Ravulizumab-cwvz (Ultomiris)

Number: 0946

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses ravulizumab-cwvz (Ultomiris) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of ravulizumab-cwvz (Ultomiris) is required of all Aetna participating providers and members in applicable plan designs. For precertification of ravulizumab-cwvz, call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

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.

1. Criteria for Initial Approval

   Aetna considers ravulizumab-cwvz (Ultomiris) medically necessary for the treatment of the following indications:

   1. Paroxysmal Nocturnal Hemoglobinuria (PNH)

      For the treatment of PNH, when all of the following criteria are met:

      1. The diagnosis of PNH was confirmed by detecting a deficiency of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as demonstrated by either of the following:

         1. At least 5% PNH cells; or
         2. At least 51% of GPI deficient poly-morphonuclear cells; and

      2. Flow cytometry is used to demonstrate GPI-APs deficiency. 

   2. Atypical hemolytic uremic syndrome (aHUS)

      For the treatment of aHUS not caused by Shiga toxin when both of the following criteria are met:

      1. Absence of Shiga toxin; and
      2. ADAMTS 13 activity level above 5%.

   3. Generalized myasthenia gravis (gMG)

      For the treatment of generalized myasthenia gravis (gMG) when all of the following criteria are met:

      1. Anti-acetylcholine receptor (AchR) antibody positive; and
      2. Myasthenia Gravis Foundation of America (MGFA) clinical classification II to IV; and
      3. MG activities of daily living (MG-ADL) total score greater than or equal to 6; and
      4. Meets both of the following:
         
         

         1. Member has had an inadequate response to at least two immunosuppressive therapies listed below:

            1. azathioprine
            2. cyclosporine
            3. mycophenolate mofetil
            4. tacrolimus
            5. methotrexate
            6. cyclophosphamide
            7. rituximab; and

         2. Member has inadequate response to chronic IVIG.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of ravulizumab-cwvz (Ultomiris) therapy medically necessary for treatment of the following indications when criteria are met:

   1. Paroxysmal nocturnal hemoglobinuria (PNH)

      For members requesting reauthorization when there is no evidence of unacceptable toxicity or disease progression while on the current regimen and demonstrate a positive response to therapy (e.g., improvement in hemoglobin levels, normalization of lactate dehydrogenase [LDH] levels);

   2. Atypical hemolytic uremic syndrome (aHUS)

      For members requesting requesting reauthorization when there is no evidence of unacceptable toxicity or disease progression while on the current regimen and demonstrate a positive response to therapy (e.g., normalization of lactate dehydrogenase (LDH) levels, platelet counts);

   3. Generalized myasthenia gravis (gMG)

      For members requesting reauthorization when there is no evidence of unacceptable toxicity or disease progression while on the current regimen and member demonstrates a positive response to therapy (e.g., improvement in MG-ADL score, changes compared to baseline in Quantitative Myasthenia Gravis (QMG) total score).

3. Related Policies

   1. CPB 0807 - Eculizumab (Soliris)

Dosage and Administration

Note: Approvals may be subject to dosing limits in accordance with FDA-approved labeling, accepted compendia, and/or evidence-based practice guidelines. Below includes dosing recommendations as per the FDA-approved prescribing information. 

Paroxysmal Nocturnal Hemoglobinuria (PNH), Atypical Hemolytic Uremic Syndrome (aHUS), and Myasthenia Gravis (gMG)

Ravulizumab-cwvz is available as Ultomiris in 300 mg/30mL (10 mg/mL), 300 mg/3mL (100 mg/mL), and 1,100 mg/11mL (100 mg/mL) in a single-dose vial for intravenous (IV) infusion.

The recommended dosing regimen in adults and pediatrics, one month of age or older weighing 5 kg or greater, with PNH and aHUS, or in adults with gMG weighing 40 kg or greater, consists of a loading dose followed by maintenance dosing, administered by intravenous infusion. The dosing is based on the person’s body weight, as shown in Table 1. Starting 2 weeks after the loading dose administration, begin maintenance doses once every 4 or 8 weeks, based on body weight. The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of Ultomiris); but the subsequent doses should be administered according to the original schedule.

