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    v1.0.28
    OpenPayerPolicy UpdatesPharmacy & Specialty DrugsUnitedHealthcare Complement Pathway Inhibitors Cov…
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    ModifiedUnitedHealthcarePolicy CS2026D0049AF

    Complement Pathway Inhibitors

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    Defines UnitedHealthcare medical benefit drug coverage rules for specified complement pathway inhibitors (C5 and related agents) and the clinical criteria required for authorization. Applies to UnitedHealthcare plans except where state-specific exclusions are listed.

    Policy Summary
    PayerUnitedHealthcare
    PolicyComplement Pathway Inhibitors
    Policy CodePolicy CS2026D0049AF
    Change TypeAdded Yartemleaupdated initial/continuation rules and codes
    Effective DateAugust 1, 2026
    Last ReviewDec 31, 2025
    Next Review DateN/A
    Key ActionSubmit prior authorization with documentation meeting Yartemlea TA‑TMA initial criteria (biopsy or ≥4 of 7 Jodele criteria) and use HCPCS J1289.
    SourceLink
    POLICY UPDATE CHANGES

    Revised list of applicable complement pathway inhibitor drug products and added Yartemlea (narsoplimab-wuug).

    Added detailed initial therapy criteria for Yartemlea in TA‑TMA, including biopsy-proven disease or meeting 4 of 7 Jodele criteria.

    Added continuation/reauthorization guidance for Yartemlea based on continued evidence of active TA‑TMA or inadequate response, with reauthorizations up to 6 months.

    Added HCPCS code J1289 and ICD-10 diagnosis code M31.11 to applicable codes.

    Title changed from 'Complement Inhibitors' to 'Complement Pathway Inhibitors'.

    6+named drugs covered or addressed
    PNH, aHUS, gMG, NMOSD

    OpenPayer is powered by Trek Health's payer performance platform. Trek continuously ingests, validates, and normalizes Transparency in Coverage data alongside payer policies and other commercial payer data to create a structured payer intelligence foundation. OpenPayer uses this foundation to deliver personalized search results, dynamically generated policy pages, and tailored policy monitoring based on each user's payers, specialties, billing codes, and areas of interest. The same intelligence powers broader payer performance workflows, including reimbursement benchmarking, contract evaluation, payer negotiations, and financial decision-making.

    major indications with criteria in this part
    6 monthsinitial period for TA‑TMA (Yartemlea)
    J1289HCPCS code added
    M31.11ICD-10 code added

    Coverage Criteria and Indications

    inv-01: COVERAGE CRITERIA — Eculizumab product preference and exceptions

    Eculizumab product preference and exceptions

    Eculizumab product selection

    • Preferred product exception path A: History of a trial of Bkemv or Epysqli resulting in minimal clinical response and residual disease activity AND physician attestation that clinical response would be expected to be superior with Soliris or other non-preferred eculizumab products

      both conditions required

    • Preferred product exception path B: History of intolerance, contraindication, or adverse event to Bkemv or Epijkstra (Epysqli) AND physician attestation that the same intolerance/contraindication/adverse event would not be expected to occur with Soliris or other non-preferred eculizumab products

      both conditions required

    Continuation for members on non-preferred product: Members already receiving Soliris or other non-preferred eculizumab biosimilars must change therapy to Bkemv or Epysqli unless they meet one of the Preferred Product Criteria exception paths

    Operational: switch required unless exception documented

    inv-02: COVERAGE CRITERIA — Atypical hemolytic uremic syndrome (aHUS) — Bkemv, Epysqli, Soliris, Ultomiris

    Atypical hemolytic uremic syndrome (aHUS) — Bkemv, Epijkstra, Soliris, Ultomiris

    aHUS initial therapy: Documentation supporting aHUS diagnosis with exclusion of STEC-HUS and TTP (e.g., ADAMTS13 testing); laboratory results/signs/symptoms attributable to aHUS (thrombocytopenia, microangiopathic hemolysis, thrombotic microangiopathy, acute renal failure, etc.); patient is treatment-naïve to the requested product; requested product dosed per U.S. FDA-labeled dosing for aHUS; prescribed by or in consultation with a hematologist or nephrologist; initial authorization up to 12 months
    aHUS continuation: Patient previously treated with the requested product; documentation demonstrating positive clinical response from baseline (e.g., reduction of plasma exchanges, reduction of dialysis, increased platelet count, reduction of hemolysis); requested product dosed per U.S. FDA-labeled dosing for aHUS; prescribed by or in consultation with a hematologist or nephrologist; reauthorization up to 12 months

    inv-03: COVERAGE CRITERIA — STEC-HUS

    STEC-HUS

    STEC-HUS stance: Bkemv, Epijkstra, PiaSky (crovalimab), Soliris (eculizumab), and Ultomiris (ravulizumab) are unproven and not medically necessary for the treatment of Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS)

    inv-04: COVERAGE CRITERIA — Paroxysmal nocturnal hemoglobinuria (PNH) — Bkemv, Epijski, PiaSky, Soliris, Ultomiris

    Paroxysmal nocturnal hemoglobinuria (PNH) — Bkemv, Epijkstra, PiaSky, Soliris, Ultomiris

