Articles
`
`Effi cacy and safety of a microsomal triglyceride
`transfer protein inhibitor in patients with homozygous
`familial hypercholesterolaemia: a single-arm, open-label,
`phase 3 study
`
`Marina Cuchel, Emma A Meagher, Hendrik du Toit Theron, Dirk J Blom, A David Marais, Robert A Hegele, Maurizio R Averna, Cesare R Sirtori,
`Prediman K Shah, Daniel Gaudet, Claudia Stefanutti, Giovanni B Vigna, Anna M E Du Plessis, Kathleen J Propert, William J Sasiela,
`LeAnne T Bloedon, Daniel J Rader, for the Phase 3 HoFH Lomitapide Study investigators
`
`Summary
`Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We
`aimed to assess the effi cacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults
`with this disease.
`
`Methods We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous
`familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through
`to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of
`60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26,
`after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline
`to week 26 was assessed with a mixed linear model.
`
`Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited
`from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the
`effi cacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol
`was reduced by 50% (95% CI –62 to –39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5];
`p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL
`cholesterol remained reduced by 44% (95% CI –57 to –31; p<0·0001) at week 56 and 38% (–52 to –24; p<0·0001) at
`week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase
`levels of more than fi ve times the upper limit of normal, which resolved after dose reduction or temporary interruption
`of lomitapide. No patient permanently discontinued treatment because of liver abnormalities.
`
`Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of
`homozygous familial hypercholesterolaemia.
`
`Funding FDA Offi ce of the Orphan Product Development, Aegerion Pharmaceuticals.
`
`Introduction
`Homozygous familial hypercholesterolaemia is a life-
`threatening disease most commonly caused by loss-of-
`function mutations in both alleles of the LDL receptor
`gene. Mutations in other genes, including APOB,
`PCSK9, and autosomal recessive hypercholesterolaemia
`LDLRAP1, which alter the function of the LDL receptor
`or its ligand ApoB, could also contribute to such a
`phenotype. As a consequence of impaired LDL-receptor
`function, untreated total plasma cholesterol levels are
`typically greater than 13 mmol/L, resulting in premature
`and progressive atherosclerosis often leading to cardio-
`vascular disease before age 20 years and death before age
`30 years.1–3 Early initiation of aggressive treatment for
`these patients is, therefore, essential.4
`Patients with homozygous familial hypercholester-
`olaemia respond inadequately to conventional drug
`therapies,2,5–7 which generally reduce LDL cholesterol
`
`through upregulation of hepatic LDL receptors. There fore,
`the current standard of care for familial hyperchol-
`esterolaemia includes LDL apheresis, which transiently
`reduces LDL cholesterol by more than 50%8,9 and can delay
`the onset and progression of atherosclerosis.7–9 However,
`even with the combined use of available drug therapies
`and apheresis, these patients still have substantially
`elevated levels of LDL cholesterol and persistently high
`risk of cardiovascular disease.10 Liver transplantation has
`also been done in patients with this disease.11,12 In recent
`years, alternative therapeutic approaches have been
`developed that target either ApoB synthesis13 or the
`production of VLDL, the precursor of LDL.14
`Lomitapide (Aegerion Pharmaceuticals, Cambridge,
`MA, USA) is an inhibitor of the microsomal triglyceride
`transport protein (MTP), a key protein in the assembly and
