ModifiedUnitedHealthcarePolicy CSOH2026D0052.E

Medical Therapies for Enzyme Deficiencies (for Ohio Only)

State-specific UnitedHealthcare medical benefit drug policy governing coverage criteria for multiple enzyme-replacement and related therapies for enzyme deficiency disorders in Ohio members.

Policy Summary

PayerUnitedHealthcare

PolicyMedical Therapies for Enzyme Deficiencies (for Ohio Only)

Policy CodePolicy CSOH2026D0052.E

Change TypeHCPCS code updates (added and removed)

Effective DateJan 1, 2026

Next Review DateN/A

Key ActionSubmit prior authorization with diagnostic confirmation and use updated HCPCS coding (J1809 added; C9399, J3490, J3590 removed).

SourceLink

POLICY UPDATE CHANGES

Added HCPCS code J1809 for Nulibry.

Removed HCPCS codes C9399, J3490, and J3590.

Archived previous policy version CSOH2025D0052.D.

15+drugs listed

12 monthstypical PA period

Ohioapplicability

3HCPCS codes changed

1HCPCS code added

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Coverage Criteria by Product

Aldurazyme — Initial and continuation

Aldurazyme (laronidase) is covered when ALL of the following are met

Aldurazyme initial therapy: Diagnosis of any MPS I syndrome (Hurler, Hurler-Scheie, or Scheie) confirmed by deficiency/absence of fibroblast or leukocyte alpha-L-iduronidase enzyme activity OR molecular genetic confirmation of mutations in the alpha-L-iduronidase gene; presence of clinical signs/symptoms consistent with MPS I; dosing per FDA-approved labeling; initial authorization will be for no more than 12 months

Aldurazyme continuation therapy: Patient has previously received laronidase therapy and experienced a positive clinical response (e.g., improved endurance, improved functional capacity, reduced urine dermatan/heparan sulfate excretion); dosing per FDA-approved labeling; reauthorization will be for no more than 12 months

Elaprase — Initial and continuation

Elaprase (idursulfase) is covered when ALL of the following are met

Elaprase initial therapy: Diagnosis of MPS II confirmed by deficiency in iduronate 2-sulfatase enzyme activity in fibroblasts or leukocytes with normal activity of another sulfatase OR molecular genetic testing for deletion/mutations in the iduronate 2-sulfatase gene; presence of clinical signs/symptoms of MPS II; dosing per FDA-approved labeling; initial authorization will be for no more than 12 months

Elaprase continuation therapy: Patient has previously received idursulfase therapy and experienced a positive clinical response (e.g., improved endurance, improved functional capacity, reduced spleen volume, reduced urine GAG excretion); dosing per FDA-approved labeling; reauthorization will be for no more than 12 months

Elfabrio — Initial and continuation

Elfabrio (pegunigalsidase alfa-iwxj) is covered 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 enzyme activity in leukocytes, dried blood spots, or serum OR by molecular genetic testing for deletion/mutations in the GLA gene; presence of clinical signs/symptoms of Fabry disease; not used in combination with other disease-modifying Fabry therapies; dosing per FDA-approved labeling; initial authorization will be for no more than 12 months

Elfabrio continuation therapy: Patient has previously received pegunigalsidase therapy and experienced a positive clinical response; remains off other disease-modifying Fabry therapies; dosing per FDA-approved labeling; reauthorization will be for no more than 12 months

Kanuma — Initial and continuation

Kanuma (sebelipase alfa) is covered when ALL of the following are met

Kanuma initial therapy: Diagnosis of lysosomal acid lipase deficiency (LAL‑D, Wolman disease, CESD) confirmed by absence/deficiency of LAL activity by dried blood spot test OR molecular genetic testing for LIPA gene mutations; presence of clinical signs/symptoms (e.g., abdominal distention, hepatosplenomegaly, liver fibrosis, ascites); dosing per FDA-approved labeling; initial authorization will be for no more than 12 months

Kanuma continuation therapy: Patient has previously received sebelipase alfa therapy and experienced a positive clinical response (e.g., improvement in symptoms, normalization or improvement in LFTs and lipid parameters); dosing per FDA-approved labeling; reauthorization will be for no more than 12 months

Lamzede — Initial and continuation

Lamzede (velmanase alfa-tycv) is covered when ALL of the following are met

Lamzede initial therapy: Diagnosis of alpha-mannosidosis confirmed by absence/deficiency (< 10% of the lab specific normal mean) of alpha-mannosidase enzyme activity OR by molecular genetic testing for MAN2B1 mutations; presence of clinical signs/symptoms consistent with alpha-mannosidosis; dosing per FDA-approved labeling; initial authorization will be for no more than 12 months

Lamzede continuation therapy: Patient has previously received velmanase alfa therapy and experienced a positive clinical response; dosing per FDA-approved labeling; reauthorization will be for no more than 12 months

Pompe disease — Lumizyme and Nexviazyme

Pompe disease therapies (Lumizyme, Nexviazyme, Pombiliti) — distinct rules

Lumizyme initial therapy (infantile-onset): Diagnosis of infantile-onset Pompe disease confirmed by absence/deficiency (< 1% of lab-specific normal mean) of acid alpha-glucosidase (GAA) activity in fibroblasts OR by molecular genetic testing for GAA mutations; presence of clinical signs/symptoms; patient is not receiving Lumizyme in combination with another disease-modifying enzyme therapy for Pompe disease (e.g., Nexviazyme, Pombiliti); dosing per FDA labeling; initial authorization ≤ 12 months