    PNH initial therapy: Documentation supporting PNH diagnosis including flow cytometry confirming presence of PNH clones AND laboratory results, signs, or symptoms attributed to PNH (e.g., abdominal pain, anemia, dyspnea, fatigue, thrombosis, hemolysis, kidney disease, pulmonary hypertension); requested product dosed per U.S. FDA-labeled dosing for PNH; for PiaSky authorization only, patient is not receiving PiaSky in combination with a complement factor D inhibitor; not used in combination with other complement inhibitors or complement pathway agents per policy; prescribed by or in consultation with a hematologist or oncologist; initial authorization up to 12 months
    PNH continuation: Patient previously treated with the requested product; documentation demonstrating positive clinical response from baseline (e.g., increased or stabilization of hemoglobin, reduction in transfusions, reduction in hemolysis, decrease in LDH); requested product dosed per U.S. FDA-labeled dosing for PNH; patient is not receiving the requested product in combination with another complement C5 inhibitor, complement C3 inhibitor, or complement factor B inhibitor; prescribed by or in consultation with a hematologist or oncologist; reauthorization up to 12 months

    inv-05: COVERAGE CRITERIA — Generalized myasthenia gravis (gMG) — Bkemv, Epijkstra, Soliris, Ultomiris

    Generalized myasthenia gravis (gMG) — Bkemv, Epijkstra, Soliris, Ultomiris

    gMG initial therapy: Submit medical records confirming: no prior failure of a complement C5 inhibitor; diagnosis of generalized myasthenia gravis; positive anti-AChR antibody test; MGFA clinical classification II–IV at initiation; MG-ADL total score ≥ 6 at initiation; either history of failure of ≥2 immunosuppressive agents over ≥12 months OR failure of at least one immunosuppressive therapy with additional qualifying criteria per policy; requested product initiated and titrated per U.S. FDA-labeled dosing for gMG; patient is not receiving the requested product in combination with B-cell depletion therapy, another complement C5 inhibitor, an FcRn blocker, or immune globulin; prescribed by or in consultation with a neurologist; initial authorization up to 12 months
    gMG continuation: Patient previously treated with the requested product; submission of medical records demonstrating ≥2-point improvement in MG-ADL from baseline and reduction in signs/symptoms; maintenance, reduction, or discontinuation of baseline immunosuppressive therapy (add-on escalation or rescue therapy = treatment failure); requested product dosed per U.S. FDA-labeled dosing for gMG; not used with specified concurrent therapies; prescribed by or in consultation with a neurologist; reauthorization up to 12 months

    inv-06: COVERAGE CRITERIA — Neuromyelitis optica spectrum disorder (NMOSD) — Bkemv, Epysqli, Soliris, Ultomiris

    Neuromyelitis optica spectrum disorder (NMOSD) — Bkemv, Epijkstra, Soliris, Ultomiris

    NMOSD initial therapy: Diagnosis of NMOSD by a neurologist with history of an NMOSD-defining clinical syndrome (optic neuritis, acute myelitis, area postrema syndrome, acute brainstem syndrome, symptomatic narcolepsy/diencephalic syndrome, or symptomatic cerebral syndrome) AND positive AQP4-IgG serologic test; multiple sclerosis and other diagnoses ruled out; patient has not failed a previous course of a complement C5 inhibitor for NMOSD; history of failure of, contraindication to, or intolerance to rituximab therapy; requested product initiated and titrated per U.S. FDA-labeled dosing for NMOSD; prescribed by or in consultation with a neurologist; four or more courses of plasmapheresis and/or IVIG over at least 12 months without symptom control; initial authorization up to 12 months
    NMOSD continuation: Patient previously treated with the requested product; documentation of positive clinical response from baseline demonstrated by reduction in relapses or signs/symptoms AND maintenance/reduction/discontinuation of baseline immunosuppressive therapy (add-on escalation or rescue therapy = treatment failure); requested product dosed per U.S. FDA-labeled dosing for NMOSD; prescribed by or in consultation with a neurologist; patient not receiving the product in combination with disease-modifying MS therapies, anti-IL6 therapy, or B-cell depletion therapy for the same indication; reauthorization up to 12 months

    inv-07: gMG / General neurology combination and prescribing requirements — Covered when ALL of the following are met

    Covered when ALL of the following are met

    gMG dosing and prescriber: Requested product is dosed per U.S. FDA-labeled dosing for gMG; prescribed by or in consultation with a neurologist; reauthorization for no more than 12 months
    No concurrent therapies: Patient is not receiving the requested product in combination with specified therapies for the same indication including B-cell depletion therapy, another complement C5 inhibitor, FcRn blockers, or an immune globulin

    inv-08: NMOSD — Initial Therapy

    Covered when ALL of the following are met

    Diagnosis and serology: Diagnosis of NMOSD by a neurologist with history of an NMOSD-defining syndrome AND positive AQP4-IgG serologic test
    Exclude other diagnoses: Multiple sclerosis or other alternative diagnoses have been ruled out
    Prior complement inhibitor and rituximab history: Patient has not failed a previous course of a complement C5 inhibitor for NMOSD AND has history of failure of, contraindication to, or intolerance to rituximab therapy
    Adjunct therapy and dosing: Requested product is initiated and titrated per U.S. FDA-labeled NMOSD dosing; prescribed by or in consultation with a neurologist; initial authorization up to 12 months

    inv-09: NMOSD — Continuation of Therapy

    Covered when ALL of the following are met

    Prior treatment and response: Patient previously treated with the requested product AND documentation of positive clinical response from baseline demonstrated by reduction in relapses or signs/symptoms AND maintenance/reduction/discontinuation of baseline immunosuppressive therapy (add-on escalation or rescue therapy = treatment failure)
    Dosing and prescriber: Requested product dosed per U.S. FDA-labeled NMOSD dosing; prescribed by or in consultation with a neurologist; reauthorization up to 12 months
    No concurrent therapies: Patient is not receiving the requested product in combination with disease-modifying MS therapies, anti-IL6 therapy, or B-cell depletion therapy for the same indication

    inv-10: TA-TMA (Yartemlea) — Initial Therapy

    Covered when ALL of the following are met

    Diagnostic confirmation: Either biopsy-proven disease (kidney or GI) OR meets at least 4 of the 7 Jodele criteria documented at two consecutive time points within 14 days: anemia, thrombocytopenia, elevated LDH, schistocytes, hypertension, elevated sC5b-9, proteinuria

