• Eculizumab is considered MEDICALLY NECESSARY for the treatment of an individual with documented PNH when ALL of the following criteria are met:

Generalized Myasthenia Gravis
Eculizumab is considered MEDICALLY NECESSARY for the treatment of generalized myasthenia gravis (gMG) in adult patients who meet the following criteria:

1. PNH as documented by flow cytometry, including the presence of either:
   1. PNH type III red cells;
   2. b. Glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient polymorphonuclear cells (PMNs);
2. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of Ravulizumab (unless the clinical record documents that the risks of delaying Ravulizumab outweigh the risk of meningococcal infection)
3. Either of the following criteria a) or b) are met:

1. 1. The individual has: Hemoglobin that is less than or equal to 7 g/dl, or the individual has symptoms of anemia and the hemoglobin is less than or equal to 9 g/dl; 
   2. Documented history of a major adverse vascular event (MAVE) from thromboembolism;

Atypical Hemolytic Uremic Syndrome (aHUS)
Ravulizumab is considered MEDICALLY NECESSARY for an initial 6-week trial for the treatment of atypical hemolytic uremic syndrome (aHUS) when ALL of the following criteria are met: 

1. The diagnosis of aHUS is supported by the absence of Shiga toxin-producing E. Coli infection;
2. Thrombotic thrombocytopenic purpura (TTP) has been ruled out (for example, normal ADAMTS 13 activity and no evidence of an ADAMTS 13 inhibitor), or if TTP cannot be ruled out by laboratory and clinical evaluation, a trial of plasma exchange did not result in clinical improvement; AND
3. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of Ravulizumab (unless the clinical record documents that the risks of delaying Ravulizumab outweigh the risk of meningococcal infection).  

CONTINUED TREATMENT  
Continuation of Ravulizumab following an initial 6-week trial for the treatment of aHUS is considered MEDICALLY NECESSARY when there is documentation of clinical improvement after the initial trial (for example, increased platelet count or laboratory evidence of reduced hemolysis). 

Generalized Myasthenia Gravis
Ravulizumab is considered MEDICALLY NECESSARY for the treatment of generalized myasthenia gravis (gMG) in adult patients who meet the following criteria:

1. Diagnosis of generalized myasthenia gravis (gMG)
2. Patient is anti-acetylcholine receptor (AChR) antibody positive
3. Both of the following:
   • Trial and failure, contraindication, or intolerance to one immunosuppressive therapy (e.g., glucocorticoids, azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, tacrolimus)
   • Trial and failure, contraindication, or intolerance to one of the following: Chronic plasmapheresis or plasma exchange (PE) or Intravenous immunoglobulin (IVIG) or rituximab 

CONTINUED TREATMENT 
Continuation of Ravulizumab following an initial 6-week trial for the treatment of gMG is considered MEDICALLY NECESSARY when member demonstrates a positive response to therapy (e.g., reduction in number of relapses). 
 

Administer Soliris at the recommended dosage regimen time points, or within two days of these time points.

• Antibody-mediated rejection in organ transplantation
• Antineutrophil cytoplasmic autoantibody (ANCA) vasculitis
• Antiphospholipid antibody syndrome (APS)
• Dense deposit disease or C3 nephropathy
• Hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia
• Hemolytic cold agglutinin disease
• Nonexudative (dry) age-related macular degeneration
• Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS)
• Systemic lupus erythematosus (SLE)
• Thrombotic thrombocytopenic purpura (TTP)