For persons switching from eculizumab to Ultomiris, administer the loading dose of Ultomiris 2 weeks after the last eculizumab infusion, and then administer Ultomiris maintenance doses once every 4 weeks or every 8 weeks (depending on body weight), starting 2 weeks after loading dose administration. Administration of plasmapheresis or plasma exchange, or fresh frozen plasma infusion, may reduce Ultomiris serum levels. There is no experience with administration of supplemental doses of Ultomiris.

Table 1: Ravulizumab-cwvz (Ultomiris) Weight-Based Dosing Regimen for PNH, aHUS, and gMG

Body Weight Range (kg)	Loading Dose (mg)	Maintenance Dose (mg) and Dosing Interval
5 to less than 10	600	300	Every 4 weeks
10 to less than 20	600	600
20 to less than 30	900	2,100	Every 8 weeks
30 to less than 40	1,200	2,700
40 to less than 60	2,400	3,000
60 to less than 100	2,700	3,300
100 or greater	3,000	3,600

Source: Alexion Pharma, 2022

Experimental and Investigational

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

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

   • Amyotrophic lateral sclerosis (ALS)
   • Aplastic anemia
   • Coronavirus disease 2019 (COVID-19)
   • Neuromyelitis optica.

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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:
J1303	Injection, ravulizumab-cwvz, 10 mg
ICD-10 codes covered if selection criteria are met:
D59.30, D59.31, D59.32, D59.39	Hemolytic-uremic syndrome
D59.5	Paroxysmal nocturnal hemoglobinuria [Marchiafava-Micheli]
G70.00 - G70.01	Myasthenia gravis
ICD-10 codes not covered for indications listed in the CPB:
D61.01 - D61.9	Other aplastic anemias and other bone marrow failure syndromes
G12.21	Amyotrophic lateral sclerosis
G36.0	Neuromyelitis optica [Devic]
J12.82	Pneumonia due to coronavirus disease 2019
U07.1	COVID-19

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Ultomiris is indicated for the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH).
• Ultomiris is indicated for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).
• Ultomiris is indicated for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive.
  
  
• Limitations of Use: Ultomiris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

Ravulizumab-cwvz is available as Ultomiris (Alexion Pharmaceuticals, Inc), a terminal complement inhibitor. 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) and complement-mediated thrombotic microangiopathy (TMA) in persons with atypical hemolytic uremic syndrome (aHUS). The precise mechanism by which ravulizumab-cwvz exerts its therapeutic effect in generalized myasthenia gravis (gMG) patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction (Alexion Pharma, 2022).

Black Box Warnings:

• Life‐threatening and fatal meningococcal infections/sepsis 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.
• Vaccination reduces, but does not eliminate, the risk of 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, or who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying Ultomiris treatment outweigh the risks of developing a meningococcal infection. The most frequent adverse reaction in persons with PNH (10 percent or more) were upper respiratory infection and headache. The most common adverse reactions in patients with aHUS (20% or more) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia. The most common adverse reactions in adult patients with gMG (incidence of 10% or more) were diarrhea and upper respiratory tract infection (Alexion Pharma, 2022).

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, 2022).

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., 2019) 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 (2019) stated 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, 2018a; 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).

In June 2021, the FDA approved the exapanded use of Ultomiris to include children (one month of age and older) and adolscents with PNH. The approval was based on "interim Phase 3 study results, which showed that Ultomiris was effective in achieving complete C5 complement inhibition through 26 weeks in children and adolescents up to 18 years of age. Additionally, Ultomiris had no reported treatment-related severe adverse events, and no patients discontinued treatment during the primary evaluation period or experienced breakthrough hemolysis, which can lead to disabling or potentially fatal blood clots. The efficacy and safety of Ultomiris in children and adolescents is consistent with the established profile of Ultomiris in clinical studies involving adults with PNH" (Alexion, 2021).

Dezern and Borowitz (2018) discuss the ICCS/ESCCA consensus guidelines regarding the clinical utility of detecting glycosyl phosphatidylinositol (GPI)-deficient cells in PNH and other bone marrow failure disorders. The authors state that flow cytometry is used to detect the deficiency in PNH. Their guidelines provide guidance to clinicians on patient selection and test interpretation (including PNH clone testing). The authors note that when PNH flow cytometry testing is interpreted correctly, the results ("including presence and size of the clonal populations and the cell types involved") will allow the clinician "to classify the disease appropriately; evaluate the risk of disease progression; and subsequently monitor response to therapy". The authors emphasize the positive contribution of flow cytometry testing in the diagnosis, classification, and monitoring of patients.