    Other causes of anemia must be ruled out

    Dosing and authorization length: Requested product (Yartemlea/narsoplimab) is initiated and titrated per U.S. FDA-labeled dosing for TA-TMA; initial authorization up to 6 months

    inv-11: TA-TMA (Yartemlea) — Continuation of Therapy

    Covered when ALL of the following are met

    Prior treatment and ongoing disease: Patient previously treated with the requested product; approval beyond the initial 6-month authorization is based on continued evidence of active TA-TMA and/or evidence of an inadequate or incomplete response based on the initial (Jodele) criteria

    Reauthorization up to 6 months

    Dosing: Requested product dosed per U.S. FDA-labeled dosing for TA-TMA

    inv-12: Covered indications with supporting trial evidence

    Clinical evidence supports coverage for these agents in their FDA-indicated populations when trial-aligned diagnostic and treatment conditions are met.

    PNH coverage evidence summary: Multiple agents (eculizumab, ravulizumab, pegcetacoplan, crovalimab) demonstrated efficacy for PNH across trials including improvements in hemoglobin, LDH, transfusion avoidance, and FACIT-F fatigue scores; pegcetacoplan showed superiority to eculizumab for hemoglobin increase in PEGASUS.
    gMG coverage evidence summary: Ravulizumab and eculizumab were studied in gMG with inclusion of MGFA class II–IV and MG-ADL ≥6; ravulizumab demonstrated statistically significant improvement in MG-ADL at 26 weeks.
    NMOSD coverage evidence summary: Ravulizumab and eculizumab are indicated for AQP4+ NMOSD with trials showing large reductions in adjudicated relapses (ravulizumab showed no adjudicated relapses in CHAMPION-NMOSD versus external comparator; eculizumab showed large relapse reduction versus placebo in PREVENT).
    TA-TMA coverage evidence summary:

    inv-13: Initial Therapy — Yartemlea (TA‑TMA)

    Yartemlea is proven and medically necessary for TA‑TMA when ALL of the following are met:

    Main: Requested product is Yartemlea (narsoplimab) for TA‑TMA; dosing per U.S. FDA-labeled dosing for TA‑TMA; initial authorization for no more than 6 months
    Diagnostic criteria: Either biopsy-proven disease (kidney or GI) OR meets at least 4 of the 7 Jodele criteria documented at two consecutive time points within 14 days

    Other causes of anemia must be ruled out

    Jodele criteria list: Seven criteria: (1) Anemia as defined by failure to achieve transfusion independence despite neutrophil engraftment, hemoglobin decline from baseline by 1 g/dL, or new transfusion dependence (other causes ruled out); (2) Thrombocytopenia as defined by failure to achieve platelet engraftment, higher than expected platelet transfusion needs, refractory to platelet transfusions, or ≥50% reduction from baseline after full engraftment; (3) Elevated LDH > ULN for age; (4) Presence of schistocytes; (5) Hypertension (>99th percentile for age <18 years; systolic ≥140 or diastolic ≥90 mmHg for ≥18 years); (6) Elevated sC5b-9 ≥ ULN; (7) Proteinuria ≥1 mg/mg random protein to creatinine ratio (rUPCR).4 of 7

    inv-14: Continuation Therapy — Yartemlea

    Continuation of therapy (reauthorization) is allowed when ALL of the following are met:

    Continuation main: Patient previously treated with Yartemlea; requested product dosed per U.S. FDA-labeled dosing for TA‑TMA; reauthorization granted only with evidence of continued active TA‑TMA and/or inadequate or incomplete response per the initial Jodele criteria; reauthorization limited to no more than 6 months

    Bkemv (eculizumab-aeeb), Epysqli (eculizumab-aagh), PiaSky (crovalimab), Soliris (eculizumab), and Ultomiris (ravulizumab) are designated in this policy as unproven and not medically necessary for the treatment of Shiga toxin E. coli–related hemolytic uremic syndrome (STEC‑HUS). The policy requires documentation that STEC‑HUS has been excluded when evaluating patients with suspected complement-mediated thrombotic microangiopathy prior to considering coverage for other indications such as aHUS.

    Requests for coverage must document that the patient is not receiving the requested complement pathway inhibitor in combination with other specified therapies for the same indication. Disallowed concurrent agents include B‑cell depletion therapies (e.g., inebilizumab/rituximab), other complement C5 inhibitors (Bkemv, Epysqli, PiaSky, Soliris, Ultomiris), FcRn blockers, immune globulin, disease‑modifying MS therapies, and anti‑IL6 agents. Use of these agents together for the same indication is a contraindication to coverage under this policy.

    Eculizumab and its referenced biosimilars (including branded Soliris and the biosimilars Bkemv and Epysqli) are not indicated for the treatment of Shiga toxin E. coli–related hemolytic uremic syndrome (STEC‑HUS). The clinical evidence is considered insufficient to support safety and effectiveness for STEC‑HUS, and the policy reflects that such use is unproven.

    Soliris, Ultomiris, Bkemv, Epysqli, and PiaSky are not indicated for Shiga toxin E. coli–related hemolytic uremic syndrome (STEC‑HUS) per FDA labeling and policy limitations of use. Yartemlea (narsoplimab‑wuug) is separately indicated and addressed only for hematopoietic stem cell transplant‑associated thrombotic microangiopathy (TA‑TMA) in this document.

    Use of the listed complement pathway inhibitors (Bkemv, Epysqli, PiaSky, Soliris, Ultomiris) for STEC‑HUS is considered not medically necessary within this policy. The policy requires exclusion of STEC‑HUS when evaluating patients for other complement‑mediated indications and explicitly treats these agents as unproven for STEC‑HUS.