Lumizyme initial therapy (late-onset): Diagnosis of late-onset Pompe disease confirmed by absence/deficiency (< 40% of lab-specific normal mean) of GAA activity in lymphocytes/fibroblasts/muscle OR by molecular genetic testing for GAA mutations; presence of clinical signs/symptoms; not used in combination with other disease-modifying enzyme therapies for Pompe; dosing per FDA labeling; initial authorization ≤ 12 months

Nexviazyme initial therapy: Diagnosis of late-onset Pompe disease confirmed by absence/deficiency (< 40% of lab-specific normal mean) of GAA activity OR molecular genetic testing; presence of clinical signs/symptoms; not used in combination with other disease-modifying enzyme therapies for Pompe; dosing per FDA labeling; initial authorization ≤ 12 months

Mepsevii — Initial and continuation

Mepsevii (vestronidase alfa-vjbk) is covered when ALL of the following are met

Mepsevii initial therapy: Diagnosis of MPS VII (Sly syndrome) confirmed by absence/deficiency of fibroblast or leukocyte beta‑glucuronidase activity OR by molecular genetic confirmation of GUSB mutations; presence of clinical signs/symptoms; dosing per FDA-approved labeling; initial authorization will be for no more than 12 months

Mepsevii continuation therapy: Patient has previously received vestronidase therapy and experienced a positive clinical response (e.g., improved endurance, functional capacity, pulmonary function); dosing per FDA-approved labeling; reauthorization will be for no more than 12 months

Naglazyme — Initial and continuation

Naglazyme (galsulfase) is covered when ALL of the following are met

Naglazyme initial therapy: Diagnosis of MPS VI confirmed by absence/deficiency of fibroblast or leukocyte N‑acetylgalactosamine 4‑sulfatase (arylsulfatase) activity OR molecular genetic confirmation of ASB gene mutations; presence of clinical signs/symptoms; dosing per FDA-approved labeling; initial authorization will be for no more than 12 months

Naglazyme continuation therapy: Patient has previously received galsulfase therapy and experienced a positive clinical response (e.g., improved endurance, functional capacity, reduced urine dermatan sulfate); dosing per FDA-approved labeling; reauthorization will be for no more than 12 months

Nulibry — Initial and continuation

Nulibry (fosdenopterin) is covered when ALL of the following are met

Nulibry initial therapy: Initial: Diagnosis of MoCD Type A confirmed by absence/deficiency of sulfite oxidase enzyme activity in fibroblasts OR molecular genetic testing for MOCS1 mutations; presence of clinical signs/symptoms within the first 28 days after birth (e.g., seizures, exaggerated startle, high‑pitched cry, hypotonia, feeding difficulties, elevated urinary SSC); dosing per FDA-approved labeling; initial authorization will be for no more than 12 months.

Nulibry continuation therapy: Continuation: Patient has previously received fosdenopterin and experienced a positive clinical response (e.g., decreased seizure activity, improved feeding/alertness/gross motor function, decreased urinary sulfite or SSC, changes in xanthine/uric acid); dosing per FDA labeling; reauthorization will be for no more than 12 months.

Nulibry (fosdenopterin)

Nulibry is covered when ALL of the following are met

Nulibry initial therapy: 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 the first 28 days after birth; dosing per FDA-approved labeling; initial authorization will be for no more than 12 months.

Nulibry continuation therapy: Continuation: Previously received fosdenopterin; demonstrated positive clinical response (examples: decreased seizures, improved feeding/alertness/gross motor function, decreased urinary SSC, changed xanthine/uric acid); dosing per FDA labeling; reauthorization ≤ 12 months.

Pombiliti (cipaglucosidase alfa-atga)

Pombiliti is covered when ALL of the following are met

Pombiliti initial therapy: Initial: Diagnosis of late-onset Pompe disease confirmed by absence/deficiency (< 40% of lab‑specific normal mean) of acid alpha‑glucosidase (GAA) activity in lymphocytes, fibroblasts, or muscle OR by 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 Opfolda (miglustat); not administered with another disease‑modifying ERT for Pompe; dosing per FDA labeling; initial authorization ≤ 12 months.

Pombiliti continuation therapy: Continuation: Patient has previously received Pombiliti and experienced a positive clinical response to Pombiliti plus Opfolda; continues Opfolda; not combined with other disease‑modifying ERTs; dosing per FDA labeling; reauthorization ≤ 12 months.

Revcovi (elapegademase - lvlr)

Revcovi is covered when ALL of the following are met

Revcovi initial therapy: Initial: Diagnosis of ADA‑SCID with ADA deficiency confirmed by deficiency/absence of ADA in plasma, lysed erythrocytes, fibroblasts OR by increased erythrocyte dATP, decreased erythrocyte ATP, molecular genetic confirmation of biallelic ADA1 mutations, OR positive TREC screening; patient is not a suitable HCT candidate OR has failed HCT OR is awaiting HCT; dosing per FDA labeling; initial authorization ≤ 12 months.

Revcovi continuation therapy: Continuation: Patient has previously received elapegademase therapy and experienced a positive clinical response (e.g., normalization of plasma ADA activity, improved erythrocyte dATP levels, clinical improvement); dosing per FDA labeling; reauthorization ≤ 12 months.

