CurrentUnitedHealthcarePolicy CS2025D0052AF

Medical Therapies for Enzyme Deficiencies

UnitedHealthcare Community Plan medical benefit drug policy governing coverage, medical necessity criteria, and authorization durations for specified enzyme replacement and related therapies for enzyme deficiencies (list of named products). Excludes certain states where state-specific policies apply.

Policy Summary

PayerUnitedHealthcare

PolicyMedical Therapies for Enzyme Deficiencies

Policy CodePolicy CS2025D0052AF

Change TypeHCPCS code update (Nulibry)

Effective DateOctober 1, 2025

Next Review Date

Key ActionDocument diagnostic confirmation (enzyme assay or molecular genetic testing), clinical signs/symptoms, and dosing per FDA labeling for initial and reauthorization requests; approvals limited to ≤ 12 months.

POLICY UPDATE CHANGES

Updated list of applicable HCPCS codes for Nulibry: replaced C9399, J3490, and J3590 with J1809.

16Products listed with drug-specific criteria

12Reauthorization limit (months)

1HCPCS codes updated (Nulibry)

8Products with HCPCS codes shown

20Reference citations approx.

Coverage Summary

This UnitedHealthcare Community Plan medical benefit drug policy governs coverage and medical necessity criteria for specified enzyme replacement and related therapies for enzyme deficiencies, including Aldurazyme (laronidase), Elaprase (idursulfase), Elfabrio (pegunigalsidase alfa-iwxj), Fabrazyme (agalsidase beta), Kanuma (sebelipase alfa), Lamzede (velmanase alfa-tycv), Lumizyme (alglucosidase alfa), Mepsevii (vestronidase alfa-vjbk), Naglazyme (galsulfase), Nexviazyme (avalglucosidase alfa-ngpt), Nulibry (fosdenopterin), Pombiliti (cipaglucosidase alfa-atga), Revcovi (elapegademase-lvlr), Vimizim (elosulfase alfa), and Xenpozyme (olipudase alfa-rpcp).

The policy defines product-specific diagnostic confirmation, dosing per FDA labeling, and authorization durations with initial and reauthorization approvals limited to 12 months. It applies to UnitedHealthcare Community Plan medical benefit members except in specified states — Arizona, Florida, Indiana, Kansas, Louisiana, North Carolina, Ohio, and Texas — where state-specific Medicaid clinical policies or alternate guidance apply.

Policy metadata and thresholds

Policy NumberCS2025D0052AF

Effective DateOctober 1, 2025

Typical reauthorization limitInitial and reauthorization approvals limited to no more than 12 months

Scope summaryUnitedHealthcare Community Plan medical benefit drug policy governing coverage, medical necessity criteria, and authorization durations for specified enzyme replacement and related therapies; excludes certain states with state-specific policies

Material coding changeYes — HCPCS codes for Nulibry updated (replaced C9399, J3490, J3590 with J1809) effective 10/01/2025

Initial Therapy Criteria (by product)

General drug-specific medical necessity structure

These general drug-specific medical necessity criteria describe the structure used across individual product sections below. Each product-specific Initial Therapy group uses the same pattern: required diagnostic confirmation, presence of clinical signs/symptoms, dosing consistent with FDA labeling, and initial authorization duration.

Diagnosis must be confirmed by laboratory testing (enzyme assay or molecular genetic testing) as specified per product.

Patient must have clinical signs or symptoms consistent with the indicated disease (examples provided in each product-specific section).

Therapy must be prescribed and dosed in accordance with the U.S. Food and Drug Administration (FDA) approved labeling.

Initial authorization duration is product-specific (commonly up to 12 months unless otherwise stated).

Continuation / Reauthorization Criteria (by product)

Reauthorization/Continuation is defined as authorization for up to 12 months contingent on prior receipt of the specific therapy and documentation of a positive clinical response. For continuation, providers must document prior treatment with the named product and objective evidence of benefit (examples vary by product such as improved endurance, functional capacity, organ volume reduction, or laboratory markers).