    The policy highlights that use of Bkemv, Epysqli, PiaSky, Soliris, or Ultomiris for STEC‑HUS is not a labeled indication. Coverage determinations should follow FDA‑labeled indications and the policy’s stated limitations of use.

    Initial Therapy Authorization Criteria

    inv-56: Initial therapy — Initial authorization criteria by indication

    Initial authorization criteria by indication

    aHUS initial: Exclude STEC-HUS and TTP (e.g., ADAMTS13); supportive labs/signs; treatment-naïve to requested product; dosing per FDA; prescribed by hematologist or nephrologist; initial authorization up to 12 months
    PNH initial: Flow cytometry confirming PNH clones; supportive labs/signs; dosing per FDA; PiaSky requires no combination with complement factor D inhibitor and other prior therapy conditions; prescribed by hematologist or oncologist; initial authorization up to 12 months
    gMG initial: Documentation: no prior complement C5 inhibitor failure; gMG diagnosis; anti-AChR positive; MGFA class II–IV; MG-ADL ≥6; prior immunosuppressive therapy failure criteria met (e.g., ≥2 agents over ≥12 months or other qualifying failure criteria); dosing per FDA; not used with specified concurrent therapies; prescribed by neurologist; initial authorization up to 12 months

    Continuation and Reauthorization Criteria

    inv-60: Continuation therapy rules — Prior treatment, documentation, and benefit requirements

    Continuation/reauthorization requirements vary by indication but consistently require prior treatment with the requested product, documentation of benefit, FDA dosing, and specialist involvement.

    aHUS continuation: Previously treated with the requested product; documentation of positive clinical response from baseline; dosing per FDA; prescribed by or in consultation with a hematologist or nephrologist; reauthorization up to 12 months
    PNH continuation: Previously treated with requested product; documentation of positive clinical response (e.g., hemoglobin stabilization, reduced transfusions, reduced LDH); dosing per FDA; not combined with other complement inhibitors; prescribed by or in consultation with a hematologist or oncologist; reauthorization up to 12 months
    gMG continuation: Previously treated; ≥2-point MG-ADL improvement from baseline; reduction in signs/symptoms; maintenance/reduction/discontinuation of baseline IST (add-on escalation/rescue therapy = treatment failure); dosing per FDA; not combined with specified therapies; prescribed by or in consultation with a neurologist; reauthorization up to 12 months

    Provider Actions, Documentation, and Requirements

    Prior Authorization

    Prior authorization required; typical 12-month initial approvals

    Prior authorization is required for requests of listed complement pathway inhibitors; initial authorizations for most indications will be for no more than 12 months and reauthorizations are also limited (typically up to 12 months) when clinical response is documented.

    Prior Authorization

    Authorization duration limits by indication (12 mo neurology; 6 mo TA‑TMA)

    Prior authorization is required and duration limits vary by indication: neurology indications (e.g., gMG, NMOSD) typically have initial and reauthorization periods up to 12 months; Yartemlea (TA‑TMA) initial authorization is limited to up to 6 months with reauthorizations up to 6 months.

    Documentation Required

    Coding: HCPCS and ICD-10

    HCPCS CodesHCPCS
    J1289Injection, narsoplimab-wuug, 1 mg
    J1299Injection, eculizumab, 2 mg
    J1303Injection, ravulizumab-cwvz, 10 mg
    J1307Injection, crovalimab-akkz, 10 mg
    Q5151Injection, eculizumab-aagh (Epysqli), biosimilar, 2 mg
    Q5152Injection, eculizumab-aeeb (Bkemv), biosimilar, 2 mg
    ICD-10 CodesICD-10
    D59.30Hemolytic-uremic syndrome, unspecified
    D59.32Hereditary hemolytic-uremic syndrome
    D59.39Other hemolytic-uremic syndrome
    D59.5Paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli)
    G36.0Neuromyelitis optica (Devic)
    G70.00Myasthenia gravis without (acute) exacerbation
    G70.01Myasthenia gravis with (acute) exacerbation
    M31.11Hematopoietic stem cell transplantation-associated thrombotic microangiopathy [HSCT-TMA]
    Applicable HCPCS Codes (added)HCPCS
    J1289HCPCS code added (document lists as added)
    Applicable ICD-10 Codes (added)ICD-10
    M31.11ICD-10 diagnosis code added
    inv-25: Elevated LDH — value > ULN
    DefinitionElevated lactate dehydrogenase (LDH) defined as greater than the upper limit of normal (ULN) for age.
    ContextListed as one of the Jodele criteria used to support diagnosis of TA‑TMA for Yartemlea initial therapy.
    DocumentationLDH value should be reported with the laboratory reference range to demonstrate > ULN.
    inv-26: Proteinuria (rUPCR) — value ≥ 1 mg/mg
    ThresholdProteinuria defined as random urine protein-to-creatinine ratio (rUPCR) ≥ 1 mg/mg.
    Role in criteria

