Results From a 12-Month Open-Label Phase 1/2 Study of Velaglucerase Alfa in Children and Adolescents With Type 3 Gaucher Disease

Tantawy, Azza A. G.; El-Beshlawy, Amal; Marzouk, Iman; Bavdekar, Ashish; Qin, Yulin; Mellgard, Björn; Turkia, Hadhami Ben

doi:10.1177/2326409818765564

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Journal of Inborn Errors of Metabolism and Screening

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Original Article • J. inborn errors metab. screen. 6 • 2018 • https://doi.org/10.1177/2326409818765564 copy

Results From a 12-Month Open-Label Phase 1/2 Study of Velaglucerase Alfa in Children and Adolescents With Type 3 Gaucher Disease

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Gaucher disease (GD) is an autosomal recessive lipid storage disorder, caused by deficient activity of the lysosomal enzyme b-glucocerebrosidase, resulting in accumulation of glucocerebroside in tissue macrophages. HGT-GCB-068 was an open-label study designed to explore the efficacy and safety of velaglucerase alfa in children and adolescents with type 3 GD, a neuronopathic form of the disease. Six treatment-naive patients received infusions of velaglucerase alfa every other week at 60 U/kg over 12 months. Velaglucerase alfa demonstrated a favorable tolerability profile, and 1 infusion-related reaction (headache) was the only drug-related adverse event reported. Numerical increases from baseline in hematological parameters and decreases in visceral parameters were seen at 12 months. http://ClinicalTrials.gov identifier NCT01685216.

Keywords
type 3 Gaucher disease; velaglucerase alfa; enzyme replacement therapy; children; adolescents

Genotype		Male, 5 years L444P/L444P		Male, 3 years F2131/F2131		Male, 2 years L444P/L444P		Female, 14 years N370S/N370S		Male, 4 years R120W/R496H	Male, 3 years L444P/-
General signs of Gaucher disease		Organomegaly, anemia, thrombocytopenia		Organomegaly thrombocytopenia		Hepatosplenomegaly, anemia, thrombocytopenia		Hepatomegaly, anemia, thrombocytopenia		Hepatosplenomegaly, anemia, thrombocytopenia, Erlenmeyer flask deformity	Organomegaly, anemia, thrombocytopenia
Neurological symptoms		Dysarthria, echolalia, perseveration, hypotonia, hyporeflexia, muscle weakness		Myoclonic epilepsy, pyramidal syndrome, speech delay, hypotonia, amyotrophy, decreased muscle power		Horizontal ophthalmoplegia, hyperreflexia, mild motor delay, hypotonia, history of choking		Horizontal oculomotor apraxia, stabilized myoclonic epilepsy, pyramidal syndrome, mild cerebellar syndrome, extrapyramidal syndrome, mild mental retardation		Horizontal ophthalmoplegia, global developmental delay, speech delay, hypotonia, hyporeflexia	Pyramidal syndrome, horizontal nystagmus, no speech, walks with support

Genotype		Male, 5 years L444P/L444P	Male, 3 years F2131/F213P^a a Patient tested positive for anti-velaglucerase alfa antibodies at week 13 and continued to test positive until the end of the study.	Male, 2 years L444P/L444P^b b Patients received supplemental therapy for anemia: the 2-year-old patient received ferric hydroxide polymaltose complex and the 3-year-old patient received vitamin B complex, folic acid, iron, and concentrated red blood cells	Female, 14 years N370S/N370S^c c Patients had clinical signs and symptoms consistent with a diagnosis of GD3, but glucocerebrosidase genotype results received subsequently were not consistent with those classically associated with neuronopathic GD.	Male, 4 years R120W/R496H^c c Patients had clinical signs and symptoms consistent with a diagnosis of GD3, but glucocerebrosidase genotype results received subsequently were not consistent with those classically associated with neuronopathic GD.	Male, 3 years L444P/–^b b Patients received supplemental therapy for anemia: the 2-year-old patient received ferric hydroxide polymaltose complex and the 3-year-old patient received vitamin B complex, folic acid, iron, and concentrated red blood cells ^,^c c Patients had clinical signs and symptoms consistent with a diagnosis of GD3, but glucocerebrosidase genotype results received subsequently were not consistent with those classically associated with neuronopathic GD.	Overall Change From Baseline to 12 Months
Hemoglobin, g/dL
	Baseline	9.0	10.1	10.5	9.9	8.9	9.3	2.2 ± 1.2%
	12 months	12.5	1 1.9	1 1.1	1 1.5	12.1	10.4^d	(n = 5)
Platelet count × 10⁹L
	Baseline	52.5	63	1 18	1 15	72.5	95	136.6 ± 51.5%
	12 months	247	191	256	172	238	85^d	(n = 5)
Spleen volume, MN^e e Organ volumes expressed in MN based on a normal spleen volume of 0.2% body weight and normal liver volume of 2.5% body weight.
	Baseline	37.6	12.9	20.4	4.5	29.0	17.5	-62.3 ± 20.0%
	12 months	10.1	^_f f Patient had only 1 postbaseline magnetic resonance imaging assessment, which was at week 25; measurements from week 25 were 8.6 MN for spleen volume and 1.6 MN for liver volume.	5.7	3.0	5.0	8.7	(n = 5)
Liver volume, MN^e e Organ volumes expressed in MN based on a normal spleen volume of 0.2% body weight and normal liver volume of 2.5% body weight.
	Baseline	2.0	1.5	2.5	1.1	1.8	2.0	-30.1 ± 10.4%
	12 months	1.4	^_f f Patient had only 1 postbaseline magnetic resonance imaging assessment, which was at week 25; measurements from week 25 were 8.6 MN for spleen volume and 1.6 MN for liver volume.	1.7	1.0	1.1	1.3	(n = 5)
Chitotriosidase activity, nmol/mL/h
	Baseline	103 910	47 758	^_g g Chitotriosidase activity not included due to patient having 1 copy of the 24-base-pair duplication in the chitotriosidase gene.	27 202	45 231	47	-58.0 ± 57.7%
	12 months	11 483	11 559	^_g g Chitotriosidase activity not included due to patient having 1 copy of the 24-base-pair duplication in the chitotriosidase gene.	5641	4318	68	(n = 5)
CCL18 level, ng/mL
	Baseline	3267	1506	1086	580	2059	231	-58.2 ± 38.5%
	12 months	565	409	394	198	361	274	(n = 6)

Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) Rua Ramiro Barcelos, 2350, CEP: 90035-903, Porto Alegre, RS - Brasil, Tel.: 55-51-3359-6338, Fax: 55-51-3359-8010 - Porto Alegre - RS - Brazil
E-mail: rgiugliani@hcpa.edu.br

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[1] Corresponding Author: Azza A. G. Tantawy, Ain Shams University Hospital, 22 Ahmed Amin Street, St Fatima Square, Heliopolis, Cairo, Egypt. Email: azazaghloul@yahoo.com