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• W2023572044 abstract "To investigate the impact of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, on intra-hepatic triglyceride content (IHTG content), we conducted a randomized, double-blind, placebo-controlled study in 21 patients with familial hypercholesterolemia (FH). Subjects received a weekly subcutaneous dose of 200 mg mipomersen or placebo for 13 weeks while continuing conventional lipid lowering therapy. The primary endpoint was change in IHTG content from week 0 to week 15 as measured by localized proton magnetic resonance spectroscopy (1H-MRS). Thirteen weeks of mipomersen administration reduced LDL-cholesterol by 22.0 (17.8) % and apoB by 19.9 (17.4) % (both P < 0.01). One of 10 patients (10%) in the mipomersen-treated group developed mild hepatic steatosis at week 15, which was reversible following mipomersen discontinuation. For the group, there was a trend toward an increase in IHTG content [placebo; baseline: 1.2% and week 15: 1.1%; change −0.1 (0.9). Mipomersen; baseline: 1.2% and week 15: 2.1%; change 0.8 (1.7) (P = 0.0513)]. Mipomersen administration for 13 weeks to subjects with FH is associated with a trend toward an increase in IHTG content. Future studies evaluating the effects of long-term use of mipomersen reaching more profound reductions in apoB are required prior to broader use of this compound. To investigate the impact of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, on intra-hepatic triglyceride content (IHTG content), we conducted a randomized, double-blind, placebo-controlled study in 21 patients with familial hypercholesterolemia (FH). Subjects received a weekly subcutaneous dose of 200 mg mipomersen or placebo for 13 weeks while continuing conventional lipid lowering therapy. The primary endpoint was change in IHTG content from week 0 to week 15 as measured by localized proton magnetic resonance spectroscopy (1H-MRS). Thirteen weeks of mipomersen administration reduced LDL-cholesterol by 22.0 (17.8) % and apoB by 19.9 (17.4) % (both P < 0.01). One of 10 patients (10%) in the mipomersen-treated group developed mild hepatic steatosis at week 15, which was reversible following mipomersen discontinuation. For the group, there was a trend toward an increase in IHTG content [placebo; baseline: 1.2% and week 15: 1.1%; change −0.1 (0.9). Mipomersen; baseline: 1.2% and week 15: 2.1%; change 0.8 (1.7) (P = 0.0513)]. Mipomersen administration for 13 weeks to subjects with FH is associated with a trend toward an increase in IHTG content. Future studies evaluating the effects of long-term use of mipomersen reaching more profound reductions in apoB are required prior to broader use of this compound. ApoB is the main structural component of all atherogenic lipid particles and is obligatory for the secretion of VLDL from the liver (1Elovson J. Chatterton J.E. Bell G.T. Schumaker V.N. Reuben M.A. Puppione D.L. Reeve Jr., J.R. Young N.L. Plasma very low density lipoproteins contain a single molecule of apolipoprotein B.J. Lipid Res. 1988; 29: 1461-1473Abstract Full Text PDF PubMed Google Scholar, 2Davis R.A. Cell and molecular biology of the assembly and secretion of apolipoprotein B-containing lipoproteins by the liver.Biochim. Biophys. Acta. 1999; 1440: 1-31Crossref PubMed Scopus (163) Google Scholar). As a consequence, apoB synthesis inhibition has been put forward as a potentially valuable approach to achieve target levels for LDL-cholesterol in subjects with heterozygous familial hypercholesterolemia (FH), who are characterized by profoundly elevated baseline cholesterol levels and are unable to achieve target levels with conventional lipid lowering therapy (3Stein E. Stender S. Mata P. Sager P. Ponsonnet D. Melani L. Lipka L. Suresh R. Maccubbin D. Veltri E. Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin.Am. Heart J. 2004; 148: 447-455Crossref PubMed Scopus (160) Google Scholar, 4Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Adult Treatment Panel III final report. 2002. Circulation.. 