Defines medical necessity, site-of-service review, and coverage criteria for specified intravenous, injectable, and oral therapies used to treat rare (often genetic) diseases; applies to providers requesting review for Premera members.
Policy Summary
PayerPremera Bluecross
PolicyDrugs for Rare Diseases (Pharmacy/Medical policy)
Policy CodePolicy N/A
Change TypeAdded and revised coverage criteria (multiple updates)
Effective DateJul 2, 202618d
Next Review DateN/A
Key ActionSubmit prior authorization with diagnostic confirmation, relevant genetic or biochemical testing, baseline labs and trial-of-therapy documentation as specified for the requested agent.
Added Background on thymidine kinase 2 deficiency (TK2d) and Summary of Evidence for Kygevvi (doxecitine and doxribtimine).
Added summary of pivotal trials and safety monitoring requirements for Aqvesme (mitapivat).
Multiple annual updates through 2019–2026 added or modified coverage criteria for many rare-disease therapies (examples: age indication changes, added drugs, site-of-service clarifications).
Added coverage for Bylvay for cholestatic pruritus in individuals 12 months and older with Alagille Syndrome (ALGS).
Updated Livmarli (maralixibat) PFIC coverage age requirement from 5 years or older to 12 months or older.
Added coverage criteria for Rivfloza (nedosiran) for primary hyperoxaluria type 1 and later updated management age from 9 years to 2 years.
Updated multiple products to preferred status and adjusted dosing/quantity limits (e.g., Lumizyme, Nexviazyme, Pombiliti; dichlorphenamide quantity limit).
Added site-of-service reviews for specific drugs (e.g., Tepezza, Givlaari, Givlaari site-of-service review effective July 2, 2026).
~30+
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Crysvita (burosumab) — pediatric and adult evidence summary and coverage criteria
ALL of the following
The individual is aged 6 months or older for XLH treatment; aged 2 years or older for TIO treatmentage
Diagnosed with X-linked hypophosphatemia (XLH) confirmed by radiographic evidence of rickets or osteomalacia or genetic test confirming PHEX mutation (for XLH)
radiographic or genetic confirmation required
TIO specific: For tumor-induced osteomalacia (TIO): tumor cannot be curatively resected or localized and individual is aged 2 years or older
Evidence summary: Evidence: pediatric Phase 2 trials (n=65) showed significant improvements in rickets severity scores (RSS) and radiographic global impression of change (RGI-C); adults Phase 3 trial (n=134) demonstrated normalization of serum phosphate in majority and improvements in fracture healing and physical function
Authorization: Initial approval may be up to 12 months; re-authorization up to 12 months if clinical benefit (improved radiographic or symptom measures) is documented
Vimizim (elosulfase alfa)
Vimizim (elosulfase alfa) — MPS IVA evidence and coverage criteria
ALL of the following
The individual is aged 5 years or olderage
Diagnosed with mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome)
clinical/genetic confirmation
Evidence summary: Evidence: randomized, double-blind, placebo-controlled trial (n=176) showed a 20-meter improvement in 6-minute walk test at Week 24 for weekly dosing vs placebo (p=0.02)
Safety: Vimizim carries boxed warning for life-threatening anaphylactic reactions; monitor during infusions and have resuscitation measures available
Keveyis (dichlorphenamide)
Keveyis (dichlorphenamide) — primary periodic paralysis evidence and coverage criteria
ALL of the following
The individual is aged 18 years or olderage
Diagnosed with primary hyperkalemic or hypokalemic periodic paralysis
clinical diagnosis
Attack frequency: Documentation of distinct regular episodes of weakness with an average frequency of at least 1 per week
TSH requirement: Normal thyroid-stimulating hormone (TSH) level
Dojolvi (triheptanoin)
Dojolvi (triheptanoin) — LC-FAOD evidence and coverage criteria
Prior therapy: Tried and failed or had intolerance to over-the-counter medium-chain triglyceride (MCT) oil unless contraindicated
Laboratory: Elevated mean creatine kinase (CK) >2x ULN matched by age/gender OR >500 units/L>2x ULN or >500 U/L
Healthcare utilization: For individuals ≥7 years, documentation of at least 4 ED visits or hospitalizations related to disease severity in the last 2 years
Imcivree (setmelanotide)
Imcivree (setmelanotide) — POMC and LEPR deficiency (and BBS) evidence and coverage criteria
ALL of the following
The individual is aged 2 years or olderage
Genetic confirmation: Obesity due to pathogenic or likely pathogenic variants (or VUS in context) in POMC, PCSK1, or LEPR confirmed by genetic testing
Weight criteria: Baseline weight criteria: BMI ≥35 kg/m2 for adults; ≥95th percentile for ages 6–17 for POMC/PCSK1/LEPR indications; for Bardet-Biedl syndrome (BBS) indication: age ≥2 years and ≥97th percentile for 6–17-year-olds
Dose and prescriber: Dose limited to 3 mg once daily; prescribed by or in consultation with geneticist or endocrinologist
Rivfloza (nedosiran)
Rivfloza (nedosiran) — PH1/PH2 evidence and coverage criteria
ALL of the following
The individual is aged 2 years or olderage
Diagnosis and renal function: Diagnosed with primary hyperoxaluria type 1 (PH1) with AGXT mutation (PH2 included per evidence) and has eGFR ≥30 mL/min/1.73 m2
Oxalate thresholds: Has 24-hour urinary oxalate (UOx) excretion ≥0.7 mmol/24hr/1.73m2 OR plasma oxalate (POx) ≥20 µmol/L
Dosing and transplant exclusion: Maintenance dose limits by age/weight per product labeling (dosing tiers for pediatric and adult weights) and no prior liver or kidney transplant
Miplyffa (arimoclomol)
Miplyffa (arimoclomol) — coverage considerations and evidence summary
ALL of the following
The individual is aged 2 years or olderage
Diagnosis and clinical status: Diagnosis of Niemann-Pick disease type C (NPC) confirmed by genetic testing (NPC1 or NPC2) per policy wording; one or more neurologic signs present; able to ambulate independently or assisted
Concomitant therapy requirements: Miplyffa must be used in combination with miglustat; not to be used with Aqneursa (levacetylleucine)
Prescriber and dosing: Prescribed by or in consultation with a pediatric neurologist, movement disorder specialist, or clinical geneticist; dosing based on weight per labeling
Kygevvi (doxecitine and doxribtimine)
Kygevvi (doxecitine and doxribtimine) — coverage considerations and evidence summary
ALL of the following
Diagnosis of thymidine kinase 2 deficiency (TK2d) confirmed by genetic testing detecting TK2 variants
Phenotype documentation: Documentation of symptom onset at age ≤12 years consistent with childhood-onset TK2d (e.g., hypotonia, limb weakness, feeding or breathing difficulties) as required by policy
Exclusions and prescriber: No other genetic, polygenic, or inborn errors of metabolism present; prescribed by or in consultation with a neurologist; dosing limited per labeling (up to 800 mg/kg/day)
Evidence summary: Evidence: single Phase II study, retrospective cohorts, and expanded access data (total N ~82) showed improved survival compared with matched external controls (approximate 86% reduction in risk of death); most common AEs GI and transaminase elevations
Zycubo (copper histidinate)
Zycubo (copper histidinate) — Menkes disease evidence and coverage considerations
ALL of the following
