Ravulizumab-cwvz (Ultomiris)

Number: 0946

Policy

Note: Site of Care Utilization Management Policy applies.  For information on site of service for Ultomiris infusions, see Utilization Management Policy on Site of Care for Specialty Drug Infusion.

Note: Ravulizumab-cwvz (Ultomiris) is considered not medically necessary and contraindicated in members with unresolved serious Neisseria meningitidis infection for all medically necessary indications. While receiving ravulizumab-cwvz (Ultomiris), the member should be revaccinated according to current medical guidelines for vaccine use while on ravulizumab-cwvz therapy [REMS program].

New Start

Aetna considers ravulizumab-cwvz (Ultomiris) medically necessary as treatment to reduce hemolysis in adults (18 years of age or older) with paroxysmal nocturnal hemoglobinuria (PNH), who are not switching to ravulizumab-cwvz (Ultomiris) from eculizumab (Soliris), and who have met all of the following criteria:

  • Documented diagnosis of PNH, with flow cytometric confirmation of at least 5 percent PNH cells; and
  • Lactate dehydrogenase (LDH) level greater than or equal to 1.5 times the upper limit of normal (ULN) at screening; and
  • Presence of 1 or more of the following PNH-related signs or symptoms within 3 months of screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin less than 10 g/dL), history of a major adverse vascular event (including thrombosis) (see Appendix), dysphagia, or erectile dysfunction; or history of pRBC transfusion due to PNH; and
  • Member has been vaccinated against meningococcal infection; and
  • Member does not meet diagnostic criteria for severe aplastic anemia (see Appendix).

Switching to ravulizumab-cwvz from eculizumab

Aetna considers switching to ravulizumab-cwvz (Ultomiris) from eculizumab (Soliris) medically necessary to reduce hemolysis in adults (18 years of age or older) with paroxysmal nocturnal hemoglobinuria (PNH) when all of the following criteria are met:

  • PNH diagnosis confirmed by flow cytometric confirmation of at least 5 percent PNH cells; and 
  • Member has been receiving treatment with eculizumab for PNH and is clinically stable; and
  • LDH level is less than or equal to 1.5 × ULN at screening; and
  • Member has been vaccinated against meningococcal infection; and
  • Member does not meet diagnostic criteria for severe aplastic anemia (see Appendix).

Continued use

Aetna considers continued use of ravulizumab-cwvz medically necessary for persons with paroxysmal nocturnal hemoglobunuria (PNH) who met medical necessity criteria at the initiation of treatment, have an LDH level less than or equal to 1.5 times the upper limit of normal, have a reduction in hemolysis as manifested by a stabilization of hemoglobin levels and who have experienced improvement of symptoms from baseline.

Experimental and Investigational

Aetna considers concurrent use of ravulizumab-cwvz and eculizumab experimental and investigational because the safety and efficacy of this combination has not been established.

Aetna considers ravulizumab-cwvz experimental and investigational when criteria are not met and for all other indications including the following (not an all-inclusive list) because the safety and effectiveness for these indications has not been established:

  • Aplastic anemia
  • Atypical hemolytic uremic syndrome (aHUS)
  • Myasthenia gravis.

See also CPB 0807 - Eculizumab (Soliris)

Background

Ultomiris (ravulizumab-cwvz), a complement inhibitor, is a humanized monoclonal antibody (mAb). Ultomiris (ravulizumab-cwvz) binds specifically to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9]) and preventing the generation of the terminal complement complex C5b9. Ultromiris inhibits terminal complement-mediated intravascular hemolysis in persons with paroxysmal nocturnal hemoglobinuria (PNH). Ultomiris was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH) (Alexion Pharma, 2018a, Alexion Pharma, 2018b).

Black Box Warnings:

  • Life‐threatening and fatal meningococcal infections have occurred in patients treated with ravulizumab (Ultomiris). Meningococcal infection may become rapidly life‐threatening or fatal if not recognized and treated early.
  • Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
  • Immunize patients with a meningococcal vaccine at least 2 weeks prior to administering the first dose of ravulizumab (Ultomiris)), unless the risks of delaying ravulizumab (Ultomiris) therapy outweigh the risk of developing a meningococcal infection.
  • Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.