`secretion of ApoB-containing lipoproteins in the liver and
`intestine.15 The drug substantially reduced levels of LDL
`
`www.thelancet.com Vol 381 January 5, 2013
`
`Lancet 2013; 381: 40–46
`Published Online
`November 2, 2012
`http://dx.doi.org/10.1016/
`S0140-6736(12)61731-0
`See Comment page 7
`Institute for Translational
`Medicine and Therapeutics,
`Cardiovascular Institute, and
`Department of Medicine,
`University of Pennsylvania,
`Philadelphia, PA, USA
`(M Cuchel MD, E A Meagher MD,
`L T Bloedon MS,
`Prof K J Propert ScD,
`Prof D J Rader MD);
`Netcare Private Hospital,
`Bloemfontein, South Africa
`(Prof H du Toit Theron MD);
`Department of Medicine
`(D J Blom PhD) and Department
`of Chemical Pathology
`(Prof A D Marais MD), University
`of Cape Town, Cape Town,
`South Africa; Medical Research
`Council of South Africa, Cape
`Heart Group, Cape Town, South
`Africa (D J Blom, A D Marais);
`Robarts Research Institute and
`Schulich School of Medicine
`and Dentistry, University of
`Western Ontario, London, ON,
`Canada (Prof R A Hegele FRCP);
`Università di Palermo, Palermo,
`Italy (Prof M R Averna MD);
`Ospedale Niguarda, Milano,
`Italy (Prof C R Sirtori MD);
`Division of Cardiology and
`Atherosclerosis Research
`Center, Cedars-Sinai Heart
`Institute, Los Angeles, CA, USA
`(Prof P K Shah MD); Department
`of Medicine, Université de
`Montreal, Chicoutimi, Quebec,
`Canada (D Gaudet MD);
`Extracorporeal Therapeutic
`Techniques Unit,
`Immunohematology and
`Transfusion Medicine,
`Department of Molecular
`Medicine, University of Rome
`‘Sapienza’, Italy
`(C Stefanutti MD); Department
`of Clinical and Experimental
`
`40
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`Medicine, Università of Ferrara,
`Italy (G B Vigna MD); Clinical
`Research Unit, University of
`Pretoria, Pretoria, South Africa
`(A M E Du Plessis MMed); and
`Aegerion Pharmaceuticals,
`Cambridge, MA, USA
`(L T Bloedon, W J Sasiela PhD)
`Correspondence to:
`Dr Marina Cuchel, University of
`Pennsylvania, Perelman School
`of Medicine, Institute for
`Translational Medicine and
`Therapeutics, 3600 Spruce
`Street, Maloney Building,
`Room 8039, PA 19104, USA
`mcuchel@mail.med.upenn.edu
`
`cholesterol in the Watanabe Heritable Hyperlipidaemic
`rabbit, an animal model of homozygous familial hyper-
`cholester olaemia.16 We have shown that lomitapide given
`orally for 16 weeks as monotherapy was eff ective in
`reducing LDL cholesterol levels in six patients with homo-
`zygous familial hypercholesterolaemia and that its effi cacy
`was mediated by a reduction in LDL production.14 To assess
`the long-term safety and effi cacy of lomitapide when added
`to currently available lipid-lowering drug therapy with or
`without apheresis (standard of care), we assessed adult
`patients with homozygous familial hyper cholester olaemia
`over a 78 week treatment period. Safety assessments
`included an analysis of the eff ects of chronic MTP
`inhibition on the liver.
`
`Methods
`Study design and patients
`In our phase 3, open-label study, patients were re-
`cruited from 11 centres in four countries (USA, Canada,
`South Africa, and Italy). Diagnostic criteria for homo-
`zygous familial hyperchol esterolaemia were based either
`on clinical criteria (history of untreated total cholesterol
`>13 mmol/L and triglycerides <3·4 mmol/L and both
`parents with history of untreated total cholesterol
`>6·5 mmol/L) or on documented mutation(s) in both
`alleles of the LDL receptor or of other genes known to
`aff ect LDL receptor function. Exclusion criteria included:
`major surgery in the previous 3 months, congestive heart
`failure, history of liver disease or transaminases greater
`than twice the upper limit of normal (ULN), serum
`creatinine >221 μmol/L, recent malignancy, alcohol or
`drug abuse, known bowel disease or malabsorption, or
`chronic lung disease.
