UnitedHealthcare enzyme-replacement Coverage & Prior Auth

inv-01: Drug-Specific Initial and Continuation Criteria

Covered when ALL of the following are met for each specific drug (initial and continuation rules specified separately).

Aldurazyme - Initial: Diagnosis of MPS I (Hurler, Hurler-Scheie, or Scheie variant) AND diagnosis confirmed by absence or deficiency of alpha-L-iduronidase enzyme activity in appropriate testing OR molecular genetic confirmation of pathogenic IDUA variants; AND presence of clinical signs/symptoms of MPS I; AND dosing per U.S. FDA labeling; AND initial authorization ≤ 12 months

Aldurazyme - Continuation: Patient previously received laronidase (Aldurazyme) therapy; AND patient experienced a positive clinical response to laronidase (e.g., improved endurance, improved functional capacity, reduced urinary dermatan/heparan sulfate); AND dosing per U.S. FDA labeling; AND reauthorization ≤ 12 months

Elaprase - Initial: Diagnosis of MPS II confirmed by iduronate 2-sulfatase deficiency in fibroblasts or leukocytes with normal other sulfatase OR molecular genetic testing showing IDS gene deletion/mutation; AND presence of clinical signs/symptoms of MPS II; AND dosing per U.S. FDA labeling; AND initial authorization ≤ 12 months

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

Elfabrio - Initial: Diagnosis of Fabry disease confirmed by absence/deficiency (<5% of mean) of alpha-galactosidase A activity in leukocytes, dried blood spot, or serum OR molecular genetic testing for pathogenic GLA variants; AND presence of clinical signs/symptoms of Fabry disease; AND patient is not receiving Elfabrio in combination with another disease-modifying Fabry therapy; AND dosing per U.S. FDA labeling; AND initial authorization ≤ 12 months

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

Fabrazyme - Initial: Diagnosis of Fabry disease confirmed by absence/deficiency (<5% of mean) of alpha-galactosidase A activity OR molecular genetic testing for GLA mutations; AND presence of clinical signs/symptoms; AND patient is not receiving Fabrazyme in combination with another disease-modifying Fabry therapy; AND dosing per U.S. FDA labeling; AND initial authorization ≤ 12 months

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

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

Kanuma - Continuation: Patient previously received sebelipase (Kanuma) therapy; AND patient experienced a positive clinical response (e.g., improved symptoms, improved laboratory values); AND dosing per U.S. FDA labeling; AND reauthorization ≤ 12 months

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

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

Lumizyme (alglucosidase) - Initial: Either: ALL criteria for infantile-onset Pompe — diagnosis confirmed by absence/deficiency (<1% of lab normal mean) of GAA activity in skin fibroblasts OR molecular genetic testing for GAA; AND presence of clinical signs/symptoms; AND not receiving Lumizyme in combination with another Pompe ERT; AND dosing per U.S. FDA labeling; AND initial authorization ≤ 12 months; OR ALL criteria for late-onset Pompe — diagnosis confirmed by absence/deficiency (<40% of lab normal mean) of GAA activity in lymphocytes, fibroblasts, or muscle OR molecular genetic testing for GAA; AND presence of clinical signs/symptoms; AND not receiving Lumizyme in combination with another Pompe ERT; AND dosing per U.S. FDA labeling; AND initial authorization ≤ 12 months

Lumizyme - Continuation: Patient previously received alglucosidase (Lumizyme) therapy; AND patient experienced a positive clinical response (e.g., improved respiratory/cardiac function, improved endurance); AND patient is not receiving Lumizyme in combination with another Pompe ERT; AND dosing per U.S. FDA labeling; AND reauthorization ≤ 12 months

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

Mepsevii - Continuation: Patient previously received vestronidase (Mepsevii); AND patient experienced a positive clinical response (e.g., improved endurance, improved pulmonary function); AND dosing per U.S. FDA labeling; AND reauthorization ≤ 12 months

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

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

inv-02: Nexviazyme (avalglucosidase alfa-ngpt)

Nexviazyme is medically necessary when the following apply.

