Medical Policy


Subject: Eculizumab (Soliris®)
Document #: DRUG.00050 Publish Date:    12/27/2017
Status: Revised Last Review Date:    11/02/2017

Description/Scope

This document addresses the use of eculizumab in the treatment of individuals with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis, and other conditions.

Eculizumab (Soliris) (Alexion Pharmaceuticals, Inc., New Haven, CT) is a recombinant humanized monoclonal antibody that binds to complement protein C5 and inhibits its enzymatic cleavage, blocks formation of the terminal complement complex, and thus prevents red cell lysis in PNH and complement-mediated thrombotic microangiopathy in aHUS.

Note: For additional information on review of clinically equivalent cost effective criteria for the product addressed in DRUG.00050, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services - Targeted Immune Modulators.

Position Statement

Medically Necessary:

  1. Paroxysmal Nocturnal Hemoglobinuria
    1. Initiation of eculizumab is considered medically necessary for the treatment of an individual with documented paroxysmal nocturnal hemoglobinuria when the following criteria are met:
      1. Paroxysmal nocturnal hemoglobinuria as documented by flow cytometry, including the presence of:
        1. Paroxysmal nocturnal hemoglobinuria type III red cells; or
        2. Glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient polymorphonuclear cells (PMNs); and
      2. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab (unless the clinical record documents that the risks of delaying eculizumab outweigh the risk of meningococcal infection); and
      3. There is no evidence of an active meningococcal infection; and
      4. Either of the following criteria a) or b) are met:
        1. The individual has:
          1. 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; or
          2. Lactate dehydrogenase that is greater than 1.5 times the upper limit of normal; or
        2. Documented history of a major adverse vascular event from thromboembolism.
    2. Continuation of therapy is considered medically necessary for the treatment of an individual with documented paroxysmal nocturnal hemoglobinuria who is currently receiving treatment with eculizumab.
  2. Atypical Hemolytic Uremic Syndrome
    1. Eculizumab is considered medically necessary in an initial 6-week trial for the treatment of atypical hemolytic uremic syndrome when the following criteria are met:
      1. The diagnosis of aHUS is supported by the absence of Shiga toxin-producing E. coli infection; and
      2. Thrombotic thrombocytopenic purpura has been ruled out (for example, normal ADAMTS 13 activity and no evidence of an ADAMTS 13 inhibitor), or if thrombotic thrombocytopenic purpura 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 eculizumab (unless the clinical record documents that the risks of delaying eculizumab outweigh the risk of meningococcal infection); and
      4. There is no evidence of an active meningococcal infection.
    2. Continuation of eculizumab following an initial 6-week trial for the treatment of atypical hemolytic uremic syndrome is considered medically necessary when there is clinical improvement after the initial trial (for example, increased platelet count or laboratory evidence of reduced hemolysis).
  3. Myasthenia Gravis
    1. Initiation of eculizumab is considered medically necessary for generalized myasthenia gravis in an individual 18 years of age or older when the following criteria are met:
      1. Individual has Myasthenia Gravis Foundation of America Clinical Classification Class II to IV disease; and
      2. Individual has a documented positive serologic test for binding anti-acetylcholine receptor antibodies (AChR-ab); and
      3. Individual has had an inadequate response to, is intolerant of, or has a medical contraindication to two or more immunosuppressive drug agents (such as, azathioprine, cyclosporine, or methotrexate) as monotherapy or in combination therapy for greater than or equal to 12 months; or
      4. Individual has had an inadequate response to, is intolerant of, or has a medical contraindication to one or more immunosuppressive drug agents as monotherapy or in combination therapy and requires chronic plasma exchange or plasmapheresis or intravenous immunoglobulin therapy; and
      5. Individual has been immunized with a meningococcal vaccine at least 2 weeks prior to administration of the first dose of eculizumab (unless the clinical record documents that the risks of delaying eculizumab outweigh the risk of meningococcal infection); and
      6. There is no evidence of an active meningococcal infection.
    2. Continuation of eculizumab therapy following an initial 26-week trial for the treatment of generalized myasthenia gravis is considered medically necessary following the initial trial when there is documentation of clinical response (that is, a reduction in signs or symptoms that impact daily function).