`Patients were screened for eligibility 12 weeks before
`the fi rst dose of lomitapide. Screening procedures
`included medical and drug history, review of current
`lipid-lowering therapies, physical examination, vital
`signs, 12-lead electrocardiograph (ECG), fasting lipid
`panel, safety laboratory assessments, and dietary coun-
`selling. All enrolled patients were required to enter a
`minimum 6-week run-in phase during which concomi-
`tant lipid-lowering therapies, including apheresis, the
`daily dietary supplementation of vitamin E, and essential
`fatty acids were initiated, and the required low-fat diet
`was stabilised. At the end of the run-in phase, patients
`entered a 26-week effi cacy phase, during which they
`received lomitapide in addition to their current lipid-
`lowering therapy. Lomitapide was initiated at a starting
`dose of 5 mg a day for the fi rst 2 weeks and then escalated
`to 10, 20, 40, and 60 mg a day at 4-week intervals or until
`an individually determined maximum dose was achieved
`on the basis of safety and tolerability. Patients remained
`at their maximum dose through to the end of the 26-week
`effi cacy phase. A fasting lipid and safety panel, including
`liver function tests, was obtained at baseline, before each
`dose escalation, and then every 4 weeks through to week
`26 (primary endpoint).
`
`After completion of the effi cacy phase, patients
`continued to receive lomitapide and entered a 52-week
`safety phase (weeks 26–78) during which concomitant
`lipid-lowering therapies, including LDL apheresis, could
`be modifi ed at the investigators discretion. Assessments
`during this phase were done every 5 weeks to 10 weeks
`and at the end of treatment. Total treatment duration was
`78 weeks. Eligible patients completing the treatment
`phase were off ered the option to enter a separate long-
`term study, in which they continued to receive lomitapide.
`Patients who did not enter the long-term study dis-
`continued lomitapide at week 78 and returned for a fi nal
`follow-up visit at week 84.
`If patients had confi rmed alanine transaminase (ALT)
`or aspartate transaminase (AST) elevations between
`5·0 and 9·9 times the ULN, or >100 U/L but <200 U/L
`above the baseline value, the dose of lomitapide was
`reduced to the previously tolerated dose level, with the
`possibility to re-escalate once transaminase elevations
`were resolved. Adverse events were coded with MedDRA
`(version 11.0). These events were
`judged by the
`investigators as: not related, unlikely, possibly, probably,
`or defi nitely related to study drug, and were reviewed
`regularly by an independent data and safety monitoring
`board. The study was approved by each institution’s
`review board or ethics committee and all patients
`provided written, informed consent.
`
`Procedures
`Blood was drawn at baseline and at each visit following a
`12 h fast. Routine testing included a standard metabolic
`panel, a complete blood count, urinalysis, and measure-
`ment of fat soluble vitamins and fatty acids. All testing
`was done at a US Centers for Disease Control and
`Prevention standardised lipid central laboratory (PPD,
`Highland Heights, KY, USA and Brussels, Belgium) or
`referred to a partnering laboratory for the measurement
`of vitamin K and essential fatty acids. In patients
`undergoing apheresis, samples for the fasting lipid
`profi le were obtained shortly before the scheduled
`apheresis treatment. The timing of treatments (eg, every
`14 days) and study blood sampling was maintained
`throughout the study so that lipid assessments would be
`done at the same point on the LDL cholesterol rebound
`curve. Lipid and lipoprotein analyses were done with
`serum. Total cholesterol, directly measured LDL chol-
`esterol and HDL cholesterol, and triglycerides were
`measured enzymatically. Non-HDL cholesterol and
`VLDL cholesterol were calculated. ApoA-I and ApoB were
`measured by immunonephelometry.
`Hepatic lipid content was assessed by nuclear magnetic
`resonance spectroscopy (NMRS) studies at baseline and
`at 6-month intervals. All quantitative measurements
`were done by a single external radiologist who was
`masked to patients’ clinical status and results of liver
`function tests. NMRS was not done in three patients who
`had contraindications to MRI. In these patients a CT
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`
`41
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`See Online for appendix
`
`scan or ultrasound was done at the discretion of the local
`physician or if recommended by the data and safety
`monitoring board.
`
`Statistical analysis
`The sample size calculation was based on an assumption
`of a 25% change from baseline in LDL cholesterol at
`week 26 with a 30% SD and 15% dropout rate. Using an
`alpha of 0·05 with 90% power, 20 patients were needed.
`The statistical analyses were done with SAS software
`(version 9.1). Continuous variables were summarised by
`descriptive statistics (sample size, mean, SD, median,
`minimum and maximum). Categorical variables were
`summarised by frequency (N) and percentages (%).
