maintained at approximately
`45% reduction at Week 56; the mean maximum tolerated dose at Week 26 and at Week 56 was
`approximately 40 mg.
`
`Categorical LDL-C response: 19 of the 29 patients (66%) had LDL-C reductions ≥ 25%, with
`8 (28%) having LDL-C levels < 100 mg/dL. Four of these 8 patients were receiving apheresis.
`The fact that HoFH patients treated with adjunctive lomitapide could attain the National
`Cholesterol Education Program’s target LDL-C treatment goal is noteworthy.
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`NDA 203858/S000 (lomitapide)
`Summary Basis for Regulatory Action
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`Apheresis: Of the 29 patients, 18 (62%) were receiving apheresis treatment at the beginning of
`the trial. Because the acute reduction and ensuing rebounds in plasma lipid levels could
`confound efficacy measurements, the protocol specified that the timing of on-treatment LDL-C
`measurements relative to the preceding apheresis was to be the same as that established at
`baseline. In general, patients on apheresis experienced a mean LDL-C reduction at Week
`26/LOCF of smaller magnitude compared to patients not on apheresis (-35% versus -49%).
`This observation may be confounded by the fact that a greater proportion of patients on
`apheresis discontinued drug treatment in the efficacy phase and the mean drug dose at Week
`26/LOCF was higher for patients not on apheresis. Taken altogether, there is no compelling
`reason to believe that apheresis negatively impacts the efficacy of lomitapide.
`
`Of the 13 apheresis-treated patients remaining in the HoFH-pivotal study at Week 26, three
`discontinued apheresis and three reduced the frequency of the procedure by Week 78. All but
`one patient either maintained the LDL reduction achieved during the efficacy phase or
`experienced slight rise in LDL-C levels, but these levels remained ≥ 50% below baseline.
`I consider these favorable alterations in apheresis to be significant in reducing the burden of
`the treatment for HoFH patients. Although decreasing the frequency of or discontinuing
`apheresis while on lomitapide may lead to less than optimal LDL-C reduction than if the
`apheresis regimen was not altered, the quality of life benefits of forgoing each apheresis
`procedure can be immediately appreciated, given the avoidance of time, cost, inconvenience,
`and risks that are incurred each time the procedure is performed.
`
`Supportive data from the HoFH-pilot study for the primary endpoint of mean % change in
`LDL-C from baseline to the end of the dosing intervals (approximately 4 weeks each) are
`shown below. This study enrolled 6 adult HoFH patients who received lomitapide once daily
`according to a prespecified dosing scheme that called for dose escalation every 4 weeks
`(starting at 0.03 mg/kg and ending at 1.0 mg/kg). LDL-C levels were measured at the end of
`every 4 weeks at a certain dose. These findings demonstrate a dose response indicating a drug
`effect of lomitapide.
`
`Table 3: Supportive Evidence of LDL-C reduction (HoFH-pilot)
`
`
`Results for the secondary endpoints from the HoFH-pivotal trial are shown in Table 4. These
`findings are reassuring in that the changes in these lipid parameters are consistent with LDL-C
`reduction, but it would be premature to conclude that these changes are adequate evidence of
`additional cardiovascular benefits beyond lowering of LDL-C. I agree with Dr. Smith’s
`recommendation that only the secondary endpoints of total cholesterol, apoB, and non-HDL-C
`should be included in the indication for lomitapide. These endpoints are reflected in changes
`
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`NDA 203858/S000 (lomitapide)
`Summary Basis for Regulatory Action
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`in LDL-C and could potentially inform drug benefit in a manner similar to LDL-C.
`Hypertriglyceridemia is not a feature of HoFH disease, and the clinical relevance of
`triglyceride reduction in a population that has normal triglyceride levels is questionable.
`
`
`Table 4: Secondary endpoints (HoFH-pivotal)
`Lipid Parameters Relative Change from Baseline to Week 26/LOCF
`N=29
`Mean change % (SD)
`-36 (28)*
`Total cholesterol
`-40 (30)*
`ApoB
`-29 (56)*
`Triglycerides
`-40 (30)*
`Non-HDL-C
`-29 (58)
`VLDL-C
`-11(34)
`Lp (a)
`Source: Adapted from primary clinical review (James Smith), Table 71
`*P < 0.01 based on paired t-test for mean % change
`
`HDL-C: Serum HDL-C levels declined from Week 0 to Week 26 (mean reduction of 7%
`[using LOCF] or 12% [using completer analysis]) but subsequently returned to baseline levels
`by Week 56. Serum levels of apoA1 followed a similar pattern. The reason for these lipid
`changes is unknown. Given the magnitude of reduction of HDL-C, the spontaneous return of
`HDL levels to baseline with continued treatment, and the uncertain effect of drug-induced
`changes in HDL-C on cardiovascular risk, I do not believe these HDL-C changes would
`significantly offset the benefit anticipated from lomitapide’s favorable effect on LDL-C.