    Step Therapy and Prior Trial Requirements

    RequirementDetails
    Required prior trial/failure or documented intolerance to preferred eculizumab products
    Coverage of Soliris (eculizumab) or other non-preferred eculizumab biosimilar products is allowed only when Preferred Product Criteria are met: either (1) history of a trial of Bkemv or Epysqli with minimal clinical response plus physician attestation that clinical response would be superior with Soliris/other non-preferred eculizumab, OR (2) history of intolerance/contraindication/adverse event to Bkemv or Epysqli plus physician attestation that same would not be expected with Soliris/other non-preferred eculizumab. Members already on Soliris or other non-preferred eculizumab must change to Bkemv or Epysqli unless they meet these criteria.
    RequirementDetails
    Prior rituximab trial or documented contraindication/intolerance required
    Initial approval for NMOSD requires history of failure of, contraindication to, or intolerance to rituximab therapy as part of diagnostic and treatment documentation (in addition to neurologist diagnosis, positive AQP4-IgG, exclusion of other diagnoses, no prior complement C5 inhibitor failure for NMOSD, FDA‑labeled dosing, specialist prescribing, and ≥4 plasmapheresis/IVIG courses over ≥12 months without control).
    RequirementDetails
    Prior eculizumab therapy documented for patients transitioning to pegcetacoplan
    Pegcetacoplan (as studied in PEGASUS) was evaluated in adults with PNH and hemoglobin <10.5 g/dL despite ≥3 months of eculizumab; trial design included a 4‑week run‑in with pegcetacoplan plus eculizumab before randomization to pegcetacoplan monotherapy. Requests to transition to pegcetacoplan for this population should document prior eculizumab therapy and inadequate response (persistent low hemoglobin despite ≥3 months of eculizumab).
    RequirementDetails
    Documentation of prior treatment with the requested product is required for continuation
    Continuation (reauthorization) requests must document prior treatment with the requested product and demonstrate ongoing clinical benefit or continued active disease per indication‑specific rules (for Yartemlea: prior treatment and evidence of active TA‑TMA or inadequate/incomplete response per Jodele criteria; reauthorizations limited to up to 6 months for TA‑TMA; other indications generally require documentation of positive clinical response and may be reauthorized up to 12 months).

    Quantity Limits and Dosing References

    inv-68: unspecified (policy references FDA-labeled dosing) — per FDA-labeled dosing
    Quantity guidanceDosing and quantity limits follow the U.S. FDA‑labeled dosing for the requested product.
    ApplicationApplies to initial and continuation authorizations across indications where FDA labeling specifies dose and schedule.
    DocumentationPrescriptions and infusion records should reflect FDA‑labeled dose and schedule to support authorization and billing.

    Site of Care Guidance

    Note

    Site‑of‑care not specified here — follow plan rules

    Site‑of‑care specifics are not detailed in this policy; follow the member’s plan or benefit contract for site‑of‑care determinations.

    Billing Rule

    Administer IV/SC per label in appropriate infusion setting

    Administer agents per their labeled route and trial settings (intravenous or subcutaneous); use an appropriate infusion center or clinic consistent with the product’s route and monitoring needs.

    Note

    Site‑of‑care decisions follow plan/contract rules

    This policy is informational regarding site‑of‑care; facility/site determinations (e.g., hospital outpatient) must follow the member's plan, federal/state/contractual rules, and billing policies.

    Biosimilar Preferences and Requirements

    Billing Rule

    Bkemv and Epquelize (Epysqli) are preferred eculizumab products

    Bkemv (eculizumab‑aeeb) and Epysqli (eculizumab‑aagh) are the preferred eculizumab products; any FDA‑approved and launched eculizumab biosimilar not listed is considered non‑preferred until reviewed by UnitedHealthcare.

    Billing Rule

    Eculizumab HCPCS codes listed for reference

    Eculizumab and its biosimilar HCPCS codes are listed for reference (policy includes HCPCS entries such as J1299 and biosimilar codes Q5151/Q5152); include the applicable HCPCS on claims/PA submissions.

    Billing Rule

    Eculizumab HCPCS entries (reference and biosimilars) included

    Eculizumab is listed with HCPCS entries (reference and biosimilar codes) in the policy’s Applicable Codes section; use the listed codes when submitting authorizations or claims.

    Definitions and Diagnostic Criteria

    inv-49: aHUS diagnostic exclusions — exclude STEC-HUS and TTP (ADAMTS13 deficiency)
    Exclusions to diagnose aHUSExclude Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS).
    TTP exclusionExclude thrombotic thrombocytopenic purpura (TTP), e.g., rule out ADAMTS13 deficiency.
    Supporting documentationMedical records should include testing/results that rule out STEC-HUS and ADAMTS13 deficiency when diagnosing aHUS for coverage.
    inv-50: PNH diagnosis — flow cytometry confirming PNH clones and clinical/lab evidence
    Required testFlow cytometry confirming presence of PNH clones.
    Clinical correlationDocumentation of clinical or laboratory evidence attributable to PNH (e.g., hemolysis, hemoglobinuria, thrombosis, anemia).

    Background and Clinical Context

    Background: Complement pathway inhibitors (primarily C5 inhibitors such as eculizumab and ravulizumab, and related agents) target terminal complement activity to treat disorders driven by complement‑mediated pathology. These agents are used in conditions including atypical HUS (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD); Yartemlea (narsoplimab) is a MASP‑2 inhibitor indicated for transplant‑associated thrombotic microangiopathy (TA‑TMA). Coverage is tied to diagnosis confirmation, required laboratory findings, prior therapy history, specialist involvement, and adherence to FDA‑labeled dosing.

    Policy Summary
    PayerUnitedHealthcare
    PolicyComplement Pathway Inhibitors
    Policy CodePolicy CS2026D0049AF
    Change TypeAdded Yartemleaupdated initial/continuation rules and codes
    Effective DateAugust 1, 2026
    Last ReviewDec 31, 2025
    Next Review DateN/A
    Key ActionSubmit prior authorization with documentation meeting Yartemlea TA‑TMA initial criteria (biopsy or ≥4 of 7 Jodele criteria) and use HCPCS J1289.
    SourceLink
    On This Page
    Coverage Criteria and IndicationsInitial Therapy Authorization CriteriaContinuation and Reauthorization CriteriaProvider Actions, Documentation, and RequirementsCoding: HCPCS and ICD-10Step Therapy and Prior Trial RequirementsQuantity Limits and Dosing ReferencesSite of Care GuidanceBiosimilar Preferences and RequirementsDefinitions and Diagnostic CriteriaBackground and Clinical Context
    Rescue therapy history:
    Four or more courses of plasmapheresis/plasma exchange and/or intravenous immune globulin over at least 12 months without symptom control
    No concurrent therapies: Patient is not receiving the requested product in combination with disease-modifying MS therapies, anti-IL6 therapy, or B-cell depletion therapy for the same indication
    Narsoplimab (Yartemlea) demonstrated a 61% response rate in a pivotal single-arm trial with improvements in laboratory and organ function endpoints and supportive expanded access survival data; response and safety data inform coverage consideration for TA-TMA.