Rationale
Eculizumab for the Treatment of PNH
The U.S. Food and Drug Administration (FDA) accelerated approval of eculizumab in March 2007 as an orphan drug for the treatment of PNH. The safety and effectiveness of eculizumab was documented in one comparative clinical trial and two open-label, single-arm studies that investigated whether eculizumab could reduce the incidence of intravascular hemolysis, hemoglobinuria, and transfusion requirements in individuals with PNH. Participants with subclinical PNH (PNH type III clone < 1%) were excluded from these pivotal studies. The initial acute-phase study was a 12-week, open-label trial where eculizumab reduced hemolysis and transfusion requirements in 11 transfusion-dependent individuals with PNH (Hillmen, 2004). Study participants were adults (18 years of age and older) with a confirmed diagnosis of PNH at least 6 months earlier, had a detectable GPI-deficient hematopoietic clone, and received at least 4 red cell transfusions in the preceding 12 months. Levels of serum LDH were markedly elevated in all participants before eculizumab treatment. Mean LDH levels decreased from 3,111 IU/L (international units per liter, ± 598 IU/L) during the 12 months before enrollment to 594 IU/L (± 32 IU/L; normal range, 150 – 480) during treatment (p = 0.002). The decrease in LDH began after a single dose of eculizumab in all participants, and remained within or just above the normal range for the duration of the study. The mean and median transfusion rates decreased from 2.1 and 1.8 units per participant per month to 0.6 and 0.0 units per participant per month, respectively (p=0.003 for the comparison of the median rates). Episodes of hemoglobinuria were reduced by 96% (p < 0.001), and quality of life measurements improved significantly. All 11 participants from the acute-phase study enrolled in the 52-week extension study (Hill, 2005). Participants were allowed concomitant therapy (with the exception of whole blood) and entered on a maintenance dose of eculizumab of 900 mg intravenously every 12 to 14 days, which continued throughout the extension study period. As in the acute-phase study, data were obtained on the pharmacokinetics, pharmacodynamics, and immunogenicity of eculizumab, indicators of hemolysis, PNH clone size, paroxysm and transfusion rates, and quality of life measurements. The trigger for transfusion before and during the study remained unchanged for each participant (that is, based on a combination of hemoglobin levels and the occurrence of symptoms resulting from anemia, hemolysis, or both). In all participants, the 12- to 14-day maintenance dose of eculizumab was sufficient to completely and consistently block complement activity with a dramatic reduction in hemolysis maintained throughout the study with a significant decrease in LDH levels pre- and post-treatment (from 3,110 IU/L before treatment to 622 IU/L; p = 0.0002). The proportion of PNH type III red cells increased from 36.7% at baseline to 58.4% (p = 0.0005). The paroxysmal rate of days with gross evidence of hemoglobinuria per participant each month decreased from 3.0 during screening to 0.2 (p < 0.001) during treatment. The median transfusion rate decreased from 1.8 units per participant each month before eculizumab treatment to 0.3 unit per participant each month (p = 0.001) during treatment. Statistically significant improvements in quality-of-life measures were also maintained during the extension study.

A subsequent double-blind, randomized, multicenter phase III trial, (Transfusion Reduction Efficacy and Safety Using Eculizumab in Paroxysmal Nocturnal Hemoglobinuria [TRIUMPH]), compared eculizumab to placebo in 87 individuals with PNH who had received at least 4 red cell transfusions in the prior 12 months, had a flow cytometric confirmation of at least 10% PNH cells, platelet counts of at least 100,000/microliter, and LDH levels at least 1.5 times the upper limit of normal (Hillmen, 2006). Concomitant administration of erythropoietin, immunosuppressive drugs, corticosteroids, coumarins, low molecular-weight heparins, iron supplements, and folic acid were permitted, provided that the doses were constant before and throughout the study. Prior to randomization, all participants underwent an initial observation period to confirm the need for transfusion of red cells and to identify the hemoglobin concentration (referred to as the "set-point"), which would define each participant's hemoglobin stabilization and transfusion outcomes. Participants who did not need a red cell transfusion during the 3-month observation were not eligible for randomization. The hemoglobin set-point was ≤ 9 g/dL in participants with symptoms and was ≤ 7 g/dL in participants without symptoms. Participants received eculizumab (600 mg) or placebo by infusion every week for 4 weeks, followed 1 week later by 900 mg given every 2 weeks through week 26. The 2 primary endpoints were the stabilization of hemoglobin levels and the number of transfused units of packed red cells. Biochemical indicators of intravascular hemolysis and quality of life were also assessed. Significant benefits were seen in eculizumab-treated participants, including: 1) a higher rate of stabilization of hemoglobin levels in the absence of transfusion (49% versus zero [21 of 43] participants remained above the prespecified median set point of 7.7 g/dl; p < 0.001); 2) fewer packed red cell transfusions (a median of 0 units of packed red cells versus 10 units in the placebo group; p<0.001); 3) reduced intravascular hemolysis (mean LDH level decreased from 2,199.7 ± 157.7 U/L at baseline to 327.3 ± 67.6 U/L at 26 weeks); and 4) clinically significant improvements in quality of life, including improvement in fatigue and the symptoms of nitric oxide depletion (for example, abdominal pain, erectile dysfunction, esophageal spasm, renal dysfunction, and pulmonary hypertension). There were no treatment-related serious adverse events.

