Lysosomal Storage Disorder Treatments
Number: 0442
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Brand Selection for Medically Necessary Indications for Commercial Medical Plans
Gaucher Disease
As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. VPRIV is more costly to Aetna than other products for Gaucher Disease. There is a lack of reliable evidence that VPRIV is superior to the lower cost products for treatment of Gaucher Disease: Cerezyme and Elelyso. Therefore, Aetna considers VPRIV to be medically necessary only for members who have a contraindication, intolerance or ineffective response to both of the available equivalent alternatives: Cerezyme and Elelyso.
Pompe Disease
As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. Lumizyme and Pombiliti are more costly to Aetna than other products for the treatment of late-onset Pompe Disease. There is a lack of reliable evidence that Lumizyme and Pombiliti are superior to the lower cost product for the treatment of late-onset Pompe Disease: Nexviazyme. Therefore, Aetna considers Lumizyme and Pombiliti to be medically necessary only for members who have a contraindication, intolerance or ineffective response to the available equivalent alternative: Nexviazyme.
Policy
Scope of Policy
This Clinical Policy Bulletin addresses treatments for lysosomal storage disorder for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.
Note: Requires Precertification:
Precertification of enzyme replacement drugs are required of all Aetna participating providers and members in applicable plan designs. For precertification of these drugs, call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.
Note: Site of Care Utilization Management Policy applies to enzyme replacement drugs (Aldurazyme, Brineura, Cerezyme, Elaprase, Elelyso, Elfabrio, Fabrazyme, Kanuma, Lamzede, Lumizyme, Mepsevii, Naglazyme, Nexviazyme, Pombiliti, Vimizim, Vpriv, and Xenpozyme). For information on site of service for these drugs, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.
Agalsidase beta (Fabrazyme)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers agalsidase beta (Fabrazyme) medically necessary for treatment of Fabry disease when all of the following criteria are met:
- Member is 2 years of age or older; and
- The diagnosis of Fabry disease was confirmed by enzyme assay demonstrating a deficiency of alpha-galactosidase enzyme activity or by genetic testing, or the member is a symptomatic obligate carrier; and
- The member exhibits clinical signs and symptoms of the disease at baseline (e.g., acroparesthesias, angiokeratomas, gastrointestinal symptoms, corneal opacities); and
- The requested medication will not be used in combination with Elfabrio or Galafold.
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of agalsidase beta (Fabrazyme) therapy medically necessary for members with Fabry disease who are responding to therapy (e.g., reduction in plasma globotriaosylceramide [GL-3, Gb3], GL-3/Gb3 inclusions or plasma lyso-GL-3, improvement and/or stabilization in renal function, pain reduction).
Alglucosidase alfa (Lumizyme)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers alglucosidase alfa (Lumizyme) medically necessary for the treatment of Pompe disease when all of the following criteria are met:
- Diagnosis of Pompe disease was confirmed by enzyme assay demonstrating a deficiency of acid alpha-glucosidase enzyme activity (less than 1% of normal controls for infantile-onset Pompe disease and less than 40% of normal controls for late-onset Pompe disease) or by genetic testing; and
- Member exhibits clinical signs and symptoms of disease at baseline for late-onset Pompe disease (e.g., progressive proximal muscle weakness, respiratory insufficiency, cardiomyopathy).
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of alglucosidase alpha (Lumizyme) therapy medically necessary for members with Pompe disease who are responding to therapy (e.g., improvement, stabilization, or slowing of disease progression for motor function, walking capacity, cardiorespiratory function, decrease in left ventricular mass index (LVMI), delay in death).
Avalglucosidase alfa-ngpt (Nexviazyme)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers avalglucosidase alfa-ngpt (Nexviazyme) medically necessary for treatment of late-onset Pompe disease when all of the following criteria are met:
- Member is 1 year of age or older; and
- Diagnosis was confirmed by enzyme assay demonstrating a deficiency of acid alpha-glucosidase enzyme activity (less than 40% of normal controls) or by genetic testing; and
- Member exhibits clinical signs and symptoms of disease at baseline (e.g., progressive proximal muscle weakness, respiratory insufficiency, cardiomyopathy).
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of avalglucosidase alfa-ngpt (Nexviazyme) therapy medically necessary for treatment in members requesting reauthorization for late-onset Pompe disease who are responding to therapy (e.g., improvement, stabilization, or slowing of disease progression for motor function, walking capacity, respiratory function, or muscle strength).
Cerliponase alfa (Brineura)
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Exclusions
Aetna considers members with either of the following exclusions not eligible for Brineura:
- Dosage of Brineura exceeds 300 mg once every other week; or
- Member has acute intraventricular access device-related complications (e.g., leakage, device failure, or device-related infection) or a ventriculoperitoneal shunt.
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers cerliponase alpha (Brineura) medically necessary for neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency and Jansky-Bielschowsky disease, when both of the following criteria are met:
- Diagnosis of CLN2 was confirmed by enzyme assay demonstrating a deficiency of tripeptidyl peptidase 1 (TPP1) enzyme activity or by genetic testing; and
- Cerliponase alfa will be administered by, or under the direction of a physician knowledgeable in intraventricular administration.
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of cerliponase alfa (Brineura) therapy medically necessary for neuronal ceroid lipofuscinosis type 2 (CLN2) when both of the following criteria are met:
- The requested medication will be administered by, or under the direction of a physician knowledgeable in intraventricular administration; and
- Member has experienced no loss of ambulation or a slowed loss of ambulation from baseline.
Cipaglucosidase alfa-atga (Pombiliti)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers cipaglucosidase alfa-atga (Pombiliti) medically necessary for treatment of late-onset Pompe disease when all of the following criteria are met:
- Member is 18 years of age or older; and
- Member weighs greater than or equal to 40 kg; and
- Diagnosis was confirmed by enzyme assay demonstrating a deficiency of acid alpha-glucosidase enzyme activity (less than 40% of normal controls) or by genetic testing; and
- Member exhibits clinical signs and symptoms of disease (e.g., progressive proximal muscle weakness, respiratory insufficiency, cardiomyopathy); and
- Member is not improving on current enzyme replacement therapy (ERT) (e.g., Lumizyme, Nexviazyme); and
- The requested medication will be taken in combination with miglustat (Opfolda).
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation cipaglucosidase alfa-atge (Pombiliti) therapy medically necessary for treatment in members requesting reauthorization for late-onset Pompe disease when both of the following criteria are met:
- Member is responding to therapy (e.g., improvement, stabilization, or slowing of disease progression for motor function, walking capacity, respiratory function, or muscle strength); and
- The requested medication will be taken in combination with miglustat (Opfolda).
Elosulfase alfa (Vimizim)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers elosulfase alfa (Vimizim) medically necessary for treatment of mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) when both of the following criteria are met:
- The diagnosis was confirmed by enzyme assay demonstrating a deficiency of N-acetylgalactosamine-6 sulfatase (GALNS) enzyme activity or by genetic testing; and
- Member exhibits clinical signs and symptoms of disease at baseline (e.g., kyphoscoliosis, genu valgum, pectus carinatum, respiratory compromise, valvular heart disease, hearing impairment, corneal clouding, hepatomegaly, neurologic impairment).
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of elosulfase alfa (Vimizim) therapy medically necessary for members requesting reauthorization for an indication listed in the Criteria for Initial Approval section who have a clinically positive response to therapy, which shall include improvement, stabilization, or slowing of disease progression (e.g., improvement, stabilization, or slowing of disease progression for 6-minute walk test, 3-minute stair climb, urine keratan sulfate levels).
Galsulfase (Naglazyme)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers galsulfase (Naglazyme) medically necessary for the treatment of members with mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome) when both of the following criteria are met:
- The diagnosis of MPS VI was confirmed by enzyme assay demonstrating a deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B) enzyme activity or by genetic testing; and
- Member exhibits clinical signs and symptoms of disease at baseline (e.g., decreased growth velocity, coarse facial features, skeletal deformities, frequent upper-airway infections, enlarged liver and spleen, hearing loss, joint stiffness, coarse hair).
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of galsulfase (Naglazyme) therapy medically necessary for members requesting reauthorization for an indication listed in the Criteria for Initial Approval section who have a clinically positive response to therapy, which shall include improvement, stabilization, or slowing of disease progression (e.g., improvement, stabilization, or slowing of disease progression for growth rate, 12-minute walk test, 3-minute stair climb test, urinary glycosaminoglycan [GAG] levels).
Idursulfase (Elaprase)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers idursulfase (Elaprase) medically necessary for the treatment of members with mucopolysaccharidosis II (MPS II, Hunter syndrome) when both of the following criteria are met:
- The diagnosis of MPS II was confirmed by enzyme assay demonstrating a deficiency of iduronate-2-sulfatase enzyme activity or by genetic testing; and
- Member exhibits clinical signs and symptoms of disease at baseline (e.g., short stature, hepatosplenomegaly, joint contractures, coarse facies, frequent ear/airway infections, umbilical hernia).
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of idursulfase (Elaprase) therapy medically necessary for members requesting reauthorization for an indication listed in the Criteria for Initial Approval section who have a clinically positive response to therapy, which shall include improvement, stabilization, or slowing of disease progression (e.g., improvement, stabilization, or slowing of disease progression for predicted forced vital capacity (FVC), 6 minute walking test, global joint range of motion, combined liver and spleen volume, urinary glycosaminoglycan levels, left ventricular mass index).
Imiglucerase (Cerezyme), Taliglucerase alfa (Elelyso), and Velaglucerase alfa (VPRIV)
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Prescriber Specialties
- Cerezyme must be prescribed by or in consultation with physicians knowledgeable in the management of persons with Gaucher disease.
- Elelyso and VPRIV must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
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Gaucher disease, type1
Aetna considers imiglucerase (Cerezyme), taliglucerase alfa (Elelyso) or velaglucerase alfa (VPRIV) medically necessary for treatment of Gaucher disease type 1 when both of the following criteria are met:
- Beta-glucocerebrosidase (glucosidase) enzyme assay or genetic testing results support diagnosis; and
- Member exhibits clinical signs and symptoms of disease at baseline (e.g., bone disease, splenomegaly, hepatomegaly, cytopenia).
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Gaucher disease, type 2
Aetna considers imiglucerase (Cerezyme), taliglucerase alfa (Elelyso) or velaglucerase alfa (VPRIV) medically necessary for treatment of Gaucher disease type 2 when both of the following criteria are met:
- Beta-glucocerebrosidase (glucosidase) enzyme assay or genetic testing results support diagnosis; and
- Member exhibits clinical signs and symptoms of disease at baseline (e.g., bone disease, splenomegaly, hepatomegaly, cytopenia).
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Gaucher disease, type 3
Aetna considers imiglucerase (Cerezyme), taliglucerase alfa (Elelyso) or velaglucerase alfa (VPRIV) medically necessary for treatment of Gaucher disease type 3 when both of the following criteria are met:
- Beta-glucocerebrosidase (glucosidase) enzyme assay or genetic testing results support diagnosis; and
- Member exhibits clinical signs and symptoms of disease at baseline (e.g., bone disease, splenomegaly, hepatomegaly, cytopenia).
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of imiglucerase (Cerezyme), taliglucerase alfa (Elelyso), or velaglucerase alfa (VPRIV) therapy medically necessary for treatment of an indication listed in the Criteria for Initial Approval section when all of the following criteria are met:
- Member meets the criteria for initial approval; and
- Member is receiving benefit from therapy (e.g., improvement in liver volume, spleen volume, hemoglobin concentration, platelet count) and is not experiencing any intolerable adverse events.
Laronidase (Aldurazyme)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers laronidase (Aldurazyme) medically necessary for treatment of mucopolysacchararidoses I (MPS I) when all of the following criteria are met:
- Diagnosis of MPS I was confirmed by enzyme assay demonstrating a deficiency of alpha-L-iduronidase enzyme activity and/or by genetic testing; and
- Member has one of the following:
- The Hurler form (i.e., severe MPS I); or
- The Hurler-Scheie form (i.e., attenuated MPS I); or
- The Scheie form (Scheie syndrome: i.e., attenuated MPS I) with moderate to severe symptoms (e.g., normal intelligence, less progressive physical problems, corneal clouding, joint stiffness, valvular heart disease); and
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Member exhibits clinical signs and symptoms of disease at baseline (e.g., coarse facial features, frequent upper respiratory infections, inguinal or umbilical hernia, hepatosplenomegaly, characteristic skeletal findings, noninflammatory arthropathy, corneal clouding, hydrocephalus, developmental delay).
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of laronidase (Aldurazyme) therapy medically necessary for members requesting reauthorization for an indication listed in the Criteria for Initial Approval section who have a clinically positive response to therapy, which shall include improvement, stabilization, or slowing of disease progression (e.g., improvement, stabilization, or slowing of disease progression in forced vital capacity, 6 minute walk test, apnea/hypoapnea index (AHI), liver volume, active joint range of motion, urinary glycosaminoglycan [GAG] levels).
Olipudase alfa-rpcp (Xenpozyme)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician knowledgeable in the management of acid sphingomyelinase deficiency (ASMD).
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Criteria for Initial Approval
Aetna considers olipudase alfa-rpcp (Xenpozyme) medically necessary for treatment of non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) when the diagnosis is confirmed by either of the following:
- A documented deficiency of acid sphingomyelinase as measured in peripheral leukocytes, cultured fibroblasts, or lymphocytes; or
- Genetic testing results documenting a pathogenic variant(s) in the sphingomyelin phosphodiesterase-1 (SMPD1) gene.
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of olipudase alfa-rpcp (Xenpozyme) therapy medically necessary for treatment in members requesting reauthorization for an indication listed in the Criteria for Initial Approval section who are responding to therapy (e.g., improvement in lung function, reduction in spleen volume, reduction in liver volume, improvement in platelet count, improvement in linear growth progression).
Pegunigalsidase alfa-iwxj (Elfabrio)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers pegunigalsidase alfa-iwxj (Elfabrio) medically necessary for treatment of Fabry disease when all of the following criteria are met:
- Member is 18 years of age or older; and
- The diagnosis of Fabry disease was confirmed by enzyme assay demonstrating a deficiency of alpha-galactosidase enzyme activity or by genetic testing, or the member is a symptomatic obligate carrier; and
- The member exhibits clinical signs and symptoms of the disease at baseline (e.g., acroparesthesias, angiokeratomas, gastrointestinal symptoms, corneal opacities); and
- The requested medication will not be used in combination with Galafold or Fabrazyme.
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of pegunigalsidase alfa-iwxj (Elfabrio) therapy medically necessary in members requesting reauthorization for treatment of Fabry disease who are responding to therapy (e.g., reduction in plasma globotriaosylceramide [GL-3, Gb3], GL-3/Gb3 inclusions or plasma lyso-GL-3, improvement and/or stabilization in renal function, pain reduction).
Sebelipase alfa (Kanuma)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers sebelipase alfa (Kanuma) medically necessary for treatment of lysosomal acid lipase (LAL) deficiency when both of the following criteria are met:
- Diagnosis of LAL deficiency was confirmed by enzyme assay demonstrating a deficiency of lysosomal acid lipase enzyme activity or by genetic testing; and
- Member has alanine aminotransferase level (ALT) greater than or equal to 1.5 times the upper limit of normal (based on the age- and gender-specific normal ranges) on two consecutive ALT measurements obtained at least one week apart; and
- Member exhibits clinical signs and symptoms of disease at baseline (e.g., hepatomegaly, splenomegaly, poor growth/failure to thrive, dyslipidemia).
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of sebelipase alfa (Kanuma) therapy medically necessary for members with LAL deficiency who are responding to therapy (e.g., improvement, stabilization, or slowing of disease progression for weight-for-age z-score if exhibiting growth failure, low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglycerides, or alanine aminotransferase [ALT]).
Tividenofusp alfa-eknm (Avlayah)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers tividenofusp alfa-eknm (Avlayah) medically necessary for treatment of mucopolysaccharidosis II (MPS II, Hunter syndrome) when all of the following criteria are met:
- Member is 3 months to 13 years of age; and
- Member weighs 5 kg or greater; and
- Diagnosis of MPS II is confirmed by both of the following:
- Enzyme assay demonstrating a deficiency of iduronate-2-sulfatase (I2S) enzyme activity (i.e., less than or equal to 10% of the lower limit of the normal range, per laboratory preforming the test) in plasma, white blood cells, and/or skin fibroblasts; and
- Pathogenic (or likely pathogenic) variant in the IDS gene; and
- Member has neuronopathic MPS II (e.g., developmental delay, cognitive impairment, behavioral issues, seizures, ataxia, gait disturbances); and
- Member does not have advanced neurologic impairment; and
- Cerebrospinal fluid, blood, or urinary heparan sulfate; hemoglobin, serum creatinine, and urinary protein to creatinine ratio have been assessed at baseline and will be monitored as clinically appropriate; and
- Member does not have documented loss of activity of sulfatases other than I2S, indicating multiple sulfatase deficiency; and
- Member does not have documented mutation of other genes, including loci adjacent to the IDS gene (e.g., fragile X mental retardation 1 [FMR1] or AF4/FMR2 family member 2 [i.e., AFF2 or FMR2]) that are known to be associated with developmental delay, seizures, or other significant central nervous system (CNS) disorders; and
- Member does not have clinically significant thrombocytopenia (i.e., platelet count less than 100,000 mm3), other clinically significant coagulation abnormality, or significant active bleeding; and
- Member does not have clinically significant anemia, defined as a hemoglobin level less than 10.0 g/dL; and
- Member does not have contraindication(s) to lumbar puncture procedure; and
- Member does not have any clinically significant CNS trauma or disorder, including severe untreated intracranial hypertension, that, in the opinion of the provider, may make treatment with the requested medication unsafe for the member; and
- Member does not have history of serious adverse reaction to the I2S enzyme or any component of the requested medication (e.g., hypersensitivity or anaphylaxis requiring hospitalization); and
- The requested medication will not be used in combination with other enzyme replacement therapies for the treatment of Hunter syndrome (e.g., Elaprase); and
- Initial and subsequent doses of the requested medication will not exceed 15 mg/kg once weekly.
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of tividenofusp alfa-eknm (Avlayah) therapy medically necessary for members requesting reauthorization for an indication listed in the Criteria for Initial Approval section who meet all of the following criteria:
- Member demonstrates a clinically positive response to therapy, which shall include improvement, stabilization, or slowing of disease progression (e.g., improvement, stabilization, or slowing of disease progression for cerebrospinal fluid, blood, or urine heparan sulfate levels; Vineland Adaptive Behavior Scale Adaptive Score Composite, liver volume, 6-minute walk test (6MWT), cognitive and language-and-motor domain age-equivalent score (AES), Bayley scales of infant and toddler development, third edition (BSID-III); or nonverbal index (NVI) of the Kaufman assessment battery for children, second edition (KABC-II)].); and
- The requested medication will not be used in combination with other enzyme replacement therapies for the treatment of Hunter syndrome (e.g., Elaprase); and
- The requested dose does not exceed 15 mg/kg once weekly.
Velmanase alfa-tycv (Lamzede)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of enzyme or metabolic disorders.
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Criteria for Initial Approval
Aetna considers velmanase alfa-tycv (Lamzede) medically necessary for treatment of non-central nervous system manifestations of alpha-mannosidosis when the following criteria are met:
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Diagnosis is confirmed by either of the following:
- A documented deficiency of alpha-mannosidase activity as measured in blood leukocytes or fibroblasts; or
- Genetic testing results documenting pathogenic variant(s) in the MAN2B1 gene; and
- Member has completed a 3-minute stair climbing test [3MSCT], 6-minutes walking test [6MWT], or forced vital capacity [FVC, % predicted] test to establish baseline age-appropriate values; and
- Member has undergone baseline serum or oligosaccharide concentration testing.
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of velmanase alfa-tycv (Lamzede) therapy medically necessary in members requesting reauthorization for an indication listed in the Criteria for Initial Approval section who are responding to therapy (e.g., improvement in 3-minutes stair climbing test [3MSCT] from baseline, improvement in 6-minute walking test [6MWT] from baseline, improvement in forced vital capacity [FVC, % predicted] from baseline, reduction in serum or urine oligosaccharide concentration from baseline).
Vestronidase alfa-vjbk (Mepsevii)
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metabolic disease and/or lysosomal storage disorders.
