UnitedHealthcare Enzyme Therapy Coverage Update

Drug-Specific Coverage Criteria

Aldurazyme (laronidase)

Aldurazyme (laronidase) is medically necessary when ALL of the following are met:

Aldurazyme initial therapy: Diagnosis of any MPS I syndrome (Hurler, Hurler‑Scheie, Scheie) confirmed by deficiency/absence of alpha‑L‑iduronidase enzyme activity in fibroblasts or leukocytes OR molecular genetic confirmation of pathogenic mutations; presence of clinical signs and symptoms of MPS I (e.g., cardiac abnormalities, corneal clouding, dysostosis multiplex, hepatomegaly, restrictive lung disease, etc.); dosing in accordance with U.S. FDA–approved labeling; initial authorization for no more than 12 months

Aldurazyme continuation: Patient has previously received laronidase (Aldurazyme); documented positive clinical response to laronidase (e.g., improved endurance, improved functional capacity, reduced urine dermatan/heparan sulfate excretion); dosing in accordance with U.S. FDA–approved labeling; reauthorization for no more than 12 months

Elaprase (idursulfase)

Elaprase (idursulfase) is medically necessary when ALL of the following are met:

Elaprase initial therapy: Diagnosis of MPS II (Hunter syndrome) confirmed by deficiency of iduronate 2‑sulfatase activity in fibroblasts or leukocytes with normal activity of another sulfatase OR molecular genetic testing demonstrating pathogenic mutations in the iduronate 2‑sulfatase gene; presence of clinical signs and symptoms of MPS II (e.g., hepatosplenomegaly, skeletal deformities, neurocognitive decline, cardiovascular disorders, etc.); dosing in accordance with U.S. FDA–approved labeling; initial authorization for no more than 12 months

Elaprase continuation: Patient has previously received idursulfase (Elaprase); documented positive clinical response to idursulfase (e.g., improved endurance, improved functional capacity, reduced spleen volume, reduced urine glycosaminoglycan excretion); dosing in accordance with U.S. FDA–approved labeling; reauthorization for no more than 12 months

Elfabrio (pegunigalsidase alfa-iwxj)

Elfabrio (pegunigalsidase alfa‑iwxj) is medically necessary for adults with confirmed Fabry disease when ALL of the following are met:

Elfabrio initial therapy: Diagnosis of Fabry disease confirmed by absence or deficiency (<5% of mean) of alpha‑galactosidase A activity in leukocytes, dried blood spots, or serum OR by molecular genetic testing showing pathogenic variants in the GLA gene; presence of clinical signs and symptoms of Fabry disease (e.g., acroparesthesias, angiokeratomas, corneal whorls, anhidrosis/hypohidrosis, renal disease, exercise/heat/cold intolerance); patient is an adult; Elfabrio is not being used in combination with another disease‑modifying Fabry therapy (e.g., Fabrazyme, migalastat); dosing in accordance with U.S. FDA–approved labeling; initial authorization for no more than 12 months

Adults only per policy statement

Elfabrio continuation: Patient has previously received pegunigalsidase alfa‑iwxj (Elfabrio); documented positive clinical response to therapy (e.g., improved renal function, reduction in mean plasma GL‑3, decreased GL‑3 inclusions); patient is not receiving Elfabrio in combination with other disease‑modifying Fabry therapies; dosing in accordance with U.S. FDA–approved labeling; reauthorization for no more than 12 months

Fabrazyme (agalsidase beta)

Fabrazyme (agalsidase beta) coverage:

Fabrazyme reference: Medical necessity clinical coverage criteria for Fabrazyme are per the current InterQual CP: Specialty Rx NonOncology, Agalsidase beta (Fabrazyme); refer to InterQual for specific diagnostic, clinical, and dosing requirements.

