Lysosomal Acid Lipase Deficiency (LAL-D) is a life-threatening disorder caused by an abnormal LAL activity, which results in widespread accumulation of cholesteryl esters and triglycerides.1 It presents a broad spectrum of clinical manifestations, including general dyslipidemia, hepatosplenomegaly and adrenal calcifications, which lead to multi-organ damage and systemic disease (particularly affecting the liver, gastrointestinal and vascular systems).1
Infantile-onset severe and lethal forms of LAL-D are known as Wolman disease (WD) while child-to-adulthood-onset attenuated and progressive forms are denominated as cholesteryl ester storage disease (CESD).2 Due to overlapping of symptoms with other cardiovascular, liver and metabolic disorders, LAL-D is often under diagnosed or misdiagnosed, which leads to inadequate management.1–3 Therefore, an early differential diagnosis is essential to establish an appropriate therapy approach and control disease progression, avoiding secondary comorbidity-associated complications.3
For a considerable time, there were only supportive therapies available for LAL-D.1,4 These were primarily symptomatic and consisted either monotherapies or combinatorial strategies of low-fat diets, statins and other lipid-lowering agents, stem cell transplant and liver transplant.4 In December 2015, the human recombinant LAL enzyme sebelipase alfa (Kanuma©, Alexion Pharmaceuticals, Inc., Cheshire, CT, USA) was approved by US Food and Drug Administration (FDA) as the first therapy that addresses the underlying cause of LAL-D.5 The goal of sebelipase alfa is to replace the defective LAL enzyme, which is referred to as enzyme replacement therapy (ERT).4 Since its development, ERT has been the preferential treatment option for LAL-D.
Low Fat Diet
Dietary manipulation has been used to control the lipid profile of LAL-D patients but with limited success when used alone.4,6 Parenteral nutrition and diets free of hydrophobic esters have been applied in WD infants, but without improvements in their long-term survival.6,7
Statins, Ezetimibe and Cholestyramine
Statins are competitive inhibitors of hydroxymethylglutaryl coenzyme A reductase (HMG-CoA-reductase).1,4 Increased HMG-CoA reductase activity promotes the upregulation of apolipoprotein (apo) B, low- and very-low-density cholesterol (LDL and VLDL), while downregulating the synthesis of high-density cholesterol (HDL), apo A1 and apo A2.8–10 Therefore, statins (such as lovastatin) were found to reduce cholesterol biosynthesis in several patients with LAL-D.4,11–15 However, cholesterol elevations and progression of hepatic damage were still reported in some patients.14,16
Ezetimibe (a cholesterol absorption inhibitor) and cholestyramine (a bile acid sequestrant) have also been used for treatment of LAL-D in combination with lovastatin, further improving the resultant lipid profile.4,17–19
Lipid-lowering drugs were the first-line therapy before ERT became available. However, their efficacy was heterogeneous, they had a poor impact on liver disease and were rarely capable of retuning the lipid profile to normal levels.3,4 This is thought to be due to the existence of other morbidity-associated mechanisms of disease beyond those attributable to disruption of lipid metabolism.4 Thus, the impact of lipid-lowering agents after ERT has been initiated to provide increased benefits to LAL-D therapy.
