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Iduronidase

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iduronidase, α-L-
Identifiers
SymbolIDUA
NCBI gene3425
HGNC5391
OMIM252800
RefSeqNM_000203
UniProtP35475
Other data
EC number3.2.1.76
LocusChr. 4 p16.3
Search for
StructuresSwiss-model
DomainsInterPro
Laronidase
INN: Laronidase
Clinical data
Trade namesAldurazyme
Other namesalpha-L-Idosiduronase, Laronidase (genetical recombination) (JAN) (JAN JP)
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		Intravenous (IV)
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)[3]
  • US: WARNING[2]Rx-only
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC3567H5645N921O1261P4S12
Molar mass82117.20 g·mol−1

Iduronidase (EC 3.2.1.76, L-iduronidase, alpha-L-iduronidase, laronidase), sold as Aldurazyme, is an enzyme with the systematic name glycosaminoglycan alpha-L-iduronohydrolase.[4][5][6] This enzyme catalyses the hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate.[7]

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 alpha-L-iduronic acid residues of these molecules, degrading them. The protein is reported as having a mass of approximately 83 kilodaltons.[7]

Pathology

A deficiency in the IDUA protein is associated with mucopolysaccharidoses (MPS). MPS, a type of lysosomal storage disease, is typed I through VII. Type I is known as Hurler syndrome and type I,S is known as Scheie syndrome, which has a milder prognosis compared to Hurler's. In this syndrome, glycosaminoglycans accumulate in the lysosomes and cause substantial disease in many different tissues of the body. IDUA mutations result in the MPS 1 phenotype, which is inherited in an autosomal recessive fashion.[8] The defective alpha-L-iduronidase results in an accumulation of heparan and dermatan sulfate within phagocytes, endothelium, smooth muscle cells, neurons, and fibroblasts. Under electron microscopy these structures present as laminated structures called Zebra bodies.

Prenatal diagnosis of this enzyme deficiency is possible.

Aldurazyme

General

Aldurazyme is the name of the commercialized variant of the enzyme iduronidase, which hydrolyzes the alpha-L-iduronic acid residues of dermatan sulfate and heparin sulfate. Produced in Chinese hamster ovaries by recombinant DNA technology, Aldurazyme is the 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.[7]

Medical use

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.[9]

Aldurazyme is indicated in the EU for long-term enzyme replacement therapy in patients with a confirmed diagnosis of mucopolysaccharidosis I (MPS I; alpha-L-iduronidase deficiency) to treat the nonneurological manifestations of the disease.[10]

Aldurazyme was approved for medical use in the United States and in the European Union in 2003.[11][12][9][10]

Pre-clinical work

Dosing for human clinical studies was based on canine MPS I studies.[13]

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 2 Young Pediatric study was also conducted.[13]

Clinical trials and post-market safety data indicate that the most common adverse side effect of Aldurazyme is allergic reaction.[13] In order to prevent allergic reaction and respiratory distress, the packet insert of Aldurazyme suggests that patients be administered antihistamines before infusion.[13] 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.[13] (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.)[13] In a 2002 memorandum, Melanie Hartsough, Ph.D., DTP of the FDA's Department of Health and Human Services stated, "Aggregation of product could enhance immune responses, specifically neutralizing antibody, which may limit the response to therapy, whereas highly deaggregated product may induce immune tolerance." It appears that she then went on to ask for further justification of some relevant aspect of the production process, though the majority of this particular memorandum has not been publicly released and it is unclear as to whether this concern is relevant to the high rate of allergic response to this drug.[14]

Additionally, it is recommended that patients be administered antipyretics before use. According to Aldurazyme's website, the most common adverse effects observed in a 26-week, placebo-controlled clinical trial of patients 6 years old or older are flushing, pyrexia, headache, and rash. Flushing was noted in 23% of patients, or five people, in this relatively small clinical study. This trial was extended. In the extension, it was noted that abdominal pain and infusion-site reaction occurred in some patients.[13]