Reauthorization approvals are limited to no more than 12 months and require that dosing remain consistent with U.S. FDA–approved labeling.

Provider Actions & Billing Requirements

Prior Authorization

Authorization required for initial and continuation therapy

Initial and reauthorization requests require documentation of diagnostic confirmation (enzyme assay or molecular genetic testing), presence of clinical signs/symptoms, dosing consistent with FDA labeling, and prior treatment/response for continuation. Authorizations (initial and reauthorization) are limited to no more than 12 months.

Documentation Required

Document genetic or enzymatic confirmation

Providers must supply laboratory or genetic evidence confirming the diagnosis as specified per product: either enzyme activity assay demonstrating absence/deficiency (product-specific thresholds referenced in drug-specific criteria) or molecular genetic testing showing pathogenic mutations.

Enzyme assay results showing absence/deficiency (product-specific thresholds; e.g., <5% α-Gal A for Fabry, <1% or <40% GAA for Pompe variants, <10% alpha-mannosidase, etc.)

Applicable Codes

Drug HCPCS/J-codes listed for referenced productsHCPCS

J1931	Injection, laronidase, 0.1 mg
J1743	Injection, idursulfase, 1 mg
J2508	Injection, pegunigalsidase alfa-iwxj, 1 mg
J0180	Injection, agalsidase beta, 1 mg
J2840	Injection, sebelipase alfa, 1 mg
J0217	Injection, velmanase alfa-tycv, 1 mg
J0221	Injection, alglucosidase alfa (Lumizyme), 10 mg
J3397	Injection, vestronidase alfa-vjbk, 1 mg
J1458	Injection, galsulfase, 1 mg
J0219	Injection, avalglucosidase alfa-ngpt, 4 mg

1–10 of 15

1/2

Updated Applicable HCPCS Codes (Nulibry)HCPCS

J1809	Injection, fosdenopterin, 0.1 mg
C9399	Formerly listed miscellaneous drug or biological (archived; replaced per policy updates)
J3490	Formerly listed unclassified drug (archived; replaced per policy updates)
J3590	Formerly listed unclassified biologic (archived; replaced per policy updates)

Drug HCPCS/J-codes listed for referenced products (duplicate group for compatibility)HCPCS

J1931	Injection, laronidase, 0.1 mg
J1743	Injection, idursulfase, 1 mg
J2508	Injection, pegunigalsidase alfa-iwxj, 1 mg
J0180	Injection, agalsidase beta, 1 mg
J2840	Injection, sebelipase alfa, 1 mg
J0217	Injection, velmanase alfa-tycv, 1 mg
J0221	Injection, alglucosidase alfa (Lumizyme), 10 mg
J3397	Injection, vestronidase alfa-vjbk, 1 mg
J1458	Injection, galsulfase, 1 mg
J0219	Injection, avalglucosidase alfa-ngpt, 4 mg

1–10 of 15

1/2

Relevant diagnosis ICD-10 codes referencedICD-10

E76.01	Hurler's syndrome
E76.02	Hurler-Scheie syndrome
E76.03	Scheie's syndrome
E76.1	Mucopolysaccharidosis, type II
E75.21	Fabry (-Anderson) disease
E75.5	Other lipid storage disorders
E77.1	Defects in glycoprotein degradation
E74.02	Pompe disease
E76.29	Other mucopolysaccharidoses (includes Sly syndrome/Maroteaux-Lamy syndrome)
D81.31	Severe combined immunodeficiency due to adenosine deaminase deficiency

1–10 of 15

1/2

Updated Applicable HCPCS Codes (Nulibry)HCPCS

J1809	Injection, fosdenopterin, 0.1 mg
C9399	Noted as replaced (formerly listed); miscellaneous not otherwise classified drug or biological (archived)
J3490	Noted as replaced (formerly listed); unclassified drugs (archived)
J3590	Noted as replaced (formerly listed); unclassified biologics (archived)