106: 3143–3421.Google Scholar). In previous clinical trials, mipomersen, a second-generation antisense oligonucleotide targeted to human apoB, has been shown to induce dose-dependent reductions in all apoB-containing lipoproteins. A drug elimination half-life of ∼30 days resulted in a prolonged pharmacological effect and the drug was overall well tolerated (5Akdim F. Stroes E.S.G. Sijbrands E.J.G. Tribble D.L. Trip M.D. Jukema J.W. Flaim J.D. Su J. Yu R.Z. Baker B.F. et al.Efficacy and safety of mipomersen, an apolipoprotein b synthesis inhibitor, in hypercholesterolemic subjects on stable statin therapy.J. Am. Coll. Cardiol. 2009; (In press.)Google Scholar, 6Kastelein J.J. Wedel M.K. Baker B.F. Su J. Bradley J.D. Yu R.Z. Chuang E. Graham M.J. Crooke R.M. Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B.Circulation. 2006; 114: 1729-1735Crossref PubMed Scopus (319) Google Scholar). Intrinsic to its mechanism of action, apoB synthesis inhibition may result in an impaired secretion of triglyceride-rich VLDL particles from the liver, potentially leading to accumulation of triglycerides in the liver. In fact, inhibition of microsomal triglyceride transfer protein (MTP), which is involved in VLDL synthesis downstream of apoB, has been shown to result in hepatic steatosis in both experimental animals and humans (7Cuchel M. Bloedon L.T. Szapary P.O. Kolansky D.M. Wolfe M.L. Sarkis A. Millar J.S. Ikewaki K. Siegelman E.S. Gregg R.E. et al.Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia.N. Engl. J. Med. 2007; 356: 148-156Crossref PubMed Scopus (453) Google Scholar, 8Chandler C.E. Wilder D.E. Pettini J.L. Savoy Y.E. Petras S.F. Chang G. Vincent J. Harwood Jr., H.J. CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans.J. Lipid Res. 2003; 44: 1887-1901Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). Indeed, hepatic enzyme increases have been observed during treatment with mipomersen, particularly following treatment with higher doses. In line with this observation, during follow up of some patients with elevated liver enzymes, hepatic steatosis was detected (9Akdim F. Visser M.E. Tribble D.L. Baker B.F. Stroes E.S.G. Yu R. Flaim J.D. Su J. Stein E.A. Kastelein J.J.P. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density- lipoprotein cholesterol in patients with familial hypercholesterolemia.Am. J. Cardiol. 2010; (In press.)Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). Since baseline values in these patients were absent and hepatic steatosis is prevalent in the general population (10Szczepaniak L.S. Nurenberg P. Leonard D. Browning J.D. Reingold J.S. Grundy S. Hobbs H.H. Dobbins R.L. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population.Am. J. Physiol. Endocrinol. Metab. 2005; 288: E462-E468Crossref PubMed Scopus (1177) Google Scholar), a definite causal relationship between administration of mipomersen and hepatic steatosis could not be established. Insight into the long-term sequelae of apoB synthesis inhibition can be obtained indirectly from the lessons learned from a “natural variant” of low apoB concentrations known as familial hypobetalipoproteinemia (FHBL). FHBL is primarily caused by mutations in the apoB gene, resulting in truncated forms of apoB (11Schonfeld G. The hypobetalipoproteinemias.Annu. Rev. Nutr. 1995; 15: 23-34Crossref PubMed Scopus (78) Google Scholar). FHBL subjects are characterized by extremely low levels of apoB and plasma LDL-cholesterol and appear to be protected against atherosclerotic disease (12Sankatsing R.R. Fouchier S.W. de Haan S. Hutten B.A. de Groot E. Kastelein J.J. Stroes E.S. Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1979-1984Crossref PubMed Scopus (90) Google Scholar). The majority of patients with FHBL are characterized by severe hepatic steatosis (13Schonfeld G. Patterson B.W. Yablonskiy D.A. Tanoli T.S. Averna M. Elias N. Yue P. Ackerman J. Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis.J. Lipid Res. 2003; 44: 470-478Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 14Tanoli T. Yue P. Yablonskiy D. Schonfeld G. Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity.J. Lipid Res. 2004; 45: 941-947Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). In contrast, hepatic steatosis is absent in a particular subset of patients with FHBL who are not characterized by truncated forms of apoB (13Schonfeld G. Patterson B.W. Yablonskiy D.A. Tanoli T.S. Averna M. Elias N. Yue P. Ackerman J. Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis.J. Lipid Res. 2003; 44: 470-478Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Therefore, the relation between decreased availability of apoB and IHTG content is not completely clear. To evaluate the effects of mipomersen on IHTG content, a randomized, double-blind, placebo-controlled study was designed in patients with heterozygous familial hypercholesterolemia (FH) on conventional lipid-lowering therapy. In addition we evaluated IHTG content over time in a “positive control group” of subjects with FHBL. Twenty-one subjects with heterozygous FH were selected for the treatment group. Men and women between the age of 18 and 75 with a diagnosis of heterozygous FH were eligible. FH had to be diagnosed either by genotyping or by fulfilling the criteria for the diagnosis of FH as outlined by the World Health Organization (15Familial Hypercholesterolemia (FH). report of the World Health Organization 1997.http://www.medped.org/who/.Google Scholar). LDL-cholesterol was > 2.6 mmol/l; plasma triglyceride levels < 2.26 mmol/l; HbA1c < 6%; plasma glucose ≤ 5.8 mmol/l; alanine amino transferase (ALT) ≤1.5 × ULN; and total bilirubin ≤1.0 × ULN at screening. All patients had been using stable lipid-lowering therapy for at least 3 months prior to screening. Alcohol consumption had to be less than three units (30 g) per day and 12 units (120 g) per week for male subjects; and less than two units (20 g) per day and eight units (80 g) per week for female subjects. Patients with IHTG content exceeding 5% at baseline were excluded from the trial. In addition, six subjects with FHBL were included as a “positive control” group that did not receive treatment. The participants in the FHBL group had to have documented disease due to an apoB-gene mutation; triglyceride levels < 2.26 mmol/l; HbA1c < 6.0%; ALT ≤ 3.0 × ULN; and total bilirubin ≤ 1.0 × ULN at screening. All study participants were enrolled at the Academic Medical Centre in Amsterdam. The study protocol was approved by the local institutional review board. All subjects gave written, informed consent. The study was performed in compliance with the standards of Good Clinical Practice (CPMP/ICH/135/95) and the declaration of Helsinki (Washington, 2002). Subjects with FH were selected to investigate the effects of mipomersen, 200 mg/wk for 13 weeks, on IHTG content assessed using 1H-MRS. Patients were randomized at a 1:1 ratio (active: placebo). Patients, investigators, and study staff were blinded to the treatment assignment with the exception of the pharmacist who prepared the study drug. Study drug was administered subcutaneously on days 1,8,15, 22, 29, 36, 43, 50, 57, 64, 71, 78 and 85 (13-week treatment period). The 200 mg/wk dose was selected based on safety and efficacy data from previous clinical trials. IHTG content was assessed at baseline, week 4, and week 15. Since ALT elevations observed in previous clinical trials clustered around week 4, this time was chosen for the first follow-up 1H-MRS. The main safety endpoint included change in IHTG content from baseline to week 15. Prespecified efficacy endpoints included percentage reduction in LDL-cholesterol and apoB from baseline. Due to the long half-life of mipomersen, efficacy and safety endpoints were analyzed 2 weeks after the last dose of study drug at week 15. The treatment period was followed by a 5-month evaluation period with monthly visits. As a comparator for the 1H-MRS values observed in patients using apoB antisense inhibition, we simultaneously assessed IHTG content in six patients with FHBL. Fasting blood samples were analyzed for lipids and lipoproteins by MedPace (Cincinnati, OH). ApoB, apoA1, and lipoprotein (a) (Lpa) concentrations were determined by rate nephelometry. Total cholesterol (TC) and triglycerides (TG) were measured by standard enzyme-based colorimetric assays. HDL-cholesterol was determined by an enzyme-based colorimetric assay after dextran-sulfate precipitation. LDL- cholesterol and non–HDL-cholesterol were calculated. 