Initial therapy criteria for Nexviazyme: 1) 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 showing deletion/mutation in GAA; AND 2) Presence of clinical signs/symptoms (e.g., cardiac hypertrophy, respiratory distress, skeletal muscle weakness); AND 3) Patient is not receiving Nexviazyme in combination with another disease-modifying ERT for Pompe disease; AND 4) Dosing per U.S. FDA labeling; AND 5) Initial authorization ≤ 12 months.< 40% of the lab specific normal mean

Continuation therapy criteria for Nexviazyme: 1) Patient previously received avalglucosidase alfa-ngpt (Nexviazyme); AND 2) Patient experienced a positive clinical response to avalglucosidase therapy (e.g., improved respiratory/cardiac function, improved endurance); AND 3) Patient is not receiving Nexviazyme in combination with another disease-modifying ERT for Pompe disease; AND 4) Dosing per U.S. FDA labeling; AND 5) Reauthorization ≤ 12 months.

inv-03: Nulibry (fosdenopterin)

Nulibry is medically necessary when all of the following are met.

Initial therapy criteria for Nulibry: 1) Diagnosis of molybdenum cofactor deficiency (MoCD) Type A confirmed by absence/deficiency of sulfite oxidase activity in fibroblasts OR molecular genetic testing for mutations in MOCS1; AND 2) Presence of clinical signs/symptoms within first 28 days after birth (e.g., seizures, exaggerated startle response, high-pitched cry, axial hypotonia, limb hypertonia, feeding difficulties, elevated urinary sulfite and/or S-sulphocysteine (SSC), elevated xanthine, low or absent uric acid); AND 3) Dosing per U.S. FDA labeling; AND 4) Initial authorization ≤ 12 months.

Continuation therapy criteria for Nulibry: 1) Patient previously received fosdenopterin (Nulibry); AND 2) Patient experienced a positive clinical response to fosdenopterin (e.g., decreased seizure activity, improved feeding/alertness/gross motor/growth, decreased urinary sulfite/SSC, decreased xanthine, increased uric acid); AND 3) Dosing per U.S. FDA labeling; AND 4) Reauthorization ≤ 12 months.

Efficacy evidence: improved overall survival versus genotype-matched natural history (HR 0.18) and reduction in urinary SSC

inv-04: Pombiliti (cipaglucosidase alfa-atga) + Opfolda

Pombiliti is medically necessary when the following are met.

Initial therapy criteria for Pombiliti: 1) Diagnosis of late-onset Pompe disease confirmed by absence/deficiency of GAA activity (<40% of lab specific normal mean) OR molecular genetic testing for GAA mutations; AND 2) Presence of clinical signs/symptoms; AND 3) Provider attests patient is not improving on current ERT and current ERT will be stopped; AND 4) Patient weight ≥ 40 kg; AND 5) Prescribed in combination with oral Opfolda (miglustat); AND 6) Patient is not receiving Pombiliti in combination with another disease-modifying Pompe ERT; AND 7) Dosing per U.S. FDA labeling; AND 8) Initial authorization ≤ 12 months.< 40% of the lab specific normal mean

Continuation therapy criteria for Pombiliti: 1) Patient previously received cipaglucosidase alfa (Pombiliti); AND 2) Patient experienced a positive clinical response to Pombiliti plus Opfolda (e.g., improved respiratory/cardiac function, improved endurance); AND 3) Continues to be prescribed with Opfolda; AND 4) Patient is not receiving Pombiliti in combination with another disease-modifying Pompe ERT; AND 5) Dosing per U.S. FDA labeling; AND 6) Reauthorization ≤ 12 months.

Provider must attest prior ERT is stopped before initiation

inv-05: Revcovi (elapegademase-lvlr)

Revcovi is medically necessary when the following are met.