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Criteria for Initial Approval
Aetna considers vestronidase alfa-vjbk (Mepsevii) medically necessary for mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) when all of the following criteria are met:
- Diagnosis of MPS VII (MPS 7) was confirmed by enzyme assay demonstrating a deficiency of beta-glucuronidase enzyme activity or by genetic testing; and
- Member has elevated urinary glycosaminoglycan (uGAG) excretion at a minimum of 2-fold over the mean normal for age at initiation of treatment with Mepsevii; and
- Member exhibits clinical signs and symptoms of disease at baseline (e.g., cholestatic jaundice, hepatosplenomegaly, characteristic musculoskeletal features, developmental delay/intellectual disability, characteristic craniofacial features, recurrent otitis media or respiratory infections, hearing loss, hernias, characteristic cardiovascular abnormalities).
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of vestronidase alfa-vjbk (Mepsevii) therapy medically necessary for members requesting reauthorization for an indication listed in the Criteria for Initial Approval section who have a clinically positive response to therapy, which shall include improvement, stabilization, or slowing of disease progression (e.g., improvement, stabilization, or slowing of disease progression in urinary glycosaminoglycan (uGAG) excretion, 6-minute walk test, predicted forced vital capacity, maximum ventilatory ventilation, shoulder flexion and extension maximum range, visual acuity).
Related Policies
For Cerdelga or Zavesca, see Pharmacy Clinical Policy Bulletins (PCPBs): Formularies & Pharmacy Clinical Policy Bulletins.
See also:
- CPB 0901 - Asfotase alfa (Strensiq)
- CPB 0933 - Pegvaliase-pqpz (Palynziq)
- CPB 1050 - ADAMTS13, Recombinant-krhn (Adzynma).
Dosage and Administration
Note: Approvals may be subject to dosing limits in accordance with FDA-approved labeling, accepted compendia, and/or evidence-based practice guidelines. See Medical Specialty Medication Quantity Limits for more information. The following information is based on highlights from the U.S. FDA-approved Prescribing Information. For dose modifications and administration instructions, please refer to the Full Prescribing Information for each product.
Aldurazyme
Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for persons with the Scheie form who have moderate to severe symptoms:
The recommended dosage is 0.58 mg/kg of body weight administered once weekly as an intravenous infusion.
Source: Genzyme, 2023
Avlayah
Avlayah is indicated for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment. Avlayah is not recommended for use in combination with other enzyme replacement therapies.
Avlayah is administered under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Avlayah is initiated in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment.
The recommended starting dosage for pediatrics weighing at least 5 kg is 3 mg/kg administered once weekly via intravenous infusion. See Avlayah Prescribing Information for dose escalation regimen, modifications, and monitoring.
The recommended maintenance dosage of Avlayah for pediatrics who weigh at least 5 kg is 15 mg/kg administered once weekly via intravenous infusion.
Source: Denali Therapeutics, 2026
Brineura
Neuronal ceroid lipofuscinosis type 2 (CLN2 disease), also known as tripeptidyl peptidase 1 (TPP1) deficiency:
- Brineura is supplied as 150 mg/5 mL (30 mg/mL) solution, two single-dose vials per carton co-packaged with Intraventricular Electrolytes Injection 5 mL in a single-dose vial;
- Brineura is administered to the cerebrospinal fluid (CSF) by infusion via a surgically implanted reservoir and catheter, administered by or under the supervision of a physician experienced in intraventricular administration;
- The recommended dosage is 300 mg administered once every other week as an intraventricular infusion followed by infusion of Intraventricular Electrolytes over approximately 4.5 hours;
- In persons less than 2 years of age, lower doses are recommended. Refer to the Full Prescribing Information for Brineura;
- Dosing is not recommended in persons less than 37 weeks post-menstrual age (gestational age at birth plus post-natal age) or those weighing less than 2.5 kg
Source: BioMarin, 2024a
Cerezyme
Gaucher disease type 1 or type 3
Cerezyme (imiglucerase for injection) is administered by intravenous infusion under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.
The recommended dosage is 2.5 units/kg of body weight 3 times a week to 60 units/kg once every 2 weeks. The dosage is titrated based on disease severity and therapeutic goals of the individual.
For adult and pediatric persons weighing greater than 20 kg, the diluted Cerezyme solution is infused over 1 to 2 hours. For pediatric persons weighing 20 kg or less, the diluted Cerezyme solution is infused over 2 hours. Titrate the dosage based on clinical manifestations of disease and therapeutic goals for the individual.
Source: Genzyme, 2026
Elaprase
Hunter syndrome (Mucopolysaccharidosis II, MPS II)
The recommended dosage is 0.5 mg per kg of body weight administered once every week as an intravenous infusion.
Source: Takeda Pharmaceuticals, 2025
Elelyso
Gaucher disease type 1
Administration of Elelyso should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.
Recommended dosage in persons 4 years and older
- Treatment-naïve: 60 units/kg of body weight administered every other week as a 60 to 120 minute intravenous infusion
- Persons switching from imiglucerase: If it is acceptable to switch from a stable imiglucerase dosage to Elelyso, initiate Elelyso intravenous treatment (60- to 120-minute infusion) with the same units/kg imiglucerase dosage and subsequently administer Elelyso every other week. Dosage adjustments can be made based on achievement and maintenance of each person's therapeutic goals.
Source: Pfizer, 2025
Elfabrio
Fabry disease
Recommended dosage is 1 mg/kg every 2 weeks administered as an intravenous infusion.
Source: Chiesi USA, 2024
Fabrazyme
Fabry disease
The recommended dosage is 1 mg/kg body weight administered every two weeks as an intravenous infusion.
Individuals who have had a positive skin test to Fabrazyme or who have tested positive for anti-Fabrazyme IgE may be rechallenged with Fabrazyme. See Full Prescribing Information.
Source: Genzyme, 2024
Kanuma
Lysosomal Acid Lipase (LAL) deficiency
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Infants with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life:
- The recommended starting dosage is 1 mg/kg as an intravenous infusion once weekly.
- For persons who do not achieve an optimal clinical response, dosage is increase to 3 mg/kg once weekly.
- For persons with continued suboptimal clinical response on the 3 mg/kg once weekly dosage, dosage is further increased to 5 mg/kg once weekly.
- A suboptimal clinical response is defined as any of the following: poor growth, deteriorating biochemical markers, or persistent or worsening organomegaly.
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Pediatric and Adult Persons with LAL Deficiency:
- The recommended dosage is 1 mg/kg as an intravenous infusion once every other week.
- For persons with a suboptimal clinical response, dosage is increased to 3 mg/kg once every other week.
- A suboptimal clinical response is defined as any of the following: poor growth, deteriorating biochemical markers [e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST)], and/or parameters of lipid metabolism [e.g., low-density lipoprotein cholesterol (LDL-c), triglycerides (TG)].
Source: Alexion, 2024
Lamzede
Treatment of non-central nervous system manifestations of alpha-mannosidosis in adults and pediatrics.
The recommended dosage of Lamzede is 1 mg/kg (actual body weight) administered once every week as an intravenous infusion.
Source: Chiesi USA, 2023
Lumizyme
Pompe disease (GAA deficiency)
The recommended dosage is 20 mg per kg body weight administered every 2 weeks as an intravenous infusion. The initial infusion rate should be no more than 1 mg/kg/hour.
Source: Genzyme, 2024
Mepsevii
Mucopolysaccharidosis VII (MPS VII, Sly syndrome)
The recommended dosage is 4 mg/kg administered every two weeks as an intravenous infusion.
Source: Ultragenyx, 2020
Naglazyme
Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome)
The recommended dosage is 1 mg per kg of body weight administered once weekly as an intravenous infusion.
Source: BioMarin, 2024
Nexviazyme
Late-onset Pompe disease
The recommended dosage for persons weighing 30 kg or more is 20 mg/kg (of actual body weight) every two weeks administered as an intravenous infusion. The recommended dosage for persons weighing less than 30 kg is 40 mg/kg (of actual body weight) every two weeks as an intravenous infusion.
Source: Genzyme, 2023
Pombiliti
Late-onset Pompe disease
The recommended dosage of Pombiliti is 20 mg/kg (of actual body weight) administered every other week as an intravenous infusion over approximately 4 hours.
Pombiliti must be administered in combination with Opfolda. If Opfolda dose is missed, Pombiliti should not be administered. Refer to the Opfolda Prescribing Information for Opfolda dosage and administration recommendations.
Start Pombiliti in combination with Opfolda 2 weeks after the last enzyme replacement therapy (ERT) dose.
Per the label, Pombiliti infusion is initiated approximately 1 hour after oral administration of Opfolda. If the Pombiliti infusion cannot be started within 3 hours of oral administration of Opfolda, reschedule Pombiliti in combination with Opfolda at least 24 hours after Opfolda was last taken. If Pombiliti in combination with Opfolda are both missed, re-start treatment as soon as possible.
Source: Amicus Therapeutics, 2024
Vimizim
Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome)
The recommended dosage is 2 mg per kg body weight administered once every week as an intravenous infusion over a minimum of 3.5 to 4.5 hours, based on infusion volume.
Source: BioMarin, 2025
VPRIV
Gaucher disease type 1
Recommended starting dose in adults and pediatrics 4 years of age or older
- Persons naïve to Enzyme Replacement Therapy: 60 Units/kg administered every other week as a 60-minute intravenous infusion. The dosage can be adjusted based on achievement and maintenance of each person’s therapeutic goals.
- Switching from imiglucerase to VPRIV: persons being treated with stable imiglucerase dosages for Gaucher disease may be switched to VPRIV by starting treatment with VPRIV at the previous imiglucerase dosage two weeks after the last imiglucerase dose. VPRIV should be administered under the supervision of a healthcare professional as a 60-minute intravenous infusion. The dosage can be adjusted based on achievement and maintenance of each person’s therapeutic goals.
Source: Takeda Pharmaceuticals, 2024
Xenpozyme
Xenpozyme is supplied as 4 mg or 20 mg of olipudase alfa-rpcp as a lyophilized powder in a single-dose vial for reconstitution.
Acid Sphingomyelinase Deficiency (ASMD)
- Adults: Recommended starting dose is 0.1 mg/kg administered as an intravenous infusion.
- Pediatrics (0 to 17 years): Recommended starting dose is 0.03 mg/kg administered as an intravenous infusion.
See Full Prescribing Information for the recommended dose escalation, missed doses, maintenance dosage, dosage modifications to reduce the risk of adverse reactions, and preparation and administration instructions.
Source: Genzyme, 2024
Experimental, Investigational, or Unproven
Aetna considers the following interventions experimental, investigational, or unproven (not an all-inclusive list) because the safety and/or efficacy have not been established:
- Concomitant use of imiglucerase, taliglucerase alfa, and velaglucerase alfa for Gaucher disease or any other indication;
- Intrathecal idursulfase for progressive cognitive impairment in individuals with MPS II;
- In utero enzyme-replacement therapy for infantile-onset Pompe disease;
- Measurements in plasma lysosphingolipids and oxysterols for routine screening of lipid storage disorders in persons without signs and symptoms of disease;
- Measurement of anti-rhGAA antibodies as a determinant of treatment outcome in adults with late-onset Pompe disease;
- The following interventions for the treatment of mucopolysaccharidoses (not an all-inclusive list):
- Enzyme replacement therapy with fusion proteins
- Gene therapy
- Hematopoietic stem cell therapy
- Intrathecal enzyme replacement therapy
- Metallothioneins
- Pharmacological chaperone therapy (also known as enzyme-enhancement therapy)
- Substrate deprivation therapy
- Substrate reduction therapy.
Background
U.S. Food and Drug Administration (FDA)-Approved Indications
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Aldurazyme (laronidase)
Aldurazyme is indicated for the treatment of adult and pediatric patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms.
Limitations of use:
- The safety and effectiveness of treating mildly affected patients with the Scheie form have not been established.
- The effect of Aldurazyme on central nervous system manifestations of the disorder has not been determined.
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Avlayah (tividenofusp alfa-eknm)
Avlayah is indicated for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment.
This indication is approved under accelerated approval based on the reduction of cerebrospinal fluid heparan sulfate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Limitations of Use: Avlayah is not recommended for use in combination with other enzyme replacement therapies for the treatment of Hunter syndrome.
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Brineura (cerliponase alfa)
Brineura is indicated to slow the loss of ambulation in pediatric patients with neuronal ceroid lipofuscinosis type 2 (CLN2 disease), also known as tripeptidyl peptidase 1 (TPP1) deficiency.
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Cerezyme (imiglucerase)
Cerezyme is indicated for treatment of non-central nervous system (CNS) manifestations of Type 1 or Type 3 Gaucher disease in adults and pediatric patients.
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Elaprase (idursulfase)
Elaprase is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). Elaprase has been shown to improve walking capacity in patients 5 years and older. In patients 16 months to 5 years of age, no data are available to demonstrate improvement in disease-related symptoms or long term clinical outcome; however, treatment with Elaprase has reduced spleen volume similarly to that of adults and children 5 years of age and older. The safety and efficacy of Elaprase have not been established in pediatric patients less than 16 months of age.
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Elelyso (taliglucerase alfa)
Elelyso is indicated for the treatment of patients 4 years and older with a confirmed diagnosis of type 1 Gaucher disease.
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Elfabrio (pegunigalsidase alfa-iwxj)
Elfabrio is indicated for the treatment of adults with confirmed Fabry disease.
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Fabrazyme (agalsidase beta)
Fabrazyme is a hydrolytic lysosomal neutral glycosphingolipid-specific enzyme indicated for the treatment of adult and pediatric patients 2 years of age and older with confirmed Fabry disease.
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Kanuma (sebelipase alfa)
Kanuma is a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency.
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Lamzede (velmanase alfa-tycv)
Lamzede is indicated for the treatment of non-central nervous system manifestations of alpha-mannosidosis in adult and pediatric patients.
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Lumizyme (alglucosidase alfa)
Lumizyme is a hydrolytic lysosomal glycogen-specific enzyme indicated for patients with Pompe disease (acid alpha-glucosidase [GAA] deficiency).
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Mepsevii (vestronidase alfa-vjbk)
Mepsevii is indicated in pediatric and adult patients for the treatment of mucopolysaccharidosis VII (MPS VII, Sly syndrome).
Limitations of use: The effect of Mepsevii on the central nervous system manifestations of MPS VII has not been determined.
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Naglazyme (galsulfase)
Naglazyme is indicated for patients with mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome). Naglazyme has been shown to improve walking and stair-climbing capacity.
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Nexviazyme (avalglucosidase alfa-ngpt)
Nexviazyme is indicated for the treatment of patients 1 year of age and older with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency).
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Pombiliti (cipaglucosidase alfa-atga)
Pombiliti is indicated, in combination with Opfolda, for the treatment of adult patients with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) weighing greater than or equal to 40 kg and who are not improving on their current enzyme replacement therapy (ERT).
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Vimizim (elosulfase alfa)
Vimizimis a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome).
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VPRIV (velaglucerase)
VPRIV is a hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy (ERT) for patients with type 1 Gaucher disease.
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Xenpozyme (olipudase alfa-rpcp)
Xenpozyme is a hydrolytic lysosomal sphingomyelin-specific enzyme indicated for treatment of non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients.
Compendial Uses
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Cerezyme (imiglucerase)
Gaucher disease type 2
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Elelyso (taliglucerase alfa)
Gaucher disease type 2 and type 3
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VPRIV (velaglucerase)
Gaucher disease type 2 and type 3
Acid Sphingomyelinase Deficiency
Acid sphingomyelinase deficiency (ASMD), a lysosomal storage disease, is a rare progressive genetic disorder that results from a deficiency of the acid sphingomyelinase enzyme, which is required to metabolize lipids called sphingomyelin. Consequently, sphingomyelin and other substances accumulate in the liver, spleen, lung, and brain. Individuals with ASMD have enlarged abdomens that can cause pain, vomiting, feeding difficulties, and falls. Persons most severely affected have profound neurologic symptoms and rarely survive beyond 2 to 3 years of age. Others may survive into adulthood but die prematurely from respiratory failure (FDA, 2022; NORD, 2019).
Diaz et al. (2021) conducted a phase 1/2, international, multicenter, open-label trial (ASCEND-Peds; NCT02292654) to assess the safety and tolerability of olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children. Patients (n=20; age range 1 year to 17 years) were administered intravenously olipudase alfa once every 2 weeks (via infusion), with intrapatient dose escalation to 3 mg/kg, for 64 weeks. Primary outcome was safety through week 64. Secondary outcomes included pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLco), lipid profiles, and height through week 52. All patients completed the study and continued in an extension trial. After one year of treatment (52 weeks), mean splenomegaly and hepatomegaly improved by greater than 40% (p < 0.0001). Mean % predicted DLco improved by 32.9% (p = 0.0053) in patients able to perform the test. Lipid profiles and elevated liver transaminase levels normalized. Mean height Z-scores improved by 0.56 (p < 0.0001). The authors concluded that olipudase alfa was generally well-tolerated with significant, comprehensive improvements in disease pathology across a range of clinically relevant endpoints in children with chronic ASMD.
Wasserstein et al. (2022) conducted a phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691) to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults. Patients (n=36) with ASMD type A/B or type B were randomized to 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Other outcomes included liver volume/function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics. Least square mean percent change from baseline to week 52 favored olipudase alfa over placebo for percent predicted diffusing capacity of the lung for carbon monoxide (22% vs 3.0% increases, p = .0004), spleen volume (39% decrease vs 0.5% increase, p < .0001), and liver volume (28% vs 1.5% decreases, p < .0001). Splenomegaly-related score decreased in both groups (p = .64). Other clinical outcomes improved in the olipudase alfa group compared with the placebo group. There were no treatment-related serious adverse events or adverse event–related discontinuations. Most adverse events were mild. The authors concluded that olipudase alfa was well tolerated and associated with significant and comprehensive improvements in disease pathology and clinically relevant endpoints compared with placebo in adults with ASMD.
In August 2022, the U.S. FDA approved Xenpozyme (olipudase alfa) intravenous infusion for treatment of non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients. Xenpozyme provides an exogenous source of the enzyme acid sphingomyelinase (ASM), thus, it is an enzyme replacement therapy that helps reduce sphingomyelin accumulation in the liver, spleen, and lung. Xenpozyme is not expected to cross the blood-brain barrier or modulate the central nervous system (CNS) manifestations of ASMD. FDA approval was based on positive results from two clinical trials involving children (ASCEND-Peds trial) and adults (ASCEND trial).
According to Wasserstein and Schuchman (2023), acid sphingomyelinase deficiency (ASMD) presents a spectrum of clinical characteristics. The severe early-onset form, known as infantile neurovisceral ASMD, was historically classified as Niemann-Pick disease type A (NPD-A), while the later-onset chronic visceral form is referred to as Niemann-Pick disease type B (NPD-B). An intermediate phenotype is recognized as chronic neurovisceral ASMD (NPD-A/B). Currently, enzyme replacement therapy (ERT) is FDA-approved for addressing non-central nervous system manifestations of ASMD, and as more patients receive ERT over extended periods, the natural history of the disease may evolve. In untreated NPD-A, hepatosplenomegaly is the most common initial symptom, typically detectable by three months of age, leading to significant organ enlargement and growth failure by the second year of life, with psychomotor development stagnating at around 12 months and subsequent neurological decline. A classic cherry-red spot in the retina appears in all affected children, although the impact of ERT on this symptom remains uncertain. Interstitial lung disease due to sphingomyelin accumulation in pulmonary macrophages can lead to frequent respiratory infections and often results in respiratory failure, with most untreated children not surviving past three years. NPD-B generally manifests later and is less severe, characterized by progressive hepatosplenomegaly and gradual declines in liver and lung function, without central nervous system involvement. Individuals with NPD-A/B exhibit symptoms that fall between those of NPD-A and NPD-B, with some central nervous system manifestations, and can survive into adulthood even without treatment. Diagnosis of ASMD is confirmed through the identification of biallelic pathogenic variants in the SMPD1 gene via molecular genetic testing and measuring residual acid sphingomyelinase enzyme activity below 10% of normal levels. Management includes targeted therapies like olipudase alfa (Xenpozyme) ERT, which reduces sphingomyelin accumulation in non-central nervous system organs but does not address neurocognitive issues. Hematopoietic stem cell transplantation (HSCT) can correct metabolic defects and improve organ function but does not stabilize neurological disease and is limited by associated risks. Supportive care may involve nutritional support, management of coagulopathy and liver disease, transfusions for severe bleeding, and therapies to enhance function and development. Preventive measures include monitoring liver function in patients on hepatotoxic medications. Regular surveillance is essential, including assessments of nutritional status, cardiac function, liver health, and developmental progress. Individuals with splenomegaly should avoid contact sports. Pregnant women with ASMD require specialized prenatal care, as olipudase alfa ERT is not recommended during pregnancy due to potential risks to fetal development. Genetic counseling is essential, as all forms of ASMD are inherited in an autosomal recessive manner, allowing for carrier testing and prenatal diagnosis for at-risk families.
