Effect of velmanase alfa (human recombinant alpha-mannosidase) enzyme-replacement therapy on quality of life and disease burden of patients with alpha-mannosidosis: Results from caregiver feedback

Lund, Allan Meldgaard; Guffon, Nathalie; Gil‐Campos, Mercedes; Cattaneo, Frederica; Héron, Bénédicte; Tylki‐Szymańska, Anna; Borgwardt, Line; Régal, Luc; Cole, Duncan; Hennermann, Julia B.

doi:10.1016/j.ymgme.2020.12.153

Cited by 4 publications

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“…Velmanase alfa (VA; Lamzede®; Chiesi Farmaceutici S.p.A. Pharmaceuticals, Parma, Italy), a recombinant human lysosomal alpha‐mannosidase approved as a product for intravenous (IV) use, is the first enzyme replacement therapy (ERT) indicated for the treatment of non‐neurological symptoms of AM 8 . Previous studies have demonstrated the safety and efficacy of VA in pediatric and adult patients and suggest that VA treatment may produce a greater clinical benefit when administered earlier in the disease course than later 9,10 . A recent case study of a 7‐month‐old infant treated with VA showed reduced oligosaccharide levels in the urine and serum after 2 months 11 .…”

Section: Introductionmentioning

confidence: 99%

“…8 Previous studies have demonstrated the safety and efficacy of VA in pediatric and adult patients and suggest that VA treatment may produce a greater clinical benefit when administered earlier in the disease course than later. 9,10 A recent case study of a 7-month-old infant treated with VA showed reduced oligosaccharide levels in the urine and serum after 2 months. 11 However, long-term clinical studies in multiple younger pediatric patients are limited, with many studies only including children 6 years of age and older.…”

Section: Introductionmentioning

confidence: 99%

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Long‐term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha‐mannosidosis: A phase 2, open label, multicenter study

Guffon

Konstantopoulou

Hennermann

et al. 2023

J of Inher Metab Disea

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Alpha‐mannosidosis (AM) is a rare, autosomal recessive, lysosomal storage disorder caused by alpha‐mannosidase deficiency that leads to the accumulation of mannose‐rich oligosaccharides. AM symptoms and severity vary among individuals; consequently, AM is often not diagnosed until late childhood. Velmanase alfa (VA), a recombinant human lysosomal alpha‐mannosidase product, is the first enzyme replacement therapy indicated to treat non‐neurological symptoms of AM in Europe. Previous studies suggested that early VA treatment in children may produce greater clinical benefit over the disease course than starting treatment in adolescents or adults; however, long‐term studies in children are limited, and very few studies include children under 6 years of age. The present phase 2, multicenter, open‐label study evaluated the safety and efficacy of long‐term VA treatment in children under 6 years of age with AM. Five children (three males) received VA weekly for ≥24 months, and all children completed the study. Four children experienced adverse drug reactions (16 events) and two experienced infusion‐related reactions (12 events). Most (99.5%) adverse events were mild or moderate, and none caused study discontinuation. Four children developed antidrug antibodies (three were neutralizing). After VA treatment, all children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreases), hearing, immunological profile, and quality of life, suggesting a beneficial effect of early treatment. Although the small study size limits conclusions, these results suggest that long‐term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to patients with AM under 6 years of age.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long‐term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha‐mannosidosis: A phase 2, open label, multicenter study

Guffon

Konstantopoulou

Hennermann

et al. 2023

J of Inher Metab Disea

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“…Numerous treatment strategies for alpha-mannosidosis have been investigated. This disease typically treated by supplying normal enzymes to abnormal cells' lysosomes [9], such as enzyme replacement therapy (recombinant α-mannosidase) [19], bone marrow transplantation [40], gene therapy and substrate reduction therapy [6]. Recombinase via cell internalization to reach the lysosome and replacing the missing endogenous enzyme has been the most promising treatment method [26].…”

Section: Introduction：mentioning

confidence: 99%

Biochemical characteristics of point mutated <i>Capra hircus</i> lysosome α-mannosidase