Note: Discontinuation of eculizumab may be associated with serious adverse clinical events including life threatening thrombosis (see Rationale for additional details).

Investigational and Not Medically Necessary:

Eculizumab is considered investigational and not medically necessary when the criteria are not met and for all other indications, including but not limited to treatment of:

Rationale

Eculizumab for the Treatment of Paroxysmal Nocturnal Hemoglobinuria (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 lactate dehydrogenase (LDH) were markedly elevated in all participants before eculizumab treatment. Mean LDH levels decreased from 3111 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 3110 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 2199.7 ± 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 5245 U/L (median: 2051 U/L). These individuals showed similar significant reductions in intravascular hemolysis as measured by serum LDH levels (87% reduction, from a mean of 2201 ± 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 preeclampsia 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=1610) 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.

DeZern and Brodsky (2015) recently reviewed the pathophysiology, clinical manifestations, and treatment of PNH. Concerning PNH as a disease of thrombosis, the author’s state:

In contrast with the mechanisms of the hemolysis or the marrow failure, less is definitively known about the pathophysiology and mechanism of the thrombophilia in PNH, especially in patients not treated with eculizumab. Clinically, the complication of thrombosis is more prevalent in patients as the PNH clone increases in size. Thrombosis may occur in any PNH patient, but those with a large percentage of PNH cells (> 50% granulocytes) are at greatest risk. This may suggest that the ultimate etiology of the thrombophilia in PNH is related to the hemolysis with complement activation.

To date, few studies have evaluated eculizumab for the treatment of PNH outside the context of the studies enrolling the 187 individuals in the clinical trials leading to the FDA approval of eculizumab for PNH. In a review article, Varela and Brodsky (2013) state that the severity of symptoms among individuals diagnosed with PNH is variable and not all individuals require treatment:

There are no clear guidelines for the use of eculizumab but it should be used for patients with disabling fatigue, thromboses, transfusion dependence, frequent pain paroxysms, renal insufficiency or other end-organ complications from the disease. Eculizumab does not treat the bone marrow failure that accompanies PNH and it leads to the development of extravascular hemolysis, which can limit its efficacy in some patients. Also it should not be routinely administered to patients who are minimally symptomatic or whose PNH clone size is very small. Given that eculizumab…does not eradicate the PNH clone, and must be given lifelong, it is best reserved for patients with prominent signs and symptoms of classical PNH.

Eculizumab for the Treatment of Atypical Hemolytic Uremic Syndrome (aHUS)

In September 2011, the FDA approved eculizumab to treat individuals with aHUS, a rare and chronic blood disease that can lead to renal failure and is associated with increased risk of stroke and death. Eculizumab is a targeted therapy that works by inhibiting proteins that play a role in aHUS. The effectiveness of eculizumab in aHUS is based on its ability to inhibit complement-mediated thrombotic microangiopathy (TMA) and thus improve renal function. There are no other FDA-approved treatments for aHUS, and the safety and effectiveness of current standard treatment, plasma therapy (plasma exchange [PE] or fresh frozen plasma infusion [PI]), have not been studied in well-controlled prospective clinical trials.