Atypical Hemolytic Uremic Syndrome (aHUS)

Atypical hemolytic uremic syndrome (aHUS) is a rare disease that is characterized by hemolytic anemia, thrombrocytopenia and kidney failure. This condition causes inflammation and the formation of blood clots in small blood vessels throughout the body (thrombotic microangiopathy [TMA]) mediated by chronic, uncontrolled activation of the complement system. TMA consists of reduced platelet count (thrombocytopenia), hemolytic anemia (as a result of hemolysis [destruction of red blood cells]) and acute kidney injury (AKI). If left untreated, significant proportions of adults (46 percent) and children (16 percent) can progress to end-stage renal disease (ESRD) or die during first clinical manifestations of aHUS despite supportive care, including plasma exchange or plasma infusion. One year following clinical manifestations, 56 percent of adults and 29 percent of children can progress to ESRD or die, if left untreated (Alexion Pharma, 2019; NIH, 2017; NORD 2016).

On October 18, 2019, the U.S. Food and Drug Administration (FDA) approved Ultomiris (ravulizumab-cwvz) for the treatment of atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA) for adult and pediatric (one month of age and older) patients. The FDA approval is based on data from two global, single-arm open-label studies of Ultomiris – one in adults and one in children with aHUS. The pediatric study is ongoing and a total of 14 out of 16 children were enrolled and included in the interim analysis. Efficacy evaluation of Complete TMA Response was defined by hematologic normalization parameters (platelet count and LDH) and improved kidney function (as measured by 25 percent and greater improvement in serum creatinine from baseline). In the initial 26-week treatment periods, 54 percent of adults and 71 percent (interim data) of children demonstrated Complete TMA Response. Study outcomes showed that treatment with Ultomiris resulted in reduced thrombocytopenia (low blood platelet count) in 84 percent of adults and 93 percent of children, reduced hemolysis in 77 percent of adults and 86 percent of children, and improved kidney function in 59 percent of adults and 79 percent (interim data) of children (for patients on dialysis at enrollment, baseline was established after they had come off dialysis).The most frequently observed adverse reactions reported in these studies were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia. Serious meningococcal infections have occurred in patients treated with Ultomiris. To minimize the risk for patients, specific risk-mitigation plans, including a REMS program, have been established for Ultomiris (Alexion Pharma, 2019).

The adult study [ALXN1210-aHUS-311; NCT02949128] was conducted in patients who were naïve to complement inhibitor treatment prior to study entry. The study consisted of a 26-week Initial Evaluation Period and patients were allowed to enter an extension period for up to 4.5 years. A total of 56 adult patients with aHUS were evaluated for efficacy. Ninety-three percent of patients had extrarenal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 71.4% (n = 40) of patients had Stage 5 chronic kidney disease (CKD). Fourteen percent had a medical history of kidney transplant and 51.8% were on dialysis at study entry. Eight patients entered the study with evidence of TMA for > 3 days after childbirth (ie, postpartum). One additional patient had a Complete TMA Response that was confirmed after the 26-week Initial Evaluation Period. Complete TMA Response was achieved at a median time of 86 days (range: 7 to 169 days). The median duration of Complete TMA Response was 7.97 months (range: 2.52 to 16.69 months). All responses were maintained through all available follow-up. Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by estimated glomerular filtration rate (eGFR). An increase in mean platelet count was observed after commencement of Ultomiris at Day 8 and remaining above 227 × 109 /L at all subsequent visits in the Initial Evaluation Period (26 weeks). Renal function, as measured by eGFR, was improved or maintained during therapy. The mean eGFR increased from 15.86 (14.82) at baseline to 51.83 (39.16) by 26 weeks. In patients with Complete TMA Response, renal function continued to improve after the Complete TMA Response was achieved. Seventeen of the 29 patients (59%) who required dialysis at study entry discontinued dialysis by the end of the available follow-up and 6 of 27 (22%) patients were off dialysis at baseline were on dialysis at last available follow-up (Alexion Pharma 2022).