Indication limited to pediatric individuals less than 17 years of age with Menkes diseaseage
Diagnosis: Presence of neurological symptoms and clinical findings suggestive of Menkes disease and diagnostic confirmation by genetic testing (ATP7A variants) or characteristic low serum copper and ceruloplasmin
Timing and dosing: Initiation by 6 weeks of age (corrected for prematurity) preferred per criteria; dosing based on age (younger than 1 year: 1.45 mg twice daily; 1–16 years: 1.45 mg once daily)
Evidence summary:
Sohonos (palovarotene)
Sohonos (palovarotene) — FOP evidence and coverage considerations
ALL of the following
Age and genetic requirement: The individual is a female aged ≥8 years or male aged ≥10 years and has documented ACVR1 R206H mutation confirmed by genetic testing
Reproductive safety: For individuals of reproductive potential: attestation NOT pregnant and informed about contraception 1 month prior, during, and 1 month after therapy
Evidence summary: Evidence: MOVE single-arm phase 3 study (n=107) interim results showed 62% reduction in mean annualized new heterotopic ossification volume versus natural history; supported by phase 2 randomized data though some endpoints limited by short duration
Authorization:
Xolremdi (mavorixafor)
Xolremdi (mavorixafor) — WHIM syndrome evidence and coverage considerations
ALL of the following
The individual is aged 12 years or olderage
Genetic confirmation: Diagnosis of WHIM syndrome confirmed by pathogenic or likely pathogenic CXCR4 variants
Laboratory, dosing, prescriber: Absolute neutrophil count (ANC) ≤400 cells/µL and symptomatic disease; dosing limited to 400 mg daily and prescribed by or in consultation with immunologist or hematologist
Evidence summary: Evidence: Phase 3 4WHIM randomized trial (n=31) demonstrated increased time above ANC and ALC thresholds and ~60% reduction in annualized infection rate; common AEs include thrombocytopenia and rash
Evidence summaries and safety/monitoring
Evidence summaries and safety/monitoring criteria (selected agents)
ANY of the following
Infusion safety: Monitor infusion-related reactions for IV enzyme replacement therapies (e.g., Fabrazyme, Vimizim, Lumizyme, Elfabrio, Xenpozyme) and have emergency management available
Boxed warnings: For agents with boxed warnings for anaphylaxis (e.g., Vimizim, Elaprase), require monitoring during and after infusion and document in chart notes
Hepatic monitoring: For therapies with hepatic risk (e.g., Aqvesme), implement REMS-required liver test monitoring at baseline and periodic intervals per labeling
Pediatric monitoring: For agents affecting growth plates or with pediatric growth concerns (e.g., Sohonos, Voxzogo), document growth plate status, monitor growth velocity and bone age as appropriate
Policy additions and updates (historical)
Policy additions and updates (historical changelog highlights)
At least 1 of the following
03/01/18: New policy effective June 1, 2018; site-of-service review added
Initial policy creation
11/01/20: Added Keveyis (dichlorphenamide) for primary periodic paralysis
Policy expansion
12/01/20–03/01/21: Added Dojolvi, Zokinvy, Oxlumo, Imcivree and others across 2020–2021 updates
Therapies added
07/01/23: Added Elfabrio coverage criteria and updated Fabrazyme/Galafold concurrency language
Fabry updates
Appendix coverage updates
Appendix coverage updates — selected entries and effective actions
ALL of the following
Recent additions: 11/01/24: Added Sohonos (palovarotene) coverage for FOP; 12/01/23: Added Cystadane and generic betaine for homocystinuria
Policy indicates for late-onset Pompe disease and similar conditions that documentation of a prior trial of ERT and inadequate response is required before approving alternative regimens (e.g., Pombiliti+Opfolda pathway requires baseline FEV1 30%–85% and inability to complete 6MWT ≥75 m despite current ERT).
Document inadequate response to prior ERT
Provide baseline FEV1 and 6MWT showing values despite current ERT (FEV1 30%–85% predicted and unable to complete 6MWT ≥75 meters) to support switch to alternative ERT/regimen; initial approval windows described (up to 12 months).
Requirement
Examples / Policy language
Prior trial of listed agents required unless contraindicated
Several drug sections require trial of specified alternatives or generics (e.g., Cystadane requires prior trial of generic betaine anhydrous; Dojolvi requires trial of OTC MCT oil unless contraindicated; Keveyis requires prior acetazolamide/generic dichlorphenamide trial).
Document trial outcome or intolerance
Prior trial must be documented with inadequate response or intolerance to support initiation of the requested agent; policy states 'tried and failed or had intolerance' language for many agents.
Requirement
Policy examples
Required prior or concomitant therapies
For PFIC/ALGS pruritus (Bylvay/Livmarli) policy requires trial of ursodiol and one of cholestyramine or rifampin prior to approval; for Enjaymo a prior rituximab trial is required unless contraindicated.
Concurrent use when specified
Some approvals require concomitant use (e.g., Pombiliti must be used concurrently with Opfolda per the Pombiliti+Opfolda pathway).
Requirement
Policy language / Rationale
Prior complement inhibitor therapy required
Voydeya (danicopan) coverage requires completion of at least 6 months of therapy with Soliris (eculizumab) or Ultomiris (ravulizumab) prior to initiation, and Voydeya is prescribed in combination with those complement inhibitors.
Requirement
Policy detail
Concomitant use required (Miplyffa + miglustat)
Policy states Miplyffa is approved only when used in combination with miglustat; prescribing information notes insufficient data for Miplyffa without miglustat. Requests must document concomitant miglustat use.
Concomitant/combo prohibitions
Policy also specifies Miplyffa must not be used in combination with Aqneursa; generic miglustat criteria specify use in combination with Miplyffa per NPC criteria.
Requirement
Policy guidance
Prior enzyme replacement therapy documentation for switching
Elfabrio trials and policy contexts included switch-over designs from other ERTs; policy may require documentation of prior ERT and rationale for switching though explicit universal step rules are not detailed in the excerpt. Chart notes and prior-therapy history should be provided.
Consideration
Policy note
Consider prior alglucosidase alfa when evaluating Pombiliti+Opfolda
Pombiliti+Opfolda pathway was studied versus alglucosidase alfa; policy indicates consideration of prior treatment history with alglucosidase alfa when evaluating use of Pombiliti+Opfolda. Baseline FEV1 and 6MWT while on current ERT support decision.
Consideration
Policy detail
Consider prior conventional therapy for XLH before biologic therapy
Policy describes oral phosphate plus calcitriol as standard care in children and notes documentation of prior or intolerance to conventional therapy may be pertinent when considering burosumab (Crysvita); normalization of serum phosphate is not the treatment goal. Providers should document prior therapy and rationale for switching.
Consideration
Policy reference
Consider prior hydroxyurea / best available therapy (BAT) before Besremi
PROUD-PV comparative data and extension results are referenced; policy notes consideration of prior hydroxyurea or BAT when evaluating Besremi (ropeginterferon alfa-2b) based on clinical judgment and trial context.