1H-MRS was used to quantify IHTG concentration. 1H-MRS is a noninvasive technique by which liver triglyceride concentrations can be quantified. This technique has been shown to be well correlated with liver biopsy data in healthy individuals and patients with hepatic steatosis (16Longo R. Pollesello P. Ricci C. Masutti F. Kvam B.J. Bercich L. Croce L.S. Grigolato P. Paoletti S. de Bernard B. et al.Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis.J. Magn. Reson. Imaging. 1995; 5: 281-285Crossref PubMed Scopus (323) Google Scholar). 1H-MRS was performed at screening, at the end of week 4 and at week 15, 2 weeks after the last dose of mipomersen. Two voxels of 20 × 20 × 20 mm (8000 mm3) were positioned in the right lobe of the liver. Spectra were acquired on a 3.0 Tesla MRI scanner (Philips Medical Systems, Best, The Netherlands) using first order iterative shimming, a PRESS sequence with TE/TR = 35/2000 ms and 64 signal acquisitions. The water and fat resonance peaks, located at 4.65 and 1.3 ppm, were integrated using jMRUI software (17Naressi A. Couturier C. Devos J.M. Janssen M. Mangeat C. de Beer R. Graveron-Demilly D. Java-based graphical user interface for the MRUI quantitation package.MAGMA. 2001; 12: 141-152Crossref PubMed Google Scholar). Relative fat content was expressed as a ratio of the fat peak area over the cumulative water and fat peak areas. Calculated peak areas of water and fat were corrected for T2 relaxation (T2 water = 34 ms, T2 fat = 68 ms) (18de Bazelaire C.M. Duhamel G.D. Rofsky N.M. Alsop D.C. MR imaging relaxation times of abdominal and pelvic tissues measured in vivo at 3.0 T: preliminary results.Radiology. 2004; 230: 652-659Crossref PubMed Scopus (614) Google Scholar), and the percentage hepatic fat content was calculated according to Szczepaniak et al. (10Szczepaniak L.S. Nurenberg P. Leonard D. Browning J.D. Reingold J.S. Grundy S. Hobbs H.H. Dobbins R.L. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population.Am. J. Physiol. Endocrinol. Metab. 2005; 288: E462-E468Crossref PubMed Scopus (1177) Google Scholar). Reproducibility of 1H-MRS to measure IHTG content using this method has been shown to be high for “between weeks” measurements in fatty livers (19van Werven J.R. Hoogduin J.M. Nederveen A.J. van Vliet A.A. Wajs E. Vandenberk P. Stroes E.S. Stoker J. Reproducibility of 3.0 Tesla magnetic resonance spectroscopy for measuring hepatic fat content.J. Magn. Reson. Imaging. 2009; 30: 444-448Crossref PubMed Scopus (62) Google Scholar). An IHTG concentration of > 5.6% was accepted as the ULN (10Szczepaniak L.S. Nurenberg P. Leonard D. Browning J.D. Reingold J.S. Grundy S. Hobbs H.H. Dobbins R.L. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population.Am. J. Physiol. Endocrinol. Metab. 2005; 288: E462-E468Crossref PubMed Scopus (1177) Google Scholar). Safety and tolerability of mipomersen was assessed by determining the incidence, severity, and possible relationship to the study drug of adverse events and laboratory parameters, including blood chemistry, routine hematology, coagulation, and urinalysis. Vital functions were recorded on visits for days 36, 60, 64, and 78. Full physical examination was performed at screening, week 15, and week 25. A 12-lead electrocardiogram was recorded at screening, week 4, and week 15. Subjects returned to the study center 2 weeks after the last dose of study drug for evaluation of liver triglyceride content by 1H-MRS. If IHTG content appeared to be > 10% or showed an increase of 100% relative to screening values or if ALT levels were > 2.0 × ULN, results were submitted to the Data and Safety Monitoring Board (DSMB). Subsequently the DSMB recommended whether another 1H-MRS evaluation should be