Due to the aggressive nature of aHUS, prompt diagnosis is essential so that treatment can be initiated for affected persons. Individuals should be evaluated for aHUS if they have signs and symptoms of a systemic TMA with impaired organ function, particularly impaired renal function without premonitory diarrheal symptoms (Peyvandi, 2010). Because clinical signs and symptoms alone cannot provide a definitive diagnosis of aHUS, it is necessary to differentiate aHUS from other TMAs (Noris, 2009) such as thrombotic thrombocytopenic purpura (TTP) and shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS). According to Loirat and Fremeaux-Bacchi (2011), the diagnosis of aHUS relies on: 1) no associated disease; 2) investigations for STEC infection at onset of aHUS with no evidence of a Shiga-toxin/EHEC positive test (stool culture and polymerase chain reaction for Shiga-toxins; serology for anti-lipopolysaccharides antibodies); and 3) ADAMTS 13 (A Disintegrin-like And Metalloprotease with ThromboSpondin type 1 motif 13) determination as manifestations of aHUS and TTP may overlap. A severe to complete deficiency of the protease in ADAMTS 13 activity is utilized to establish the diagnosis of TTP (for example, ADAMTS 13 activity below 10% of normal is significant for TTP; severely reduced ADAMTS 13 activity < 5% ± the presence of an inhibitor or IgG antibodies, confirms the diagnosis), thus indicating a person may have aHUS (Peyvandi, 2004; Peyvandi, 2008; Peyvandi, 2010; Scully, 2012). ADAMTS 13 plasma concentration can be determined within < 24 hours by Elisa technique. Based on expert consensus opinion, plasma exchange has demonstrated efficacy as the first line treatment for aHUS and should be started as early as possible, typically within 24 hours of presentation (Ariceta, 2009; Lapeyraque, 2011; Loirat and Fremeaux-Bacchi, 2011; Taylor 2010). Loirat and Fremeaux-Bacchi (2011) also recommend “Plasma exchange (PE) should be performed daily until platelet count, LDH, and hemoglobin levels are normalized and renal function clearly improving since several days.” In addition:

Persistence of hemolysis or lack of improvement of renal function after 3-5 daily PE have to be regarded as criterium for uncontrolled TMA even if platelet count has normalized…and as an indication to maintain daily PE or, in recent days, to switch the patient to eculizumab.

Additional recommendations in persons identified as having aHUS include evaluation of the complement system and involve testing of C3, C4 (plasma/serum), Factor H, Factor I, and Factor B (plasma/serum), anti-factor H autoantibodies, member cofactor protein (MCP) surface expression on leukocytes, and gene mutation analysis in Factor H, Factor I, MCP, C3, and Factor B (Loirat and Fremeaux-Bacchi, 2011).

aHUS Clinical Trial Experience

According to the product information (PI) label (Soliris, 2017), three single-arm studies (two prospective: aHUS Studies 1 and 2) and one unpublished, retrospective cohort study (aHUS Study 3) evaluated the safety and efficacy of eculizumab for the treatment of aHUS. Participants with aHUS received meningococcal vaccination prior to receipt of eculizumab or received prophylactic treatment with antibiotics until 2 weeks after vaccination. Efficacy evaluations were based on TMA endpoints, related to the following: 1) platelet count change from baseline; 2) hematologic normalization (maintenance of normal platelet counts and LDH levels for at least 4 weeks); 3) complete TMA response (hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of 4 weeks); 4) TMA-event free status (absence for at least 12 weeks of a decrease in platelet count of > 25% from baseline, PE or PI, and new dialysis requirement); and 5) daily TMA intervention rate (defined as the number of PE or PI interventions and the number of new dialyses required per participant per day).

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 into 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 into 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 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.

