Atypical Hemolytic Uremic Syndrome

Summary Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The atypical form of HUS is a disease characterized by complement overactivation. Inherited defects in complement genes and acquired autoantibodies against complement regulatory proteins have been described. Incomplete penetrance of mutations in all predisposing genes is reported, suggesting that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The underlying genetic defect predicts the prognosis both in native kidneys and after renal transplantation. The successful trials of the complement inhibitor eculizumab in the treatment of atypical HUS will revolutionize disease management.


III. Initial Approval Criteria 1
Site of care specialty infusion program requirements are met (refer to Moda Site of Care Policy).
Coverage is provided in the following conditions: • Patient is at least 18 years of age (unless otherwise specified); AND • Prescriber is enrolled in the Soliris Risk Evaluation and Mitigation Strategy (REMS) program; AND • Patient must be vaccinated against meningococcal disease at least two weeks prior to initiation of therapy and will continue to be revaccinated according to current medical guidelines for vaccine use (Note: if urgent Soliris therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide patients with two weeks of antibacterial drug prophylaxis); AND     − 300 mg weekly x 1 dose, 300 mg at week 2, then 300 mg every 3 weeks 10 kg -<20 kg: − 600 mg weekly x 1 dose, 300 mg at week 2, then 300 mg every 2 weeks 20 kg -<30 kg: − 600 mg weekly x 2 doses, 600 mg at week 3, then 600 mg every 2 weeks 30 kg -<40 kg: − 600 mg weekly x 2 doses, 900 mg at week 3, then 900 mg every 2 weeks ≥ 40 kg: − 900 mg weekly x 4 doses, 1200 mg at week 5, then 1200 mg every 2 weeks Generalized Myasthenia Gravis (gMG) and Neuromyelitis Optica Spectrum Disorder (NMOSD) Loading dose: − 900 mg intravenously every 7 days for the first 4 weeks, followed by 1,200 mg intravenously for the fifth dose 7 days later Maintenance dose: − 1200 mg intravenously every 14 days *Doses should be administered at the above intervals, or within two days of these time points.

Neuromyelitis 24 •o 24 ▪••o•o•o−−
Optica Spectrum Disorder (NMOSD) † Ф 1,13-15,Patient has a confirmed diagnosis based on the following: Patient was found to be seropositive for aquaporin-4 (AQP4) IgG antibodies; AND o Patient has at least one core clinical characteristic § (*Note: some core clinical characteristics require both clinical and typical MRI findings); AND o Alternative diagnoses have been excluded [e.g., myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD), multiple sclerosis, sarcoidosis, cancer, chronic infection, etc.]; AND • Patient has a history of at least 2 relapses in the last 12 months OR 3 relapses in the last 24 months, with at least 1 relapse in the last 12 months; AND • Patient has an Expanded Disability Status Score (EDSS) of ≤ 7.0 (i.e., presence of at least limited ambulation with aid); AND • Patients who are receiving concurrent corticosteroid therapy are on ≤20 mg per day and those receiving immunosuppressive therapy (e.g.azathioprine, glucocorticoids, mycophenolate, etc.) are on a stable dose regimen; AND • Patient has not received therapy with rituximab or mitoxantrone in the last 3 months; AND • Patient has not received intravenous immune globulin (IVIG) in the last 3 weeks; AND • Patient had an inadequate response, or has a contraindication or intolerance, to rituximab OR inebilizumab; AND • Patient will not concomitantly receive therapy with any of the following: o IL-6 inhibitor (e.g., satralizumab) o Anti-CD20-directed antibody (e.g., rituximab) o Anti-CD19-directed antibody (e.g., inebilizumab) § Core Clinical Characteristics of NMOSD Acute optic neuritis ▪ Acute myelitis ▪ Acute area postrema syndrome (APS): episode of otherwise unexplained hiccups and/or nausea and vomiting (lasting for at least 48 hours or with MRI evidence of a dorsal brainstem lesion) ▪ Acute brainstem syndrome other than APS ▪ Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic lesion on MRI ¥ ▪ Acute cerebral syndrome with NMOSD-typical brain lesion on MRI ψ ¥ Diencephalic syndrome: Periependymal lesion (3rd ventricle) OR hypothalamic/thalamic lesion ψ Cerebral syndrome: Extensive periependymal lesion (lateral ventricle; often with Gd) OR long (> 1⁄2 length), diffuse, heterogeneous or edematous corpus callosum lesion OR long corticospinal tract lesion (unilateral or bilateral, contiguously involving internal capsule and cerebral peduncle) OR large, confluent (unilateral or bilateral) subcortical or deep white matter lesion † FDA Approved Indication(s); ‡ Compendia Recommended Indication(s); Ф Orphan Drug IV.Renewal Criteria 1-6,23 Coverage may be renewed based upon the following criteria: Patient continues to meet the universal and other indication-specific relevant criteria identified in section III; AND • Absence of unacceptable toxicity from the drug.Examples of unacceptable toxicity include: serious meningococcal infections (septicemia and/or meningitis), infusion reactions, serious infections, etc.; AND Paroxysmal Nocturnal Hemoglobinuria (PNH) Patient has not developed severe bone marrow failure syndrome (i.e., aplastic anemia or myelodysplastic syndrome) OR experienced a spontaneous disease remission OR received curative allogeneic stem cell transplant; AND • Disease response indicated by one or more of the following: Decrease in serum LDH from pretreatment baseline o Stabilization/improvement in hemoglobin level from pretreatment baseline o Decrease in packed RBC transfusion requirement from pretreatment baseline (i.e., reduction of at least 30%) o Reduction in thromboembolic events Atypical Hemolytic Uremic Syndrome (aHUS) Disease response indicated by one or more of the following: Decrease in serum LDH from pretreatment baseline o Stabilization/improvement in serum creatinine/eGFR from pretreatment baseline o Increase in platelet count from pretreatment baseline o Decrease in plasma exchange/infusion requirement from pretreatment baseline Generalized Myasthenia Gravis (gMG) Patient has had an improvement (i.e., reduction) of at least 1-point from baseline in the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score Δ; AND • Improvement in muscle strength testing with fatigue maneuvers as evidenced on neurologic examination when compared to baseline [Δ May substitute an improvement of at least 1-point from baseline in the Quantitative Myasthenia Gravis (QMG) total score, if available] Neuromyelitis Optica Spectrum Disorder (NMOSD) • Disease response as indicated by stabilization and/or improvement of neurologic symptoms as evidenced by one or more of the following: Decrease in acute relapses o Improvement in EDSS o Reduced hospitalizations o Reduction/discontinuation in plasma exchange treatments 600 mg intravenously every 7 days for the first 4 weeks, followed by 900 mg intravenously for the fifth dose 7 days later Maintenance dose: 900 mg intravenously every 7 days for the first 4 weeks, followed by 1,200 mg intravenously for the fifth dose 7 days later Maintenance dose: − 1200 mg intravenously every 14 days Patients < 18 years 5 kg -<10 kg: 1,2-6,9,16,23

