Velmanase alfa-tycv

Alpha-mannosidosis is an ultra-rare lysosomal disease that is caused by variants of the MAN2B1 gene on chromosome 19p13. These variants result in faulty or absent alpha-mannosidase in lysosomes, which leads to intracellular accumulation of mannose-containing oligosaccharides. Diagnosis of alpha-mannosidosis is often delayed, in part because of the rarity of the disease, its gradual onset and heterogeneity of presentation, but also because of the similarity of many signs and symptoms of the disease to those of other lysosomal diseases. Treatment of alpha-mannosidosis was previously limited to hematopoietic stem cell transplantation, but outcomes are variable and not all patients are eligible or have a suitable donor. Recently, an enzyme replacement therapy, recombinant human alpha-mannosidase (velmanase alfa), was approved for the treatment of non-neurological manifestations in adult and pediatric patients with alpha-mannosidosis. Treatment with velmanase alfa reduces serum levels of oligosaccharides, increases levels of immunoglobulin G, and improves patients' functional capacity and quality of life, although it is not effective for the neurologic phenotype because it does not cross the blood-brain barrier. Since the effects of velmanase alfa are more marked in children than adults, early diagnosis to allow early initiation of treatment has become more important. To support this, patient, parent/caregiver, and clinician awareness and education is imperative. A number of approaches can be taken to meet this goal, such as the development of disease registries, validated diagnostic algorithms, and screening tools, improved under-/post-graduate clinician education, easily accessible and reliable information for patients/families (such as that made available on the internet), and the formation of patient advocacy groups. Such approaches may raise awareness of alpha-mannosidosis, reduce the diagnostic delay and thus improve the lives of those affected.

Disclaimer: This therapeutics bulletin is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. It is reflective of information available at the time of acceptance to publication and may not include newer updates that have since become available. Adherence to this therapeutics bulletin is completely voluntary and does not necessarily assure a successful medical outcome. This therapeutics bulletin should not be considered inclusive of all proper procedures, treatments, and tests or exclusive of other procedures, treatments, and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure, treatment or test, clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.Clinicians are encouraged to document the reasons for the use of a particular procedure, treatment, or test, whether or not it is in conformance with this therapeutics bulletin. Clinicians also are advised to take notice of the date this therapeutics bulletin was accepted to publication, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Where individual authors are listed, the views expressed may not reflect those of authors' employers or affiliated institutions.The mention of any therapeutic approach, product, or sponsor in this therapeutics bulletin does not constitute endorsement or sponsorship by the American College of Medical Genetics and Genomics (ACMG). The ACMG does not endorse or recommend any specific therapeutic approach or product mentioned in this therapeutics bulletin. Disclaimer: This therapeutics bulletin is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. It is reflective of information available at the time of acceptance to publication and may not include newer updates that have since become available. Adherence to this therapeutics bulletin is completely voluntary and does not necessarily assure a successful medical outcome. This therapeutics bulletin should not be considered inclusive of all proper procedures, treatments, and tests or exclusive of other procedures, treatments, and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure, treatment or test, clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure, treatment, or test, whether or not it is in conformance with this therapeutics bulletin. Clinicians also are advised to take notice of the date this therapeutics bulletin was accepted to publication, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Where