Vimizim (elosulfase alfa)

Vimizim is covered when ALL of the following are met

Vimizim initial therapy: Initial: Diagnosis of Morquio A (MPS IVA) confirmed by absence/deficiency of GALNS enzyme activity AND molecular genetic testing for GALNS mutations; presence of clinical signs/symptoms; dosing per FDA labeling; initial authorization ≤ 12 months.

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

Xenpozyme (olipudase alfa-rpcp)

Xenpozyme is covered when ALL of the following are met

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

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

Use of one disease-modifying enzyme therapy concurrently with another for the same condition is not permitted. Examples in this policy include Lumizyme (alglucosidase alfa) not to be given in combination with Nexviazyme (avalglucosidase alfa-ngpt) or Pombiliti (cipaglucosidase alfa-atga) for Pompe disease, and Elfabrio (pegunigalsidase alfa-iwxj) not to be used in combination with other Fabry disease disease-modifying therapies (e.g., Fabrazyme, Galafold).

Pombiliti (cipaglucosidase alfa-atga) must not be administered in combination with another disease-modifying enzyme replacement therapy for Pompe disease (for example, Lumizyme or Nexviazyme). Initial use requires documentation of diagnosis (GAA activity < 40% of the lab specific normal mean or molecular confirmation) and a provider attestation that the patient is not improving on current ERT and that current ERT will be stopped when Pombiliti plus miglustat (Opfolda) is initiated; patient weight must meet labeled requirements.

Xenpozyme (olipudase alfa-rpcp) is not authorized for treatment of central nervous system manifestations of acid sphingomyelinase deficiency (ASMD). Coverage is limited to non‑CNS manifestations as defined in the policy (e.g., hepatosplenomegaly, transaminase elevations, pulmonary dysfunction).

Coverage determinations in this policy are guided by federal, state (Ohio Administrative Code), and contractual requirements; in the event of a conflict those governing requirements take precedence. FDA approval is informational and does not alone establish coverage under the policy.

Requests for services described as unproven or subject to coverage/quantity limits will be evaluated for medical necessity using Ohio Administrative Code 5160-1-01. Providers should reference applicable federal, state (OAC), or contractual requirements when submitting requests because those requirements govern coverage decisions.

Reiterating exclusions: concurrent use of Pombiliti with other disease-modifying ERTs for Pompe disease is disallowed and will preclude medical necessity; use of Xenpozyme for CNS manifestations of ASMD is expressly not authorized.

The final pages of this document do not add standalone statements labeling specific services as 'not medically necessary' beyond the policy’s exclusion language; instead, coverage is determined by applying the policy criteria together with governing federal, state (OAC), and contractual plan requirements.

HCPCS and Diagnosis Codes

Aldurazyme HCPCSHCPCSCovered

J1931

Injection, laronidase, 0.1 mg

Elaprase HCPCSHCPCSCovered

J1743

Injection, idursulfase, 1 mg

Elfabrio HCPCSHCPCSCovered

J2508

Injection, pegunigalsidase alfa-iwxj, 1 mg

Multiple referenced HCPCSHCPCS

J0180	Injection, agalsidase beta, 1 mg
J0221	Injection, alglucosidase alfa (Lumizyme), 10 mg
J3397	Injection, vestronidase alfa-vjbk, 1 mg
J0217	Injection, velmanase alfa-tycv, 1 mg

Nulibry HCPCSHCPCSCovered

J1809

HCPCS code referenced for Nulibry (fosdenopterin)

Pombiliti HCPCSHCPCSCovered

J1203

Pombiliti HCPCS

Revcovi HCPCSHCPCSCovered

J3590

Revcovi HCPCS

Vimizim HCPCSHCPCSCovered

J1322

Vimizim HCPCS

Xenpozyme HCPCSHCPCSCovered

J0218

Injection, olipudase alfa-rpcp, 1 mg

Diagnosis 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
E74.02	Pompe disease
E72.19	Disorders of sulfur-bearing amino-acid metabolism, unspecified
D81.31	Severe combined immunodeficiency due to adenosine deaminase deficiency
E76.210	Mucopolysaccharidosis type IVA
E75.241	Niemann-Pick disease type B; ASMD type B

1–10 of 11

1/2

Applicable HCPCS Codes (updated)HCPCS

J1809	HCPCS code added for Nulibry (per policy history)
C9399	HCPCS code removed (previously used)
J3490	HCPCS code removed (previously used)
J3590	HCPCS code removed (previously used)

inv-33: Alpha-mannosidase activity threshold

Alpha-mannosidase activity thresholdAbsence or deficiency (< 10% of the lab specific normal mean) of alpha-mannosidase enzyme activity

Diagnostic methodsMeasured in laboratory enzyme activity assays or via MAN2B1 molecular genetic testing

Indication contextUsed to confirm diagnosis of alpha-mannosidosis for Lamzede initial therapy

inv-34: Acid alpha-glucosidase (GAA) activity thresholds

Prior Authorization, Documentation, and Billing Actions

Prior Authorization

Prior Authorization Required and Duration

Prior authorization is required for the drugs covered by this policy. Initial authorizations are time-limited and, unless otherwise noted at the product level, will be approved for no more than 12 months. Reauthorizations (continuation of therapy) likewise require documentation of prior treatment and a positive clinical response and will be approved for no more than 12 months.

