CurrentBlue Cross Blue Shield - IowaPolicy 05.02.91

Enzyme Replacement Therapy (ERT) — Coverage Criteria

Governs medical necessity and prior authorization requirements for enzyme replacement therapies and related products when benefits apply.

Policy Summary

PayerBlue Cross Blue Shield - Iowa

PolicyEnzyme Replacement Therapy (ERT) — Coverage Criteria

Policy CodePolicy 05.02.91

Change TypeNo material change

Effective DateMar 19, 2026

Next Review DateJan 1, 2026

Key ActionSubmit prior authorization with diagnostic confirmation (enzyme assay and/or genetic testing) and documentation of clinical response for continuation requests.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

18+FDA‑approved ERTs listed

PA tests listedRequired documentation

12 monthsTypical approval duration

Xenpozyme/LamzedeBlack box warnings

Coverage Criteria — Initial and Continuation

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Initial Therapy Diagnostic and Product-Specific Requirements

Initial therapy diagnostic requirements

Initial requests require diagnostic confirmation via enzyme assay and/or genetic testing specific to the disorder and product.

Initial diagnostic requirement: Enzyme assay and/or genetic testing results supporting diagnosis for the requested ERT product.

Initial therapy requirements — disease-specific confirmation and drug-specific age/weight/prior-therapy conditions

Initial therapy requires disease-specific diagnostic confirmation and any drug-specific age/weight or prior-therapy conditions.

General initial requirement: Therapy initiation requires enzyme assay or genetic testing results supporting the diagnosis per drug-specific instructions; additional criteria such as age, weight, uGAG thresholds, ALT criteria, prior BMT failure, or combination therapy requirements apply per product.

Initial therapy (trial-derived context)

Initial therapy indications are tied to FDA approvals and diagnostic confirmation; clinical trial entry criteria provide context for initial-use documentation.

Brineura initial use: Symptomatic pediatric patients with CLN2 and confirmed TPP1 deficiency are FDA-indicated for Brineura to slow loss of ambulation; trials enrolled children aged 3-8 and used Motor/Language CLN2 scores for selection/analysis.

Nulibry initial use: Patients with genetically confirmed MoCD Type A are indicated for Nulibry to reduce mortality; initial dosing titrated to a maximum of 0.9 mg/kg IV once daily in studies and urinary SSC is a monitored biomarker.

Xenpozyme initial context: Xenpozyme approvals and trials demonstrated improvements in lung function, organ volumes, and platelets in adults and pediatric patients, informing baseline and monitoring expectations for ASMD treatment.

Continuation Therapy — Response and Monitoring Requirements

Continuation therapy requirements

Continuation requests require documentation of clinical benefit or specified biomarker/functional improvements, depending on product.

General continuation: Chart notes or lab results documenting improvement, stabilization, or slowing of disease progression; product-specific biomarkers or functional tests referenced per product (e.g., GL-3, 3MSCT, 6MWT, FVC, LVMI, urinary SSC).

Continuation requirements — clinical evidence and therapy-specific markers

Continuation requires clinical evidence of benefit and therapy-specific markers.

General continuation requirement: Chart notes documenting a clinically positive response to therapy (improvement, stabilization, or slowing of disease progression); examples and objective markers are provided for specific drugs (e.g., normalization of plasma ADA activity for Revcovi; reduction in spleen volume for Xenpozyme).

Continuation therapy specifics — typical 12-month approvals and response domains

Continuation approvals (typically 12 months) are allowed when the member is responding to therapy; product-specific response domains are noted.

General 12-month continuation: Continuation approvals are generally for 12 months when the member is responding to therapy, with response defined by product-specific clinical or biomarker improvements (e.g., motor function, respiratory function, organ volume reductions, biochemical markers).

Continuation therapy / monitoring (trial-based)

Continuation/assessment information described in trials and extensions; continued therapy monitoring expectations implied by study follow-up.

Brineura continuation evidence: Brineura-treated patients were assessed in extension studies up to 96 weeks using the CLN2 Motor domain; sustained lack of decline versus natural history was used to evaluate ongoing benefit.

Nulibry continuation evidence: Nulibry-treated patients had sustained reductions in urinary S-sulfocysteine over 48 months and improved survival versus historical controls; monitoring of urinary SSC and survival is part of continued assessment.