The Pediatric Study [ALXN1210-aHUS-312; NCT03131219] is a 26-week ongoing, multicenter, single-arm study conducted in 16 pediatric patients. A total of 14 eculizumab-naïve patients with documented diagnosis of aHUS were enrolled and included in this interim analysis. The median age at the time of first infusion was 5.2 years. The overall mean weight at Baseline was 19.8 kg; half of the patients were in the baseline weight category ≥ 10 to < 20 kg. The majority of patients (71%) had pretreatment extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 35.7% (n = 5) of patients had a CKD Stage 5. Seven percent had history of prior kidney transplant and 35.7% were on dialysis at study entry. Efficacy evaluation was based upon Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet all Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between. Complete TMA Response was observed in 10 of the 14 patients (71%) during the 26-week Initial Evaluation Period. Complete TMA Response during the Initial Evaluation Period was achieved at a median time of 30 days. The median duration of Complete TMA Response was 5.08 months. All responses were maintained through all available follow-up. Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by eGFR. An increase in mean platelet count was observed after commencement of Ultomiris, increasing from 60.50 × 109 /L at baseline to 296.67 × 109 /L at Day 8 and remained above 296 × 109 /L at all subsequent visits in the Initial Evaluation Period (26 weeks). The mean eGFR increased from 28.4 at baseline to 108.0 by 26 weeks. Four of the 5 patients who required dialysis at study entry were able to discontinue dialysis after the first month in study and for the duration of treatment. No patient started dialysis during the study (Alexion Pharma, 2022).

Generalized Myasthenia Gravis (gMG)

In April 2022, the U.S. FDA approved Ultomiris (ravulizumab) or the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive, which represents 80% of people living with the disease. FDA approval was based on results from the CHAMPION-MG Phase III trial which showed Ultomiris was superior to placebo in the primary endpoint of change from baseline in the Myasthenia Gravis-Activities of Daily Living Profile (MG-ADL) total score at Week 26, a patient-reported scale that assesses patients’ abilities to perform daily activities (AstraZeneca, 2022).

The CHAMPION-MG Phase III trial is a randomized, double-blind, placebo-controlled, multicenter 26-week trial that evaluated the safety and efficacy of ravulizumab in adults with gMG. The trial enrolled 175 patients across North America, Europe, Asia-Pacific and Japan. Participants were required to have a confirmed myasthenia gravis diagnosis at least six months prior to the screening visit with a positive serologic test for anti-AChR antibodies, MG-ADL total score of at least 6 at trial entry and Myasthenia Gravis Foundation of America Clinical Classification Class II to IV at screening. Patients could stay on stable standard of care medicines, with a few exceptions, for the duration of the randomized control period. Patients were randomized 1:1 to receive ravulizumab or placebo for a total of 26 weeks. Patients received a single weight-based loading dose on Day 1, followed by regular weight-based maintenance dosing beginning on Day 15, every eight weeks. The primary endpoint of change from baseline in the MG-ADL total score at Week 26 was assessed along with multiple secondary endpoints evaluating improvement in disease-related and quality-of-life measures. Treatment with ravulizumab demonstrated a statistically significant change in the MG-ADL and Quantitative Myasthenia Gravis (QMG) total scores from baseline at Week 26 as compared to placebo. Patients who completed the randomized control period were eligible to continue into an open-label extension period evaluating the safety and efficacy of ULTOMIRIS, which is ongoing (Alexion Pharma, 2022; AstraZeneca, 2022).

Other Indications

Amyotrophic Lateral Sclerosis

Chen (2020) noted that amyotrophic lateral sclerosis (ALS) is a devastating, fatal neuromuscular disease.  Most patients die within 2 to 5 years of diagnosis.  The disease stems from death of upper and lower motor neurons leading to degeneration of motor pathways and the paralytic effects of the disease.  Two drugs, riluzole and edaravone, are currently FDA-approved for the treatment of ALS, and each provides modest benefits in mortality and/or function.  Recent developments in the understanding of the underlying pathophysiologic processes that contribute to ALS have led to the development of numerous investigational therapies, with several now in phase-III clinical trials.  The author highlighted the oral tyrosine kinase inhibitor masitinib; the antisense drug tofersen; the humanized monoclonal antibody C5 complement inhibitor ravulizumab-cwvz; and mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells, a proprietary platform that induces autologous bone marrow-derived MSCs to secrete high levels of NTFs.

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).