Document references InterQual criteria

Kanuma (sebelipase alfa)

Kanuma (sebelipase alfa) is medically necessary when ALL of the following are met:

Kanuma initial therapy: Diagnosis of lysosomal acid lipase deficiency (LAL‑D; Wolman disease or CESD) confirmed by absence/deficiency of lysosomal acid lipase activity on dried blood spot testing OR molecular genetic testing demonstrating pathogenic LIPA mutations; presence of clinical signs and symptoms (e.g., abdominal distention, hepatosplenomegaly, liver fibrosis, ascites); dosing in accordance with U.S. FDA–approved labeling; initial authorization for no more than 12 months

Kanuma continuation: Patient has previously received sebelipase alfa (Kanuma); documented positive clinical response to therapy (e.g., improvement in disease symptoms, normalization or improvement of laboratory values such as LFTs, cholesterol, triglycerides); dosing in accordance with U.S. FDA–approved labeling; reauthorization for no more than 12 months

Lamzede (velmanase alfa-tycv)

Lamzede (velmanase alfa‑tycv) is medically necessary when ALL of the following are met:

Lamzede initial therapy: Diagnosis of alpha‑mannosidosis confirmed by absence/deficiency (<10% of lab‑specific mean) of alpha‑mannosidase enzyme activity OR by molecular genetic testing for MAN2B1 mutations; presence of clinical signs and symptoms (e.g., hepatosplenomegaly, skeletal abnormalities, ataxia, intellectual disability, hearing loss); Lamzede is not being used to treat CNS manifestations of alpha‑mannosidosis; dosing in accordance with U.S. FDA–approved labeling; initial authorization for no more than 12 months

Not for CNS manifestations

Lamzede continuation: Patient has previously received velmanase alfa‑tycv (Lamzede); documented positive clinical response to therapy (e.g., improved motor function, improved pulmonary function); dosing in accordance with U.S. FDA–approved labeling; reauthorization for no more than 12 months

Mepsevii (vestronidase alfa-vjbk)

Mepsevii (vestronidase alfa‑vjbk) is medically necessary when ALL of the following are met:

Mepsevii initial therapy: Diagnosis of mucopolysaccharidosis VII (MPS VII, Sly syndrome) confirmed by absence/deficiency of beta‑glucuronidase enzyme activity in fibroblasts or leukocytes OR molecular genetic confirmation of GUSB mutations; presence of clinical signs and symptoms (e.g., organomegaly, joint limitations, airway obstruction, limitation of mobility while ambulatory); dosing in accordance with U.S. FDA–approved labeling; initial authorization for no more than 12 months

Mepsevii continuation: Patient has previously received vestronidase alfa‑vjbk (Mepsevii); documented positive clinical response to therapy (e.g., improved endurance, improved functional capacity, improved pulmonary function); dosing in accordance with U.S. FDA–approved labeling; reauthorization for no more than 12 months

Naglazyme (galsulfase)

Naglazyme (galsulfase) is medically necessary when ALL of the following are met:

Naglazyme initial therapy: Diagnosis of mucopolysaccharidosis VI (MPS VI, Maroteaux‑Lamy) confirmed by absence/deficiency of N‑acetylgalactosamine 4‑sulfatase (arylsulfatase) activity in fibroblasts or leukocytes OR molecular genetic confirmation of ASB gene mutations; presence of clinical signs and symptoms (e.g., kyphoscoliosis, genu valgum, pectus carinatum, gait disturbance, growth deficiency); dosing in accordance with U.S. FDA–approved labeling; initial authorization for no more than 12 months

Naglazyme continuation: Patient has previously received galsulfase (Naglazyme); documented positive clinical response to therapy (e.g., improved endurance, improved functional capacity, reduced urine dermatan sulfate excretion); dosing in accordance with U.S. FDA–approved labeling; reauthorization for no more than 12 months

Nulibry (fosdenopterin)

Nulibry (fosdenopterin) is medically necessary for MoCD type A when ALL of the following are met:

Nulibry initial therapy: Diagnosis of molybdenum cofactor deficiency (MoCD) type A confirmed by absence/deficiency of sulfite oxidase activity in fibroblasts OR molecular genetic testing demonstrating MOCS1 mutations; presence of clinical signs and symptoms within the first 28 days after birth (e.g., seizures, exaggerated startle, high‑pitched cry, axial hypotonia, limb hypertonia, feeding difficulties, elevated urinary sulfite or S‑sulphocysteine [SSC], elevated xanthine, low/absent uric acid); dosing in accordance with U.S. FDA–approved labeling; initial authorization for no more than 12 months