Xenpozyme carries a boxed warning for severe hypersensitivity reactions, including anaphylaxis. Other labeled warnings and precautions include elevated transaminases (ALT and AST), and risk of fetal malformations during dosage initiation or escalation in pregnancy.
The most common adverse reactions in adult patients (incidence of 10% or more) are headache, cough, diarrhea, hypotension and ocular hyperemia. The most common adverse reactions in pediatric patients (incidence of 20% or more) are pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue and pharyngitis.
Alpha-Mannosidosis
Alpha-mannosidosis (AM) is a rare genetic lysosomal storage disorder in which mutations in the MAN2B1 gene inhibits the ability of the alpha-mannosidase enzyme to perform its role in breaking down complexes of sugar molecules (mannose-containing oligosaccharides). This gene mutation results in accumulation of oligosaccharides in the lysosomes which cause cells to malfunction and eventually die, leading to tissue and organ damage. Alpha-mannosidosis encompasses a continuum of signs and symptoms, ranging from mild to severe. Severe cases often result in either fetal death or death in childhood. Individuals with a milder phenotype have mild-to-moderate intellectual disability, impaired hearing, weakened immune system, distinctive facial features (e.g., a large head, prominent forehead, and protruding jaw), skeletal abnormalities, and muscle weakness. Individuals may experience primary central nervous system disease which typically includes cerebellar involvement causing ataxia. Associated medical problems can include corneal opacities, hepatosplenomegaly, aseptic destructive arthritis, and metabolic myopathy. Alpha-mannosidosis is gradually progressive in which some individuals may live into the fifth or sixth decade (FDA, 2023; NIH/NLM, 2023; Malm and Nilssen, 2019).
Velmanase alfa is a recombinant human alpha-mannosidase that has been in development for weekly intravenously administered (IV) enzyme replacement therapy (ERT) for AM. Borgwardt et al (2018) report on the results of a 52 week, phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel group trial (NCT01681953) that evaluated velmanase alfa (VA) in adult and pediatric patients with AM. Twenty-five patients (13 adults, 12 pediatrics) were randomized to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-minute stair-climb test (3MSCT). The secondary endpoints were change from baseline to week 52 in the 6-minute walk test (6MWT) and in forced vital capacity percentage (FVC %, measured by spirometry) of predicted normal value. The authors reports that the mean relative change in S-oligo in the VA arm was -77.6% [95% confidence interval (CI) -81.6 to -72.8] at week 52 and -62.9% (95% CI -85.8 to -40.0) at LO; mean relative change in the placebo arm was -24.1% (95% CI -40.3 to -3.6) at week 52 and -55.7% (95% CI -76.4 to -34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was -1.1% (95% CI -9.0 to 7.6) and - % (95% CI -13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI -5.5 to 13.2) in the VA arm and 9.0% (95% CI -10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age. The authors concluded the efficacy results for the clinical endpoints assessed at 12 months, 3MSCT, 6MWT and FVC % predicted, favored the VM group and were supported by a reduction in serum oligosaccharide concentration.
Velmanase alfa (VA) was also investigated in a single arm trial in pediatric alpha-mannosidosis (AM) patients less than 6 years of age (NCT02998879). All patients had AM activity below 10% of normal at baseline. The trial enrolled five patients ranging from 3.7 to 5.9 years of age, with a mean age of 4.5 years. Patients received VA 1 mg/kg as intravenous infusion once weekly (4 patients for 24 months, 1 patient for 40 months). The mean (SD) absolute and percentage changes from baseline for serum oligosaccharides at 24 months were -7.7 (4.27) μmol/L and -65.8% (23.1%) respectively (Chiesi USA, 2023; FDA, 2023).
In February 2023, the U.S. FDA approved velmanase alfa, brand name Lamzede (Chiesi USA, Inc.), for for the treatment of non-central nervous system (CNS) manifestations of alpha-mannosidosis in adult and pediatric patients. Approval was based on outcomes from the phase 3 trial summarized by Borgwardt et al. (2018) above.
Although there are no known contraindications, the most common adverse reactions (incidence greater than 20%) include hypersensitivity reactions including anaphylaxis, nasopharyngitis, pyrexia, headache, and arthralgia.
Ficicioglu and Stepien (2024) state that management of alpha-mannosidosis includes targeted therapies such as velmanase alfa (Lamzede), an enzyme replacement therapy (ERT) that has been well tolerated and is now considered a standard treatment, with reported improvements in both biochemical and functional parameters among treated individuals. Hematopoietic stem cell transplantation (HSCT) is also an option for severe cases, showing better outcomes when performed early, despite associated risks. Long-term outcomes of velmanase alfa treatment are still being studied; however, it has been shown to reduce serum oligosaccharide levels and increase serum immunoglobulin G levels, with only 12% of patients developing treatment-related anti-drug antibodies (ADAs) after up to 48 months of therapy. Clinical assessments, including the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT), indicated similar outcomes regardless of genotype or ADA status. A study involving six children under 6 years old receiving weekly intravenous velmanase alfa for at least 24 months demonstrated improvements in serum oligosaccharide concentrations, hearing, immunologic profiles, and quality of life, suggesting that early treatment may be beneficial and well tolerated. The long-term prognosis for individuals receiving velmanase alfa treatment remains to be determined.
Anderson-Fabry Disease
El Dib and colleagues (2017) stated that Anderson-Fabry disease (AFD) is an X-linked recessive inborn error of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A. Renal failure, heart and cerebrovascular involvement reduce survival. A Cochrane review provided little evidence on the use of ERT. hese investigators complemented this review through a linear regression and a pooled analysis of proportions from cohort studies. They evaluated the safety and efficacy of ERT for AFD. For the systematic review, a literature search was performed, from inception to March 2016, using Medline, Embase and LILACS. Inclusion criteria were cohort studies, patients with AFD on ERT or natural history, and at least 1 patient-important outcome (all-cause mortality, renal, cardiovascular or cerebrovascular events, and AEs) reported. The pooled proportion and the CI were shown for each outcome. Simple linear regressions for composite endpoints were performed. A total of 77 cohort studies involving 15,305 participants proved eligible. The pooled proportions were as follows: For renal complications, agalsidase alfa 15.3% [95% CI: 0.048 to 0.303; I2 = 77.2%, p = 0.0005]; agalsidase beta 6% [95% CI: 0.04 to 0.07; I2 = not applicable]; and untreated patients 21.4% [95% CI: 0.1522 to 0.2835; I2 = 89.6%, p < 0.0001]. Effect differences favored agalsidase beta compared to untreated patients; for cardiovascular complications, agalsidase alfa 28% [95% CI: 0.07 to 0.55; I2 = 96.7%, p < 0.0001]; agalsidase beta 7% [95% CI: 0.05 to 0.08; I2 = not applicable]; and untreated patients 26.2% [95% CI: 0.149 to 0.394; I2 = 98.8%, p < 0.0001]. Effect differences favored agalsidase beta compared to untreated patients; and for cerebrovascular complications, agalsidase alfa 11.1% [95% CI: 0.058 to 0.179; I2 = 70.5%, p = 0.0024]; agalsidase beta 3.5% [95% CI: 0.024 to 0.046; I2 = 0%, p = 0.4209]; and untreated patients 18.3% [95% CI: 0.129 to 0.245; I2 = 95% p < 0.0001]. Effect differences favored agalsidase beta over agalsidase alfa or untreated patients. A linear regression showed that Fabry patients receiving agalsidase alfa were more likely to have higher rates of composite end-points compared to those receiving agalsidase beta. The authors concluded that agalsidase beta was associated with a significantly lower incidence of renal, cardiovascular and cerebrovascular events than no ERT, and to a significantly lower incidence of cerebrovascular events than agalsidase alfa. They stated that in view of these results, the use of agalsidase beta for preventing major organ complications related to AFD can be recommended.
Fabry Disease
Fabry disease is a progressive, X-linked genetic disorder resulting from a defect in the gene for the lysosomal enzyme alpha-GAL. This enzyme deficiency results in an accumulation of globotriosylceramide (GL-3) and other lipids in tissues throughout the body. The inability to catabolize GL-3 can lead to renal failure, cardiomyopathy, and cerebrovascular accidents. The estimated incidence of Fabry disease is 1 in 40,000 males. Diagnosis of Fabry disease is confirmed by low or absent alpha-galactosidase activity in plasma or serum, leukocytes, tears, biopsied tissues, or cultured skin fibroblasts.
Fabrazyme (agalsidase beta) is a recombinant human α-galactosidase A enzyme indicated for the treatment of Fabry disease. Agalsidase beta is internalized and transported into lysosomes, where it exerts enzymatic activity and reduces accumulated GL-3.
Fabrazyme (Genzyme Corporation) was FDA approved in 2003. The safety and efficacy of Fabrazyme were assessed in four clinical studies in patients with Fabry disease and one matched analysis based on data from observational studies.
In the first clinical trial of agalsidase beta submitted to the FDA for approval, 58 Fabry patients were randomly assigned to 5 months of treatment with either agalsidase beta or placebo. The primary efficacy endpoint of GL-3 inclusions in renal interstitial capillary endothelial cells was assessed by light microscopy and was graded on an inclusion severity score ranging from 0 (normal or near normal) to 3 (severe inclusions). A GL-3 inclusion score of 0 was achieved by 20 of 29 (69%) patients treated with agalsidase beta compared to 0 of 29 patients treated with placebo (p < 0.001). Similar reductions in GL-3 inclusions were observed in the capillary endothelium of the heart and skin. However, during this 5-month study, no differences between groups in symptoms or renal function were observed.
The second study was a randomized, double-blind, placebo-controlled, multinational, multicenter trial of 82 patients with Fabry disease who were naïve to enzyme replacement therapy. Of the 82 enrolled patients, 51 were randomized to the Fabrazyme group and 31 to the placebo group. Patients received either 1 mg/kg intravenous Fabrazyme or placebo every 2 weeks for up to 35 months (median follow-up 18.5 months). The primary efficacy endpoint was the time to first occurrence of a clinically significant event (renal, cardiac, or cerebrovascular event, or death). A total of 14 of 51 (28%) Fabrazyme-treated patients and 13 of 31 (42%) placebo-treated patients experienced a clinically significant event (HR 0.57, 95% CI: 0.27, 1.22).
The third study was an open-label, single-arm, multinational, multicenter pediatric study in which the safety and efficacy were established in patients (n=16) aged 8 to 16 years. All patients received Fabrazyme 1 mg/kg every two weeks for up to 48 weeks.
A long-term, observational study was conducted that assessed the rate of decline in renal function (eGFR slope) in 122 patients with Fabry disease aged 16 years and older treated with Fabrazyme. Treated patients were matched 1:1 based on age (at initiation), sex, Fabry disease subtype (classic or non-classic), and baseline eGFR to a historical cohort of untreated patients with Fabry disease. The median follow-up time was 3 years in the untreated group and 4.5 years in the treated group (maximum follow-up time 5 years in both groups). The estimated mean eGFR slope was -1.5 mL/min/1.73 m²/year in the Fabrazyme-treated group and -3.2 mL/min/1.73 m²/year in the untreated group (eGFR slope difference: 1.7 mL/min/1.73 m²/year; 95% CI: 0.5, 3.0).
In an analysis of 24 Fabrazyme-treated pediatric patients with Fabry disease aged 2 to less than 8 years at Fabrazyme initiation and with elevated plasma GL-3 levels (i.e., >7.03 μg/mL) at baseline, plasma GL-3 levels fell within the normal range (i.e., ≤7.03 μg/mL) in 91% (20/22), 95% (18/19), and 92% (12/13) of patients at 6, 12, and 24 months, respectively.
Boxed warnings for Fabrazyme include hypersensitivity reactions, including anaphylaxis. Moreover, infusion-associated reactions may occur, in which Fabrazyme infusion is to be discontinued immediately with appropriate medical treatment initiated. Thus, the manufacturer recommends that patients be administered antihistamines, antipyretics, and/or corticosteroids prior to infusion.
The most common adverse reactions (20% or more) include upper respiratory tract infection, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness, and rash.
Ishii et al. (2012) stated that Fabry disease is an inherited lysosomal storage disorder caused by deficient α-galactosidase A activity. Many missense mutations in Fabry disease often cause misfolded gene products, which leads to their retention in the endoplasmic reticulum by the quality control system; they are then removed by endoplasmic reticulum-associated degradation. These researchers discovered that a potent α-galactosidase A inhibitor, 1-deoxygalactonojirimycin, acts as a pharmacological chaperone to facilitate the proper folding of the mutant enzyme by binding to its active site, thereby improving its stability and trafficking to the lysosomes in mammalian cells. The oral administration of 1-deoxygalactonojirimycin to transgenic mice expressing human mutant α-galactosidase A resulted in significant increases in α-galactosidase A activity in various organs, with concomitant reductions in globotriaosylceramide, which contributes to the pathology of Fabry disease. A total of 78 missense mutations were found to be responsive to 1-deoxygalactonojirimycin. The authors concluded that these data indicated that many patients with Fabry disease could potentially benefit from pharmacological chaperone therapy.
Pisani and co-workers (2017) noted that in 2009, the agalsidase beta shortage resulted in switching to agalsidase alfa treatment for many Fabry disease patients, offering the unique opportunity to compare the effects of the two drugs. Because single studies describing the effects of switching on the disease course were limited and inconclusive, these researchers performed a systematic review and meta-analysis of existing data. Relevant studies were identified in the PubMed, Cochrane, ISI Web, and SCOPUS databases from July 2009 to September 2015. The following parameters were analyzed: clinical events, changes in organ function or structure, disease-related symptoms, lyso-Gb3 plasma levels, and AEs. The nine studies (217 patients) included in this systematic review showed only marginal differences in most of the evaluated parameters; seven of these studies were included in the meta-analysis (176 patients). The pooled incidence rate of major AEs was reported for five studies (150 patients) and was equal to 0.04 events per person-year. No significant change was observed after the shift in glomerular filtration rate, whereas left ventricular mass index, left ventricular posterior wall dimension, and ejection fraction were significantly reduced over time. The authors concluded that these findings showed that the switch to agalsidase alfa was well-tolerated and associated with stable clinical conditions.
Sheng and colleagues (2019) noted that Fabry's disease is the most prevalent lysosomal storage disorder and is notorious for its early multi-organ involvement leading to complications, including ischemic strokes and transient ischemic attacks (TIAs). Since 2001, ERT has become the mainstay treatment for Fabry's patients, but the indications are not clearly defined. In a meta-analysis, these investigators reviewed the benefit of ERT for stroke prevention in Fabry's patients. They carried out a literature search from the National Center for Biotechnology Information (NCBI)/PubMed database without restriction of years for systematic review purposes. A systematic review of clinical cohort studies and trials was performed with pooled analysis of proportions. The pooled proportions and the CIs for stroke recurrence ratio were calculated for both the ERT treatment group and native treatment groups. A total of seven cohort studies and two RCTs involving 7,513 subjects (1,471 on ERT versus 6,042 on native treatment) met inclusion criteria. The pooled proportions analysis showed that the stroke recurrence ratio in the ERT treatment group was 8.2% [95% CI: 0.038 to 0.126], and in the native treatment group was 16% [95% CI: 0.102 to 0.217]. Effect differences favored the ERT treatment group over the native treatment group (p = 0.03). The authors concluded that this meta-analysis based on the currently available data showed that ERT for Fabry's disease has a beneficial effect on stroke prevention. Female carriers and atypically affected males could be started on ERT as soon as a diagnosis is made. These researchers stated that further studies are needed to support the role of ERT in stroke prevention.
In May 2023, the FDA approved Elfabrio (pegunigalsidase alfa-iwxj; Chiesi Farmaceutici S.p.A./Protalix Ltd.), a PEGylated enzyme replacement therapy (ERT), for the treatment of adults with confirmed Fabry disease. FDA approval was based on data outcomes from two clinical trials.
Trial 1 (NCT01678898) was an open-label dose-ranging study that evaluated Elfabrio in adults (n=18) diagnosed with Fabry disease who were ERT-naïve or who had not received ERT for more than 26 weeks and had a negative test for anti-pegunigalsidase alfa-iwxj IgG antibodies prior to enrollment. Two patients in the 1 mg/kg treatment group discontinued the trial after their first infusion; one of them discontinued due to a severe hypersensitivity reaction. The average number of globotriaosylceramide (Gb3) inclusions per renal peritubular capillary (PTC) in renal biopsy specimens of patients was assessed by light microscopy using the quantitative Barisoni Lipid Inclusion Scoring System (BLISS). Evaluable renal biopsies were obtained at baseline and at 26 weeks of treatment in 14 of the 16 patients who completed the study. The mean change from baseline at week 26 in the BLISS score (average number of Gb3 inclusions per renal PTC) for Elfabrio-treated patients was -3.1 (-4.8, -1.4) (95% CI) (Chiesi USA, 2023).
Trial 2 (NCT03566017) was a randomized, double-blind, and active-controlled study in ERT-experienced adults diagnosed with Fabry disease. Eligible patients were treated with agalsidase beta for at least one year prior to trial entry (the mean duration of agalsidase beta treatment prior to enrollment was 5.7 years). In the study, patients were randomly assigned to receive at least one dose of Elfabrio (pegunigalsidase alfa) (n=52) or agalsidase beta (n=25). The primary efficacy endpoint was the annualized rate of change in estimated glomerular filtration rate (eGFR slope) assessed over 104 weeks. The study found that Elfabrio was noninferior to agalsidase beta in controlling eGFR decline. The estimated mean eGFR slope was -2.4 and -2.3 mL/min/1.73 m²/year on Elfabrio and agalsidase beta, respectively. The estimated treatment difference was -0.1 mL/min/1.73 m²/year (95% CI, -2.3, 2.1) (Chiesi USA, 2023).
The most common adverse reactions (≥15%) for Elfabrio include infusion-associated reactions, nasopharyngitis, headache, diarrhea, fatigue, nausea, back pain, pain in extremities, and sinusitis.
Gaucher Disease
Gaucher's disease, the most prevalent lysosomal storage disorder, results from a deficiency of the enzyme glucocerebrosidase, leading to the accumulation of its substrate, glucocerebroside. This substrate can build up in various organs, including the spleen, liver, kidneys, lungs, brain, and bone marrow. Symptoms of the disease may include splenomegaly (enlarged spleen), hepatomegaly (enlarged liver), liver dysfunction, skeletal abnormalities, painful bone lesions, severe neurological complications, swollen lymph nodes and, occasionally, adjacent joints, abdominal distension, a brownish skin discoloration, anemia, low platelet counts, and yellow fatty deposits on the sclera. The disease follows an autosomal recessive inheritance pattern, affecting both males and females equally.
There are three primary clinical subtypes of Gaucher's disease. Type 1 (non-neuronopathic) is the most common form and can manifest in childhood or adulthood. Depending on the age of onset and severity, individuals with this subtype may live well into adulthood.
Type 2 (acute neuronopathic) typically presents within the first six months of life. In addition to the usual symptoms, this subtype is characterized by extensive and progressive brain damage, resulting in affected children usually not surviving beyond the age of two.
Type 3 (subacute or chronic neuronopathic) can begin in either childhood or adulthood, with individuals potentially living into their teenage years and beyond.
Type 1 Gaucher disease accounts for nearly 90% of diagnosed cases and does not affect the nervous system, whereas Types 2 and 3 involve neurological complications that often lead to intellectual disabilities. Approximately 55-60% of patients with Type 1 Gaucher disease present symptoms before the age of 20.
There are 34 known mutations associated with Gaucher disease, but four specific genetic mutations account for 95% of cases in the Ashkenazi Jewish population and 50% of cases in the general population. The incidence of Gaucher disease is approximately 1 in 75,000 births, with equal prevalence among males and females. In the Ashkenazi Jewish community, the prevalence is about 1 in 1,000, and 1 in every 12 to 15 individuals are carriers of the disease allele.
Currently, treatments available for Type 1 (non-neuronopathic) Gaucher disease include imiglucerase (Cerezyme), miglustat (Zavesca), taliglucerase alfa (Elelyso), and velaglucerase (VPRIV).
Alglucerase (Ceredase) was the first-generation enzyme replacement therapy (ERT) for Gaucher's disease, marketed by Genzyme Corp. (Cambridge, MA), while imiglucerase is Genzyme's second-generation product. Alglucerase has since been withdrawn from the market.
Cerezyme (imiglucerase) is a recombinant analogue of the human enzyme β-glucocerebrosidase, produced using recombinant DNA technology. β-Glucocerebrosidase is a lysosomal glycoprotein enzyme that catalyzes the hydrolysis of the glycolipid glucocerebroside into glucose and ceramide.
