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A Phase 3 Study of the Microsomal Triglyceride Transfer Protein (MTP) Inhibitor Lomitapide in Patients with Homozygous Familial Hypercholesterolemia
282
Journal of Clinical Lipidology, Vol 6, No 3, June 2012
median percent change in non-HDL-C was 235.2% in the pitavastatin 4 mg group and 224.3% in the pravastatin 40 mg group; the treatment difference (211.0%) was statistically significant (P , .0001). There were no clinically important differences in the safety profiles between treatment groups (Table 2). Conclusions: Pitavastatin 4 mg provided significantly greater LDL-C reduction compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed dyslipidemia.
154 Vitamin D3 Alters the Crystallization and Volume Expansion of Cholesterol* Toufic R. Jildeh, BSc, Abed Janoudi, PhD, George S. Abela, MD, (East Lansing, MI) Synopsis: Cholesterol crystals develop within the lipid core of atherosclerotic plaques. We demonstrated that cholesterol crystals form early in atherogenesis inducing inflammation and that free cholesterol occupies a greater volume as it changes from liquid to crystalline form. In atherosclerotic plaques sharp-edged crystals penetrate the intima, weakening the plaque cap and potentially causing rupture. Vitamin D3 is a derivative of cholesterol and they share structural similarities. We hypothesized that vitamin D3 could act physicochemically by interfering with cholesterol-cholesterol molecular interactions thus disrupting crystallization. Purpose: To demonstrate that vitamin D3 can: 1- Decrease cholesterol crystallization and 2- Inhibit volume expansion that occurs with crystallization. Methods: Cholesterol has a maximum solubility of 4% in corn oil and crystals form at higher concentrations. (1) To assess the effect of vitamin D3 on cholesterol crystal formation, we made supersaturated solutions by dissolving 4.25% to 5% cholesterol in oil either with or without vitamin D3 (1.26%–2.1%). The solutions were incubated at 37 C for 3 days to allow for crystallization of excess cholesterol. The crystals were separated by centrifugation and the concentration of free cholesterol remaining in the
Figure 2
Effect of vitamin D3 on cholesterol volume expansion.
clear liquid was measured. (2) The effect of vitamin D3 on volume expansion was measured by melting 3 g of cholesterol powder in graduated cylinders in the presence or absence of vitamin D3 (0.33%21.67% w/w). The liquid was allowed to completely crystallize at room temperature and volume change after crystallization was measured. Results: (1) Vitamin D3 reduced cholesterol crystallization but the effect varied with both the concentrations of vitamin D3 and the concentration of cholesterol in the solution (Figure 1). Up to 30% more cholesterol was in solution in the presence of vitamin D3 as compared with control. However, at a higher cholesterol concentration (5%), vitamin D3 enhanced crystallization. These results indicate that vitamin D3 can interfere with crystal formation while an excess of vitamin D3 can promote crystal formation. (2) Vitamin D3 at concentrations of $1% prevented volume increase that occurs upon crystallization indicating that vitamin D3 promotes a more compact arrangement of crystals (Figure 2). Conclusions: Vitamin D3 reduces cholesterol crystallization and inhibits the volume increase associated with crystallization. Despite the supra-physiological concentrations used, these results present a proof of principle that vitamin D3 can act physicochemically to alter cholesterol crystallization. Vitamin D3 accumulation in the lipid core of plaques could potentially inhibit cholesterol crystallization and limit volume expansion to avert plaque disruption.
155 A Phase 3 Study of the Microsomal Triglyceride Transfer Protein (MTP) Inhibitor Lomitapide in Patients with Homozygous Familial Hypercholesterolemia Daniel J. Rader, MD, (Philadelphia, PA) Figure 1
Effect of vitamin D3 on cholesterol solubility in oil.