performed at week 25. Study endpoints were analyzed on the intention-to-treat population, consisting of all 21 subjects randomized as well as on the 6 FHBL positive controls. Missing lipid parameter and liver triglyceride content values at day 99 were replaced by the last observation carried forward method (LOCF). Demographic and baseline characteristics were summarized using descriptive statistics. Baseline was defined as the last value prior to the first dose both for lipid parameters and IHTG content. Efficacy endpoints were analyzed 2 weeks after the last dose, at day 99 with a window of +6/−7 days. Percentage change from baseline for lipid parameters and absolute change from baseline for IHTG content were compared between the two treatment groups using the analysis Exact Wilcoxon Rank Sum test with a 0.050 two-sided significance level. Sample size was based upon a standard deviation of 0.65 in the absolute percentage change for IHTG -content and analysis of the data between the two treatment groups (19van Werven J.R. Hoogduin J.M. Nederveen A.J. van Vliet A.A. Wajs E. Vandenberk P. Stroes E.S. Stoker J. Reproducibility of 3.0 Tesla magnetic resonance spectroscopy for measuring hepatic fat content.J. Magn. Reson. Imaging. 2009; 30: 444-448Crossref PubMed Scopus (62) Google Scholar). Under these assumptions, a sample size of 7 per group would provide 80% power to detect a 2% difference in change for IHTG content with a 0.050 two-sided significance level. Software utilized for the analyses was SAS version 8.2 (SAS Institute, Cary, NC). Twenty-one subjects with heterozygous FH and fulfilling all other entry criteria were randomly assigned to either mipomersen or placebo treatment. Demographics and baseline lipid-lowering therapy by treatment group are summarized in Table 1. All subjects were on stable lipid-lowering therapy. Baseline lipid parameters were comparable between the treatment groups (Table 2). Twenty subjects completed the study protocol. One mipomersen-treated subject discontinued treatment after the first dose due to flu-like symptoms.TABLE 1Demographics and baseline lipid-lowering therapyPlacebo N = 11Mipomersen N = 10FHBL N = 6Gender (M:F)aValues are the mean and (standard deviation).3:86:45:1Age46 (1)aValues are the mean and (standard deviation).49 (12)aValues are the mean and (standard deviation).49 (16)aValues are the mean and (standard deviation).BMI26aValues are the mean and (standard deviation).27aValues are the mean and (standard deviation).30aValues are the mean and (standard deviation).Statin (mg/day) Atorvastatin201 (10)bValues are the number of subjects (and percentage) by drug type and dose.401 (9)bValues are the number of subjects (and percentage) by drug type and dose.2 (20)bValues are the number of subjects (and percentage) by drug type and dose.804 (36)bValues are the number of subjects (and percentage) by drug type and dose.1 (10)bValues are the number of subjects (and percentage) by drug type and dose. Rosuvastatin52 (18)bValues are the number of subjects (and percentage) by drug type and dose.201 (9)bValues are the number of subjects (and percentage) by drug type and dose.1 (10)bValues are the number of subjects (and percentage) by drug type and dose.402 (18)bValues are the number of subjects (and percentage) by drug type and dose.4 (40)bValues are the number of subjects (and percentage) by drug type and dose. Simvastatin801 (10)bValues are the number of subjects (and percentage) by drug type and dose. Pravastatin401 (9)bValues are the number of subjects (and percentage) by drug type and dose. Ezetemibe107 (64)bValues are the number of subjects (and percentage) by drug type and dose.9 (90)bValues are the number of subjects (and percentage) by drug type and dose.Other1 (9)bValues are the number of subjects (and percentage) by drug type and dose.1 (10)bValues are the number of subjects (and percentage) by drug type and dose.BMI, body mass index; F, female; FHBL, familial hypobetalipoproteinemia; M, male.a Values are the mean and (standard deviation).b Values are the number of subjects (and percentage) by drug type and dose. Open table in a new tab TABLE 2Baseline lipid parametersLipids (mg/dl)Placebo (N = 11)Mipomersen (N = 10)FHBL (N = 6)LDL-C155 ± 31155 ± 3746 ± 18VLDL-C18 ± 620 ± 78 ± 3Non-HDL-C173 ± 35175 ± 3854 ± 19HDL-C46 ± 1047 ± 1356 ± 6TC219 ± 29222 ± 37110 ± 20TG91 (52–133)aData are presented as the median (min–max).102 (51–166)aData are presented as the median (min–max).32 (23–63)aData are presented as the median (min–max).Apo A1144 ± 19149 ± 26156 ± 20Apo B124 ± 24131 ± 2935 ± 10Lp(a)50 ± 6278 ± 7422 ± 22Data are presented as the mean ± standard deviation. Apo, apolipoprotein; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; LP(a), lipoprotein (a); TC, total cholesterol TG, triglycerides; VLDL-C, VLDL-cholesterol.a Data are presented as the median (min–max). Open table in a new tab BMI, body mass index; F, female; FHBL, familial hypobetalipoproteinemia; M, male. Data are presented as the mean ± standard deviation. Apo, apolipoprotein; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; LP(a), lipoprotein (a); TC, total cholesterol TG, triglycerides; VLDL-C, VLDL-cholesterol. Thirteen weeks of treatment with mipomersen 200 mg/wk resulted in significant reductions in apoB of 19.9% (P < 0.001) with a mean apoB at week 15 of 104.7 mg/dl and concomitant reductions in LDL-cholesterol of 22% (P < 0.01) with a mean LDL-cholesterol at week 15 of 118.1 mg/dl (Table 3).TABLE 3Percentage change in lipid parameters after 13 weeks of treatmentChange from baseline lipid parameter (%)Placebo (N = 11)Mipomersen (N = 10)LDL-C1.0 ± 16.5−22.0 ± 17.8aP < 0.01 compared with placebo using the Exact Wilcoxon Rank sum test.VLDL-C−3.1 ± 24.8−13.2 ± 13.8Non-HDL-C0.4 ± 16.3−21.3 ± 16.6bP < 0.05 compared with placebo using the Exact Wilcoxon Rank sum test.HDL-C7.5 ± 12.74.0 ± 9.2TC1.9 ± 14.9−16.4 ± 13.4aP < 0.01 compared with placebo using the Exact Wilcoxon Rank sum test.TG−7 (−45.9–42.3)cData are presented as the median (min–max).−16.3 (−35.1–9.8)cData are presented as the median (min–max).Apo A12.2 ± 12.0−1.3 ± 8.6Apo B5.7 ± 13.1−19.9 ± 17.4dP < 0.001 compared with placebo using the Exact Wilcoxon Rank sum test.Lp(a)8.0 ± 16.1−19.6 ± 14.9dP < 0.001 compared with placebo using the Exact Wilcoxon Rank sum test.Data was analyzed at week 15. Data are presented as the mean ± standard deviation. Apo, apolipoprotein; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; LP(a), lipoprotein (a); TC, total cholesterol TG, triglycerides; VLDL-C, VLDL-cholesterol.a P < 0.01 compared with placebo using the Exact Wilcoxon Rank sum test.b P < 0.05 compared with placebo using the Exact Wilcoxon Rank sum test.c Data are presented as the median (min–max).d P < 0.001 compared with placebo using the Exact Wilcoxon Rank sum test. Open table in a new tab Data was analyzed at week 15. Data are presented as the mean ± standard deviation. Apo, apolipoprotein; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; LP(a), lipoprotein (a); TC, total cholesterol TG, triglycerides; VLDL-C, VLDL-cholesterol. Baseline IHTG content was similar between the two treatment groups with a mean of 1.2% and a range of 0.2–3.2% for the placebo and 0.3–3.8% for the treatment group (Table 4). Thirteen weeks of treatment with mipomersen resulted in a mean change from baseline for IHTG content of 0.8 percentage points compared with −0.1 percentage points in the placebo group at week 15 (P = 0.0513). One subject treated with mipomersen exceeded the upper limit of normal for IHTG content of 5.6%. In this particular subject, IHTG content increased from 0.6% at baseline to 5.7% at week 15. During follow-up IHTG content dropped to 5.6% at week 25 and to 2.5% at week 35 (Fig. 1A). In two other subjects in the mipomersen group and in three subjects in the placebo group, additional IHTG content measurements at week 25 were performed on recommendation of the DSMB because of increases in IHTG content > 100% relative to screening values. Both subjects in the mipomersen treatment group showed reduction in IHTG content at week 25 compared with week 15 (Fig. 