UnitedHealthcare complement inhibitors Coverage Update

Coverage and Medical Necessity Criteria

inv-01: aHUS - Initial Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

aHUS Initial Therapy: 1) Documentation supporting diagnosis of aHUS by ruling out STEC-HUS and thrombotic thrombocytopenic purpura (e.g., rule out ADAMTS13 deficiency); 2) Laboratory results, signs, and/or symptoms attributed to aHUS (e.g., thrombocytopenia, microangiopathic hemolysis, thrombotic microangiopathy, acute renal failure); 3) Patient is treatment-naïve with the requested product; 4) Requested product is dosed according to US FDA labeled dosing for aHUS; 5) Prescribed by or in consultation with a hematologist or nephrologist; 6) Initial authorization will be for no more than 12 months

inv-02: aHUS - Continuation of Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

aHUS Continuation: 1) Patient has previously been treated with the requested product; 2) Documentation demonstrating a positive clinical response from baseline (e.g., reduction of plasma exchanges, reduction of dialysis, increased platelet count, reduction of hemolysis); 3) Requested product is dosed according to US FDA labeled dosing for aHUS; 4) Prescribed by or in consultation with a hematologist or nephrologist; 5) Reauthorization will be for no more than 12 months

inv-03: STEC-HUS - Not Medically Necessary — 1 top-level node

STEC-HUS: Bkemv, Epysqli, Soliris, and Ultomiris are unproven and not medically necessary for treatment of Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

explicit exclusion

inv-04: PNH - Initial and Continuation Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

PNH Initial Therapy: 1) Flow cytometry confirming presence of PNH clones AND laboratory results, signs, and/or symptoms attributed to PNH (e.g., abdominal pain, anemia, dyspnea, extreme fatigue, smooth muscle dystonia, unexplained/unusual thrombosis, hemolysis/hemoglobinuria, kidney disease, pulmonary hypertension); 2) Requested product is dosed according to US FDA labeled dosing for PNH; 3) For PiaSky authorization only: history of trial and failure, contraindication, or intolerance to a complement C5 inhibitor, Empaveli (pegcetacoplan), or Fabhalta (iptacopan), and patient is not receiving PiaSky in combination with a complement factor D inhibitor; 4) Patient is not receiving the requested product in combination with another complement C5 inhibitor, a complement C3 inhibitor, or a complement factor B inhibitor; 5) Prescribed by or in consultation with a hematologist or oncologist; 6) Initial authorization will be for no more than 12 months

PiaSky-specific step/failure requirements and combination therapy prohibitions included

PNH Continuation: 1) Patient has previously been treated with the requested product; 2) Documentation demonstrating a positive clinical response from baseline (e.g., increased or stabilization of hemoglobin, reduction in transfusions, improvement in hemolysis, decrease in LDH); 3) Requested product is dosed according to US FDA labeled dosing for PNH; 4) Patient is not receiving the requested product in combination with another complement C5 inhibitor, a complement C3 inhibitor, or a complement factor B inhibitor; 5) For PiaSky, patient is not combined with a complement factor D inhibitor; 6) Prescribed by or in consultation with a hematologist or oncologist; 7) Reauthorization will be for no more than 12 months

inv-05: gMG - Initial Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

gMG Initial Therapy: 1) Medical records confirming: no prior failure of a complement C5 inhibitor; diagnosis of generalized myasthenia gravis (gMG); positive anti-AChR antibodies; MGFA Clinical Classification class II, III, or IV at initiation; MG-ADL total score ≥ 6 at initiation; 2) One of: history of failure of at least two immunosuppressive agents over ≥12 months OR failure of at least one immunosuppressive therapy plus ≥4 courses of plasmapheresis/IVIG over ≥12 months without symptom control; 3) Requested product is initiated and titrated per US FDA labeled dosing for gMG; 4) Patient is not receiving the requested product in combination with another complement C5 inhibitor or an FcRn blocker; 5) Prescribed by or in consultation with a neurologist; 6) Initial authorization will be for no more than 12 monthsMG-ADL ≥ 6

Includes prohibited concomitant agents list and specialist prescriber requirement

inv-06: gMG - Continuation of Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

gMG Continuation: 1) Patient has previously been treated with the requested product; 2) Submission of medical records demonstrating improvement and/or maintenance of at least a 2 point improvement (reduction) in MG-ADL score from pre-treatment baseline and reduction in signs and symptoms of myasthenia gravis; 3) Maintenance, reduction, or discontinuation of baseline immunosuppressive therapy (add-on, dose escalation, or additional rescue therapy is considered treatment failure); 4) Requested product is dosed according to US FDA labeled dosing for gMG; 5) Patient is not receiving the requested product in combination with another complement C5 inhibitor or an FcRn blocker; 6) Prescribed by or in consultation with a neurologist; 7) Reauthorization will be for no more than 12 months≥2 point MG-ADL improvement