Synopsis: Patients with homozygous familial hypercholesterolemia (HoFH) are at very high risk for premature
Abstracts
283
cardiovascular disease and are refractory to existing lipid lowering drug therapy. MTP is a key protein regulating the assembly and secretion of apolipoproteinB-containing lipoproteins. Purpose: We conducted a phase 3 study to assess the efficacy safety of the MTP inhibitor lomitapide in adults with HoFH when added to concomitant lipid lowering therapies, including apheresis. Methods: HoFH subjects enrolled into the single arm, open label study were instructed to maintain current lipid lowering therapy unchanged from six weeks prior to baseline through week 26. Lomitapide was initiated at 5 mg and escalated individually to a maximum tolerated dose up to 60 mg/day. The primary endpoint was mean percent change in LDL-C from baseline at week 26 (intent to treat analysis), after which patients remained on lomitapide for assessment of safety and long-term effects and were permitted to modify concomitant lipid lowering therapy. Results: Of the 29 HoFH subjects enrolled, 23 completed weeks 26, 56 and 78 (end of study) evaluations. Median dose was 40 mg/day. As compared with baseline, LDL-C levels were reduced by 40% at week 26 (336 6 114 mg/dl vs. 190 6 104 mg/dl, P , .001). In the subjects that completed week 26, mean change was 250% and was maintained through weeks 56 and 78 (244% and 238% respectively, P , .001 for all). Similar % reductions were observed for apoB. Eight subjects had LDL-C levels ,100 mg/dl at week 26. Four of these either discontinued LDL apheresis or increased the time interval between apheresis treatments and were able to maintain decreased LDL-C levels until the end of the study. Lomitapide was generally well tolerated. Gastrointestinal symptoms were the most common adverse events observed. Four patients had confirmed elevations in aminotransferases between 5 and 11! ULN. All 4 were able to continue in the study with temporary dose reduction or temporary suspension of study medication. There were no concomitant changes in bilirubin or alkaline phosphatase. No patients discontinued treatment due to liver function abnormalities. Liver fat content assessed by NMRS was 0.9 6 1.0% at baseline,
9.0 6 7.9% at week 26 and remained stable at weeks 56 and 78 evaluations (7.3% and 8.2%, respectively). Conclusions: These data demonstrate robust and durable efficacy with an acceptable safety profile in this high risk patient population. Lomitapide is a promising agent as therapy for patients with HoFH
Category: Pharmacological Control of Lipids and Lipoproteins 156 Lipoprotein Effects of Exenatide in Diabetic Subjects with Elevated Pretreatment Levels of Serum Lipoprotein(a) Cholesterol Steven R. Jones, MD, Peter P. Toth, MD, PhD, Krishnaji Kulkarni, PhD, Elaine Chiquette, PharmD, (Baltimore, MD) Synopsis: Elevated lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease (CVD), amplifying high CVD risk in patients with type 2 diabetes (T2DM). The GLP-1 receptor agonist exenatide has been demonstrated to reduce glucose in T2DM. Purpose: We report the effects of exenatide on lipoproteins in patients with T2DM and elevated Lp(a)-C from a post hoc analysis of the DURATION-1 trial. Methods: By vertical autoprofile ultracentifugation, Lp(a)C.10 mg/dL is abnormal. Among patients with Lp(a) .10 mg/dL enrolled in DURATION-1, a 30-week trial of two exenatide formulations, Lp(a) whole particle concentration [Lp(a)-P], ApoB, ApoAI, and high-sensitivity C-reactive protein (hsCRP) were measured post-hoc in pretreatment (PRE) and end-of-trial (EOT) serum. Results: Of the 211 patients with available data, 58 subjects had PRE Lp(a)-C.10 mg/dL; 41 had complete data (Table 1). VLDL-C and subfractions, IDL-C, TC/HDL-C and non-HDL-C, HDL-C, ApoAI, HDL-C/ApoAI, and HDL2C/HDL3-C did not change significantly with exenatide.
Table 1 Pre
PRE Median
25th percentile
75th percentile
EOT Median
25th percentile
75th percentile
Wilcoxon matched pairs P value
Lp(a)-C, mg/dL Lp(a)-P, nmol/L Lp(a)-C/Lp(a)-P TG, mg/dL TG/HDL-C VLDL-C/TG TG/TC ApoB/ApoAI hsCRP, mg/L
15.5 25.4 0.512 206.0 6.33 0.128 1.36 0.892 3.3
13.0 2.3 0.104 129.0 3.24 0.071 0.91 0.681 1.5
21.0 113.2 3.529 347.0 10.36 0.156 2.67 0.991 7.2
10.0 27.3 0.402 162.5 4.72 0.149 1.17 0.722 2.2
7.0 4.1 0.081 116.0 2.45 0.106 0.77 0.629 1.0
15.0 136.1 1.212 260.0 7.73 0.173 1.63 1.007 5.1
.000014 NS .010 .00047 .00047 .0012 .0018 .0087 .0080
Journal of Clinical Lipidology, Vol 6, No 3, June 2012
median percent change in non-HDL-C was 235.2% in the pitavastatin 4 mg group and 224.3% in the pravastatin 40 mg group; the treatment difference (211.0%) was statistically significant (P , .0001). There were no clinically important differences in the safety profiles between treatment groups (Table 2). Conclusions: Pitavastatin 4 mg provided significantly greater LDL-C reduction compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed dyslipidemia.