Initial authorization typically: up to 12 months
Reauthorization (continuation): up to 12 months

Prior Authorization

Authorization Period (Product-Level)

Authorization periods are specified per product in the coverage criteria. For each product, initial and reauthorization time limits are stated (commonly up to 12 months). Providers should request authorization for the indicated duration and submit reauthorization requests prior to the end of the approved period with supporting documentation of clinical benefit.

Follow product-level request periods (most products: initial and reauth ≤ 12 months)

Initial Therapy — Product-Specific Criteria and Trial Dosing

inv-71: Aldurazyme initial criteria

Aldurazyme initial criteria

Aldurazyme initial: Diagnosis of MPS I confirmed by enzyme deficiency (fibroblast or leukocyte alpha-L-iduronidase) or genetic testing; presence of clinical signs/symptoms; dosing per FDA labeling; initial authorization ≤ 12 months

inv-72: Elaprase initial criteria

Elaprase initial criteria

Elaprase initial: Diagnosis of MPS II confirmed by iduronate 2-sulfatase deficiency in fibroblasts or leukocytes with normal other sulfatase activity OR genetic testing; presence of clinical signs/symptoms; dosing per FDA labeling; initial authorization ≤ 12 months

inv-73: Nulibry initial

Nulibry initial

Continuation (Reauthorization) Criteria

inv-80: Aldurazyme continuation

Aldurazyme continuation criteria

Aldurazyme continuation: Previously received laronidase and experienced positive clinical response; dosing per FDA labeling; reauthorization ≤ 12 months

inv-81: Elfabrio continuation

Elfabrio continuation criteria

Elfabrio continuation: Previously received pegunigalsidase and experienced positive clinical response; not in combination with other disease‑modifying Fabry therapies; dosing per FDA labeling; reauthorization ≤ 12 months

inv-82: Nulibry continuation

Nulibry continuation

Step Therapy and Switching Requirements

Combination(s) prohibited	Example(s) from policy	Coverage status
Use of multiple disease-modifying enzyme therapies for the same condition	Pompe disease: Lumizyme (alglucosidase alfa) must not be used in combination with Nexviazyme (avalglucosidase alfa-ngpt) or Pombiliti (cipaglucosidase alfa-atga)	Covered
Concurrent disease-modifying therapies for Fabry disease	Elfabrio (pegunigalsidase alfa-iwxj) must not be used in combination with Fabrazyme (agalsidase beta) or Galafold (migalastat)	Covered
General monotherapy requirement for listed ERTs	Policy specifies that patients should not receive listed enzyme replacement therapies in combination with another disease-modifying ERT for the same indication	Covered

Requirement	Provider attestation / documentation	Coverage status
Patient is not improving on current enzyme replacement therapy (ERT)	Provider must attest the patient is not improving on current ERT (examples: Lumizyme, Nexviazyme) and that the current ERT will be stopped when initiating Pombiliti	Covered
Weight and concomitant therapy requirement	Document patient weight ≥ 40 kg and that Pombiliti will be prescribed in combination with oral Opfolda (miglustat)	Covered
No concurrent ERT	Attestation must confirm patient will not receive Pombiliti in combination with another disease-modifying ERT for Pompe disease (e.g., Lumizyme, Nexviazyme)	Covered

Head-to-head trial	Policy implication	Operational step requirement
Avalglucosidase alfa-ngpt vs alglucosidase alfa (Nexviazyme trial)	Randomized, double-blind trial compared avalglucosidase alfa-ngpt to alglucosidase alfa with primary endpoint change in FVC at Week 49; secondary 6MWD favored avalglucosidase alfa-ngpt
Policy statement regarding step therapy	Although a head-to-head comparison was performed, the policy does not specify an operational step-therapy requirement based on this trial

Indication / requirement	Required documentation	Coverage status
Indication: Late-onset Pompe disease (adults)	Diagnosis confirmed by absent/deficient GAA activity (<40% of lab-specific normal mean) or molecular genetic testing; presence of clinical signs/symptoms	Covered
Weight requirement	Document patient weight ≥ 40 kg	Covered
Lack of improvement on prior ERT	Provider attestation that the patient is not improving on current ERT and that prior ERT will be stopped; trial evidence includes cipaglucosidase alfa-atga combined with miglustat in ERT-experienced patients	Covered

Administration Site and Infusion Setting

Note

Infusions administered in infusion‑capable clinical or outpatient settings

All therapies summarized in the policy were administered intravenously in clinical trials; administration should occur in infusion‑capable settings consistent with the trial methods (clinic/infusion center or hospital outpatient).

Plan for infusion‑capable site of care when scheduling treatment and include site in PA where required.

Note

Trial dosing implies infusion‑capable site of care — document setting

Trial dosing regimens (e.g., weekly or every‑other‑week intravenous schedules) imply administration in infusion‑capable settings; ensure infusion center or equivalent is available and documented for PA.

Examples: elosulfase alfa weekly or QOW dosing; sebelipase alfa 1 mg/kg every other week.

Background and Scope

This policy addresses enzyme replacement and related therapies for inherited enzyme deficiency disorders, including multiple mucopolysaccharidoses, Pompe disease, Fabry disease, LAL deficiency, alpha-mannosidosis, and molybdenum cofactor deficiency Type A. Coverage requires biochemical or molecular diagnostic confirmation, clinical signs/symptoms consistent with the diagnosis, dosing in accordance with FDA labeling, and prior authorization generally limited to 12 months.