`
`Efficacy conclusion
`Lomitapide was efficacious in reducing serum LDL-C in HoFH patients on a low-fat diet and
`maximally tolerated lipid lowering treatment. Drug benefit was also observed for other lipid
`parameters, such as total cholesterol, apo B, and non-HDL-C. In some patients, lomitapide led
`to beneficial alterations in apheresis regimen or the attainment of NCEP’s LDL-C target
`treatment goal. I consider these drug benefits to be clinically important.
`
`4. Safety
`The clinical safety findings of lomitapide have been thoroughly discussed in Dr. Smith’s
`review. This safety assessment focuses on safety findings in the HoFH population, and is
`limited to significant safety issues of interest identified by the review teams. Although 915
`individuals (most were healthy volunteers, patients with renal/hepatic impairment, or non-
`HoFH patients with hypercholesteremia) received at least one dose of lomitapide in the 24
`studies provided in the NDA, the phase 3 safety database to support the intended use for
`lomitapide only consists of 29 HoFH patients enrolled in the HoFH-pivotal trial and its
`extension. Such a small safety database could only provide assurance that the true incidence
`of an adverse outcome is no greater than 10% when the outcome is not observed in the trial.
`
`Death: One death (myocardial infarction) occurred in the entire drug development program
`(54 year-old man with factor V Leiden, a history of deep vein thrombosis, morbid obesity
`(BMI 42 kg/m2)). Although a potential drug association could not be completely excluded, I
`believe it is unlikely that lomitapide caused the event.
`
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`NDA 203858/S000 (lomitapide)
`Summary Basis for Regulatory Action
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`Non-fatal serious adverse events (SAEs): All narratives were reviewed by Dr. Smith. I
`agree with Dr. Smith’s assessment that lomitapide may have contributed to the SAEs
`experienced by the following 2 patients:
`
`
`1. Subject 11-004: This case of “hepatoxicity” occurred in a 54 year-old man with
`elevated liver enzyme tests at baseline and throughout the phase 3 trial (1.5X to 5X
`ULN). His liver biopsy, obtained at baseline as workup for elevated liver enzymes,
`showed mild steatosis. At the scheduled Week 138 visit, his ALT was 24X ULN, AST
`13X ULN, and alkaline phosphatase 2.5X ULN, with normal bilirubin levels. Prior to
`this visit, he was treated with clarithromycin (a strong CYP3A4 inhibitor) and the
`antidepressant agomelatine (known to increase hepatic aminotransferases), and had
`increased his alcohol intake. He was otherwise asymptomatic. His liver enzymes
`normalized several months after all drugs were discontinued. His follow-up liver
`biopsy showed simple steatosis that had increased from his previous biopsy, without
`histologic evidence of inflammation or fibrosis.
`
` I
`
` concur with Dr. Smith’s assessment that this was a case of (multi) drug-induced
`hepatoxicity, given all the culprits involved. This case illustrates the need to
`emphasize through labeling the potential serious sequelae of drug-drug interactions
`(DDI) of lomitapide with CYP3A4 inhibitors or with hepatotoxic drugs or substances.
`
`2. Subject 01-1003: This patient experienced multiple SAE’s related to over-
`anticoagulation that may have resulted from the now known drug-drug interaction
`between lomitapide and warfarin. Labeling will address this DDI and recommend
`monitoring for INR levels when warfarin is administered concomitantly with
`lomitapide.
`
`
`Drug discontinuation due to adverse events: In the HoFH-pivotal trial, 6 of 29 patients
`(21%) discontinued drug treatment prior to Week 26: 3 discontinued for gastrointestinal
`symptoms; 2 withdrew consent with AEs of headaches, unstable INR, and gastrointestinal
`symptoms; and 1 discontinued because of anxiety about gastrointestinal side effects. In the
`ongoing HoFH-extension study, 2 of 18 patients discontinued due to AE’s (hepatotoxicity,
`aminotransferase elevations).