Stem Cell and Liver Transplantation
Hematopoietic stem cell transplantation (HSCT) and liver transplantation have both been performed in LAL-D patients, mainly in WD infants, but with limited success in halting disease progression and several reports of procedure-related morbidities, particularly for the most severe cases have been reported.4,20–26
There are no reported cases of patients with LAL deficiency subjected to both HSCT and liver transplantation.4 Alone, these approaches have revealed their inadequacy, as they fail to address the multi-system nature of LAL-D; yet the outcome of each procedure following pretreatment or in combination with ERT remains to be investigated.4
Sebelipase Alfa (Kanuma©)
The first human investigational study using sebelipase alfa (LAL-CL01) was described in 2013 by Balwani and colleagues.27 9 CESD patients received 4 once-weekly intravenous infusions (0.35, 1, or 3 mg·kg−1) of sebelipase alfa and, of those, 7 patients enrolled in the extension study (LAL-CL04) in which they received another 4 once-weekly intravenous infusions (0.35, 1, or 3 mg·kg−1). Long-term dosing was then performed weekly (1 or 3 mg·kg−1). Data revealed that sebelipase alfa treatment was well tolerated and did not generate anti-drug antibodies. Moreover, administration of sebelipase alfa rapidly decreased serum transaminases in both studies and improved the serum lipid profile (decreased triglycerides, total and LDL cholesterols, as well as increased HDL cholesterol) sustained by longterm dosing.
A pediatric study (LAL-CL03) was conducted in 9 WD patients treated with sebelipase alfa.28 56% infants survived to 24 months of age with sebelipase alfa therapy, well beyond the historical life expectancy for WD. Patients exhibited significant improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, as well as improvements in anemia and gastrointestinal symptoms. One patient presented serious adverse effects related to treatment, including tachycardia, pallor, chills, and pyrexia.
Get detailed prescribing information on the Kanuma monograh page on MPR.
Kanuma was approved by US FDA to treat LAL-D patients of all ages.5 Indications for dosage and administration are 1 mg·kg−1 once a week for infants presenting with rapidly progressive LAL-D within the first six months of life, and once every other week for children and adults.5 Kanuma needs to be given indefinitely and, in case of LAL-D infantile severe patients who do not achieve an optimal clinical response, dosage should be increased to 3 mg·kg−1.
Common side effects of Kanuma in infants (≥30%) include diarrhea, vomiting, fever, rhinitis, cough, anemia and urticaria.5 In children and adults (≥8%), these include headache, fever, asthenia, oropharyngeal pain, constipation and nausea.
The outcome of ERT clinical trials in LAL-D patients indicate that sebelipase alfa has a favorable impact on disease course and therapy is beneficial for a significant proportion of patients. Given the limited success and procedure-related morbidity risks of other therapies, sebelipase alfa treatment will likely become the standard of care for LAL-D, at least in jurisdictions where available.
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2. Pericleous M, Kelly C, Wang T, Livingstone C, Ala A. Wolman’s disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol Hepatol. 2017;2(9):670-679. doi:10.1016/S2468-1253(17)30052-3
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5. Kanuma (Sebelipase alfa). accessdata.fda.gov. Accessed on June 15, 2021.
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17. Abello F, Guardamagna O, Baracco V, Bonardi R. P55 the treatment of cholesteryl storage disease (cesd) by ezetimibe monotherapy. Atheroscler Suppl. 2010;11(2):28. doi:https://doi.org/10.1016/S1567-5688(10)70122-7
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21. Tolar J, Petryk A, Khan K, et al. Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman disease. Bone Marrow Transplant. 2009;43(1):21-27. doi:10.1038/bmt.2008.273
22. Gramatges MM, Dvorak CC, Regula DP, Enns GM, Weinberg K, Agarwal R. Pathological evidence of Wolman’s disease following hematopoietic stem cell transplantation despite correction of lysosomal acid lipase activity. Bone Marrow Transplant. 2009;44(7):449-450. doi:10.1038/bmt.2009.57
23. Yanir A, Allatif MA, Weintraub M, Stepensky P. Unfavorable outcome of hematopoietic stem cell transplantation in two siblings with Wolman disease due to graft failure and hepatic complications. Mol Genet Metab. 2013;109(2):224-226. doi:https://doi.org/10.1016/j.ymgme.2013.03.007
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28. Jones SA, Rojas-Caro S, Quinn AG, et al. Survival in infants treated with sebelipase alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study. Orphanet J Rare Dis. 2017;12(1):25. doi:10.1186/s13023-017-0587-3
Reviewed by Harshi Dhingra, MD, on 7/1/2021.