The safety and efficacy of eculizumab was evaluated in a 1-year follow-up phase III study (Safety in Hemolytic PNH Patients Treated with Eculizumab: A Multi-Centre Open-Label Research Design Study [SHEPHERD]) in 97 participants who had received at least one transfusion in the prior 24 months for anemia or anemia-related symptoms, a PNH type III red blood cell proportion of 10% or more as assessed by flow cytometry, platelet counts of 30,000 or higher, and LDH levels of 1.5 times or more the upper limit of the normal range. The primary efficacy endpoint was hemolysis as assessed by LDH levels under the curve (AUC). Secondary efficacy endpoints included fatigue as measured by the validated Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) instrument and LDH change from baseline. The trial included a diverse population of participants. The median age was 41 years, and the median duration of PNH was 4.9 years. Baseline laboratory values for study participants ranged from platelet counts of 23 to 355 x109/L, prestudy transfusion requirements from 0 to 66 units in the 12 months before the study, and levels of LDH at baseline from 537 to 5,245 U/L (median: 2,051 U/L). These individuals showed similar significant reductions in intravascular hemolysis as measured by serum LDH levels (87% reduction, from a mean of 2,201 ± 105 U/L at baseline to 297 ± 21 U/L at 52 weeks, p < 0.001, mixed model analysis), decreases in the degree of anemia and transfusion requirement (52% reduction, 12.3 units per participant pretreatment to 5.9 units during eculizumab), increased transfusion independence (51% or 49 participants for the entire 52 weeks of eculizumab treatment; p < 0.001), and improvement in fatigue and quality of life. Two participants with a history of thrombosis had a thrombotic event during the study (Brodsky, 2008; Schubert, 2008).

Hillmen and colleagues (2013) reported on the long-term safety and efficacy of maintenance eculizumab in participants in one of the three prospective trials. At the end of these initial studies, 187 of 195 individuals enrolled in an open-label extension study. The entire period of eculizumab administration across the parent and extension trials was 66 months (median eculizumab treatment duration was 30.3 months), although a 36-month cut-off was used for safety and efficacy assessments. Of the original 195 participants, 19 (9.7%) discontinued treatment over a period of 66 months: 9 participants discontinued because of an adverse event, 7 participants withdrew consent, 2 participants based on the decision of the investigator, and 1 participant due to noncompliance with the protocol. The decrease in serum LDH was sustained with continued treatment: the median LDH value at 36 months was 279 U/L (range, 88 – 1417 U/L), a relative reduction from baseline of 86.9%. Participants who achieved transfusion independence increased with sustained treatment: 82.1% (64 of 78) by the last 6 months of treatment, compared with only 8.2% (16 of 195) in the 6 months prior to the start of treatment, a relative increase of 90%. A total of 14 of 78 participants (17.9%) continued to require transfusions between months 30 and 36. The percentage of participants remaining free of thrombotic events during treatment was reported at 96.4%, with 84 participants receiving concomitant anticoagulation therapy both before and during treatment with eculizumab. Of the 7 participants (3.6%) reporting a total of 10 thrombotic events over 467.1 patient-years, 5 participants had a history of thrombotic events prior to starting treatment with eculizumab and 4 received concomitant anticoagulation therapy. Eleven participants, 6 of whom had a prior history of thrombotic events, discontinued anticoagulant therapy while receiving eculizumab; none of these 11 participants experienced a thrombotic event after discontinuation of anticoagulant therapy. Thrombotic events were observed in 16% (3 of 19) of the participants who discontinued eculizumab treatment, all within 8 weeks of taking their last dose. Participants showing improvement, worsening, or no change in chronic kidney disease were 25.4%, 6.1% and 68.5%, respectively at 6 months compared with 44.8%, 6.9% and 48.3% respectively, at 36 months. Four deaths were reported, all unrelated to treatment, resulting in a 3-year survival estimate of 97.6%. Serious adverse events were reported in 75 of the 195 individuals (38.5%), most frequently adverse events typically seen in individuals with PNH, such as hemolysis, abdominal pain and anemia. These results establish both long-term safety and a sustained treatment response to eculizumab in the study participants.

PNH is associated with a marked increase in venous thrombosis in the hepatic, other intra-abdominal, and peripheral veins. Although the mechanism is not fully understood, hemolysis has been implicated in the initiation of platelet activation and aggregation. According to Hillmen and colleagues (2007), thromboembolic events have been linked to this hemolysis in persons with PNH, potentially through the buildup of cell-free plasma hemoglobin. While this predisposition to thrombosis is not well understood, it is thought to be due to activation of complement on the platelet surface. The effect of free hemoglobin on platelet function and hypercoagulability and the recognized increase in thrombotic tendencies in PNH may be largely due to its ability to scavenge nitric oxide. Other potential mechanisms of thrombosis in PNH include the generation of procoagulant platelet microvesicles due to the absence of the terminal complement inhibitor CD59, and the interaction of red cell microvesicles and soluble urokinase plasminogen activator receptor.

