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Introduction Methods Results Conclusions 133 Sebelipase Alfa Improves Atherogenic Biomarkers in Adults and Children With Lysosomal Acid Lipase Deficiency Don P Wilson,1 Sachin Marulkar,2 Radhika Tripuraneni,2 and Barbara K Burton3 1Cook Children’s Medical Center, Fort Worth, TX; 2Alexion Pharmaceuticals, Inc, New Haven, CT; 3Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL • Management with lipid-lowering medications10: INTRODUCTION RESULTS Table 4. Effect of Sebelipase Alfa on Atherogenic Biomarkers in LAL-D Subjects – HMG CoA reductase inhibitors disrupt synthesis of FC, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors Stratified by Use of Lipid-Lowering Medication (LLM) at 20 Weeks of Treatment • Lysosomal acid lipase deficiency (LAL-D) is a rare, autosomal recessive lysosomal storage disorder (Online Mendelian prevent degradation of LDL receptors, and both types of lipid-lowering medications can markedly increase LDL uptake and increase lysosomal accumulation of LDL (Figure 2)2,10 Subject Characteristics Subjects Using LLM Subjects Not Using LLM Inheritance in Man [OMIM] #278000), historically called Wolman disease in infants and cholesteryl ester storage disease (n=24) (n=37) in older children and adults, that is associated with accumulation of cholesteryl esters and triglycerides in the liver and – Although statin therapy may improve lipid parameters, clinical reports have noted progression of liver disease in • Complete data on atherogenic biomarkers were available from 61 of 66 subjects (N=33 for sebelipase alfa and N=28 for 1 other organs1-3 patients with LAL-D despite long-term treatment with HMG-CoA reductase inhibitors placebo) Mean (SD) Percentage Mean (SD) Percentage Change From Baseline Change From Baseline – Hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase inhibitor (statin) therapy may improve lipid parameters but 2 • Subjects had marked dyslipidemia at baseline (Table 2), and 39% (24/61) were using lipid-lowering medication – LAL maintains cholesterol homeostasis in hepatocytes (Figure 1A) does not improve liver disease associated with LAL-D, and, in some patients, it may be associated with progression of Sebelipase Percentage Sebelipase Percentage LAL catalyzes hydrolysis of low-density lipoprotein cholesterol (LDL-C)–derived cholesteryl esters to free liver disease over time1,4 – Mean LDL-P, LDL-C, and apoB levels were elevated compared with normal ranges; mean apoA1 level was at the low Atherogenic Alfa Placebo Point Alfa Placebo Point cholesterol (FC) and triglycerides to free fatty acids (FFA) end of the normal range Biomarker (n=14) (n=10) Difference P Value (n=19) (n=18) Difference P Value Increased levels of cytosolic FC and FFA downregulate sterol regulatory element–binding protein (SREBP) Figure 2. Lipid-Lowering Medications May Exacerbate the Underlying Mechanism of – Overall, the mean total LDL-P concentration at baseline was 2151 nmol/L (reference value: very high, >2000 nmol/L) LDL-P number, −34.2 (13.6) −1.6 (11.3)a 32.6 0.0002 −21.7 (20.6) 1.9 (20.7) 23.6 0.0017 transcription factors to decrease LDL uptake and production of FC and fatty acids Disease in LAL-Da nmol/L – LAL-D is characterized by lysosomal accumulation of lipids enhanced by increased LDL uptake and upregulation of LDL-C, mg/dL −36.1 (16.4) −10.3 (15.9) 25.8 0.0034 −27.4 (18.8) −4.6 (11.8) 22.8 0.0003 LDL LDL Table 2. Atherogenic Biomarkers and Lipid-Lowering Medication Use at Baseline in lipid production in response to decreased cytosolic FC (Figure 1B)2 ARISE Trial Subjects apoB, mg/dL −29.1 (12.3) −6.5 (10.4) 22.6 0.0005 −26.2 (14.3) −3.2 (7.3) 23.0 <0.0001 a Figure 1. Lipid Metabolism in Normal and LAL-D Hepatocytes Lysosome Sebelipase Alfa Placebo apoA1, mg/dL 10.2 (14.3) −2.5 (10.7) 12.7 0.0224 8.9 (9.2) −2.1 (13.2) 11.0 0.0041 Parameter N=33 N=28 Reference Value LDL-P size, nm −1.0 (2.2)b 0.4 (2.8)a 1.4 0.1927 −0.8 (3.9) 0.1 (2.3) 0.9 0.3302 LDLR A. Normal Hepatocyte B. LAL-D Hepatocyte LAL a b Mean LDL-P number, nmol/L 1942 2414 Very high, >2000 nmol/L apo, apolipoprotein; LAL-D, lysosomal acid lipase deficiency; LDL-C, low-density lipoprotein cholesterol; LDL-P, low-density lipoprotein particle. an=9; bn=13. LDL LDL LDL LDL Mean LDL-C, mg/dL 189.1 233.0 Normal, <130 mg/dL Increased LDLR uptake Mean apoB, mg/dL 148.0a 168.9 ULN, 120 mg/dL Lysosome FA synthesis pathway Lysosome SREBP CONCLUSIONS a LDLR Mean apoA1, mg/dL 102.5 102.1 LLN, 100 mg/dL LAL Nucleus LDLR LAL ACAT TG • Dyslipidemia in LAL-D resembles heterozygous familial hypercholesterolemia (HeFH) and familial combined HMG - Mean LDL-P size, nm 21.6a 21.7b — FC & FFA CoA FC CE hyperlipidemia (FCH) Feedback inhibition FA synthesis pathway Increased LDLR uptake and cellular production LLM use, n (%) 14 (42) 10 (36) – Given their similar lipid profiles, LAL-D should be considered in children and adults