Requirement
Evidence / Policy language
Require documentation of concomitant miglustat use with Miplyffa
Prescribing information and policy state Miplyffa efficacy was demonstrated with background miglustat; requests must document concomitant miglustat use prior to or concurrent with Miplyffa.
Requirement
Policy instruction
General step therapy requirements
The policy includes step therapy requirements for some drugs; providers should refer to the specific drug sections for drug-specific prior-trial or concomitant therapy rules and applicable benefit routing. Prior trials, intolerances, or contraindications must be documented.
Requirement (historical)
Policy note
Historical step therapy sequencing required for amifampridine products
Policy history documents prior trial sequencing requirements for amifampridine products (e.g., Ruzurgi/Firdapse) historically; note that market changes removed some products and historical sequencing may no longer apply. Refer to current drug-specific criteria.
Requirement
Action
Follow drug-specific criteria and applicable benefit assignment
Coverage and step requirements vary by agent and may depend on medical vs pharmacy benefit routing; providers must follow the specific drug coverage criteria and route prior authorization to the appropriate benefit as indicated in the policy and coding sections.
Billing Codes and Coding Updates
Covered HCPCS / J-codes (selected)HCPCSCovered
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 (Opfolda with Pombiliti).
Unclassified biologics (Use to report: Cablivi, Besremi, Imcivree, Revcovi, and Voxzogo).
1–10 of 11
1/2
Covered HCPCS/J Codes (partial list)HCPCSCovered
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 (Opfolda with Pombiliti).
HCPCS code previously used for Adakveo; removed in 2024
J1202
HCPCS code added (April 2024 update)
J1203
HCPCS code added (April 2024 update)
J1302
HCPCS code added for Adakveo
J2998
HCPCS code added
1–10 of 25
1/3
HCPCS/J-code updatesHCPCS
G0138
New HCPCS code added
J1202
New HCPCS code added
J1203
New HCPCS code added
J0791
Removed from this policy and moved to policy 5.01.640
C9090
Removed effective 7/1/2022; see J2998
J3590
Unlisted HCPCS; drug names added (e.g., Rivfloza, Nexviazyme)
J3490
Added for Rivfloza
J1809
Added for Nulibry
J0219
Referenced for Nexviazyme naming
inv-102: FEV1 (forced expiratory volume in 1 second) threshold
FEV1 thresholdBetween 30% and 85% predicted (baseline FEV1 required for Pombiliti+Opfolda pathway)
Test contextBaseline FEV1 documented despite current ERT (Nexviazyme or Lumizyme)
PurposeUsed to establish eligibility for Pombiliti (cipaglucosidase alfa-atga) plus Opfolda
inv-103: 6-Minute Walk Test (6MWT) threshold
6MWT thresholdUnable to complete a 6-minute walk test (6MWT) of at least 75 meters despite current ERT
Prior Authorization, Documentation, and Denial Risks
Prior Authorization
Prior authorization and site-of-service review
Prior authorization is required for many drugs listed in this policy. In addition to drug-specific medical necessity review, intravenous and injectable therapies may be subject to a Site-of-Service (SOS) medical necessity review for individuals aged 13 years and older; SOS review does NOT apply to Alaska fully‑insured members. Contact Customer Service for benefit routing questions (medical vs pharmacy).
Site-of-Service review applies to administration locations (hospital outpatient, infusion center, physician office, home) for individuals ≥13 years, except Alaska fully-insured members.
Pharmacy vs Medical benefit routing is specified in the policy (see managed lists); some agents are pharmacy-managed, some medical, and some both.
Non-formulary exception authorizations may be approved up to 12 months.
Prior Authorization
Drug-specific prior authorization
Many agents in this policy require drug-specific prior authorization and will be reviewed against the listed coverage criteria (diagnosis confirmation, age, prescriber specialty, concomitant therapy restrictions, dosing limits, and trial/failure requirements). Initial approvals are typically limited (commonly 6–12 months) with re-authorization dependent on documented clinical response and required follow-up testing.
Categorize intended administration location according to policy site‑of‑care categories (home, office, infusion center, hospital outpatient) and document why the chosen site meets medical‑necessity criteria if SOS review applies.
Hospital outpatient setting is medically necessary for the first 90 days or when no home/infusion center is available within 50 miles, or when clinical risk requires hospital setting.
Note
Drugs subject to site‑of‑service review (examples)
When a drug is subject to site‑of‑service review (examples listed in the policy), document the recommended administration setting and supporting clinical rationale (safety monitoring needs, infusion‑reaction risk, vascular access issues).
Examples of drugs commonly subject to SOS review include Aldurazyme, Elaprase, Crysvita, Vimizim, Naglazyme, Mepsevii, and Givlaari.
Note
Clinical Background and Definitions
Background: many rare genetic disorders in this policy (for example, thymidine kinase 2 deficiency) are caused by enzyme or mitochondrial defects leading to progressive organ dysfunction. TK2 deficiency is a mitochondrial myopathy with variable age of onset and progression; policy background notes the clinical phenotypes, typical age‑onset distributions, and the rationale for nucleoside replacement therapy to restore mtDNA replication and function.
ERT definitionEnzyme replacement therapy (ERT): treatment that provides functional enzyme to replace a deficient lysosomal enzyme to reduce substrate accumulation and restore cellular function
ScopePrimary treatment modality for many lysosomal storage diseases referenced in policy
Clinical useOften requires genetic or enzyme testing to confirm appropriateness
inv-177: Site of Service (SOS) definition
Site of Service (SOS)
Policy Change Log
2018-03-01policy_created
New Drugs for Rare Diseases policy approved Feb 13, 2018 and effective June 1, 2018; initial set of drugs added with site-of-service review noted.
Added Oxbryta, Adakveo, Givlaari, and Gattex to policy; HCPCS codes C9053/C9056 and later adjustments to J0791 and J0223 documented.
Policy Summary
PayerPremera Bluecross
PolicyDrugs for Rare Diseases (Pharmacy/Medical policy)
Policy CodePolicy N/A
Change TypeAdded and revised coverage criteria (multiple updates)
Effective DateJul 2, 202618d
Next Review DateN/A
Key ActionSubmit prior authorization with diagnostic confirmation, relevant genetic or biochemical testing, baseline labs and trial-of-therapy documentation as specified for the requested agent.