Coronavirus Disease (COVID-19)

Smith et al (2020) presented the protocol of an open-label, randomized-controlled, multi-center, phase-III clinical trial that will examine to the effect of ravulizumab plus best supportive care (BSC) compared with BSC alone on the survival of patients with COVID-19.  Secondary objectives of this trial include number of days free of mechanical ventilation at day 29, duration of ICU stay at day 29, change from baseline in sequential organ failure assessment (SOFA) score at day 29, change from baseline in peripheral capillary oxygen saturation/ fraction of inspired oxygen (SpO2 /FiO2) at day 29, duration of hospitalization at day 29, survival (based on all-cause mortality) at day 60 and day 90.  Safety outcomes include incidence of treatment-emergent AEs and treatment-emergent serious AEs.  PK/PD/Immunogenicity parameters include change in serum ravulizumab concentrations over time, change in serum free and total C5 concentrations over time, incidence and titer of anti-ALXN1210 antibodies biomarkers, change in absolute level of soluble biomarkers in blood associated with complement activation, inflammatory processes, and hypercoagulable states over time.  Exploratory parameters include incidence of progression to renal failure requiring dialysis at day 29, time to clinical improvement (based on a modified 6-point ordinal scale) over 29 days, SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores at day 29 (or discharge), day 60, and day 90, EuroQol 5-dimension 5-level (EQ-5D-5L) scores at day 29 (or discharge), day 60, and day 90.  The trial is being carried out in acute care hospital settings in the U.S., U.K., Spain, France, Germany, and Japan.

Participants: Male or female patients at least 18 years of age, weighing 40 kg or more, admitted to a designated hospital facility for treatment will be screened for eligibility in this study.  Key Inclusion criteria entail confirmed diagnosis of SARS-CoV-2 infection (e.g., via polymerase chain reaction [PCR] and/or antibody test) presenting as severe COVID-19 requiring hospitalization, severe pneumonia, acute lung injury (ALI), or acute respiratory distress syndrome (ARDS) confirmed by computed tomography (CT) or X-ray at screening or within the 3 days before screening, as part of the patient's routine clinical care, respiratory distress requiring mechanical ventilation, which can be either invasive (requiring endotracheal intubation) or non-invasive (with continuous positive airway pressure [CPAP] or bi-level positive airway pressure [BiPAP]).  Key exclusion criteria: Patient is not expected to survive for more than 24 hours, patient is on invasive mechanical ventilation with intubation for more than 48 hours before screening, severe pre-existing cardiac disease (i.e., New York Heart Association [NYHA] Class 3 or Class 4, acute coronary syndrome [ACS], or persistent ventricular tachyarrhythmias [VTs]), patient has an unresolved Neisseria meningitidis infection.  Excluded medications and therapies: Current treatment with a complement inhibitor, intravenous immunoglobulin (IVIg) within 4 weeks before randomization on day 1.  Excluded prior/concurrent clinical study experience: Treatment with investigational therapy in a clinical trial within 30 days before randomization, or within 5 half-lives of that investigational therapy, whichever is greater.  Exceptions: (a) -- Investigational therapies will be allowed if received as part of BSC via an expanded access protocol or emergency approval for the treatment of COVID-19;and (b) -- Investigational anti-viral therapies (such as remdesivir) will be allowed even if received as part of a clinical study.  Intervention and comparator: The study consists of a screening period of up to 3 days, a primary evaluation period of 4 weeks, a final assessment at day 29, and a follow-up period of 8 weeks.  For patients randomized to ravulizumab plus BSC, a weight-based dose of ravulizumab (40 or higher to less than 60 kg/2,400 mg, 60 to less than 100 kg/2,700 mg, 100 kg or higher/3,000 mg) will be administered on day 1.  On day 5 and day 10, additional doses of 600 mg (40 or higher to less than 60 kg) or 900 mg (greater than 60 kg) ravulizumab will be administered and on day 15 patients will receive 900 mg ravulizumab.  There is no active or placebo comparator in this open-label clinical trial.  The total duration of each patient's participation is anticipated to be approximately 3 months.

Main outcomes: The primary efficacy outcome of this study is survival (based on all-cause mortality) at day 29.  Randomisation: Patients will be randomized in a 2:1 ratio (ravulizumab plus BSC:BSC alone).  Randomization will be stratified by intubated or not intubated on day 1.  Computer-generated randomization lists will be prepared by a 3rd party under the direction of the sponsor.  Investigators, or designees, will enroll patients and then obtain randomization codes using an interactive voice/web response system.  The block size will be kept concealed so that investigators cannot select patients for a particular treatment assignment.  Blinding (masking): This is an open-label study.  Numbers to be randomized (sample size): Approximately 270 patients will be randomly assigned in a 2:1 ratio to ravulizumab plus BSC (n = 180) or BSC alone (n = 90).  Trial status: Recruitment was initiated on May 11, 2020, and expected to be completed by November 30, 2020.