`Baseline values of lipid parameters were the average of
`two measurements taken 2 weeks apart (after 4 weeks and
`6 weeks of entering the run-in phase). The primary
`effi cacy endpoint measure was the percent change from
`baseline in concentration of LDL cholesterol at the
`maximum tolerated dose after 26 weeks of treatment.
`Prespecifi ed secondary endpoints
`included percent
`changes in other lipid parameters, long-term safety, and
`changes in hepatic-fat content. All patients who received
`at least one dose of the study drug were in the assess-
`ment of the primary and secondary endpoints (intention-
`to-treat analysis) up to the end of the effi cacy phase
`(week 26). Signifi cance of the percent changes in LDL
`cholesterol from baseline to 26 weeks was assessed with a
`mixed linear model, which assumes a missing-at-random
`mechanism. An additional secondary statistical analysis
`was done imputing missing data with the last-observation-
`carried-forward method, because this was the statistical
`approach described in the original statistical analysis
`plan. Further secondary effi cacy and safety analyses were
`done during the safety phase (weeks 26–78); an on-sample
`t test was used to assess percent change from baseline at
`
`week 56 and week 78. Correlations were assessed with
`Spearman’s rank-correlation. Statistical signifi cance was
`defi ned as p≤0·05.
`This study
`is registered with ClinicalTrials.gov
`(NCT00730236).
`
`Role of the funding source
`The sponsor of the study had no role in study design, data
`collection, primary data analysis, data interpretation, or
`initial writing of the report, but was invited to comment
`on the written report. The corresponding author had full
`access to all the data in the study and had fi nal
`responsibility for the fi nal content of the report and the
`decision to submit for publication.
`
`Results
`Of the 32 patients with homozygous familial hyper-
`cholesterolaemia who were screened for eligibility,
`31 entered the run-in period and 29 men and women
`were enrolled in the effi cacy phase. All patients were
`18 years or older and met diagnostic criteria. 23 of
`29 enrolled patients completed both the effi cacy phase
`(26 weeks) and the full study (78 weeks; appendix). Six
`patients discontinued the study during the effi cacy
`phase (the fi rst 4 days after enrolment and the last at
`week 22): four patients discontinued because of adverse
`events (three were gastrointestinal events and one was
`headache); one was withdrawn for non-compliance
`with the protocol; and one withdrew consent for
`personal reasons.
`The baseline characteristics of the patients enrolled
`in the study are shown in the appendix. Briefl y, all
`29 patients were either homozygotes or compound
`heterozygotes for mutations in the LDLR gene or
`genes aff ecting LDL-receptor functionality. 27 patients
`were treated with statins, primarily rosuvastatin or
`
`Baseline (n=29) Week 26 (n=23)
`
`Concen trations
`
`Change from
`baseline (%)
`
`Week 56 (n=23)
`
`p value†
`
`Concen trations
`
`Change from
`baseline (%)
`
`Week 78 (n=23)
`