Authorization: Initial approval may be up to 12 months; re-authorization up to 12 months if clinical response or stability is documented in chart notes
Prior therapy requirement: Prior therapy with acetazolamide was ineffective, not tolerated, or contraindicated; has tried generic dichlorphenamide or Ormalvi and had inadequate response or intolerance to dichlorphenamide
Dose limited to 200 mg daily (4 tablets daily)
Evidence and authorization: Evidence: randomized 9-week Phase III trial and 52-week extension showed improvement in median weekly attack rate and severity-weighted attack rate; initial approval up to 3 months, re-authorization up to 12 months with documented benefit
Dietary management: Provider attestation that the individual is on a low-fat/high-carbohydrate diet
Evidence summary: Evidence: Phase 2 randomized trial vs trioctanoin showed cardiac mass and function improvements; supportive single-arm and extension studies available but with limitations; common AEs GI-related and SAEs often related to intercurrent illness
Authorization: Initial authorization may be up to 12 months; re-authorization up to 12 months with documented clinical response
Evidence and safety: Evidence: Phase 3 trials in POMC and LEPR deficiency met primary endpoints (≥10% weight loss), with substantial mean weight loss; common AEs include injection site reactions, hyperpigmentation, GI symptoms; suicidal ideation/behavior observed in some patients requiring monitoring
Authorization: Initial approval up to 6 months for POMC/PCSK1/LEPR; up to 12 months for BBS; re-authorization up to 12 months if weight loss criteria met (adults ≥5% baseline; pediatrics positive response) and chart notes document benefit
Evidence summary: Evidence: PHYOX2 Phase 2 randomized trial showed significant reductions in 24-hour urinary oxalate versus placebo (between-group difference ~49% overall; 56% in PH1 subgroup). Injection site reactions were the most common AE; extension data indicate maintained reductions
Authorization: Initial authorization up to 6 months; re-authorization up to 12 months if urinary or plasma oxalate levels decrease from baseline and patient is tolerating therapy
Evidence summary: Evidence: randomized, double-blind, placebo-controlled 12-month trial showed benefit on the rescored 4-domain NPC Clinical Severity Scale when Miplyffa was combined with miglustat (0.2-point decrease vs 1.9-point increase on placebo+ miglustat); limited data on monotherapy efficacy
Authorization: Initial approval up to 12 months; re-authorization up to 12 months if clinical stabilization or improvement documented (ambulation, fine motor, swallowing, speech)
Authorization: Initial approval up to 12 months; re-authorization up to 12 months with documentation of clinical benefit (survival, functional improvement) and tolerability
Evidence: two open-label single-arm trials compared treated cohort to contemporaneous external controls and demonstrated substantial survival benefit (78% reduction in risk of death) and long-term survival in treated cohort; SAEs reported include infections and respiratory events
Authorization: Initial approval may be up to 6 months; re-authorization up to 12 months if clinical benefit and tolerability documented
Initial approval up to 12 months; re-authorization up to 12 months with documentation of reduced new HO volume or clinical benefit
Safety monitoring: Note safety considerations: palovarotene associated with growth plate effects — monitor pediatric growth and bone age per labeling
Authorization: Initial authorization up to 12 months; re-authorization up to 12 months with demonstrated sustained improvement in neutrophil/lymphocyte counts and reduction in infections
Prescriber requirement: For Xolremdi, Kygevvi, and other genetic-targeted therapies, require prescriber specialty (neurology, geneticist, hematology, immunology) per product-specific criteria
01/01/24: Added Rivfloza coverage criteria for PH1
PH1 update
03/01/26: Added Kygevvi and Aqvesme coverage criteria; effective July 2, 2026 site-of-service update for Givlaari
Most recent additions
Coding history: 03/01/24 & ongoing: Coding updates and HCPCS additions/changes documented — see full appendix for code histories and effective dates
Test context
Baseline 6MWT documented despite current enzyme replacement therapy
PurposeUsed to support eligibility for Pombiliti+Opfolda in late-onset Pompe disease
inv-104: GFR threshold
GFR thresholdGreater than or equal to 30 mL/min/1.73 m2 required for Galafold initiation (and referenced for rivfloza/lumasiran trial inclusion)
Clinical useDocumented recent GFR used to determine eligibility for Galafold and for some PH1 trial-based criteria
PurposeEnsure sufficient renal function for drug use and trial applicability
inv-105: Albumin-adjusted serum calcium threshold
Albumin-adjusted serum calciumAt least 7.8 mg/dL required for Yorvipath initiation
Associated requirementsAlso requires normal serum 25(OH) vitamin D and concurrent calcium/vitamin D therapy
PrescriberPrescribed by or in consultation with an endocrinologist
inv-106: Creatine kinase (CK) threshold
Creatine kinase (CK) thresholdElevated mean CK >2x upper limit of normal matched by age/gender OR >500 units/L
ContextRequired for Dojolvi (triheptanoin) eligibility in LC-FAOD
ReferenceSee Appendix pediatric CK reference ranges for age/sex-specific ULN
inv-107: Porphyria biomarkers requirement
Porphyria biomarker requirementElevated urinary or plasma porphobilinogen (PBG) or aminolevulinic acid (ALA) greater than the upper limit of normal at diagnosis
Genetic confirmationGenetic testing confirming mutation in an AHP-related gene (ALAD, CPOX, HMBS, or PPOX) is also required
PurposeSupports Givlaari (givosiran) medical necessity for acute hepatic porphyria
inv-108: Oxlumo maintenance dosing by weight
Oxlumo maintenance dosing (weight-based)<10 kg: 3 mg/kg once monthly; 10 to <20 kg: 6 mg/kg once every 3 months; ≥20 kg: 3 mg/kg once every 3 months (maintenance begins 1 month after last loading dose)
Initiation contextMaintenance dosing specified to begin 1 month after loading dosing per policy
PrescriberPrescribed by or in consultation with nephrologist, urologist, or geneticist
inv-109: Hemangeol dosing
Hemangeol dosingDose limited to 1.7 mg/kg twice daily for proliferating infantile hemangioma
Initial approvalInitial therapy may be approved up to 12 months; re-authorization requires documentation of tolerability and response
Tepezza Clinical Activity Score (CAS) requirementDocumented Clinical Activity Score (CAS) of at least 4 is required for Tepezza initiation
Additional requirementsEuthyroid or near-euthyroid thyroid function and prior glucocorticoid trial unless contraindicated; contraception for reproductive potential
PrescriberPrescribed by or in consultation with an ophthalmologist or endocrinologist
inv-111: 24-hour urinary oxalate (UOx) threshold
24-hour urinary oxalate (UOx) thresholdAt least 0.7 mmol/24 hr/1.73 m2 required for Oxlumo or Rivfloza consideration
Pediatric alternativeFor ≤5 years of age, an elevated spot UOx/creatinine ratio above age-specific ULN may be used
PurposeDiagnostic/eligibility criterion for primary hyperoxaluria type 1 therapies
Use alongside UOxPOx may be used when 24-hour UOx not available or in advanced renal impairment
PurposeUsed for Oxlumo and Rivfloza eligibility and monitoring
inv-113: Hemoglobin thresholds for anemia indications
Hemoglobin thresholdsHemoglobin thresholds for anemia indications are generally ≤10.0 to ≤10.5 g/dL depending on the drug (examples: Enjaymo ≤10.0 g/dL; Pyrukynd ≤10.0 g/dL)
ContextUsed to document severity for eligibility (e.g., PKD, CAD, thalassemia indications)
PrescriberTypically prescribed by or in consultation with a hematologist for anemia indications
inv-114: DLCO (adult ASMD) threshold