Eculizumab for the Treatment of Generalized Myasthenia Gravis

On October 23, 2017, the FDA expanded approval of eculizumab for use in the treatment of adults with generalized myasthenia gravis who are anti-acetylcholine receptor (AchR) antibody positive. The efficacy and safety of eculizumab was evaluated in a phase II, multicenter, randomized, double-blind, placebo-controlled, crossover trial (Howard, 2013) and phase III, randomized, double-blind, placebo-controlled, multicenter (REGAIN) registration study (Howard, 2017b; NCT01997229) in adults 18 years of age or older with refractory generalized myasthenia gravis (n=125). Study participants were required to have Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, a Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score ≥ 6 at study entry, vaccination against Neisseria meningitides, and previously failed treatment with at least two immunosuppressive agents or one immunosuppressive agent and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Individuals were excluded from study participation 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 randomization, or rituximab within 6 months before screening. Participants were randomized 1:1 to receive 900 mg of eculizumab (n=62) or placebo (n=63) weekly for 4 weeks followed by 1200 mg of eculizumab or placebo 1 week later, and then 1200 mg of eculizumab or placebo every 2 weeks for a total of 26 weeks. Participants were able to continue to receive stable dose and type of supportive immunosuppressive therapy (but no new immunosuppressive therapies and no increase in dosage during the trial), unless the participant required rescue therapy for worsening disease. Clinical deterioration was defined as one of the following: myasthenia gravis crisis, substantial symptomatic worsening (to a score of 3 or a 2-point worsening on any single MG-ADL item, excluding ocular items), or health in jeopardy if rescue therapy was not given, as determined by the treating physician. The primary efficacy endpoint of changes in baseline at week 26 in MG-ADL total score was reported as least-square mean (SEM) rank for prespecified and post-hoc sensitivity worst-rank ANCOVA scores, and SEM for prespecified sensitivity repeated-measures model analysis with immunosuppressive treatments as covariates. ANCOVA analyses used last observation carried forward for missing week 26 assessments. No imputation of missing data was done for the repeated-measures analyses. Three secondary endpoints were also assessed using a worst-rank analysis of changes from baseline in Quantitative Myasthenia Gravis (QMG) score, Myasthenia Gravis Composite (MGC) scale, and the 15-item Myasthenia Gravis Quality Of Life (MG-QOL15) score. All randomized participants who received eculizumab or placebo were included in the safety analysis which reported incidence of adverse events, serious adverse events, admissions to hospital, protocol-defined clinical deterioration with or without rescue medication use, changes in vital signs, electrocardiography, and clinical laboratory variables. Of the 25 treated participants, 118 completed the study and 7 dropped out prematurely, primarily because of adverse events. For the primary endpoint, the difference between the groups in mean-ranked difference in change in MG-ADL total score from baseline to week 26 for the eculizumab and placebo groups (least-SEM rank 56.6 [SEM 4.5]) vs. 68.3 [4.5]; rank-based treatment difference did not achieve statistical significance (-11.7, 95% CI, -24.3 to 0.96; p=0.0698). The change in QMG total score from baseline to week 26 as measured by the worst-rank ANCOVA was reported as showing a treatment benefit with eculizumab compared with placebo (p=0.0129); however, the worst-rank ANCOVA for MGC did not differ between groups. 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 (10 [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by 6 (10%) participants in the eculizumab group and 15 (24%) in the placebo group. A total of 6 (10%) and 12 (19%) participants required rescue therapy in the eculizumab group and placebo group, respectively. A major limitation of this study was use of pre-specified worst-rank statistical analysis that included participants who needed temporary rescue medication or were discontinued from the study for any reason; thus, the efficacy analysis included data of negative outcomes. In addition, the study sample size may not have been of sufficient size to allow for use of the worst-rank analytical approach.

The FDA PI label for eculizumab (Soliris PI, 2017) reports the outcomes of the phase III REGAIN trial using a least square mean difference analysis. A statistically significant difference (mean change from baseline to week 26 in MG-ADL total score; at least a 3-point improvement) was reported in the eculizumab-treated group versus the placebo-treated group (-4.2 points vs. -2.3 points, respectively) (-1.9 least mean difference, 95% CI: -3.3, -0.61; p=0.006). A key secondary endpoint was the change from baseline in the QMG total score at week 26, reported as a statistically significant difference in the eculizumab-treated group versus the placebo-treated group (-4.6 points vs. -1.6 points, respectively; -3.0 least mean difference, 95% CI: -4.6, -1.3; p=0.001). The proportion of clinical responders at week 26 with no rescue therapy was significantly higher in the eculizumab-treated group compared to the placebo-treated group for both measures. For both endpoints, and also at higher response thresholds (≥ 4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and ≥ 6-, 7-, 8-, 9-, or 10-point improvement on QMG), the proportion of clinical responders was consistently greater in the eculizumab-treated group compared to the placebo-treated group.

In a subanalysis of the phase II trial, Howard and colleagues (2017a) evaluated correlations between QMG and MG-ADL scores at baseline and for change from baseline to week 16. The strength and statistical significance of correlations between QMG and MG-ADL scores were greater for change from baseline at week 16 (correlation coefficient [R]=0.726; 95% CI, 0.264-0.907; p=0.0036) than for baseline scores (R=0.552; 95% CI, -0.022-0.839; p=0.0495). The authors suggests that MG-ACL profiling may be more sensitive in assessing treatment response to eculizumab than for assessing point-in time disease status.

