sierra health and life enzyme therapy Coverage Update

Drug-Specific Coverage Criteria

Aldurazyme (laronidase) — Initial and continuation

Covered when ALL of the following are met:

Aldurazyme initial therapy: Diagnosis of MPS I (Hurler, Hurler-Scheie, or Scheie) confirmed by deficient fibroblast or leukocyte alpha-L-iduronidase enzyme activity OR molecular genetic confirmation; presence of clinical signs/symptoms of MPS I; dosing in accordance with U.S. FDA labeling; initial authorization ≤ 12 months

Aldurazyme continuation: Patient previously received laronidase therapy; patient experienced a positive clinical response to laronidase (e.g., improved endurance, functional capacity, reduced urine dermatan/heparan sulfate); dosing in accordance with U.S. FDA labeling; reauthorization ≤ 12 months

Aldurazyme continuation

Covered when ALL of the following are met:

Aldurazyme continuation: Patient has previously received laronidase therapy; documented positive clinical response to laronidase (e.g., improved endurance, improved functional capacity, reduced urine glycosaminoglycan excretion); dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Elaprase (idursulfase)

Covered when ALL of the following are met:

Elaprase initial: Diagnosis of MPS II confirmed by deficiency in iduronate 2-sulfatase activity in fibroblasts or leukocytes with normal activity of another sulfatase OR molecular genetic testing for mutations/deletions in the iduronate 2-sulfatase gene; presence of clinical signs/symptoms of MPS II; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Elaprase continuation: Patient previously received idursulfase therapy; patient experienced a positive clinical response to idursulfase (e.g., improved endurance, functional capacity, reduced spleen volume, reduced urine GAG); dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Elfabrio (pegunigalsidase alfa-iwxj)

Covered when ALL of the following are met:

Elfabrio initial: Diagnosis of Fabry disease confirmed by absence/deficiency of alpha-Gal A activity (<5% of mean) in leukocytes, dried blood spot, or serum OR molecular genetic testing for GLA mutations; presence of clinical signs/symptoms of Fabry disease; not used in combination with other disease-modifying Fabry therapies; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Elfabrio continuation: Patient previously received pegunigalsidase alfa-iwxj therapy; patient experienced a positive clinical response (e.g., improved renal function, reduction in plasma GL-3, decreased GL-3 inclusions); not receiving Elfabrio in combination with another disease-modifying Fabry therapy; dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Fabrazyme (agalsidase beta)

Covered when ALL of the following are met:

Fabrazyme initial: Diagnosis of Fabry disease confirmed by absence/deficiency of alpha-Gal A activity (<5% of mean) in leukocytes, dried blood spot, or serum OR molecular genetic testing for GLA mutations; presence of clinical signs/symptoms of Fabry disease; not used in combination with other disease-modifying Fabry therapies; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Fabrazyme continuation: Patient previously received agalsidase therapy; patient experienced a positive clinical response to agalsidase (e.g., improved renal function, reduction in plasma GL-3, decreased GL-3 inclusions); not receiving Fabrazyme in combination with another disease-modifying Fabry therapy; dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Kanuma (sebelipase alfa)

Covered when ALL of the following are met:

Kanuma initial: Diagnosis of lysosomal acid lipase deficiency (LAL-D, Wolman disease, CESD) confirmed by absence/deficiency of lysosomal acid lipase activity by dried blood spot OR molecular genetic testing for LIPA mutations; presence of clinical signs/symptoms of LAL-D; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Kanuma continuation: Patient previously received sebelipase alfa therapy; patient experienced a positive clinical response to sebelipase (e.g., improved symptoms, improved laboratory values such as LFTs, cholesterol); dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Lamzede (velmanase alfa-tycv)

Covered when ALL of the following are met:

Lamzede initial: Diagnosis of alpha-mannosidosis confirmed by absence/deficiency of alpha-mannosidase activity (<10% of lab-specific normal mean) OR molecular genetic testing for MAN2B1 mutations; presence of clinical signs/symptoms of alpha-mannosidosis; Lamzede is not being used to treat CNS manifestations; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Lamzede continuation: Patient previously received velmanase alfa-tycv therapy; patient experienced a positive clinical response to velmanase (e.g., improved motor or pulmonary function); dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Pompe disease therapies (Lumizyme, Nexviazyme, Pombiliti)

Covered when ALL of the following are met:

Pompe initial options: Infantile-onset: diagnosis confirmed by absence/deficiency of acid alpha-glucosidase (GAA) activity (<1% of lab-specific normal mean) in skin fibroblasts OR molecular genetic testing; presence of clinical signs/symptoms; not receiving Lumizyme/Nexviazyme/Pombiliti in combination with another Pompe ERT; dosing per U.S. FDA labeling; initial authorization ≤ 12 months; OR Late-onset: diagnosis confirmed by absence/deficiency of GAA activity (<40% of lab-specific normal mean) in lymphocytes, fibroblasts, or muscle OR molecular genetic testing; presence of clinical signs/symptoms; not receiving Lumizyme/Nexviazyme/Pombiliti in combination with another Pompe ERT; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Pompe continuation: Patient previously received the respective alglucosidase/avalglucosidase/cipaglucosidase therapy; patient experienced a positive clinical response (e.g., improved respiratory/cardiac function, improved endurance); not receiving the agent in combination with another disease-modifying Pompe therapy; dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Mepsevii (vestronidase alfa-vjbk)

Covered when ALL of the following are met:

Mepsevii initial: Diagnosis of MPS VII confirmed by absence/deficiency of beta-glucuronidase enzyme activity OR molecular genetic confirmation of GUSB mutations; presence of clinical signs/symptoms of MPS VII; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Mepsevii continuation: Patient previously received vestronidase alfa-vjbk therapy; patient experienced a positive clinical response to vestronidase (e.g., improved endurance, functional capacity, pulmonary function); dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Naglazyme (galsulfase)

Covered when ALL of the following are met:

Naglazyme initial: Diagnosis of MPS VI confirmed by absence/deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase) activity OR molecular genetic confirmation of ASB gene mutations; presence of clinical signs/symptoms of MPS VI; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Naglazyme continuation: Patient previously received galsulfase therapy; patient experienced a positive clinical response to galsulfase (e.g., improved endurance, functional capacity, reduced urine dermatan sulfate excretion); dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Nulibry (fosdenopterin)

Covered when ALL of the following are met:

Nulibry initial: Diagnosis of MoCD type A confirmed by absence/deficiency of sulfite oxidase activity in fibroblasts OR molecular genetic testing for MOCS1 mutations; presence of clinical signs/symptoms within first 28 days after birth (e.g., seizures, exaggerated startle, high-pitched cry, axial hypotonia, limb hypertonia, feeding difficulties, elevated urinary sulfite/SSC, elevated xanthine, low/absent uric acid); dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Nulibry continuation: Patient previously received fosdenopterin therapy; patient experienced a positive clinical response to fosdenopterin (e.g., decreased seizures, improved feeding/alertness, improved motor function/growth, decreased urinary sulfite or SSC, decreased xanthine, increased uric acid); dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Nexviazyme (avalglucosidase alfa-ngpt)

Covered when ALL of the following are met:

Nexviazyme initial: Diagnosis of late-onset Pompe disease confirmed by absence/deficiency of GAA activity (<40% of lab-specific normal mean) in lymphocytes, fibroblasts, or muscle OR molecular genetic testing for GAA mutations; presence of clinical signs/symptoms; not receiving Nexviazyme in combination with another disease-modifying Pompe ERT; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Nexviazyme continuation: Patient previously received avalglucosidase alfa-ngpt therapy; patient experienced a positive clinical response to avalglucosidase (e.g., improved respiratory/cardiac function, improved endurance); not receiving Nexviazyme in combination with another Pompe ERT; dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Nulibry (fosdenopterin) — MoCD type A

Covered when ALL of the following are met:

Nulibry (MoCD type A) initial: Diagnosis of MoCD type A confirmed by absence/deficiency of sulfite oxidase activity in fibroblasts OR molecular genetic testing for MOCS1 mutations; presence of clinical signs/symptoms within first 28 days after birth; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Nulibry (MoCD type A) continuation: Patient previously received fosdenopterin therapy; patient experienced a positive clinical response to fosdenopterin; dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Pombiliti (cipaglucosidase alfa-atga) plus Opfolda

Covered when ALL of the following are met:

Pombiliti initial: Diagnosis of late-onset Pompe disease confirmed by absence/deficiency of GAA activity (<40% of lab-specific normal mean) in lymphocytes, fibroblasts, or muscle OR molecular genetic testing for GAA mutations; presence of clinical signs/symptoms; provider attests patient is not improving on current ERT and that current ERT will be stopped; patient weighs ≥ 40 kg; prescribed in combination with oral miglustat (Opfolda); not used in combination with another disease-modifying Pompe ERT; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Pombiliti continuation: Patient previously received cipaglucosidase alfa-atga plus miglustat; patient experienced a positive clinical response to Pombiliti plus Opfolda (e.g., improved respiratory/cardiac function, improved endurance); continues to be prescribed with Opfolda; not receiving Pombiliti with another ERT; dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Revcovi (elapegademase-lvlr)