The risk of thrombosis appears to be significantly related to the size of the PNH clone. Subcategories of PNH are based in part on clone size, which varies widely among individuals. Hall and colleagues (2003) retrospectively reviewed 163 individuals with PNH with a median follow-up of 6 years. Of these individuals, 29 developed thrombosis, with a 10-year incidence of 23%. Granulocyte clone sizes larger than 50% were found to be highly predictive of thrombotic risk, with the 10-year risk reported at 44% compared with 5.8% in individuals with small clones (p < 0.01). Those with large PNH clones have signs of classic PNH, while individuals with small clones may have only biochemical evidence of hemolysis with minimal or no clinical manifestations. Individuals who are likely to benefit from eculizumab treatment have large clones and clinical manifestations that are primarily a consequence of intravascular hemolysis (that is, classic PNH). An element of bone marrow failure is present in all persons with PNH, although the degree of marrow dysfunction is variable. Those with small clone size whose primary clinical manifestations are a consequence of another bone marrow disorder (for example, aplastic anemia, myelodysplastic syndrome or other myelopathies) are unlikely to benefit from eculizumab. The focus of treatment in individuals with small clone size (subclinical) PNH is on the process that underlies the bone marrow failure. In addition, PNH phenotype affects the rate of hemolysis, as PNH II red blood cells are significantly more resistant to complement-mediated injury than PNH III red blood cells.

Anticoagulation therapy is commonly used in individuals with PNH who have a history of thrombosis and has been proposed as a prophylaxis for higher risk individuals (Hall, 2003; Parker, 2005). Hall and colleagues (2003) further evaluated 67 high-risk individuals with PNH who were not taking prophylactic anticoagulants, and estimated a thromboembolic event rate of 3.7 events per 100 patient years (19 thromboembolic events in 511.5 patient years), with an absence (zero) of thromboembolic events in 117.8 patient-years observed in a heterogeneous group of 239 individuals with PNH treated with anticoagulants as primary prophylaxis. Single and small case series, however, have reported that new thromboembolic events, as well as progression of existing thromboembolic events, have been observed in individuals with PNH despite the use of anticoagulants and/or antiplatelet agents.

While reduction in thromboembolic events is a relevant outcome for eculizumab therapy, it has been difficult to study due to the confounding factor of anticoagulation therapy. Some studies report a marked reduction in the thromboembolic event rates in participants with PNH taking eculizumab when compared with rates prior to treatment. For example, Hillmen and colleagues (2007) compared retrospectively collected data to observational data in 195 individuals from the three eculizumab PNH clinical studies conducted between 2002 and 2005; 187 participants from these studies continued treatment in the current multi-national open-label extension study lasting 102 weeks. Of the 187 participants, 109 were on anticoagulation therapy and 62 participants experienced thrombosis or a thromboembolic event prior to initiation of eculizumab. Thromboembolic events (for example, thrombophlebitis, deep vein thrombosis, pulmonary embolism, cerebrovascular accident, amputation, myocardial infarction, unstable angina, and sudden death) with eculizumab treatment were compared with the pretreatment rate in the same participants. The thromboembolic event rate with eculizumab treatment was 1.07 events/100 participant years compared with 7.37 events/100 participant years (p < 0.001) prior to eculizumab treatment (relative reduction, 85%; absolute reduction, 6.3 events/100 participant years). With equalization of the duration of exposure before and during treatment for each participant, thromboembolic events were reduced from 39 events before eculizumab to 3 events during eculizumab (p < 0.001). The thromboembolic event rate in antithrombotic-treated participants (n = 103) was reduced from 10.61 to 0.62 events/100 participant years with eculizumab treatment (p < 0.001). However, the majority of participants received concomitant anticoagulants and the doses could be altered at the discretion of the treating physician; the effects of anticoagulant withdrawal during eculizumab therapy were not studied. In addition, no data were provided to determine whether the degree of reduction in thromboembolic events observed during eculizumab treatment was the same or different across different types of thromboembolic events.