Initial therapy criteria for Revcovi: 1) Diagnosis of ADA‑SCID; AND 2) Deficiency of adenosine deaminase confirmed by deficiency/absence of ADA in plasma, lysed erythrocytes, fibroblasts, or by increased erythrocyte dATP or decreased ATP OR molecular genetic confirmation of biallelic ADA1 mutations OR positive TREC screening; AND 3) One of: patient not suitable for HCT OR failed HCT OR awaiting HCT; AND 4) Dosing per U.S. FDA labeling; AND 5) Initial authorization ≤ 12 months.

Continuation therapy criteria for Revcovi: 1) Patient previously received elapegademase (Revcovi); AND 2) Patient experienced a positive clinical response to elapegademase (e.g., normalization of plasma ADA activity, improvement in erythrocyte dATP levels, symptom improvement); AND 3) Dosing per U.S. FDA labeling; AND 4) Reauthorization ≤ 12 months.

inv-06: Vimizim (elosulfase alfa)

Vimizim is medically necessary when all of the following are met.

Initial therapy criteria for Vimizim: 1) Diagnosis of Morquio A syndrome (MPS IVA) confirmed by absence/deficiency of GALNS enzyme activity in fibroblasts or leukocytes OR molecular genetic testing for GALNS mutations; AND 2) Presence of clinical signs/symptoms (e.g., kyphoscoliosis, genu valgum, pectus carinatum, gait disturbance, growth deficiency); AND 3) Dosing per U.S. FDA labeling; AND 4) Initial authorization ≤ 12 months.

Continuation therapy criteria for Vimizim: 1) Patient previously received elosulfase alfa (Vimizim); AND 2) Patient experienced a positive clinical response (e.g., improved endurance, improved functional capacity, reduced urine keratan sulfate); AND 3) Dosing per U.S. FDA labeling; AND 4) Reauthorization ≤ 12 months.

inv-07: Xenpozyme (olipudase alfa-rpcp)

Xenpozyme is medically necessary when all of the following are met.

Initial therapy criteria for Xenpozyme: 1) Diagnosis of acid sphingomyelinase deficiency (ASMD) type A/B or B confirmed by absence/deficiency of acid sphingomyelinase activity OR molecular genetic testing for SMPD1 mutations; AND 2) Dosing per U.S. FDA labeling; AND 3) Initial authorization ≤ 12 months; AND 4) Not expected to treat CNS manifestations (informational).

Olipudase alfa is not expected to cross the blood-brain barrier

Use of specified enzyme therapies in combination with another disease-modifying therapy for the same disorder is prohibited. Examples include Fabry disease therapies (e.g., Elfabrio, Fabrazyme, Galafold) and Pompe disease therapies (e.g., Lumizyme, Nexviazyme, Pombiliti) — patients must not receive more than one disease-modifying enzyme replacement or approved disease-modifying therapy for the same condition simultaneously as a condition of coverage.

Concurrent administration of therapies listed in this policy with another disease-modifying enzyme replacement therapy for the same disease is not allowed. Coverage requires that the patient is not receiving the requested ERT in combination with another disease-modifying ERT for that indication (for example, Nexviazyme, Lumizyme, and Pombiliti are each restricted from simultaneous use with alternative Pompe disease ERTs).

Olipudase alfa (Xenpozyme) is designed to treat non‑central nervous system manifestations of acid sphingomyelinase deficiency and is not expected to cross the blood‑brain barrier; therefore it is not expected to treat CNS manifestations of ASMD.

FDA approvals and product labeling are included for informational purposes only. FDA approval alone is not a basis for coverage; coverage determinations are made according to the medical necessity criteria in this policy.

Covered Indications for Enzyme-Related Therapies

inv-44: Molecular genetic testing to confirm diagnosis of listed enzyme deficiency disorders when enzyme activity assays are not definitive or to provide genetic confirmation.