Dose escalation or additional rescue therapy from baseline while on product = treatment failure

inv-07: Initial Therapy (gMG) — Covered when ALL of the following are met

Covered when ALL of the following are met

gMG initial: Patient has diagnosis of generalized myasthenia gravis (gMG); positive anti-AChR antibodies; MGFA Clinical Classification class II, III, or IV at initiation; MG-ADL total score ≥ 6 at initiation; patient has not failed prior complement C5 inhibitor therapy; requested product initiated and titrated per US FDA gMG dosing; not receiving excluded concomitant therapies (other C5 inhibitors or FcRn blockers); prescribed by or in consultation with a neurologist; initial authorization ≤ 12 months; AND (operator nested) one of: history of failure of ≥2 immunosuppressive agents over ≥12 months OR history of failure of ≥1 immunosuppressive therapy PLUS ≥4 courses of plasmapheresis/IVIG over ≥12 months without symptom controlMG-ADL ≥ 6

Includes prohibited concomitant agents list and specialist prescriber requirement

inv-08: Continuation of Therapy (gMG) — Covered when ALL of the following are met

Covered when ALL of the following are met

gMG continuation: Patient previously treated with the requested product; documentation shows improvement and/or maintenance of at least a 2 point improvement in MG-ADL from pre-treatment baseline; reduction in signs and symptoms of myasthenia gravis; maintenance, reduction, or discontinuation of baseline immunosuppressive therapy (increase or escalation is considered treatment failure); product dosed per US FDA gMG dosing; not receiving excluded concomitant therapies (other C5 inhibitors or FcRn blockers); prescribed by or in consultation with a neurologist; reauthorization ≤ 12 months≥2 point MG-ADL improvement

Dose escalation or additional rescue therapy from baseline while on product = treatment failure

inv-09: Initial Therapy (NMOSD) — Covered when ALL of the following are met

Covered when ALL of the following are met

NMOSD initial: 1) Diagnosis of NMOSD by a neurologist with qualifying clinical history (optic neuritis, acute myelitis, area postrema syndrome, acute brainstem syndrome, symptomatic narcolepsy/diencephalic syndrome with NMOSD-typical MRI lesions, or symptomatic cerebral syndrome with NMOSD-typical lesions); 2) Positive serologic test for anti-AQP4-IgG/NMO-IgG antibodies and alternative diagnoses (e.g., multiple sclerosis) ruled out; 3) Patient has not failed a previous course of a complement C5 inhibitor for NMOSD; 4) History of failure, contraindication, or intolerance to rituximab therapy; 5) One of: ≥2 relapses in prior 12 months OR ≥3 relapses in prior 24 months with ≥1 in last 12 months; 6) Requested product is initiated and titrated per US FDA NMOSD dosing; 7) Prescribed by or in consultation with a neurologist; 8) Patient is not receiving excluded concomitant therapies (MS DMTs, anti-IL6, B-cell depletion); 9) Initial authorization will be for no more than 12 monthsrelapse counts as specified

Prior rituximab failure/intolerance required

inv-10: Continuation of Therapy (NMOSD) — Covered when ALL of the following are met

Covered when ALL of the following are met

NMOSD continuation: 1) Patient has previously been treated with the requested product; 2) Documentation of positive clinical response from baseline demonstrated by reduction in number and/or severity of relapses or signs/symptoms of NMOSD AND maintenance, reduction, or discontinuation of baseline immunosuppressive therapy (add-on, escalation, or additional rescue therapy considered treatment failure); 3) Requested product is dosed according to US FDA labeled dosing for NMOSD; 4) Prescribed by or in consultation with a neurologist; 5) Patient is not receiving excluded concomitant therapies (MS DMTs, anti-IL6, B-cell depletion); 6) Reauthorization will be for no more than 12 monthsdocumented reduction in relapses

Treatment failure defined by escalation/add-on of IST or rescue therapy

inv-11: FDA Indications and Supporting Trial Evidence — FDA-indicated uses and supporting trial outcomes described

FDA-indicated uses and supporting trial outcomes described for each agent in this segment:

PNH: Eculizumab, ravulizumab, crovalimab and pegcetacoplan have demonstrated efficacy for PNH in trials, including LDH reduction, transfusion avoidance, stabilized hemoglobin, and FACIT-F improvements as reported in PEGASUS and COMMODORE 2.