`
`Common adverse events of interest: Gastrointestinal side effects, such as diarrhea, nausea,
`vomiting, dyspepsia, abdominal pain, were nearly universal, occurring in > 90% of HoFH
`patients. The most common severe AEs were also GI related. A decrease in weight was
`reported as an adverse event in 7 (24%) of the 29 HoFH patients. The largest change in mean
`weight was observed at Week 26 (-5% relative to baseline), with attenuation of weight
`decrease thereafter. It is, however, reassuring that the incidence of these AEs declined after the
`initial 26 weeks, despite the fact that no patients withdrew between Week 26 and Week 78 in
`the pivotal study. This pattern suggests possible tolerance or adaptation to these AEs.
`
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`NDA 203858/S000 (lomitapide)
`Summary Basis for Regulatory Action
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`Special Safety Issues
`
` •
`
` Liver abnormalities
`
`All HoFH-
`pivotal
`(N=29)
`4 (14%)
`6 (21%)*
`3 (10%)
`1 (3%)
`0
`
`HoFH-
`extension
`(N=18)
`0
`2 (11%)
`1 (6%)
`2 (11%)
`1 (6%)
`
`All HoFH
`(N=29)
`3 (10%)
`4 (14%)*
`4 (14%)
`2 (7%)
`1 (3%)
`
`
`Hepatic transaminase elevations:
`The incidence of peak ALT elevations at various thresholds in the 78-week HoFH-pivotal
`(Week 0 – 26 efficacy phase and Week 26 – 78 safety phase) trial and its ongoing extension
`(HoFH-extension) is shown below:
`
`Table 4: Peak ALT elevations (HoFH)
`Efficacy
`Peak ALT
`Safety Phase
`Phase
`(N=23)
`During Period
`(N=29)
`≥2x, <3x ULN
`3 (10%)
`4 (17%)
`≥3x, <5x ULN
`4 (14%)
`3 (13%)
`≥5x, <10x ULN
`3 (10%)
`2 (9%)
`≥10x, <20x ULN
`1 (3%)
`0
`≥20x ULN
`0
`0
`Source: Primary clinical review (James Smith), Table 86
`*Although 6 patients had peak ALT between 3-5X ULN, two of those experienced higher peak ALT elevations (5-10X ULN, >20X
`ULN) during the extension study, leaving 4 subjects in the 3-5X ULN category when the pivotal and extension studies are
`combined.
`
`In the combined HoFH-pivotal and extension trials, 38% (11 of 29) of HoFH patients
`experienced at least one ALT value ≥ 3X ULN. These changes were not accompanied by
`laboratory changes indicating liver dysfunction, such as elevations in total bilirubin or INR.
`The median time to first ALT elevation was 126 days ([IQR 43, 155] for the 10 patients who
`had a peak ALT value ≥ 3X ULN during HoFH-pivotal. The remaining patient had her first
`ALT elevation during the HoFH-extension when she was found to have ALT elevations 10X
`ULN found on routine testing. She had been taking cold medications for the preceding several
`weeks. Her transaminase values decreased to near normal levels with dose interruption, and
`lomitapide was restarted at a lower dose 5 weeks later.
`
`The single patient with ALT elevation > 20X ULN in the HoFH-extension trial was discussed
`earlier in the “Non-fatal SAE” section. Increased ALT ≥ 5X ULN was observed in 4 patients
`during the HoFH-pivotal trial and occurred across a wide range of lomitapide doses (10 mg, 10
`mg, 20 mg, and 60 mg). Liver enzyme levels improved with dose modifications, and all four
`patients completed Week 78, with three of them ultimately tolerating doses equal to or
`exceeding the dose being taken at the time of their first ALT exceeding 5x ULN. One of the
`four patients subsequently experienced an ALT elevation > 10X ULN in the HoFH-extension
`trial and permanently discontinued lomitapide.
`
`Of the six patients with peak ALT ≥ 3X ULN < 5X ULN, five had resolution to <3x ULN
`without dose reduction or interruption.
`
`The temporal trend in median ALT and AST values up to Week 56 in the HoFH-pivotal trial is
`shown below. The shifts in aminotransferases are evident but there were no cases of “Hy’s
`Law.” One must be mindful, however, of the very small safety database when interpreting
`these findings.
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`Summary Basis for Regulatory Action
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`Figure 1: Median ALT and AST over time (HoFH-pivotal)
`
`
`
`Source: Primary clinical review (James Smith), Figure 34
`
`In the 16-week HoFH-pilot trial, 3 of 6 patients experienced on-treatment ALT/AST elevations
`≥ 5X ULN. Liver enzymes declined between dose titration, and all patients eventually received
`the highest daily dose of 1.0 mg/kg. All aminotransferase elevations normalized after drug
`discontinuation. There were no changes in other liver laboratory parameters, including total
`bilirubin, outside the normal range.
