Case series of sebelipase alfa hypersensitivity reactions and successful sebelipase alfa rapid desensitization

Huffaker, Michelle F.; Liu, Anne Y.; Enns, Gregory M.; Vijay, Suresh; Amor, Antonio J.; Adkinson, N. Franklin

doi:10.1002/jmd2.12066

“…Desensitization was required for 1 patient in CL08. This involved administration of lower-concentration solutions of sebelipase alfa over prolonged infusion times, and ultimately led to the ability to administer the full planned dose, demonstrating that successful implementation of rapid desensitization is possible in affected patients [16]. The incidence of neutralizing antibodies was higher in CL08 (100% of patients with ADAs) than in VITAL (75% of patients are consistent with a rare disease study and make it di cult to distinguish dose effects and do not allow for statistical comparisons.…”

Section: Discussionmentioning

confidence: 99%

“…The most frequently reported IARs in VITAL were pyrexia (33%), urticaria (33%), vomiting (33%), tachycardia (22%), and pallor (22%); in CL08, they were tachycardia (70%), pyrexia (60%), irritability (50%), agitation (40%), and urticaria (40%). One patient in CL08 experienced IARs that required a per-protocol desensitization procedure involving administration of lower concentration solutions of sebelipase alfa over prolonged infusion times, with stepwise increases in infusion rate and an increase in dose from 0.35 mg/kg once weekly (qw) to the full planned dose of 3.0 mg/kg qw over the initial 4 infusions of the desensitization period [16]. In all other patients IARs were successfully managed and resolved using local regular treatment protocols, as in studies of other enzyme replacement therapies [17].…”

Section: Safetymentioning

confidence: 99%

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

Vijay

¹

,

Brassier

²

,

Ghosh

³

et al. 2020

Preprint

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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.

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“…The most frequently reported IARs in VITAL were pyrexia (33%), urticaria (33%), vomiting (33%), tachycardia (22%), and pallor (22%); in CL08, they were tachycardia (70%), pyrexia (60%), irritability (50%), agitation (40%), and urticaria (40%). One patient in CL08 experienced IARs that required a per-protocol desensitization procedure involving administration of lower concentration solutions of sebelipase alfa over prolonged infusion times, with stepwise increases in infusion rate and an increase in dose from 0.35 mg/kg once weekly (qw) to the full planned dose of 3.0 mg/kg qw over the initial 4 infusions of the desensitization period [16]. In all other patients…”

Section: Growth and Functional Developmentmentioning

confidence: 99%

“…Desensitization was required for 1 patient in CL08. This involved administration of lower-concentration solutions of sebelipase alfa over prolonged infusion times, and ultimately led to the ability to administer the full planned dose, demonstrating that successful implementation of rapid desensitization is possible in affected patients [16]. The incidence of neutralizing antibodies was higher in CL08 (100% of patients with ADAs) than in VITAL (75% of patients with ADAs).…”

Section: Growth and Functional Developmentmentioning

confidence: 99%

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

Vijay

¹

,

Brassier

²

,

Ghosh

³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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.

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“…In this paper, 1 the footnote in Table 2 incorrectly states the concentration of drug in the 2 solutions used for the desensitization.…”

mentioning

confidence: 99%

Correction to: Case series of sebelipase alfa hypersensitivity reactions and successful sebelipase alfa rapid desensitization.

2020

JIMD Reports

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Case series of sebelipase alfa hypersensitivity reactions and successful sebelipase alfa rapid desensitization

Cited by 18 publications

References 12 publications

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

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

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

Correction to: Case series of sebelipase alfa hypersensitivity reactions and successful sebelipase alfa rapid desensitization.

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