Complement Inhibitors

Coverage Summary

Coverage stance: covered with criteria for specified complement inhibitors used in defined indications. This policy applies to Bkemv (eculizumab-aeeb), Epysqli (eculizumab-aagh), PiaSky (crovalimab-akkz), Soliris (eculizumab), and Ultomiris (ravulizumab-cwvz) and defines diagnosis-specific medical necessity criteria, preferred product rules, initial/continuation authorization limits, excluded uses, and applicable HCPCS/J-codes and ICD-10 diagnoses.

Products covered: eculizumab variants (Soliris and eculizumab biosimilars including Bkemv and Epysqli), ravulizumab (Ultomiris), and crovalimab (PiaSky) are included in the policy coverage rationale and criteria.

Primary covered indications: the policy includes proven/medically necessary criteria for atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), generalized myasthenia gravis (gMG, anti-AChR+), and neuromyelitis optica spectrum disorder (NMOSD, AQP4-IgG+).

Scope summary: defines coverage and preferred products, detailed diagnosis-specific medical necessity criteria (including documentation requirements and specialist prescribing/consultation), continuation/initial authorization limits (authorization durations up to 12 months), excluded uses (e.g., STEC-HUS), and applicable HCPCS/J-codes and ICD-10 diagnoses for these complement inhibitor products under Colorado Rocky Mountain Health Plans.

Policy thresholds and operational flags

EDSS score (PREVENT trial inclusion)<= 7

REMS + meningococcal vaccinationProducts available only through REMS; vaccinate per ACIP ≥2 weeks before Soliris/Ultomiris when possible

Preferred product (definition)Bkemv (eculizumab-aeeb) and Epysgol/ Epysqli (eculizumab-aagh) are the preferred eculizumab products; coverage contingent on diagnosis-specific criteria

Non-preferred eculizumab (definition)Soliris and any other eculizumab biosimilars not listed as preferred are non-preferred; coverage requires meeting Preferred Product Criteria (trial/failure or intolerance plus physician attestation)

Authorization duration limitInitial and reauthorization approvals limited to no more than 12 months

Preferred Product Criteria (exceptions for non-preferred eculizumab)

Treatment with Soliris or other non-preferred eculizumab biosimilar products is medically necessary for the indications specified in the policy when both of the following criteria are met:

ALL of the following

ONE of
- Both of the following
  - History of a trial of Bkemv (eculizumab-aeeb) or Epysqli (eculizumab-aagh) resulting in minimal clinical response to therapy and residual disease activity.
  - Physician attests that, in their clinical opinion, the clinical response would be expected to be superior with Soliris or other non-preferred eculizumab products than experienced with Bkemv or Epysqli.
- Both of the following

Atypical Hemolytic Uremic Syndrome (aHUS) — Initial and Continuation Criteria

STEC-HUS — Not Medically Necessary

Unproven / Not indicated: Eculizumab is not indicated for the treatment of Shiga toxin E. coli–related hemolytic uremic syndrome (STEC-HUS); available studies are insufficient to establish safety and effectiveness for this indication and the label notes this limitation.

Paroxysmal Nocturnal Hemoglobinuria (PNH) — Initial and Continuation Criteria

Generalized Myasthenia Gravis (gMG, anti-AChR+) — Initial and Continuation Criteria

Coverage constraint change for gMG: the policy now requires that patients receiving complement inhibitor therapy for generalized myasthenia gravis are not concurrently treated with B-cell depletion therapy (e.g., inebilizumab/Uplizna) or with an immune globulin product (e.g., Hizentra, Privigen, Gammagard) for the same indication; claims may be denied if these disallowed combinations are present.

Neuromyelitis Optica Spectrum Disorder (NMOSD) — Initial and Continuation Criteria

NMOSD evidence and indication notes: both ravulizumab (Ultomiris) and eculizumab (Soliris) are indicated for treatment of AQP4-IgG–positive NMOSD. The CHAMPION-NMOSD trial of ravulizumab (weight‑based IV loading on day 1, maintenance on day 15 then every 8 weeks) met its primary endpoint: 0/58 adjudicated relapses in ravulizumab-treated patients versus 20/47 in the external PREVENT placebo comparator (relapse risk reduction 98.6%, p < 0.0001). The PREVENT eculizumab trial (randomized 2:1 eculizumab vs placebo) enrolled patients with prior relapse requirements (history of ≥2 relapses in prior 12 months or ≥3 in prior 24 months, with ≥1 in past 12 months, and EDSS ≤ 7) and showed 3/96 relapses with eculizumab vs 20/47 with placebo with significant relapse reduction.

Policy-level operational change: the policy history documents removal of the prior initial-therapy relapse-count eligibility requirement for NMOSD—the policy no longer requires the previous '≥2 relapses in 12 months or ≥3 relapses in 24 months with ≥1 in past 12 months' for initiation.