Cerezyme (imiglucerase) is indicated for long‐term enzyme replacement in pediatric and adult members with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions: anemia, thrombocytopenia, bone disease, hepatomegaly or splenomegaly. In January 2026, the FDA expanded the indication to include treatment of Type 3 Gaucher disease, non-central nervous system (CNS) manifestations, in both pediatric and adult patients. FDA approval was granted based on an observational study utilizing data from the International Collaborative Gaucher Group Gaucher Disease Registry (NCT00358943) involving patients with type 1 and type 3 Gaucher disease (GD). After two years of treatment with imiglucerase, significant improvements were observed in mean changes from baseline in hemoglobin, platelet count, liver volume, spleen volume, and height Z-score. Specifically, among 118 patients with type 3 GD, the mean baseline hemoglobin level was 10 g/dL, with a mean increase of 1.8 g/dL. Additionally, among 116 patients with type 3 GD, the mean baseline platelet count was 149×103/mm3, which increased by an average of 105×103/mm3.
Although there are no known contraindications, Cerezyme (imiglucerase) should be used with caution in members with: a known hypersensitivity to imiglucerase; who are pregnant or breastfeeding; less than two years of age as data in this population is not available; or a high risk for pulmonary hypertension. Members with respiratory symptoms should be evaluated for the presence of pulmonary hypertension. Adverse reactions reported in adults and pediatric patients include back pain, chills, dizziness, fatigue, headache, hypersensitivity reactions, nausea, pyrexia, and vomiting.
The use of Cerezyme (imiglucerase) should be directed by a qualified health care professional knowledgeable in the management of Gaucher's disease.
The International Collaborative Gaucher Group (ICGG) U.S. Regional Coordinators recommend that all children diagnosed with Gaucher disease receive enzyme replacement therapy (ERT). Children with Gaucher disease are at a high risk for irreversible and serious complications. A diagnosis of Gaucher disease during the first or second decade of life typically indicates a rapidly progressive disease course. Therefore, early intervention is crucial for these children, particularly while their skeletons are still developing, to help them achieve peak skeletal mass by early adulthood.
Velaglucerase alfa (gene-activated human glucocerebrosidase) (VPRIV) is an ERT used for treating Gaucher disease. Velaglucerase alfa is a hydrolytic enzyme that specifically targets glucocerebroside. It catalyzes the hydrolysis of glucocerebroside, thereby reducing the accumulation of this substrate.
Velaglucerase is produced using a human cell line through gene-activation technology and has an amino acid sequence identical to that of the naturally occurring human enzyme. Unlike imiglucerase, velaglucerase alfa contains the native human enzyme sequence. The kinetic parameters (K(m) and V(max)) and specific activities of velaglucerase alfa and imiglucerase are comparable. However, differences in glycosylation patterns reveal that velaglucerase alfa has a distinct structure compared to imiglucerase. The predominant glycan on velaglucerase alfa is a high-mannose type with nine mannose units, whereas imiglucerase features a chitobiose tri-mannosyl core glycan with fucosylation. These glycosylation differences influence cellular internalization; the rate of velaglucerase alfa internalization into human macrophages is at least twice that of imiglucerase (Brumshtein et al., 2010).
In 2010, Shire Human Genetic Therapies, Inc. reported positive outcomes from its first phase III study of velaglucerase alfa for treating Type 1 Gaucher disease. This trial was a 12-month, randomized, double-blind, parallel-group global study involving 25 treatment-naïve patients aged 2 years and older, evaluating velaglucerase alfa at doses of 45 U/kg and 60 U/kg. The primary endpoint, mean changes in hemoglobin concentration from baseline, showed a statistically significant increase of 23.3% (+2.43 ± 0.32 g/dL, p < 0.0001) at 12 months in the 60 U/kg group. Secondary endpoints for both doses included changes in platelet counts, organ volumes, surrogate markers of Gaucher disease, and for the 45 U/kg dose, changes in hemoglobin concentrations from baseline.
In January 2010, the FDA approved velaglucerase alfa for injection (VPRIV) for the treatment of children and adults with Type 1 Gaucher disease. This approval was based on a priority review of data from three clinical studies involving 82 patients aged 4 years and older, some of whom transitioned from imiglucerase therapy. The recommended regimen for velaglucerase is 60 IU/kg administered every other week as a one-hour intravenous infusion. The most common adverse reactions associated with VPRIV are allergic reactions. Other reported adverse effects include headache, dizziness, abdominal pain, back pain, joint pain, nausea, fatigue/weakness, fever, and prolongation of activated partial thromboplastin time. Pediatric patients were more likely than adults (with a greater than 10% difference) to experience rash, upper respiratory tract infections, prolonged partial thromboplastin time, and fever.
Caution should be exercised when administering VPRIV to patients who have shown symptoms of hypersensitivity to the active ingredient, excipients in the drug product, or other enzyme replacement therapies.
VPRIV carries a boxed warning for hypersensitivity reactions, including anaphylaxis, which occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Patients were not routinely pre‐medicated prior to infusion of VPRIV during clinical studies. The most commonly observed symptoms of hypersensitivity reactions were: headache, dizziness, hypotension, hypertension, nausea, fatigue/asthenia, and pyrexia/body temperature increased. Generally the reactions were mild and, in treatment‐naïve patients, onset occurred mostly during the first 6 months of treatment and tended to occur less frequently with time. Additional hypersensitivity reactions of chest discomfort, dyspnea, and pruritus have been reported in post‐marketing experience.
As with any intravenous protein product, hypersensitivity reactions are possible, therefore appropriate medical support including personnel adequately trained in cardiopulmonary resuscitative measures and access to emergency measures should be readily available when VPRIV is administered. If anaphylactic or other acute reactions occur, immediately discontinue the infusion of VPRIV and initiate appropriate medical treatment. The management of hypersensitivity reactions should be based on the severity of the reaction, e.g., slowing the infusion rate, treatment with medications such as antihistamines, antipyretics and/or corticosteroids, and/or stopping and resuming treatment with increased infusion time. In cases where patients have exhibited symptoms of hypersensitivity to the active ingredient or excipients in the drug product or to other enzyme replacement therapy, pre‐treatment with antihistamines and/or corticosteroids may prevent subsequent reactions.
The most common adverse reactions (10% or more) with VPRIV treatment include hypersensitivity reactions, headache, dizziness, abdominal pain, nausea, back pain, joint pain, prolonged activated PTT, fatigue/asthenia, and pyrexia.
Miglustat (Zavesca) is an oral ERT that has been approved by the FDA for the treatment of adult patients with mild-to-moderate Type 1 Gaucher disease for whom infusion/injection ERT is not a therapeutic option (e.g., due to constraints such as allergy, hypersensitivity, or poor venous access).
Zavesca (miglustat) is a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme responsible for the synthesis of glucosylceramide. Type 1 Gaucher patients are deficient in the enzyme glucocerebrosidase which is responsible for the degradation of glucosylceramide. Zavesca (miglustat) acts as a substrate reducer and allows the available glucocerebrosidase to act more efficiently.
In clinical studies, the most frequently reported adverse events associated with miglustat included weight loss, diarrhea, and hand tremors. The most common serious adverse reaction was peripheral neuropathy, characterized by tingling or numbness in the hands or feet, with or without pain. The labeling for Zavesca indicates that patients should undergo a neurological examination at the beginning of treatment and every six months thereafter. Additionally, Zavesca should be re-evaluated in patients who develop symptoms of peripheral neuropathy.
Approximately 85% of patients treated with Zavesca (miglustat) experienced diarrhea, with or without accompanying weight loss. The incidence of diarrhea tends to decrease over time, and patients are advised to avoid foods high in carbohydrates. If diarrhea persists despite standard interventions (such as dietary modifications), the patient should be assessed for any underlying gastrointestinal conditions.
Peripheral neuropathy has been reported, and all patients should receive regular neurological evaluations.
Around 30% of patients receiving Zavesca (miglustat) reported tremors or worsening of pre-existing tremors. A dose reduction may alleviate tremors within a few days, although some patients may need to discontinue the medication.
Pregnancy Category C: There are no adequate and well-controlled studies of Zavesca (miglustat) in pregnant women. It should only be used during pregnancy if the potential benefits outweigh the risks to the fetus.
Miglustat is available as Zavesca in 100 mg capsules. According to the labeling, the recommended dosage for treating adult patients with Type 1 Gaucher disease is one 100 mg capsule taken orally three times a day at regular intervals. The dosage may be reduced to 100 mg once or twice daily if tremors or diarrhea occur.
Combination therapy with Cerezyme (imiglucerase) and Zavesca (miglustat) is not recommended.
Taliglucerase alfa (Elelyso) is a recombinant human β-glucocerebrosidase derived from plant cells, used for the treatment of Gaucher disease.
Taliglucerase alfa is a hydrolytic enzyme that specifically targets glucocerebroside. It catalyzes the hydrolysis of glucocerebroside into glucose and ceramide. Taliglucerase is believed to function by facilitating the targeted delivery and uptake of tissue macrophages through the mannose lectin membrane system. Once inside the macrophage, taliglucerase degrades the accumulated glucocerebroside. While taliglucerase does not cure Gaucher disease, it helps reduce the clinical manifestations of hepatosplenomegaly and improves anemia and thrombocytopenia.
Zimran et al. (2011) conducted a phase III, double-blind, randomized, parallel-group, comparison-dose clinical trial (30 versus 60 U/kg body weight/infusion) across multiple countries. This 9-month study involved 20 infusions and included treatment-naïve adult patients with splenomegaly and thrombocytopenia, adhering to specific inclusion and exclusion criteria. Safety endpoints focused on drug-related adverse events, including antibody formation and hypersensitivity reactions. The primary efficacy endpoint was the reduction in splenic volume, measured by magnetic resonance imaging. Secondary endpoints included changes in hemoglobin levels, hepatic volume, and platelet counts, while exploratory parameters encompassed biomarkers and bone imaging. A total of 29 patients from 11 centers completed the protocol. No serious adverse events were reported; drug-related adverse events were mild to moderate and transient. Two patients (6%) developed non-neutralizing IgG antibodies, and two others (6%) experienced hypersensitivity reactions. Statistically significant reductions in spleen size were observed at 9 months: 26.9% (95% confidence interval [CI]: -31.9 to -21.8) in the 30-unit dose group and 38.0% (95% CI: -43.4 to -32.8) in the 60-unit dose group (both p < 0.0001). Significant improvements were also noted in all secondary efficacy endpoints, except for platelet counts in the lower dose group. These findings support the safety and efficacy of taliglucerase alfa for the treatment of Gaucher disease.
On May 1, 2012, the FDA approved taliglucerase alfa (Elelyso) for long-term enzyme replacement therapy for Type 1 Gaucher disease. Due to the limited number of affected patients, the effectiveness of Elelyso was assessed in a total of 56 patients with Type 1 Gaucher disease who participated in two clinical trials, many of whom continued treatment in a longer-term extension study. In a multi-center, double-blind, parallel-dose trial, the effectiveness of Elelyso as an initial therapy was evaluated in 31 adult patients who had not previously received enzyme replacement therapy. Patients were randomly assigned to receive Elelyso at a dose of either 30 or 60 units/kg. Both doses demonstrated effectiveness in reducing spleen volume, the primary endpoint of the study, with an average reduction of 29% in the 30 units/kg group and 40% in the 60 units/kg group after 9 months of treatment. Improvements were also observed in liver volume, blood platelet counts, and hemoglobin levels.
The effectiveness of Elelyso was further evaluated in another study involving 25 patients with Type 1 Gaucher disease who were switched from imiglucerase. In this multi-center, open-label, single-arm trial, patients who had been receiving imiglucerase for at least 2 years were transitioned to Elelyso infusions every other week at the same dosage as their previous imiglucerase treatment. Results indicated that Elelyso was effective in maintaining spleen and liver volumes, blood platelet counts, and hemoglobin levels over a 9-month evaluation period.
The most frequently reported adverse reactions for taliglucerase alfa (Elelyso) include the following:
- Treatment-naïve adults (occurring in 5% or more of patients) are headache, arthralgia, fatigue, nausea, dizziness, abdominal pain, pruritus, flushing, vomiting, and urticaria
- Patients who switched from imiglucerase after 9 months of treatment, the adverse reactions reported in 10% or more of cases include arthralgia, headache, and pain in the extremities.
Anaphylaxis has been observed in some patients treated with Elelyso. If anaphylaxis occurs, immediately discontinue infusion and initiate appropriate treatment
Cerdelga (eliglustat) is a glucosylceramide synthase inhibitor, targeting the enzyme responsible for producing glucosylceramide, which is the primary substrate of β-glucosidase, the enzyme that is deficient in Gaucher disease. In Gaucher disease, macrophages become engorged with glucosylceramide, leading to cellular and organ dysfunction. By inhibiting the formation of glucosylceramide, Cerdelga helps to mitigate the effects of the disease.
The U.S. Food and Drug Administration (FDA) approved eliglustat (Cerdelga) capsules for certain adult patients with Type 1 Gaucher disease (Genzyme, 2014) who are classified as CYP2D6 poor metabolizers (PMs), intermediate metabolizers (IMs), or extensive metabolizers (EMs). Eliglustat is a specific ceramide analogue that inhibits glucosylceramide synthase (IC50 = 10 ng/mL) and has a broad tissue distribution, resulting in decreased production of glucosylceramide, the substance that accumulates in the cells and tissues of individuals with Gaucher disease.
The FDA's approval was based on efficacy data from two positive Phase 3 studies of eliglustat: one involving treatment-naïve patients (Trial 1) and the other involving patients switching from approved enzyme replacement therapies (Trial 2) (Genzyme, 2014). The submission also included four years of efficacy data from the Phase 2 study of Cerdelga.
In Trial 1, significant improvements were observed across several endpoints after 9 months of treatment with eliglustat, including reductions in spleen size, increases in platelet levels, improvements in hemoglobin levels, and decreases in liver volume (Genzyme, 2014). Patients continued to receive eliglustat during the extension period, with most remaining on treatment for over eighteen months. Trial 2 demonstrated non-inferiority to enzyme replacement therapy (imiglucerase) based on a composite endpoint that included spleen volume, hemoglobin levels, platelet counts, and liver volume. Most patients in this trial have been on treatment for over two years.
The most common adverse reactions (occurring in ≥10% of patients) include fatigue, headache, nausea, diarrhea, back pain, pain in the extremities, and upper abdominal pain (Genzyme, 2014).
Eliglustat capsules are indicated for the long-term treatment of adults with Type 1 Gaucher disease (GD1) who are classified as CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as determined by an FDA-cleared test (Genzyme, 2014). Patients identified as CYP2D6 ultra-rapid metabolizers (URMs) may not achieve sufficient concentrations of Cerdelga to obtain a therapeutic effect. The labeling for Cerdelga specifies that a specific dose cannot be recommended for patients whose CYP2D6 genotype is indeterminate.
Eliglustat is contraindicated in patients who may experience significantly increased plasma concentrations of eliglustat, which could lead to prolongation of the PR, QTc, and/or QRS cardiac intervals, potentially resulting in cardiac arrhythmias. This includes EMs or IMs taking a strong or moderate CYP2D6 inhibitor alongside a strong or moderate CYP3A inhibitor, as well as IMs or PMs taking a strong CYP3A inhibitor (Genzyme, 2014).
The labeling indicates that drugs inhibiting CYP2D6 and CYP3A may significantly elevate eliglustat exposure, necessitating dose adjustments based on the patient's metabolizer status (Genzyme, 2014).
Due to the potential for increased ECG intervals at significantly elevated plasma concentrations, eliglustat is not recommended for patients with pre-existing cardiac conditions, long QT syndrome, or in combination with Class IA and Class III antiarrhythmic medications (Genzyme, 2014).
The labeling advises that eliglustat should only be used during pregnancy if the potential benefits outweigh the risks, as animal studies suggest it may cause fetal harm (Genzyme, 2014). It also recommends considering the importance of the drug to the mother when deciding whether to discontinue nursing. Eliglustat is not recommended for patients with moderate to severe renal impairment or those with hepatic impairment.
Cerdelga (eliglustat) therapy should be avoided in persons with the following concomitant conditions:
- Concurrent use of a strong or moderate CYP2D6 inhibitor (eg. paroxetine, terbinafine) with a strong or moderate CYP3A inhibitor (eg. ketoconazole) in patients who are extensive metabolizers (Ems) or IMs (intermediate metabolizers)
- Concurrent use of a strong CYP3A inhibitor in patients who are intermediate metabolizers (IMs) or poor metabolizers (PMs) (eg. ketoconazole, fluconazole).
Pastores and colleagues (2016) highlighted that anti-drug antibodies (ADA) can develop in response to biological therapies, potentially leading to decreased treatment efficacy and causing allergic reactions and other adverse effects. In clinical studies of velaglucerase alfa enzyme replacement therapy (ERT), patients with Gaucher disease were monitored for ADA every 6 to 12 weeks as part of various safety endpoints. A total of 289 patients aged 2 to 84 years (with a median age of 43) were evaluated for the development of anti-velaglucerase alfa antibodies across 10 studies conducted between April 2004 and March 2015. Among these, 64 patients were treatment-naïve at baseline, while 225 patients transitioned from imiglucerase to velaglucerase alfa treatment. The median duration of velaglucerase alfa treatment was 36.4 weeks (interquartile range [IQR]: 26.4 to 155.4 weeks). Only 4 patients (1.4%) tested positive for anti-velaglucerase alfa IgG antibodies, with 2 of these patients exhibiting neutralizing antibodies in vitro. Importantly, there were no significant changes in platelet counts, hemoglobin levels, or levels of CCL18 and chitotriosidase that would suggest clinical deterioration following the detection of anti-velaglucerase alfa antibodies, and no infusion-related adverse events were reported. The authors concluded that less than 2% of patients exposed to velaglucerase alfa developed antibodies, and there was no evident correlation between the presence of these antibodies and adverse events, pharmacodynamics, or clinical responses.
Lysosomal Acid Lipase Deficiency
Kanuma (sebelipase alfa) is a recombinant human lysosomal acid lipase (rhLAL) produced through recombinant DNA technology in the egg whites of genetically engineered chickens. The FDA has approved sebelipase alfa (Kanuma) for the treatment of patients diagnosed with lysosomal acid lipase deficiency (LAL-D).
LAL-D is a genetic, chronic, and progressive metabolic disorder that can lead to significant morbidity and premature mortality. It is classified as an ultra-rare disease, affecting fewer than 20 individuals per 1,000,000 in the general population.
The condition arises from genetic mutations that result in a significant decrease or complete loss of LAL enzyme activity in lysosomes across various body tissues. This deficiency leads to the chronic accumulation of cholesteryl esters and triglycerides in the liver, blood vessel walls, and other organs. Without treatment, infants with LAL-D often experience rapid disease progression, typically resulting in fatal outcomes within a few months. These infants may suffer from severe growth failure, liver fibrosis, and cirrhosis, with a median age of death at 3.7 months. An observational study indicated that approximately 50% of children and adults with LAL-D progressed to fibrosis, cirrhosis, or required liver transplantation within three years. The median age of onset for LAL-D is 5.8 years, and many older patients may remain asymptomatic while being at increased risk for developing fibrosis, cirrhosis, liver failure, accelerated atherosclerosis, and cardiovascular disease.
Prior to the approval of sebelipase alfa, there were no approved therapies for treating LAL deficiency. The standard of care consisted of supportive measures, including lipid-lowering therapies, vitamin E supplementation, hematopoietic stem cell transplantation (HSCT), and liver transplantation.
LAL enzyme activity can be measured using a Dried Blood Spot (DBS) test with the fluorimetric substrate 4-methylumbelliferyl palmitate. This method was the primary approach used in the clinical development program, including pivotal trials.
Sebelipase alfa functions as an enzyme replacement therapy that addresses the underlying cause of LAL-D by reducing substrate accumulation in lysosomes throughout the body. It binds to cell surface receptors via glycans on the protein and is subsequently internalized into lysosomes, where it catalyzes the hydrolysis of cholesteryl esters and triglycerides into free cholesterol, glycerol, and free fatty acids. Clinical studies have shown that treatment with Kanuma improved survival in infants with LAL-D and resulted in significant reductions in ALT levels and liver fat content, as well as notable improvements in lipid parameters in children and adults with the condition.
The FDA's approval of sebelipase alfa was based on data from two clinical studies and a supporting open-label extension study involving infants, pediatric, and adult patients with LAL-D. Results indicated a significant survival benefit (67%, or 6 out of 9 patients) in those with the infant form of LAL-D after 12 months of treatment, compared to 0 out of 21 patients in an untreated historical cohort. In pediatric and adult patients aged 4 to 58 years, treatment with sebelipase alfa led to greater reductions in ALT values and liver fat content, as measured by MRI, compared to placebo. Additionally, treated patients exhibited significant improvements in lipid parameters, including LDL-C, HDL-C, non-HDL-C, and triglycerides, compared to those receiving placebo. However, the clinical significance of these findings regarding cardiovascular morbidity and mortality or the progression of liver disease in LAL deficiency has not yet been established.