Myasthenia Gravis Foundation of America (MGFA) Disease Clinical Classification 19 :
Patient had an inadequate response, or has a contraindication or intolerance, to efgartigimod alfa-fcab [Vyvgart™] or fgartigimod alfa and hyaluronidase-qvfc [Vyvgart Hytrulo™] or rozanolixizumab-noli [Rystiggo®] § − Class I: Any ocular muscle weakness; may have weakness of eye closure.All other muscle strength is normal.− Class II: Mild weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.• IIa.Predominantly affecting limb, axial muscles, or both.May also have lesser involvement of oropharyngeal muscles.• IIb.Predominantly affecting oropharyngeal, respiratory muscles, or both.May also have lesser or equal involvement of limb, axial muscles, or both.− Class III: Moderate weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.• IIIa.Predominantly affecting limb, axial muscles, or both.May also have lesser involvement of oropharyngeal muscles.• IIIb.Predominantly affecting oropharyngeal, respiratory muscles, or both.May also have lesser or equal involvement of limb, axial muscles, or both.− Class IV: Severe weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.
• Patient is at least 2 months of age; AND • Thrombotic Thrombocytopenic Purpura (TTP) has been ruled out by evaluating ADAMTS-13 level (i.e., ADAMTS-13 activity level ≥ 10%); AND• Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS) has been ruled out; AND • Other causes have been ruled out such as coexisting diseases or conditions (e.g., bone marrow transplantation, solid organ transplantation, malignancy, autoimmune disorder, drug-induced, malignant hypertension, HIV infection, Streptococcus pneumoniae sepsis or known genetic defect in cobalamin C metabolism, etc); AND • Documented baseline values for one or more of the following (necessary for renewal): serum lactate dehydrogenase (LDH), serum creatinine/eGFR, platelet count, and plasma exchange/infusion requirement; AND • Patient had an inadequate response, contraindication, or intolerance to a trial of ravulizumab (Ultomiris®) Generalized Myasthenia Gravis (gMG) † Ф 1,11,12, 18-22 • Patient has Myasthenia Gravis Foundation of America (MGFA) Clinical Classification of Class II to IV disease §; AND • Patient has a positive serologic test for anti-acetylcholine receptor (AChR) antibodies; AND • Patient has had a thymectomy (Note: Applicable only to patients with thymomas OR nonthymomatous patients who are 50 years of age or younger); AND • Physician has assessed objective signs of neurological weakness and fatiguability on a baseline neurological examination [e.g., including, but not limited to, the Quantitative Myasthenia Gravis (QMG) score, etc.]; AND • Patient has a baseline MG-Activities of Daily Living (MG-ADL) total score of ≥6; AND o Patient had an inadequate response after a minimum one-year trial of concurrent use with two (2) or more immunosuppressive therapies (e.g., corticosteroids plus an immunosuppressant such as azathioprine, cyclosporine, mycophenolate, etc.); OR o Patient required chronic treatment with plasmapheresis or plasma exchange (PE) or intravenous immunoglobulin (IVIG) in addition to immunosuppressant therapy • Patient will avoid or use with caution medications known to worsen or exacerbate symptoms of MG (e.g., certain antibiotics, beta-blockers, botulinum toxins, hydroxychloroquine, etc.); AND • Patient had an inadequate response, contraindication, or intolerance to a trial of ravulizumab (Ultomiris®); AND • • IVa.Predominantly affecting limb, axial muscles, or both.May also have lesser involvement of oropharyngeal muscles.•IVb.Predominantly affecting oropharyngeal, respiratory muscles, or both.May also have lesser or equal involvement of limb, axial muscles, or both.− Class V: Defined as intubation, with or without mechanical ventilation, except when employed during routine postoperative management.The use of a feeding tube without intubation places the patient in class IVb.