`
`In summary, lomitapide increases aminotransferases at a high frequency. The mechanism of
`action responsible for this adverse outcome is not well understood and may or may not be
`entirely related to hepatic fat accumulation; however,
`• Extreme transaminase elevations > 10X ULN occurred in the presence of other factors
`known to increase the risk of hepatic injury (drug-drug interactions, exposure to other
`hepatotoxins).
`• Hepatic enzyme elevations, even those of substantial magnitude, were reversible within
`weeks of drug interruption or dose reduction. Rechallenges were usually successful in
`patients who required drug interruption.
`• More modest elevations of < 5X ULN can resolve despite continued dosing, suggesting
`possible adaptation.
`• The serum aminotransferase elevations were not accompanied by evidence of impaired
`liver function, and there were no cases of Hy’s law, albeit the available safety data are very
`limited.
`
`
`For the reasons listed above, I believe that this significant risk of lomitapide can be
`appropriately managed in clinical practice, with available risk management strategies of
`labeling and REMS. That said, the risk of serious liver injury with lomitapide is undefined at
`this time due to a very small safety database, and will need to be further characterized in the
`postmarket long-term observational study.
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`Hepatic steatosis
`Hepatic fat accumulation is an expected pharmacodynamic effect of lomitapide by virtue of its
`mechanism of action. Measurement of hepatic fat was performed using nuclear magnetic
`resonance spectroscopy (NMRS)/MRI in the HoFH-pivotal trial (at weeks 0, 26, 56, and 78)
`and in the ongoing HoFH-extension trial (every 6 months). The table below shows the
`temporal trend of hepatic fat accumulation observed in the HoFH-pivotal and HoFH-extension
`trials. In general, hepatic steatosis persisted, or increased modestly, with continued lomitapide
`treatment.
`
`
`Table 5: Hepatic fat accumulation over time (HoFH-pivotal, HoFH-extension)
`
`
`
`
`
`Source: Primary clinical review (James Smith), Table 89
`
`Categorical maximum changes in hepatic fat observed in the HoFH-pivotal and HoFH-
`extension trials are shown below. Overall, 11 (48%) of 23 patients with hepatic fat data had a
`peak increase in hepatic fat content > 10%.
`
`Table 6: Categorical maximum hepatic fat changes (HoFH-pivotal, HoFH-extension)
`
`Source: Primary clinical review (James Smith), Table 90
`
`Multiple analyses conducted by Dr. Smith indicated that neither the magnitude of LDL-C
`reduction nor aminotransferase elevations could reliably predict the presence or severity of
`hepatic steatosis. Dr. Smith’s analysis of the temporal trend of hepatic fat accumulation in
`affected individuals showed a general trend of initial increase in the first 26 weeks with
`stabilization thereafter in most, but not all, patients. Dr. Smith also concluded that the
`“plateaus or observed reductions in hepatic fat cannot often be explained by a decrease in
`dose.” Off-treatment imaging data available for the 7 HoFH patients who discontinued
`lomitapide indicate reversibility of fat accumulation on imaging weeks to months after drug
`discontinuation.
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`All 6 HoFH patients enrolled in the 16-week HoFH-pilot trial had increased hepatic fat on
`imaging, with peak values ranging from 9% to 44%. These imaging changes returned to
`baseline 4 to 14 weeks after drug discontinuation. In a non-HoFH phase 2 trial evaluating the
`reversibility of fat accumulation, lomitapide treatment (25 mg daily) resulted in a placebo-
`adjusted mean ~20% increase in hepatic fat after 4 weeks of treatment. These imaging
`changes were reversible 6 weeks after drug discontinuation. There were no data on
`reversibility based on histopathology in the lomitapide safety database.
`
`Liver biopsies were not protocol-mandated in lomitapide trials. In the entire clinical safety
`database, “for-cause” liver biopsy results from two patients treated with lomitapide for an
`extended duration were available for review. Biopsy from the patient with the SAE of
`“hepatoxicity” at Week 138 in the HoFH-extension trial showed worsening of simple steatosis,
`but without evidence of inflammation or fibrosis, compared to his biopsy obtained at baseline.
`A 2012 biopsy from a patient with familial chylomicronemia treated with lomitapide for 13
`years in a compassionate care program showed progression of inflammation and fibrosis
`compared to biopsy results obtained in 2008. The role of lomitapide in the patient’s worsening
`liver histopathology could not be discerned in light of her underlying disease.