In a review of the Hillmen (2007) study, Parker (2009) states the results "suggest that eculizumab ameliorates the thrombophilia of PNH, but the study design makes assessment of the effect of treatment nebulous." In addition, in the only part of the Hillmen study that was randomized and included a placebo control (TRIUMPH study), 1 thromboembolic event occurred in the placebo group (11 of 44 participants were taking anticoagulants) and no thromboembolic events occurred in the eculizumab-treated group (21 of 43 participants were taking anticoagulants). Parker (2009) also observed: A large difference in the pretreatment thromboembolic rate was also seen among the treatment groups. For example, in the placebo group of TRIUMPH, the thromboembolic event rate was 2.34 per 100 patient-years versus 12.67 per 100 patient-years for SHEPHERD. This difference does not seem to be due to differences in baseline characteristics of the patients because the PNH clone size on the basis of the percentage of GPI-AP deficient granulocytes was equivalent.

A high rate of pretreatment thromboembolic events (10.31 per 100 patient-years) in individuals treated with antithrombotic drugs was reported in the Hillmen study, whereas Parker noted that "complete protection against thromboembolism in patients with PNH treated with warfarin … was reported" in the earlier retrospective study by Hall and colleagues (2003). Parker suggests the effects of eculizumab on the thrombophilia of PNH should be measured in a randomized study; however, "because a placebo control would be difficult to justify in view of the efficacy of eculizumab in controlling intravascular haemolysis and improving quality of life for patients with PNH," such a study is unlikely.

Kelly and colleagues (2015) assessed the safety and efficacy of eculizumab in pregnant women with PNH by examining the birth and developmental records of the children born and adverse events in the mothers. The investigators designed a questionnaire to collect data on pregnancies in women with PNH, sending it to the members of the International PNH Interest Group and to the physicians participating in the International PNH Registry. A total of 75 of 94 questionnaires were returned (80%). Data analyzed on 75 pregnancies in 61 women with PNH identified no maternal deaths and 3 fetal deaths (4%). Six miscarriages (8%) occurred during the first trimester. Requirements for transfusion of red cells increased during pregnancy, from a mean of 0.14 units per month in the 6 months before pregnancy to 0.92 units per month during pregnancy. Platelet transfusions were given in 16 pregnancies. The dose or the frequency of use of eculizumab was increased in 54% of pregnancies that progressed past the first trimester. Low-molecular-weight heparin was used in 88% of the pregnancies. Thrombotic events were documented as follows: 10 hemorrhagic events and 2 thrombotic events; both thrombotic events occurred during the postpartum period. A total of 22 births (29%) were premature; the presence of eculizumab was not detected in any of the breast milk samples (n = 10) available for evaluation. Due to the high rates of hemolysis and premature births, the authors cited the importance of careful monitoring throughout pregnancy in women with PNH highlights. In addition, the authors stated:

Because terminal complement activation is elevated in women during the third trimester and in women with preeclampsia, eculizumab may be a useful agent in other high-risk situations, such as the HELLP syndrome (which is characterized by hemolysis, elevated liver-enzyme levels, and low platelet counts), or in the case of pre eclampsia itself, in which complement dysregulation has been reported.

Summary of Eculizumab for the Treatment of PNH
PNH is a clonal hematopoietic stem cell disease that can present with bone marrow failure, hemolytic anemia, smooth muscle dystonias, and thrombosis. Hemolysis is the primary clinical manifestation of PNH and is associated with serious morbidities in PNH, including thromboembolic events. In a treatment-focused article, Brodsky (2009) states there are no widely accepted evidence-based indications for the treatment of PNH, but complement inhibition with eculizumab is an effective therapy for those individuals with classic PNH "with disabling fatigue, thromboses, transfusion dependence, frequent pain paroxysms, renal insufficiency, or other end-organ complications from disease." Thrombosis should be treated promptly with anticoagulation and sometimes thrombolytic therapy, depending on the location of the thrombus; however, prophylactic anticoagulation has never been proven to prevent thrombosis in individuals with PNH, and, "discontinuing anticoagulation in patients on eculizumab with a previous thrombosis is even more controversial, and there are insufficient data to make strong recommendations" (Brodsky, 2009). The available studies in the peer-reviewed medical literature demonstrate that eculizumab is effective and well-tolerated in reducing hemolysis in the management of individuals with PNH. Although studies suggest that eculizumab ameliorates the risk of thromboembolic complications, no randomized controlled study measuring the effect of eculizumab on the thrombophilia of PNH exists. A retrospective analysis performed on 301 individuals from a South Korean National PNH Registry (Lee, 2013) attempted to describe the disease burden and identify thromboembolism-associated risk factors in PNH; however, the authors concluded that "… future prospective observations, perhaps from the international PNH registry, will further support the associations of hemolysis and other risk factors with TE." Schrezenmeier and colleagues (2014) reported on data from a European Registry of individuals with PNH (n = 1,610) stating:  

