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New Drug Approvals 2014 - Pt. I Elosulfase Alfa (Vimizim™)


 ATC code: A16AB12
ChEMBL: CHEMBL2108676

On February 14, 2014, the FDA approved elosulfase alfa for the treatment of Mucopolysaccharidosis Type IVA (Morquio A syndrome). Elosulfase alfa is intended to replace the missing GALNS enzyme involved in an important metabolic pathway. Absence of this enzyme leads to problems with bone development, growth and mobility.

Mucopolysaccharidoses comprise a group of lysosomal storage disorders caused by the deficiency of
specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis IVA (MPS IVA, Morquio A Syndrome) is characterized by the absence or marked reduction in N-acetylgalactosamine-6-sulfatase activity. The sulfatase activity deficiency resultsin the accumulation of the GAG substrates, KS and C6S, in the lysosomal compartment of cells throughout the body. The accumulation leads to widespread cellular, tissue, and organ dysfunction. It is a rare autosomal recessive disease, affecting approximately 800 people in the US, and significantly shortens life expectancy, with most patients dying at an early age. Sulfonase alfa is the first approved treatment for Morquio A syndrome.

Elosulfase alfa is intended to provide the exogenous enzyme N-acetylgalactosamine-6-sulfatase that will be taken up into the lysosomes and increase the catabolism of the GAGs KS and C6S. Elosulfase alfa uptake by cells into lysosomes is mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of elosulfase alfa to mannose-6-phosphate receptors.

 
N-acetylgalactosamine-6-sulfatase homodimer (from PDB 4FDI)
Elosulfase alfa is a soluble glycosylated dimeric protein with two oligosaccharide chains per monomer. Each monomeric peptide chain contains 496 amino acids and has an approximate molecular mass of 55 kDa (59 kDa including the oligosaccharides). One of the oligosaccharide chains contains bis-mannose­ 6-phosphate (bisM6P). bisM6P binds a receptor at the cell surface and the binding mediates cellular uptake of the protein to the lysosome. 

Its sequence is the following:

>Elosulfase-alfa
APQPPNILLLLMDDMGWGDLGVYGEPSRETPNLDRMAAEGLLFPNFYSAN
PLCSPSRAALLTGRLPIRNGFYTTNAHARNAYTPQEIVGGIPDSEQLLPE
LLKKAGYVSKIVGKWHLGHRPQFHPLKHGFDEWFGSPNCHFGPYDNKARP
NIPVYRDWEMVGRYYEEFPINLKTGEANLTQIYLQEALDFIKRQARHHPF
FLYWAVDATHAPVYASKPFLGTSQRGRYGDAVREIDDSIGKILELLQDLH
VADNTFVFFTSDNGAALISAPEQGGSNGPFLCGKQTTFEGGMREPALAWW
PGHVTAGQVSHQLGSIMDLFTTSLALAGLTPPSDRAIDGLNLLPTLLQGR
LMDRPIFYYRGDTLMAATLGQHKAHFWTWTNSWENFRQGIDFCPGQNVSG
VTTHNLEDHTKLPLIFHLGRDPGERFPLSFASAEYQEALSRITSVVQQHQ
EALVPAQPQLNVCNWAVMNWAPPGCEKLGKCLTPPESIPKKCLWSH

The recommended dose is 2mg per kg given intravenously over a minimum range of 3.5 to 4.5 hours, based on infusion volume, once every week. Pre-treatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion. The mean AUC0-t at first administration is 238 min x μg/mL, but increases to 577 by week 22 of treatment, likely due to the development of neutralising antibodies. The mean elimination half-life likewise was measured as 7.52 min at first dosage, and 35.9 min at week 22 of treatment.

Elosulfase alfa comes with a boxed warning for potentially life-threatening anaphylactic reactions in some patients.

The license holder for Vimizim™is BioMarin, and the full prescribing information can be found here.

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