`p value‡
`
`Concen trations
`
`Change from
`baseline (%)
`
`p value‡
`
`11·1 (3·5)
`
`6·1 (2·9)
`
`–46% (–56 to –35) <0·0001
`
`7·1 (3·7)
`
`–39% (–51 to –27) <0·0001
`
`7·3 (3·9)
`
`–35% (–48 to –22) <0·0001
`
`8·7 (2·9)
`
`4·3 (2·5)
`
`–50% (–62 to –39)
`
`<0·0001
`
`5·1 (3·2)
`
`–44% (–57 to –31) <0·0001
`
`5·4 (3·4)
`
`–38% (–52 to –24)
`
`0·0001
`
`0·5 (0·3)
`
`0·3 (0·3)
`
`–45% (–61 to –29) <0·0001
`
`0·4 (0·4)
`
`–28% (–48 to –10)
`
`0·0185
`
`0·4 (0·4)
`
`–31% (–54 to –7)
`
`0·0389
`
`10·0 (3·4)
`
`5·1 (2·8)
`
`–50% (–61 to –39) <0·0001
`
`5·9 (3·6)
`
`–44% (–57 to –31) <0·0001
`
`6·2 (3·8)
`
`–39% (–53 to –25) <0·0001
`
`1·0 (0·4 to 2·9) 0·5 (0·1 to 1·7)
`2·6 (0·8)
`1·3 (0·7)
`2·4 (0·6 to 2·1)
`1·7 (0·3 to 7·1)
`1·1 (0·3)
`1·0 (0·4)
`
`–45% (–61 to –29) <0·0001
`–49% (–60 to –38)
`<0·0001
`–15% (–30 to 0·9)
`0·0003
`–12% (–20 to –4)
`0·0001
`
`0·7 (0·2 to 2·9)
`1·5 (0·8)
`2·0 (0·5 to 8·6)
`1·2 (0·4)
`
`0·0157
`–29% (–47 to –11)
`–45% (–57 to –33) <0·0001
`–19% (–31 to –8)
`0·0111
`1% (–13 to 15)
`0·954
`
`0·7 (0·2 to 4·1)
`1·5 (0·9)
`2·6 (0·6 to 7·0)
`1·1 (0·3)
`
`0·0368
`–31% (–54 to –8)
`–43% (–56 to –29) <0·0001
`–1% (–17 to 6)
`0·5827
`–5% (–13 to 3)
`0·1396
`
`1·2 (0·3)
`
`1·0 (0·2)
`
`–14% (–17 to –4)
`
`0·0003
`
`1·1 (0·3)
`
`1% (–11 to 13)
`
`0·568
`
`1·1 (0·3)
`
`–4% (–10 to 3)
`
`0·1155
`
`Total cholesterol,
`mmol/L
`LDL cholesterol,
`mmol/L
`VLDL cholesterol,
`mmol/L
`Non-HDL cholesterol,
`mmol/L
`Triglycerides, mmol/L
`ApoB, g/L
`Lipoprotein (a), μmol/L
`HDL cholesterol,
`mmol/L
`ApoA-I, g/L
`
`Data are mean (SD), median (range) for triglycerides and lipoprotein (a) at baseline, weeks 26, 56, and 78, or mean (95% CI) for percent change. †p values from mixed model. ‡p values from one-sample t test.
`
`Table: Lipid and lipoprotein concentrations at baseline and weeks 26, 56, and 78 (end of study)
`
`42
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`6
`
`8
`
`10
`
`14
`12
`Study week
`
`16
`
`18
`
`20
`
`22
`
`24
`
`26
`
`LDL cholesterol
`Total cholesterol
`ApoB
`2
`
`4
`
`20
`
`0
`
`–20
`
`–40
`
`–60
`
`–80
`
`Change from baseline (%)
`
`–100
`
`0
`
`Figure 1: Mean percent changes in LDL cholesterol, total cholesterol, and ApoB levels from baseline to
`week 26 (end of effi cacy phase)
`Data available at each time point are expressed as mean (SD).
`
`Alanine transaminase
`Aspartate transaminase
`
`B
`
`2
`
`6 10 14 18 22 26 31 36 41 46 51 56 66 78
`Study week
`
`Baseline
`
`Week 26
`
`Week 56
`
`Week 78
`
`A
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`B
`25
`
`20
`
`15
`
`10
`
`05
`
`Transaminases (IU/L)
`
`Hepatic fat (%)
`
`Figure 2: Alanine transaminase and aspartate transaminase levels and
`percentage of hepatic fat in the liver
`Data are mean, 95% CI. Laboratory reference ranges for alanine transaminase
`levels were 10–40 U/L in men and 10–33 U/L in women; reference ranges for
`aspartate transaminase levels were 10–43 U/L in men and 10–36 U/L in
`women (A). Percentage of fat in the liver, as measured by nuclear magnetic
`resonance spectroscopy at baseline and 26, 56, and 78 weeks of lomitapide
`treatment (n=20; B).