Ultomiris is contraindicated in persons with unresolved Neisseria Meningitidis infection. The most frequent adverse reaction (greater than 10 percent) were upper respiratory infection and headache (Alexion Pharma, 2018b).

Due to the risk of meningococcal infections, Ultomiris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Ultomiris REMS, prescribers must enroll in the program (Alexion Pharma, 2018b).

Paroxysmal Nocturnal Hemoglobinuria (PNH)

On December 21, 2018, the FDA approved Ultomiris (ravulizumab-cwvz) (Alexion Pharmaceuticals, Inc) injection, a long-acting C5 complement inhibitor, for the treatment of adult patients with PNH. FDA approval was based on the results of two Phase 3 studies (301 and 302 study) (Alexion Pharma, 2018a; FDA, 2018).

The 301 study was a phase 3, open-label trial which assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor-naive adults with paroxysmal nocturnal hemoglobinuria (PNH).  A total of 246 patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal, confirmation of at least 5% PNH cells per flow cytometry, and with at least one PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days. Primary efficacy endpoints included proportion of patients remaining transfusion-free, and LDH normalization. Secondary endpoints included percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. The authors found that ravulizumab was noninferior to eculizumab for both co-primary and all key secondary endpoints (Pinf < .0001): transfusion avoidance (73.6% versus 66.1%; difference of 6.8% [95% confidence interval (CI), -4.66, 18.14]), LDH normalization (53.6% versus 49.4%, odds ratio [1.19 (0.80, 1.77)]), percent reduction in LDH (-76.8% versus -76.0%; difference [95% CI], -0.83% [-5.21, 3.56]), change in FACIT-Fatigue score (7.07 versus 6.40; difference [95% CI], 0.67 [-1.21, 2.55]), breakthrough hemolysis (4.0% versus 10.7%; difference [95% CI], -6.7% [-14.21, 0.18]), and stabilized hemoglobin (68.0% versus 64.5%; difference [95% CI], 2.9 [-8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar, and no meningococcal infections occurred. The authors concluded that ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy endpoints, and had similar safety profiles (Lee et al., 2018) ClinicalTrials.gov #NCT02946463.

ClinicalTrials.gov Identifier: NCT02946463 study inclusion criteria included the following:

  • Male or female ≥ 18 years of age
  • PNH diagnosis confirmed by documented by high-sensitivity flow cytometry (confirmation of at least 5% PNH cells)
  • Presence of 1 or more of the following PNH-related signs or symptoms within 3 months of Screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin <10 g/dL), history of a major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction; or history of pRBC transfusion due to PNH
  • LDH level ≥ 1.5 × ULN at screening
  • Documented meningococcal vaccination not more than 3 years prior to, or at the time of, initiating study treatment
  • Female patients of childbearing potential must use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ALXN1210
  • Willing and able to give written informed consent and comply with study visit schedule.

Kulasekararaj et al. (2018) state that ravulizumab was found to be noninferior to eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) who were previously treated with eculizumab and switched to ravulizumab. The authors conducted a phase 3, open-label, multicenter study (302 study) which assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy.  A total of 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for greater than 6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy endpoint was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary endpoints included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. The authors found that In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (Pinf<.0006 for all endpoints), including percentage change in LDH (p = 0.058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI: -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI: -0.21 to 3.15]), transfusion avoidance (difference of 5.5 [95% CI: -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI: -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. The authors concluded that patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. (Funded by Alexion Pharmaceuticals, Inc., ClinicalTrials.gov: NCT03056040).

ClinicalTrials.gov Identifier: NCT03056040 study inclusion criteria included the following:

  • Male or female ≥18 years of age
  • Treated with eculizumab for PNH for at least 6 months prior to Day 1
  • LDH level ≤ 1.5 × ULN at screening
  • PNH diagnosis confirmed by documented by high-sensitivity flow cytometry
  • Documented meningococcal vaccination not more than 3 years prior to, or at the time of, initiating study treatment
  • Female patients of childbearing potential must use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ALXN1210
  • Willing and able to give written informed consent and comply with study visit schedule.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, progressive, life-threatening, multi-systemic clonal blood disorder which leads to impaired production and premature death of blood cells. It is estimated to affect between 1 and 5 per million of people. Although this disorder can affect leukocytes (white blood cells) and thrombocytes (platelets), it has specifically been associated with the abnormal development and destruction of erythrocytes (red blood cells), known as PNH cells, which are deficient in a protein that protects RBCs from being destroyed by a component of the body’s immune system, known as the complement system. People with PNH have sudden, recurring episodes of hemolysis, which can present as hemoglobinuria and anemia. In addition to hemolysis, those with PNH are susceptible to developing thrombosis, pulmonary hypertension, and damage to organs such as the brain, liver, gastro-intestinal system, and kidneys. Individuals may also experience a variety of symptoms that can interfere with quality of life including: abdominal pain, difficulty swallowing, poor physical function, shortness of breath, erectile dysfunction, and debilitating fatigue. The specific symptoms of PNH vary greatly from one person to another and affected individuals usually do not exhibit all of the symptoms associated with the disorder. PNH can occur at any age, although it is most often diagnosed in young adulthood (Alexion Pharma, 2018s; Besa, 2018; FDA, 2018; NIH/NLM, 2018; NORD, 2016).

PNH originates from a somatic mutation of the X-linked phosphatidylinositol glycan class A (PIGA) gene. In PNH, this mutation results in hematopoietic stem cells that are deficient in glycosyl-phosphatidylinositol anchor protein (GPI-AP), which is necessary to protect cells from complement-mediated lysis. The absence of these complement-regulating surface proteins results in uncontrolled amplification of the complement system. This leads to intravascular destruction of the RBC membrane of these PNH cells which results in low RBC counts that causes the symptoms of PNH, and can lead to disability and premature death (Besa, 2018; Brodsky, 2017a).

Flow cytometry is the most useful and accepted method to confirm the diagnosis of PNH. Flow cytometry measures the percentage of cells that are deficient in the GPI-APs and identifies discrete populations with different degrees of deficiency. Because of the missing GPI-APs, RBCs and other cells in persons with PNH lack DAF (CD55) and MIRL (CD59), which regulate complement. The diagnosis of PNH is made by demonstrating that peripheral blood cells are deficient in GPI-linked proteins, in the appropriate clinical setting (e.g., Coombs-negative hemolytic anemia). Absence or reduced expression of both CD59 and CD55 on RBCs is diagnostic of PNH. Since different blood cell lineages display different combinations of GPI-linked proteins, and some proteins bind to cell surfaces via both GPI-linked and GPI-independent mechanisms, it is recommended that at least two independent flow cytometry reagents be used on at least two cell lineages (e.g., RBCs and WBCs) to establish the diagnosis of PNH. Bone marrow examination is not required for the diagnosis of PNH, but is recommended in patients with significant pancytopenia (Besa, 2018; Brodsky, 2017b).

“Complement-mediated intravascular hemolysis is the most prominent clinical feature in classical PNH. Evidence of intravascular hemolysis includes the presence of free hemoglobin in the serum or urine, decreased serum haptoglobin, and elevated serum lactate dehydrogenase (LDH). Elevation of the LDH level to >1.5 times the upper limit of normal can be seen with as few as 3 percent PNH RBCs. Hemolysis in PNH is not exclusively nocturnal, and may be seen continuously by sensitive methods including the serum haptoglobin and LDH” (Brodsky, 2017a).

Historically, treatment of PNH had largely been supportive care measures including anti-coagulation, folic acid supplementation, hydration, and red blood cell (RBC) transfusion.  According to Besa (2018), the “ideal treatment is to replace the defective hematopoietic stem cell with a normal equivalent by stem cell transplantation; however, this is not realistic for many patients, because stem cell transplantation requires a histocompatible donor and is associated with significant morbidity and mortality. This form of treatment is reserved for severe cases of PNH with aplastic anemia or transformation to leukemia, both of which are life-threatening complications.” In 2007, the U.S. Food and Drug Administration [FDA] approved a complement inhibitor called eculizumab (Soliris, Alexion Pharmaceuticals, Inc.) for the treatment of patients with PNH to reduce hemolysis.  Eculizumab is a recombinant humanized monoclonal antibody that works by binding to complement protein C5, inhibiting its enzymatic cleavage, blocking formation of the terminal complement complex, and thus preventing red cell lysis; however, eculizumab requires maintenance administration dosing every 2 weeks. Therefore, the development of a longer-acting infusion may decrease the burden of frequent dosing, without compromising safety and efficacy (Alexion Pharma, 2018a; Besa, 2018; Brodsky, 2018; FDA, 2018). Ravulizumab was engineered from eculizumab to have a substantially longer terminal half-life, permitting longer dosing intervals for patients with PNH (Roth et al. 2018).