DLCO threshold (adult ASMD)DLCO less than or equal to 70% predicted (for individuals ≥18 years) required for Xenpozyme eligibility
Diagnostic confirmationASMD confirmation via biochemical enzyme assay and SMPD1 gene sequencing also required
Dose limitMaintenance dose limited to 3 mg/kg every 2 weeks
inv-115: PNH clone size threshold
PNH clone size thresholdGranulocyte or monocyte clone size of at least 15% required to confirm PNH diagnosis for Voydeya consideration
Additional requirementsCompleted ≥6 months of Soliris or Ultomiris and residual anemia (Hgb <10.5 g/dL) with LDH ≥1.5x ULN
PrescriberPrescribed by or in consultation with a hematologist
inv-116: Enjaymo hemoglobin threshold
Enjaymo hemoglobin thresholdHemoglobin less than or equal to 10.0 g/dL required for Enjaymo initiation in CAD
Other criteriaTried and failed rituximab unless contraindicated; not used in combination with rituximab; vaccination requirements prior to initiation
PrescriberPrescribed by or in consultation with a hematologist
inv-117: DLCO threshold for ASMD adults
DLCO threshold for ASMD adultsDLCO ≤ 70% predicted required for adult ASMD patients to be considered for Xenpozyme
Diagnostic confirmationRequires ASMD biochemical enzyme assay and SMPD1 gene sequencing
Dose limitMaintenance dose 3 mg/kg every 2 weeks
inv-118: Minimum weight for Aqneursa use
Minimum weight for Aqneursa useIndividual must weigh at least 15 kg (and be aged ≥4 years) for Aqneursa initiation
DiagnosisNPC1 or NPC2 confirmed by genetic testing (or genotype plus supportive testing) required
Concomitant useAqneursa must not be used concomitantly with Miplyffa
inv-119: Antigenic levels of α 1-PI
Antigenic levels of α1-PIMaintenance of blood serum α1-PI levels above 11 µM considered therapeutically relevant
ContextThreshold used in defining therapeutic goals for α1-PI replacement
ReferenceDefined in policy definitions / term list
inv-120: Serum phosphorus lower limit of normal
Serum phosphorus lower limitLower limit of normal referenced as 2.5 mg/dL (used in burosumab studies/endpoints)
Clinical relevanceProportion achieving serum phosphorus >2.5 mg/dL was a trial primary endpoint for Crysvita in adults
CautionNormalization of serum phosphate is not the treatment goal in XLH and may represent overtreatment
inv-121: Normal 24-hour urinary oxalate (BSA-corrected)
Normal 24-hour UOx (BSA-corrected)Normal defined as ≤0.514 mmol/24 hr/1.73 m2 (ILLUMINATE-A trial benchmark)
Clinical useUsed to define achievement of normal UOx in lumasiran trials and as an efficacy target
PurposeHelps determine biochemical response to Oxlumo
inv-122: Creatine kinase pediatric reference
Creatine kinase pediatric referenceAge- and sex-specific CK reference ranges as listed in Appendix Table 1 (e.g., 0–90 days male 28–300 U/L; 15–18 years male 33–145 U/L)
UseReferenced to interpret CK thresholds for LC-FAOD eligibility (e.g., >2x ULN)
LocationAppendix Table 1 of policy provides full ranges
Initial approval durations vary by drug (e.g., 6 months for some agents, up to 12 months for most listed therapies).
Re-authorization requires documentation of continued clinical benefit as defined in each drug's criteria.
Prescriber specialty requirements are specified for certain agents (e.g., nephrologist/geneticist for Oxlumo/Rivfloza; hematologist/hepatologist for Givlaari).
Prior Authorization
Agent-specific prior authorization required
Agent-specific prior authorization is required for individual drugs and may include unique requirements such as REMS monitoring (e.g., Aqvesme), combination‑use restrictions, or limited dosing schedules. Verify the agent’s managed benefit (medical, pharmacy, or both) before submitting authorization requests.
Aqvesme (mitapivat) requires REMS liver monitoring and baseline/periodic LFTs per label.
Some drugs are pharmacy benefit only, medical benefit only, or managed under both — confirm benefit routing prior to authorization.
Combination restrictions: many agents are not to be used concurrently with other listed therapies (see each drug's criteria).
Prior Authorization
Confirm diagnosis and indication for prior authorization
Prior authorization requests must confirm the diagnosis and the specific FDA‑labeled indication (or permitted off-label criteria) for which the drug is requested. Genetic or laboratory confirmation is required where specified.
Diagnosis confirmation examples: Givlaari — genetic testing confirming mutation in relevant porphyria genes plus elevated ALA/PBG; Pompe disease agents — documented GAA enzyme deficiency OR genetic testing with ≥1 GAA mutation.
Primary hyperoxaluria agents require genetic mutation documentation (AGXT for Oxlumo/Rivfloza) or liver biopsy evidence when listed.
For rare metabolic/genetic diseases, genetic confirmation (pathogenic/likely pathogenic variants) is often mandatory.
Documentation Required
Genetic confirmation and study-based efficacy documentation
When approval hinges on genetic confirmation or study-based efficacy, provide the genetic test report and relevant clinical trial endpoints or measures demonstrating expected benefit (e.g., survival, biomarker reduction, functional tests).
Kygevvi (TK2d) approvals require genetic confirmation of TK2 deficiency and supporting evidence of benefit (survival or functional outcomes from published studies/registries).
Nulibry (MoCD Type A) required genetic confirmation and survival/efficacy data from the studies used for approval.
Oxlumo and Rivfloza require mutation confirmation in AGXT (PH1) and documentation of urinary/plasma oxalate reductions from baseline.
Prior Authorization
Site-of-Service applicability
Site-of-Service review applies to medical benefit administrations for individuals aged 13 and older (see age exceptions). Pediatric considerations may exempt younger individuals from SOS review. Alaska fully‑insured members are exempt from SOS medical necessity review.
SOS review threshold: age ≥13 years for medical necessity SOS review.
Alaska fully-insured members: SOS medical necessity criteria do not apply (follow infusion/injection drug medical necessity criteria only).
Certain clinical exceptions to SOS rules (for example, cytokine release syndrome treatments) are noted in the policy; review the policy appendix/updates for details.
Denial may result when required diagnostic tests, laboratory values, or specialist involvement are missing or insufficient. Ensure documentation addresses all listed criteria before submission.
Common denial triggers include absence of required genetic testing, missing baseline labs (e.g., urinary oxalate, PBG/ALA, GAA enzyme levels), or lack of specialist prescriber/consultation when required.
Concurrent use of contraindicated therapies (e.g., agents listed as not to be used together) can lead to denial.
Age or dosing outside specified limits and failure to document prior therapy/step requirements are frequent denial reasons.
Denial Risk
General re-authorization risk
Re-authorization carries general risk of denial if ongoing documentation of benefit or required monitoring is not provided. Provide the specified efficacy measures and evidence of tolerance at each renewal.
Re-authorization typically requires chart notes documenting clinical response, stability/improvement in disease‑specific measures (e.g., 6MWT, FEV1, lab biomarkers), and adherence to dosing/monitoring schedules.
Failure to show positive clinical response or to submit required follow-up tests can result in non-renewal.
Most authorizations are granted for up to 12 months when re-authorization criteria are met.
Denial Risk
Age-based site-of-service denial risk
Age-based site-of-service denials are possible when SOS review criteria are applied to individuals younger than policy-specified thresholds (e.g., SOS applies only to age ≥13). Verify age-based rules before requesting SOS exceptions.