Clinical Evidence Highlights

Remaining evidence summaries: Ravulizumab demonstrated noninferiority to eculizumab in PNH pivotal trials (e.g., Study 301/302) with coprimary endpoints including transfusion avoidance and LDH normalization met; Ultomiris showed similar transfusion avoidance and LDH normalization compared with eculizumab. Crovalimab (PiaSky) met noninferiority endpoints versus eculizumab in the COMMODORE 2 study for hemolysis control and transfusion avoidance, with similar proportions achieving LDH ≤1.5×ULN and transfusion avoidance. For aHUS, ravulizumab achieved a complete thrombotic microangiopathy response in 53.6% of patients in a phase 3 single-arm study, with platelet normalization in 83.9%, LDH normalization in 76.8%, and ≥25% serum creatinine improvement in 58.9%.

Safety, REMS, and Vaccination Requirements

Safety definitions and REMS: REMS (Risk Evaluation and Mitigation Strategy) denotes the restricted distribution programs for Bkemv, Epysqli, PiaSky, Soliris, and Ultomiris; prescribers must enroll in the applicable REMS prior to prescribing. The policy defines AQP4-IgG as the anti-aquaporin-4 antibody used to identify seropositive NMOSD patients. Provider obligations: prescribers must enroll in REMS and follow meningococcal vaccination guidance; REMS enrollment contact and web details are provided in the policy for each product.

Provider Actions and Operational Requirements

Documentation Required

Specialist prescription/consultation requirement

Prescriptions must be written by, or in consultation with, the specialist specified for the indication: hematologist or nephrologist for aHUS; hematologist or oncologist for PNH; neurologist for gMG and NMOSD.

aHUS — hematologist or nephrologist
PNH — hematologist or oncologist
gMG — neurologist
NMOSD — neurologist

Prior Authorization

Authorization duration limits

Initial authorizations and reauthorizations (continuation) for indicated diagnoses are limited to no more than 12 months per approval period.

Applicable Codes

J-codes / HCPCS for complement inhibitorsHCPCS

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 diagnosis 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

Not present in this part (no procedure/drug codes listed)mixed

No codes listed

Background and Definitions

Mechanism and therapeutic context: eculizumab and ravulizumab are monoclonal antibodies that bind complement protein C5, inhibiting cleavage to C5a and C5b and preventing formation of the terminal complement complex (C5b-9 or MAC). This mechanism reduces terminal complement–mediated intravascular hemolysis in PNH and limits complement-mediated thrombotic microangiopathy in aHUS; a presumed reduction of C5b-9 at the neuromuscular junction underlies benefit in gMG.

Products covered and purpose: the policy covers specific complement inhibitors—eculizumab (Soliris and listed biosimilars), ravulizumab (Ultomiris), and crovalimab (PiaSky)—and summarizes clinical indications (aHUS, PNH, gMG, NMOSD) and evidence to guide medical necessity determinations and utilization management.

Preferred product: Bkemv (eculizumab-aeeb) and Epijkstra/Epysqli (eculizumab-aagh) are designated as the preferred eculizumab products under this policy and are covered when Diagnosis-Specific Criteria are met.

Non-preferred eculizumab: Soliris (eculizumab) and other non-preferred eculizumab biosimilars are considered non-preferred; coverage is contingent on meeting the Preferred Product Criteria (trial/failure, intolerance, or attestation) before continuing or initiating non-preferred eculizumab.

REMS: Risk Evaluation and Mitigation Strategy (REMS) is the FDA-required restricted distribution program for these complement inhibitors; prescribers must enroll in the applicable REMS program prior to prescribing (contact and website details are provided in the policy).

AQP4-IgG: AQP4-IgG refers to anti-aquaporin-4 antibody used to identify seropositive NMOSD patients for trial inclusion and treatment decisions.

EDSS: Expanded Disability Status Scale (EDSS) is a neurologic disability scale referenced for PREVENT trial eligibility (EDSS ≤ 7).

Revision History

2026-04-01revisedLatest

Revised coverage criteria for Generalized Myasthenia Gravis requiring patients not to receive the requested product in combination with B-cell depletion therapy or an immune globulin for the same indication. Detail: Added criterion disallowing concurrent use with B-cell depletion therapy (e.g., Uplizna/inebilizumab) and immune globulin products (e.g., Hizentra, Privigen, Gammagard).

2026-04-01revisedLatest

Alters eligibility for initial therapy in NMOSD by removing the prior relapse-count requirement. Detail: Removed initial therapy requirement that previously required history of ≥2 relapses in prior 12 months or ≥3 relapses in prior 24 months with ≥1 in past 12 months.