Definitions and Diagnostic Criteria

inv-61: MPS I definition

MPS I definitionMucopolysaccharidosis I (MPS I) syndromes including Hurler, Hurler-Scheie, and Scheie variants confirmed by enzyme deficiency or molecular genetic testing

Diagnostic confirmationDiagnosis confirmed by enzyme deficiency testing (α-L-iduronidase) or molecular genetic testing

Clinical applicationUsed to determine eligibility for Aldurazyme (laronidase) therapy

inv-62: MPS II definition

MPS II definitionMucopolysaccharidosis II (Hunter Syndrome) confirmed by deficiency in iduronate 2-sulfatase enzyme activity or molecular genetic testing

Diagnostic specificsEnzyme deficiency measured in fibroblasts or leukocytes combined with normal activity of another sulfatase, or molecular testing for IDS gene mutations/deletions

Policy Changes and Updates

Policy coding updates effective 01/01/2026: HCPCS code J1809 was added for Nulibry, and the policy removed HCPCS codes C9399, J3490, and J3590 (previously referenced).

Policy Summary

PayerUnitedHealthcare

PolicyMedical Therapies for Enzyme Deficiencies (for Ohio Only)

Policy CodePolicy CSOH2026D0052.E

Change TypeHCPCS code updates (added and removed)

Effective DateJan 1, 2026

Next Review DateN/A

Key ActionSubmit prior authorization with diagnostic confirmation and use updated HCPCS coding (J1809 added; C9399, J3490, J3590 removed).

SourceLink

On This Page

Infantile-onset GAA threshold

Absence or deficiency (< 1% of the lab specific normal mean) acid alpha-glucosidase (GAA) activity in skin fibroblasts

Late-onset GAA thresholdAbsence or deficiency (< 40% of the lab specific normal mean) acid alpha-glucosidase (GAA) activity in lymphocytes, fibroblasts, or muscle

Diagnostic methodsConfirmed by enzyme assay (fibroblasts, lymphocytes, or muscle) or molecular genetic testing for GAA gene mutations/deletions

inv-35: Alpha-galactosidase A activity (Fabry)

Alpha-galactosidase A activity thresholdAbsence or deficiency (< 5% of mean) of normal alpha-galactosidase A (α-Gal A) enzyme activity in leukocytes, dried blood spots, or serum

Diagnostic methodsMeasured by enzyme activity assays or confirmed by molecular genetic testing for GAL gene mutations

Indication contextUsed to confirm Fabry disease for Elfabrio initial therapy

inv-36: GAA activity threshold for Pompe diagnosis

GAA activity threshold for Pompe diagnosisAbsence or deficiency (< 40% of the lab specific normal mean) acid alpha-glucosidase (GAA) activity in lymphocytes, fibroblasts, or muscle for late-onset Pompe disease

Infantile-onset threshold (contrast)Infantile-onset Pompe defined by GAA activity < 1% in skin fibroblasts

Diagnostic confirmation methodsEnzyme assay in relevant tissue (fibroblasts, lymphocytes, or muscle) or molecular genetic testing for GAA gene mutations/deletions

inv-37: Pombiliti weight requirement

Weight requirement for Pombiliti initiationPatient must weigh ≥ 40 kg to be eligible for Pombiliti (cipaglucosidase alfa-atga)

Concomitant therapy requirementPombiliti must be prescribed in combination with oral Opfolda (miglustat)

Combination exclusionPatient must not receive Pombiliti in combination with another disease-modifying ERT for Pompe disease (e.g., Lumizyme, Nexviazyme)

Submit reauthorization with evidence of continued benefit

Note

No Additional Explicit PA Statements in Certain Sections

Some source chunks do not add additional or unique prior authorization statements beyond the general product-level PA and duration language. Providers should rely on the drug-specific criteria sections for explicit authorization requirements.

No additional PA beyond product criteria in several efficacy/trial description sections

Prior Authorization

Indication-Specific Prior Authorization Guidance

Prior authorization criteria are indication-specific. Each drug’s section lists required diagnostic confirmation, clinical signs/symptoms, dosing per FDA labeling, combination exclusions or required concomitant therapy, and other product-specific conditions (e.g., weight thresholds, failure or non-improvement on prior ERT). Providers must meet the listed indication-specific criteria when requesting authorization.

Diagnostic confirmation (enzyme assay or molecular testing) required per indication
Presence of clinical signs/symptoms required
Adherence to FDA dosing required
Product-specific combination exclusions or required concomitant agents (see product criteria)

Billing Rule

Applicable Coding for Authorization and Claims

Use the listed HCPCS/NDC/CPT codes when requesting authorization or submitting claims. Refer to the policy's Applicable Codes section for the current code set; the policy was updated 01/01/2026 to add and remove specific HCPCS codes (see Policy History).

Check policy Applicable Codes for current HCPCS/CPT/NDC mappings (01/01/2026 update)
Example: Nulibry HCPCS J1809 added; obsolete/removed codes archived

Note

State Medical Necessity Evaluation (Ohio)

This policy applies to the state of Ohio. Medical necessity determinations for services stated as unproven or for services with coverage/quantity limits will be evaluated using Ohio Administrative Code 5160-1-01.