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

Treatment Discontinuation for PNH

Treatment Discontinuation for aHUS

Parker (2009) reported that eculizumab does not increase the risk of catastrophic hemolytic crisis if the drug is discontinued. 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.

In an international consensus document, Loirat and colleagues (2016) reviewed approaches to the clinical management of aHUS in children. The authors evaluated the reasons to reconsider the recommendation of life-long complement blockage treatment with eculizumab after a first episode of aHUS involving native kidneys. Concerning the “risk of relapse,” the consensus document states:

The authors note that experience with eculizumab withdrawal is limited, and no data is published about the subjects treated within the prospective trials who stopped treatment:

In practice, prospective studies under strict monitoring, involving patients with and without mutations, are required to establish whether treatment withdrawal is feasible and safe, in which patients and when. In our opinion, withdrawal should not be considered in patients who had life-threatening initial presentation or relapses (e.g. severe neurologic manifestations, myocardial failure) or in children who did not fully recover normal renal function. Except for children with MCP mutations, withdrawal should probably be postponed until the child is more than 3 to 5 years old, the age when seasonal infections, which may trigger relapse, become less frequent.

Other Proposed Uses of Eculizumab

Age-Related Macular Degeneration

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.

Other Conditions

Eculizumab has being studied for the treatment of other disorders and syndromes including, but not limited to, antibody-mediated rejection (AMR) in organ transplantation (not related to aHUS) (Dhakal , 2015; Kocak, 2013; Orandi, 2014), antiphospholipid antibody syndrome (APS) (Canaud, 2013; Lonze, 2014), dense deposit disease and C3 nephropathy (glomerulonephritis) (Bombeck, 2012; McCaughan, 2012; Oosterveld, 2015), Guillain-Barre syndrome (NCT02493725), preeclampsia/hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in pregnancy (Burwick, 2013), STEC-HUS (Lapeyraque, 2011), NMO (Pittock, 2013), systemic lupus erythematosus (SLE), and TTP (Chapin, 2012). The peer-reviewed literature includes open-label studies, registry databases, retrospective analyses, single case reports, and small case series. To date, the FDA has not approved eculizumab for use in the treatment of any of these conditions.

Background/Overview

PNH

PNH is an acquired clonal hemopoietic stem cell disorder that causes red blood cells to be deficient in GPI-anchored complement inhibitor proteins susceptible to complement-mediated lysis leading to chronic intravascular hemolysis (destruction of red blood cells). LDH is released during red blood cell destruction and a grossly elevated serum LDH is a common finding in individuals with PNH (Parker, 2005; Young, 2005). Analysis of LDH has not been standardized and normal ranges vary greatly between laboratories, reported at ranges from 103-223 U/L to 150-480 U/L, with the upper limit of normal higher in pregnant women. LDH levels in some cases can exceed 20 times the upper limit of normal during an exacerbation of the disease. This hemolysis can result in a spectrum of mild to severe symptoms. Hemolysis in PNH most likely contributes to initiation of platelet activation and aggregation, resulting in thromboembolism. Individuals with larger PNH clones have a higher incidence of thromboembolic events.

PNH consists of 3 disease subcategories: 1) classic PNH; 2) PNH in the setting of a bone marrow failure syndrome; and 3) subclinical PNH. The red cells in individuals with PNH are a mosaic of normal and abnormal cells, with the clinical course related to the size of the abnormal PNH clone. The prevalence of PNH ranges from 1 to 5 cases per 1,000,000 people, and is encountered in all populations throughout the world. The condition may occur more often in Southeast Asia and in the Far East. In the United States, estimates of the occurrence of PNH are fewer than 500 cases. PNH can be present in young children but has never been reported as a congenital disease or with inherited susceptibility. Most individuals with PNH are young adults, but the disease can occur in persons 70 years of age and older. According to Parker and colleagues (2005), the clinical course of PNH varies across ethnic groups, with thrombosis and infection more common in the American and European populations. Persons of Asian/Pacific Island and Hispanic descent experience more bone marrow failure.

