elosulfase alfa - Vimizim; N-acetylgalactosamine-6-sulfatase; BMN-110, elosulfase alfa; rhGALNS; chondroitin sulfatase; rhGALNS
Status - BLA approved in Feb. 2014; pending in EU
Organizations involved:
BioMarin Pharmaceutical – Manuf.; R&D; Tech.; World mark.
Description: Vimizim is a formulation of a elosulfase alfa or recombinant N-acetylgalactosamine-6-sulfatase (rhGALNS) dimer, expressed in Chinese hamster ovary (CHO-K1) cells.
The rhGALNS has the same amino acid sequence and asparagine-linked glycosylation sites as the human enzyme. Oligosaccharides contain
mannose-6-phosphate moieties.
Elosulfase alfa has a calculated molecular formula of C5020H7588N1364O1418S34, with a molecular weight of 110.8 kDa. Disulfide bridges are at:
139-139':
282-393;
282'-393';
463-492;
463'-492';
475-481; and
475'-481'.
Glycosylation sites (N) are at:
Asn-178;
Asn-178';
Asn-397; and
Asn-397'.
Nomenclature: Vimizim [TR];
elosulfase alfa [INN];
N-acetylgalactosamine-6-sulfatase [SY];
Human N-acetylgalactosamine-6-sulfatase (chondroitinsulfatase, galactose-6-sulfate sulfatase, EC=3.1.6.4) dimer (139-139')-disulfide glycosylated (produced by CHO cells) [CAS];
9025-60-9 [CAS RN];
BMN-110 [SY];
chondroitin sulfatase [SY];
rhGALNS [SY]
Biological: Elosulfase alpha (rhGALNS) is transported to
lysosomes where it is active at the lysosomal pH.
Company: Vimizim was developed and is manufactured by BioMarin Pharmaceutical.
Ongoing production of bulk drug substance and drug product while applications were still pending was undertaken to allow for a global launch following approvals in multiple countries.
FDA class: Biologics BLA
Status: BioMarin filed its BLA and MAA in April 2013. The BLA sought approval as an enzyme replacement therapy under evaluation for the treatment of patients with the rare lysosomal storage disorder Mucopolysaccharidosis Type IVA (MPS IVA), also called Morquio A Syndrome.
The FDA granted Vimizim priority review designation. During the initial review of the application, the FDA requested additional Chemistry, Manufacturing and Controls (CMC) information. The company provided the information, and the FDA designated it as a major amendment to the application thus extending the PDUFA action date by three months. The extended PDUFA action date is Fen. 28, 2014. An advisory committee meeting will be held prior to approval.
The EMA was filed in April 2013 and granted accelerated review status.
Vimizim has received orphan designation in the U.S. and EU.
FDA approval of VIMIZIM not only marked the first approved product for Morquio A syndrome, a rare, severely debilitating and progressive disease that previously had no standard accepted treatment other than supportive care, but also the first time a company has secured a Rare Pediatric Disease Priority Review Voucher (“Pediatric PRV”).
Disease: Mucopolysaccharidosis IVA is a severely debilitating and progressive disease for which there is no current treatment. Mucopolysaccharidosis IVA (MPS IVA, also known as Morquio A Syndrome) is a disease characterized by deficient activity of N-acetylgalactosamine-6-sulfatase (GALNS) causing excessive lysosomal storage of glycosaminoglycans such as keratan sulfate and chondroitin sulfate. This excessive storage causes a systemic skeletal dysplasia, short stature, and joint abnormalities, which limit mobility and endurance. Malformation of the chest impairs respiratory function, and looseness of joints in the neck cause spinal instability and potentially spinal cord compression. Other symptoms may include hearing loss, corneal clouding, and heart disease. Initial symptoms often become evident in the first five years of life. The disease substantially limits both the quality and length of life of those affected.