State reference: Ohio Administrative Code 5160-1-01
Policy applicability: Ohio only

Note

No Authorization Requirements Implied by Trial Descriptions

Although many sections specify authorization requirements, some clinical trial, efficacy, and background sections do not impose operational authorization requirements themselves. Providers should not assume trial discussion text replaces the product-specific PA criteria.

Trial and outcome descriptions are informational only and do not modify PA rules

Note

FDA Approval Alone Is Not a Basis for Coverage

FDA approval or labeling is informational and does not by itself establish coverage under UnitedHealthcare. Coverage decisions require that the plan’s medical necessity criteria and any applicable federal/state/contractual requirements be met.

FDA approval is not a sole basis for coverage

Note

Plan and Regulatory Alignment Required

Coverage decisions must align with federal, state (Ohio Administrative Code), and contractual requirements. If there is a conflict between this policy and governing law or contract terms, the federal/state/contractual requirements take precedence. Verify applicable regulatory or plan contract requirements before relying on this policy.

In the event of conflict, federal/state/contractual requirements govern
Check plan and regulatory requirements prior to using this policy

Documentation Required

Diagnostic Confirmation and Required Clinical Documentation

Diagnostic confirmation and clinical documentation are required with PA requests. For most indications this includes enzyme assay results (deficiency/absence) OR molecular genetic testing confirming pathogenic mutations, plus documentation of clinical signs and symptoms consistent with the disease.

Provide enzyme activity assay results (e.g., fibroblast or leukocyte) OR molecular genetic test results
Document clinical signs/symptoms referenced in the product criteria (e.g., respiratory compromise, hepatosplenomegaly, cardiac findings, functional limitations)
Include prior-treatment history when applicable (ERT exposure, response)

Documentation Required

Pombiliti-Specific Documentation Requirements

For Pombiliti (cipaglucosidase alfa-atga) specifically, include documentation that the patient: is ≥ 40 kg, is not improving on their current ERT and the prior ERT will be stopped, will receive cipaglucosidase in combination with Opfolda (miglustat), and is not receiving it concurrently with another disease-modifying ERT. For continuation, document prior Pombiliti + Opfolda treatment and clinical benefit.

Weight documentation: patient ≥ 40 kg
Provider attestation that prior ERT is inadequate and will be discontinued
Prescription and plan to co-administer Opfolda (miglustat)
Exclude concurrent use with other disease-modifying ERTs
For reauthorization: evidence of clinical response to Pombiliti + Opfolda

Documentation Required

Clinical Trial Endpoints as Supporting Documentation

Clinical trial endpoints such as changes in % predicted FVC and 6-minute walk distance (6MWT), reduction in organ volumes, and biomarker changes (e.g., urine GAG, plasma GL-3) are used in the evidence summaries and may be acceptable supporting measures of response when submitted with reauthorization requests.

Common endpoints: % predicted FVC, 6MWT distance, organ volume changes, biomarker reductions (urine GAG, GL-3)
Include objective measures of clinical benefit in reauthorization requests

Documentation Required

Supportive Documentation to Include with PA Requests

Supportive documentation referenced in the policy includes FDA-approved prescribing information, pivotal trial publications (summarized in the evidence sections), and, where applicable, InterQual® criteria used by UnitedHealthcare to assist administration. Include copies or extracts of relevant reports as needed to support medical necessity.

Include relevant prescribing information and pivotal trial outcome data when available
InterQual® criteria may be used by UnitedHealthcare in administration

Note

Reference to Governing Requirements

This policy and its requirements are governed by the stated federal, state (OAC), and contractual authorities. Providers must follow the governing requirements and recognize this policy as an interpretation for UnitedHealthcare standard plans rather than a replacement for regulatory or contractual mandates.

Reference governing authorities (federal, Ohio Administrative Code, contractual) when disputes arise
Policy is informational and does not supersede governing law or contract

Denial Risk

Monotherapy Requirement and Combination Exclusions

Monotherapy and combination rules vary by product. Many enzyme therapies explicitly prohibit concurrent use of another disease-modifying enzyme therapy for the same indication (e.g., Lumizyme, Nexviazyme, Pombiliti exclusions). Some products require coadministration (e.g., Pombiliti requires Opfolda). Providers must adhere to the combination exclusion or co-therapy requirements in the product-specific criteria.

Do not combine two disease-modifying ERTs for the same condition unless expressly allowed
Pombiliti requires coadministration with Opfolda (miglustat)

Step Therapy

Pombiliti Step/Step-Down Requirement (Operational)

The Pombiliti product section includes a step/step-down implication: the provider must attest the patient is not improving on current ERT and the prior therapy will be stopped before initiating Pombiliti. This functions operationally as a step requirement (failure or inadequate response to prior ERT) though not labeled as an automated step-edit; include documentation of prior ERT and lack of improvement.

Provider attestation that prior ERT did not result in improvement and will be discontinued
Documentation of prior ERT duration and clinical course

Note

Head-to-Head Trial Mention (Operational Impact)

A head-to-head randomized trial compared cipaglucosidase alfa plus miglustat to a non-U.S.-approved alglucosidase alfa product; while efficacy endpoints favored Pombiliti plus miglustat numerically for some outcomes, the policy uses the clinical criteria and FDA labeling to define authorization rules rather than automatic step edits based solely on trial results.