Provider Actions — Authorization, Documentation, and Billing

Prior Authorization

Prior Authorization Required

Prior authorization is required for all enzyme replacement therapy (ERT) drugs and related products listed in this policy. Requests must include the clinical documentation specified for the requested product and meet the policy's initial or continuation criteria. Failure to obtain prior authorization or to provide required documentation may result in denial of the request as not medically necessary.

Prior authorization required for all medications listed in this policy
Include initial diagnostic testing (enzyme assay or genetic testing) for initial requests and documentation of clinical response for continuation requests

Prior Authorization

Prior Authorization — Meet Listed Initial Approval Criteria

Initial approvals must meet the listed product-specific criteria in the policy (see Criteria for Initial Approval). Continue-to-approve requests must demonstrate a clinical response (improvement, stabilization, or slowing of disease progression) per the continuation criteria. Approval durations vary by product (commonly 12 months; some initial approvals may be shorter — see product criteria).

Meet all product-specific initial approval criteria in the policy
Continuation approvals require documentation of clinical benefit; lack of response may result in denial

Prior Authorization

Prior Authorization — Continuation Approvals and Dosing Limits

Continuation approvals are typically granted for 12 months when the member is responding to therapy. Requests for continuation must include chart notes, lab results, or other medical records documenting clinical benefit. Approvals may be subject to dosing limits consistent with FDA labeling and evidence-based guidelines.

Continuation approvals generally: 12 months
Provide documentation of improvement, stabilization, or slowing of disease progression
Approvals may be subject to dosing limits per FDA labeling and compendia

Billing Rule

Prior Authorization Required for Listed J- and C-Codes; Use Exact HCPCS/G-Code

Use the exact HCPCS (J-/C-/G-) codes listed in the policy when submitting claims for ERT drugs and related services. Claims submitted with procedure codes not matching the exact listed HCPCS/infusion codes may be denied. For J- or C-code medications listed in this policy, prior authorization is required and the request must reference the exact HCPCS code.

Use the listed HCPCS J-codes, C-codes, and G-code when billing
Claims with procedure codes not matching listed HCPCS/infusion codes may be denied
Prior authorization requests must reference the exact HCPCS code for ERT drugs

Step Therapy

Steering to Cost‑Effective Therapy / Combination Requirement

Steering to cost‑effective therapy: when clinically appropriate, prescribers should select the most cost‑effective ERT option within the therapeutic class and follow any combination/step requirements in the policy (for example, Opfolda + Pombiliti combination required for late-onset Pompe in eligible patients). Requests for combination therapy must document the rationale and meet the policy's combination criteria.

Steer to the most cost‑effective therapy within the class when clinically appropriate
Opfolda (miglustat) must be prescribed in combination with Pombiliti for indicated late-onset Pompe patients per policy
Pombiliti continuation requires combination with Opfolda and evidence of response

Documentation Required

Required Documentation for PA — Initial Diagnostic Testing and Continuation Evidence

Required documentation must be submitted to initiate a prior authorization review. For initial requests, include diagnostic confirmation (enzyme assay or genetic testing) as specified for the requested product. For continuation requests, include medical records (chart notes, lab reports) demonstrating clinical benefit (improvement, stabilization, or slowing of disease progression) as described in the product-specific continuation criteria.

Initial requests: submit enzyme assay or genetic testing results supporting diagnosis as listed for the requested drug
Continuation requests: submit chart notes or lab results documenting response to therapy (improvement, stabilization, or slowing of progression)
Specific documentation requirements for Brineura and Nulibry (e.g., TPP1 assay for Brineura; MOSC1 mutation for Nulibry) must be provided when applicable

Note

Hypersensitivity Safety Risk and Monitoring

Severe hypersensitivity or anaphylaxis risks are associated with certain ERTs (e.g., Xenpozyme, Lamzede). Ensure appropriate monitoring and availability of resuscitation equipment during administration. Consider desensitization procedures if severe hypersensitivity occurs. Include documentation of safety monitoring where relevant.