`
`treatment with lomitapide were gastro intestinal in nature
`(27 patients during the effi cacy phase, and 17 during the
`safety phase). The three patients who discontinued the
`study because of gastrointestinal disorders permanently
`stopped lomitapide by week 12 (appendix). No patients
`died during the study. Three (10%) of 29 patients had
`serious adverse events: one had acute coronary syndrome
`and angina pectoris and lower respiratory tract infection,
`one had elective hysterectomy for menorrhagia, and one
`had chest pain. All serious adverse events were assessed as
`
`atorvastatin, 22 with ezetimibe (all in combination with a
`statin), three with niacin, one with a fi brate, and one with
`a bile acid sequestrant. 18 patients regularly underwent
`apheresis with a frequency that ranged from weekly to
`every 6 weeks. Despite aggressive lipid lowering treat-
`ment, total cholesterol, LDL cholesterol, and ApoB were
`substantially elevated at baseline (table).
`Compliance with study drug dosing, defi ned as more
`than 80% of capsules taken, was 28 (93%) during the
`effi cacy phase and 22 (95%) during the safety phase. Of
`the six patients who discontinued lomitapide treatment,
`two were receiving 5 mg, two were receiving 10 mg, one
`was receiving 20 mg, and one was receiving 40 mg.
`Among the 23 patients who completed the study, the
`maximum dose was 5 mg in one patient; 20 mg in fi ve;
`40 mg in six, and 60 mg in 11 at the end of the effi cacy
`phase. The dose distribution remained similar at week 78.
`Mean levels of LDL cholesterol remained stable during
`the run-in phase, as shown by a mean percent change
`from screening in LDL cholesterol of –1·20% (95% CI
`–15·66 to 13·18) at week 0. Mean percent changes in LDL
`cholesterol during the effi cacy phase are shown in
`fi gure 1. Mean LDL cholesterol signifi cantly decreased by
`50% from baseline to the end of the effi cacy phase
`(week 26; table). Percent changes from baseline for key
`secondary endpoints (total cholesterol, ApoB, and tri-
`glycerides) were consistent with those for LDL cholesterol
`at week 26 (table). Analysis done with the last observation
`carried forward gave similar results.
`Overall, 19 of 23 patients with data at week 26 had
`decreased concentrations of LDL cholesterol of more
`than 25% with 12 having more than a 50% reduction.
`Eight patients had LDL cholesterol levels lower than
`2·6 mmol/L at week 26, with one having levels lower
`than 1·8 mmol/L. On the basis of LDL cholesterol
`response, three patients permanently discontinued LDL
`apheresis and three permanently increased the time
`interval between apheresis treatments at some point
`during the safety phase (weeks 26–78). Lomitapide
`signifi cantly reduced LDL cholesterol at week 78, despite
`changes in concomitant lipid lowering therapy or any
`adjustment in lomitapide dose (table). Similar effi cacy
`results were reported for total cholesterol, ApoB, and
`triglycerides (table). Lipoprotein (a) levels were sig nifi -
`cantly reduced from baseline at week 26 and 56, but were
`not sig nifi cantly diff erent at week 78 (table).
`Concentrations of HDL cholesterol were signifi cantly
`reduced at week 26, and mirrored the reduction in the
`levels of ApoA-I (table). HDL cholesterol and ApoA-I
`returned to levels similar to those at baseline by week 78
`(table).
`A summary of adverse events reported during the
`effi cacy and safety phase is shown in the appendix.
`Most patients had at least one adverse event during both
`the effi cacy (27 of 29 patients) and safety (21 of 23) phases.
`Most adverse events were assessed as mild to moderate in
`intensity. The most commonly reported events during
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`Panel: Research in context
`
`Systematic review
`We searched PubMed for intervention studies of homozygous familial
`hypercholesterolaemia between January, 1980, and August, 2012. Patients with this rare
`disease have untreated cholesterol levels greater than 13 mmol/L. Drug-based treatments
`were scarcely eff ective until the introduction of HMG-CoA reductase inhibitors (statins).