SOS medical necessity review is limited to individuals aged 13 and older due to pediatric care considerations.
Requests for SOS exceptions for younger pediatric individuals should reference the policy's pediatric guidance and may require specialty justification.
Alaska fully-insured members are not subject to SOS medical necessity review regardless of age.
Documentation Required
Clinical baseline and follow-up documentation
Provide clear clinical baseline and follow-up documentation with initial and renewal requests. Baseline measures and the specific follow-up metrics required vary by drug and indication.
Examples of baseline documentation: Pompe disease — baseline FEV1 and 6MWT; PH1 agents — baseline 24‑hour urinary oxalate or spot UOx/Cr and plasma oxalate; Givlaari — baseline urinary/plasma ALA or PBG levels.
Follow-up documentation: objective evidence of improvement or stabilization (e.g., decreased urinary oxalate, improved 6MWT/FVC, reduced attack frequency for porphyria).
Include dates, numeric lab values with reference ranges, and comparison to prior results where applicable.
Documentation Required
Required clinical documentation for prior authorization (re-authorization)
Re-authorization requests must include the specific clinical data listed in each drug's re-authorization criteria (objective measures of benefit, monitoring labs, and documentation of tolerability).
Provide chart notes showing sustained clinical response and the objective endpoints specified (e.g., improvement/stability in functional tests, biomarker reductions, reduced transfusion requirements).
Include recent labs, specialist progress notes, and any adverse event documentation relevant to ongoing therapy.
For agents with safety programs (REMS) or required monitoring (e.g., Aqvesme liver labs), include evidence of adherence to monitoring schedules.
Step Therapy
Step or prior-therapy considerations
Step therapy or prior‑therapy requirements apply to selected agents; provide documented trials and reasons for failure/intolerance when required by the drug criteria.
Examples: Some agents require prior trial of generic or older agents (e.g., trial of generic betaine anhydrous before Cystadane approval; trial of dichlorphenamide before brand formulations for periodic paralysis).
For Pombiliti + Opfolda, baseline failure or insufficient response to prior ERTs may be required depending on the criteria.
Document treatment duration, dose, and objective evidence of inadequate response or intolerance.
Billing Rule
Site-of-service / step edits and benefit routing
Site‑of‑service edits and step edits may interact; verify both SOS applicability and any step therapy rules when submitting authorization. Note policy exceptions (e.g., Alaska, CRS) and recent updates affecting SOS or step edits.
Some therapies are subject to both SOS review and step/sequence requirements — ensure both sets of criteria are documented.
Policy updates (see Appendix) list additions to SOS review (e.g., Tepezza, Givlaari) and should be checked for effective dates.
Provider notification periods and effective dates for changes are documented in the Appendix — confirm the policy version/effective date for applicability.
Prescriber
Prescribed by or in consultation with a hematologist
Oxlumo maintenance dosing (policy ref)Maintenance dosing is weight-based per table: <10 kg 3 mg/kg monthly; 10–<20 kg 6 mg/kg q3 months; ≥20 kg 3 mg/kg q3 months
Quantity limit notePolicy references weight-based maintenance dosing for Oxlumo as the quantity limit basis
Initiation timingMaintenance begins 1 month after last loading dose
inv-251: Rivfloza / Oxlumo dosing limits
Rivfloza / Oxlumo dosing limitsPolicy specifies age/weight-based maintenance dosing limits for Rivfloza and weight-based maintenance dosing for Oxlumo per tables in policy
Rivfloza exampleE.g., aged ≥12 yrs & ≥50 kg: 160 mg once monthly; other age/weight bands specified in policy
PurposeUsed to set quantity limits and verify appropriate prescribing
inv-252: Voydeya (danicopan) quantity limit
Voydeya quantity limitDose limited to 600 mg daily for Voydeya (danicopan)
Use conditionsRequires prior ≥6 months Soliris/Ultomiris and residual anemia/LDH criteria; prescribed with complement inhibitor
PrescriberPrescribed by or in consultation with a hematologist
inv-253: Voxzogo (vosoritide) quantity limit
Voxzogo quantity/dosingWeight-band specific once-daily dosing (examples: 10-11 kg 0.24 mg; up to 60-89 kg 0.7 mg once daily)
ContextDose prescribed must match actual body weight band per policy
AuthorizationInitial therapy and re-authorization criteria reference growth velocity and open epiphyses
Keveyis / Ormalvi quantity limits updatedPolicy updated quantity limits for dichlorphenamide (Keveyis) and added Ormalvi; specific limits described in drug-specific criteria (e.g., 200 mg daily)
ImplementationChanges reflected in Appendix coding/quantity updates effective per history entries
Step requirementPrior generic dichlorphenamide trial documentation may be required for brand alternatives
Livmarli quantity limits clarifiedPolicy clarifies quantity limits and subgroup exclusions for maralixibat (Livmarli)
Age expansionHistory notes age requirement updated previously (to 12 months or older) and quantity clarifications added
Clinical noteRefer to Livmarli drug-specific section for exact dosing bands and exclusions
Kanuma IV subject to site‑of‑service review
Kanuma (sebelipase alfa) IV is subject to site‑of‑service review and should be documented as administered in an infusion setting unless the clinical rationale supports an alternative site.
Include prescriber specialty and reasons if requesting non‑infusion setting.
Billing Rule
IV biologics and HCPCS J‑codes imply infusion settings
When HCPCS J‑codes indicate IV biologic administration, document that an infusion setting is planned and include monitoring plans for infusion‑related reactions as part of the authorization.
Use the code list to identify agents implying infusion administration.
Note
Site‑of‑service review age limitation (≥13 yrs) and settings
Site‑of‑service review applies for individuals aged ≥13 years and includes hospital outpatient, infusion center, physician office, or home infusion settings; document age and proposed site when submitting authorization.
If patient is under 13, SOS criteria generally do not apply; provide clinical justification if hospital outpatient is requested for younger patients.
Note
Infusion setting requirements for ERTs and anaphylaxis monitoring
For enzyme replacement therapies and agents with anaphylaxis risk, request administration in an infusion center or site prepared to manage severe infusion reactions and document monitoring plans.
Examples include multiple IV ERTs where infusion‑reaction monitoring is essential.
Vimizim administration requires infusion setting preparedness and documentation of plans to mitigate anaphylaxis given the boxed warning; include that plan with the prior authorization.
Document prescriber specialty and infusion site readiness for severe allergic reactions.
Note
Administration settings for biologic and RNAi agents
Most biologic and RNAi agents are administered IV or subcutaneously per labeling; select a site of care that supports required monitoring (office, infusion center, or home) and document that choice in the authorization.
Ensure the chosen site has capability for monitoring injection/infusion‑related adverse events.
Note
Nulibry infusion setting and catheter management
For Nulibry, due to frequent catheter‑related complications in clinical studies, document infusion setting and catheter management plans when seeking authorization for outpatient administration.
Consider infusion center administration if catheter care cannot be reliably managed at home.
Note
Lamzede infusion and hypersensitivity monitoring
Lamzede infusions require monitoring for hypersensitivity and infusion‑associated reactions; document infusion‑site monitoring capability and prescriber specialty on the authorization.