Covered when ALL of the following are met:

Revcovi initial: Diagnosis of ADA-SCID with ADA deficiency confirmed by absence/deficiency of ADA in plasma, lysed erythrocytes, fibroblasts, or chorionic villi; or increased erythrocyte dATP; or decreased erythrocyte ATP; or molecular genetic confirmation of mutations in both alleles of ADA1; or positive TREC screen; and patient is not a suitable HCT candidate, has failed HCT, or is awaiting HCT; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Revcovi continuation: Patient previously received elapegademase therapy; patient experienced a positive clinical response to elapegademase (e.g., normalization of plasma ADA activity, erythrocyte dATP levels, improvement in disease symptoms); dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Vimizim (elosulfase alfa)

Covered when ALL of the following are met:

Vimizim initial: Diagnosis of Morquio A (MPS IVA) confirmed by absence/deficiency of GALNS enzyme activity OR molecular genetic testing for GALNS mutations; presence of clinical signs/symptoms (e.g., kyphoscoliosis, genu valgum, pectus carinatum, gait disturbance, growth deficiency); dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Vimizim continuation: Patient previously received elosulfase alfa therapy; patient experienced a positive clinical response to elosulfase (e.g., improved endurance, functional capacity, reduced urine keratan sulfate); dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Xenpozyme (olipudase alfa-rpcp)

Covered when ALL of the following are met:

Xenpozyme initial: Diagnosis of ASMD (type A/B or B) confirmed by absence/deficiency of ASM enzyme activity OR molecular genetic testing for SMPD1 mutations; presence of clinical signs/symptoms (e.g., hepatosplenomegaly, elevated transaminases, mixed dyslipidemia, abnormal pulmonary function); not used to treat CNS manifestations of ASMD; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Xenpozyme continuation: Patient previously received olipudase alfa therapy; patient experienced a positive clinical response to olipudase alfa (e.g., reduced spleen/liver volume, improved transaminases, lipid profile, pulmonary function); dosing per U.S. FDA labeling; reauthorization ≤ 12 months

FDA-indication aligned coverage

Coverage aligns with FDA-labeled indications; where the FDA label specifies patient characteristics, those apply.

FDA-indication aligned therapies: Coverage may be considered for FDA-indicated uses summarized in this policy (e.g., Pombiliti with miglustat for adults ≥40 kg not improving on current ERT; Revcovi for ADA-SCID; Vimizim for MPS IVA; Xenpozyme for non-CNS ASMD); verify exact medical necessity criteria (age, prior therapy failure, weight, diagnostic confirmation) in agent-specific sections.

Elfabrio (pegunigalsidase alfa-iwxj) is noted in the policy as typically excluded from coverage. Coverage requests for Elfabrio may still be subject to review when required by law or the member's benefit plan; refer to the Medical Benefit Drug Policy titled "Medical Benefit Therapeutic Equivalent Medications - Excluded Drugs" for preferred alternatives and any coverage review procedures.

Xenpozyme (olipudase alfa-rpcp) is approved for non‑CNS manifestations of acid sphingomyelinase deficiency (ASMD) and the policy explicitly states it is not to be used to treat central nervous system (CNS) manifestations of ASMD. Coverage requires diagnostic confirmation, relevant clinical signs or symptoms, and dosing consistent with U.S. FDA labeling.

Coverage of therapies in this policy may be benefit‑dependent. The member's Certificate of Coverage and plan terms must be consulted because some Certificates of Coverage allow coverage of investigational or off‑label uses and some state mandates may supersede plan language. In addition, excluded‑drug lists and plan provisions (for example the excluded status of Elfabrio) can affect whether a particular request will be accepted or denied.

Pombiliti (cipaglucosidase alfa‑atga) is indicated for adults with late‑onset Pompe disease who are not improving on their current enzyme replacement therapy (ERT) and must be prescribed in combination with miglustat (Opfolda). The policy requires the provider to attest that the patient is not improving on current ERT and that the current ERT will be stopped prior to initiating Pombiliti; additionally, the patient must weigh ≥ 40 kg and dosing must follow the U.S. FDA‑approved labeling.

The policy includes an operational note that certain newly launched agents have been added to the Review at Launch program. Specifically, Loargys (pegzilarginase‑nbln) and Avlayah (tividenofusp alfa‑eknm) were added and, as a result, some members may not be eligible for coverage at this time. For prior authorization and eligibility determinations, refer to the Medical Benefit Drug Policy titled "Review at Launch for New to Market Medications."