Xenpozyme and Lamzede carry boxed warnings for severe hypersensitivity/anaphylaxis — ensure immediate availability of medical support measures during administration
Consider desensitization if severe hypersensitivity reaction occurs
Document baseline and periodic ALT/AST for Xenpozyme as recommended

Billing and Coding — HCPCS / J / G Codes and Key Parameters

Listed J/C codes (group 1)HCPCS

J1931	Injection, laronidase, (Aldurazyme), 0.1 mg
J0567	Injection, cerliponase alfa, (Brineura), 1 mg
J1743	Injection, idursulfase, (Elaprase), 1 mg
J0180	Injection, agalsidase beta, (Fabrazyme), 1 mg
J2840	Injection, sebelipase alfa, (Kanuma), 1 mg
J0221	Injection, alglucosidase alfa, (Lumizyme), 10 mg
J3397	Injection, vestronidase alfa-vjbk, (Mepsevii), 1 mg
J1458	Injection, galsulfase, (Naglazyme),1 mg
J1322	Injection, elosulfase alfa, (Vimizim), 1 mg
J0220	Injection, alglucosidase alfa, 10 mg, not otherwise specified

1–10 of 19

1/2

Listed J/C/G and unclassified codes (group 2)HCPCS | CPT | mixed

J2508	Injection, pegunigalsidase alfa-iwxj, 1 mg (effective 1/1/2024)
J7171	Injection, adamts13, recombinant-krhn, 10 iu (effective 7/1/2024)
J3490	Unclassified drugs
J3590	Unclassified biologics
G0138	Intravenous infusion of cipaglucosidase alfa-atga, including provider/supplier acquisition and clinical supervision of oral administration of miglustat in preparation of receipt of cipaglucosidase alfa-atga (effective 4/1/2024)

Covered HCPCS / Infusion CodesHCPCSCovered

J2508	Injection, pegunigalsidase alfa-iwxj, 1 mg (effective 1/1/2024)
J7171	Injection, adamts13, recombinant-krhn, 10 iu (effective 7/1/2024)
J3490	Unclassified drugs
J3590	Unclassified biologics
G0138	Intravenous infusion of cipaglucosidase alfa-atga, including provider/supplier acquisition and clinical supervision of oral administration of miglustat in preparation of receipt of cipaglucosidase alfa-atga (effective 4/1/2024)

inv-44: Weight requirement for Opfolda and Pombiliti (>= 40 kg)

Weight requirement>= 40 kg required for Opfolda and Pombiliti use in late-onset Pompe disease

Related useRequired when Opfolda (miglustat) and Pombiliti (cipaglucosidase alfa-atga) are prescribed in combination for adults not improving on current ERT

Approval durationInitial and continuation approvals for the combination are for 12 months when criteria met

inv-45: Age requirement (>= 18 years for Opfolda and Pombiliti)

Age requirement>= 18 years required for Opfolda and Pombiliti

ContextApplies to adults with late-onset Pompe disease receiving the Opfolda + Pombiliti combination

Combination ruleMember must be >=18 years AND meet weight requirement (>=40 kg) to qualify

inv-46: ADAMTS13 activity threshold for ADZYNMA (< 10%)

ADAMTS13 activity thresholdADAMTS13 activity level < 10% at time of diagnosis required for Adzynma (ADZYNMA)

Diagnostic confirmationDiagnosis of cTTP must be confirmed by genetic testing with biallelic ADAMTS13 mutations in addition to activity <10%

Approval duration noteInitial approval for Adzynma is for 6 months when criteria met

inv-47: uGAG threshold for Mepsevii (>= 2-fold over mean normal for age)

uGAG threshold>= 2-fold over mean normal for age required at initiation of Mepsevii (vestronidase)

Diagnostic confirmationDiagnosis of MPS VII must be confirmed by beta-glucuronidase enzyme assay or genetic testing

Approval durationInitial approval for Mepsevii is for 12 months when criteria met

inv-48: Brineura dose limit (does not exceed 300 mg once every other week)

Brineura dosing limitDose does not exceed 300 mg administered once every other week (q2w)

Indication contextApproved to slow loss of ambulation in CLN2 (TPP1 deficiency); trials used 300 mg q2w

Baseline requirementBaseline motor function confirming ambulatory status at initiation is required per criteria

inv-49: Kanuma ALT requirement (>= 1.5 x ULN on two measurements)

Kanuma ALT requirementALT >= 1.5 x ULN on two consecutive measurements obtained at least one week apart is required for Kanuma initiation

Diagnostic confirmationDiagnosis of LAL deficiency must be confirmed by enzyme assay or genetic testing

Monitoring notePeriodic liver transaminase monitoring is recommended during therapy per product guidance

inv-50: Lamzede dose limit (does not exceed 1 mg/kg once weekly)