    Must be met at 2 consecutive time points within 14 days

    NMOSD initial: Neurologist diagnosis with NMOSD-defining syndrome AND positive AQP4-IgG AND exclusion of other diagnoses; no prior complement C5 inhibitor failure for NMOSD; history of failure/contraindication/intolerance to rituximab; four or more plasmapheresis/IVIG courses over ≥12 months without control; dosing per FDA; prescribed by neurologist; initial authorization up to 12 months

    inv-57: Initial therapy requirements — Diagnosis-specific criteria and prior therapy history

    Initial therapy coverage conditioned on diagnosis-specific criteria and prior therapy history.

    NMOSD initial (summary): Neurologist diagnosis with NMOSD-defining clinical history AND positive AQP4-IgG AND exclusion of alternative diagnoses AND prior rituximab failure/contraindication/intolerance AND not previously failed a complement C5 inhibitor AND four or more plasmapheresis/IVIG courses over 12 months without control; product dosed per FDA labeling; prescribed by or in consultation with a neurologist; initial authorization up to 12 months
    TA-TMA initial (summary): Either biopsy-proven kidney or GI disease OR meeting ≥4 of 7 Jodele criteria at two consecutive time points within 14 days; other causes of anemia ruled out; product dosed per FDA labeling for TA-TMA; initial authorization up to 6 months

    inv-58: Initial therapy scenarios — Trial-aligned initiation scenarios and dosing approaches

    Key trial-aligned initiation scenarios and dosing approaches described in clinical trials and FDA labeling.

    Pegcetacoplan initiation (PNH refractory to eculizumab): Pegcetacoplan was studied in patients with PNH and hemoglobin <10.5 g/dL despite ≥3 months of eculizumab; initial run-in included combined therapy then pegcetacoplan monotherapy
    Crovalimab initiation (PNH): Crovalimab dosing included weight-based loading and maintenance with subcutaneous and IV scheduling as in COMMODORE 2; studied versus eculizumab
    Ravulizumab/Eculizumab initiation (gMG, NMOSD, PNH, aHUS): Ravulizumab and eculizumab were initiated per trial dosing with weight-based/loading regimens and required meningococcal vaccination prior to initiation in trials; trial inclusion criteria included antibody status for some indications (AQP4+ for NMOSD, AChR+ for gMG)
    Narsoplimab initiation (TA-TMA): In the pivotal TA-TMA trial, narsoplimab was administered IV once weekly for 4–8 weeks with response defined by laboratory and organ function improvement; expanded access used high-risk enrollment criteria

    inv-59: Initial Therapy — Yartemlea

    Initial authorization rules for Yartemlea in TA‑TMA

    Initial Yartemlea: Initiation and titration per U.S. FDA-labeled dosing for TA‑TMA; meet diagnostic criteria (biopsy-proven disease or ≥4 of 7 Jodele criteria at two time points within 14 days); initial authorization up to 6 months

    inv-61: Continuation requirements — Prior treatment and documented benefit or ongoing active disease

    Continuation requests require prior treatment and documented benefit or ongoing active disease depending on indication.

    NMOSD continuation: Previously treated with requested product AND documentation of positive clinical response from baseline demonstrated by both reduction in relapses or signs/symptoms AND maintenance/reduction/discontinuation of baseline immunosuppressive therapy (add-on escalation or rescue therapy = treatment failure); dosing per FDA; prescribed by or in consultation with a neurologist; reauthorization up to 12 months
    TA-TMA continuation: Previously treated AND evidence of continued active TA-TMA or inadequate/incomplete response per initial Jodele criteria; requested product dosed per FDA-labeled dosing for TA-TMA; reauthorization up to 6 months

    inv-62: Continuation/long-term data — Long-term use and extension-phase data inform continuation decisions

    Long-term use and extension-phase data inform continuation decisions.

    Eculizumab long-term continuation: Long-term continuous eculizumab demonstrated sustained LDH reduction, decreased thrombotic events, improved/stabilized renal function, and transfusion reduction; continued monitoring for infections and vaccination status recommended
    Narsoplimab continuation evidence: Pivotal narsoplimab treatment courses were weekly for 4–8 weeks; expanded access data include longer-term outcomes and survival metrics which may inform continuation decisions in responders

    inv-63: Yartemlea continuation — Continuation/reauthorization for Yartemlea

    Continuation/reauthorization for Yartemlea

    Continuation: Patient previously treated with Yartemlea; continued dosing per U.S. FDA-labeled dosing for TA‑TMA; reauthorization requires evidence of active TA‑TMA or inadequate response to initial therapy per Jodele criteria; reauthorizations limited to 6 months

    Confirm diagnosis and antibody status (AQP4‑IgG for NMOSD)

    Confirm diagnosis and, where applicable, relevant antibody status before submitting a prior authorization (e.g., neurologist diagnosis of NMOSD with positive AQP4‑IgG is required for NMOSD approvals).

    Prior Authorization

    Yartemlea (narsoplimab) requires prior authorization (HCPCS J1289)

    Prior authorization is required for Yartemlea (narsoplimab); use HCPCS code J1289 and include documentation that the request meets the initial TA‑TMA therapy criteria (biopsy-proven disease or Jodele criteria).