Include prior infusion reaction history if switching ERTs.
Some agents are suitable for subcutaneous or home administration per trial examples (e.g., Forzinity, other SC agents); document that home administration matches safety and monitoring needs when requesting a non‑facility site.
Provide training/agency support plans when home infusion is proposed.
Note
Mixed site‑of‑service clarifications and Alaska exception
When mixed site‑of‑service arrangements exist or state exceptions apply, document the member’s benefit type and clinical justification (Alaska fully‑insured members are exempt from SOS review).
Verify benefit routing and SOS applicability prior to submission.
Note
Site‑of‑service reviews added for multiple drugs (effective dates)
Site‑of‑service reviews were added for multiple drugs with specified effective dates in the appendix; confirm whether the requested date of service falls under an SOS requirement and include required documentation.
Providers should check appendix effective dates for newly added SOS reviews (e.g., Tepezza, Givlaari additions).
Note
Site‑of‑Service review applies for certain drugs; Alaska fully‑insured members exempt
The Site‑of‑Service review applies to certain drugs while Alaska fully‑insured members remain exempt; for drugs added to SOS review (effective dates listed), include site‑of‑service justification with the authorization.
Example: SOS review added for Tepezza and Givlaari with specified effective dates.
The physical location where a drug is administered (hospital outpatient, infusion center, physician office, home); SOS medical necessity review applies to medical benefit reviews and to members aged 13+ except Alaska fully-insured members
Review applicabilitySOS criteria applied to many IV/SC biologics; providers should consult policy for specific drugs and dates of service
ExceptionsDoes NOT apply to Alaska fully‑insured members per policy note
inv-178: PH1 (Primary Hyperoxaluria Type 1) definition
PH1 definitionPrimary Hyperoxaluria Type 1 (PH1): diagnosis by AGXT gene mutation or liver biopsy showing AGT deficiency; treatment criteria reference 24-hour urinary oxalate or plasma oxalate thresholds
Diagnostic metrics24-hour UOx ≥0.7 mmol/24hr/1.73 m2 or plasma oxalate ≥20 µmol/L or age-appropriate spot UOx/Cr for ≤5 years
PrescriberTherapies prescribed by or in consultation with nephrologist, urologist, or geneticist
inv-179: ASMD definition
ASMD definitionAcid sphingomyelinase deficiency (ASMD): confirmed via ASMD biochemical enzyme assay and SMPD1 gene sequencing; Xenpozyme coverage tied to non‑CNS manifestations with DLCO thresholds in adults
Diagnostic requirementBiochemical and genetic confirmation required for Xenpozyme consideration
Clinical focusCoverage targets non‑CNS manifestations such as pulmonary impairment and anemia
inv-180: Chronic neurovisceral ASMD (Niemann-Pick disease A/B or B variant)
Chronic neurovisceral ASMDDefined by ASMD biochemical enzyme assay confirmation and SMPD1 gene sequencing documenting pathogenic variants
Coverage implicationUsed to determine eligibility for Xenpozyme for non‑CNS disease manifestations
Age considerationDLCO threshold applies to individuals ≥18 years per policy
inv-181: 6-minute walk distance (6MWD) definition
6MWD definition6-minute walk distance (6MWD): distance walked on a flat surface in 6 minutes to evaluate integrated cardiopulmonary and neuromuscular function
UseUsed as baseline and outcome measure in multiple trial contexts (e.g., MPS IVA, Pompe, LC-FAOD) and for eligibility criteria
AdministrationStandardized test performed on flat, hard surface per definitions section
inv-182: 3-minute stair climb test definition
3-minute stair climb testMeasures total time to ascend and descend steps in 3 minutes to assess functional strength, balance, and agility
UseUsed as functional endpoint in trials (e.g., Lamzede) and referenced in definitions
AdministrationStandardized protocol described in definitions section
inv-183: GL-3 Inclusion Score definition
GL-3 Inclusion ScoreHistologic measure of globotriaosylceramide in renal endothelial cells graded 0 (normal) to 3 (severe)
UseUsed as a biochemical/histologic endpoint in Fabrazyme trials and coverage evidence
InterpretationLower scores indicate reduction in substrate accumulation
inv-184: CRIM status definition
CRIM statusCross-reactive immunologic material (CRIM) status in Pompe disease: CRIM‑negative individuals have increased risk of death or invasive ventilation after therapy and may have different immune responses to ERT
Diagnostic roleCRIM status influences treatment risk stratification and monitoring for Pompe disease
TestingCRIM determined by presence/absence of endogenous cross-reactive immunologic material
inv-185: XLH definition (brief)
XLH definition (brief)X-linked hypophosphatemia (XLH): PHEX gene-mediated disorder causing renal phosphate wasting via elevated FGF23, leading to rickets/osteomalacia and bone deformities
Laboratory featuresLow serum phosphate, reduced tubular reabsorption of phosphate; alkaline phosphatase elevated in children
Treatment goalAim to improve pain and bone deformity rather than normalization of serum phosphate
inv-186: XLH definition (expanded)
XLH definition (expanded)PHEX gene–related disorder with elevated FGF23, renal phosphate wasting, low serum phosphate, rickets in children and osteomalacia in adults; treatment includes oral phosphate/calcitriol in children and burosumab per criteria
Clinical noteNormalization of serum phosphate is not the treatment goal and may cause overtreatment complications
Trial endpointSerum phosphorus >2.5 mg/dL used as adult trial endpoint for burosumab
inv-187: MPS IVA definition
MPS IVA definitionMucopolysaccharidosis type IVA (Morquio A): GALNS deficiency leading to accumulation of keratan sulfate and chondroitin-6-sulfate with skeletal, respiratory, and other organ manifestations
Clinical impactProminent skeletal involvement, respiratory complications, shortened lifespan without treatment
Diagnostic confirmationEnzyme assay and genetic testing as per policy guidance
inv-188: Primary Periodic Paralysis definition
Primary Periodic Paralysis (PP)Group of autosomal‑dominant channelopathies (hyperkalemic, hypokalemic, Andersen's syndrome) causing episodic muscle weakness associated with serum potassium disturbances
Diagnostic featuresEpisodes frequency, normal TSH, and prior therapy response (acetazolamide) considered in eligibility
Treatment noteDichlorphenamide (Keveyis/Ormalvi) criteria reference prior trial and dose limits
POMC/PCSK1/LEPR deficiency obesityGenetic forms of severe early‑onset obesity due to defects in leptin‑melanocortin pathway causing hyperphagia and resistance to lifestyle interventions
TherapyImcivree (setmelanotide) indicated for POMC/PCSK1/LEPR deficiency with genetic confirmation and weight/BMI thresholds
AgePolicy allows use in individuals aged ≥2 years when criteria met
inv-191: Primary Hyperoxaluria Type 1 (PH1) detailed definition
PH1 detailed definitionPrimary Hyperoxaluria Type 1 (PH1): autosomal recessive AGXT defect causing glyoxylate accumulation and excessive oxalate production; diagnosis via AGXT mutation or liver biopsy; criteria reference 24‑hr UOx or plasma oxalate
Clinical courseLeads to nephrolithiasis, nephrocalcinosis, and progressive kidney disease; therapies aim to lower urinary and plasma oxalate
