Iduronidase

Iduronidase (, L -iduronidase, α- L -iduronidase, laronidase), sold as Aldurazyme, is an enzyme with the systematic name glycosaminoglycan α- L -iduronohydrolase.[1][2][3] It catalyses the hydrolysis of unsulfated α- L -iduronosidic linkages in dermatan sulfate.[4]

It is a glycoprotein enzyme found in the lysosomes of cells. It is involved in the degeneration of glycosaminoglycans such as dermatan sulfate and heparan sulfate. The enzyme acts by hydrolyzing the terminal α- L -iduronic acid residues of these molecules, degrading them. The protein is reported as having a mass of approximately 83 kDa.[4]

Pathology

Aldurazyme

General

Aldurazyme is the name of the commercialized variant of the enzyme iduronidase, which hydrolyzes the α- L -iduronic acid residues of dermatan sulfate and heparin sulfate. Produced in Chinese hamster ovaries by recombinant DNA technology, Aldurazyme is manufactured by BioMarin Pharmaceutical Inc. and distributed by Genzyme Corporation (a subsidiary of Sanofi). Aldurazyme is administered as a slow intravenous infusion. The recombinant enzyme is 628 amino acids in length with 6 N-linked oligosaccharide modification sites and two oligosaccharide chains terminating in mannose sugars.[4]

Medical uses

Aldurazyme is indicated in the US for people with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for people with the Scheie form who have moderate to severe symptoms.[8]

Aldurazyme is indicated in the EU for long-term enzyme replacement therapy in patients with a confirmed diagnosis of mucopolysaccharidosis I (MPS I; α- L -iduronidase deficiency) to treat the nonneurological manifestations of the disease.[9]

Aldurazyme was approved for medical use in the United States and in the European Union in 2003.[10][11][8][9]

Pre-clinical work

Dosing for human clinical studies was based on canine MPS I studies.[12]

Clinical trials

Three clinical trials were performed to establish the pharmacology, efficacy, and safety of weekly intravenous administration of the drug. These studies included a Phase I open-label study, a Phase III randomized, double-blind, placebo-controlled study, and a Phase III open-label extension study. A Phase II Young Pediatric study was also conducted.[12]

Clinical trials and post-market safety data indicate that the most common adverse side effect of Aldurazyme is allergic reaction.[12] In order to prevent allergic reaction and respiratory distress, the packet insert of Aldurazyme suggests that patients be administered antihistamines before infusion.[12] Allergic reaction occurs in approximately 1% of patients. It is recommended that patients who are high-risk for respiratory distress be given their infusion in a facility equipped to deal with an anaphylactic response.[12] (High-risk factors include sleep apnea, respiratory impairment, respiratory illness, or previous experience with allergic reaction to Aldurazyme. It is noted that risk-benefit must be weighed for patients with history of severe allergic response as to whether the drug should be administered again.)[12]

Regulation

Aldurazyme was the first drug approved by the United States Food and Drug Administration to be marketed as a treatment for MPS I. It was approved in April 2003. Marketing authorization in the European Union was granted in June 2003 by the European Commission. Aldurazyme enjoys orphan drug status in both the United States and the European Union, though in both its orphan drug exclusivity period has expired. (Orphan drug exclusivity, which prevents the FDA or similar European body from approving the same drug proposed by another company for the same listed use lasts only seven years in the United States and ten years in the European Union.) Aldurazyme was granted orphan designation for Treatment of patients with mucopolysaccharidosis-I on 24 September 1997.[15][16][17]

As of 2014, Aldurazyme was mandated to be produced using Good Manufacturing Practices (GMP) and, along with several other recombinant enzyme products produced by Biomarin, was manufactured at the production facility located in Novato, California. Both packaging and vialing were performed by contractors. All suppliers and contractors also are mandated to follow GMP, and they, as well as BioMarin, are subject to inspection and review. BioMarin's facility has received both FDA and European Commission approval.[18]

usan	Laronidase
jan	Laronidase (genetical recombination)
tradename	Aldurazyme
dailymedid	Laronidase
pregnancy au	B2
pregnancy au comment	‡R6R‡
routes of administration	Intravenous
atc prefix	A16
atc suffix	AB05
legal uk	POM
legal uk comment	‡R7R‡
legal us	Rx-only
legal eu	Rx-only
legal status	Rx-only
cas number	210589-09-6
drugbank	DB00090
unii	WP58SVM6R4
kegg	D04670
chembl	1201595
synonyms	alpha-L-Idosiduronase
c	3567
h	5645
n	921
o	1261
s	12
p	4