Lamzede dose limitDose does not exceed 1 mg/kg once weekly for Lamzede (velmanase alfa-tycv)

Indication constraintFor non‑CNS manifestations of alpha-mannosidosis; member must not be treated for CNS disease manifestations

Prescriber requirementMust be prescribed by or in consultation with a specialist experienced in non‑CNS alpha-mannosidosis management

inv-51: CLN2 Motor/Language combined score (< 6) used in Brineura analyses

CLN2 Motor/Language combined scoreScreening combined Motor plus Language CLN2 score < 6 was used in Brineura efficacy analyses and patient selection

Assessment timingMotor domain assessed at 48, 72, and 96 weeks in clinical study and extension

Efficacy comparisonBrineura-treated patients with baseline combined score <6 showed reduced decline versus natural history cohorts through 96 weeks

Step Therapy and Combination Requirements

Step	Requirement	Coverage
1
Opfolda (miglustat) must be prescribed and taken in combination with Pombiliti (cipaglucosidase alfa-atga) for adult patients with late-onset Pompe disease who weigh ≥ 40 kg and are not improving on their current ERT.
Opfolda + Pombiliti combination required for adults ≥ 40 kg not improving on current ERT; prior inadequate response to another ERT must be documented.

Step	Requirement	Coverage
1
Opfolda (miglustat) and Pombiliti (cipaglucosidase alfa-atga) are to be used in combination for treatment of late-onset Pompe disease in adults (≥ 18 years) weighing ≥ 40 kg and only when the member is not improving on current ERT (e.g., Lumizyme, Nexviazyme).
Combination therapy is required and documentation of inadequate clinical response to current ERT must be provided with the prior authorization request.

Step	Requirement	Coverage
1
Pombiliti (cipaglucosidase alfa-atga) is indicated for adult patients (≥ 18 years) with late-onset Pompe disease who weigh ≥ 40 kg, who are not improving on their current ERT, and must be taken in combination with Opfolda (miglustat).
Prior inadequate response to current ERT and plan to co-administer Opfolda must be documented for coverage consideration.

Step	Notes	Codes / Remarks
1
This policy does not define an explicit sequential step-therapy ordering among the listed enzyme replacement therapies; instead, several products are listed with coverage criteria and coding.
Refer to listed HCPCS/J-codes when submitting prior authorization requests and claims (see coding section for full code list).

Site of Care and Infusion Requirements

Note

Infusion center — IV infusion per labeling; dosing limits noted

Administer listed ERTs as intravenous infusions per product labeling; approvals may be subject to dosing limits and labeled administration schedules.

Follow product‑specific infusion schedules and dosing (e.g., Nexviazyme dosing 20 mg/kg ≤30 kg, 40 mg/kg >30 kg every other week).
Dosing limits and administration routes per FDA labeling must be observed for PA and claims.

Note

Emergency resuscitation required at administration setting

Administration must occur in a setting with immediate availability of emergency resuscitation and management for severe hypersensitivity/anaphylaxis for high‑risk products.

Settings include infusion center, hospital outpatient department, or office capable of emergency resuscitation.
This requirement is especially important for products carrying boxed hypersensitivity warnings (Xenpozyme, Lamzede).

Billing Rule

Infusion-related services — bill with specified infusion codes (e.g., G0138)

Bill infusion‑related services for specified products with the appropriate infusion code when applicable (e.g., G0138 for cipaglucosidase alfa‑atga infusion plus supervised miglustat administration).

Use G0138 for IV infusion of cipaglucosidase alfa‑atga that includes supervision of oral miglustat administration.
Ensure infusion CPT/HCPCS codes match the product and services provided to avoid claim issues.