individual authors are listed, the views expressed may not reflect those of authors' employers or affiliated institutions. The mention of any therapeutic approach, product, or sponsor in this therapeutics bulletin does not constitute endorsement or sponsorship by the American College of Medical Genetics and Genomics (ACMG). The ACMG does not endorse or recommend any specific therapeutic approach or product mentioned in this therapeutics bulletin. Alpha-mannosidosis is an autosomal recessive lysosomal disorder caused by pathogenic variants in MAN2B1, which leads to deficient or absent acid alpha-mannosidase enzyme activity. Alpha-mannosidase hydrolyzes terminal residues of alpha-D-mannosides during glycoprotein degradation. Deficient enzyme activity results in the accumulation of oligosaccharides or glycopeptides in lysosomes, thus impairing lysosomal function and harming cellular functions, such as autophagy, exocytosis, and calcium and pH regulation.1Schultz M.L. Tecedor L. Chang M. Davidson B.L. Clarifying lysosomal storage diseases.Trends Neurosci. 2011; 34: 401-410https://doi.org/10.1016/j.tins.2011.05.006Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar Affected individuals may present with a spectrum of symptoms, including hearing loss, progressive myopathy, coarse facial features, skeletal abnormalities, and immune deficiency. Central nervous system traits include intellectual disability and cerebellar ataxia. Alpha-mannosidosis may be categorized into 3 subtypes—mild, moderate, and severe forms; however, the clinical manifestations fall along a continuum of disease severity. Except for the severe early lethal form, progression can be insidious with some individuals living into the sixth decade of life.2Malm D. Nilssen Ø. Alpha-mannosidosis.in: Adam M.P. Feldman J. Mirzaa G.M. GeneReviews [Internet]. University of Washington, 2019Google Scholar No management guidelines have been published for alpha-mannosidosis. Surveillance may include skeletal assessments to include pain and range of motion, audiometry and otolaryngology screening to evaluate for hearing loss and ear infections, neuropsychological testing, ophthalmologic exams, and regular multi-systemic monitoring by a physician. Signs and symptoms are treated per standard of care.2Malm D. Nilssen Ø. Alpha-mannosidosis.in: Adam M.P. Feldman J. Mirzaa G.M. GeneReviews [Internet]. University of Washington, 2019Google Scholar Before 2023, there were no US Food and Drug Administration (FDA)-approved therapies for alpha-mannosidosis. Bone marrow transplantation has been utilized with variable improvement in neurocognitive function and stabilization in several clinical parameters. However, transplant also carries a high risk of complications or even death.3Ceccarini M.R. Codini M. Conte C. et al.Alpha-mannosidosis: therapeutic strategies.Int J Mol Sci. 2018; 19: 1500https://doi.org/10.3390/ijms19051500Crossref Scopus (37) Google Scholar,4Mynarek M. Tolar J. Albert M.H. et al.Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients.Bone Marrow Transplant. 2012; 47: 352-359https://doi.org/10.1038/bmt.2011.99Crossref PubMed Scopus (62) Google Scholar Velmanase alfa-tycv (trade name: LAMZEDE) is an enzyme replacement therapy approved by the FDA for treatment of non-central nervous system manifestations of alpha-mannosidosis in adult and pediatric patients. Velmanase alfa received orphan drug designation and FDA approval was obtained via the regular (non-accelerated) approval pathway. It was approved by the European Medicines Agency in 2018. Velmanase alfa is a recombinant human alpha-mannosidase protein with conjugated mannose-6-phosphate (M6P) residues (0.4-0.8 mol M6P/mol enzyme) that is internalized via binding to the M6P receptor on the cell surface and transported into lysosomes where it catalyzes the degradation of mannose-containing oligosaccharides. It is administered as an intravenous infusion once weekly.5Highlights of prescribing information. LAMZEDE (velmanase alfa-tycv) for injection, for intravenous use. United States Food and Drug Administration.https://www.fda.gov/media/165488/download?attachmentDate accessed: November 30, 2023Google Scholar Velmanase alfa was evaluated in a phase III multicenter, double anonymized, randomized, placebo-controlled trial of 25 individuals ages 5 to 35 years with the co-primary endpoints of change in