Subcategories of PNH identified in the peer-reviewed literature (Brodsky, 2010; Parker, 2005; Parker, 2009):

  1. Classic PNH:
  1. PNH in the setting of another specified bone marrow disorder:
  1. Subclinical PNH: 

Individuals with PNH experience increased hemolysis at night, thought to result from decreased blood pH and activation of the complement system leading to characteristic bloody morning urination. Other symptoms relate to anemia, hemoglobinuria, and hemorrhage. The clinical course is chronic with acute exacerbations caused by complement activation (for example, in response to infection, pregnancy, surgery, trauma, or unusual stress). Excessive or persistent intravascular hemolysis causes anemia, hemoglobinuria, and complications related to the presence of plasma free hemoglobin, including thrombosis, abdominal pain, dysphagia, erectile dysfunction, and pulmonary hypertension. Many individuals are dependent on blood transfusions. Thromboembolism is the leading cause of mortality in individuals with PNH and an initial thrombotic event increases the relative risk of death 5- to 10-fold. Thrombi are characteristic in unusual sites (for example, hepatic, mesenteric, cerebral, and dermal veins). The probability of a thromboembolic event appears to be directly related to the size of the PNH clone. PNH may progress into aplastic anemia, and develop in individuals who previously had aplastic anemia. Flow cytometric analysis using antibodies directed against GPI-anchor proteins (GPI-AP) is considered the principal diagnostic test for PNH. For initial diagnosis, quantitation of at least 2 GPI-APs (CD55 and CD59) is recommended to exclude the possibility that an inherited, isolated deficiency of a single GPI-AP is responsible for the clinical picture. Flow cytometric analysis not only determines the percentage of cells that are abnormal, it also identifies discrete populations with different degrees of deficiency. Red blood cells with complete deficiency of GPI-APs are called PNH III, those with subtotal deficiency (that is, with approximately 10% of normal expression) are called PNH II, and those with normal expression are called PNH I (Parker, 2005). In an individual with PNH who has anemia with an inappropriately low reticulocyte count, an element of bone marrow failure is possibly a contributing factor.

aHUS (Atypical Hemolytic Uremic Syndrome/Complement-Mediated aHUS)

Hemolytic uremic syndrome (HUS) is a condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS and TTP are the two main variants of TMA and related disorders. Typical or post-diarrheal (diarrhea-positive) STEC-HUS (non-compliment-mediated syndrome [toxin-mediated]), describes the most frequent form of HUS in children, primarily resulted from STEC infections, and less frequently from Shigella dysenteriae type 1 infection. Typical HUS is the most common form accounting for > 90% of cases.

All other causes of HUS were referred to as aHUS, or assigned to diarrhea-negative HUS, even though some individuals with non-STEC-HUS also present with diarrhea. aHUS is a rare genetic disease of defective complement regulation leading to widespread thrombotic microangiopathy and accounts for 5% to 10% of all cases of HUS. aHUS is more appropriately described as complement-mediated aHUS or complement-HUS. According to Loirat and Fremeaux-Bacchi (2011), aHUS is divided into primary causes without coexisting disease, such as cases due to complement dysregulation (not due to STEC) including complement gene mutations, most commonly, antibodies to the complement factor H (CFH) gene (Loirat, 2016). Other causes of aHUS have been reported in individuals with gene mutations in membrane cofactor protein precursor (CD46), complement factor I (CFI), complement factor 3 (C3), complement factor B (CFB), thrombomodulin (THBD), diacylglycerol kinase epsilon (DGKE), and the gene that encodes plasminogen (PLG) (Bu, 2014). Secondary aHUS is attributed to a variety of causes, including infectious agents (mostly Streptococcus pneumonia/S pneumoniae), human immunodeficiency virus (HIV) and H1N1 influenza A, malignancy, drug toxicity associated with cancer chemotherapy, ionizing radiation, bone marrow or solid organ transplantation, calcineurin inhibitors, sirolimus or antivascular endothelial growth factor (VEGF) agents, pregnancy, HELLP syndrome, malignant hypertension, glomerulopathies, systemic diseases (SLE and APS, scleroderma) or, in children, with methylmalonic acidemia with homocystinuria, cblC type (a rare hereditary defect of cobalamine metabolism) (Loriat and Fremeaux-Bacchi, 2011).