The website also states that in a 52-week open-label uncontrolled clinical trial, the most common serious reactions in children younger than 6 were "otitis media (20%), and central venous catherization required for ALDURAZYME infusion (15%). The most commonly reported adverse reactions in patients 6 years and younger were infusion reactions reported in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), blood pressure increased (10%), tachycardia (10%), and oxygen saturation decreased (10%). Other commonly reported infusion reactions occurring in ≥5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritus, and rash."[13]

A phase-four clinical trial is currently[when?] recruiting participants to investigate whether Aldurazyme passes through breastmilk and whether it has any effect on nursing infants.[15] [needs update]

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 September 24, 1997.[16][17][18]

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.[19]

Commercialization plan

Aldurazyme is manufactured by BioMarin in California. It is commercialized and distributed by Genzyme in the United States, the European Union, and worldwide.[16] The patent for Aldurazyme was filed by BioMarin on November 12, 1999, patent no. US 6426208 B1, "Recombinant α-L-iduronidase, methods for producing and purifying the same and methods for treating diseases caused by deficiencies thereof".[20]

BioMarin reported their common stock to be $.001 par value at the conclusion of the 2014 fiscal year. Aldurazyme yielded a net $105.6 million net product revenue out of $738.4 million in net profit revenues in 2014, $83.6 million out of $538.4 million in 2013, and $82.2 million out of $496.5 million in 2012, making it BioMarin's third-most profitable product behind Naglazyme and Kuvan.[19] In 2011, Aldurazyme yielded a net product revenue of $82.8 million out of $437.6 million net revenue, and in 2010 it netted $71.2 million out of $369.7 million in net product revenues.[21] Aldurazyme netted $70.2 million in profit revenues in 2009 out of a total $315.7 $72.5 million in revenue were netted in 2008 out of Biomarin's $251.9 million in product revenues that year.[17][22]

BioMarin described its business strategy as the following in their 2014 United States Securities and Exchange Commission Form 10-K:

BioMarin Pharmaceutical Inc. (BioMarin, we, us or our) develops and commercializes innovative pharmaceuticals for serious diseases and medical conditions. We select product candidates for diseases and conditions that represent a significant unmet medical need, have well-understood biology and provide an opportunity to be first-to-market or offer a significant benefit over existing products.

— BioMarin Pharmaceuticals' 2014 United States Securities and Exchange Commission Form 10-K

Based on this business model, it is easy to understand why BioMarin would have targeted a disease like MPS I for treatment. It is, as described, an orphan condition with a well-defined mechanism. Furthermore, before the development of Aldurazyme, there were no drugs to treat MPS I, allowing BioMarin to be first-to-market with its new pharmaceutical. Since the release of Aldurazyme, one more drug has been released to treat MPS; Elaprase is a treatment for MPS II.

In 2016, Aldurazyme had an average cost-per-patient of $355,816.[23]

Collaboration between BioMarin and Genzyme

BioMarin/Genzyme is a 50/50 Limited Liability Company which co-owns the intellectual rights to Aldurazyme and works collaboratively on research and development. BioMarin is responsible for the production of Aldurazyme. It sells the finished product to Genzyme, which is a fully owned subsidiary of Sanofi. Genzyme pays a 39.5% - 50% royalty quarterly on worldwide net product sales to BioMarin. A portion of this royalty is considered to be product transfer royalties, meaning that if any Aldurazyme goes unsold, BioMarin merely retains the product transfer royalty, while not receiving any further royalties. Only in the case of defective product is Genzyme reimbursed for Aldurazyme product.[19]