serum oligosaccharides (S-oligo) and the 3-minute stair-climb test (3MSCT). After 52 weeks, the treatment group demonstrated a statistically significant improvement in S-oligo clearance. No statistically significant changes in motor or pulmonary function were detected, although there were trends toward improved 3MSCT, 6 minute walk test (6MWT), and forced vital capacity (FVC) (% predicted), particularly in the pediatric cohort.6Borgwardt L. Guffon N. Amraoui Y. et al.Efficacy and safety of velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial.J Inherit Metab Dis. 2018; 41: 1215-1223https://doi.org/10.1007/s10545-018-0185-0Crossref Scopus (33) Google Scholar Integrated data of 33 individuals from the phase I/II and III trials and rhLAMAN-07 (NCT01908712), rhLAMAN-09 (NCT01908725), and rhLAMAN-10 (NCT02478840) studies demonstrated statistically significant improvements in S-oligo clearance, 3MSCT, 6MWT, and FVC after a mean treatment exposure of 29.3 months.7Lund A.M. Borgwardt L. Cattaneo F. et al.Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis.J Inherit Metab Dis. 2018; 41: 1225-1233https://doi.org/10.1007/s10545-018-0175-2Crossref Scopus (34) Google Scholar Improvements in S-oligo clearance, hearing, serum immunoglobulin levels, and/or quality of life were seen in a phase II study with 5 children under 6 years of age.8Guffon N. Konstantopoulou V. Hennermann J.B. et al.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.J Inherit Metab Dis. 2023; 46: 705-719https://doi.org/10.1002/jimd.12602Crossref Scopus (4) Google Scholar Velmanase alfa carries a boxed warning of hypersensitivity reactions including anaphylaxis. Hypersensitivity reactions were reported in 36% of adults and 58% of pediatric participants. The most common symptoms included nasopharyngitis, pyrexia, headache, and arthralgia. One individual was withdrawn from the clinical trial because of repeated infusion-associated reactions and resumed treatment after 89 weeks. Major visceral malformations were observed when velmanase alfa was administered to pregnant animals.5Highlights of prescribing information. LAMZEDE (velmanase alfa-tycv) for injection, for intravenous use. United States Food and Drug Administration.https://www.fda.gov/media/165488/download?attachmentDate accessed: November 30, 2023Google Scholar There are no human data on velmanase alfa use in pregnant people. At the time of this writing, there are ongoing clinical trials for the neurologic symptoms of alpha-mannosidosis, including augmented stem cell transplantation (NCT02254863),9Kurtzberg J. UCB transplant of inherited metabolic diseases with administration of intrathecal UCB derived oligodendrocyte-like cells (DUOC-01); ClinicalTrials.gov.https://www.clinicaltrials.gov/study/NCT02254863Date accessed: November 30, 2023Google Scholar in which umbilical cord blood-derived oligodendrocyte-like cells are administered intrathecally to individuals with metabolic disorders undergoing standard treatment with umbilical cord blood transplantation. Likewise, NCT0217110410Masonic Cancer Center, University of MinnesotaAllo HCT for metabolic disorders and severe osteopetrosis. ClinicalTrials.gov.https://clinicaltrials.gov/study/NCT02171104Date accessed: November 30, 2023Google Scholar is evaluating busulfan- and fludarabine-based conditioning regimens to try and improve the engraftment of donor hematopoietic stem cell transplant. Preclinical animal studies investigating molecular chaperones11Rísquez-Cuadro R. Matsumoto R. Ortega-Caballero F. et al.Pharmacological chaperones for the treatment of α-mannosidosis.J Med Chem. 2019; 62: 5832-5843https://doi.org/10.1021/acs.jmedchem.9b00153Crossref Scopus (24) Google Scholar or gene therapy12Yoon S.Y. Hunter J.E. Chawla S. et al.Global CNS correction in a large brain model of human alpha-mannosidosis by intravascular gene therapy.Brain. 2020; 143: 2058-2072https://doi.org/10.1093/brain/awaa161Crossref Scopus (13) Google Scholar for alpha-mannosidosis have also been published. V. Reid Sutton has consulted with Chiesi to develop educational materials for alpha-mannosidosis. All other authors declare no conflicts of interest. The authors would like to thank Sandor Roberts, Sheri Poskanzer, Loren Pena, and Lindsay Burrage from the ACMG Therapeutics Committee who helped with the selection of the authors and the review of the final manuscript.