Aplastic anemia (AA) with underlying PNH

PNH defect have been detected by flow cytometry in approximately half of persons with AA (Schrier, 2017). An UpToDate review on “Treatment of aplastic anemia in adults” (Shrier, 2018) states that “there is substantial overlap between AA and PNH. Patients with AA have an increased risk of developing PNH, and patients with PNH have an increased risk of developing AA. Therapy for AA in patients with a PNH clone is similar to that for patients without PNH. For those who undergo HCT, this may result in elimination of the PNH clone.” Furthermore, complement inhibitors (i.e., eculizumab and ravulizumab-cwvz) were not listed as a treatment option. Persons who meet criteria for severe aplastic anemia (AA) with a PNH clone (AA/PNH) should be managed with either allogeneic HCT or immunosuppressive therapy for AA (Brodsky, 2018).

Appendix

Ravulizumab-cwvz is available as Ultomiris in 300 mg/30mL (10 mg/mL) single-dose vial for intravenous infusion.

Recommended weight-based dosage regimen of ravulizumab-cwvz for paroxysmal nocturnal hemoglobinuria:

  • The recommended dosing regimen for adults  (18 years of age and older) consists of a loading dose followed by maintenance dosing, administered by intravenous infusion based on the person’s body weight, as shown in Table 1.
  • Starting 2 weeks after the loading dose administration, begin maintenance doses at a once every 8-week interval. The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ravulizumab-cwvz (Ultomiris) but the subsequent dose should be administered according to the original schedule.
  • For persons switching from eculizumab to ravulizumab-cwvz (Ultomiris), administer the loading dose of Ultomiris 2 weeks after the last eculizumab infusion, and then administer maintenance doses once every 8 weeks, starting 2 weeks after loading dose administration, as shown in Table 1.

Table 1: Ravulizumab-cwvz (Ultomiris) Weight-Based Dosing Regimen
Body Weight Range (kg) Loading Dose (mg) Maintenance Dose (mg)
greater than or equal to 40 to less than 60 2,400 3,000
greater than or equal to 60 to less than 100 2,700 3,300
greater than or equal to 100 3,000 3,600

Source: Alexion Pharma, 2018b

Major Adverse Vascular Events (MAVE)

Venous thrombosis

  • Acute peripheral vascular occlusion,
  • Clinically apparent distal embolization (e.g., lower extremity ulceration, tissue necrosis, gangrene, limb amputation or other end-organ damage)
  • Deep vein thrombosis,
  • Hepatic/portal vein thrombosis,
  • Mesenteric/splenic vein thrombosis,
  • Pulmonary embolus, 
  • Renal vein thrombosis,
  • Thrombophlebitis

Arterial thrombosis

  • Acute peripheral vascular occlusion
  • Cerebrovascular accident,
  • Myocardial infarction,
  • Transient ischemic attack,
  • Unstable angina

Source: Hillmen 2007, 2019.

Criteria for Diagnosis of Severe Aplastic Anemia

The diagnostic criteria for severe aplastic anemia are:

  • Bone marrow cellularity less than 25 percent (or cellularity 25 to 50 percent if less than 30 percent of residual cells are hematopoietic); and
  • At least 2 among the following:
     
    • Peripheral blood absolute reticulocyte count less than 20,000 per microL (<20 × 10⁹/L )
    • Peripheral blood platelet count less than 20,000 per microL (<20 × 10⁹/L)
    • Peripheral blood absolute neutrophil count (ANC) less than 500 per microL (<0.5 × 10⁹/L).