The most commonly reported adverse events in clinical trials for infants included diarrhea, vomiting, fever, rhinitis, anemia, cough, nasopharyngitis, and urticaria. In pediatric and adult patients, the most frequently reported adverse events were headache, fever, oropharyngeal pain, nasopharyngitis, asthenia, constipation, and nausea.
Hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with sebelipase alfa. In clinical trials, 3 out of 106 (3%) patients experienced signs and symptoms consistent with anaphylaxis during infusion, including chest discomfort, conjunctival injection, dyspnea, generalized itchy rash, hyperemia, eyelid swelling, rhinorrhea, severe respiratory distress, tachycardia, tachypnea, and urticaria. Anaphylaxis has been observed as early as the sixth infusion and as late as one year after treatment initiation.
In clinical trials, 21 out of 106 (20%) patients treated with sebelipase, including 9 out of 14 (64%) infants and 12 out of 92 (13%) pediatric patients aged 4 years and older, exhibited signs and symptoms consistent with or potentially related to hypersensitivity reactions. Common signs and symptoms included abdominal pain, agitation, fever, chills, diarrhea, eczema, edema, hypertension, irritability, laryngeal edema, nausea, pallor, pruritus, rash, and vomiting. Most reactions occurred during or within four hours of completing the infusion. Patients were not routinely pre-medicated prior to receiving sebelipase in these clinical trials.
Administration of sebelipase alfa should be supervised by a healthcare provider experienced in managing hypersensitivity reactions, including anaphylaxis. Additionally, the prescribing information advises providers to weigh the risks and benefits of treatment in patients with known systemic hypersensitivity reactions to eggs or egg products.
The most common adverse reactions listed in the prescribing information include:
- In infants with rapidly progressive LAL deficiency presenting within the first 6 months of life (30% or more): diarrhea, vomiting, fever, rhinitis, anemia, cough, nasopharyngitis, and urticaria.
- In pediatric and adult patients with LAL deficiency (8% or more): headache, fever, oropharyngeal pain, nasopharyngitis, asthenia, constipation, and nausea.
Mucopolysaccaridosis
Mucopolysaccharidosis (MPS) refers to a group of inherited metabolic disorders caused by the absence or dysfunction of specific enzymes necessary for the proper breakdown of glycosaminoglycans (formerly known as mucopolysaccharides), which are long chains of sugar molecules. This enzymatic deficiency leads to the accumulation of sugars in cells, blood, and connective tissues, resulting in various health complications. MPS is classified under a broader category of disorders known as lysosomal storage diseases. There are seven distinct forms of mucopolysaccharidosis, along with several subtypes: MPS I (Hurler, Hurler-Scheie, Scheie), MPS II (Hunter syndrome), MPS III (Sanfilippo syndrome), MPS IV (Morquio syndrome), MPS VI (Maroteaux-Lamy syndrome), MPS VII (Sly syndrome), and MPS IX. The associated signs, symptoms, and severity of the condition can vary significantly depending on the specific form. Generally, most individuals appear healthy at birth and undergo a period of normal development before experiencing a decline in physical and/or mental function. As the disease progresses, it can impact appearance, physical abilities, organ and system function, and, in most cases, cognitive development. The underlying genetic causes differ by form, with most cases inherited in an autosomal recessive manner, while MPS II follows an X-linked inheritance pattern. Treatment is tailored to the specific signs and symptoms present in each individual (NIH, 2020).
Noh and Lee (2014) noted that MPSs are a group of rare inherited metabolic disorders resulting from genetic defects in lysosomal enzyme production. Mucopolysaccharidoses are clinically diverse and are characterized by progressive deterioration in visceral, skeletal, and neurological functions. The authors reviewed the classification and pathophysiology of MPSs, as well as current therapies and new targeted agents under development. They conducted a Medline search through PubMed for relevant articles and treatment guidelines on MPSs published in English from 1970 to September 2013. The references in the identified articles, prescribing information for approved drugs, and recent clinical trial data from ClinicalTrials.gov were also reviewed. Until recently, supportive care was the only management option for MPSs. In the early 2000s, enzyme replacement therapy (ERT) was approved by the FDA for MPS I, II, and VI. Clinical trials demonstrated substantial improvements in somatic symptoms; however, no benefits were observed for neurological symptoms, as the enzymes do not effectively cross the blood-brain barrier (BBB). Hematopoietic stem cell transplantation (HSCT), another potential curative treatment, is not routinely recommended due to its high risk and lack of evidence for efficacy, except in preserving cognition and prolonging survival in young patients with severe MPS I. Recently, substrate reduction therapy (SRT) and gene therapy have gained recognition as promising therapeutic options. SRT employs an orally available small molecule drug (e.g., miglustat or eliglustat) that inhibits the initial step in glycosphingolipid biosynthesis, aiming to reduce the rate of biosynthesis to balance the catabolic defect. The authors concluded that ERT is effective for treating many somatic symptoms, particularly walking ability and respiratory function, and remains the cornerstone of MPS treatment. They noted that the utility of HSCT has not been adequately established for most MPSs, while SRT and gene therapy are still under investigation but hold promise for preventing neurodegeneration not addressed by ERT.
Parenti et al. (2014) highlighted that pharmacological chaperone therapy is an emerging strategy for treating lysosomal storage diseases. Small-molecule chaperones interact with mutant enzymes to promote their correct conformation and enhance stability. This approach offers significant advantages over existing therapies, particularly regarding drug bioavailability, oral administration, and positive impacts on patients' quality of life. However, future research must address important challenges, including the identification of novel chaperones to expand the patient population eligible for this treatment and optimize therapeutic efficacy. Developing new allosteric drugs is also crucial to mitigate the risk of inhibiting target enzymes. The authors concluded that future research should focus on exploring synergies between chaperone therapy and other treatment modalities.
In a subsequent publication, Parenti et al. (2015) stated that lysosomal storage diseases are rare, inherited metabolic disorders characterized by deficiencies in normal lysosomal function and the accumulation of undegraded substrates within lysosomes. Over the past 25 years, there has been remarkable progress in treating these diseases and developing multiple therapeutic strategies. These strategies include approaches aimed at increasing the residual activity of missing enzymes (such as ERT, HSCT, pharmacological chaperone therapy, and gene therapy) and methods focused on reducing substrate flux to lysosomes.
Giugliani et al. (2016) noted that mucopolysaccharidoses (MPSs) are progressive and often severe, with cognitive impairment occurring in a significant number of cases. This review did not cover established treatments (e.g., bone marrow/hematopoietic stem cell transplantation and traditional intravenous ERT), whose long-term outcomes have already been documented for MPS I, MPS II, and MPS VI. Instead, it focused on emerging therapies for MPSs, including intravenous ERT for MPS IVA and VII, intrathecal ERT, ERT with fusion proteins, substrate reduction therapy, gene therapy, and other novel approaches.
Mucopolysaccharidosis I (Hurler, Hurler-Scheie, and Scheie)
Mucopolysaccharidoses (MPSs) are a group of inherited lysosomal storage disorders caused by deficiencies in specific enzymes necessary for the degradation of glycosaminoglycans (GAGs), also known as mucopolysaccharides. Mucopolysaccharidosis I (MPS I) is a progressive, autosomal recessive genetic disorder resulting from a defect in the gene encoding the lysosomal enzyme alpha-L-iduronidase. It is estimated that around 1,000 individuals in the U.S. are affected by MPS I. The deficiency of this enzyme leads to the accumulation of glycosaminoglycans, specifically dermatan sulfate and heparan sulfate, which are components of the extracellular matrix and connective tissues throughout the body. The inability to break down GAGs results in their accumulation in lysosomes, causing dysfunction in cells, tissues, and organs.
MPS I presents a variety of clinical manifestations, including umbilical and inguinal hernias, skeletal abnormalities, recurrent upper respiratory tract infections, coarse facial features, arthropathy, hydrocephalus, spinal root and peripheral nerve entrapment, obstructive airway disease, sleep apnea, hearing loss, hepatosplenomegaly, corneal clouding, glaucoma, retinal degeneration, optic atrophy, and cardiac valvular and ischemic myocardial damage. Diagnosis of MPS I is confirmed through an enzyme assay that measures alpha-L-iduronidase activity in leukocytes, plasma, or cultured skin fibroblasts, with affected patients showing markedly deficient enzyme activity (less than 1% of normal). Prenatal diagnosis is also possible by measuring alpha-L-iduronidase activity in cultured amniocytes or chorionic villi.
MPS I is categorized into three broad groups based on the severity of symptoms: Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome. Scheie syndrome was previously classified as MPS V before being included under MPS I. MPS I can be viewed as a continuous spectrum of disease, with the most severely affected individuals at one end (Hurler syndrome) and those with milder symptoms (attenuated) at the other end (Scheie syndrome), with a range of severities in between. All individuals with MPS I exhibit an absence or insufficient levels of the enzyme alpha-L-iduronidase, which is essential for breaking down glycosaminoglycans (NIH, 2020).
Aldurazyme (laronidase) is an enzyme replacement therapy indicated for the treatment of mucopolysaccharidosis I (MPS I), a rare autosomal recessive lysosomal storage disorder caused by a deficiency of alpha-L-iduronidase. The lack of this enzyme leads to the accumulation of glycosaminoglycans (GAGs) in cells, resulting in various manifestations, including growth and developmental delays, enlargement of the spleen and liver, skeletal deformities, cardiac and pulmonary impairments, vision or hearing loss, and cognitive dysfunction.
Aldurazyme is indicated for enzyme replacement in patients with the Hurler and Hurler-Scheie forms of MPS I, as well as for Scheie patients with moderate to severe symptoms. Laronidase is administered to provide exogenous enzyme for uptake into lysosomes, thereby increasing the catabolism of GAGs. Clinical studies have demonstrated that enzyme replacement therapy with laronidase offers significant benefits, such as improved pulmonary function, enhanced walking ability, and reduced excess carbohydrate storage in organs.
In a randomized, placebo-controlled clinical trial conducted for FDA approval, 45 MPS I patients were assigned to receive either laronidase or placebo. After 26 weeks, those treated with laronidase exhibited statistically significant improvements in forced vital capacity (FVC) (median difference of 2% [95% CI: 0.4 to 7]) compared to the placebo group. Additionally, laronidase-treated patients showed a trend toward improvement in the distance walked in 6 minutes (median difference of 39 meters [95% CI: -2 to 79]) compared to placebo, although this difference was not statistically significant. Patients receiving laronidase also experienced reductions in liver size and urinary GAG levels compared to those on placebo.
Following the double-blind period, all 45 patients received open-label laronidase for 36 weeks. Patients who continued on laronidase maintained mean FVC and showed additional improvements in the distance walked in 6 minutes compared to the start of the open-label period. Those initially randomized to placebo also demonstrated improvements in mean FVC and distance walked in 6 minutes from baseline during the open-label phase.
Aldurazyme (laronidase) is available as a 0.58 mg/mL solution for injection in a 5 mL vial and is administered intravenously once weekly. The recommended dosage is 0.58 mg/kg of body weight given as an intravenous infusion. It is advised to pre-treat patients with antipyretics and/or antihistamines 60 minutes prior to the infusion. There is no published data on the effects of increasing laronidase doses beyond the FDA-recommended dosage. The FDA has mandated that the manufacturer conduct post-marketing studies to evaluate different dosages and schedules of laronidase in clinical response. Currently, there is no evidence supporting dosing laronidase beyond the recommended levels in the product labeling.
The most common adverse reactions (occurring in 10% or more of patients) associated with laronidase include:
- For patients aged 6 months and older: infusion reactions (such as pyrexia, chills, increased blood pressure, tachycardia, and decreased oxygen saturation).
- For patients aged 6 years and older: rash, upper respiratory tract infections, injection site reactions, hyperreflexia, paresthesia, flushing, and poor venous access.
- Aldurazyme (laronidase) should be used with caution and under close monitoring in patients with a history of hypersensitivity to laronidase.
Corrective surgery may be necessary for MPS I patients with joint contractures or deformities of the hands and feet. Corneal transplants may be required if vision problems become severe.
Grewal and colleagues (2005) reported their initial experience with the combined use of laronidase and hematopoietic stem cell transplantation in treating patients with Hurler syndrome (n = 12). They concluded that the combination of laronidase and HSCT is feasible and well-tolerated in children with Hurler syndrome. The development of antibodies against the exogenous enzyme did not appear to correlate with infusion reactions or responses to laronidase, indicating a need for a prospective study to assess the impact of concomitant ERT on transplant outcomes.
Xue and colleagues (2016) emphasized that ERT with laronidase plays a crucial role in treating patients with MPS I. Laronidase is considered safe and has demonstrated effectiveness in stabilizing or improving conventional clinical and laboratory markers of the disease. However, like most ERTs, laronidase induces an anti-drug IgG antibody response in over 90% of patients during the initial months of treatment. Preclinical data from an MPS I canine model suggested that these antibodies may impair enzyme uptake in target tissues. While direct evaluation of the effects on tissue GAG clearance is challenging, clinical studies have indicated a potential association between antibody development and reduced pharmacodynamic response, as well as hypersensitivity reactions. The authors conducted a comprehensive meta-analysis of pooled data from three clinical studies of laronidase (including one study with an extension) to provide a more robust assessment of the relationship between the antibody response to laronidase, clinical and laboratory markers of MPS I, and hypersensitivity reactions. The meta-analysis revealed an inverse relationship between the antibody response and the percentage reduction in urinary GAG (uGAG) levels. However, no significant relationships were found between the antibody response and changes in percent predicted forced vital capacity or the 6-minute walk test. The study also re-assayed stored serum samples from the original trials using a novel method to determine the inhibitory effect of antibodies. Patients with higher antibody exposure over time exhibited greater inhibition of enzyme uptake into cells. The authors concluded that high antibody exposure could lead to a corresponding level of enzyme uptake inhibition, diminishing the pharmacodynamic effect of the exogenously administered therapeutic enzyme, although no clear impact on clinical efficacy was observed.
Mucopolysaccharidosis II (Hunter Syndrome)
Mucopolysaccharidosis II (MPS II), also known as Hunter syndrome, is an X-linked recessive lysosomal storage disorder caused by a defect in the iduronate-2-sulfatase gene, which is responsible for breaking down the glycosaminoglycans heparan sulfate and dermatan sulfate within cells. MPS II is unique among mucopolysaccharidosis disorders in that only mothers can pass the defective gene to their sons, making affected females rare (NIH, 2020). The condition is diagnosed in approximately 1 in 65,000 to 132,000 births and typically becomes evident in children between 1 and 3 years of age. Symptoms include growth delays, joint stiffness, and coarsening of facial features. In severe cases, patients may experience neurological deficits, enlargement of the liver and spleen, cardiac and respiratory issues, and potentially death.
On July 24, 2006, the FDA approved idursulfase (Elaprase) from Shire Human Genetic Therapies, Inc. for the treatment of Hunter syndrome. Idursulfase was designated as an orphan drug and received approval following a randomized, double-blind, placebo-controlled clinical trial involving 96 patients, which demonstrated that treated subjects had improved walking capacity. At the conclusion of the 53-week study, patients receiving idursulfase infusions showed an average increase of 38 yards in the distance walked in 6 minutes compared to those on placebo. The most serious side effects reported during the trial included hypersensitivity reactions to idursulfase, which could be life-threatening, such as respiratory distress, drops in blood pressure, and seizures. Other common but less severe side effects included fever, headache, and joint pain. The recommended dosage regimen for idursulfase is 0.5 mg/kg administered weekly as an intravenous infusion.
Muenzer et al. (2012) noted that intravenous enzyme replacement therapy (ERT) with idursulfase for Hunter syndrome has not been shown to cross the blood-brain barrier and is not expected to do so. Most published experiences with ERT using idursulfase have involved patients without cognitive impairment (attenuated phenotype). There is limited formal guidance regarding ERT for cognitively impaired patients with the severe phenotype. An expert panel was convened to address these issues, and their clinical experience with 66 patients suggested that somatic improvements (such as reduced liver volume, increased mobility, and decreased frequency of respiratory infections) may occur in most severely affected patients, although cognitive benefits have not been observed. The panel agreed that severe patients should be considered candidates for at least a 6- to 12-month trial of ERT, excluding those who are severely neurologically impaired, in a vegetative state, or facing imminent death. It is crucial for the treating physician to discuss treatment goals, assessment methods, and criteria for discontinuation with the family before initiating ERT. The authors concluded that the decision to start ERT in severe Hunter syndrome should be made collaboratively by the physician and parents, based on realistic expectations of benefits and risks, with the understanding that ERT may be discontinued if no demonstrable benefits are observed.
Muenzer et al. (2016) reported that approximately two-thirds of patients with MPS II experience progressive cognitive impairment. Intravenous ERT does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. In a phase I/II study, these researchers investigated the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) using an intrathecal drug delivery device (IDDD). A secondary endpoint was the change in glycosaminoglycan concentration in cerebrospinal fluid (CSF). Sixteen cognitively impaired males with MPS II, who had previously received weekly intravenous idursulfase (0.5 mg/kg) for at least 6 months, were enrolled. Patients were randomized to receive no treatment or 1 mg, 10 mg, or 30 mg of idursulfase-IT monthly for 6 months (4 patients per group) while continuing weekly intravenous idursulfase. No serious adverse events related to idursulfase-IT were reported, although surgical revision or removal of the IDDD was necessary in 6 of 12 patients. A total of 12 doses were administered via lumbar puncture. Mean CSF glycosaminoglycan concentrations decreased by approximately 90% in the 10 mg and 30 mg groups and about 80% in the 1 mg group after 6 months. The authors concluded that these preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have only mild to moderate cognitive impairment.
In a 109-week, non-randomized observational study of MPS II patients already enrolled in the Hunter Outcome Survey (HOS), Giugliani and colleagues (2017) evaluated the long-term immunogenicity of idursulfase and examined the impact of idursulfase-specific antibody generation on treatment safety (via infusion-related adverse events [IRAEs]) and pharmacodynamics (via urinary glycosaminoglycans [uGAGs]). Male patients aged 5 years and older, enrolled in HOS regardless of their idursulfase treatment status, were eligible. Blood and urine samples for anti-idursulfase antibody testing and uGAG measurement were collected every 12 weeks. Due to challenges in enrolling treatment-naïve patients, data collection was limited to 26 enrolled patients out of a planned 100 (aged 5.1 to 35.5 years), with 15 (58%) completing the study. At baseline, 11 out of 26 (42%) patients were seropositive for antibodies (Ab+), and 2 out of 26 (8%) developed intermittent seropositivity by week 13. A total of 9 out of 26 patients (35%) had at least one sample positive for neutralizing antibodies. Baseline uGAG levels were low due to prior idursulfase treatment and did not change significantly thereafter. Ab+ patients consistently had higher uGAG levels at entry and throughout the study compared to Ab- patients; 9 out of 26 (34%) patients reported IRAEs. Ab+ patients appeared to have a higher risk of developing IRAEs than Ab- patients, although the relative risk (RR) was not statistically significant and decreased after adjusting for age. The authors concluded that 50% of study patients developed antibodies to idursulfase; notably, Ab+ patients had persistently higher average uGAG levels, but a clear association between IRAEs and antibody development was not established.
Muenzer et al. (2026) conducted a phase 1-2, open-label study (NCT04251026) on tividenofusp alfa, which consists of iduronate-2-sulfatase fused to an engineered transferrin receptor-binding Fc domain, aimed at treating the neurologic and peripheral manifestations of MPS II, a rare lysosomal disorder characterized by progressive multisystem and neurologic decline. In this study, 47 male participants (3 months to 13 years of age) with confirmed MPS II received weekly intravenous tividenofusp alfa for 24 weeks, followed by an 80-week safety extension and a 157-week open-label extension, with the primary objective being the evaluation of the drug's safety. Secondary objectives included assessing central nervous system (CNS) and peripheral effects through cerebrospinal fluid (CSF) and urinary heparan sulfate levels, adaptive behavior using the Vineland Adaptive Behavior Scales, and liver volume. At the 24-week primary analysis, all participants reported at least one adverse event, predominantly infusion-related reactions such as pyrexia, urticaria, and vomiting, affecting over 40% of participants despite routine premedication. Three participants experienced serious treatment-related adverse events but continued treatment. Notably, CSF and urinary heparan sulfate levels decreased significantly from baseline by 91% and 88%, respectively, and while adverse events remained common throughout the study, reductions in heparan sulfate levels were sustained through week 153, with adaptive behavior stabilizing or improving and liver volumes normalizing or remaining normal. The authors concluded that while tividenofusp alfa treatment was frequently associated with adverse events, it effectively reduced heparan sulfate levels to those comparable to unaffected children. A randomized trial is ongoing to further investigate these effects.