`
`Our understanding of non-alcoholic fatty liver disease (NAFLD), a primary disease not
`secondary to other known causes of hepatic fat accumulation, sheds some light on the natural
`history of chronic liver injury from hepatic fat accumulation. Simple steatosis of NAFLD
`generally has a benign course, whereas steatosis associated with inflammation and necrosis
`(non-alcoholic steatohepatitis, or NASH) can progress to cirrhosis in up to 10 to 20% of the
`cases. There are no non-invasive biomarkers that could reliably predict the progression from
`simple steatosis to NASH or allow for early detection of NASH.
`
`The risk of chronic liver injury, including steatohepatitis, from lomitapide-induced hepatic
`steatosis is unknown at this time. Whether the clinical course of hepatic steatosis caused by
`lomitapide follows a similar path as NAFLD is uncertain. Published literature on marketed
`drugs implicated in chronic steatosis and steatohepatitis (e.g., amiodarone) is not likely to be
`generalizable, as the risks may be drug-, patient-, or disease-specific. No evidence currently
`exists to inform the routine use of biomarkers or imaging studies to screen for drug-induced
`steatohepatitis or to guide treatment decisions, such as when to contraindicate or discontinue
`treatment.
`
`Regardless of the aforementioned informational gaps, for lomitapide-treated patients, hepatic
`fat could be monitored by imaging studies, and a liver biopsy could be performed to inform
`histopathological changes and provide an opportunity to discontinue treatment prior to the
`development of more serious liver injury. Lomitapide-induced fat accumulation measured by
`imaging study appears to be reversible with drug discontinuation.
`
`• Dietary fat malabsorption
`
`Lomitapide interferes with dietary fat absorption from the intestine by virtue of its mechanism
`of action. The HoFH-pilot trial showed statistically significant reduction in systemic levels of
`fatty acid nutrients at lomitapide doses ≥ 0.3 mg/kg. Subsequently, all patients in the HoFH-
`
`
`
`Reference ID: 3236195
`
`11
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`Page 12 of 18
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`PENN EX. 2016
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`NDA 203858/S000 (lomitapide)
`Summary Basis for Regulatory Action
`
`
`
`pivotal trial received dietary supplements containing vitamin E (400 IU), linoleic acid (200
`mg), alpha-linolenic acid (220 mg), EPA (110 mg), and DHA (80 mg). With supplementation,
`the median levels of serum vitamin E, beta-carotene, ALA, linoleic acid, EPA, DHA, and
`arachidonic acid decreased from baseline to Week 26, but remained above the lower limit of
`the reference range, with subsequent stabilization or trends toward baseline.
`
`It appears that dietary supplements, which are available over the counter, provided adequate
`coverage for lomitapide-induced reduced absorption of fat-soluble nutrients in adults, although
`no information is available in pediatric HoFH patients.
`
` •
`
` Preclinical safety signals
`
`
`Teratogenicity: Embryo-fetal developmental studies in rats and ferrets showed major
`teratogenic effects during the organogenesis period at clinically relevant exposures. Fetal
`malformations affecting the eye, brain, and limb, and increased perinatal mortality were also
`observed at relevant human exposure in the peri-and post-natal development toxicity study in
`the rat. The review teams, OSE, and the Pediatric and Maternal Health Team all concluded
`that this risk could be managed with labeling (Pregnancy Category X, and Medication Guide
`to advise patients of this risk with an emphasis on the use of effective contraception) and the
`recommendation that pregnancy should be excluded prior to initiating lomitapide treatment.
`
` I
`
` agree with this approach. The most important risk management strategy lies in the
`prevention of an unintended pregnancy, as 50% of pregnancies in the US are unplanned and
`the teratogenic effects in the preclinical studies occurred during organogenesis, a period where
`most women are often not aware that they are pregnant. Because lomitapide will be used in a
`small at-risk population managed primarily by healthcare providers familiar with prescribing
`products with similar teratogenic profile, requirements such as ongoing pregnancy testing or a
`patient’s attestation of compliance with effective contraception are not warranted at this time.
`
`Neoplasms: A two-year carcinogenicity study in mice showed a statistically significant
`increase in hepatocellular and small intestinal neoplasms at clinically relevant exposures. A
`two-year carcinogenicity study in rats did not demonstrate any drug-related neoplastic
`findings. No malignancies were reported in the small clinical safety database of lomitapide.
`
`Important Clinical Pharmacology findings affectin