Enzymatic replacement therapy for lysosomal adic lipase deficiency in adult patients with lysosomal acid lipase deficiency
EAS Academy. Sharma R. 04/24/17; 175510 Topic: Therapy
Reena Sharma
Reena Sharma

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Dr Reena Sharma started her presentation with an overview on the Lysosomal Acid Lipase (LAL) Deficiency (LAL-D). LAL-D is a rare, autosomal recessive disorder caused by a marked decrease in LAL activity which plays a key role in the degradation of LDL particles. This enzyme deficiency results in cholesteryl ester and triglyceride accumulation. There are two major phenotypes of this deficiency, an early onset (Wolman disease), which occurs in infants, and a late onset known as Cholesteryl Ester Storage Disease (CESD), which affects children and adults.
Subsequently, Dr Sharma described the main clinical and epidemiological characteristics of the late onset LAL-D phenotype, which is an underappreciated cause of cirrhosis and early death. In 27% of patients the disease is presented before the 1st year of life, whereas in the 62% of patients the disease is presented between 3 – 12 years of age. In the 73% of cases, the liver failure is the cause of death which occurs at the age range between 7 and 546 years old. The 64% of patients has fibrosis and / or cirrhosis, whereas the 29% has cirrhosis.
The lipid metabolism in the LAL-D in comparison with normal hepatocytes was then presented, discussing how the deficiency of this enzyme leads to the deficiency of free cholesterol and free fatty acids in the cell, leading to a higher expression of the LDL receptor and also to a much more production and release of VLDL particles in the circulation. Next, Dr Sharma presented the management of LAL-D in adults. Treatment of these patients with statins may exacerbate the lipid storage in the liver and can actually worsen the liver disease. Supportive nutrition, lipid lowering therapy may manage the CV risk, whereas liver transplantation may be helpul in the future. The most recent therapeutical approach is the enzyme replacement therapy (ERT) which is in trials since 2011.  Sebelipase alpha (Kanuma) is recently in the market and available in the clinical practice. It is a recombinant glycoprotein with a molecular weight of 55kDa synthesized in genetically modified hens (Gallus gallus) with secretion of the protein into the egg white. The carbohydrate-containing moieties of the drug include various glycan moieties that confer specificity, allowing targeted delivery of LAL to the lysosomal compartment by means of the macrophage mannose receptor on reticuloendothelial cells and the mannose-6-phosphate receptor.
Next, Dr Sharma presented the clinical trials LAL-CL01 (administration of 3 different doses for 4 weeks in 9 patients) and LAL-CL04 (continuation of the CL01 trial for 52 weeks in 8 patients, after variable washout periods ranging from 9-28 weeks). Participants were patients (18-65 years) with LAL deficiency, hepatomegaly and /or transaminase levels ≥ 1.5xULN. The drug induced a dramatical reduction in both transaminases ALT and AST and a reduction in the liver volume and fat fraction. At 52 weeks of treatment (in the CL04 trial) there was a reduction in Total cholesterol, LDL-cholesterol and Triglycerides whereas there was a modest increase in the HDL-cholesterol levels. The next trial presented was the phase 3 ARISE trial, a randomized, double-blind, placebo controlled multi-center global trial, having as a primary endpoint the normalization in ALT levels. There was a double-blind period of 20 weeks in which 36 patietns received Sebelipase alfa, 1mg/Kg qow, and 20 patients received placebo, followed by an open-label period during which 65 patients received 1mg/Kg qow for 16 weeks. There was a dramatical reduction in the ALT levels in the patients treated with the drug compared with placebo group during the double-blind period and also during the open-label period in patients receiving placebo in the first period. There was also a reduction in hepatic fat content and in steatosis. Sebelipase alfa also induced an increase in the HDL-cholesterol levels.
Serious avers events were anaphylaxis and hypersensitivity, whereas there were several very common side effects (≥10%) including pyrexia, chills, dermatological, gastrointestinal, respiratory, cardiovascular and central nervous system side effects.  Subsequently, Dr Sharma presented a case with LAL-D and then she concluded that ERT normalizes /significantly improves LFTs, lipid profile, hepatic steatosis, volume and fat fraction in patients with late onset LAL-D and also it is fairly well tolerated. However it remains to be established whether the drug prevents the need for liver transplant, premature atherosclerosis, premature mortality and morbidity and whether there is a role of this drug in patients who have received liver transplant. 
