Sebelipase alfa for lysosomal acid lipase deficiency: 5-year treatment experience from a phase 2 open-label extension study

Abstract

Background and aims: Lysosomal acid lipase deficiency is characterized by hepatomegaly and dyslipidaemia, which can lead to cirrhosis and premature atherosclerosis. Sebelipase alfa is an approved recombinant human lysosomal acid lipase. In an open-label extension study of adults with lysosomal acid lipase deficiency (LAL-CL04), sebelipase alfa treatment for 1 year reduced serum transaminase levels and liver fat content and improved serum lipid levels.

Methods: Final data from LAL-CL04 are reported herein for patients who received sebelipase alfa infusions (1.0 or 3.0 mg/kg every other week) for up to 5 years.

Results: Of 8 patients enrolled, 7 received sebelipase alfa for 224-260 weeks; 1 was lost to follow-up. Median baseline levels of alanine aminotransferase and aspartate aminotransferase (81.5 and 50.0 U/L, respectively) were decreased through the end-of-study visit (54.0 and 34.0 U/L). Median low-density lipoprotein cholesterol decreased from 113 to 78 mg/dL, total cholesterol decreased from 171 to 132 mg/dL, and high-density lipoprotein cholesterol increased from 37 to 42 mg/dL. Most treatment-emergent adverse events were nonserious (99%), mild/moderate (98%) and unrelated to sebelipase alfa (87%); no patient discontinued as a result of treatment-emergent adverse events. One patient had 2 serious treatment-emergent adverse events (cholecystitis and cholelithiasis; assessed as unlikely related to sebelipase alfa). Two patients had 20 nonserious infusion-associated reactions in weeks 6-38; all were manageable. One patient tested positive for antidrug antibodies (single occurrence).

Conclusions: Sebelipase alfa was well tolerated and improved serum transaminase and lipid levels for up to 5 years in adults with lysosomal acid lipase deficiency.

Trial registration number: ClinicalTrials.gov record NCT01488097.

Keywords: enzyme replacement therapy; lipids; liver; lysosomal storage diseases; transaminases.

Conflict of interest statement

VM received funding for participation as a study investigator and an honorarium for chairing an educational session from Alexion Pharmaceuticals, Inc JBA and RS have received honoraria for educational sessions and funding from Alexion Pharmaceuticals, Inc for participation as study investigators. JK has given lectures on this topic supported by Alexion Pharmaceuticals, Inc, and has received funding from Alexion Pharmaceuticals, Inc for participation as a study investigator. MB is a member of the LALD scientific registry and has received honoraria for participation in advisory boards and funding from Alexion Pharmaceuticals, Inc for participation as a study investigator. CBW received consultancy fees and funding from Alexion Pharmaceuticals, Inc for providing education on lysosomal diseases. SM and FA are employees of and may own stock/options in Alexion Pharmaceuticals, Inc

© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Changes in median ALT (A) and AST (B) over time. Data were collected every 4 weeks through week 24, at weeks 25, 32, 38, and every 12‐14 weeks thereafter (weeks 52, 66, 78, 90, 104, 118, 130, 142, 156, 170, 182, 194, 208, 222, 234, 246, 260), and at end of study (EOS). Patients were allowed to schedule week 25 visit at week 25, 27 or 29. ALT, alanine aminotransferase; AST, aspartate aminotransferase

FIGURE 2

Changes in median LDL‐C (A) and HDL‐C (B) over time. Data were collected every 4 weeks through week 24, at weeks 25, 32, 38, and every 12‐14 weeks thereafter (weeks 52, 66, 78, 90, 104, 118, 130, 142, 156, 170, 182, 194, 208, 222, 234, 246 and 260) and at end of study (EOS). Patients were allowed to schedule week 25 visit at week 25, 27 or 29. HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol

FIGURE 3

Change in liver fat content over time. Assessed by multi‐echo gradient‐echo magnetic resonance imaging of right lobe. Data were collected at baseline, weeks 10 or 12, 24, 52, 104, 156, 208, 260, and end of study (30 days after last dose of sebelipase alfa with a +7‐day window); week 208 = last time point with n >2. The final assessment for patient 1 was an unscheduled visit at week 92. Pt, patient

FIGURE 4

Liver biopsy findings in 1 patient with pre‐ and post‐treatment assessments. Pretreatment biopsy (A) shows microvesicular steatosis with fibrosis. Post‐treatment biopsy approximately 2 years after sebelipase alfa treatment initiation (B) shows mild microvesicular steatosis with no significant fibrosis

FIGURE 5

Liver biopsy findings in 1 patient with post‐treatment assessment approximately 1.5 years after sebelipase alfa treatment initiation showing steatosis with mild microvesicular predominance (20%‐30%) and periportal fibrosis with some septa (F2 Metavir score)