Pombiliti was compared directly to a non-U.S.-approved alglucosidase alfa product in Trial NCT#03729362
Trial outcomes provide supportive evidence but do not independently change PA mechanics

Step Therapy

Implied Step Requirement for Pombiliti (Provider Action)

The Pombiliti criteria in the policy imply a step requirement (prior ERT inadequate) rather than an explicit numeric step-therapy algorithm. Operational requests should include prior ERT history and clinician attestation of inadequate response to satisfy this implied step requirement.

Implied step: inadequate response to current ERT required before Pombiliti initiation
Submit prior ERT history and clinician attestation

Nulibry initial: Diagnosis of MoCD Type A confirmed by sulfite oxidase deficiency in fibroblasts OR MOCS1 molecular genetic testing; presence of clinical signs/symptoms within first 28 days after birth; dosing per FDA labeling; initial authorization ≤ 12 months

inv-74: Pombiliti initial

Pombiliti initial

Pombiliti initial: Diagnosis of late-onset Pompe disease confirmed by absent/deficient GAA activity (<40% of lab normal) OR molecular genetic testing; clinical signs present; provider attests lack of improvement on current ERT and current ERT will be stopped; patient weight ≥ 40 kg; prescribed with Opfolda (miglustat); not used with another disease-modifying ERT; dosing per FDA labeling; initial authorization ≤ 12 months

inv-75: Revcovi initial

Revcovi initial

Revcovi initial: Diagnosis of ADA‑SCID with ADA deficiency confirmed by specified laboratory tests or molecular confirmation or positive TREC; patient not a suitable HCT candidate OR failed HCT OR awaiting HCT; dosing per FDA labeling; initial authorization ≤ 12 months

inv-76: Vimizim initial

Vimizim initial

Vimizim initial: Diagnosis of Morquio A confirmed by absence/deficiency of GALNS enzyme activity AND molecular genetic testing; presence of clinical signs/symptoms; dosing per FDA labeling; initial authorization ≤ 12 months

inv-77: Xenpozyme initial

Xenpozyme initial

Xenpozyme initial: Diagnosis of ASMD type A/B or B confirmed by ASM enzyme deficiency OR SMPD1 genetic testing; presence of clinical signs/symptoms; not for CNS manifestations; dosing per FDA labeling; initial authorization ≤ 12 months

inv-78: Trial-reported dosing

Trial-reported dosing

Kanuma dosing: Sebelipase alfa administered intravenously at 1 mg/kg every other week in the phase 3 trial

chunk 48

Lumizyme dosing: Alglucosidase alfa 20 mg/kg every 2 weeks in the late‑onset Pompe disease trial

chunk 52

Nexviazyme dosing: Avalglucosidase alfa‑ngpt 20 mg/kg every 2 weeks compared to alglucosidase alfa in the pivotal trial

chunk 54

Lamzede dosing: Velmanase alfa 1 mg/kg weekly in the phase 3 trial

chunk 50

inv-79: Pivotal trial evidence informing initiation

Pivotal trial evidence informing initiation

Nexviazyme pivotal trial: Randomized double‑blind trial in treatment‑naïve late‑onset Pompe patients comparing avalglucosidase alfa‑ngpt to alglucosidase alfa with primary endpoint change in upright FVC at Week 49; LS mean change favored avalglucosidase alfa‑ngpt (2.9% vs 0.5%; treatment difference 2.4%, 95% CI -0.1,5) and 6MWD secondary endpoint favored avalglucosidase alfa‑ngpt (30 m, 95% CI 1.3,58.7)week 49

statistical noninferiority achieved; superiority not statistically significant

Pombiliti pivotal trial: Randomized 2:1 trial of cipaglucosidase alfa‑atga + miglustat vs non‑US alglucosidase alfa + placebo in adults with LOPD (ERT‑experienced and naïve); sitting FVC and 6MWD at Week 52 showed numerical improvements favoring cipaglucosidase alfa‑atga + miglustatweek 52

included many ERT‑experienced patients

Vimizim pivotal trial: Phase 3 MOR‑004 trial in Morquio A randomized to weekly or QOW dosing vs placebo with primary endpoint 6MWT at 24 weeks: weekly dosing improved 6MWT vs placebo (22.5 m, 95% CI 4.0,40.9; p=0.017); QOW did not differ from placeboweek 24

Xenpozyme pivotal trial: Randomized placebo‑controlled trial in adults with ASMD showed at Week 52 improvements in % predicted DLco (+20.9%), spleen volume (-39.4%), liver volume (-24.7%), and platelet count (+15.6%) versus placebo (statistically significant)week 52

Nulibry continuation: Previously received fosdenopterin; demonstrated positive clinical response (e.g., decreased seizures, improved feeding/alertness/gross motor function, decreased urinary SSC, changes in xanthine/uric acid); dosing per FDA labeling; reauthorization ≤ 12 months.

inv-83: Pombiliti continuation

Pombiliti continuation

Pombiliti continuation: Previously received Pombiliti; demonstrated positive clinical response to Pombiliti plus Opfolda; continues Opfolda; not used with other disease‑modifying ERTs; dosing per FDA labeling; reauthorization ≤ 12 months.

inv-84: Revcovi continuation

Revcovi continuation

Revcovi continuation: Previously received elapegademase; demonstrated positive clinical response (e.g., normalization of plasma ADA activity, improved dATP levels, clinical improvement); dosing per FDA labeling; reauthorization ≤ 12 months.

inv-85: Vimizim continuation

Vimizim continuation

Vimizim continuation: Previously received elosulfase alfa; demonstrated positive clinical response (improved endurance/functional capacity, reduced urine keratan sulfate); dosing per FDA labeling; reauthorization ≤ 12 months.

inv-86: Xenpozyme continuation

Xenpozyme continuation

Xenpozyme continuation: Previously received olipudase alfa; demonstrated positive clinical response (e.g., reduced spleen and liver volumes, improved liver transaminases, improved lipid profile, improved pulmonary function); dosing per FDA labeling; reauthorization ≤ 12 months.