thought to have HeFH or FCH SREBP FA synthesis pathway SREBP VLDL Nucleus ACAT FC FC TG Nucleus ABCA1 Statin 14 (42) 8 (29) • Baseline atherogenic markers were elevated in LAL-D patients, often beginning in childhood. This life-long exposure HMG - ACAT TG FC CoA CE HMG - — represents significant atherosclerotic risk in patients with this disease FC CoA CE LCAT Other LLM 5 (15)c 3 (11)d VLDL apoA1 HDL FC FC • Sebelipase alfa treatment resulted in statistically significant decreases in mean LDL-P number, LDL-C level, and apoB ABCA1 FC FC VLDL ABCA1 ABCA1, adenosine triphosphate–binding cassette transporter A1; ACAT, acyl-coenzyme A:cholesterol acyltransferase; apoA1, apolipoprotein A1; CE, cholesteryl esters; Combination therapy 5 (15) 1 (4) level, and a significant increase in mean apoA1 level, representing an improved cardiovascular risk profile for these LCAT apoA1 HDL LCAT FA, fatty acid; FC, free cholesterol; HDL, high-density lipoprotein; HMG-CoA, hydroxymethylglutaryl-coenzyme A; LAL, lysosomal acid lipase; LAL-D, lysosomal acid lipase apo, apolipoprotein; ARISE, Acid Lipase Replacement Investigating Safety and Efficacy; LDL-C, low-density lipoprotein cholesterol; LDL-P, low-density lipoprotein particle; patients compared with placebo recipients apoA1 HDL deficiency; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, LDL receptors; SREBP, sterol regulatory element–binding proteins; TG, triglycerides; LLM, lipid-lowering medication; LLN, lower limit of normal; ULN, upper limit of normal. – These improvements were observed even in LAL-D patients who were receiving concomitant lipid-lowering VLDL very-low-density lipoprotein. aN=34; bN=27; cOther LLM category included ezetimibe (n=3), cholestyramine (n=1), colestilan (n=1), fenofibrate (n=1), and fish oil (n=1); dOther LLM category included ABCA1, adenosine triphosphate–binding cassette transporter A1; ACAT, acyl-coenzyme A:cholesterol acyltransferase; CE, cholesteryl esters; FA, fatty acid; FC, free aAdapted from Reiner et al.2 medication, suggesting that use of lipid-lowering medication alone is not sufficient cholesterol; FFA, free fatty acids; HDL, high-density lipoprotein; HMG-CoA, hydroxymethylglutaryl-coenzyme A; LAL, lysosomal acid lipase; LAL-D, LAL deficiency; LCAT, lecithin- cholestyramine (n=2) and fish oil (n=1). cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, LDL receptors; SREBP, sterol regulatory element–binding proteins; TG, triglycerides; VLDL, very-low-density • The observed reduction in LDL-C with sebelipase alfa appears to be associated with a reduction in LDL-P number, lipoprotein. • Sebelipase alfa is a recombinant human LAL that catalyzes the hydrolysis of cholesteryl esters to FC and triglycerides to aAdapted from Reiner et al.2 glycerol and FFA; it is indicated for treatment of patients of all ages with a diagnosis of LAL-D11 Efficacy suggesting that cardiovascular disease risk in LAL-D patients may be reduced with sebelipase alfa treatment • Clinical manifestations of LAL-D include severe dyslipidemia and hepatic steatosis, fibrosis, and cirrhosis1,4 • In the Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) study, sebelipase alfa normalized serum • Treatment with sebelipase alfa significantly improved key atherogenic biomarkers from baseline compared with placebo • Treatment with sebelipase alfa improves lipid biochemistry and other atherogenic biomarkers in LAL-D by addressing aminotransferase levels; improved LDL-C, non-high-density lipoprotein cholesterol (HDL-C), triglyceride, and HDL-C levels; the underlying pathogenetic mechanism of disease and is the recommended treatment for LAL-D patients of all ages – The dyslipidemia may cause accelerated atherosclerosis in LAL-D patients, increasing the risk of premature ischemia, (Table 3) 8 myocardial infarction, and stroke1 and decreased hepatic fat content in children and adults with LAL-D – The atherogenic biomarker profile associated with LAL-D is similar to that observed in heterozygous familial Table 3. Effect of Sebelipase Alfa on Atherogenic Biomarkers in LAL-D Subjects at hypercholesterolemia (HeFH) and familial combined hyperlipidemia (FCH, Table 1) REFERENCES METHODS 20 Weeks of Treatment Table 1. Atherogenic Biomarker Profiles in HeFH, FCH, and LAL-D 1. Bernstein DL, et al. J Hepatol. 2013;58:1230-43. 2. Reiner Z, et al. Atherosclerosis. 2014;235:21-30. 3. Lysosomal acid lipase deficiency (#278000). Mean (SD) Percentage OMIM database. 2015. http://omim.org/entry/278000. Accessed April 27, 2016. 4. Grabowski GA, et al. In: Valle D, et al, eds. Metabolic and Molecular LAL-Da Objective Change From Baseline Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2012. 5. Kusters DM, et al. JAMA. 2014;312:1055-7. 6. Wiegman A, et al. JAMA. HeFH FCH SA Placebo 2004;292:331-7. 7. Veerkamp MJ, et al. Circulation. 2004;109:2980-5. 8. Burton BK, et al.
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