`Patients with homozygous familial hypercholesterolaemia have an inadequate response to
`existing lipid-lowering drug therapies such as statins and ezetimibe7,17–19 and remain at very
`high risk for cardiovascular events and mortality. Treatment at high doses of atorvastatin
`and rosuvastatin results in about 27% reduction in LDL cholesterol.19 Addition of ezetimibe
`to statin treatment can result in an additional 20% reduction in LDLcholesterol.7 Apheresis
`treatment can acutely lower LDL cholesterol levels by 70–80% and result in a time-average
`reduction by 40–50% when done regularly.20 A phase 3, randomised study assessing the
`effi cacy of an anti-ApoB antisense oligonucleotide, mipomersen, showed a reduction in
`LDL cholesterol of about 25% in patients with homozygous familial hypercholesterolaemia
`treated with maximum-tolerated lipid-lowering drug therapy.13
`
`Interpretation
`Our study expands the results obtained in a previous phase 2 study.14 We report that
`lomitapide, when given in addition to currently available lipid-lowering therapy, results in
`an additional 50% reduction in LDL cholesterol, potentially bringing these high-risk
`patients closer to target levels. The limitations due to the single-arm, open-label design
`and the safety considerations of potential dose-related transaminase elevations, and
`liver-fat accumulation are counterbalanced and outweighed by the signifi cant LDL
`cholesterol-lowering eff ects of lomitapide in this severe disorder of unmet medical need.
`Our study suggests that treatment with lomitapide could be a valuable drug in the
`management of homozygous familial hypercholesterolaemia.
`
`unrelated or unlikely related to study treatment. No serious
`adverse events were reported between weeks 26 and 78.
`Ten patients had elevated levels of ALT, AST, or both of
`more than three times the ULN at least once during the
`study (fi gure 2). Four of these patients had ALT increases
`more than fi ve times the ULN and one patient had a
`similar elevation in AST; these elevations occurred at
`lomitapide doses of 10 mg, 20 mg, 40 mg, and 60 mg. No
`patient discontinued treatment permanently because
`of elevations in liver-function-test parameters and all
`elevations were managed either by dose reduction or
`temporary inter ruption of lomitapide as per protocol. Of
`note, three of four patients with elevations of more than
`fi ve times the ULN in liver-function-test parameters
`reported consuming quantities of alcohol higher than
`those allowed per protocol. No patient had elevations in
`bilirubin or alkaline phosphatase levels.
`Hepatic fat was measured non-invasively with NMRS.
`Mean hepatic fat in the 20 patients with evaluable NMRS
`scans was 1·0% (range 0–5·0) at baseline, 8·6% (0–33·6)
`at week 26, 5·8% (0–16·5%) at week 56, and 8·3%
`(0–19·0%) at week 78 (fi gure 2). Percent change in
`hepatic fat was negatively associated with change in LDL
`cholesterol. This association was signifi cant at week 26
`(r=–0·50, 95% CI –0·76 to –0·09; p=0·0161) and week 56
`(r=–0·55, –0·79 to –0·15; p=0·0083), but was not signifi -
`cant at week 78 (r=–0·21, –0·59 to 0·25; p=0·3618).
`
`Discussion
`Our open-label study shows that lomitapide, admin-
`istered concurrently with background lipid-lowering
`therapies including LDL apheresis, sig nifi cantly reduced
`LDL cholesterol in patients with homozygous familial
`hypercholesterolaemia. This reduction is similar to that
`reported during lomitapide monotherapy in patients
`with the disorder,14 and shows that lomitapide had
`similar effi cacy when added to existing concomitant
`treatment (panel).
`While studies of cardiovascular outcome are not
`feasible in view of the rarity of homozygous familial
`hypercholesterolaemia, retrospective studies show that
`even a modest reduction in LDL cholesterol, either by
`pharmacological intervention or LDL apheresis, results
`in apparent improvement in morbidity and mortality.6,8,9,21
`Furthermore, observa tional studies clearly show that
`patients with homozygous familial hyper cholesterol-
`aemia and some LDL-receptor function (receptor-
`defective) have lower levels of LDL cholesterol and better
`prognosis than those with no LDL-receptor function
`(receptor-negative).4 Thus, although we are unable to
`provide direct evidence,
`the magnitude of LDL
`cholesterol reduction with lomitapide would be expected
`to reduce cardiovascular risk and improve survival.
`Reduction of LDL cholesterol levels was somewhat
`attenuated at the end of the study. This eff ect could be
`explained by the changes during the safety phase that
`were made in apheresis treatment or in concomitant
`lipid lowering therapy in some of the better responders,
`as well as reductions in lomitapide dose in some of the
`patients that had elevated liver enzymes or gastro-
`intestinal tolerability issues.