Source: Epocrates, 2019; Schrier, 2018



Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

HCPCS codes covered if selection criteria are met:

Ravulizumab-cwvz (Ultomiris) - no specific code:

Other HCPCS codes related to the CPB:

J1300 Injection, eculizumab, 10 mg

ICD-10 codes covered if selection criteria are met:

D59.5 Paroxysmal nocturnal hemoglobinuria [Marchiafava-Micheli]

ICD-10 codes not covered for indications listed in the CPB:

D59.3 Hemolytic-uremic syndrome
D61.01 - D61.9 Other aplastic anemias and other bone marrow failure syndromes
G70.00 - G70.01 Myasthenia gravis

The above policy is based on the following references:

  1. Alexion Pharmaceuticals, Inc. Alexion received early FDA approval for Ultomiris (ravulizumab-cwvz) in adults with paroxysmal nocturnal hemoglobinuria (PNH). Press Release. Boston, MA: Alexion Pharma; December 21, 2018a. Available at: https://news.alexion.com/press-release/product-news/alexion-receives-early-fda-approval-ultomiris-ravulizumab-cwvz-adults-par. Accessed December 28, 2018.
  2. Alexion Pharmaceuticals. Inc. Ultomiris (ravulizumab-cwvz) injection, for intravenous use. Prescribing Information. Reference ID: 4367173. Boston, MA: Alexion Pharma; revised December 2018b.
  3. Alexion Pharmaceuticals, Inc. ALXN1210 versus eculizumab in complement inhibitor treatment-naïve adult patients with paroxysmal nocturnal hemoglobinuria (PNH). ClinicalTrials.gov Identifier: NCT02946463. Bethesda, MD: National Library of Medicine; updated February 14, 2018c.
  4. Alexion Pharmaceuticals, Inc.  ALXN1210 versus eculizumab in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) currently treated with eculizumab. ClinicalTrials.gov Identifier: NCT03056040. Bethesda, MD: National Library of Medicine; updated March 26, 2018d.
  5. Besa EC. Paroxysmal nocturnal hemoglobinuria. Medscape. New York, NY: Medscape; updated December 23, 2018. Available at: https://emedicine.medscape.com/article/207468-overview. Accessed December 28, 2018.
  6. Brodsky RA. Pathogenesis of paroxysmal nocturnal hemoglobinuria. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed November 2017a.
  7. Brodsky RA. Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed November 2017b.
  8. Brodsky RA. Treatment and prognosis of paroxysmal nocturnal hemoglobinuria. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed August 2018.
  9. Epocrates. Aplastic anemia: Diagnostic criteria. Epocrates [online serial]. San Francisco, CA: Epocrates; 2019. Available at: https://online.epocrates.com/diseases/9636/Aplastic-anemia/Diagnostic-Criteria. Accessed January 2, 2019.
  10. Hillmen P. PNH and thrombosis: Who to treat and how. Medscape. New York, NY: Medscape. Available at: https://www.medscape.org/viewarticle/577318. Accessed January 2, 2019.
  11. Hillmen P, Muus P, Duhrsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007; 110(12):4123-4128.
  12. Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: The 302 study. Blood. 2018 Dec 3; pii: blood-2018-09-876805. [Epub ahead of print]
  13. Lee JW, Sicre de Fontbrune F, Wong LL, et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: The 301 study. Blood. 2018 Dec 3; pii: blood-2018-09-876136. [Epub ahead of print]
  14. National Institutes of Health (NIH), National Library of Medicine (NLM). Paroxysmal nocturnal hemoglobinuria. Genetics Home Reference. Bethesda, MD: NIH; December 2018. Available at: https://ghr.nlm.nih.gov/condition/paroxysmal-nocturnal-hemoglobinuria#. Accessed December 28, 2018.
  15. National Organization for Rare Disorders (NORD). Paroxysmal nocturnal hemoglobinuria. Rare Disease Database. Danbury, CT; 2016. Available at: https://rarediseases.org/rare-diseases/paroxysmal-nocturnal-hemoglobinuria/. Accessed December 28, 2018.
  16. Roth A, Rottinghaus ST, Hill A, et al. Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: Results of 2 phase 1b/2 studies. Blood Advances. 2018;2:2176-2185.
  17. Schrier SL. Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2017.
  18. Schrier SL. Treatment of aplastic anemia. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed July 2018.
  19. U.S Food and Drug Administration (FDA). FDA approves new treatment for adult patients with rare, life-threatening blood disease. FDA News Release. Silver Spring, MD: FDA; December 21, 2018.