Neonatal presentation required

Nulibry continuation: Patient has previously received fosdenopterin (Nulibry); documented positive clinical response to therapy (e.g., decreased seizure activity, improved feeding/alertness/responsiveness, improved gross motor function/growth, decreased urinary sulfite or SSC, decreased xanthine, increased uric acid); dosing in accordance with U.S. FDA–approved labeling; reauthorization for no more than 12 months

Revcovi (elapegademase-lvlr)

Revcovi (elapegademase‑lvlr) is medically necessary for ADA‑SCID when ALL of the following are met:

Revcovi initial therapy: Diagnosis of ADA‑SCID with confirmed adenosine deaminase deficiency by assay of ADA in plasma, erythrocytes, fibroblasts, or by increased erythrocyte dATP and decreased ATP OR by molecular genetic confirmation of biallelic ADA1 mutations; positive TREC screening; and one of: patient is not a candidate for hematopoietic cell transplantation (HCT), has failed HCT, or is awaiting HCT; dosing in accordance with U.S. FDA–approved labeling; initial authorization for no more than 12 months

Revcovi continuation: Patient has previously received elapegademase‑lvlr (Revcovi); documented positive clinical response to therapy (e.g., normalization of plasma ADA activity, erythrocyte dAXP levels, improvement of disease symptoms); dosing in accordance with U.S. FDA–approved labeling; reauthorization for no more than 12 months

Vimizim (elosulfase alfa)

Vimizim (elosulfase alfa) is medically necessary for MPS IVA when ALL of the following are met:

Vimizim initial therapy: Diagnosis of Morquio A (MPS IVA) confirmed by absence/deficiency of GALNS enzyme activity in fibroblasts or leukocytes OR molecular genetic testing demonstrating GALNS mutations; presence of clinical signs and symptoms (e.g., kyphoscoliosis, genu valgum, pectus carinatum, gait disturbance, growth deficiency); dosing in accordance with U.S. FDA–approved labeling; initial authorization for no more than 12 months

Vimizim continuation: Patient has previously received elosulfase alfa (Vimizim); documented positive clinical response to therapy (e.g., improved endurance, improved functional capacity, reduced urine keratan sulfate excretion); dosing in accordance with U.S. FDA–approved labeling; reauthorization for no more than 12 months

Xenpozyme (olipudase alfa-rpcp)

Xenpozyme (olipudase alfa‑rpcp) is medically necessary for ASMD when ALL of the following are met:

Xenpozyme initial therapy: Diagnosis of ASMD (type A/B or B) confirmed by absent/deficient acid sphingomyelinase (ASM) enzyme activity OR by molecular genetic testing for SMPD1 mutations; presence of clinical signs and symptoms of ASMD (e.g., hepatosplenomegaly, elevated transaminases, mixed dyslipidemia, abnormal pulmonary function); Xenpozyme is not being used to treat CNS manifestations of ASMD; dosing in accordance with U.S. FDA–approved labeling; initial authorization for no more than 12 months

Not for CNS manifestations

Xenpozyme continuation: Patient has previously received olipudase alfa‑rpcp (Xenpozyme); documented positive clinical response to therapy (e.g., reduced spleen volume, reduced liver volume, improved liver transaminases, improved lipid profile, improved pulmonary function); dosing in accordance with U.S. FDA–approved labeling; reauthorization for no more than 12 months

Initial Therapy

Covered when ALL of the following are met for initial therapy:

Initial therapy requirements: 1) Diagnosis of ASMD type A/B or B confirmed by absent/deficient ASM enzyme activity OR SMPD1 molecular genetic testing; 2) Presence of clinical signs and symptoms of disease (e.g., hepatosplenomegaly, elevated transaminases, mixed dyslipidemia, abnormal pulmonary function); 3) Xenpozyme is not being used to treat CNS manifestations of ASMD; 4) Dosing per U.S. FDA–approved labeling; 5) Initial authorization limited to no more than 12 months

Includes documentation and billing note (e.g., HCPCS J0218, ICD‑10 codes E75.241/E75.244)

Continuation Therapy

Covered when ALL of the following are met for continuation (reauthorization):