In March 2026, the FDA granted accelerated approval of tividenofusp alfa-eknm, a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme branded as Avlayah (Denali Therapeutics, Inc.), for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment. Approval is based on results from a phase 1/2 multi-cohort, single-arm, open-label trial that enrolled 47 pediatric patients with Hunter syndrome aged 3 months to 13 years. In the trial, Avlayah was found to significantly reduce cerebrospinal fluid heparan sulfate (CSF HS), a type of glycosaminoglycan. The 44 patients with measurements at Week 24 had a 91% average decrease from baseline in CSF HS. The minimum and maximum percentage change in CSF HS from baseline were 72% and 98%, respectively. At baseline, no patients had CSF HS levels below the upper limit of normal (ULN). At Week 24, 93% of Avlayah-treated patients with CSF measurements had CSF HS levels below the ULN (FDA, 2026).
The FDA labeling for Avlayah includes a boxed warning for potential allergic reactions, including anaphylaxis, necessitating that therapy be initiated in a healthcare setting with appropriate medical monitoring. Warnings and precautions also includes risk for infusion-associated reaction (IAR), anemia, and membranous nephropathy. The most common adverse effects (20% or more) include IAR, upper respiratory tract infections, ear infection, pyrexia, anemia, cough, vomiting, diarrhea, rash, COVID-19, rhinorrhea, nasal congestion, falls, headache, skin abrasions, and urticaria.
Mucopolysaccharidosis IV (Morquio Syndrome)
Mucopolysaccharidosis IV (MPS IV A and B), commonly referred to as Morquio syndrome, is an autosomal recessive mucopolysaccharide storage disorder. There are two forms of Morquio syndrome: Type A and Type B, both of which exhibit similar clinical features and follow autosomal inheritance patterns. MPS IV A is caused by mutations in the gene encoding galactosamine-6-sulfatase (GALNS), located at 16q24.3, while MPS IV B results from a deficiency of beta-galactosidase. The clinical manifestations of these conditions arise from the accumulation of keratan sulfate and chondroitin-6-sulfate.
The enzymes that are deficient in Morquio syndrome (MPS IV) are galactosamine-6-sulfatase (N-acetyl-galactosamine-6-sulfate sulfatase) and β-galactosidase. Diagnosis is confirmed through direct enzymatic assays conducted on leukocytes or fibroblasts.
The deficiency of these enzymes leads to excessive lysosomal storage of keratan sulfate in various tissues and organs. This accumulation results in systemic skeletal dysplasia, short stature, and joint abnormalities that limit mobility and endurance. Thoracic malformations can impair respiratory function, while malformations of the cervical vertebrae and ligamentous weakness may lead to cervical spinal instability and potential cord compression. Other symptoms may include hearing loss, corneal clouding, and heart valve disease. Morquio A syndrome is estimated to occur in approximately 1 in 200,000 to 300,000 live births, with symptoms typically beginning between the ages of 1 and 3.
Vimizim (elosulfase alfa) is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme that has been approved by the FDA for the treatment of Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome). The FDA's approval of elosulfase was based on a randomized controlled clinical trial and an uncontrolled extension study.
A 24-week, randomized, double-blind, placebo-controlled clinical trial involving 176 patients with MPS IVA, aged 5 to 57 years, was conducted. Patients were assigned to one of three treatment groups: elosulfase alfa 2 mg/kg once weekly (n = 58), elosulfase alfa 2 mg/kg once every other week (n = 59), or placebo (n = 59). All patients received antihistamines prior to each infusion. The primary endpoint was the change from baseline in the distance walked in 6 minutes (6-minute walk test, 6-MWT) at Week 24. Secondary endpoints included changes from baseline in the rate of stair climbing over 3 minutes (3-minute stair climb test, 3-MSCT) and changes in urine keratan sulfate (KS) levels at Week 24. The treatment effect for the distance walked in 6 minutes, compared to placebo, was 22.5 meters (95% CI: 4.0 to 40.9; p = 0.0174) for patients receiving elosulfase 2 mg/kg once weekly. No significant difference was observed in the rate of stair climbing between the elosulfase once-weekly group and the placebo group. Patients receiving elosulfase 2 mg/kg every other week performed similarly in both the 6-MWT and 3-MSCT compared to those on placebo. The reduction in urinary KS levels from baseline, indicating pharmacodynamic effect, was greater in the elosulfase treatment groups compared to placebo. However, the FDA labeling states that the relationship between urinary KS levels and other measures of clinical response has not been established.
Patients who participated in the placebo-controlled trial were eligible to continue treatment in an open-label extension trial, with 173 of the 176 patients enrolling. In this extension trial, patients received elosulfase 2 mg/kg once weekly (n = 86) or elosulfase 2 mg/kg once every other week (n = 87). Among those who continued receiving elosulfase 2 mg/kg once weekly for an additional 48 weeks (for a total of 72 weeks of exposure), walking ability showed no further improvement beyond the first 24 weeks of treatment in the placebo-controlled trial.
The most common side effects reported in patients treated with elosulfase alfa during clinical trials included fever, vomiting, headache, nausea, abdominal pain, chills, and fatigue. The FDA-approved labeling indicates that the safety and effectiveness of elosulfase alfa have not been established in pediatric patients under 5 years of age.
Elosulfase alfa was approved with a boxed warning regarding the risk of anaphylaxis. During clinical trials, some patients experienced life-threatening anaphylactic reactions during Vimizim infusions. Symptoms of anaphylaxis included cough, erythema, throat tightness, urticaria, flushing, cyanosis, hypotension, rash, dyspnea, chest discomfort, and gastrointestinal symptoms, which occurred during infusions regardless of the duration of treatment. Patients should be closely monitored during and after Vimizim administration, and they should be informed about the signs and symptoms of anaphylaxis, seeking immediate medical attention if symptoms arise. Patients with acute respiratory illnesses may be at increased risk for serious exacerbations of their respiratory compromise due to hypersensitivity reactions and require additional monitoring.
Elosulfase alfa is available as Vimizim in 5 mg/5 mL single-use vials for intravenous infusion. The recommended dose is 2 mg/kg administered intravenously over a minimum of 3.5 to 4.5 hours, depending on infusion volume, once weekly. The most common adverse reactions (10% or more) include pyrexia, vomiting, headache, nausea, abdominal pain, chills, and fatigue.
Melton and colleagues (2017) noted that many enzyme replacement therapies (ERTs) for lysosomal storage disorders utilize the cation-independent mannose-6-phosphate receptor (CI-M6PR) on the cell surface to facilitate delivery to lysosomes. However, neutralizing antibodies (NAbs) may interfere with this process. These researchers previously reported that most individuals with Morquio A who received elosulfase alfa in the phase III MOR-004 trial tested positive for NAbs capable of interfering with binding to the CI-M6PR ectodomain in an ELISA-based assay. However, no correlation was found between the occurrence of NAbs and clinical efficacy or pharmacodynamics. To quantify and better characterize the impact of NAbs, the investigators developed a functional cell-based flow cytometry assay with a titer step to detect antibodies that could interfere with elosulfase alfa uptake. Serum samples collected during the MOR-004 trial were tested, and titers were determined. Consistent with earlier findings regarding NAb positivity, no correlations were observed between NAb titers and clinical outcomes in elosulfase alfa-treated individuals with Morquio A.
Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome)
Naglazyme (galsulfase) is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for the treatment of Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome). MPS VI is an autosomal recessive disorder caused by a deficiency in arylsulfatase B activity, which is essential for the breakdown of glycosaminoglycans (GAGs). The accumulation of GAG residues within cells disrupts normal cellular function, leading to progressive dysfunction in cells, tissues, and organs. Naglazyme (galsulfase) is specifically indicated for patients with MPS VI.
Mucopolysaccharidosis VI (MPS VI), also known as Maroteaux-Lamy syndrome, is a debilitating and life-threatening genetic disorder resulting from a deficiency of the enzyme N-acetylgalactosamine 4-sulfatase. This deficiency leads to the accumulation of glycosaminoglycans in lysosomes, causing progressive dysfunction across cellular, tissue, and organ systems. It is estimated that around 1,100 individuals in the developed world are affected by MPS VI. While some patients experience rapid disease progression, others may not show signs and symptoms until adolescence. Nevertheless, the multisystemic abnormalities and significant functional disabilities associated with MPS VI can be life-altering. Most patients with MPS VI succumb to disease-related complications between childhood and early adulthood.
Harmatz and colleagues (2004) evaluated the safety and efficacy of weekly treatment with human recombinant N-acetylgalactosamine 4-sulfatase (rhASB) in individuals with MPS VI. Patients were randomized to receive weekly infusions of either a high dose (1.0 mg/kg) or a low dose (0.2 mg/kg) of rhASB. Six patients (3 males and 3 females, aged 7 to 16 years) completed at least 24 weeks of treatment, with 5 of them completing at least 48 weeks. The study found no drug-related serious side effects, significant laboratory abnormalities, or allergic reactions. The high-dose group demonstrated a more rapid and sustained relative reduction in urinary glycosaminoglycan levels through week 48. Improvements in the 6-minute walk test were noted in all patients, with particularly dramatic gains in those who initially walked less than 100 meters. Additionally, shoulder range of motion improved in all patients by week 48, and joint pain decreased in those who had significant pain at baseline. The authors concluded that rhASB treatment was well-tolerated and led to a dose-dependent reduction in lysosomal storage, as indicated by decreased urinary glycosaminoglycan levels. Clinical responses were observed in all patients, with the most significant improvements seen in those with advanced disease receiving high-dose rhASB.
On June 1, 2005, galsulfase (Naglazyme, BioMarin Pharmaceutical Inc., Novato, CA) received orphan drug status from the FDA for the treatment of MPS VI. Galsulfase has been reported to enhance endurance, as evidenced by improvements in the 12-minute walk test and the 3-minute stair climb test. It also reduces urinary excretion of glycosaminoglycans, indicating enzymatic bioactivity in patients with MPS VI.
Naglazyme (galsulfase) is available as a 1 mg/mL solution for injection in 5 mL vials. The recommended dosage of Naglazyme (galsulfase) is 1 mg per kg of body weight, administered once weekly as an intravenous infusion.
The most common adverse reactions (occurring in 10% or more of patients) include rash, pain, urticaria, fever, itching, chills, headache, nausea, vomiting, abdominal pain, and dyspnea. Infusion-related reactions are the most frequent adverse reactions that require medical intervention.
Decker et al. (2010) report that growth failure is a hallmark of untreated mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy syndrome). The authors examined growth in 56 MPS VI patients aged 5 to 29 years before and during up to 240 weeks of weekly infusions of recombinant human arylsulfatase B (rhASB) at a dosage of 1 mg/kg across various clinical trial phases (Phase 1/2, Phase 2, Phase 3, and Phase 3 Extension). Data on height, weight, and Tanner stages were collected and analyzed to assess mean height increase by treatment week, as well as the effects of pubertal status, baseline urinary glycosaminoglycans (GAG), and age at treatment initiation. The growth rate for approximately two years before and after treatment initiation was evaluated using longitudinal modeling. Results indicated a mean height increase of 2.9 cm after 48 weeks and 4.3 cm after 96 weeks of enzyme replacement therapy (ERT), with no correlation found between growth on ERT and baseline urinary GAG levels. Patients under 16 years of age experienced the most significant height increases during treatment. The analysis of pooled data revealed a notable improvement in growth rate over the 96 weeks of ERT compared to the equivalent pretreatment period. Among the 10 patients who exhibited delayed pubertal onset or progression upon entering the trials, all advanced at least one Tanner stage during the two years on ERT, with 6 (60%) completing puberty. In conclusion, the analysis of mean height and longitudinal modeling demonstrates a significant increase in height and growth rate in MPS VI patients receiving long-term ERT, particularly in those younger than 16 years. This height increase may be attributed to bone growth and/or a reduction in joint contractures, with improvements in general health, bone cell health, nutrition, endocrine function, and reduced inflammation potentially contributing to enhanced bone growth and resolution of delayed puberty.
Mucopolysaccharidoses VII (Sly Syndrome)
MPS VII is an autosomal recessive lysosomal storage disorder caused by deficiency of beta-glucuronidase (NORD, 2017). The deficiency in beta-glucuronidase leads to the accumulation of mucopolysaccharides in many tissues and organs of the body. MPS VII affects less than 150 patients worldwide (FDA, 2017). The features of MPS VII vary, but most affected individuals have skeletal abnormalities that become more pronounced with age, including short stature and changes in bones visible on X-rays (dysostosis multiplex). Patients can also develop aortic regurgitation, hepatomegaly, splenomegaly, and narrowed airways which can lead to pulmonary infections and trouble breathing. The life expectancy of individuals with MPS VII depends on the severity of symptoms. Some affected individuals do not survive infancy, while others may live into adolescence or adulthood. Heart disease and airway obstruction are major causes of death in people with MPS VII. Affected individuals may have developmental delay and progressive intellectual disability.
Urinary levels of the mucopolysaccharides (dermatan sulfate, heparan sulfate, and chondroitin sulfate) are increased in affected individuals (NORD, 2017). The diagnosis of MPS VII may be confirmed by specialized tests that measure the level of beta-glucuronidase activity in blood or skin cells. Molecular genetic testing for mutations in the GUSB gene is available to confirm the diagnosis.
The U.S. Food and Drug Administration (FDA) approved vestronidase alfa-vjbk (Mepsevii) to treat pediatric and adult patients with an MPS VII (FDA, 2017). The safety and efficacy of vestronidase alfa-vjbk were established in clinical trial and expanded access protocols enrolling a total of 23 patients ranging from 5 months to 25 years of age. Patients received treatment with vestronidase alfa-vjbk at doses up to 4 mg/kg once every two weeks for up to 164 weeks. Efficacy was primarily assessed via the six-minute walk test in ten patients who could perform the test. After 24 weeks of treatment, the mean difference in distance walked relative to placebo was 18 meters. Additional follow-up for up to 120 weeks suggested continued improvement in three patients and stabilization in the others. Two patients in the vestronidase alfa-vjbk development program experienced marked improvement in pulmonary function. The product labeling for Mepsevii states that the effect of vestronidase alfa-vjbk on the central nervous system manifestations of MPS VII has not been determined.
The FDA is requiring the manufacturer to conduct a post-marketing study to evaluate the long-term safety of the product (FDA, 2017).
The most common side effects after treatment with vestronidase alfa-vjbk include infusion site reactions, diarrhea, rash and anaphylaxis (FDA, 2017).
The labeling includes a black box warning about anaphylaxis with Mepsevii administration (Ultragenyx, 2017).
Mepsevii is available as 10 mg/5 mL (2 mg/mL) in a single-dose vial (Ultragenyx, 2017). The recommended dosage is 4 mg/kg administered every two weeks as an intravenous infusion.
Neuronal Ceroid Lipofuscinosis type 2 (CLN2)
The U.S. Food and Drug Administration (FDA) has approved cerliponase alfa (Brineura) to slow the loss of ambulation in symptomatic pediatric patients aged 3 years and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency, a variant of Batten disease.
CLN2 disease is a rare and rapidly progressive fatal neurological condition that affects fewer than one in a million residents in the U.S. Approximately 20 children are born with CLN2 disease each year in the U.S. Affected children typically lose the ability to walk and talk by around 6 years of age. In the later stages of the disease, daily activities such as feeding become increasingly difficult, with death often occurring between the ages of 8 and 12.
Children with CLN2 disease usually begin experiencing seizures between the ages of 2 and 4, often preceded by delays in language development. The disease progresses quickly, with most children losing the ability to walk and talk by approximately 6 years of age. Initial symptoms are followed by movement disorders, motor deterioration, dementia, blindness, and ultimately death, typically occurring between 8 and 12 years of age. As the disease advances, managing daily needs becomes increasingly challenging.
Neuronal ceroid lipofuscinoses (NCLs) are a diverse group of lysosomal storage disorders that include the autosomal recessive neurodegenerative disorder CLN2 disease. This condition is caused by mutations in the TPP1 gene, leading to deficient activity of the enzyme tripeptidyl peptidase 1 (TPP1). In the absence of TPP1, lysosomal storage materials that are normally metabolized by this enzyme accumulate in various organs, particularly in the brain and retina. The buildup of these materials in nervous system cells contributes to progressive neurodegeneration, resulting in the loss of cognitive, motor, and visual functions.
Cerliponase alfa is a recombinant form of human tripeptidyl peptidase 1 (TPP1), the enzyme that is deficient in patients with CLN2 disease. It is an enzyme replacement therapy designed to restore TPP1 activity and break down the storage materials that cause CLN2 disease. To reach the brain and central nervous system, the treatment is delivered directly into the cerebrospinal fluid surrounding the brain using BioMarin's patented technology.
Cerliponase alfa is a prescription medication indicated to slow the loss of ambulation in symptomatic pediatric patients aged 3 years and older with CLN2 disease. It is administered via infusion directly into the cerebrospinal fluid through an intraventricular injection, using sterile techniques to minimize the risk of infection. An intraventricular access device or port must be in place at least 5 to 7 days prior to the first infusion. Intraventricular access device-related infections have been reported with cerliponase alfa treatment, and patients should be monitored for signs of infection. The access device may need to be replaced over time.
In clinical trials, cerliponase alfa demonstrated the ability to slow the loss of ambulation in symptomatic pediatric patients with CLN2 disease. It is the first enzyme replacement therapy to be directly administered to the brain, addressing the underlying cause of the condition by replacing the deficient TPP1 enzyme. The therapy is delivered directly into the cerebrospinal fluid using an established technique commonly used in oncology—intravenous administration.
The approval was supported by safety and efficacy data collected over 96 weeks in a non-randomized, single-arm dose escalation clinical study involving patients with CLN2 disease. Patients treated with cerliponase alfa were compared to untreated patients from a natural history cohort.
Patients were evaluated for decline in the motor domain of the CLN2 Clinical Rating Scale, which measures mobility performance, with a normal function score of 3 and no function score of 0. A decline was defined as a sustained 2-point decrease or an unreversed score of 0 in the motor domain of the scale.
Twenty-four patients aged 3 to 8 years were enrolled in the clinical study. One patient withdrew after week 1 due to an inability to continue with study procedures, leaving 23 patients who received cerliponase alfa every other week for 48 weeks and continued treatment during the extension phase.
Results from the 96-week analysis indicated that the odds of cerliponase alfa-treated patients not experiencing a decline were 13 times greater than those in the natural history cohort (Odds Ratio (95% Confidence Interval): 13.1 (1.2, 146.9)).
Of the 22 patients treated with cerliponase alfa and evaluated for efficacy at week 96, 21 (95%) did not show a decline, while the only patient who terminated early was the only one to have a decline in the motor domain of the CLN2 Clinical Rating Scale. In contrast, 50% of patients in an independent natural history cohort exhibited progressive decline in motor function. Two cerliponase alfa-treated patients with maximum scores were excluded from the analyses, as they maintained that score throughout the study.
In the clinical study, intraventricular access device-related infections were reported in two patients. In both cases, antibiotics were administered, the access device was replaced, and the patients continued treatment with cerliponase alfa. Hypotension was observed in 2 (8%) patients, occurring during or up to 8 hours after cerliponase alfa infusion. These patients did not require treatment alterations, and the reactions resolved spontaneously or after intravenous fluid administration.
Hypersensitivity reactions were reported in 11 (46%) of the cerliponase alfa-treated patients during the clinical studies. Undesirable or hypersensitivity reactions related to cerliponase alfa treatment, including fever, vomiting, and irritability, may occur during treatment and as late as 24 hours after infusion. Patients may receive medications such as antihistamines prior to cerliponase alfa infusions to mitigate the risk of reactions. Serious allergic reactions, including anaphylaxis, may occur. If a severe reaction occurs, the infusion should be stopped immediately, and appropriate medical treatment should be initiated.
The most common adverse reactions (occurring in 8% or more of patients) include fever, ECG abnormalities, decreased cerebrospinal fluid (CSF) protein, vomiting, seizures, device-related complications, hypersensitivity, increased CSF protein, hematoma, headache, irritability, pleocytosis, device-related infections, bradycardia, feelings of jitteriness, and hypotension.
The Brineura label includes the following contraindications:
- Any sign or symptom of acute or unresolved localized infection at or around the device insertion site (e.g., cellulitis or abscess) or suspected or confirmed central nervous system infection (e.g., cloudy CSF, positive CSF gram stain, or meningitis).