References

  1. ^ a b "Laronidase (Aldurazyme) Use During Pregnancy". Drugs.com. 11 December 2019. Retrieved 14 April 2020.
  2. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  3. ^ "Aldurazyme 100 U/ml concentrate for solution for infusion - Summary of Product Characteristics (SmPC)". (emc). 2 January 2019. Retrieved 14 April 2020.
  4. ^ Matalon R, Cifonelli JA, Dorfman A (January 1971). "L-iduronidase in cultured human fibroblasts and liver". Biochemical and Biophysical Research Communications. 42 (2): 340–5. doi:10.1016/0006-291x(71)90108-2. PMID 4993544.
  5. ^ Rome LH, Garvin AJ, Neufeld EF (August 1978). "Human kidney alpha-L-iduronidase: purification and characterization". Archives of Biochemistry and Biophysics. 189 (2): 344–53. doi:10.1016/0003-9861(78)90221-7. PMID 30407.
  6. ^ Srivastava RM, Hudson N, Seymour FR, Weissman B (1978). "Preparation of (aryl α-L-idopyranosid)uronic acids". Carbohydr. Res. 60: 315–326. doi:10.1016/s0008-6215(78)80038-x.
  7. ^ a b c Aldurazyme (Laronidase). BioMarin Pharmaceuticals Inc. FDA website. Retrieved December 6, 2015.
  8. ^ Scott HS, Nelson PV, Litjens T, Hopwood JJ, Morris CP (September 1993). "Multiple polymorphisms within the alpha-L-iduronidase gene (IDUA): implications for a role in modification of MPS-I disease phenotype". Human Molecular Genetics. 2 (9): 1471–3. doi:10.1093/hmg/2.9.1471. PMID 8242073.
  9. ^ a b "Aldurazyme- laronidase injection, solution, concentrate". DailyMed. 12 December 2019. Retrieved 14 April 2020.
  10. ^ a b "Aldurazyme EPAR". European Medicines Agency (EMA). Retrieved 14 April 2020.
  11. ^ "Laronidase Product Approval Information - Licensing Action". U.S. Food and Drug Administration (FDA). 30 September 2016. Archived from the original on 18 January 2017. Retrieved 14 April 2020.
  12. ^ "Aldurazyme: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 14 April 2020.
  13. ^ a b c d e f g h "Clinical Trials Summary." Adurazyme (Laronidase) website. Accessed December 7, 2015.
  14. ^ Hartsough, Melanie (28 August 2002). "Aldurazyme CMC Product Review" (PDF). United States Food and Drug Administration. Archived from the original (PDF) on 22 November 2010. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  15. ^ "A Study of the Effect of Aldurazyme (Laronidase) Treatment on Lactation in Female Patients With Mucopolysaccharidosis I (MPS I) and Their Breastfed Infants". ClinicalTrials.gov. 5 January 2007. Retrieved 14 April 2020.
  16. ^ a b Aldurazyme (laronidase) for MPS I. Biomarin website. Accessed December 6, 2015.
  17. ^ a b United States Securities and Exchange Commission Form 10-K. BioMarin Pharmaceuticals. February 24, 2011. Accessed December 7, 2015.
  18. ^ FDA Orphan Drug Designations and Approvals. FDA website. Accessed December 15, 2015.
  19. ^ a b c United States Securities and Exchange Commission Form 10-K. BioMarin Pharmaceuticals. For the fiscal year ended December 31, 2014. Accessed December 6, 2015.
  20. ^ WO application 9958691, Kakkis ED, Tanamachi B, "Recombinant α-L-iduronidase, methods for producing and purifying the same and methods for treating diseases caused by deficiencies thereof", published 18 November 1999 =, assigned to Harbor UCLA 
  21. ^ United States Securities and Exchange Commission Form 10-K. BioMarin Pharmaceuticals. For the fiscal year ended December 31, 2012. Accessed December 6, 2015.
  22. ^ BioMarin Pharmaceutical (BMRN). wikinvest. Accessed on December 6, 2015.
  23. ^ https://www1.magellanrx.com/media/604882/2016mrxtrendreport_final.pdf

Further reading

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