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The Biochemical Basis of MPS VI

MPS VI is caused by an inherited deficiency in the enzyme N‐acetylgalactosamine‐4‐sulfatase (arylsulfatase B or ASB).1

ASB regulates the catabolism of a glycosaminoglycan (GAG) called dermatan sulfate and is one of 5 enzymes necessary for stepwise degradation of dermatan sulfate.1

  • GAGs have important roles in cellular structure and cell interactions, especially in connective tissue and its extracellular matrix2

GAG accumulation in MPS VI

In the absence of ASB, partially degraded GAGs accumulate in cell lysosomes.3

healthy cell

Healthy cell

MPS cell excess Gag

Lysosomal storage disorder cell full of GAGs

  • Replete with excess GAGs, lysosomes crowd the nucleus and other critical organelles, engorging the cell
  • This leads to cellular malfunction, multisystemic organ damage, and an extensive range of symptoms1,4

GAGs are a major component of connective tissues and organs throughout the body, including vessel linings, bone marrow, heart, lung, liver, and spleen stroma. As a result, MPS VI affects many organ systems.4,5

Learn more about the different ways MPS VI affects organ systems »

References:

  1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet al, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw‐Hill; 2001:3421‐3452.
  2. Aquino R S et al. Academic Press 2010; 93: 373-394.
  3. Swiedler SJ, Beck M, Bajbouj M, et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux‐Lamy syndrome). Am J Med Genet A. 2005;134A(2):144-150.
  4. Akyol MU, Alden TD, Amartino H, et al. Recommendations for the management of MPS VI: systematic evidence- and consensus-based guidance. Orphanet J Rare Dis. 2019;14(1):118.
  5. MPS VI https://medlineplus.gov/genetics/condition/mucopolysaccharidosis-type-vi/ Accessed May 2023

INDICATION AND IMPORTANT SAFETY INFORMATION

WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS
Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. These reactions have occurred during and up to 24 hours after completion of the NAGLAZYME infusion. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.

Administration of NAGLAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions, including anaphylaxis.

Initiate NAGLAZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue NAGLAZYME and immediately initiate appropriate medical treatment, including use of epinephrine. In patients who have experienced anaphylaxis or other severe allergic reactions during infusion with NAGLAZYME, caution should be exercised upon rechallenge. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur.

Immune-Mediated Reactions
As with other enzyme replacement therapies, immune-mediated reactions, including membranous glomerulonephritis have been observed. If immune-mediated reactions occur, consider discontinuing Naglazyme administration and initiate appropriate medical treatment. Consider the risks and benefits of re-administering Naglazyme following an immune-mediated reaction. Some patients have successfully been rechallenged and have continued to receive Naglazyme under close clinical supervision.

Risk of Acute Cardiorespiratory Failure
Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload because congestive heart failure may result. Consider a decreased total infusion volume and infusion rate when administering NAGLAZYME to these patients.

Acute Respiratory Complications Associated with Administration
Consideration to delay NAGLAZYME infusion should be given when treating patients who present with an acute febrile or respiratory illness. Sleep apnea is common in MPS VI patients and antihistamine pretreatment may increase the risk of apneic episodes. Evaluation of airway patency should be considered prior to the initiation of treatment. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction, or extreme drowsiness/sleep induced by antihistamine use.

Infusion Reactions
Pretreatment with antihistamines with or without antipyretics is recommended prior to the start of infusion to reduce the risk of infusion reactions. If infusion reactions occur, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antihistamines and/or antipyretics is recommended.

Spinal or Cervical Cord Compression
Spinal/cervical cord compression is a known and serious complication that is expected to occur during the natural course of MPS VI. Signs and symptoms of spinal/cervical cord compression include back pain, paralysis of limbs below the level of compression, and urinary or fecal incontinence. Patients should be evaluated for spinal/cervical cord compression prior to initiation of NAGLAZYME to establish a baseline and risk profile. Patients treated with NAGLAZYME should be regularly monitored for the development or progression of spinal/cervical cord compression and be given appropriate clinical care.

Adverse Reactions
During infusion, serious adverse reactions included laryngeal edema, apnea, pyrexia, urticaria, respiratory distress, angioedema, and anaphylactoid reaction; severe adverse reactions included urticaria, chest pain, rash, abdominal pain, dyspnea, apnea, laryngeal edema, and conjunctivitis. The most common adverse events (≥10%) observed in clinical trials in patients treated with NAGLAZYME were rash, pain, urticaria, pyrexia, pruritus, chills, headache, nausea, vomiting, abdominal pain and dyspnea. The most common adverse reactions requiring interventions are infusion-related reactions.

 

To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-888-906-6100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information with Boxed Warning for risk of anaphylaxis or visit www.Naglazyme.com.

What is NAGLAZYME used for?
NAGLAZYME® (galsulfase) is indicated for patients with mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome). NAGLAZYME has been shown to improve walking and stair-climbing capacity