Wang

Zhang

Teng

et al. 2023

The Journal of Veterinary Medical Science

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Locoweeds, a type of poisonous weedare, are widely distributed throughout the world and have a significant impact on the development of herbivore animal husbandry. Swainsonine (SW), the main toxin in locoweeds, can competitively inhibit lysosomes α-mannosidase (LAM) in animal cells, resulting in α-mannosidosis. However, the specifics of the interaction between SW and LAM are still unclear. Here, we used molecular docking to predicte the interaction points between SW and LAM, built mutated lysosomes α-mannosidase (LAM M ), and analyzed its biochemical properties changes in presumption points. The Trp at the 28th position and the Tyr at the 599th position of the LAM were interaction point candidates, and the above two amino acids in Capra hircus LAM (chLAM), were successfully mutated to glycine by constructing recombinant yeast GS115/PIC9K-LAM M . The results showed that the sensitivity of Capra hircus LAM M (chLAM M ), to SW decreased significantly compared with wild-type LAM, the enzyme activity of LAM decreased approximately threefold, the optimum temperature of LAM M decreased from 55℃to 50℃, the optimum pH value increased from 4.5 to 5.0, and the effects of Mn 2+ , Fe 3+ , Al 3+ , Co 2+ , Cr 3+ , and Ethylene Diamine Tetraacetic Acid (EDTA) on LAM enzyme activity before and after point mutation changed significantly. These findings help us better understanding the molecular mechanism of the interaction mechanism between SW and chLAM, and provide new reference for solving locoweeds poisoning.

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“…In 2018, European Medicines Agency approved Velmanase alfa, a recombinant human alpha-mannosidase (rhLAMAN), for long-term enzyme replacement therapy (ERT) for AM patients [5]. Administration of ERT, especially after an early diagnosis, is effective in slowing the progression of mild to moderate non-neurological AM, lowering disease biomarkers' levels, and improving the quality of life [6,7].…”

Section: Introductionmentioning

confidence: 99%

The Application of HPLC-FLD and NMR in the Monitoring of Therapy Efficacy in Alpha-Mannosidosis

Krchňák

Kodríková

Matulovà

et al. 2023

Front. Biosci. (Landmark Ed)

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Background: Alpha-mannosidosis is a rare lysosomal storage disorder, caused by decreased activity of α-D-mannosidase. This enzyme is involved in the hydrolysis of mannosidic linkages in N-linked oligosaccharides. Due to the mannosidase defect, undigested mannoserich oligosaccharides (Man2GlcNAc -Man9GlcNAc) accumulating in cells are excreted in large quantities in urine. Methods: In this work, we determined the levels of urinary mannose-rich oligosaccharides in a patient subjected to novel enzyme replacement therapy. Urinary oligosaccharides were extracted using solid phase extraction (SPE), labeled by fluorescent tag 2-aminobenzamide, and quantified by high-performance liquid chromatography (HPLC) with fluorescence detector (FLD). The identity of peaks was determined by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometry. In addition, the levels of urinary mannose-rich oligosaccharides were also quantified by 1 H nuclear magnetic resonance (NMR) spectroscopy. The data were analyzed using one-tailed paired t-test and Pearson's correlation tests. Results: Compared to levels before the administration of therapy, an approximately two-folds decrease in total mannose-rich oligosaccharides after one month of treatment was observed by NMR and HPLC. After four months, an approximately ten-folds significant decrease in total urinary mannose-rich oligosaccharides was detected, suggesting therapy effectiveness. A significant decrease in the levels of oligosaccharides with 7-9 mannose units was detected by HPLC. Conclusions: The application of both HPLC-FLD and NMR in quantification of oligosaccharide biomarkers is a suitable approach for monitoring of therapy efficacy in alpha-mannosidosis patients.

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Effect of velmanase alfa (human recombinant alpha-mannosidase) enzyme-replacement therapy on quality of life and disease burden of patients with alpha-mannosidosis: Results from caregiver feedback

Cited by 4 publications

References 0 publications

Long‐term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha‐mannosidosis: A phase 2, open label, multicenter study

Long‐term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha‐mannosidosis: A phase 2, open label, multicenter study

Biochemical characteristics of point mutated <i>Capra hircus</i> lysosome α-mannosidase

The Application of HPLC-FLD and NMR in the Monitoring of Therapy Efficacy in Alpha-Mannosidosis

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