Continuation therapy requirements: 1) Patient has previously received olipudase alfa‑rpcp (Xenpozyme); 2) Patient has experienced a positive clinical response (e.g., reduced spleen volume, reduced liver volume, improved liver transaminases, improved lipid profile, improved pulmonary function); 3) Dosing per U.S. FDA–approved labeling; 4) Reauthorization limited to no more than 12 months

Derived from policy continuation bullets

Fabrazyme — efficacy and safety findings

Fabrazyme (agalsidase beta) — trial evidence summary

Fabrazyme trial results: Multicenter randomized double‑blind trial (n=82) showed delayed time to first composite clinical event (renal, cardiac, cerebrovascular, or death) with agalsidase beta versus placebo (ITT adjusted HR 0.47; 95% CI 0.21–1.03; p=0.06); protocol‑adherent analysis showed HR 0.39 (95% CI 0.16–0.93; p=0.034). Infusion‑associated reactions were common (reported in 55% of treated patients). Larger benefit observed in patients with baseline eGFR >55 mL/min/1.73 m2.

Evidence supports clinical benefit in advanced Fabry disease

Kanuma — efficacy and safety findings

Kanuma (sebelipase alfa) — trial evidence summary

Kanuma trial results: Phase 3 randomized trial (n=66) of sebelipase alfa 1 mg/kg IV every other week showed significantly higher rate of alanine aminotransferase normalization versus placebo at 20 weeks (31% vs 7%, p=0.03) and significant improvements in multiple hepatic and lipid secondary endpoints; adverse events similar between groups.

Primary endpoint: ALT normalization at 20 weeks

Lamzede — efficacy and safety findings

Lamzede (velmanase alfa) — trial evidence summary

Lamzede trial results: Phase 3 trial (n=25) at 1 mg/kg weekly for 52 weeks demonstrated significant reduction in serum oligosaccharides versus placebo (mean relative change −77.6% vs −24.1%; p<0.001); mixed effects on functional endpoints with no significant 3MSCT change and non‑significant small increase in 6MWT; long‑term extension data supported sustained biochemical reductions and some functional improvements; one serious TEAE related to drug (acute renal failure) resolved after interruption.

Naglazyme — efficacy and safety findings

Naglazyme (rhASB) — trial evidence summary

Naglazyme trial results: Phase 3 randomized trial (n=39) in MPS VI showed improvement in endurance (12MWT +92 m; p=0.025), a trend for stair climb, and significant urine GAG reduction; infusions generally safe and tolerated despite antibody formation.

Primary endpoint: 12‑minute walk test

Nulibry — efficacy and safety findings

Nulibry (fosdenopterin) — trial evidence summary

Nulibry trial results: Pooled data from three studies (13 treated patients) versus genotype‑matched natural history cohort (n=18) showed improved overall survival with fosdenopterin/rcCMP (HR 0.18; 95% CI 0.04–0.72) and sustained reductions in urine SSC through 48 months; small sample sizes noted.

Evidence from pooled studies compared to historical controls

Revcovi — efficacy and safety findings

Revcovi (elapegademase‑lvlr) — trial evidence summary

Revcovi trial results: Phase 3 open‑label single‑arm studies demonstrated biochemical detoxification (erythrocyte dAXP ≤0.02 mmol/L), increased trough plasma ADA activity, and improved lymphocyte counts in most patients; metabolic detoxification maintained for ≥2 years in treated patients.

Endpoints biochemical (dAXP, ADA activity) and immune cell counts

Vimizim — efficacy and safety findings

Vimizim (elosulfase alfa) — trial evidence summary

Vimizim trial results: Phase 3 randomized MOR‑004 trial (n=176) showed weekly elosulfase alfa improved 6MWT versus placebo (mean effect +22.5 m; p=0.017) while every‑other‑week dosing did not; high rates of total and neutralizing antibodies were observed but immunogenicity did not correlate with reduced efficacy in trial analyses; long‑term extension (up to 72 weeks) showed no further walking improvement beyond initial 24 weeks.

Immunogenicity observed but not linked to reduced efficacy

Xenpozyme — efficacy and safety findings

Xenpozyme (olipudase alfa) — trial evidence summary

Xenpozyme trial results: Randomized adult trial (n=31) showed at week 52 improvements in % predicted DLco (+20.9%), spleen volume (−39.4%), liver volume (−24.7%), and platelet count (+15.6%); pediatric open‑label and extension data (8 children treated 2.5–3.2 years) demonstrated continued improvements in DLco (3 patients), platelets (6 patients), spleen and liver volumes (8 patients), and increased height Z‑score through 24 months.