There are an estimated 300 to 600 cases annually of aHUS in the United States. Onset occurs at any age (1 day to 83 years), although it is disproportionally more common in children and young adults. The clinical course of aHUS, including the response to therapy and prognosis, are dependent on which genetic factors are present, in that 60% to 70% of individuals with aHUS have one or more identified mutations in complement factors or complement regulatory proteins or have acquired auto-antibodies to complement regulatory proteins (for example, mutations in CD46 CFH, and CHI genes). Thus, aHUS is a chronic condition with relapses of acute illness and is often complicated by renal failure and severe hypertension. Approximately 25% of individuals die from an acute episode and 50% progress to end-stage renal disease.

Young children with aHUS present with a sudden onset of symptoms, including pallor, general distress, poor feeding, vomiting, fatigue, drowsiness and, sometimes, edema. In a retrospective case series by Geerdink and colleagues (2012), aHUS onset followed a triggering event in 38 of 45 children, including gastrointestinal symptoms (74%), upper respiratory infection (45%) and fever (32%). At onset, diarrhea was observed in 11 (25%) of children, 5 of whom also had fever. Adult complaints include fatigue and general distress. The condition can progress rapidly to life-threatening hyperkalemia, acidosis, volume overload, severe hypertension, and hyponatremia, and in some individuals, cardiac failure, severe arterial hypertension and neurological complications. Dialysis is required in 50% of children at the time of hospitalization. Approximately 5% of individuals present with life-threatening multivisceral failure due to TMA. The optimal primary management of aHUS remains unclear. Because aHUS is severe with high mortality, and difficult to distinguish from another disorder, TTP, treatment is started immediately with plasma therapy (PE or PI) if aHUS is suspected and has generally been the first-line therapy during an acute episode of aHUS. The response to plasma treatment appears to vary depending on the affected complement component. In individuals with either factor H or factor I deficiencies, about two-thirds of those will remit with plasma therapy. Individuals with mutations in genes for factor H, factor I, or C3 who fail to respond to plasma therapy and/or have recurrent disease are likely to progress to end-stage renal disease and require long-term renal dialysis. Eculizumab is utilized to treat individuals who fail to respond to plasma therapy and those with impaired renal function and on renal dialysis. Individuals have exhibited improvement in platelet counts and other blood parameters that correlate with aHUS disease activity. Some individuals have been able to discontinue dialysis as a result of improved renal function.

aHUS, in association with hematopoietic stem cell transplantation, has been referred to as transplant-associated TMA (TA-TMA) and is a distinct entity from TTP. The etiology of TA-TMA is multifactorial, and its risk factors include high-dose chemotherapy, radiation therapy, unrelated donor, and human leukocyte antigen (HLA) mismatch. Use of compliment blocking with eculizumab for aHUS following hematopoietic stem cell transplantation may improve outcomes and survival when aHUS is related to transplant-associated TMA (Rosenthal, 2016).

Myasthenia Gravis

Myasthenia gravis is a rare autoimmune disease in which an immunological attack on the neuromuscular junction produces ineffective transmission of impulses from motor nerves to muscle, resulting in weakness. The incidence of myasthenia gravis in the United States (U.S.) is approximately 5000 new cases per year, with an estimated U.S. prevalence of 35,000 to 70,000 cases. According to an international consensus guidance document for management of myasthenia gravis (Sanders, 2016), the incidence of myasthenia gravis ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.