In patients who had not received eculizumab in the 12 months prior to enrollment, there was a positive correlation between history of thrombosis and clone size at enrollment: 5.3% of patients with clone size less than 10% had a history of thrombosis and 7.7% of patients with clone size 10% – 49% had such a history, whereas 15.4% of patients with clone size 50% or over had such a history (p < 0.001). In addition, a larger percentage of patients with LDH ≥ 1.5 x ULN at enrollment, compared with LDH < 1.5 x ULN at enrollment reported a history of thrombosis (15.6% vs. 8.4%; p < 0.001) ... Our analyses suggested an association between PNH granulocyte clone size and LDH levels; in patients with a clone size less than 10%, median LDH levels were towards the ULN, with only 8% of patients having LDH ≥ 1.5 x ULN, whereas in patients with a clone size 50% or over, median levels were to > 4.0 x ULN and 62% of patients had LDH ≥ 1.5 x ULN. Elevated LDH levels were also associated with higher prevalence of TE and symptoms such as abdominal pain, chest pain, and hemoglobinuria, all significant risk factors for TE ... It should be noted that not all of the transfusion, symptom and other data collected at enrollment may be directly related to hemolysis due to PNH, though collection and analysis of all such data are important in order to provide greater insight into the course of the disease and help to identify patients at risk of TE ... Our results showed that patients were significantly more likely to have been prescribed anticoagulant therapy if they had a history of TE, a larger granulocyte clone size, or elevated LDH concentrations. It must be remembered that these factors are not mutually exclusive but interrelated.

aHUS Resistant to Plasma Therapy: aHUS Study 1
aHUS Study 1 (Legendre, 2013) enrolled 17 participants who displayed signs of TMA despite receiving at least 4 plasma therapy treatments the week prior to screening. One participant had no plasma therapy the week prior to screening because of intolerance. In order to qualify for enrollment, participants were required to have a platelet count ≤ 150 x 109/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median participant age was 28 (range, 17 to 68 years). A total of 76% of participants had an identified complement regulatory factor mutation or auto-antibody. After completion of the initial 26-week treatment period, most participants continued to receive eculizumab by enrolling in an extension study. The median duration of eculizumab therapy was approximately 38 weeks (range, 2 weeks to 64 weeks). Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Overall, eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline with the treatment effect maintained through 26 weeks. Renal function improved during eculizumab therapy. A total of 4 of 5 participants who required dialysis at study entry were able to discontinue dialysis for the duration of eculizumab treatment; 1 participant developed a new dialysis requirement. Responses to eculizumab were similar in participants with and without identified mutations in genes encoding complement regulatory factor proteins.

aHUS Sensitive to Plasma Therapy: aHUS Study 2
aHUS Study 2 (Legendre, 2013) enrolled 20 participants undergoing chronic plasma therapy who generally did not display hematologic signs of ongoing TMA. All participants had received plasma therapy at least once every 2 weeks, but no more than 3 times per week, for a minimum of 8 weeks prior to the first dose of eculizumab. Participants on chronic dialysis were permitted to enroll in aHUS Study 2. The median participant age was 28 years (range, 13 to 63 years). A total of 70% of participants had an identified complement regulatory factor mutation or auto-antibody. After completion of the initial 26-week treatment period, most participants continued to receive eculizumab by enrolling in an extension study. The median duration of eculizumab therapy was approximately 40 weeks (range, 26 to 52 weeks). Responses to eculizumab were similar in participants with and without identified mutations in genes encoding complement regulatory factor proteins. Reduction in terminal complement activity was observed in all participants after the start of eculizumab. Signs of complement-mediated TMA activity were reduced, as shown by an increase in mean platelet counts from baseline to 26 weeks. Platelet counts were maintained at normal levels despite the elimination of plasma therapy. Renal function was maintained during eculizumab therapy and no participant required new dialysis.