Clinical Evidence and Trial Results

37 mElaprase 6MWT increase at 53 weeks

22.5 mVimizim 6MWT improvement at 24 weeks

25.1 mLumizyme mean 6MWT increase at 78 weeks

20.9%Xenpozyme % predicted DLco increase at 52 weeks

HR 0.18Nulibry overall survival vs historical control

Key clinical trials and findings supporting efficacy of listed products include:

Aldurazyme (Wraith et al.): randomized, double-blind placebo-controlled trial (n=45) showed improvements in % predicted FVC and 6MWT, reduced hepatomegaly and urinary GAGs.

Elaprase (Muenzer et al.): randomized multicenter trial (n=96) demonstrated significant improvement in a composite endpoint (FVC and 6MWT) versus placebo with a 37‑meter increase in 6MWT at 53 weeks for the weekly dosing group (p=0.013) and overall composite significance (p=0.0049).

Vimizim (elosulfase alfa): phase 3 trial (MOR-004) showed a 22.5 m improvement in 6MWT versus placebo at 24 weeks (p=0.017) for the weekly regimen.

Background

Specified enzyme activity thresholds

Elfabrio alpha-Gal A activity< 5% of mean

Lamzede alpha-mannosidase activity< 10% of lab specific normal mean

Lumizyme (infantile) GAA activity< 1% of lab specific normal mean

Lumizyme / Nexviazyme / Pombiliti (late-onset) GAA activity< 40% of lab specific normal mean

Aldurazyme confirmationEnzyme deficiency OR molecular genetic confirmation (no numeric threshold)

Revision History

10/01/2025material_changeLatest

Material coding update per Summary of Changes: updated applicable HCPCS codes for Nulibry — replaced C9399, J3490, and J3590 with J1809; archived previous policy version CS2025D0052AE (marking as material).

Policy Summary

PayerUnitedHealthcare

PolicyMedical Therapies for Enzyme Deficiencies

Policy CodePolicy CS2025D0052AF

Change TypeHCPCS code update (Nulibry)

Effective DateOctober 1, 2025

Next Review Date

On This Page

Combination therapy restrictions or contraindications (e.g., not in combination with other disease-modifying therapies) are specified per product and must be followed.

Aldurazyme - Initial therapy

Aldurazyme (laronidase) - Initial therapy: Covered when ALL of the following are met:

Diagnosis of any MPS I syndrome confirmed as one of: Hurler (MPS IH), Hurler-Scheie (MPS IHS), or Scheie (MPS IS).

Diagnosis confirmed by one of: deficiency/absence of alpha-L-iduronidase enzyme activity (fibroblast or leukocyte) OR molecular genetic confirmation of pathogenic variants in the IDUA gene.

Presence of clinical signs and symptoms of MPS I (e.g., cardiac abnormalities, corneal clouding, dysostosis multiplex, hepatomegaly, restrictive lung disease, or other disease manifestations).

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Elaprase - Initial therapy

Elaprase (idursulfase) - Initial therapy: Covered when ALL of the following are met:

Diagnosis of MPS II confirmed by one of: deficiency in iduronate-2-sulfatase enzyme activity in fibroblasts or leukocytes (with normal activity of another sulfatase) OR molecular genetic testing identifying pathogenic variants in the IDS gene.

Presence of clinical signs and symptoms of MPS II (e.g., hepatosplenomegaly, skeletal deformities, dysostosis, neurocognitive decline, cardiovascular involvement).

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Elfabrio - Initial therapy

Elfabrio (pegunigalsidase alfa-iwxj) - Initial therapy: Covered when ALL of the following are met:

Diagnosis of Fabry disease confirmed by one of: absence or deficiency (<5% of mean) of alpha-galactosidase A (α-Gal A) enzyme activity in leukocytes, dried blood spot, or serum OR molecular genetic testing identifying pathogenic GLA variants.