In the MOR‑004 Phase 3 trial of Vimizim (elosulfase alfa) for Morquio A, the every‑other‑week (QOW) 2.0 mg/kg regimen did not show a significant improvement in the primary endpoint (6‑minute walk test) versus placebo, whereas the weekly 2.0 mg/kg regimen did. The policy therefore highlights that every‑other‑week dosing did not demonstrate significant benefit versus placebo in this trial and that QOW dosing may be considered not medically necessary for improvement in endurance compared with weekly dosing based on these results.

Initial Authorization Requirements

Initial therapy requirements — common structure

Initial therapy requirements (common structure):

Initial therapy general: Diagnostic confirmation by specified enzyme assay or molecular genetic testing; presence of clinical signs/symptoms appropriate to the disease; dosing per U.S. FDA labeling; initial authorization ≤ 12 months

Initial therapy (general) — diagnostic confirmation, signs/symptoms, FDA dosing

Initial therapy — agent-specific requirements (general):

Agent-specific initial criteria: See individual drug sections for required diagnostic confirmation (enzyme assay or molecular testing), clinical signs/symptoms, dosing per U.S. FDA labeling, and initial authorization limited to no more than 12 months.

Examples of trial regimens (informational)

Informational examples of trial regimens (not coverage directives):

Reauthorization / Continuation Rules

Continuation therapy rules — common requirements

Continuation/reauthorization common requirements:

General continuation: Patient previously received the specified therapy; documented positive clinical response as defined per agent; dosing consistent with U.S. FDA labeling; reauthorization ≤ 12 months

Continuation criteria (general) — prior receipt and documented response

Continuation (reauthorization) general criteria:

Continuation criteria (general): Previously received specified therapy; documented positive clinical response per agent-specific definitions; dosing per U.S. FDA labeling; reauthorization ≤ 12 months

Vimizim continuation — long-term extension data

Long-term continuation data (Vimizim):

Billing and Diagnosis Codes

HCPCS codesHCPCS

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
J0219	Injection, avalglucosidase alfa-ngpt, 4 mg
J1809	Injection, fosdenopterin, 0.1 mg
J1203	Injection, cipaglucosidase alfa-atga, 5 mg

1–10 of 13

1/2

Diagnosis codesICD-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
E74.02	Pompe disease
E76.210	Morquio A mucopolysaccharidoses
E75.241	Niemann-Pick disease type B; ASMD type B
E75.244	Niemann-Pick disease type A/B; ASMD type A/B
E72.10	Disorders of sulfur-bearing amino-acid metabolism, unspecified

1–10 of 15

1/2

GAA activity thresholds for Pompe disease

Infantile-onset Pompe diseaseGAA activity < 1% of the lab-specific normal mean

Late-onset Pompe diseaseGAA activity < 40% of the lab-specific normal mean

Specimen typesMeasured in skin fibroblasts, lymphocytes, or muscle as specified per agent

alpha-Gal A activity threshold for Fabry disease

Diagnostic thresholdAlpha-galactosidase A (α-Gal A) activity < 5% of mean

Specimen typesMeasured in leukocytes, dried blood spots, or serum analysis

Authorization, Documentation, and Denial Risk

Prior Authorization

Prior Authorization Required

Prior authorization is required for these therapies. Requests must include clinical documentation supporting diagnosis, prior therapy history, and that dosing aligns with FDA‑approved labeling. Initial authorizations are generally limited to up to 12 months; continuation/reauthorization requires evidence of prior treatment and positive clinical response. Consult member-specific Certificate of Coverage and applicable federal/state mandates to confirm benefit eligibility.

Prior authorization required — documentation and clinical criteria must be met
Initial authorization typically ≤ 12 months; reauthorization requires prior therapy and clinical response
Member benefit and state/federal mandates may override policy — verify member-specific coverage

Prior Authorization

Plan-Dependent Prior Authorization and Benefit Checks

Plan-dependent prior authorization and benefit checks are required. Some Certificates of Coverage permit coverage for experimental/investigational/unproven treatments under specific conditions; others exclude certain products (for example, Elfabrio is typically excluded). Always verify plan benefits before approving coverage.

Sequencing and Step Requirements

Restriction	Policy detail
Mutual exclusivity of disease‑modifying enzyme therapies
Drugs should not be used in combination with other disease‑modifying enzyme replacement or similar therapies for the same condition (e.g., Pompe and Fabry therapies). Individual agent sections specify that the patient must not be receiving the listed drug in combination with another disease‑modifying enzyme therapy; dosing must follow U.S. FDA labeling and authorizations are limited to no more than 12 months.