Retrospective Cohort Study in Children and Adolescents with aHUS: aHUS Study 3
The efficacy results for the aHUS retrospective study that enrolled 19 children and adolescents (ages 2 months to 17 years) were generally consistent with results of the 2 prospective studies. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 1 week after therapy; this effect was maintained through 26 weeks. Overall, platelet counts were normalized in 17 of 19 (89%) participants, a complete TMA response was observed in 8 of 19 (42%) participants, and the daily TMA intervention rate was reduced from a median 0.31 per day before eculizumab to 0.00 after treatment. The median duration of eculizumab therapy was 16 weeks (range, 4 to 70 weeks) for children < 2 years of age (n = 5), 31 weeks (range, 19 to 63 weeks) for children 2 to < 12 years of age (n = 10), and 38 weeks (range, 1 to 69 weeks) for adolescents 12 to 17 years of age (n = 4). A total of 53% of participants had an identified complement regulatory factor mutation or auto-antibody. Overall, the efficacy results for these participants appeared consistent with what was observed in participants enrolled in aHUS Studies 1 and 2. No pediatric or adolescent participants required new dialysis during treatment with eculizumab. The most common side effects seen in individuals treated with eculizumab for aHUS included hypertension, diarrhea, headache, anemia, vomiting, nausea, upper respiratory and urinary tract infections, and leukopenia.

Licht and colleagues (2015) assessed the efficacy and safety outcomes of eculizumab in aHUS after 2 years of therapy. The investigators originally conducted two phase II studies (Legendre, 2013) (26 weeks and 1 year) evaluating eculizumab in individuals with progressing thrombotic microangiopathy (TMA) (trial 1) and those with a long duration of aHUS and chronic kidney disease (trial 2). In the two phase II trials, the median exposure to eculizumab was 100 and 114 weeks, respectively. At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 participants, platelet counts were significantly improved from baseline, and hematologic normalization was achieved in 13 participants at week 26 and in 15 participants at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2, TMA event-free status was achieved by 16 of 20 participants at week 26, 17 of 20 participants at year 1, and 19 of 20 participants at year 2. The criteria for hematologic normalization were met by 18 participants at each time point. Improvement of 15 ml/min per 1.73 m2 or more in eGFR was achieved by 1 participant at week 26, 3 participants at 1 year, and 8 participants at 2 years. No new safety concerns or meningococcal infections were reported. This analysis reported that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up.

Treatment Discontinuation and Increased Risk of Thrombosis
Discontinuation of eculizumab may be associated with an increased risk of serious thrombosis. The prescribing information includes guidance: 

5.4 Monitoring After Soliris Discontinuation 

• Monitor patients after discontinuing Soliris for at least 8 weeks to detect hemolysis. 

• After discontinuing Soliris, monitor patients with aHUS for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. In aHUS clinical studies, 18 patients (5 in the prospective studies) discontinued Soliris treatment. TMA complications occurred following a missed dose in 5 patients, and Soliris was reinitiated in 4 of these 5 patients.
• Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of two, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during Soliris treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during Soliris treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during Soliris treatment.
• If TMA complications occur after Soliris discontinuation, consider reinstitution of Soliris treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures.

Parker (2009) reported that eculizumab does not increase the risk of catastrophic hemolytic crisis if the drug is discontinued. In 2010, the Canadian Agency for Technology Assessment in Health (CADTH) also noted that despite the theoretical possibility of a rebound effect upon discontinuation of eculizumab, no cases had not been identified to date. However, in 2012, Van Bijnen and colleagues reported on a case of serious thrombosis after discontinuation of eculizumab in an individual with PNH. It is apparent that increased awareness and close monitoring for thrombosis is appropriate in individuals discontinuing eculizumab.

Eculizumab for Other Conditions
Eculizumab is currently being studied for the treatment of other disorders and syndromes, including, but not limited to, antibody-mediated rejection in organ transplantation (Dhakal, 2015; Kocak, 2013; Orandi, 2014), antiphospholipid antibody syndrome (Canaud, 2013; Lonze, 2014), dense deposit disease and C3 nephropathy (glomerulonephritis) (Bombeck, 2012; McCaughan, 2012; Oosterveld, 2015), myasthenia gravis (Howard, 2013), pre eclampsia/HELLP syndrome in pregnancy (Burwick, 2013), Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS) (Lapeyraque, 2011), neuromyelitis optica (Pittock, 2013), systemic lupus erythematosus, and thrombotic thrombocytopenic purpura (TTP) (Chapin, 2012). The peer-reviewed literature includes registry databases, retrospective analyses, single case reports, and small case series.

Yehoshua and colleagues (2014) performed a prospective, double-blind, phase II clinical trial of 30 individuals with geographic atrophy in age-related macular degeneration to receive eculizumab or placebo over 6 months. After 2:1 randomization, participants in the treatment arm (n = 20) received either a high-dose (n = 10) or low-dose dose (n = 10) regimen every week for 4 weeks, followed by dose escalation every 2 weeks until week 24. All participants were observed off treatment or placebo (saline infusion) for an additional 26 weeks. Eculizumab was well tolerated through 26 weeks; however, the primary outcome measure was not met, as geographic atrophy enlarged by a mean of 0.19 ± 0.12 and 0.18 ± 0.15 mm in both the eculizumab and placebo groups, respectively (p = 0.96). The investigators suggested the lack of a treatment effect could be attributed to the dosing of eculizumab (too low) or the drug should have been delivered as a direct intravitreal injection to achieve an adequate level of drug. Other limitations include the small sample size and evaluation of the treatment effect at the short endpoint of 26 weeks.