Molecular genetic testing is covered to confirm diagnosis of the listed enzyme deficiency disorders when enzyme activity assays are not definitive or to provide genetic confirmation.

Molecular genetic testing - general: Molecular genetic testing for the disease-specific gene (e.g., IDUA, IDS, GLA, GAA, LIPA, MAN2B1, GUSB, ASB, SMPD1, MOCS1, ADA1, GALNS) is covered to confirm diagnosis when enzyme activity assays are inconclusive or as an alternative confirmatory method; AND testing must demonstrate pathogenic or likely pathogenic variants consistent with the clinical phenotype.

inv-45: Molecular genetic testing to confirm diagnoses when enzyme assays are not used or as an alternative (e.g., GAA for Pompe, MOCS1 for MoCD Type A, ADA1 for ADA‑SCID, GALNS for MPS IVA, SMPD1 for ASMD).

Molecular genetic testing is an acceptable diagnostic confirmation method alongside enzyme activity assays for the indicated disorders.

Acceptable genetic confirmatory testing: For specific disorders (examples): GAA for Pompe disease; MOCS1 for MoCD Type A; ADA1 for ADA‑SCID; GALNS for MPS IVA; SMPD1 for ASMD — molecular genetic testing demonstrating pathogenic variants is acceptable to confirm diagnosis in lieu of or in addition to enzyme activity assays; AND clinical signs/symptoms consistent with the disorder must be present for therapy eligibility.

inv-46: Use of enzyme replacement or enzyme-related biologic therapies for diagnosed inherited enzyme deficiency disorders (examples described: MPS I, MPS II, Fabry disease, Pompe disease, LAL deficiency, alpha-mannosidosis, ASMD).

Enzyme replacement and enzyme-related biologic therapies are covered for diagnosed inherited enzyme deficiency disorders when criteria are met.

Use of ERTs and related biologics: Enzyme replacement and enzyme-related biologic therapies (examples: Aldurazyme, Elaprase, Elfabrio, Fabrazyme, Lumizyme, Nexviazyme, Pombiliti, Kanuma, Lamzede, Mepsevii, Naglazyme, Vimizim, Xenpozyme, Revcovi, Nulibry) are covered when the specific drug criteria for diagnosis confirmation (enzyme assay or molecular genetic testing), presence of clinical signs/symptoms, dosing per FDA labeling, and initial/continuation authorization limits are satisfied; AND objective baseline and follow-up measures relevant to the disease should be submitted to support initiation and continuation decisions (e.g., 6MWT, %FVC, liver/spleen imaging/volume, disease-specific biomarkers).

inv-47: Molybdenum cofactor deficiency (MoCD) Type A — reduction in mortality with fosdenopterin.

Fosdenopterin (Nulibry) demonstrated mortality benefit in MoCD Type A in clinical studies compared to genotype-matched natural history controls.

MoCD Type A - fosdenopterin evidence: Clinical studies of fosdenopterin (and rcCMP) in pediatric patients with MoCD Type A demonstrated improved overall survival compared to an untreated genotype-matched natural history cohort (HR 0.18) and sustained reduction in urine S-sulphocysteine (SSC); these data support use of fosdenopterin for MoCD Type A when the drug-specific criteria are met.

Billing and Coding

AldurazymemixedCovered

J1931	Injection, laronidase, 0.1 mg
E76.01	Hurler's syndrome
E76.02	Hurler-Scheie syndrome
E76.03	Scheie's syndrome

ElaprasemixedCovered

J1743	Injection, idursulfase, 1 mg
E76.1	Mucopolysaccharidosis, type II

Various enzyme therapies (Elfabrio, Fabrazyme, Kanuma, Lamzede, Naglazyme, Mepsevii, etc.)mixedCovered

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
E75.21	Fabry (-Anderson) disease
E75.5	Other lipid storage disorders
E76.29	Other mucopolysaccharidoses