Dr Reena Sharma started her presentation with an overview on the Lysosomal Acid Lipase (LAL) Deficiency (LAL-D). LAL-D is a rare, autosomal recessive disorder caused by a marked decrease in LAL activity which plays a key role in the degradation of LDL particles. This enzyme deficiency results in cholesteryl ester and triglyceride accumulation. There are two major phenotypes of this deficiency, an early onset (Wolman disease), which occurs in infants, and a late onset known as Cholesteryl Ester Storage Disease (CESD), which affects children and adults.
Subsequently, Dr Sharma described the main clinical and epidemiological characteristics of the late onset LAL-D phenotype, which is an underappreciated cause of cirrhosis and early death. In 27% of patients the disease is presented before the 1st year of life, whereas in the 62% of patients the disease is presented between 3 – 12 years of age. In the 73% of cases, the liver failure is the cause of death which occurs at the age range between 7 and 546 years old. The 64% of patients has fibrosis and / or cirrhosis, whereas the 29% has cirrhosis.
The lipid metabolism in the LAL-D in comparison with normal hepatocytes was then presented, discussing how the deficiency of this enzyme leads to the deficiency of free cholesterol and free fatty acids in the cell, leading to a higher expression of the LDL receptor and also to a much more production and release of VLDL particles in the circulation. Next, Dr Sharma presented the management of LAL-D in adults. Treatment of these patients with statins may exacerbate the lipid storage in the liver and can actually worsen the liver disease. Supportive nutrition, lipid lowering therapy may manage the CV risk, whereas liver transplantation may be helpul in the future. The most recent therapeutical approach is the enzyme replacement therapy (ERT) which is in trials since 2011.  Sebelipase alpha (Kanuma) is recently in the market and available in the clinical practice. It is a recombinant glycoprotein with a molecular weight of 55kDa synthesized in genetically modified hens (Gallus gallus) with secretion of the protein into the egg white. The carbohydrate-containing moieties of the drug include various glycan moieties that confer specificity, allowing targeted delivery of LAL to the lysosomal compartment by means of the macrophage mannose receptor on reticuloendothelial cells and the mannose-6-phosphate receptor.
Next, Dr Sharma presented the clinical trials LAL-CL01 (administration of 3 different doses for 4 weeks in 9 patients) and LAL-CL04 (continuation of the CL01 trial for 52 weeks in 8 patients, after variable washout periods ranging from 9-28 weeks). Participants were patients (18-65 years) with LAL deficiency, hepatomegaly and /or transaminase levels ≥ 1.5xULN. The drug induced a dramatical reduction in both transaminases ALT and AST and a reduction in the liver volume and fat fraction. At 52 weeks of treatment (in the CL04 trial) there was a reduction in Total cholesterol, LDL-cholesterol and Triglycerides whereas there was a modest increase in the HDL-cholesterol levels. The next trial presented was the phase 3 ARISE trial, a randomized, double-blind, placebo controlled multi-center global trial, having as a primary endpoint the normalization in ALT levels. There was a double-blind period of 20 weeks in which 36 patietns received Sebelipase alfa, 1mg/Kg qow, and 20 patients received placebo, followed by an open-label period during which 65 patients received 1mg/Kg qow for 16 weeks. There was a dramatical reduction in the ALT levels in the patients treated with the drug compared with placebo group during the double-blind period and also during the open-label period in patients receiving placebo in the first period. There was also a reduction in hepatic fat content and in steatosis. Sebelipase alfa also induced an increase in the HDL-cholesterol levels.
Serious avers events were anaphylaxis and hypersensitivity, whereas there were several very common side effects (≥10%) including pyrexia, chills, dermatological, gastrointestinal, respiratory, cardiovascular and central nervous system side effects.  Subsequently, Dr Sharma presented a case with LAL-D and then she concluded that ERT normalizes /significantly improves LFTs, lipid profile, hepatic steatosis, volume and fat fraction in patients with late onset LAL-D and also it is fairly well tolerated. However it remains to be established whether the drug prevents the need for liver transplant, premature atherosclerosis, premature mortality and morbidity and whether there is a role of this drug in patients who have received liver transplant. 
Bernstein , et al. Hepatology. 2013.
Valayannopoulos V et al. J Hepatol. 2014;61:1135-1142
Burton et al. NEJM 2015;373
Su et al. The Applications of Clinical Genetics. 2016.
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