Presence of clinical signs and symptoms of Fabry disease (e.g., acroparesthesias, angiokeratomas, corneal whorling, anhidrosis/hypohidrosis, renal disease, exercise/heat/cold intolerance).

Patient is not receiving Elfabrio in combination with another disease-modifying therapy for Fabry disease (e.g., Fabrazyme, migalastat).

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Fabrazyme - Initial therapy

Fabrazyme (agalsidase beta) - Initial therapy: Covered when ALL of the following are met:

Presence of clinical signs and symptoms of Fabry disease (e.g., acroparesthesias, angiokeratomas, corneal whorling, anhidrosis/hypohidrosis, renal disease, exercise/heat/cold intolerance).

Patient is not receiving Fabrazyme in combination with another disease-modifying therapy for Fabry disease (e.g., Elfabrio, migalastat).

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Kanuma - Initial therapy

Kanuma (sebelipase alfa) - Initial therapy: Covered when ALL of the following are met:

Diagnosis of lysosomal acid lipase deficiency (LAL-D, including Wolman disease or cholesteryl ester storage disease) confirmed by one of: absence or deficiency of lysosomal acid lipase activity by dried blood spot test OR molecular genetic testing identifying pathogenic variants in the LIPA gene.

Presence of clinical signs and symptoms of the disease (e.g., abdominal distention, hepatosplenomegaly, liver fibrosis, ascites).

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Lamzede - Initial therapy

Lamzede (velmanase alfa-tycv) - Initial therapy: Covered when ALL of the following are met:

Diagnosis of alpha-mannosidosis confirmed by one of: absence or deficiency (<10% of lab-specific normal mean) of alpha-mannosidase enzyme activity OR molecular genetic testing identifying pathogenic variants in MAN2B1.

Presence of clinical signs and symptoms of alpha-mannosidosis (e.g., hepatosplenomegaly, skeletal abnormalities, ataxia, intellectual disability, hearing loss).

Lamzede is not being used to treat central nervous system (CNS) manifestations of alpha-mannosidosis.

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Lumizyme - Initial therapy

Lumizyme (alglucosidase alfa) - Initial therapy: For Pompe disease, one of the following applies depending on age of onset.

Infantile-onset Pompe disease: All of the following:

- Diagnosis of infantile-onset Pompe disease confirmed by one of: absence or deficiency (<1% of lab-specific normal mean) of acid alpha-glucosidase (GAA) enzyme activity OR molecular genetic testing identifying pathogenic GAA variants.

- Presence of clinical signs consistent with infantile-onset Pompe (e.g., cardiomyopathy, hypotonia, feeding difficulties, respiratory insufficiency).

- Dosing consistent with U.S. FDA approved labeling for infantile-onset Pompe.

- Initial authorization limited to no more than 12 months.

Late-onset Pompe disease: All of the following:

- Diagnosis of late-onset Pompe disease confirmed by one of: decreased GAA enzyme activity above the infantile threshold (as per lab reference) OR molecular genetic testing identifying pathogenic GAA variants consistent with late-onset phenotype.

- Presence of clinical signs consistent with late-onset Pompe (e.g., progressive proximal muscle weakness, respiratory insufficiency, decreased endurance).

- Dosing consistent with U.S. FDA approved labeling for late-onset Pompe.

- Initial authorization limited to no more than 12 months.

Mepsevii - Initial therapy

Mepsevii (vestronidase alfa-vjbk) - Initial therapy: Covered when ALL of the following are met:

Diagnosis of mucopolysaccharidosis VII (Sly syndrome) confirmed by one of: deficiency of beta-glucuronidase enzyme activity OR molecular genetic testing identifying pathogenic GUSB variants.

Presence of clinical signs and symptoms of MPS VII (e.g., hepatosplenomegaly, skeletal abnormalities, airway disease, developmental delay).