Nexviazyme, Pombiliti, Vimizim, Xenpozyme, othersmixedCovered

J0219	Injection, avalglucosidase alfa-ngpt, 4 mg
J1203	Injection, cipaglucosidase alfa-atga, 5 mg
J1322	Injection, elosulfase alfa, 1 mg
J0218	Injection, olipudase alfa-rpcp, 1 mg
E74.02	Pompe disease
E76.210	Morquio A mucopolysaccharidoses
E75.241	Niemann-Pick disease type B
E75.244	Niemann-Pick disease type A/B
D81.31	Severe combined immunodeficiency due to adenosine deaminase deficiency

Unclassified drug/biologic codes referencedHCPCS

J3490	Unclassified drugs
J3590	Unclassified biologics

inv-17: alpha-galactosidase A activity diagnostic threshold

Alpha-galactosidase A activity thresholdAbsence or deficiency defined as < 5% of the normal mean measured in leukocytes, dried blood spots, or serum

Sample types for testingLeukocytes, dried blood spot, or serum analysis as acceptable specimen types for alpha-Gal A activity measurement

Alternative confirmationMolecular genetic testing for GLA gene deletion or pathogenic mutations can be used when enzyme assay is inconclusive

inv-18: acid alpha-glucosidase (GAA) activity diagnostic thresholds

Infantile-onset GAA activity thresholdAbsence or deficiency defined as < 1% of the lab-specific normal mean in skin fibroblasts (infantile-onset Pompe)

Late-onset GAA activity thresholdAbsence or deficiency defined as < 40% of the lab-specific normal mean in lymphocytes, fibroblasts, or muscle (late-onset Pompe)

Genetic confirmation optionMolecular genetic testing for deletions or mutations in the GAA gene is an alternative diagnostic confirmation

inv-19: alpha-Mannosidase activity diagnostic threshold

Alpha-mannosidase activity thresholdAbsence or deficiency defined as < 10% of the lab-specific normal mean

Diagnostic specimen and methodsEnzyme activity measured in appropriate tissue (e.g., leukocytes, fibroblasts) or molecular genetic testing for MAN2B1 mutations

CNS treatment limitationLamzede is not indicated for treatment of central nervous system manifestations of alpha-mannosidosis (policy notes)

inv-20: GAA enzyme activity diagnostic threshold

GAA diagnostic threshold (late-onset)Absence or deficiency defined as < 40% of the lab-specific normal mean in lymphocytes, fibroblasts, or muscle

Sample types referencedLymphocytes, fibroblasts, or muscle are cited specimen types for measuring GAA activity

Use with genetic testingMolecular genetic testing for GAA gene deletions/mutations may be used as diagnostic confirmation when appropriate

Prior Authorization, Documentation, and Operational Requirements

Prior Authorization

Prior Authorization Required — Diagnostic, Clinical, Dosing, and Outcome Documentation

Prior authorization required — Prior authorization is required with documentation of diagnostic confirmation, clinical signs/symptoms, dosing per U.S. FDA labeling, and objective baseline and follow-up measures relevant to the specific disease and therapy (examples: 6-minute walk test, percent predicted FVC, liver/spleen volume by imaging, laboratory biomarkers such as urinary glycosaminoglycans or serum oligosaccharides). Initial authorizations are generally limited to no more than 12 months; reauthorizations require documentation of continued benefit and dosing in accordance with FDA labeling.

Submit confirmed diagnosis by enzyme assay (fibroblast/leukocyte/dried blood spot) or molecular genetic testing.
Document presence of clinical signs/symptoms relevant to the indicated disease.
Provide dosing consistent with FDA-approved labeling.
Include objective baseline measures (e.g., 6MWT, % predicted FVC, liver/spleen volume, relevant biomarkers) and planned follow-up assessment schedule.
Initial authorization duration: ≤ 12 months; reauthorization: ≤ 12 months with evidence of positive clinical response.