See PEGASUS, COMMODORE 2 summaries

aHUS: Eculizumab and ravulizumab are indicated for inhibition of complement-mediated TMA in aHUS per FDA labeling.

FDA indications listed for Bkemv, Epysqli, Ultomiris.

gMG: Eculizumab and ravulizumab are indicated for anti-AChR antibody-positive generalized myasthenia gravis in adults; clinical trials (e.g., CHAMPION MG, REGAIN) used MG-ADL ≥6 and MGFA Class II-IV entry criteria and reported efficacy outcomes.

MG-ADL and MGFA criteria used in trials

inv-12: Preferred Product Criteria / Soliris Exceptions — Soliris coverage contingent on Preferred Product Criteria; exceptions described

Soliris (eculizumab) is covered only when Preferred Product Criteria are met for Medical Necessity Plans; otherwise Bkemv or Epysqli are preferred.

Preferred-product exception for Soliris

Trial failure path: Documentation of a trial of at least 14 weeks of Bkemv and Epysqli resulting in minimal clinical response and residual disease activity, and physician attests that clinical response would be expected to be superior with Soliris than with Bkemv and Epysqli.>=14 weeks trial
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Intolerance/contraindication path: Documentation of intolerance, contraindication, or adverse event to Bkemv and Epysqli and physician attests the same would not be expected with Soliris.
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Maintenance response path:

Bkemv, Epysqli, Soliris, and Ultomiris are considered not medically necessary for the treatment of Shiga toxin E. coli–related hemolytic uremic syndrome (STEC‑HUS). The policy explicitly states these agents are unproven for STEC‑HUS and therefore will not be approved for this indication.

Requests for complement inhibitor therapy are excluded when the patient is receiving the requested product concomitantly with other prohibited agents for the same indication. Specifically, coverage is not allowed for combination use with another complement C5 inhibitor (e.g., Bkemv, Epysqli, PiaSky, Soliris, Ultomiris, Zilbrysq) or with an FcRn blocker when treating the same condition. For NMOSD, concomitant use with MS disease‑modifying therapies, anti‑IL6 therapies, or B‑cell depletion therapies is also prohibited.

Eculizumab (Soliris) and the related agents Bkemv, Epysqli, PiaSky, and Ultomiris are not indicated for Shiga toxin E. coli–related hemolytic uremic syndrome (STEC‑HUS). The FDA and prescribing information state these products are not approved for STEC‑HUS and available study data are insufficient to establish safety and effectiveness for this indication.

Ultomiris (ravulizumab) is specifically listed in its FDA prescribing information as not indicated for the treatment of Shiga toxin E. coli–related hemolytic uremic syndrome (STEC‑HUS), and the policy mirrors this limitation of use.

The policy identifies Bkemv, Epysqli, Soliris, and Ultomiris as unproven and not medically necessary for the treatment of STEC‑HUS. This statement reinforces that these complement C5 inhibitors lack an established indication for Shiga toxin E. coli–related HUS and will not be authorized for that diagnosis.

Continuation criteria define treatment failure to include add‑on therapy, dose escalation of baseline immunosuppressive therapy, or additional rescue therapy given to treat the condition or an exacerbation while the patient is receiving the requested product. Such actions are considered treatment failure and will preclude approval for continuation.

Policy history notes the removal of a prior statement that PiaSky was unproven and not medically necessary for STEC‑HUS; this revision is documented in the policy history and indicates PiaSky’s STEC‑HUS exclusion language was intentionally removed from the current policy version.

Initial Authorization Requirements

inv-53: Initial Therapy — Initial therapy authorization requirements vary by indication

Initial therapy authorization requirements vary by indication

Initial Therapy - aHUS/PNH/gMG/NMOSD: Meet diagnosis-specific requirements as specified in the Diagnosis-Specific Criteria sections (rule-outs for aHUS, flow cytometry for PNH, antibody confirmation for gMG and NMOSD), product dosing per US FDA labeling, specialist prescriber or consultation as specified, and initial authorization will be for no more than 12 months.