There is currently a lack of sufficient evidence in the peer-reviewed medical literature to support the use of eculizumab for any other conditions beyond the FDA label indications.

2019 Update
Ravulizumab
A phase 3 study showed Ravulizumab (ALXN1210), a new complement C5 inhibitor, provided immediate, complete, and sustained C5 inhibition. This phase 3, open-label study (Lee, JW, Sicre de Fontbrune, F, Wong Lee Lee, L, et al. 2018), assessed the non-inferiority of ravulizumab to eculizumab in complement inhibitor-naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥ 1.5 times the upper limit of normal and at least one PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Co-primary efficacy endpoints were proportion of patients remaining transfusion-free and LDH normalization. Secondary endpoints were 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. Ravulizumab was non-inferior 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; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved non-inferiority compared with eculizumab given every 2 weeks for all efficacy endpoints, with a similar safety profile. This trial was registered at https://ClinicalTrials.gov #NCT02946463.

A second study has shown that Ravulizumab administered every 8 weeks was non-inferior to eculizumab administered every 2 weeks in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study (Kulasekararaj AG, Hill A, Rottinghause, ST, et al. 2018), assessed non-inferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 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. In 191 patients completing 183 days of treatment, ravulizumab was non-inferior to eculizumab (Pinf<.0006 for all endpoints), including percentage change in LDH (difference, 9.21% [95% CI: -0.42 to 18.84], 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. 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).

2019 Update
Eculizumab for Myasthenia Gravis
(Howard JF Jr, Utsugisawa K. Benatar M, et al.) performed a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. Participants were randomly assigned (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1,200 mg at week 4; and 1,200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo.

Between April 30, 2014, and Feb 19, 2016, 125 patients were randomly assigned and treated, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p = 0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy.

The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. This trial is registered with ClinicalTrials.gov, number NCT01997229.

1. Ardissino G, Testa S, Possenti I, et al.(2014) Discontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome: a report of 10 cases. Am J Kidney Dis. 2014; 64(4):633-637.
2. Ariceta G, Besbas N, Johnson S, et al.(2009) Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009; 24(4):687-696.
3. Bomback AS, Smith RJ, Barile GR, et al.(2012) Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol. 2012; 7(5):748-756.
4. Brodsky RA, Young NS, Antonioli E, et al.(2008) Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008; 111(4):1840-1847.
5. Brodsky RA.(2010) Stem cell transplantation for paroxysmal nocturnal hemoglobinuria. Haematologica. 2010; 95(6):855-856.
6. Burwick RM, Feinberg BB.(2013) Eculizumab for the treatment of preeclampsia/HELLP syndrome. Placenta. 2013; 34(2):201-203.
7. Canaud G, Kamar N, Anglicheau D, et al.(2013) Eculizumab improves posttransplant thrombotic microangiopathy due to antiphospholipid syndrome recurrence but fails to prevent chronic vascular changes. Am J Transplant. 2013; 13(8):2179-2185.
8. Chapin J, Weksler B, Magro C, Laurence J.(2012) Eculizumab in the treatment of refractory idiopathic thrombotic thrombocytopenic purpura. Br J Haematol. 2012; 157(6):772-774.
9. Howard JF Jr, Utsugisawa K. Benatar M, et al.(2017) Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017; Dec;16(12):976-986. doi: 10.1016/S1474-4422(17)30369-1. Epub 2017 Oct 20.
10. Howard JF Jr, Utsugisawa K. Benatar M, et al.(2017) Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017; Dec;16(12):976-986. doi: 10.1016/S1474-4422(17)30369-1. Epub 2017 Oct 20.
11. Kulasekararaj AG, Hill A,Rottinghause, ST, et al.(2018) Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2018 Dec 3. pii: blood-2018-09-876805. doi: 10.1182/blood-2018-09-876805. 
12. Lee, JW, Sicre deFontbrune F, Wong Lee Lee L, et al(2018) Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naïve to complement inhibitors: the 301 study. Blood. 2018 Dec 3. Pii:blood-2018-09-876136. doi: 10.1182/blood-2018-09-876136.  

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