Clinical applicationUsed to determine eligibility for Elaprase (idursulfase) therapy

inv-63: MoCD Type A diagnostic confirmation

MoCD Type A diagnostic confirmationDiagnosis confirmed by absence or deficiency of sulfite oxidase enzyme activity in fibroblasts OR by molecular genetic testing for mutations in the MOCS1 gene

Clinical timeframeClinical signs/symptoms within the first 28 days after birth are referenced for Nulibry initial therapy

Treatment contextUsed to determine eligibility for Nulibry (fosdenopterin)

inv-64: Late-onset Pompe diagnostic confirmation

Late-onset Pompe diagnostic confirmationDiagnosis confirmed by absence or deficiency of acid alpha-glucosidase (GAA) activity (< 40% of the lab specific normal mean) in lymphocytes, fibroblasts, or muscle OR by molecular genetic testing for GAA gene mutations/deletions

Distinguishing infantile vs late-onsetInfantile-onset Pompe is distinguished by GAA activity < 1% in fibroblasts

Clinical applicationUsed for eligibility determination for Nexviazyme, Lumizyme, and Pombiliti therapies

inv-65: ADA-SCID diagnostic confirmation

ADA-SCID diagnostic confirmationDiagnosis confirmed by deficiency or absence of adenosine deaminase (ADA) in plasma, lysed erythrocytes, or fibroblasts; or increased dATP in erythrocyte lysates; or decreased erythrocyte ATP; or molecular genetic confirmation of biallelic ADA1 mutations; or positive TREC screen

Transplant contextRevcovi may be used when patient is not a suitable hematopoietic cell transplantation (HCT) candidate, has failed HCT, or is awaiting HCT

Clinical applicationUsed to determine eligibility for Revcovi (elapegademase-lvlr)

inv-66: Mannose-6-phosphate (M6P) receptor-mediated uptake

M6P receptor-mediated uptakeMany recombinant lysosomal enzymes bear mannose-6-phosphate (M6P)-terminated oligosaccharide chains that bind M6P receptors on the cell surface, are internalized and transported to lysosomes where they exert enzymatic activity

ExamplesDescribed for velmanase alfa (Lamzede), avalglucosidase alfa (Nexviazyme), cipaglucosidase alfa-atga (Pombiliti), and elosulfase alfa (Vimizim)

Mechanistic relevanceM6P-mediated uptake is central to cellular delivery of exogenous recombinant enzymes in ERT programs

inv-67: Enzyme replacement therapy (ERT)

Enzyme replacement therapy (ERT) definitionProvision of an exogenous recombinant form of a deficient lysosomal enzyme to reduce substrate accumulation and improve organ function

Administration routeMost ERTs in the document are administered by intravenous infusion (clinic/infusion center or hospital outpatient settings)

Clinical endpoints usedERT efficacy is often supported by functional endpoints such as FVC (% predicted), 6MWT/6MWD, organ volume reductions, and biomarker normalization

inv-68: 6MWT / 6MWD definition

6MWT / 6MWD definitionSix-minute walk test (6MWT) — measure of functional exercise capacity; total distance walked in 6 minutes (6MWD) used as a primary or secondary endpoint in pivotal trials (e.g., Vimizim MOR-004, Nexviazyme)

Clinical useUsed as a primary endpoint in trials assessing endurance and functional capacity; mean changes reported at specified trial weeks (e.g., week 24, 49, 52)

InterpretationReported as change from baseline and used to support clinical benefit in authorization decisions

inv-69: FVC (% predicted) definition

FVC (% predicted) definitionForced vital capacity expressed as percent predicted (upright or sitting) used as a primary endpoint in Pompe disease trials (e.g., Nexviazyme primary endpoint change in upright FVC at week 49; Pombiliti assessed sitting FVC at week 52)

Clinical measurementReported as least squares mean change from baseline and used to compare treatment effects between arms

RelevanceImportant for assessing pulmonary function and informing authorization for Pompe disease therapies

inv-70: Package/prescribing information cited as references

Package/prescribing information citedSelected product prescribing information and package inserts are cited as references (examples: Nulibry, Nexviazyme, Xenpozyme, Lamzede, Pombiliti package inserts)

Reference examplesNulibry [prescribing information] (Origin Biosciences, Oct 2022); Nexviazyme [prescribing information] (Genzyme, Sep 2023); Xenpozyme [prescribing information] (Genzyme, Dec 2023); Lamzede [prescribing information] (Chiesi, Feb 2023)

PurposePrescribing information is referenced to support diagnostic criteria, dosing, and efficacy evidence in the policy