- Any acute complication related to the intraventricular access device (e.g., leakage, fluid extravasation, or device failure).
- Patients with ventriculoperitoneal shunts.
A phase 2, open-label clinical trial (NCT02678689) was conducted to evaluate cerliponase alfa in symptomatic and presymptomatic CLN2 patients under 18 years of age. The trial enrolled 14 patients aged 1 to 6 years at baseline, including 8 patients under 3 years of age. Patients received cerliponase alfa at the recommended dose every 2 weeks via intraventricular infusion for 144 weeks (1 patient withdrew to receive commercial treatment). The mean baseline CLN2 Motor score was 2.3 (standard deviation (SD) 0.83), with a range from 1 to 3. Thirteen of the 14 treated patients were matched with up to 3 natural history comparators based on age within 3 months, equal CLN2 Motor score, and genotype (0, 1, or 2 key mutations). None of the cerliponase alfa-treated patients (N=14) experienced a 2-point decline or a score of zero in the Motor scale by Week 169. Among the matched natural history comparators (N=31), 20 subjects (65%) had an unreversed 2-point decline or a score of zero by the last assessment. The median time to an unreversed 2-point decline in Motor score or a score of 0 was 133 weeks among the natural history comparators, which was not reached by the last assessment (Week 169) in patients treated with cerliponase alfa. In patients under 3 years of age, none (0%) of the cerliponase alfa-treated patients (N=8) experienced a 2-point decline or a score of zero in the Motor score by Week 169. Among the 8 treated patients, 7 were matched to 18 untreated patients from the natural history cohort. Among the matched natural history comparators (N=18), 11 subjects (61%) had an unreversed 2-point decline or a score of zero in the Motor score by the last assessment. All seven treated patients under 3 years of age with a motor score of 3 at baseline maintained that score at the last measured timepoint, indicating grossly normal gait. In this population, cerliponase alfa-treated patients demonstrated a delay in disease onset.
In July 2024, the FDA approved a supplemental Biologics License Application (sBLA) for cerliponase alfa (Brineura) to slow the loss of ambulation in children of all ages with neuronal ceroid lipofuscinosis type 2 (CLN2 disease). This expanded indication now includes children of all ages with CLN2 disease, regardless of whether they are symptomatic or presymptomatic. The sBLA was supported by data from the phase 2, open-label, multicenter trial (NCT02678689) that evaluated Brineura treatment over approximately three years in children aged 1 to 6 years at baseline, including eight children under 3 years of age who received cerliponase alfa according to the recommended dosing regimen based on age for up to 144 weeks. The data demonstrated that intraventricular-administered Brineura slowed the decline in motor function and delayed disease onset in children with CLN2 disease, including those under 3 years of age. The safety profile in this population was similar to the known safety profile of the medication. Furthermore, the data indicated that early initiation of treatment before 3 years of age may result in a delay in disease onset.
Niemann-Pick Disease, Type C
According to the National Organization for Rare Disorders (NORD, 2017), Niemann-Pick disease type C (NPC) is a rare progressive genetic disorder characterized by an inability of the body to transport cholesterol and other lipids inside of cells, which leads to abnormal accumulation within various tissues of the body, including brain tissue. Individuals with NPC have mutations in one of two genes, NPC1 or NPC2. Symptoms can present from the perinatal period until late adulthood.NPC affects neurologic and psychiatric functions, as well as various visceral organs. Symptoms arise at different times and follow independent progression. Visceral symptoms are more typically seen in individuals presenting at a younger age. Neurologic and psychiatric symptoms often occur slowly over time, and thus feature more prominently in individuals presenting in the later age groups.Current treatment is directed toward the specific symptoms apparent in each individual. Miglustat (Zavesca) may be able to slow the progression of neurological symptoms associated with NPC. Miglustat blocks the synthesis of glycosphingolipids, one of the substances that accumulates in the brain of individuals with NPC. Miglustat has been used off-label in the U.S. to treat individuals with NPC.
Pineda et al. (2018) state that miglustat is indicated for the treatment of progressive neurological manifestations in both adults and children. The authors conducted a comprehensive review of published data from studies of cellular neuropathological markers and structural neurological indices in the brain, clinical impairment/disability, specific clinical neurological manifestations, and patient survival. The authors found that "cranial diffusion tensor imaging and magnetic resonance spectroscopy studies have shown reduced levels of choline (a neurodegeneration marker), and choline/N-acetyl aspartate ratio (indicating increased neuronal viability) in the brain during up to 5 years of miglustat therapy, as well as a slowing of reductions in fractional anisotropy (an axonal/myelin integrity marker). A 2-year immunoassay study showed significant reductions in CSF-calbindin during treatment, indicating reduced cerebellar Purkinje cell loss. Magnetic resonance imaging studies have demonstrated a protective effect of miglustat on cerebellar and subcortical structure that correlated with clinical symptom severity. Numerous cohort studies assessing core neurological manifestations (impaired ambulation, manipulation, speech, swallowing, other) using NP-C disability scales indicate neurological stabilization over 2–8 years, with a trend for greater benefits in patients with older (non-infantile) age at neurological onset. A randomized controlled trial and several cohort studies have reported improvements or stabilization of saccadic eye movements during 1–5 years of therapy. Swallowing was also shown to improve/remain stable during the randomized trial (up to 2 years), as well as in long-term observational cohorts (up to 6 years). A meta-analysis of dysphagia – a potent risk factor for aspiration pneumonia and premature death in NP-C – demonstrated a survival benefit with miglustat due to improved/stabilized swallowing function". The authors concluded that the effects of miglustat on neurological manifestations has been assessed using a range of approaches, with benefits ranging from cellular changes in the brain through to visible clinical improvements and improved survival.
Pompe Disease
Infantile Pompe disease (IPD), also known as infantile acid maltase deficiency and type 2 glycogen storage disease, is an autosomal recessive muscle-wasting disorder due to a deficiency of the lysosomal enzyme acid alpha-glucosidase. The deficiency results in accumulation of glycogen in lysosomes and is characterized by progressive cardiomyopathy, skeletal muscle weakness and respiratory insufficiency leading to death in early infancy. Pompe disease is estimated to occur in about 1 in 40,000 live births.
Recombinant human alglucosidase alfa (rhGAA; Myozyme) provides exogenous human lysosomal acid alpha‐glucosidase. Once available systemically, alglucosidase alfa mimics endogenous acid alpha‐glucosidase. Alglucosidase alfa is indicated for use in members with Pompe disease (GAA deficiency).
On April 28, 2006, the FDA approved alglucosidase alfa, rhGAA (Myozyme), the first treatment for IPD. Alglucosidase alfa had been granted FDA orphan drug status and was approved under a priority review. Myozyme is indicated for the treatment of Pompe disease and has been shown to improve ventilator‐free survival in members with infantile‐onset (initiated in children 1 month‐ 3.5 years) Pompe disease, use of Myozyme in members with other forms of Pompe disease has not been adequately studied to assure safety and efficacy.
Initiating alglucosidase alfa therapy at the earliest stages of Pompe disease is associated with the greatest clinical benefits. Infusions should be administered in a stepwise manner using an infusion pump. The initial infusion rate should not exceed 1 mg/kg/hr. After establishing patient tolerance to the infusion rate, it may be increased by 2 mg/kg/hr every 30 minutes until a maximum rate of 7 mg/kg/hr is reached. Vital signs should be monitored at the end of each step.
The safety and efficacy of alglucosidase alfa were evaluated in two separate clinical trials involving 39 patients with infantile-onset Pompe disease, aged between 1 month and 3.5 years at the time of their first infusion. The results indicated that survival without the need for invasive ventilatory support was significantly higher in infants treated with alglucosidase alfa compared to what would be expected given the high mortality rate among untreated patients of similar age and disease severity. According to the FDA, the safety and effectiveness of the drug in other forms of Pompe disease have not been adequately studied.
A clinical study assessing the efficacy of alglucosidase alfa in individuals with late-onset Pompe disease found statistically significant but modest effects (van der Ploeg et al., 2010). Ninety patients aged 8 years and older, who were ambulatory and not on invasive ventilation, were randomly assigned to receive bi-weekly intravenous alglucosidase alfa (20 mg/kg) or placebo for 78 weeks across eight centers in the U.S. and Europe. The two primary endpoints were the distance walked during a 6-minute walk test and the percentage of predicted forced vital capacity (FVC). At 78 weeks, the estimated mean changes from baseline in the primary endpoints favored alglucosidase alfa, with an increase of 28.1 ± 13.1 meters on the 6-minute walk test and an absolute increase of 3.4 ± 1.2 percentage points in FVC (p = 0.03 and p = 0.006, respectively). The authors concluded that their data indicated a positive, albeit modest, effect of alglucosidase alfa treatment on walking distance and pulmonary function in patients with late-onset Pompe disease, potentially stabilizing proximal limb and respiratory muscle strength. They acknowledged several limitations in the study, noting that while 90 patients is a substantial population for a clinical trial of an orphan disease, it is relatively small for assessing the progression of a clinically heterogeneous condition. Prior to this trial, no longitudinal data were available on changes in the 6-minute walk test over time in untreated Pompe disease patients, and the mean decline in distance walked was minimal in the placebo group. "Longer follow-up will be needed to confirm our results, given the variable presentation and rate of deterioration among the patients in our study and the possible effect of the degree of muscle destruction at baseline on their response to treatment" (van der Ploeg et al., 2010).
In this study, similar proportions of patients in both groups experienced adverse events, serious adverse events, and infusion-associated reactions. Events that occurred exclusively in patients receiving the active study drug included anaphylactic reactions and infusion-associated reactions such as urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each occurring in 5% to 8% of patients) (van der Ploeg et al., 2010). The most serious adverse reactions reported with alglucosidase alfa included heart and lung failure and allergic shock. Common reactions included pneumonia, respiratory failure and distress, infections, and fever. A black box warning is included in the Myozyme label to alert about the potential for life-threatening allergic reactions.
Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disorder caused by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. It is characterized by respiratory and skeletal muscle weakness and atrophy, leading to functional disability and reduced lifespan. Since 2006, alglucosidase alfa has been licensed for the treatment of all types of GSD2/Pompe disease. Strothotte et al. (2010) presented an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 44 late-onset GSD2 patients with varying stages of disease severity. Alglucosidase alfa was administered intravenously at the standard dose of 20 mg/kg every other week. Assessments included serial arm function tests, the Walton Gardner Medwin scale, timed 10-meter walk tests, 4-stair climb tests, modified Gowers' maneuvers, 6-minute walk tests, MRC sum score, FVC, creatine kinase (CK) levels, and SF-36 self-reporting questionnaires. All tests were performed at baseline and every three months for 12 months of ERT. The researchers found significant changes from baseline in the modified Gowers' test, CK levels, and the 6-minute walk test (341 ± 149.49 m, median 342.25 m at baseline; 393 ± 156.98 m; median 411.50 m at endpoint; p = 0.026), while all other tests remained unchanged. ERT over 12 months revealed minor allergic reactions in 10% of patients, with no serious adverse events reported. None of the patients died or required new ventilation. The authors concluded that the clinical outcome data suggest stabilization of neuromuscular deficits over one year with mild functional improvement.
On March 25, 2010, the FDA approved alglucosidase alfa (Lumizyme) for patients aged 8 years and older with late-onset (non-infantile) Pompe disease. Lumizyme is believed to function by replacing the deficient GAA, thereby reducing glycogen accumulation in heart and skeletal muscle cells. On August 1, 2014, the FDA approved a supplement to expand the indication for Lumizyme to all Pompe patients. The FDA reviewed newly available information and determined that Lumizyme and Myozyme are chemically and biochemically comparable, leading to the conclusion that their safety and effectiveness are expected to be similar. Additionally, a single-center clinical study involving 18 infantile-onset Pompe disease patients aged 0.2 to 5.8 months at the time of their first infusion provided further support that infantile-onset patients treated with Lumizyme would experience similar improvements in ventilator-free survival as those treated with Myozyme.
Currently, the only other treatment for Pompe disease available in the U.S. is Myozyme, also manufactured by Genzyme. Myozyme has been in short supply due to limited manufacturing capacity, and the manufacturer has reserved it for treating infants and children with Pompe disease, as younger patients typically have a more aggressive form of the disease. Some adult patients in the U.S. have received Lumizyme under a temporary access program. The approval of Lumizyme ensures that treatment is available for all adult Pompe patients in need. However, Lumizyme’s safety and effectiveness have not been evaluated in patients with infantile-onset Pompe disease or in patients aged 8 years and younger with late-onset disease; these patients should be treated with Myozyme, not Lumizyme.
Both Myozyme and Lumizyme (alglucosidase alfa) are produced by the same manufacturer. Once Lumizyme (alglucosidase alfa) was approved for patients with Pompe disease, production of Myozyme was discontinued, and all patients were transitioned to Lumizyme.
Recombinant human alglucosidase alfa (rhGAA; Lumizyme) is a hydrolytic lysosomal glycogen-specific enzyme that provides exogenous human lysosomal acid alpha-glucosidase. Alglucosidase alfa is primarily used in patients with Pompe disease, an inherited disorder of glycogen metabolism caused by the relative or absolute absence of acid alpha-glucosidase. Once administered systemically, alglucosidase alfa mimics endogenous acid alpha-glucosidase.
Alglucosidase alfa (Lumizyme) is available in 50 mg vials for reconstitution. The recommended dosage is 20 mg/kg body weight administered every two weeks as an intravenous infusion. The total volume of the infusion is determined by the patient’s body weight and should be administered over approximately four hours.
Initiating alglucosidase alfa therapy at the earliest stages of the disease process is associated with the most clinical benefit. Infusions should be administered in a stepwise manner using an infusion pump. The initial infusion rate should not exceed 1 mg/kg/hr. After establishing patient tolerance, the infusion rate may be increased by 2 mg/kg/hr every 30 minutes until a maximum rate of 7 mg/kg/hr is reached. Vital signs should be monitored at the end of each step. If the patient is stable, Lumizyme may be administered at the maximum rate of 7 mg/kg/hr until the infusion is completed. The infusion rate may be slowed or temporarily stopped in the event of infusion reactions.
Hypersensitivity reactions, including anaphylaxis, immune-mediated reactions, and the risk of acute cardiorespiratory failure, have been observed in some patients during and after treatment with alglucosidase alfa. Healthcare providers should ensure that appropriate medical support measures, including cardiopulmonary resuscitation equipment, are readily available. If anaphylaxis or severe hypersensitivity reactions occur, the infusion should be stopped immediately, and appropriate medical treatment should be initiated.
Patients should be monitored for the development of systemic immune-mediated reactions involving the skin and other organs.
Patients with compromised cardiac or respiratory function may be at risk of acute cardiorespiratory failure. Caution should be exercised when administering alglucosidase alfa to patients susceptible to fluid volume overload. Appropriate medical support and monitoring measures should be available during infusion.
There is a risk of cardiac arrhythmia and sudden cardiac death during general anesthesia for central venous catheter placement; caution should be exercised when administering general anesthesia for the placement of a central venous catheter intended for alglucosidase alfa infusion.
Cupler and colleagues (2012) proposed consensus-based treatment and management recommendations for late-onset Pompe disease. A systematic review of the literature by a panel of specialists with expertise in Pompe disease was conducted. A multidisciplinary team should be involved to properly address the pulmonary, neuromuscular, orthopedic, and gastrointestinal aspects of late-onset Pompe disease. Pre-symptomatic patients with subtle objective signs of Pompe disease (and symptomatic patients at diagnosis) should begin treatment with enzyme replacement therapy (ERT) immediately; pre-symptomatic patients without symptoms or signs should be observed without ERT. After one year of ERT, patients' conditions should be re-evaluated to determine whether ERT should be continued.
On August 6, 2021, the U.S. FDA approved avalglucosidase alfa-ngpt, branded as Nexviazyme (Genzyme Corporation), for the treatment of patients one year of age and older with late-onset Pompe disease (LOPD). Nexviazyme is an enzyme replacement therapy (ERT) designed to specifically target the mannose-6-phosphate (M6P) receptor, which is the key pathway for cellular uptake of enzyme replacement therapy in Pompe disease. FDA approval was based on results from the COMET study, which compared Nexviazyme to alglucosidase alfa in LOPD.
The COMET study (NCT02782741) was a randomized, double-blinded, multinational, multicenter, phase 3 trial comparing the efficacy and safety of Nexviazyme to alglucosidase alfa in 100 treatment-naive patients with LOPD. Patients were randomized in a 1:1 ratio based on baseline forced vital capacity (FVC), gender, age, and country to receive 20 mg/kg of Nexviazyme or alglucosidase alfa administered intravenously once every two weeks for 49 weeks. The trial included an open-label, long-term follow-up phase of up to five years, during which patients in the alglucosidase alfa arm were switched to Nexviazyme treatment. Of the 100 randomized patients, the baseline median age was 49 years (ranging from 16 to 78), with a median time since diagnosis of 6.9 months, a mean age at diagnosis of 46.4 years (ranging from 11 to 78), a mean FVC (% predicted) at baseline of 62.1% (ranging from 32 to 85%), and a mean 6-minute walk test (6MWT) distance at baseline of 388.9 meters (ranging from 118 to 630 meters). The primary endpoint was the change in FVC (% predicted) in the upright position from baseline to Week 49. At Week 49, the least squares (LS) mean change in FVC (% predicted) for patients treated with Nexviazyme was 2.9%, compared to 0.5% for those treated with alglucosidase alfa. The estimated treatment difference was 2.4% (95% CI: -0.1, 5.0) favoring Nexviazyme. In summary, patients treated with Nexviazyme showed a 2.9-point improvement (SE=0.9) in FVC percent-predicted at Week 49, meeting the non-inferiority measurement compared to alglucosidase alfa (p=0.0074). However, statistical superiority of Nexviazyme over alglucosidase alfa was not achieved (p=0.06). A key secondary endpoint in the trial measured functional endurance using the 6MWT. Compared to baseline, patients treated with Nexviazyme walked an average of 32.2 meters farther (SE=9.9) at Week 49, while those treated with alglucosidase alfa walked an average of 30 meters farther. According to the study protocol, formal statistical testing for all secondary endpoints was not conducted (Genzyme, 2021; Sanofi, 2021).
Nexviazyme carries a boxed warning for severe hypersensitivity reactions, infusion-associated reactions, and the risk of acute cardiorespiratory failure in susceptible patients. The most common adverse reactions (occurring in 5% or more of patients) in clinical trials included hypersensitivity reactions such as anaphylaxis, rash, fever, flushing, urticaria, headache, hyperhidrosis, nausea, cough, decreased oxygen saturation, tachycardia, tachypnea, chest discomfort, dizziness, muscle twitching, agitation, cyanosis, erythema, hypertension, pallor, rigors, tremor, vomiting, fatigue, and myalgia.
In September 2023, the FDA approved Pombiliti (cipaglucosidase alfa-atga) infusion in combination with Opfolda (miglustat) 65 mg capsules for the treatment of adults with late-onset Pompe disease (LOPD) weighing 40 kg or more who are not improving on their current enzyme replacement therapy (ERT). Pombiliti is a recombinant human lysosomal acid alpha-glucosidase enzyme (rhGAA) that replaces the missing enzyme acid alpha-glucosidase (cipaglucosidase alfa-agta). Once absorbed into muscle cells, Pombiliti is converted to GAA, enabling the breakdown of glycogen and reducing toxic glycogen levels. Opfolda is an enzyme stabilizer designed to stabilize the enzyme in the bloodstream.
FDA approval of Pombiliti is based on clinical data from a randomized, double-blind, active-controlled, international, multicenter, phase 3 study (PROPEL). ERT-experienced patients treated with Pombiliti in combination with Opfolda showed a numerically favorable change in sitting forced vital capacity (FVC) and 6-minute walk distance (6MWD) from baseline at Week 52. Results indicated that at Week 52, patients treated with Pombiliti plus Opfolda experienced a mean change in sitting FVC of -1.1% compared to -3.3% for those treated with alglucosidase alfa (estimated treatment difference, 2.3% [95% CI, 0.02-4.62]). Among ERT-experienced patients, the Pombiliti plus Opfolda group showed a numerically favorable change in sitting FVC at Week 52 (nominal p = 0.006). Additionally, patients treated with Pombiliti walked an average of 21 meters farther from baseline compared to 8 meters for those treated with alglucosidase alfa (estimated treatment difference of 14 meters [95% CI, -1, 28]), with a numerically favorable change in 6MWD at Week 52 (nominal p = 0.047) (Amicus Therapeutics US, 2023).