    • Use HCPCS J1289 for narsoplimab (1 mg units)
    Step Therapy

    Preferred eculizumab products required; exceptions require Preferred Product Criteria

    Preferred eculizumab biosimilars Bkemv and Epysql i are favored; coverage for Soliris or other non-preferred eculizumab products requires meeting the Preferred Product Criteria (prior trial with Bkemv or Epysqli with minimal response or documented intolerance/contraindication plus physician attestation).

    • Members on non-preferred products must change to Bkemv or Epysqli unless Preferred Product Criteria are met
    • Preferred Product Criteria include trial/failure or intolerance to Bkemv/Epysqli and physician attestation
    Step Therapy

    Prior rituximab trial (or documented contraindication/intolerance) required for NMOSD

    For NMOSD initial therapy requests, document prior trial and failure of, contraindication to, or intolerance to rituximab before approval.

    Step Therapy

    Document prior eculizumab therapy for pegcetacoplan switch per PEGASUS

    When requesting pegcetacoplan for patients studied in PEGASUS, document prior anti‑C5 therapy (eculizumab) per the trial population (persistent anemia despite ≥3 months of eculizumab).

    Prior Authorization

    Yartemlea continuation requires prior treatment and evidence of active TA‑TMA or inadequate response

    Continuation (reauthorization) of Yartemlea requires prior evidence of treatment with the requested product and documentation demonstrating ongoing active TA‑TMA or an inadequate/incomplete response based on the initial Jodele criteria.

    • Reauthorizations limited to no more than 6 months
    Denial Risk

    Denial risk for missing clinical documentation or lack of specialist involvement

    Requests lacking required indication-specific documentation, specialist prescribing/consultation, or necessary laboratory/clinical findings may be denied.

    • Specialist prescriber requirement (hematologist, nephrologist, neurologist, or oncologist depending on indication) must be met
    • Missing labs (e.g., ADAMTS13 to exclude TTP, flow cytometry for PNH) or serology (AQP4‑IgG, anti‑AChR) increases denial risk
    Documentation Required

    Required supporting documentation: medical records, labs, and prior therapy history

    Submit medical records to support the diagnosis and prior therapies: chart notes, laboratory values (including ADAMTS13, Shiga toxin testing to exclude STEC‑HUS where applicable), flow cytometry for PNH, MG‑ADL scores, AQP4‑IgG serology, and plasmapheresis/IVIG history.

    • ADAMTS13 testing to exclude TTP and Shiga toxin testing to exclude STEC‑HUS for aHUS
    • Flow cytometry results for PNH
    • MG‑ADL and MGFA class documentation for gMG
    • AQP4‑IgG serology and neurologist clinical notes for NMOSD
    • Plasmapheresis/IVIG course history when required
    Documentation Required

    Required clinical documentation for NMOSD (neurologist diagnosis, AQP4‑IgG, prior rituximab history)

    NMOSD requests must include a neurologist diagnosis with supporting clinical history, positive AQP4‑IgG serology, exclusion of alternative diagnoses (e.g., MS), prior rituximab failure/contraindication/intolerance, initiation per FDA dosing, and baseline/continuation response data for reauthorization.

    • Four or more courses of plasmapheresis/IVIG over ≥12 months without symptom control when specified for initiation
    • For continuation, document reduction in relapses or signs/symptoms and maintenance/reduction/discontinuation of baseline IST
    Documentation Required

    Required clinical documentation for TA‑TMA: biopsy or ≥4 of 7 Jodele criteria documented

    For TA‑TMA (Yartemlea) initial requests, include either biopsy-proven disease (kidney or GI) or documentation that the patient meets at least 4 of 7 Jodele criteria at two consecutive time points within 14 days, with supporting labs for each criterion.

    • Jodele criteria include anemia (as defined), thrombocytopenia (as defined), elevated LDH > ULN, schistocytes, hypertension (age‑based or adult thresholds), elevated sC5b‑9 ≥ ULN, and proteinuria ≥1 mg/mg rUPCR
    Documentation Required

    Meningococcal vaccination required and must be documented per ACIP/FDA guidance

    Vaccination against Neisseria meningitidis is required per FDA/ACIP guidance for specified complement inhibitors; vaccination should be completed or updated at least 2 weeks prior to initiation when possible and counseling/monitoring for meningococcal risk must be documented.

    • If urgent therapy is required, vaccinate as soon as possible and document the decision
    • Monitor and counsel patients for early signs of invasive meningococcal disease
    Documentation Required

    Document meningococcal vaccination details (dates, vaccine type, revaccination plan)

    Document meningococcal vaccination status and timing according to ACIP recommendations for patients receiving PiaSky, Soliris, Ultomiris, Bkemv, or Epysqli; include evidence of completed or updated vaccination or urgency rationale.

    • Record vaccine type(s), dates administered, and any revaccination per ACIP
    • If vaccinated less than 2 weeks before initiation, document rationale for urgent therapy
    Denial Risk

    Non‑preferred eculizumab requests without Preferred Product Criteria may be denied

    Requests for non‑preferred eculizumab biosimilars (e.g., Soliris or other non‑preferred agents) that do not meet the Preferred Product Criteria (trial/failure or intolerance to preferred agents with physician attestation) may be denied.

    Denial Risk

    Denial risk if specialist involvement or required diagnostic documentation is missing

    Lack of required diagnosis documentation, absence of specified laboratory or clinical findings, or failure to have the requested product prescribed by or in consultation with the appropriate specialist (hematologist, nephrologist, neurologist, or oncologist as indicated) may lead to denial.

    Denial Risk

    Concurrent therapy with listed agents for same indication is disqualifying

    Use of listed agents in combination with other specified therapies for the same indication (e.g., another complement C5 inhibitor, B‑cell depletion therapy, FcRn blockers, immune globulin) is prohibited for coverage and may trigger denial.