Endpoints included DLco, organ volumes, platelets, and growth

Coverage Rationale (summary)

Policy-level coverage rationale and scope changes

Policy changes and applicability: Coverage list of enzyme deficiency therapies revised; certain therapies (e.g., Lumizyme, Nexviazyme) were removed from this policy and their coverage is now contingent on the state's Medicaid clinical policy; providers should consult state Medicaid guidance for those products.

Effective 03/01/2026; see Policy History

Coverage for Lumizyme (alglucosidase alfa), Nexviazyme (avalglucosidase alfa-ngpt), and Pombiliti is not governed by the Drug‑Specific Criteria in this policy and is instead contingent on the applicable state's Medicaid clinical policy. Providers should follow the state's Medicaid criteria when requesting coverage or prior authorization for these products; requests submitted under this policy for those therapies may not be processed here.

Use of Xenpozyme (olipudase alfa‑rpcp) to treat central nervous system (CNS) manifestations of acid sphingomyelinase deficiency (ASMD) is excluded. Xenpozyme provides exogenous acid sphingomyelinase to reduce sphingomyelin accumulation in visceral organs but is not expected to cross the blood‑brain barrier, and the policy explicitly states it is not to be used for CNS manifestations of ASMD.

FDA approval statements in this policy are provided for informational purposes only. The policy notes that FDA approval alone is not a basis for coverage and lists the labeled indications for the referenced agents (for example, Aldurazyme for certain MPS I presentations, Elaprase for MPS II, Lamzede for non‑CNS manifestations of alpha‑mannosidosis, and Xenpozyme for non‑CNS manifestations of ASMD).

Lumizyme and Nexviazyme have been removed from the list of therapies governed by this policy; the Summary of Changes indicates their coverage guidelines and associated codes were deleted and that coverage for these products is now contingent on the state's Medicaid clinical policy. Providers should consult state Medicaid guidance for coverage and coding for these products.

Within the excerpt provided, there are no explicit statements categorizing any therapy as 'not medically necessary.' The document instead frames FDA approvals as informational and defers coverage determinations to the policy criteria and supporting documentation.

The policy reiterates that FDA approvals alone are informational and are not the sole basis for coverage determinations. Coverage decisions require evaluation against the Drug‑Specific Criteria, required documentation, and applicable benefit terms.

Requirements for Initial Authorization

Requirements for Reauthorization / Ongoing Therapy

Billing and Diagnosis Codes

Covered HCPCS Codes (Xenpozyme)HCPCSCovered

J0218

Injection, olipudase alfa-rpcp, 1 mg

Other referenced HCPCS codes (enzyme therapies)HCPCS

J1931	Injection, laronidase, 0.1 mg
J1743	Injection, idursulfase, 1 mg
J2840	Injection, sebelipase alfa, 1 mg
J0217	Injection, velmanase alfa-tycv, 1 mg
J3397	Injection, vestronidase alfa-vjbk, 1 mg
J1458	Injection, galsulfase, 1 mg

Referenced ICD-10 Diagnosis CodesICD-10

E75.241	Niemann-Pick disease type B; ASMD type B & Chronic visceral acid sphingomyelinase deficiency
E75.244	Niemann-Pick disease type A/B; ASMD type A/B & Chronic neurovisceral acid sphingomyelinase deficiency

Previously applicable HCPCS codes (removed)HCPCSNot Covered

J0221	Lumizyme (alglucosidase alfa) HCPCS code (removed from list)
J0219	Nexviazyme (avalglucosidase alfa-ngpt) HCPCS code (removed from list)

Previously applicable ICD-10 diagnosis codes (removed)ICD-10Not Covered

E74.02

ICD-10 code previously listed for Lumizyme/Nexviazyme (removed)

Prior Authorization & Documentation Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required for covered enzyme deficiency therapies listed in this policy. Initial authorizations will be for no more than 12 months; reauthorizations (continuation therapy) will also be granted for no more than 12 months when documentation requirements are met.