Step Therapy

Step / Switching Requirement for Pombiliti

Prior authorization required — Prior authorization requests for Pombiliti (cipaglucosidase alfa-atga) must include the provider attestation that the patient is not improving on their current enzyme replacement therapy (e.g., Lumizyme, Nexviazyme) and that the current ERT will be stopped. Pombiliti must be prescribed in combination with oral Opfolda (miglustat) and the patient must meet weight and other prescribing requirements (e.g., patient weight ≥ 40 kg where specified). Dosing must follow U.S. FDA labeling. Initial and continuation authorizations will be for no more than 12 months and continuation requires documentation of positive clinical response to the Pombiliti plus Opfolda regimen.

Provider must attest patient is not improving on current ERT and current ERT will be discontinued before initiating Pombiliti.
Pombiliti must be prescribed in combination with Opfolda (miglustat).
Patient must meet any FDA-labeled weight and other requirements (e.g., ≥ 40 kg where specified).
Patient must not be receiving Pombiliti in combination with another disease-modifying enzyme therapy for Pompe disease.
Dosing per U.S. FDA-approved labeling; initial and reauthorization durations ≤ 12 months.

Documentation Required

Prior Authorization: Submit Objective Baseline and Follow-up Measures

Prior authorization: submit objective baseline and follow-up measures — Authorization requests should include baseline and planned follow-up objective measures relevant to the specific disease and enzyme therapy to demonstrate benefit and support reauthorization. Examples of appropriate objective measures include, but are not limited to: 6-minute walk test (6MWT) distance, percent predicted forced vital capacity (FVC), imaging-based organ volumes (liver, spleen), and disease-specific biomarkers (e.g., urinary glycosaminoglycans, serum oligosaccharides, plasma GL-3).

Baseline values for the selected objective measures must be provided with the initial request.
Planned follow-up assessment schedule and subsequent results should be submitted for reauthorization (for example, 6MWT and % predicted FVC at intervals consistent with clinical practice or trial endpoints).
Lack of documented objective improvement or stabilization on these measures may be a denial trigger for continuation.

Denial Risk

Combination Therapy Restriction

Combination therapy restriction — Certain therapies must not be used in combination with another disease-modifying enzyme therapy for the same condition. Prior authorization requests should confirm the patient is not receiving contraindicated combination therapy (examples provided in product-specific criteria: e.g., Lumizyme, Nexviazyme, Pombiliti for Pompe disease; Elfabrio, Fabrazyme or Galafold for Fabry disease).

Attest that the requested therapy is not being given concurrently with another disease-modifying enzyme therapy for the same indication.
Requests may be denied if evidence of concurrent prohibited combination therapy is present.

Denial Risk

Denial Triggers for Missing Diagnostic, Clinical, or Dosing Documentation

Denial triggers for missing documentation — Requests lacking required diagnostic confirmation, absence of clinical signs/symptoms, missing dosing information inconsistent with FDA labeling, or lacking objective baseline and follow-up outcome data may be denied. Specifically, missing enzyme assay or molecular genetic testing confirmation, failure to document provider attestation where step/switching requirements apply (e.g., Pombiliti), or absence of planned follow-up measures are common denial reasons.

Missing confirmed diagnosis by enzyme assay or molecular genetic testing.
No documentation of clinical signs/symptoms consistent with the disease.
Dosing not in accordance with U.S. FDA-approved labeling.
Missing baseline and follow-up objective outcome measures.
For Pombiliti: missing attestation that prior ERT is ineffective and will be stopped, or missing documentation of concomitant Opfolda (miglustat) use.