1A and Fig. 2A).TABLE 4Changes in intra-hepatic triglyceride contentIHTG content (%)FHBL no-dosing (n = 6)HeFH placebo (n = 11)Mipomersen (n = 10)Baseline Mean ± SD21.9 ± 6.51.2 ± 1.01.2 ± 1.0 Range13.2 – 30.10.2 – 3.20.3 – 3.8Week 4 Mean ± SD21.7 ± 5.91.2 ± 1.11.0 ± 0.5 Range11.9 – 27.60.2 – 3.30.4 – 1.9Week 15 Mean ± SD22.6 ± 6.81.1 ± 0.82.1 ± 1.5 Range12.7 – 31.00.2 – 2.50.8 – 5.7Change from baseline to week 15 Mean ± SD0.7 ± 2.1−0.1 ± 0.90.8 ± 1.7aP = 0.0513 compared with placebo using the Exact Wilcoxon Rank sum test. Range−2.0 – 4.3−1.5 – 1.3−1.7 – 5.1FHBL, familial hypobetalipoproteinemia; HeFH, heterozygous familial hypercholesterolemia; IHTG, intra-hepatic triglyceride content.a P = 0.0513 compared with placebo using the Exact Wilcoxon Rank sum test. Open table in a new tab Fig. 2IHTG content (A) and ALT (B) in time for mipomersen treatment group. Dotted line represents ULN = 5.6% for IHTG content. ALT, alanine aminotransferase; IHTG, intra-hepatic triglyceride content; ULN, upper limit of normal.View Large Image Figure ViewerDownload Hi-res image Download (PPT) FHBL, familial hypobetalipoproteinemia; HeFH, heterozygous familial hypercholesterolemia; IHTG, intra-hepatic triglyceride content. 1H-MRS measurements in FHBL subjects at baseline showed a mean IHTG content of 21.9% with a range of 13.2–30.1%. Mean change from baseline to week 15 for this group was 0.7 percentage points (Table 4 and Fig. 3). No serious adverse events occurred in this study. The most common adverse events were injection site reactions (ISR) following subcutaneous administration of mipomersen (Table 5). ISRs were generally characterized by erythema that occurred within 24 h after the injection. ISRs did not worsen on repeated dosing. All subjects treated with mipomersen experienced at least one ISR. Of all injections with mipomersen 19% (22/118) resulted in ISR compared with 9% (13/142) in the placebo group. Other adverse events with > 10% incidence in the mipomersen treatment group were influenza-like illness, influenza, nasopharyngitis, headache, fatigue, mylagia, back pain, abdominal pain, nausea, and cough.TABLE 5Treatment-emergent adverse events (>10% Mipomersen)EventPlacebo (n = 11)Mipomersen (n = 10)Injection site reaction8 (73)10 (100)Influenza-like illness2 (18)7 (70)Influenza1 (9)3 (30)Nasopharyngitis4 (36)3 (30)Headache6 (55)3 (30)Fatigue5 (46)2 (20)Myalgia1 (9)2 (20)Back pain0 (0)2 (20)Upper abdominal pain0 (0)2 (20)Nausea0 (0)2 (20)Cough0 (0)2 (20)The numbers in parentheses are percentages. Open table in a new tab The numbers in parentheses are percentages. There were no clinically significant increases in ALT (>3 × ULN) (Fig. 1, Fig. 2) or other measures of liver function, such as prothrombin time, albumin, or bilirubin. Vital signs, electrocardiogramm and urinalysis did not show any clinically significant changes. Mipomersen at a dose of 200 mg/wk for 13 weeks in patients with FH achieved incremental reductions in LDL-cholesterol with a concomitant trend toward increased IHTG content, which did not reach statistical significance. New-onset hepatic steatosis was observed in one patient, which was reversible after discontinuation of the compound. There were no increases in hepatic transaminase levels exceeding 3 × ULN. The findings in this study may have divergent implications. On the one hand, there was no profound change in IHTG content following 13 weeks of apoB synthesis inhibition. This observation is in apparent contradiction with the severe hepatic steatosis observed in patients with FHBL as well as patients receiving MTP inhibition (7Cuchel M. Bloedon L.T. Szapary P.O. Kolansky D.M. Wolfe M.L. Sarkis A. Millar J.S. Ikewaki K. Siegelman E.S. Gregg R.E. et al.Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia.N. Engl. J. Med. 2007; 356: 148-156Crossref PubMed Scopus (453) Google Scholar, 8Chandler C.E. Wilder D.E. Pettini J.L. Savoy Y.E. Petras S.F. Chang G. Vincent J. Harwood Jr., H.J. CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in" @default.
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