Long-Term Survival With Sebelipase Alfa Enzyme Replacement Therapy in Infants With Rapidly Progressive Lysosomal Acid Lipase Deficiency Final Results From 2 Open-Label Studies

Abstract

Background: If symptomatic in infants, the autosomal recessive disease lysosomal acid lipase deficiency (LAL-D; sometimes called Wolman disease or LAL-D/Wolman phenotype) is characterized by complete loss of LAL enzyme activity. This very rare, rapidly progressive form of LAL-D results in severe manifestations leading to failure to thrive and death, usually by 6 months of age. We report results from 2 open-label studies of enzyme replacement therapy with sebelipase alfa, a recombinant human LAL, in infants with LAL-D: the phase 2/3 Survival of LAL-D Infants Treated With Sebelipase Alfa (VITAL) study (NCT01371825) and a phase 2 dose-escalation study (LAL-CL08 [CL08]; NCT02193867). In both, infants received once-weekly intravenous infusions of sebelipase alfa.Results: The analysis population contained 19 patients (9 in VITAL; 10 in CL08). Kaplan-Meier estimates of survival to 12 months and 5 years of age were 79% and 68%, respectively, in the combined population, and the median age of surviving patients was 5.2 years in VITAL and 3.2 years in CL08. In both studies, median weight-for-age, length-for-age, and mid-upper arm circumference-for-age z scores increased from baseline to end of study. Decreases in median liver and spleen volume over time were noted in both studies. Short-term transfusion-free hemoglobin normalization was achieved by 100% of patients eligible for assessment in VITAL, in an estimated median (95% confidence interval [CI]) time of 4.6 (0.3–16.6) months. In CL08, short-term transfusion-free hemoglobin normalization was achieved by 70% of patients eligible for assessment, in an estimated median (95% CI) time of 5.5 (3.7–19.6) months. No patient discontinued treatment because of treatment-emergent adverse events. Most infusion-associated reactions (94% in VITAL and 88% in CL08) were mild or moderate in severity.Conclusions: The findings of these 2 studies of infants with rapidly progressive LAL-D demonstrated that enzyme replacement therapy with sebelipase alfa prolonged survival with normal psychomotor development, improved growth, hematologic, and liver parameters, and was generally well tolerated, with an acceptable safety profile.

Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease

“…7. A key consideration is the likely overlap between arms as some of the patients within the group that survived on ERT and DSR, also received HCT [13]. The multimodality survival curve demonstrates 80% survival in a difficult group of Wolman disease patients where ERT efficacy was severely reduced.…”

“…However, this includes patients who had also received HCT, and not just those on ERT and DSR alone. The combined data also assesses functional development of the children through the trial which remained stable throughout [13].…”

“…ERT is not curative, and residual disease manifestations remain. For example, most of the surviving patients reported in the combined studies continued to require highly modified specialised diets [13].…”

“…In 3/6, ADAs were considered clinically significant and were associated with reduced ERT efficacy, such that HCT and/or immunomodulatory therapy was given. Of the cases discussed in this review, 3/5 patients had significant ADAs as part of their indication for HCT [13].…”

Correction to: Long-term survival with sebelipase alfa enzyme replacement therapy in infants with rapidly progressive lysosomal acid lipase deficiency: final results from 2 open-label studies

“…Following the publication of the original article [ 1 ], we were informed that the Plain Language Summary had inadvertently been omitted during typesetting.…”