See indication-specific criteria

inv-54: Initial Therapy — Diagnosis-specific entry criteria, prior therapy history, antibody testing, prescriber specialty noted

Initial authorization requires meeting diagnosis-specific entry criteria, prior therapy history, antibody testing, prescriber specialty noted

Initial Therapy Requirements: Submit medical records confirming diagnosis-specific entry criteria: anti-AChR serology and MGFA/MG-ADL for gMG; AQP4-IgG and qualifying clinical history for NMOSD; prior therapy failures as specified (e.g., prior immunosuppressive regimens for gMG; rituximab failure/intolerance for NMOSD); product dosing per FDA label; prescribed by or in consultation with appropriate specialist (neurologist, hematologist, nephrologist); initial authorization ≤ 12 months.

Reauthorization and Ongoing Therapy Requirements

inv-57: Continuation Therapy — Continuation authorization requirements

Continuation authorization requirements

General continuation: Previously treated with the requested product; documentation of positive clinical response from baseline; dosing per US FDA labeled dosing; specialist involvement as specified; reauthorization will be for no more than 12 months.

Applies across indications with indication-specific response measures

inv-58: Continuation Therapy — Prior treatment and documentation of clinical benefit required for reauthorization

Continuation authorization requires prior treatment and documentation of clinical benefit

Continuation requirements: Previously treated with the requested product; documentation of clinical improvement (gMG: ≥2 point MG-ADL improvement; NMOSD: reduction in relapses/severity); maintenance/reduction/discontinuation of baseline immunosuppressive therapy (add-on or escalation considered treatment failure); product dosed per FDA labeling; not receiving excluded concomitant therapies; prescribed by/consultation with appropriate specialist; reauthorization ≤ 12 months.

Billing and Coding

HCPCS/Drug J-codes and Q-codesHCPCS

J1299	Injection, eculizumab, 2 mg
J1303	Injection, ravulizumab-cwvz, 10 mg
J1307	Injection, crovalimab-akkz, 10 mg
Q5151	Injection, eculizumab-aagh (epysqli), biosimilar, 2 mg
Q5152	Injection, eculizumab-aeeb (bkemv), biosimilar, 2 mg

ICD-10 Codes referencedICD-10

D59.30	Hemolytic-uremic syndrome, unspecified
D59.32	Hereditary hemolytic-uremic syndrome
D59.39	Other hemolytic-uremic syndrome
D59.5	Paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli)
G36.0	Neuromyelitis optica (Devic)
G70.00	Myasthenia gravis without (acute) exacerbation
G70.01	Myasthenia gravis with (acute) exacerbation

inv-22: MG-ADL change — Initiation & Continuation

Initiation thresholdMG-ADL total score ≥ 6 at initiation

Continuation thresholdAt least a 2-point improvement (reduction) in MG-ADL from pre-treatment baseline for continuation/reauthorization

Authorization durationInitial and reauthorization approvals limited to no more than 12 months

inv-23: Preferred-product trial duration

Required trial duration>= 14 weeks trial of preferred eculizumab products (Bkemv and Epysqli) to support Soliris exception

Purpose of trialDocument minimal clinical response and residual disease activity after trial to justify switch to Soliris

Prior Authorization, Documentation, and Provider Responsibilities

Prior Authorization

Prior Authorization and Duration

Prior authorization is required for Soliris and other listed complement inhibitors. Initial authorizations are time-limited (generally up to 12 months) and reauthorization is also limited (generally up to 12 months) consistent with the Diagnosis‑Specific Criteria. Requests must include submission of medical records demonstrating the indication, prior therapy history, and the specific documentation elements required for the diagnosis (see Diagnosis‑Specific Criteria).

Initial authorization typically ≤ 12 months; reauthorization typically ≤ 12 months
Submit chart notes, labs, antibody test results, flow cytometry, and documentation of prior therapies where applicable

Denial Risk

Denial Risk for Inadequate Documentation

Requests lacking required documentation will be at high risk of denial. Ensure records fully document diagnostic workup (e.g., rule‑outs for STEC‑HUS and TTP when aHUS is claimed), required antibody or flow testing, baseline clinical measures, and prior therapy trials or intolerances as applicable to the diagnosis.