`We noted a signifi cant decrease in lipoprotein (a) levels
`at week 26, that persisted up to week 56. The mechanism
`underlying this eff ect is not known, but a similar fi nding
`has been reported with other drugs aff ecting the
`secretion of ApoB-containing lipoproteins by the liver.13
`The reason for loss of signifi cance in lipoprotein (a)
`reduction at week 78 is not clear. Lipoprotein (a) levels
`are substantially aff ected by apheresis treatment,22,23 thus
`changes in apheresis treatment that were allowed during
`the safety phase could have confounded the eff ect on
`lipoprotein (a). Further studies are needed to test this
`hypothesis and clarify these fi ndings.
`HDL cholesterol and ApoA-I levels were transiently
`decreased during the effi cacy phase, a fi nding reported in
`previous studies with lomitapide.14,24 The mechanism(s)
`underlying these changes are not known and further
`studies will be necessary to explain this eff ect. Possible
`reasons might include the low-fat diet or the inhibitory
`eff ects of lomitapide on dietary fat absorption; the
`reduced secretion of triglyceride-rich lipoproteins, which
`carry ApoA-I, from the gut or liver, as a direct consequence
`of MTP inhibition; or a reduction in ApoA-I production.
`The decrease in levels of HDL cholesterol occurred
`during the titration period, when the dose was gradually
`
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`www.thelancet.com Vol 381 January 5, 2013
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`Page 5 of 7
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`CFAD V. UPENN
`IPR2015-01835
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`Articles
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`increased, and subsequently returned to levels approach-
`ing those at baseline once the dose was stabilised,
`suggesting the existence of a compensatory mechanism.
`The clinical implications of this temporary reduction in
`levels of HDL cholesterol are unknown.
`Our study was the fi rst long-term study of any MTP
`inhibitor in human beings, and safety and tolerability
`were carefully assessed. Lomitapide, initiated at a low
`dose and escalated to an individualised maximum dose in
`the presence of a low-fat diet, was generally well tolerated.
`All three discontinuations due to gastrointestinal events
`occurred during the titration phase. The incidence and
`the number of patients who experienced gastrointestinal
`events improved during the safety phase suggesting that
`patients become more tolerant or learnt to control their
`diet better, similar to patients with abetalipoproteinaemia.15
`Indeed, of the 23 patients who completed the effi cacy
`phase, all 23 remained on lomitapide for another
`12 months and completed the entire protocol. Investi-
`gators and patients were aware of the lomitapide dose and
`the lipid response because of the open-label design of the
`study, therefore, we cannot exclude the possibility that
`this factor infl uenced the reporting and assessment of
`adverse events.
`Accumulation of liver fat is intrinsically linked to the
`mechanism of action of MTP inhibitors, and has been
`the basis of concerns regarding the clinical use of this
`class of agents. The 18-month duration of this study
`aff orded the fi rst opportunity to assess the eff ect of
`chronic MTP inhibition on liver safety and liver fat.
`While ALT levels more than three times the ULN were
`seen in ten of 29 patients, these changes were generally
`transient or resolved with dose reduction and were not
`associated with elevated bilirubin or alkaline phosphatase
`or evidence of impaired synthetic function.
`As expected, mean hepatic fat increased from 1·0% to
`8·6% at week 26, but no further increase was reported
`for the remainder of the study. Since the clinical
`signifi cance and long-term implications of the increase
`in hepatic fat as a result of lomitapide therapy is not
`clearly understood, rigorous and standardised long-term
`monitoring will be necessary.
`Our study has several limitations that need to be taken
`into account when interpreting the results. The study was
`a non-randomised, open-label study. Since homo zygous
`familial hypercholesterolaemia is a rare disease, our
`intent was to expose the maximum number of patients to
`treatment for the duration of the study so that safety
`(especially the potential liver adverse events) could be
`assessed fully. Furthermore, in view of the striking
`changes in LDL cholesterol and ApoB that were reported
`in the phase 2 study14 we expected to be able to easily
`discern the eff ect of lomitap