McEneny-King and colleagues (2021) noted that terminal complement amplification is hypothesized to be a key contributor to the clinical manifestations of severe COVID-19.  Ravulizumab binds with high affinity to complement protein C5 and inhibits terminal complement activation, is being examined as a treatment for COVID-19-related severe pneumonia, acute lung injury, and acute respiratory distress syndrome in an ongoing phase-III randomized controlled trial (RCT; ALXN1210-COV-305).  To address the over-activation of terminal complement in severe COVID-19 compared to the diseases in which ravulizumab is currently approved, a modified dosing regimen was adopted.  This analysis examined preliminary pharmacokinetic/pharmacodynamic data to confirm the modified dosing regimen.  Weight-based ravulizumab doses were administered on days 1, 5, 10, and 15.  Serum levels of ravulizumab and free C5 were measured before and after administration of ravulizumab and any time on day 22.  Free C5 levels of less than 0.5 μg/ml indicated complete C5 inhibition.  The pharmacokinetic target was defined as ravulizumab concentrations at the end of the dosing interval of greater than 175 μg/ml, the concentration above which C5 was completely inhibited.  A total of 22 patients were included in this study.  At baseline, mean C5 concentration was 240 ± 67 μg/ml.  In all patients and at all individual timepoints after the 1st dose was administered, ravulizumab concentrations remained greater than 175 μg/ml and free C5 concentrations remained less than 0.5 μg/ml.  The authors concluded that high levels of baseline C5 observed in patients with severe COVID-19 contributed to the growing body of evidence that suggested this disease is marked by amplification of terminal complement activation.  Data from this preliminary pharmacokinetic/pharmacodynamic study of 22 patients with severe COVID-19 showed that the modified ravulizumab dosing regimen achieved immediate and complete terminal complement inhibition, which could be sustained for up to 22 days.  These researchers stated that these findings supported the continued use of this dosage regimen in the ongoing phase-III clinical trial. 

The authors stated that this study had several drawbacks.  This PK/PD evaluation did not include clinical outcomes; thus, no inferences regarding the impact of ravulizumab on the course of disease could be made.  The baseline C5 data suggested an association between severe COVID-19 and terminal complement up-regulation; but did not inform whether C5 is a marker of disease severity or a contributor to the pathobiology.  Furthermore, as there is a paucity of data describing C5 levels in viral infections, interpreting baseline C5 levels in the context of infectious disease is difficult.  A control group was not included in this analysis; thus, inhibition of C5 levels could only be presumed to reflect ravulizumab inhibition of terminal complement.  Descriptions of the change in free C5 levels in patients on BSC would be needed to support this conclusion.  In this cohort, no patients weighed less than 60 kg.  These researchers stated that although additional data are needed, drug exposures are expected to be no lower in patients less than 60 kg than those achieved in this evaluation.  A full PK/PD characterization using model-based techniques and an outcome analysis of the whole cohort of study ALXN1210-COV-305 are planned.