    • Do not combine a complement C5 inhibitor with another complement inhibitor, complement C3 inhibitor, or complement factor B/D inhibitor for the same indication
    Denial Risk

    NMOSD continuation: no concurrent MS DMTs, anti‑IL6, or B‑cell depletion

    For NMOSD continuation, the patient must not be receiving the requested product in combination with disease‑modifying MS therapies, anti‑IL6 therapy, or B‑cell depletion therapy for the same indication; concurrent use is a disqualifying condition for reauthorization.

    Denial Risk

    Indication‑based denial risk (e.g., eculizumab not indicated for STEC‑HUS)

    Use of complement pathway inhibitors for indications explicitly not labeled by the FDA (for example, eculizumab for STEC‑HUS) may be considered not medically necessary and subject to denial.

    One of seven Jodele criteria used to establish TA‑TMA when ≥4 criteria are met at two consecutive time points within 14 days.
    Supporting evidencerUPCR ≥1 mg/mg identified as a high‑risk feature in expanded access data referenced for narsoplimab.
    inv-27: Hypertension (adult) — systolic ≥ 140 mmHg or diastolic ≥ 90 mmHg
    Adult thresholdHypertension defined for adults as systolic blood pressure ≥ 140 mmHg OR diastolic blood pressure ≥ 90 mmHg.
    Pediatric thresholdFor patients <18 years, hypertension is defined as >99th percentile for age (per Jodele criteria).
    Use in TA‑TMA criteriaHypertension is one of seven Jodele criteria considered for initial Yartemlea authorization when ≥4 criteria are met at 2 consecutive time points within 14 days.
    inv-28: Jodele criteria count — meet at least 4 of 7 at 2 consecutive time points within 14 days
    RequirementMeet at least 4 of the 7 specified Jodele criteria at two consecutive time points within a 14‑day window.
    TimingCriteria must be documented at two separate time points within 14 days to support TA‑TMA diagnosis for Yartemlea initial authorization.
    ApplicationUsed as an alternative to biopsy-proven disease when confirming TA‑TMA for initial Yartemlea coverage.
    PrescriberPrescribed by or in consultation with a hematologist or oncologist per initial therapy criteria for PNH.
    inv-51: MASP-2 inhibitor (narsoplimab-wuug) — definition and mechanism
    MechanismMASP-2 inhibitor (narsoplimab-wuug) inhibits mannan-binding lectin-associated serine protease 2 (MASP‑2), blocking lectin-pathway activation of C3 and C4 without affecting classical or alternative pathways.
    IndicationNarsoplimab (Yartemlea) is indicated for hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA‑TMA).
    Therapeutic rationaleMASP‑2 inhibition is thought to prevent lectin pathway–mediated endothelial injury in TA‑TMA.
    inv-52: C5 inhibitor — definition and mechanism
    DefinitionC5 inhibitors are monoclonal antibodies that bind complement protein C5 and prevent its cleavage to C5a and C5b, inhibiting formation of the membrane attack complex (MAC) and terminal complement activity.
    ExamplesIncludes eculizumab, ravulizumab, and crovalimab as described in the policy background and clinical evidence sections.
    Clinical roleUsed to inhibit terminal complement–mediated intravascular hemolysis in PNH and to reduce complement‑mediated injury in aHUS, gMG, and AQP4+ NMOSD per indications.
    inv-53: TA-TMA — transplant-associated thrombotic microangiopathy definition
    DefinitionTransplant‑associated thrombotic microangiopathy (TA‑TMA) is a TMA that occurs after hematopoietic stem cell transplant, characterized by thrombocytopenia and evidence of microangiopathy and organ dysfunction.
    Clinical featuresTA‑TMA diagnosis can be supported by biopsy or by meeting clinical/laboratory criteria (Jodele criteria) including anemia, thrombocytopenia, elevated LDH, schistocytes, hypertension, elevated sC5b‑9, and proteinuria.
    Therapy relevanceNarsoplimab (Yartemlea) is indicated for TA‑TMA and initial authorization requires biopsy‑proven disease or meeting Jodele criteria; dosing per FDA label.
    inv-54: AQP4+ NMOSD — definition and relevance to coverage
    DefinitionAQP4+ NMOSD refers to neuromyelitis optica spectrum disorder with anti‑aquaporin‑4 antibody positivity.
    Relevance to coverageEculizumab and ravulizumab have demonstrated efficacy in AQP4+ NMOSD and coverage requires neurologist diagnosis and positive AQP4‑IgG serology per the policy.
    DocumentationAuthorization requires neurologist confirmation of characteristic NMOSD syndromes and positive AQP4‑IgG testing, plus exclusion of alternative diagnoses.
    inv-55: Jodele criteria — set of clinical and laboratory criteria for TA‑TMA (meet ≥4 of 7 at 2 consecutive time points within 14 days)
    DefinitionJodele criteria are a set of seven clinical and laboratory findings used to diagnose TA‑TMA: anemia (specific transfusion/hemoglobin criteria), thrombocytopenia (specified platelet criteria), elevated LDH > ULN, presence of schistocytes, hypertension (>99th percentile for age in children or systolic ≥140/diastolic ≥90 mmHg in adults), elevated sC5b‑9 ≥ ULN, and proteinuria (rUPCR ≥1 mg/mg).
    Diagnostic thresholdDiagnosis via Jodele requires meeting at least 4 of the 7 criteria at two consecutive time points within 14 days to support initiation of Yartemlea.
    Use in authorizationJodele criteria may be used instead of biopsy‑proven disease to fulfill initial TA‑TMA authorization requirements for Yartemlea; supporting lab values and documentation must be submitted.