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Naglazyme - Initial therapy

Naglazyme (galsulfase) - Initial therapy: Covered when ALL of the following are met:

Diagnosis of mucopolysaccharidosis VI (MPS VI) confirmed by one of: deficiency of N-acetylgalactosamine 4-sulfatase enzyme activity OR molecular genetic testing identifying pathogenic ARSB variants.

Presence of clinical signs and symptoms of MPS VI (e.g., short stature, skeletal dysplasia, corneal clouding, cardiac disease, airway obstruction).

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Nexviazyme - Initial therapy (late-onset Pompe)

Nexviazyme (avalglucosidase alfa-ngpt) - Initial therapy for late-onset Pompe disease: Covered when ALL of the following are met:

Diagnosis of late-onset Pompe disease confirmed by decreased acid alpha-glucosidase (GAA) enzyme activity and/or molecular genetic testing identifying pathogenic GAA variants consistent with late-onset phenotype.

Presence of clinical signs consistent with late-onset Pompe (e.g., progressive proximal muscle weakness, respiratory insufficiency, decreased endurance).

Dosing consistent with U.S. FDA approved labeling for late-onset Pompe.

Initial authorization limited to no more than 12 months.

Nulibry - Initial therapy (MoCD Type A)

Nulibry (fosdenopterin) - Initial therapy: Covered when ALL of the following are met for molybdenum cofactor deficiency (MoCD) Type A:

Diagnosis of MoCD Type A confirmed by molecular genetic testing or biochemical testing per FDA labeling.

Presence of clinical signs consistent with MoCD Type A as described in product labeling.

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Pombiliti - Initial therapy

Pombiliti (cipaglucosidase alfa-atga) - Initial therapy: Covered when ALL of the following are met. Note: additional requirements apply if used in combination with miglustat per product guidance.

Diagnosis of Pompe disease confirmed by enzyme assay (acid alpha-glucosidase) or molecular genetic testing identifying pathogenic GAA variants.

Presence of clinical signs consistent with Pompe disease appropriate to the treated phenotype (infantile or late-onset).

If prescribed in combination with miglustat, documentation of compliance with product-specific combination therapy requirements.

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Revcovi - Initial therapy (ADA-SCID)

Revcovi (elapegademase-lvlr) - Initial therapy: Covered when ALL of the following are met for ADA-SCID:

Diagnosis of adenosine deaminase severe combined immunodeficiency (ADA-SCID) confirmed by enzyme assay or molecular genetic testing.

Presence of clinical signs consistent with ADA-SCID as described in product labeling.

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Vimizim - Initial therapy (MPS IVA)

Vimizim (elosulfase alfa) - Initial therapy: Covered when ALL of the following are met for Morquio A syndrome (MPS IVA):

Diagnosis of MPS IVA confirmed by one of: deficiency of N-acetylgalactosamine-6-sulfatase (GALNS) enzyme activity OR molecular genetic testing identifying pathogenic GALNS variants.

Presence of clinical signs and symptoms of MPS IVA (e.g., skeletal abnormalities, short stature, respiratory compromise, corneal clouding).

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Xenpozyme - Initial therapy (ASMD)

Xenpozyme (olipudase alfa-rpcp) - Initial therapy: Covered when ALL of the following are met for acid sphingomyelinase deficiency (ASMD):

Diagnosis of ASMD confirmed by enzyme assay demonstrating deficiency of acid sphingomyelinase OR molecular genetic testing identifying pathogenic SMPD1 variants.

Presence of clinical signs and symptoms of ASMD (e.g., hepatosplenomegaly, pulmonary disease, lipid abnormalities).

Dosing consistent with U.S. FDA approved labeling.

Initial authorization limited to no more than 12 months.