TestingGenetic confirmation and baseline UOx/POx measurements required per policy
inv-192: MoCD Type A definition
MoCD Type A definitionMolybdenum cofactor deficiency Type A: autosomal recessive MOSC1 mutations causing inability to synthesize cPMP with toxic sulfite accumulation; diagnosis via urine sulfite dipstick, urinary cPMP testing, and genetic testing
Clinical onsetMost present in first days of life with seizures, lethargy, intractable seizures and autonomic dysfunction
TherapyNulibry considered for MoCD Type A per policy with genetic confirmation
inv-193: Achondroplasia (ACH) definition
Achondroplasia (ACH)Skeletal dysplasia due to heterozygous FGFR3 gain-of-function mutations causing impaired endochondral ossification and short stature with associated complications
Clinical concernsAssociated complications include otitis media, sleep apnea, spinal stenosis; therapy (vosoritide) indicated in children with open growth plates and growth velocity criteria
Diagnostic confirmationGenetic testing for FGFR3 mutation required per policy
inv-194: Rett Syndrome (RTT) definition
Rett Syndrome (RTT)Progressive neurodevelopmental disorder usually due to MECP2 mutations characterized by loss of hand skills and spoken language, gait abnormalities, and stereotypic hand movements; treatment includes symptomatic and supportive care
Drug indicationDaybue (trofinetide) indicated for RTT aged ≥2 years with genetic confirmation
MonitoringPolicy requires documented clinical response measures for continuation
inv-195: Heterotopic ossification (HO) definition
Heterotopic ossification (HO)Ectopic bone formation measured as new HO volume (mm3); used as a primary endpoint in FOP palovarotene studies (MOVE) comparing to natural history
Clinical useReduction in new HO volume used to assess palovarotene efficacy
Trial contextMOVE study interim results reported percent reduction vs untreated natural history controls
inv-196: Menkes disease definition
Menkes diseaseGenetic disorder caused by ATP7A mutations leading to systemic copper deficiency, neurological decline beginning in early infancy, and high mortality without treatment
DiagnosisGenetic testing for ATP7A and biochemical measures (serum copper, ceruloplasmin) support diagnosis
TherapyZycubo (copper histidinate) criteria require early initiation and genetic/clinical confirmation per policy
TK2d definitionThymidine kinase 2 deficiency (TK2d): autosomal recessive mitochondrial myopathy caused by TK2 mutations leading to mtDNA depletion and progressive muscle weakness with variable age of onset and prognosis
Clinical subtypesOnset <1 year (severe), 1–12 years (intermediate), >12 years (slower progression) with differing prognosis
DiagnosisGenetic testing for TK2 variants required for Kygevvi consideration
inv-198: TK2d concise definition
TK2d concise definitionRare autosomal recessive mitochondrial myopathy caused by pathogenic TK2 variants resulting in impaired mtDNA replication and progressive muscle weakness
Policy implicationKygevvi coverage limited to patients with genetic confirmation and clinical onset consistent with studied populations
MonitoringAdverse reactions include GI symptoms and transaminase elevations; monitor per policy guidance
2021-03-01coverage_update
Added Dojolvi, Sucraid, Zokinvy, Oxlumo and later Imcivree, Aldurazyme, Naglazyme, Brineura, Sylvant, and Kanuma with effective dates and HCPCS additions noted.
2022-04-01coverage_update
Annual review updated Oxbryta age criteria and added Besremi, Voxzogo, Enjaymo, Pyrukynd and coding updates including J0219 and C9090.
2022-12-01coverage_update
Added Xenpozyme coverage for non‑CNS ASMD and added dosage limits and other ERT and MPS product updates; coding and site-of-service edits applied for multiple agents.
2023-03-01coverage_update
Interim updates added Elfabrio coverage (adult Fabry) and clarified non‑concurrent use of Fabrazyme/Galafold/Elfabrio plus other drug additions and generic dichlorphenamide rules.
2023-09-01coverage_update
Added Bylvay coverage for ALGS pruritus (age ≥12 months) and other benefit changes; ongoing changelog entries continued to expand drug coverage.
2024-02-01policy_revision
Annual review removed select sickle cell drugs from this policy (moved to policy 5.01.640) and updated multiple criteria including Rivfloza addition earlier in Jan 2024.
2024-04-01coding_update
Added HCPCS codes G0138, J1202, and J1203 to the policy coding appendix.
2025-02-01policy_revision
Policy updated to exempt Alaska fully‑insured members from Site‑of‑Service criteria and clarified authorization durations up to 12 months; additional indications and products added through 2025.
2026-03-01annual_review
Annual review approved February 10, 2026 with additions including Zycubo, Forzinity, and updates to Cablivi age threshold and Daybue durations.
2026-04-01coverage_additionLatest
Interim review approved March 10, 2026 added coverage criteria for Kygevvi (TK2 deficiency) and Aqvesme (mitapivat) and noted site-of-service review additions effective July 2, 2026.
2018-06-01effective_date
Policy became effective June 1, 2018 with initial changelog entries recording drug additions and site-of-service notes.
2021-09-03site_of_service_additions
Naglazyme, Brineura, Sylvant, and Kanuma site-of-service reviews became effective for dates of service on or after Sept 3, 2021 following 90‑day provider notification.
2022-08-05site_of_service_additions
Tepezza site-of-service criteria revisions became effective for dates of service on or after Aug 5, 2022; Nexviazyme site‑of‑service review effective Aug 5, 2022.
2023-07-01coverage_addition
Elfabrio coverage criteria for adult Fabry disease added (interim review approved June 13, 2023).
2023-09-01coverage_addition
Bylvay coverage for ALGS pruritus added effective Sept 1, 2023 (interim review approved Aug 8, 2023).
2024-04-01coding_appendix_update
Coding appendix updated with new HCPCS codes G0138, J1202, and J1203 on April 1, 2024.
2025-10-03site_of_service_notification
Provider notification that several changes (including site-of-service reviews) become effective Oct 3, 2025 following 90‑day notice.
2026-03-10interim_update
Interim review March 10, 2026 added Kygevvi and Aqvesme coverage criteria; appendix notes site-of-service review additions with effective dates (e.g., Givlaari site-of-service effective July 2, 2026).
2026-07-02site_of_service_effectiveLatest
Site‑of‑service review additions listed in the appendix take effect July 2, 2026 (provider notification period applied where noted).
Material change: the policy now includes a new clinical background and evidence summary for Kygevvi (doxecitine and doxribtimine). The summary cites Phase II, retrospective, and expanded‑access data totaling treated individuals and reports a matched analysis suggesting a survival benefit in treated TK2‑deficient patients.
Material change: the policy adds detailed evidence summaries and explicit safety and monitoring requirements for Kygevvi and Aqvesme (mitapivat). Kygevvi coverage guidance references survival analyses and common adverse reactions; Aqvesme guidance incorporates results from ENERGIZE‑T and ENERGIZE and mandates REMS liver monitoring with baseline and every‑4‑week labs for the initial 24 weeks.