Definitions and Diagnostic Criteria

inv-38: Confirmed diagnosis

Definition of confirmed diagnosisDiagnosis confirmed by laboratory demonstration of absence or deficient enzyme activity in leukocytes, fibroblasts, dried blood spot, or tissue, or by molecular genetic testing demonstrating pathogenic mutations

Acceptable assay specimensLeukocytes, fibroblasts, dried blood spots, serum, lymphocytes, muscle (as specified per condition)

When to use genetic testingMolecular genetic testing is acceptable when enzyme assays are not definitive or to provide genetic confirmation of the disease gene

inv-39: Diagnostic confirmation

Diagnostic confirmation definitionEither absence or deficiency of the disease-specific enzyme activity in appropriate tissue (lymphocytes, fibroblasts, muscle, plasma, etc.) or molecular genetic testing demonstrating pathogenic mutations in the disease gene

Listed specimen typesLymphocytes, fibroblasts, muscle, plasma, erythrocytes, dried blood spot depending on the disorder

Examples of genes for genetic confirmationExamples include GAA (Pompe), MOCS1 (MoCD Type A), ADA1 (ADA‑SCID), GALNS (MPS IVA), SMPD1 (ASMD)

inv-40: Mannose-6-phosphate (M6P) targeting

M6P targeting definitionA glycan modification on recombinant enzymes (bis‑M6P/M6P-terminated oligosaccharide chains) that mediates binding to cell-surface mannose-6-phosphate receptors for lysosomal uptake

Examples of M6P-tagged therapiesAvalglucosidase (Nexviazyme), cipaglucosidase (Pombiliti), elosulfase (Vimizim) are described as having M6P modifications facilitating uptake

Functional roleM6P-mediated receptor binding leads to internalization and transport to lysosomes where enzymes become active

inv-41: cPMP / fosdenopterin

cPMP / fosdenopterin descriptionCyclic pyranopterin monophosphate (cPMP) is available exogenously as fosdenopterin to be converted into molybdopterin and then molybdenum cofactor, enabling activation of molybdenum-dependent enzymes such as sulfite oxidase

Therapeutic effect in MoCDExogenous cPMP (fosdenopterin) reduces neurotoxic sulfites by enabling sulfite oxidase activity; clinical trials showed reduced urinary SSC and improved survival in MoCD Type A

Clinical evidenceThree clinical studies (total n=13 treated) demonstrated improved overall survival vs genotype-matched natural history controls and sustained reduction in urinary SSC

inv-42: MoCD Type A

MoCD Type A definitionMolybdenum cofactor deficiency Type A is a genetic disorder caused by mutations (e.g., MOCS1) leading to deficient molybdenum cofactor and impaired activity of molybdenum-dependent enzymes such as sulfite oxidase

Clinical presentation and timingClinical signs include seizures, exaggerated startle, feeding difficulties, elevated urinary sulfite and S-sulphocysteine (SSC), elevated xanthine, and low/absent uric acid, typically within first 28 days after birth

Treatment evidenceFosdenopterin reduced mortality (HR 0.18) and decreased urinary SSC in treated pediatric patients compared to genotype-matched natural history controls

inv-43: ASMD

ASMD definitionAcid sphingomyelinase deficiency (ASMD) is caused by pathogenic variants in SMPD1 resulting in deficient acid sphingomyelinase (ASM) activity and sphingomyelin accumulation

Therapeutic target and limitationsOlipudase alfa (Xenpozyme) is a recombinant human ASM designed to reduce sphingomyelin accumulation in liver, spleen, and lung; it is not expected to cross the blood-brain barrier and therefore is not expected to treat CNS manifestations

Clinical outcomes observedTrials demonstrated improvements in % predicted DLco, spleen and liver volume reductions, and increased platelet counts in non‑CNS ASMD manifestations

OpenPayer

Medical Therapies for Enzyme Deficiencies

Coverage and Medical Necessity Criteria

Covered Indications for Enzyme-Related Therapies

Billing and Coding

Prior Authorization, Documentation, and Operational Requirements

Eligibility Requirements

Definitions and Diagnostic Criteria

Background and Evidence Summary