MPS IVA is a rare inherited autosomal recessive disorder. Mutations cause a deficiency in the lysosomal enzyme
N-acetylgalactosamine-6-sulfatase (GALNS). As a result, Keratan Sulfate (KS) and other glycosaminoglycans
(GAGs) accumulate in the lysosomes of multiple tissues. Multisystemic clinical impairments result including:
• Decreased mobility and endurance
• Impaired respiratory function
• Reduced quality of life; and
• Early mortality
The rate of incidence of MPS IVA is as yet unconfirmed and varies among different populations but estimates vary between 1 in 200,000 live births and 1 in 250,000 live births. The estimated prevalence is between 1,000 and 1,500 patients in the U.S., EU and Japan and between 1,500 to 2,000 patients in the rest of the world for a total of 2,500 to 3,000 patients.
Tech. transfer: Patent applications assigned to BioMarin include U.S. 20120189605 filed Jul. 22, 2010 concerning methods for manufacture of active highly phosphorylated recombinant human N-acetylgalactosamine-6-sulfatase. Related patents include:
U.S., 6,866,844 and 6,972,124, "Precursor of N-acetylgalactosamine-4-sulfatase, methods of treatment using said enzyme and methods for producing and purifying said enzyme."
U.S. 6,972,124;
U.S. 8,420,368, "Manufacture of active highly phosphorylated human lysosomal sulfatase enzymes and uses thereof;" and
U.S. 8,128,925, "Manufacture of active highly phosphorylated human lysosomal sulfatase enzymes and uses thereof ,"
Trials: Topline results from the MOR-004 PIII study were reported in Nov. 2012. MOR-004 was the largest enzyme replacement therapy (ERT) study done to date with a total of 176 patients enrolled.
The randomized, double-blind study evaluated GALNS at 2mg/kg/week and 2mg/kg/every other week in 176 patients with Mucopolysaccharidosis Type IVA (Morquio A Syndrome). The study met the primary endpoint with a mean increase of 22.5 meters in six-minute walk distance vs placebo at 24 weeks in subjects on GALNS weekly (p=0.0174); GALNS given every 2 weeks did not differ from placebo. The weekly dose also showed a trend in improvement in a number of secondary endpoints. GALNS demonstrated statistical significance in one secondary endpoint – consistent reduction in the urinary keratan sulfate biomarker – and a trend toward improvement in another – the three-minute stair climb.
The most common adverse events occurring in >25% of treated patients included vomiting, pyrexia, headache, nausea and cough. Serious AEs thought to be drug-related occurred in 3.4% of the weekly group, 1.7% of the every other week group and 0% in the placebo group. There were no deaths and no patients withdrew from the study due to an AE. Preliminary data from the MOR-005 extension study suggest that clinical benefits continue to improve with further dosing with GALNS, but only a limited number of patients have reached the 36 or 48 week points. A separate arm of the MOR-004 trial testing a less frequent dosing schedule – 2 mg/kg every other week – failed to show a statistically significant improvement.
Market: Prior to approval, Jefferies' analysts assumed a $330,000 per-year cost, with peak sales of about $600 million in 2019, while Deutsche Bank analysts predicted peak worldwide sales of about $640 million with an annual cost per patient of about $350,000.
Whatever the pricing of Vimizim, approval is expected to take BioMarin to profitability, with sales revenue from Vimizimd anticipated to double the company's top-line earnings.
Index Terms:
Companies involvement:
Full monograph
231.1 N-acetylgalactosamine-6-sulfatase, rDNA
Nomenclature:
Vimizim [TR]
elosulfase alfa [INN]
N-acetylgalactosamine-6-sulfatase [SY]
Human N-acetylgalactosamine-6-sulfatase (chondroitinsulfatase, galactose-6-sulfate sulfatase, EC=3.1.6.4) dimer (139-139')-disulfide glycosylated (produced by CHO cells) [CAS]
9025-60-9 [CAS RN]
BMN-110 [SY]
chondroitin sulfatase [SY]
rhGALNS [SY]
molecular weight (kDa) = 110.8
FDA Class: Biologics BLA
biopharmaceutical products
hamster source materials
recombinant DNA
Chinese hamster ovary (CHO) cells
chlortetracycline
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
orphan status
priority review status
radioimmune conjugates<!-- radioconjugates -->
EU002 EU application pending
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
Copyright© 2020, Biotechnology Information Institute