Annane et al (2023) noted that the complement pathway is a potential target for the treatment of severe COVID-19.  In an open-label, randomized controlled, multi-center, phase-III clinical trial, these researchers examined the safety and effectiveness of ravulizumab in patients hospitalized with severe COVID-19 requiring invasive or non-invasive mechanical ventilation.  They enrolled adult patients (aged18 years or older) from 31 hospitals in France, Japan, Spain, the U.K., and the U.S.  Eligible patients had a confirmed diagnosis of SARS-CoV-2 that required hospitalization and either invasive or non-invasive mechanical ventilation, with severe pneumonia, ALI, or ARDS confirmed by CT scan or X-ray.  These investigators randomly assigned subjects (2:1) to receive IV ravulizumab plus BSC or BSC alone using a web-based interactive response system.  Randomization was in permuted blocks of 6 with stratification by intubation status.  Bodyweight-based intravenous doses of ravulizumab were administered on days 1, 5, 10, and 15.  The primary effectiveness endpoint was survival based on all-cause mortality at day 29 in the intention-to-treat (ITT) population.  Safety endpoints were analyzed in all randomly assigned patients in the ravulizumab plus BSC group who received at least 1 dose of ravulizumab, and in all randomly assigned patients in the BSC group.  Between May 10, 2020, and January 13, 2021, a total of 202 patients were enrolled in this phase-III trial and were randomly assigned to ravulizumab plus BSC or BSC.  A total of 201 patients were included in the ITT population (135 in the ravulizumab plus BSC group and 66 in the BSC group).  The ravulizumab plus BSC group comprised 96 (71 %) men and 39 (29 %) women with a mean age of 63.2 years (SD 13.23); the BSC group comprised 43 (65 %) men and 23 (35 %) women with a mean age of 63.5 years (12.40).  Most patients (113 [84 %] of 135 in the ravulizumab plus BSC group and 53 [80 %] of 66 in the BSC group) were on invasive mechanical ventilation at baseline.  Overall survival estimates based on multiple imputation were 58 % for patients receiving ravulizumab plus BSC and 60 % for patients receiving BSC (Mantel-Haenszel analysis: risk difference -0.0205; 95 % CI: -0.1703 to 0.1293; 1-sided p = 0·61).  In the safety population, 113 (89 %) of 127 patients in the ravulizumab plus BSC group and 56 (84 %) of 67 in the BSC group had a treatment-emergent AE.  Of these events, infections and infestations (73 [57 %] versus 24 [36 %] patients) and vascular disorders (39 [31 %] versus 12 [18 %]) were observed more frequently in the ravulizumab plus BSC group than in the BSC group.  A total of 5 patients had serious AEs considered to be related to ravulizumab.  These events were bacteremia, thrombocytopenia, esophageal hemorrhage, cryptococcal pneumonia, and pyrexia (in 1 patient each).  The authors concluded that addition of ravulizumab to BSC did not improve survival or other secondary outcomes.  Safety findings were consistent with the known safety profile of ravulizumab in its approved indications.  Despite the lack of effectiveness, this trial added value for future research into complement therapeutics in critical illnesses by showing that C5 inhibition can be accomplished in severely ill patients.

The authors stated that several factors might have limited the interpretation of effectiveness, as discussed, including the timing of intervention or the severity of disease at baseline, imbalance in medical history between study groups, and heterogeneity of BSC regimens across centers.  Furthermore, the study was limited by the fact that these researchers did not analyze secondary endpoints beyond day 29 (other than survival); thus, they could not exclude a negative effect of the increased rate of treatment-emergent serious AEs in the ravulizumab plus BSC group with regard to hospital-free days and ICU-free days later in the study.  Nevertheless, these investigators found no evidence for differences in mortality or quality of life (QOL) at 90 days.  The open-label design was also a limitation; however, the manufacture of matching placebo would have caused several months of delay in starting the study, which was not considered appropriate in the setting of the emerging pandemic.  Finally, it was noteworthy that the estimated 29-day survival rate of 60 % in the control group was in accordance with the prospectively defined sample size calculation of 60 % survival.  As such, the negative results of this trial could not be attributed to a lack of statistical power, despite early termination.

Neuromyelitis Optica

Duchow and colleagues (2020) stated that evidence-based therapeutic options for patients with neuromyelitis optica spectrum disorders (NMOSD) are beginning to enter the market; where previously, there was only the exclusive use of empiric and off-label immunosuppressants in this rare and devastating central nervous system (CNS) autoimmune disease.  In accordance to expanding pathogenetic insights, drugs in phase-II and phase-III clinical trials are presented in the context of the current treatment situation for acute attacks and immuno-preventative strategies in NMOSD.  Some such drugs are the 2019-approved complement inhibitor eculizumab, other compounds in late development include its modified successor ravulizumab, IL-6 receptor antibody satralizumab, CD19 targeting antibody inebilizumab and the TACI-Fc fusion protein telitacicept.  The authors concluded that moving from broad immunosuppression to tailored treatment strategies, the prospects for efficient NMOSD therapy are positive.  For the first time in this disease, class I treatment evidence is available, but long-term data are needed to confirm the overall promising findings of the compounds close to approval.  While drug development still centers around AQP4 antibody sero-positive patients, current and future research requires consideration of possible diverging treatment demands for the smaller group of sero-negative patients and patients with presence of MOG antibodies.

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Appendix

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

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References