Molecular genetic testing demonstrating pathogenic/deleterious mutations in the disease gene (product-specific gene noted in criteria)

Documentation Required

Document clinical response for continuation

For continuation (reauthorization), document prior receipt of the specific therapy and objective evidence of a positive clinical response. Examples of acceptable evidence are product-specific and include improved endurance or functional capacity (6MWT/12MWT), improved pulmonary function (% predicted FVC or DLco), reduced organ volumes (liver/spleen), decreased disease biomarkers (urine GAGs, SSC, GL-3), or other clinical improvements cited in the drug-specific criteria.

Improved endurance/walking distance (6MWT, 12MWT) or stair-climb
Improved pulmonary function (% predicted FVC or DLco)
Reduction in liver or spleen volume on imaging
Decreased disease biomarkers (e.g., urine GAGs, SSC, GL-3)
Improved clinical signs/symptoms as described per product

Billing Rule

Use specified HCPCS/J-codes for claims

Submit drug administration using the listed HCPCS/J-codes corresponding to each product. Use the policy’s code list to bill claims for the referenced enzyme therapies.

J1931
J1743
J2508
J0180
J2840
J0217
J0221
J3397
J1458
J0219
J1809
J1203
J3590
J1322
J0218

Billing Rule

HCPCS code updates for Nulibry

Effective 10/01/2025 the policy updated applicable HCPCS codes for Nulibry: the prior miscellaneous/unclassified codes C9399, J3490, and J3590 were replaced with J1809. Providers should bill Nulibry using J1809 going forward.

Prior Authorization

State-specific applicability

This policy does not apply in the following states; providers in these states must refer to the state-specific Medicaid clinical policy or state guidance as noted: Arizona, Florida, Indiana, Kansas, Louisiana, North Carolina, Ohio, and Texas.

Excluded states: AZ, FL, IN, KS, LA, NC, OH, TX
Refer to the noted state Medicaid clinical policy or state-specific guidance

Documentation Required

Use FDA labeling for indications

FDA approval and labeling are provided for informational purposes. Coverage decisions remain subject to federal, state, or contractual benefit plan requirements; FDA approval alone is not a basis for coverage.

Documentation Required

Pombiliti additional requirements

Pombiliti-specific requirements for initial approval: provider attestation that the patient is not improving on current ERT and that current ERT will be stopped; patient weight ≥ 40 kg; and Pombiliti must be prescribed in combination with miglustat (Opfolda). Bill Pombiliti using its HCPCS code J1203 as listed in the policy.

Attestation patient is not improving on current ERT and current ERT will be stopped
Patient weight ≥ 40 kg
Prescribed in combination with miglustat (Opfolda)
HCPCS code: J1203

Lumizyme (alglucosidase alfa): randomized trial in late-onset Pompe disease found a mean increase of 25.1 m on the 6MWT versus a 3.0 m decrease with placebo at 78 weeks (p=0.03) and stabilization/improvement in FVC.

Naglazyme (rhASB): phase 3 trial showed patients walked on average 92 m more in the 12‑minute walk test versus placebo at 24 weeks (p=0.025) with reductions in urinary GAGs.

Xenpozyme (olipudase alfa): randomized trial in adults with ASMD reported a mean increase in % predicted DLco of 20.9% versus placebo at 52 weeks (p=0.0003) with significant reductions in spleen and liver volumes.

Nulibry (fosdenopterin): pooled clinical data compared to historical controls showed improved overall survival (HR 0.18, 95% CI 0.04–0.72) in MoCD Type A patients.

Nexviazyme (avalglucosidase alfa-ngpt): randomized trial versus alglucosidase alfa in late-onset Pompe disease showed a favorable change in 6MWT (estimated treatment difference ~30 meters, p=0.04) and noninferiority on FVC at week 49.

Pombiliti (cipaglucosidase alfa + miglustat): randomized active-controlled trial in late-onset Pompe disease reported modest benefit in sitting FVC and a mean ~14–21 meter favorable change in 6MWD at Week 52 in treated patients depending on population analyzed.