Step Therapy and Sequencing Rules

Step	Requirement	Supporting details / attestation
1
For Soliris coverage under Preferred Product Criteria, documentation of a trial of at least 14 weeks of Bkemv and Eponjwa (Epysqli) resulting in minimal clinical response and residual disease activity OR documentation of intolerance/contraindication/adverse event to both preferred eculizumab products
Physician attestation that clinical response would be expected to be superior with Soliris than with Bkemv and Epijkstra (Epysqli), or that the same intolerance/AE would not be expected to occur with Soliris; patient must not have lost a favorable response after established maintenance therapy with an eculizumab product

Step	Requirement	Notes
1
History of failure of, contraindication to, or intolerance to rituximab required prior to initiation for NMOSD
Also requires positive AQP4-IgG, MS/other diagnoses ruled out, relapse-count thresholds, neurologist prescriber, and other NMOSD-specific criteria per Diagnosis-Specific Criteria

Step	Observation	Implication for step therapy
1
Comparative clinical trials versus eculizumab exist for pegcetacoplan (PEGASUS) and crovalimab (COMMODORE 2)
No explicit requirement in this segment to fail these agents before eculizumab; step-fail-first sequence not specified here

Step	Requirement	Exceptions / attestation
1
A documented trial of Bkemv and Epigslist (Epijkstra/Epysqli) is required before Soliris coverage (trial duration ≥ 14 weeks) unless intolerance/contraindication or other exception is documented
Exceptions include documented intolerance/contraindication/adverse event to both preferred products with physician attestation that same would not occur with Soliris, or maintained favorable response after established maintenance therapy; physician attestation required regarding superiority or non-recurrence of intolerance/AE

Service Setting and Administration

Billing Rule

Policy covers the drug only; drug administration billed per member benefit

This policy addresses drug only; coverage for drug administration (e.g., infusion in a hospital outpatient department) is determined by the member‑specific benefit plan—refer to the plan document for administration coverage.

Note

Dosing schedules include IV and subcutaneous routes with regular maintenance intervals

Dosing schedules in the policy include both intravenous and subcutaneous administration options with regular maintenance intervals (e.g., IV maintenance every 2 or 8 weeks; crovalimab has subcutaneous loading then q4 weeks maintenance), which may determine site‑of‑care selection.

IV and subcutaneous dosing schedules described in clinical trial dosing sections.
Maintenance intervals vary by product and weight based dosing.

Preferred Products and Biosimilar Guidance

Billing Rule

Bkemv and Epijkstra are preferred; Soliris patients may be required to switch

Bkemv (eculizumab‑aeeb) and Epysqli (eculizumab‑aagh) are designated as the preferred eculizumab products; members on Soliris may be required to change to these preferred products unless they meet the Soliris exception criteria.

Billing Rule

Epallugu (eculizumab‑aagh) classified as HCPCS Q5151

Eculizumab biosimilar Epysqli is listed as HCPCS Q5151 (Injection, eculizumab‑aagh, 2 mg).

Billing Rule

Bkemv (eculizumab‑aeeb) classified as HCPCS Q5152

Eculizumab biosimilar Bkemv is listed as HCPCS Q5152 (Injection, eculizumab‑aeeb, 2 mg).

Billing Rule

Soliris coverage restricted to Preferred Product Criteria or diagnosis‑specific criteria

Key Terms and Abbreviations

inv-43: Initial therapy definition

DefinitionTreatment-naïve patients with documentation supporting the diagnosis and dosing per US FDA labeling

Prescriber requirementPrescribed by or in consultation with a hematologist, nephrologist, or other specialty as indicated by diagnosis

Authorization durationInitial authorization will be for no more than 12 months

inv-44: Continuation of therapy definition

DefinitionPrior treatment with the requested product with documentation of clinical benefit from baseline

Dosing and prescriberDosed per US FDA labeling and prescribed by or in consultation with the appropriate specialist (e.g., hematologist, neurologist)

Policy Background and Clinical Context

This policy addresses the use of terminal complement (C5) inhibitors and related complement pathway agents for multiple indications, including aHUS, PNH, gMG (anti‑AChR positive), and NMOSD (AQP4‑IgG positive). It summarizes FDA‑labeled indications and limitations of use, documents required diagnostic confirmation and specialist prescriber involvement, and references mandatory safety requirements such as REMS enrollment and meningococcal vaccination guidance prior to initiating therapy.

OpenPayer

Complement inhibitor drugs (eculizumab, ravulizumab, crovalimab) — Medical Benefit Drug Policy (Individual Exchange)

Coverage and Medical Necessity Criteria

Initial Authorization Requirements

Reauthorization and Ongoing Therapy Requirements

Billing and Coding

Prior Authorization, Documentation, and Provider Responsibilities

Step Therapy and Sequencing Rules

Service Setting and Administration

Preferred Products and Biosimilar Guidance

Key Terms and Abbreviations

Policy Background and Clinical Context