Prior authorization required for initial and continuation therapy
Initial authorization duration: up to 12 months
Reauthorization duration: up to 12 months

Documentation Required

Documentation Required for Initial and Continuation Therapy

Providers must submit documentation confirming diagnostic testing and clinical signs/symptoms for the specific enzyme deficiency per the Drug-Specific Criteria. Documentation should include diagnostic confirmation (enzyme assay and/or molecular genetic testing), description of relevant signs and symptoms, and dosing consistent with the U.S. FDA–approved labeling.

Sequencing and Step-Therapy Notes

Requirement	Details
Do not combine with other disease‑modifying Fabry therapies	Elfabrio must not be used in combination with another disease‑modifying therapy for Fabry disease (e.g., Fabrazyme, Galafold).
Fabrazyme criteria reference	Medical necessity clinical coverage criteria for Fabrazyme are per the current InterQual® guideline CP: Specialty Rx NonOncology, Agalsidase beta (Fabrazyme).

Step therapy statement	Notes
No specific step‑therapy pathways described	The excerpt does not describe step‑therapy pathways or prior biologic failure requirements for these therapies.

Step therapy requirement	Guidance
No step therapy requirements specified	The document segment does not specify step therapy; UnitedHealthcare may use external tools (e.g., InterQual®) to assist in administering benefits.

Infusion & Administration Setting

Billing Rule

Infusion center — site-of-care expectation

All therapies referenced in this policy were administered as intravenous infusions in clinical trials; initiation and maintenance are typically delivered in an infusion center or hospital outpatient/infusion suite.

Therapies were given as IV infusions in trials
Infusion center or hospital outpatient/infusion setting expected for administration

Note

Infusion center policy note — informational guidance

This site‑of‑care guidance is informational only; the policy does not impose specific site‑of‑care restrictions and plan‑specific benefit terms should be consulted.

No site‑of‑care restrictions specified in this policy segment

Key Terms and Clinical Definitions

Diagnostic confirmation — accepted methods

Diagnostic confirmation methodsConfirmed by absence or deficiency of specific enzyme activity measured in fibroblasts, leukocytes, dried blood spots, or serum analysis, or by molecular genetic testing showing pathogenic mutations as specified per disease.

Enzyme assay examplesDisease-specific enzyme assays referenced include alpha-L-iduronidase (MPS I), iduronate 2-sulfatase (MPS II), lysosomal acid lipase (LAL-D), GALNS (MPS IVA), acid sphingomyelinase (ASMD), beta glucuronidase (MPS VII), arylsulfatase B (MPS VI), sulfite oxidase (MoCD-A).

Molecular genetic testingMolecular genetic testing (gene-specific deletion or mutation analysis) is an alternative confirmatory method when enzyme testing is insufficient or to confirm carrier/status (examples: SMPD1 for ASMD, LIPA for LAL-D, GALNS for MPS IVA, GUSB for MPS VII, MOCS1 for MoCD-A).

Specimen typesAccepted specimen types for enzyme assays include fibroblasts, leukocytes, dried blood spots, or serum depending on the disorder and assay availability.

Documentation for prior authorizationProviders must include diagnostic confirmation (enzyme assay results or molecular genetic testing) with initial and continuation authorization requests per the policy requirements.

Clinical and Policy Background

Inherited enzyme deficiencies (for example, mucopolysaccharidoses, Fabry disease, lysosomal acid lipase deficiency, ADA‑SCID, molybdenum cofactor deficiency type A, and ASMD) are managed with disease‑specific enzyme replacement or replacement‑like therapies. Diagnostic confirmation is by enzyme activity assay or molecular genetic testing, and treatment eligibility under this policy requires documented clinical signs or symptoms consistent with the specific disorder and dosing consistent with the U.S. FDA label.

Policy Changes and Version History

This policy was revised effective 03/01/2026. Material changes include a revised list of applicable enzyme deficiency therapies and removal of Lumizyme (alglucosidase alfa) and Nexviazyme (avalglucosidase alfa‑ngpt) from the policy; associated HCPCS and ICD‑10 codes for those products were also removed. The previous policy version CSIND0052.15 has been archived.

OpenPayer

Medical Therapies for Enzyme Deficiencies (for Indiana Only)