In the PROPEL study, Schoser and colleagues (2021) evaluated the safety and efficacy of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease who were still ambulatory, able to breathe without ventilation support, had an enzyme assay confirming a deficiency of acid alpha-glucosidase enzyme activity or a diagnosis confirmed by genetic testing, weighed 40 kg or more, and had either been receiving alglucosidase alfa for at least two years or were ERT-naïve. Patients aged 18 years and older were randomized in a 2:1 ratio to receive intravenous cipaglucosidase alfa (20 mg/kg) plus oral miglustat or intravenous alglucosidase alfa (20 mg/kg) plus oral placebo every two weeks for 52 weeks. Patients, investigators, and outcome assessors were blinded to treatment assignments. The primary endpoint was the change from baseline to Week 52 in 6MWD, assessed using a mixed-effect model for repeated measures analysis to compare superiority in the intention-to-treat population (all patients who received at least one dose of the study drug). Of the patients screened for eligibility, 125 were enrolled and randomly assigned to receive cipaglucosidase alfa plus miglustat (n=85) or alglucosidase alfa plus placebo (n=40). Two patients in the alglucosidase alfa plus placebo group did not receive any doses due to the absence of genotype confirmation of late-onset Pompe disease and were excluded from analysis. Six patients discontinued (one in the alglucosidase alfa plus placebo group and five in the cipaglucosidase alfa plus miglustat group), and 117 completed the study. At Week 52, the mean change from baseline in 6MWD was 20.8 m (SE 4.6) in the cipaglucosidase alfa plus miglustat group versus 7.2 m (SE 6.6) in the alglucosidase alfa plus placebo group, with a between-group difference of 13.6 m (95% CI -2.8 to 29.9). A total of 118 (96%) of 123 patients experienced at least one treatment-emergent adverse event during the study; the incidence was similar between the cipaglucosidase alfa plus miglustat group (n=81 [95%]) and the alglucosidase alfa plus placebo group (n=37 [97%]). The most frequently reported treatment-emergent adverse events included falls (25 [29%] in the cipaglucosidase alfa plus miglustat group vs 15 [39%] in the alglucosidase alfa plus placebo group), headache (20 [24%] vs 9 [24%]), nasopharyngitis (19 [22%] vs 3 [8%]), myalgia (14 [16%] vs 5 [13%]), and arthralgia (13 [15%] vs 5 [13%]). The investigators noted that 12 serious adverse events occurred in eight patients in the cipaglucosidase alfa plus miglustat group, with one event (anaphylaxis) deemed related to the study drug. One serious adverse event (stroke) occurred in the alglucosidase alfa plus placebo group, which was considered unrelated to the study drug. No deaths were reported. The investigators concluded that cipaglucosidase alfa plus miglustat did not achieve statistical superiority over alglucosidase alfa plus placebo for improving 6MWD in their overall population of patients with late-onset Pompe disease. Further studies are needed to investigate the long-term safety and efficacy of cipaglucosidase alfa plus miglustat and whether this investigational two-component therapy might provide benefits, particularly in respiratory function and in patients who have been receiving enzyme replacement therapy for more than two years, as suggested by their secondary and subgroup analyses.
Pombiliti carries a boxed warning for severe hypersensitivity reactions, infusion-associated reactions, and the risk of acute cardiorespiratory failure in susceptible patients. Patients susceptible to fluid volume overload, or those with acute underlying respiratory illness or compromised cardiac or respiratory function, may be at risk of serious exacerbation of their cardiac or respiratory status during infusion therapy. Additional warnings and precautions include the risk of embryo-fetal toxicity and risks associated with Opfolda. The most common adverse reactions (occurring in 5% or more of patients) include headache, diarrhea, fatigue, nausea, abdominal pain, and fever. Breastfeeding is not recommended.
Miscellaneous Interventions
Hematopoietic Stem Cell Therapy
Biffi (2017) stated that lysosomal storage disorders (LSDs) are a broad class of monogenic diseases with an overall incidence of 1:7,000 newborns, due to the defective activity of one or more lysosomal hydrolases or related proteins, resulting in the storage of undegraded substrates in the lysosomes. The over 40 different known LSDs share a life-threatening nature, but they present with extremely variable clinical manifestations, determined by the characteristics and tissue distribution of the material accumulating due to the lysosomal dysfunction. The majority of LSDs lack a curative treatment. This is particularly true for LSDs severely affecting the central nervous system (CNS). Based on current preclinical and clinical evidence, among other treatment modalities, hematopoietic stem cell therapy (HSCT) could potentially result in robust therapeutic benefits for LSD patients, with particular indication for those characterized by severe brain damage. The authors concluded that optimization of current approaches and technology, as well as the implementation of clinical trials for novel indications and prolonged and more extensive follow-up of already treated patients, will allow translating this promise into new medicinal products.
Azario and associates (2017) noted that umbilical cord blood (UCB) is a promising source of stem cells to use in early HSCT approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by a deficiency of the lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcomes, suggesting that such therapy should be administered as early as possible. Given that the best-characterized MPS-I murine model is an immunocompetent mouse, these researchers developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, these investigators first defined the features of murine UCB cells and demonstrated that they were capable of multi-lineage hematopoietic repopulation of myeloablated adult mice, similarly to bone marrow cells. They then assessed the effectiveness of murine UCB cell transplantation in busulfan-conditioned newborn MPS-I mice; 20 weeks after treatment, iduronidase activity was increased in the visceral organs of MPS-I animals, glycosaminoglycan storage was reduced, and the skeletal phenotype was ameliorated. The authors concluded that this study explored a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases.
Somaraju and Tadepalli (2017) stated that Gaucher disease is the most common LSD caused by a deficiency of the enzyme glucocerebrosidase. Current treatment of the disease involves a choice among ERT, substrate reduction therapy, and HSCT. Hematopoietic stem cell therapy is a high-risk procedure with possible long-term benefits in the regression of skeletal and neurological changes in people with Gaucher disease. This is an update of a previously published Cochrane Review. These investigators determined the role of HSCT in people with Gaucher disease in relation to mortality risk associated with the procedure, efficacy in modifying the course of the disease, and arrest or regression of neurological manifestations in neuronopathic forms (types 2 and 3). They searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register, which comprises references identified from comprehensive electronic database searches and hand searches of relevant journals and abstract books of conference proceedings. The date of the most recent search of the Group's Hemoglobinopathies Trials Register was January 19, 2017. These investigators also searched the websites: www.clinicaltrials.gov, WHO International Clinical Trials Registry Platform portal, and www.genzymeclinicalresearch.com. The date of the most recent search of these sites was March 2, 2017. All randomized, quasi-randomized, and controlled clinical trials comparing SCT with ERT, substrate reduction therapy, symptomatic treatment, or no treatment in people with Gaucher disease of all ages were selected for analysis. The authors independently assessed trials for inclusion; however, no relevant trials were identified. A total of 32 trials were identified by the searches; however, these were not suitable for inclusion in the review. The authors concluded that HSCT is a form of treatment that offers the potential for a permanent cure. However, there were no clinical trials that have assessed the safety and efficacy of this treatment in comparison to other conservative measures (ERT, substrate reduction therapy) now in use. There were no trials included in the review, and these researchers had not identified any relevant trials up to March 2017.
Wright and colleagues (2017) described long-term outcomes of children with early-infantile Krabbe disease who underwent HSCT in the first 7 weeks of life. In this prospective longitudinal study, evaluations were performed at baseline and follow-up, including brain imaging, neurodiagnostic tests, and neurobehavioral evaluations. Of the 18 patients in this study (11 girls, 7 boys; mean follow-up of 9.5 years, range of 4 to 15), 5 died (3 of peri-transplant complications, 1 of a surgical complication unrelated to Krabbe disease, and 1 of disease progression). One of the surviving patients had normal cognitive function, and 10 continued to develop cognitive skills at a slightly slower rate than normal. All surviving patients continued to gain receptive language skills, with 7 falling within the normal range; 10 patients received speech therapy, and 2 of these patients required augmentative communication devices. Gross motor development varied widely, but 3 patients could walk independently, and 7 walked with assistive devices. Spasticity ranged from mild to severe, and 12 patients wore orthotics. Fine motor skills were generally preserved. Brain myelination and atrophy stabilized in 8 patients, improved in 4 patients, and worsened in 1 patient. Nerve conduction velocities initially improved but continued to be abnormal in most patients. The authors concluded that surviving patients functioned at a much higher level than untreated children or symptomatic children who underwent HSCT. They stated that these results showed that early HSCT changed the natural history of this disease by improving both lifespan and functional abilities. Moreover, the authors stated that continued follow-up studies are needed to monitor the long-term outcomes of treated patients as they age into adolescence and young adulthood. It will also be critical to identify a pre-symptomatic diagnostic biomarker that will enable clinicians to confidently follow babies at moderate and high risk for Krabbe disease identified through newborn screening programs and those treated with HSCT or any other future therapies. This study provided Class IV evidence that for children with early-infantile Krabbe disease, early HSCT improved lifespan and functional abilities.
In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe Disease
Cohen et al. (2022) stated that patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. These investigators reported the safety and effectiveness of in-utero ERT in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe disease. The family history was positive for infantile-onset Pompe disease with cardiomyopathy in two previously affected deceased siblings. After receiving in-utero ERT and standard postnatal therapy, the patient exhibited normal cardiac function and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age. Moreover, these researchers stated that, similar to any fetal intervention, this procedure is associated with a risk of preterm delivery. Non-directive counseling for parents of affected pregnancies is paramount to ensure informed choices regarding the risk-benefit profile of this new therapeutic approach. These investigators noted that their phase-I clinical trial of in-utero ERT for fetuses with genetically confirmed early-onset lysosomal storage diseases will enable the collection of additional safety and effectiveness data in a larger cohort.
In an editorial on the aforementioned study by Cohen et al. (2022), van der Ploeg (2022) stated that an issue that needs to be clarified is whether initiation of therapy at 24 weeks of gestation sufficiently precedes the formation of the blood-brain barrier to prevent the neurologic phenotypes observed in many lysosomal storage disorders. Unfortunately, the short half-life of the lysosomal (replacement) enzyme weighs against the likelihood that neurologic phenotypes can be entirely prevented. The editorialist stated that further follow-up of this patient will be important; Cohen and colleagues are conducting a phase-I clinical trial of in-utero ERT in 10 fetuses with a genetically diagnosed lysosomal storage disorder. The outcomes of this phase-I clinical trial are eagerly awaited; in the meantime, the developmental course of this patient is encouraging.
Measurement of Anti-rhGAA Antibodies as Determinant of Treatment Outcome in Adults with Late-Onset Pompe Disease
Ditters et al. (2023) noted that Pompe disease is a lysosomal storage disease characterized by skeletal and respiratory muscle weakness. Since 2006, ERT with alglucosidase alfa has been available. ERT significantly improves the prognosis of patients with Pompe disease. The effect of high antibody titers on treatment response in adults with LOPD remains unclear but may contribute to inter-patient variation. In a systematic review on this subject, these investigators carried out a literature search in Embase, Medline Ovid, Web of Science, Psych Info Ovid, Cochrane (Clinical Trials only), and Google Scholar (random top-200). Studies were included if they involved adults with LOPD treated with alglucosidase alfa and mentioned anti-rhGAA antibodies or antibody titers. Furthermore, studies mentioning dosages different from the standard recommended dosage were included. The literature search retrieved 2,562 publications, and 17 fulfilled the selection criteria, describing 443 cases. Seven studies reported on anti-rhGAA antibody titers on a group level, with the percentage of patients with a high titer, as defined in the included articles, ranging from 0% to 33%; six studies reported on the effect of anti-rhGAA antibody titer on clinical course, and four found no correlation. Two studies reported a negative effect on treatment. The first study found a greater improvement in the Medical Research Council (MRC) score in patients with no detectable antibody titer. In the second study, a patient discontinued ERT due to a declining neuromuscular state as a result of high anti-rhGAA antibody titers. Seven studies reported on 17 individual patients with a high antibody titer (range of 1:12,800 to 1:3,906,250). In only two cases were high-sustained neutralizing antibodies reported to interfere with treatment effectiveness. The authors concluded that no clear effect of anti-rhGAA IgG antibodies on therapeutic response could be established for the majority of LOPD patients with a high antibody titer. In a minority of patients, a clinical decline related to (possible) interference of anti-rhGAA antibodies was described. These researchers stated that further prospective, long-term studies are needed to evaluate this relation. They advised that for future investigations, researchers should standardize the definition of a high antibody titer (greater than or equal to 31,250) and of a high sustained antibody titer (high antibody titer on two or more occasions at or beyond six months of ERT) to improve comparability; perform regular, standardized follow-up of antibody titers (with collection of samples before ERT infusion), which will provide insight into the development and course of antibody titers over time and prevent sampling bias; and describe patient characteristics and standardize clinical follow-up to enable assessment of the effect of antibody formation on the outcome of ERT in individual patients.
The authors stated that this analysis had several drawbacks. First, different definitions of a high antibody titer as well as a high sustained antibody titer were given, making it difficult to compare study outcomes in this regard. The definition of a high antibody titer ranged from 1:12,800 to greater than or equal to 1:51,200, which may be partially dependent on the titration steps used. Most studies did not specify what the source was for the reference values for (highly sustained) antibodies. It has been demonstrated in the serum of classic-infantile Pompe patients that there is probably no effect on enzyme activity or uptake of alglucosidase alfa with an antibody titer of less than or equal to 1:6250. Alglucosidase alfa activity in the medium was not inhibited until titers of 1:31,250 were reached, indicating that it was only useful to measure neutralizing antibodies for a titer of greater than or equal to 1:31,250. This same study also arithmetically estimated that, whereas titers of 1:31,250 may counteract ERT at a dosage of 20 mg/kg, titers above 1:60,000 are expected to counteract ERT when a dosage of 40 mg/kg is administered. These estimates are consistent with the suggested cut-off value for a high titer of 1:51,200 and demonstrate that, to interpret the clinical effect of anti-rhGAA antibodies, the dosage of ERT must be known as well. These researchers suggested using the following definitions of a high and high sustained antibody titer: a high titer means a titer of greater than or equal to 31,250, and a high sustained antibody titer means a titer of greater than or equal to 31,250 on two or more occasions at or beyond six months of ERT. Second, the level of evidence of the included studies was variable, with five out of 17 included studies being case reports, and the outcome of interest (antibody titer and ERT dosage) was often not the main outcome of the paper. As some patients were reported in multiple publications—these investigators were aware of at least one patient for whom this was the case—the number of unique patients described in this review was lower than 443. Multiple studies included patients with different phenotypes that contributed to a larger clinical heterogeneity than intended for this study. Third, due to the heterogeneity of clinical outcome parameters, the different definitions of high (sustained) antibody titers, different time points at which antibody titers were measured, as well as limited data regarding dosing, these researchers could not analyze antibodies over time, nor could a meta-analysis be carried out. These investigators resolved this by using the definition of a high (sustained) titer as used in the original publication and by looking at the highest antibody titer reported per patient. Fourth, there might be a selection bias in that patients with high antibody titers or infusion-associated reactions (IARs) were more likely to be reported, and follow-up was not always continuous over time and varied between studies.
Measurement of Plasma Lysosphingolipids and Oxysterols for Screening Lipid Storage Disorders
Voorink-Moret and colleagues (2018) highlighted that confirming a diagnosis in patients suspected of having a lipid storage disorder (such as sphingolipidoses and lipidoses) primarily depends on measuring specific enzymatic activities and conducting genetic studies. Recently developed UPLC-MS/MS methods allow for the measurement of lysosphingolipids and oxysterols, which, when combined with chitotriosidase activity, may serve as a rapid first-tier screening approach for lipid storage disorders.
In their study, a lysosphingolipid panel was analyzed, which included lysoglobotriaosylceramide (LysoGb3), lysohexosylceramide (LysoHexCer, encompassing both lysoglucosylceramide and lysogalactosylceramide), lysosphingomyelin (LysoSM), and its carboxylated analogue, lysosphingomyelin-509 (LysoSM-509). This panel was measured in plasma samples from control subjects and predominantly untreated patients diagnosed with lipid storage disorders (n = 74). Additionally, the oxysterols cholestane-3β,5α,6β-triol and 7-ketocholesterol were measured in a subset of these patients (n = 36), along with chitotriosidase activity (n = 43). A systematic review of the literature was conducted to evaluate the utility of these biochemical markers.
The study found specific elevations of metabolites that did not overlap between control subjects and other lipid storage disorders for several lysosomal storage diseases: increased LysoSM levels were observed in acid sphingomyelinase deficiency (Niemann-Pick disease types A/B), elevated LysoGb3 levels were noted in males with classical phenotype Fabry disease, and increased LysoHexCer levels (i.e., lysoglucosylceramide/lysogalactosylceramide) were found in Gaucher and Krabbe diseases. While elevated levels of LysoSM-509 and cholestane-3β,5α,6β-triol did not differentiate between Niemann-Pick disease type C and acid sphingomyelinase deficiency, the ratio of LysoSM-509 to LysoSM was specifically elevated in Niemann-Pick disease type C. In Gaucher disease type I, mild increases in several lysosphingolipids were observed, including LysoGb3, with levels comparable to those seen in non-classical Fabry males and females. Chitotriosidase activity showed specific elevations in symptomatic Gaucher disease and was mildly elevated in other lipid storage disorders.
The literature review identified 44 publications, most of which aligned with the findings of this study cohort. Several moderate elevations of biochemical markers were noted across a broad range of other inherited metabolic diseases. The authors concluded that measuring lysosphingolipids and oxysterols in plasma using UPLC-MS/MS, in conjunction with chitotriosidase activity, provides a valuable first-tier screening method for patients suspected of having lipid storage diseases. They also noted that the LysoSM-509/LysoSM ratio is a promising parameter for Niemann-Pick disease type C. However, they emphasized the need for further studies involving larger groups of untreated patients and controls to enhance the specificity of these findings.
Metallothioneins
Cavalca and colleagues (2018) noted that LSDs are a broad class of inherited metabolic diseases caused by the defective activity of lysosomal enzymes; CNS manifestations are present in roughly 50% of LSD patients and represent an unmet medical need for them. These researchers examined the therapeutic potential of metallothioneins (MTs), a newly identified family of proteins with reported neuroprotective roles, in the murine models of 2 LSDs with CNS involvement. MT-1 over-expressing transgenic mice (MTtg) were crossed with the murine models of Batten and Krabbe diseases. Changes in the survival and manifestations of the disease in the MTtg setting were assessed. In addition, these researchers analyzed the therapeutic effects of MT-1 CNS gene delivery in one of these LSD models. Constitutive expression of MT-1 exerted favorable phenotypic effects in both LSD models. MT-LSD mice showed a 5% to 10% increase in survival and slower disease progression as compared to not-transgenic LSD mice. Rescue of Purkinje cells from degeneration and apoptosis was also observed in the MT-LSD models. This phenotypic amelioration was accompanied by a modulation of the disease-associated activated inflammatory microglia phenotype, and by a reduction of oxidative stress. Importantly, for the clinical translation of these findings, the very same effects were obtained when MTs were delivered to brains by systemic AAV gene transfer. The authors concluded that MTs can be considered novel therapeutic agents (and targets) in LSDs and potentiate the effects of approaches aiming at correction of the disease-causing enzyme deficiency in the CNS.
Substrate Deprivation Therapy
Derrick-Roberts and colleagues (2017) stated that MPS I is the most common form of the MPS group of genetic diseases; it results from a deficiency in the lysosomal enzyme α-l-iduronidase, leading to accumulation of un-degraded heparan and dermatan sulphate glycosaminoglycan (GAG) chains in patient cells. Children with MPS suffer from multiple organ failure and die in their teens to early 20s. In particular, MPS I children also suffer from profound mental retardation and skeletal disease that restricts growth and movement. Neither neurological nor skeletal disease is adequately treated by current therapy approaches. To overcome these barriers to effective therapy these researchers have developed and tested a treatment called substrate deprivation therapy (SDT). MPS I knockout mice were treated with weekly intravenous injections of 1 mg/kg rhodamine B for 6 months to assess the efficacy of SDT. Mice were assessed using biochemistry, micro-CT and a battery of behavioral tests to determine the outcome of treatment. A reduction in female body-weight gain was observed with the treatment as well as a decrease in lung GAG. Behavioral studies showed slight improvements in inverted grid and significant improvements in learning ability for female MPS I mice treated with rhodamine B. Skeletal disease also improved with a reduction in bone mineral volume observed. The authors concluded that rhodamine B is safe to administer to MPS I knockout mice where it had an effect on improving aspects of neurological and skeletal disease symptoms and may therefore provide a potential therapy or adjunct therapy for MPS I patients.
Appendix
| Hurler | Hurler-Scheie | Scheie |
|---|---|---|
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Source: Hahn, 2019
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