Restriction

Policy detail

Mutual exclusivity of disease‑modifying enzyme therapies

Drugs should not be used in combination with other disease‑modifying enzyme replacement or similar therapies for the same condition (e.g., Pompe and Fabry therapies). Individual agent sections specify that the patient must not be receiving the listed drug in combination with another disease‑modifying enzyme therapy; dosing must follow U.S. FDA labeling and authorizations are limited to no more than 12 months.

Requirement	Details / provider attestation
Provider attestation to stop current ERT
Provider must attest the patient is not improving on their current enzyme replacement therapy (ERT) and that the current ERT will be stopped prior to initiating Pombiliti; Pombiliti must be prescribed in combination with oral miglustat (Opfolda).

Step therapy sequence	Policy note
Formal step therapy sequence
No formal step therapy sequence is specified in the provided excerpt; coverage sequencing may consider prior ERT history and is determined by agent‑specific criteria and the member's benefit plan.

Prior therapy requirement	Evidence/documentation needed
Documentation of prior ERT and inadequate response
Prior therapy with an enzyme replacement therapy and documentation that the patient is not improving on the current ERT may be required before authorizing Pombiliti (cipaglucosidase alfa‑atga); clinical notes should document lack of improvement and planned discontinuation of prior ERT. Pombiliti is indicated for adults ≥40 kg and must be given with miglustat (Opfolda).

Infusion and Administration Setting

Note

Infusion center — typical site of care per clinical trials

Most agents in this policy were administered intravenously in clinical trials; the typical site of administration is an infusion center or hospital outpatient infusion setting.

Plan for infusion center or hospital outpatient administration consistent with trial settings.

Billing Rule

Infusion center — trial infusion interruptions/medical interventions reported; consider site-of-care

Infusion-based ERTs had reported infusion interruptions and medical interventions in trials; consider site-of-care capabilities for monitoring and managing infusion reactions when arranging administration.

Document capability to monitor for and manage infusion-related adverse events when requesting site‑of‑care billing/authorization.

Policy Scope and Background

This policy covers multiple inherited enzyme deficiency disorders treated with exogenous enzyme or related therapies. Conditions and therapies explicitly addressed include MPS I (Aldurazyme), MPS II (Elaprase), Fabry disease (Elfabrio, Fabrazyme), LAL‑D (Kanuma), alpha‑mannosidosis (Lamzede), Pompe disease (Lumizyme, Nexviazyme, Pombiliti), MPS VII (Mepsevii), MPS VI (Naglazyme), MoCD type A (Nulibry), ADA‑SCID (Revcovi), MPS IVA (Vimizim), and ASMD (Xenpozyme). For each agent the policy requires diagnostic confirmation (enzyme assay or molecular genetic testing where specified), documentation of clinical signs/symptoms, dosing per U.S. FDA labeling, and prior authorization for initial and continuation authorizations typically limited to no more than 12 months.

Key Definitions

Diagnostic confirmation — enzyme activity or molecular testing definitions

DefinitionDiagnostic confirmation is either deficiency/absence of the specific enzyme activity in an appropriate specimen (leukocytes, fibroblasts, dried blood spot, serum) or molecular genetic testing confirming pathogenic mutations in the disease gene

Specimen examplesCommon specimens include leukocytes, fibroblasts, dried blood spots, lymphocytes, skin fibroblasts, or muscle depending on the enzyme/test

Agent-specific applicationPolicy requires enzyme assay or molecular testing per agent (e.g., GAA for Pompe, α-Gal A for Fabry, MAN2B1 for alpha-mannosidosis)

Exogenous enzyme replacement definition

DefinitionExogenous enzyme replacement: administration of a recombinant human enzyme to provide the deficient lysosomal enzymatic activity and reduce accumulated substrates in lysosomal storage disorders

Policy Updates

2026-05-01material_additionLatest

Added language to Coverage Rationale indicating Loargys (pegzilarginase-nbln) and Avlayah (tividenofusp alfa-eknm) were added to the Review at Launch program and that some members may not be eligible for coverage at this time; refer to the Review at Launch policy for details.

2026-05-01references_update

Updated CMS and References sections to reflect the most current information.

OpenPayer

Medical Therapies for Enzyme Deficiencies

Drug-Specific Coverage Criteria

Initial Authorization Requirements

Reauthorization / Continuation Rules

Billing and Diagnosis Codes

Authorization, Documentation, and Denial Risk

Sequencing and Step Requirements

Infusion and Administration Setting

Policy Scope and Background

Key Definitions

Policy Updates