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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003ELysosomal acid lipase deficiency (LAL-D) is an autosomal genetic recessive disorder that leads to an inability to break down lipid particles in the lysosome, and it is associated with early-onset cirrhosis and cardiovascular disease. This article discusses the Acid Lipase Replacement Investigating Safety and Efficacy trial [ARISE; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01757184\u0026amp;atom=%2Fspmdc%2F14%2F48%2F14.atom\u0022\u003ENCT01757184\u003C\/a\u003E] was a randomized, double-blind, placebo-controlled phase 3 study designed to evaluate sebelipase alfa in patients with LAL-D.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ELiver Conditions\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ELipid Disorders Hepatology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDeficiency Disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ELiver Conditions\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ELipid Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHepatology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHepatology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDeficiency Disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003ELysosomal acid lipase deficiency (LAL-D) is an autosomal genetic recessive disorder that leads to an inability to break down lipid particles in the lysosome, and it is associated with early-onset cirrhosis and cardiovascular disease. Enzyme replacement therapy has been transformational for patients with LAL-D. Sebelipase alfa is a recombinant form of the human lysosomal acid lipase (LAL) enzyme used to replace the deficient enzyme in LAL-D.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe Acid Lipase Replacement Investigating Safety and Efficacy trial [ARISE; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01757184\u0026amp;atom=%2Fspmdc%2F14%2F48%2F14.atom\u0022\u003ENCT01757184\u003C\/a\u003E] was a randomized, double-blind, placebo-controlled phase 3 study designed to evaluate sebelipase alfa in 66 patients with LAL-D. Patients were randomized to receive 1 mg\/kg sebelipase alfa or placebo every other week for 20 weeks during the double-blind phase, after which all patients continued on the study drug. LAL-D patients aged \u2265 4 years with an elevated alanine transaminase (ALT) level (\u2265 1.5 \u00d7 the upper limit of normal) were enrolled and permitted to continue on stable doses of background lipid-lowering medications. Patients with a history of liver or hematopoietic stem cell transplant were excluded, as were those with Child-Pugh C status. The primary study end point was liver injury as measured by normalization of ALT. Other end points included the effect on lipid metabolism, as well as a reduction in liver volume and fat content.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EParticipants had a median age of 13 years, with the majority being younger than 18 years. As expected, the baseline serum transaminases in this group were elevated. Mean gamma-glutamyl transferase (GGT) was normal, whereas low-density lipoprotein (LDL) levels were very high (mean, 190 to 230 mg\/dL). Baseline liver biopsy was available for 32 participants (mean age, 12 years). All of these patients had fibrosis; 47% had bridging fibrosis, and 31% cirrhosis. Dyslipidemia was present in 58% (38\/66) of patients, including the 24% who were taking lipid-lowering medications.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EHierarchical fixed sequence testing was used to test across the secondary end points. In this method, if one of the secondary end points did not achieve significance, the subsequent end points were nullified. Treatment with sebelipase alfa was associated with ALT normalization in significantly more patients compared with placebo (31% vs 7%; \u003Cem\u003EP\u003C\/em\u003E = .027). Patients treated with sebelipase alfa had a mean reduction in ALT units\/L of 58 (53%) compared with 7 (6%) for placebo-treated patients (\u003Cem\u003EP\u003C\/em\u003E \u0026lt; .001). Significant effects were also seen for 6 of the secondary end points (\u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/15568\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/15568\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15568\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-6\u0022 class=\u0022first-child\u0022\u003EPrimary and Secondary End Points\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-10\u0022\u003EThe reduction in ALT was accompanied by a reduction in liver fat content of 32% for patients treated with sebelipase alfa versus 4% for placebo-treated patients (\u003Cem\u003EP\u003C\/em\u003E \u0026lt; .001). Other liver assessments are shown in \u003Ca id=\u0022xref-table-wrap-2-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T2\u0022\u003ETable 2\u003C\/a\u003E.\u003C\/p\u003E\u003Cdiv id=\u0022T2\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/15569\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/15569\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15569\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003EAdditional Liver Assessments, ARISE Results\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-15\u0022\u003EPatients treated with sebelipase alfa also realized significant reductions in LDL (\u221228%) and increases in HDL (+20%) compared with placebo-treated patients (\u22126% and \u22120.3% LDL and HDL, respectively; both \u003Cem\u003EP\u003C\/em\u003E \u0026lt; .001).\u003C\/p\u003E\u003Cp id=\u0022p-16\u0022\u003EMost adverse events were mild and not related to the study drug. There were 2 serious adverse events in the sebelipase alfa group (an atypical infusion reaction and gastritis).\u003C\/p\u003E\u003Cp id=\u0022p-17\u0022\u003EALT levels normalized in placebo-treated patients after they were switched to sebelipase alfa. Patients treated with sebelipase alfa had a sustained response and improvement in ALT up to week 36.\u003C\/p\u003E\u003Cp id=\u0022p-18\u0022\u003EConsistent with other forms of enzyme replacement therapy, sebelipase alfa addresses the cause of LAL-D by replacing the deficient enzyme.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/48\/14.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzof32\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_tables.js?nzof32\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}