154 Vitamin D3 Alters the Crystallization and Volume Expansion of Cholesterol* Toufic R. Jildeh, BSc, Abed Janoudi, PhD, George S. Abela, MD, (East Lansing, MI) Synopsis: Cholesterol crystals develop within the lipid core of atherosclerotic plaques. We demonstrated that cholesterol crystals form early in atherogenesis inducing inflammation and that free cholesterol occupies a greater volume as it changes from liquid to crystalline form. In atherosclerotic plaques sharp-edged crystals penetrate the intima, weakening the plaque cap and potentially causing rupture. Vitamin D3 is a derivative of cholesterol and they share structural similarities. We hypothesized that vitamin D3 could act physicochemically by interfering with cholesterol-cholesterol molecular interactions thus disrupting crystallization. Purpose: To demonstrate that vitamin D3 can: 1- Decrease cholesterol crystallization and 2- Inhibit volume expansion that occurs with crystallization. Methods: Cholesterol has a maximum solubility of 4% in corn oil and crystals form at higher concentrations. (1) To assess the effect of vitamin D3 on cholesterol crystal formation, we made supersaturated solutions by dissolving 4.25% to 5% cholesterol in oil either with or without vitamin D3 (1.26%–2.1%). The solutions were incubated at 37 C for 3 days to allow for crystallization of excess cholesterol. The crystals were separated by centrifugation and the concentration of free cholesterol remaining in the
Figure 2
Effect of vitamin D3 on cholesterol volume expansion.
clear liquid was measured. (2) The effect of vitamin D3 on volume expansion was measured by melting 3 g of cholesterol powder in graduated cylinders in the presence or absence of vitamin D3 (0.33%21.67% w/w). The liquid was allowed to completely crystallize at room temperature and volume change after crystallization was measured. Results: (1) Vitamin D3 reduced cholesterol crystallization but the effect varied with both the concentrations of vitamin D3 and the concentration of cholesterol in the solution (Figure 1). Up to 30% more cholesterol was in solution in the presence of vitamin D3 as compared with control. However, at a higher cholesterol concentration (5%), vitamin D3 enhanced crystallization. These results indicate that vitamin D3 can interfere with crystal formation while an excess of vitamin D3 can promote crystal formation. (2) Vitamin D3 at concentrations of $1% prevented volume increase that occurs upon crystallization indicating that vitamin D3 promotes a more compact arrangement of crystals (Figure 2). Conclusions: Vitamin D3 reduces cholesterol crystallization and inhibits the volume increase associated with crystallization. Despite the supra-physiological concentrations used, these results present a proof of principle that vitamin D3 can act physicochemically to alter cholesterol crystallization. Vitamin D3 accumulation in the lipid core of plaques could potentially inhibit cholesterol crystallization and limit volume expansion to avert plaque disruption.
155 A Phase 3 Study of the Microsomal Triglyceride Transfer Protein (MTP) Inhibitor Lomitapide in Patients with Homozygous Familial Hypercholesterolemia Daniel J. Rader, MD, (Philadelphia, PA) Figure 1
Effect of vitamin D3 on cholesterol solubility in oil.