Definitions and Key Terms

inv-73: Enzyme Replacement Therapy (ERT) definition

ERT definitionEnzyme replacement therapy (ERT) — pharmacologic replacement of a deficient enzyme to treat inherited metabolic or lysosomal storage diseases

PurposeUsed to replace deficient enzymes to reduce substrate accumulation and improve disease manifestations across multiple disorders

Product typesTypically recombinant or biologic enzymes administered intravenously per product labeling

inv-74: Diagnostic confirmation definition

Diagnostic confirmationConfirmation by enzyme assay demonstrating deficient enzyme activity and/or by genetic testing documenting pathogenic mutations as specified per disease/drug

Required documentationInitial prior authorization requests require submission of enzyme assay and/or genetic testing results supporting diagnosis

Continuation contextContinuation requests require chart notes or lab results documenting clinical benefit or disease stabilization per product-specific criteria

inv-75: Lysosomal storage diseases definition

Lysosomal storage diseasesInherited metabolic diseases caused by enzyme deficiencies leading to cellular accumulation of toxic substrates and progressive symptoms

Clinical impactCan affect multiple organs including skeleton, brain, heart, and respiratory function with progressive course

Treatment approachSome disorders have FDA‑approved ERTs that can improve quality of life when diagnostic and clinical criteria are met

inv-76: Pompe disease subtypes

Pompe disease subtypesIncludes classic infantile-onset, non-classic infantile-onset, and late-onset forms with variable cardiac and respiratory involvement

Clinical featuresInfantile forms present early with cardiomyopathy and severe weakness; late-onset presents later with progressive muscle weakness and respiratory involvement

Relevance to therapyLate-onset Pompe is the indication for Opfolda + Pombiliti combination in adults meeting weight/age criteria

inv-77: MPS IVA definition

MPS IVA definitionMucopolysaccharidosis Type IVA (MPS IVA, Morquio A) is caused by N-acetylgalactosamine-6-sulfatase deficiency with predominant skeletal manifestations; only MPS IVA (not IVB) is treatable with exogenous enzyme (elosulfase alfa/Vimizim)

Subtypes noteMPS IV has two subtypes: IVA (enzyme-replaceable) and IVB (beta-galactosidase deficiency) which is not treatable with exogenous enzyme

TherapyVimizim (elosulfase alfa) is FDA‑approved for MPS IVA

inv-78: CLN2 definition

CLN2 definitionCLN2 (late infantile neuronal ceroid lipofuscinosis type 2) is a TPP1 deficiency causing progressive neurodegeneration and loss of ambulation; Brineura is FDA‑approved to slow loss of ambulation

Typical onsetLate infantile form signs typically begin between ages 2 and 4 with language delay, seizures, ataxia, myoclonus, and progressive motor loss

Clinical assessmentBrineura efficacy assessed using Motor and Language CLN2 Clinical Rating Scale; baseline combined Motor+Language score used for analyses

inv-79: ASMD definition

ASMD definitionAcid sphingomyelinase deficiency (ASMD, Niemann-Pick disease) is caused by SMPD1 mutations leading to ASM deficiency and accumulation of sphingomyelin with hepatosplenomegaly, lung disease, and other manifestations

Therapy noteXenpozyme (olipudase alfa-rpcp) is FDA‑approved for non‑CNS manifestations of ASMD

Safety noteXenpozyme carries a black box warning for severe hypersensitivity/anaphylaxis requiring immediate availability of resuscitation measures

inv-80: MoCD Type A definition

MoCD Type A definitionMolybdenum cofactor deficiency Type A (MoCD Type A) is a neonatal-onset disorder caused by MOCS1 mutations leading to toxic sulfite accumulation; Nulibry (cPMP/fosdenopterin) is approved to reduce mortality

Genetic basisType A is caused by MOCS1 mutations; diagnosis confirmed by genetic testing documenting MOSC1 mutation

Treatment effectNulibry treatment improved survival vs genotype-matched historical controls and reduced urinary S-sulfocysteine

inv-81: ERT therapeutic definition (alternate)

ERT therapeutic definitionTherapeutic replacement of deficient or absent lysosomal enzymes using recombinant or biologic products as described in package inserts and clinical studies

MechanismReplacement enzymes reduce substrate accumulation and can improve organ/system function depending on disease and timing of therapy

AdministrationMost ERTs are administered intravenously per product labeling with monitoring for infusion reactions and specific lab testing as indicated

OpenPayer

Enzyme Replacement Therapy (ERT) — Coverage Criteria

Coverage Criteria — Initial and Continuation

Initial Therapy Diagnostic and Product-Specific Requirements

Continuation Therapy — Response and Monitoring Requirements

Provider Actions — Authorization, Documentation, and Billing

Billing and Coding — HCPCS / J / G Codes and Key Parameters

Step Therapy and Combination Requirements

Quantity Limits and Unit Billing Notes

Site of Care and Infusion Requirements

Background — Enzyme Replacement Therapy Overview

Definitions and Key Terms