Enzyme replacement therapy in lysosomal acid lipase deficiency (LAL-D): a systematic literature review.

BACKGROUND

Lysosomal acid lipase deficiency (LAL-D) is a very rare genetic abnormality caused by LIPA gene mutation. The disease has two distinct clinical variants in humans: Wolman disease in infants and cholesteryl ester storage disease in children and adults. Both conditions are characterized by elevated serum transaminases, dyslipidaemia, severe liver steatosis and accelerated fibrosis or cirrhosis, contributing to its high rate of early mortality. Recently sebelipase alfa (recombinant human LAL) was launched to address its underlying pathology. This systematic review evaluates the safety and efficacy of sebelipase alfa for LAL-D.

METHODS

This systematic review was performed following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Clinical trial records were systematically searched in , and up to September 2020. Records that have reported at least one of the included outcomes were included. Baseline and endpoint mean and standard deviation (SD) for all outcomes were recorded. For safety, frequency and overall distribution of different adverse events were included.

RESULTS

A total of seven records from five individual studies with 110 LAL-D patients were included into this study. The mean age ranged from 2.57 months in infants to 31.6 years among adults. Serum transaminases (alanine aminotransferase and aspartate aminotransferase), serum lipids (total cholesterol, triglycerides, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol), gamma-glutamyl transferase and liver volume were included as efficacy outcomes. Final pooled results were synthesized as a change from baseline to end of the treatment. A significant effect on both serum transaminases and other serum lipid was achieved ( < 0.01), while non-significant differences were seen for GGT and liver volume as  = 0.35 and  = 0.08 was observed. Mostly the adverse events related to the infusions were infrequent and mild-to-moderate in severity.

CONCLUSION

Sebelipase alfa as an enzyme replacement provides an effective, safe and well tolerated treatment in both variants of LAL-D.

PLAIN LANGUAGE SUMMARY

Lysosomal acid lipase deficiency (LAL-D) is a rare, progressive, genetic disorder caused by functional mutations in the LIPA gene, which encodes LAL enzyme. This enzyme maintains lipid homeostasis by hydrolysing the cholesterol esters and triglycerides. Patients with deficient LAL activity are seen with abnormal liver functions which keep them at a high risk of early mortality. Clinical diagnosis of this disease is very challenging due to both its low prevalence and low awareness among patients/clinicians and additionally due to its overlap with other liver/lipid disorders. Also, owing to lack of safe and effective treatment, dietary modifications and some lipid modifying drugs are usually used to control the LAL-D manifestations. Recently, recombinant human LAL named as sebelipase alfa (Kanuma™, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, USA) was approved in 2015 for the European Union and subsequently in the United States as an enzyme replacement therapy for LAL deficiency. The initial clinical trial data indicate that sebelipase alfa produces a significant improvement in all of the wide range of LAL-D manifestations. However, the cumulative evidence is not reported regarding its safety and effective use. Therefore, a systematic literature review of all the clinical trial records by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines was undertaken. From all of the available clinical trial records, 110 LAL-D patients treated with sebelipase alfa were included. Serum transaminases, serum lipids, gamma-glutamyl transferase (GGT) and liver volume were included as efficacy outcomes. Final pooled results were synthesized as a change from baseline to end of the treatment. A significant effect on both serum transaminases and other serum lipids was achieved ( < 0.01), while non-significant differences were observed for GGT and liver volume, with  = 0.35 and  = 0.08 respectively. Mostly the adverse events related to the infusions were infrequent and mild-to-moderate in severity. The enzyme replacement provides an effective, safe and well tolerated treatment in both variants of LAL-D.