Synopsis: Patients with homozygous familial hypercholesterolemia (HoFH) are at very high risk for premature
Abstracts
283
cardiovascular disease and are refractory to existing lipid lowering drug therapy. MTP is a key protein regulating the assembly and secretion of apolipoproteinB-containing lipoproteins. Purpose: We conducted a phase 3 study to assess the efficacy safety of the MTP inhibitor lomitapide in adults with HoFH when added to concomitant lipid lowering therapies, including apheresis. Methods: HoFH subjects enrolled into the single arm, open label study were instructed to maintain current lipid lowering therapy unchanged from six weeks prior to baseline through week 26. Lomitapide was initiated at 5 mg and escalated individually to a maximum tolerated dose up to 60 mg/day. The primary endpoint was mean percent change in LDL-C from baseline at week 26 (intent to treat analysis), after which patients remained on lomitapide for assessment of safety and long-term effects and were permitted to modify concomitant lipid lowering therapy. Results: Of the 29 HoFH subjects enrolled, 23 completed weeks 26, 56 and 78 (end of study) evaluations. Median dose was 40 mg/day. As compared with baseline, LDL-C levels were reduced by 40% at week 26 (336 6 114 mg/dl vs. 190 6 104 mg/dl, P , .001). In the subjects that completed week 26, mean change was 250% and was maintained through weeks 56 and 78 (244% and 238% respectively, P , .001 for all). Similar % reductions were observed for apoB. Eight subjects had LDL-C levels ,100 mg/dl at week 26. Four of these either discontinued LDL apheresis or increased the time interval between apheresis treatments and were able to maintain decreased LDL-C levels until the end of the study. Lomitapide was generally well tolerated. Gastrointestinal symptoms were the most common adverse events observed. Four patients had confirmed elevations in aminotransferases between 5 and 11! ULN. All 4 were able to continue in the study with temporary dose reduction or temporary suspension of study medication. There were no concomitant changes in bilirubin or alkaline phosphatase. No patients discontinued treatment due to liver function abnormalities. Liver fat content assessed by NMRS was 0.9 6 1.0% at baseline,
9.0 6 7.9% at week 26 and remained stable at weeks 56 and 78 evaluations (7.3% and 8.2%, respectively). Conclusions: These data demonstrate robust and durable efficacy with an acceptable safety profile in this high risk patient population. Lomitapide is a promising agent as therapy for patients with HoFH
Category: Pharmacological Control of Lipids and Lipoproteins 156 Lipoprotein Effects of Exenatide in Diabetic Subjects with Elevated Pretreatment Levels of Serum Lipoprotein(a) Cholesterol Steven R. Jones, MD, Peter P. Toth, MD, PhD, Krishnaji Kulkarni, PhD, Elaine Chiquette, PharmD, (Baltimore, MD) Synopsis: Elevated lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease (CVD), amplifying high CVD risk in patients with type 2 diabetes (T2DM). The GLP-1 receptor agonist exenatide has been demonstrated to reduce glucose in T2DM. Purpose: We report the effects of exenatide on lipoproteins in patients with T2DM and elevated Lp(a)-C from a post hoc analysis of the DURATION-1 trial. Methods: By vertical autoprofile ultracentifugation, Lp(a)C.10 mg/dL is abnormal. Among patients with Lp(a) .10 mg/dL enrolled in DURATION-1, a 30-week trial of two exenatide formulations, Lp(a) whole particle concentration [Lp(a)-P], ApoB, ApoAI, and high-sensitivity C-reactive protein (hsCRP) were measured post-hoc in pretreatment (PRE) and end-of-trial (EOT) serum. Results: Of the 211 patients with available data, 58 subjects had PRE Lp(a)-C.10 mg/dL; 41 had complete data (Table 1). VLDL-C and subfractions, IDL-C, TC/HDL-C and non-HDL-C, HDL-C, ApoAI, HDL-C/ApoAI, and HDL2C/HDL3-C did not change significantly with exenatide.
Table 1 Pre
PRE Median
25th percentile
75th percentile
EOT Median
25th percentile
75th percentile
Wilcoxon matched pairs P value
Lp(a)-C, mg/dL Lp(a)-P, nmol/L Lp(a)-C/Lp(a)-P TG, mg/dL TG/HDL-C VLDL-C/TG TG/TC ApoB/ApoAI hsCRP, mg/L
15.5 25.4 0.512 206.0 6.33 0.128 1.36 0.892 3.3
13.0 2.3 0.104 129.0 3.24 0.071 0.91 0.681 1.5
21.0 113.2 3.529 347.0 10.36 0.156 2.67 0.991 7.2
10.0 27.3 0.402 162.5 4.72 0.149 1.17 0.722 2.2
7.0 4.1 0.081 116.0 2.45 0.106 0.77 0.629 1.0
15.0 136.1 1.212 260.0 7.73 0.173 1.63 1.007 5.1
.000014 NS .010 .00047 .00047 .0012 .0018 .0087 .0080