In most individuals with myasthenia gravis, the eye muscles are affected first, producing double vision or drooping eyelids. As weakness progresses, other muscles that control chewing, swallowing and talking are affected. Weakness in myasthenia gravis can be mild or severe and life-threatening when it affects respiratory or oropharyngeal muscles. Approximately 10% to 15% of individuals with myasthenia gravis are considered to be treatment-refractory. Myasthenic crisis, an acute weakness of respiratory or oropharyngeal muscles, may require ventilator support and can occur with a precipitating event, such as an infection, change in medication, or systemic disease (for example, hyperthyroidism).

In October 2013, the Myasthenia Gravis Foundation of American appointed a Task Force to develop guidance statements and definitions for symptomatic and immunosuppressive treatments, IVIG, plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile myasthenia gravis, myasthenia gravis associated with antibodies to muscle-specific tyrosine kinase (MuSK-MG), and myasthenia gravis in pregnancy (Sanders, 2016) . Use of nonsteroidal immunosuppressive agents in myasthenia gravis “…include azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, and tacrolimus”; however, the guidance states there is “widespread variation in practice with respect to choice of immunosuppressive (IS) agents since there is little literature comparing them.” Individuals with refractory myasthenia gravis “should be referred to a physician or a center with expertise in management” of the condition.

Adverse Events and Warnings for Eculizumab

Eculizumab has a Black Box Warning as follows (Soliris PI Label, 2017):

Warning: Serious Meningococcal Infections

Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris REMS, prescribers must enroll in the program.

Contraindications

Other Warnings and Precautions

Treatment Discontinuation (See Rationale: Treatment Discontinuation and Increased Risk of Thrombosis)

Use in Specific Populations

Definitions

Complement system: A set of over 20 different protein molecules found in the blood that work together to destroy foreign pathogens (such as bacteria and viruses), trigger inflammation, and remove debris from cells and tissues. Mutations in the genes associated with aHUS lead to uncontrolled activation of the complement system.

Flow cytometry: A blood test (assay) used for the diagnosis of PNH that measures the expression pattern of GPI-linked proteins on red cells, monocytes, and B-lymphocytes.

Hemolysis: The breakdown of red blood cells.

Lactate dehydrogenase (LDH): A protein that is present in red blood cells. An LDH blood test is used as a measure of hemolysis (breakdown of red blood cells) in PNH when performed in conjunction with other laboratory tests and assessments.

Major adverse vascular events (MAVE): As described by Hillmen and colleagues (2007), MAVE include, but are not limited to the following:

Microangiopathic hemolytic anemia: A disorder in which narrowing or obstruction of small blood vessels results in distortion and fragmentation of red blood cells (erythrocytes), hemolysis, and anemia.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Myasthenia Gravis-Activities of Daily Living (MG-ADL) profile: An eight-item patient-reported scale developed to assess myasthenia gravis symptoms and their effects on daily activities. Parameters include talking, chewing, swallowing, breathing, impairment of ability to brush teeth or comb hair, impairment of ability to arise from a chair, double vision, and eyelid droop. Each item is scored a 0 (normal or no symptoms) to 3 (for example, when talking, difficult to understand speech or, requiring a gastric tube for chewing or swallowing), with a total score equal to the sum of points for all applicable parameters (minimum score: 0; maximum score: 24). The higher the score, the greater the disease severity. A 2-point improvement in the MG-ADL profile indicates clinical improvement.

PNH III cells, or Type III cells: These cells are extremely sensitive to the complement system and missing all the proteins that protect normal cells from attack. Most people with PNH have Type I and Type III cells; however, the amount of each type of cell can vary greatly. PNH cells are classified by using a flow cytometry test to determine if any proteins are missing from an individual’s red blood cells. Flow cytometry can also be performed on certain white blood cells called granulocytes. Cells that are completely without GPI-anchored proteins are known as PNH Type III red cells. These red cells are found to be extremely sensitive to activated complement as compared to normal red cells. The CD59 deficient PNH Type III erythrocyte is highly sensitive to C5-9 complement mediated lysis and is responsible for hemolytic anemia, which is characteristic of PNH. PNH Type III clones with complete deficiency of GPI- anchored proteins, PNH Type II clones with partial deficiency of GPI anchored proteins, and normal cells exist in almost all cases of PNH.

Quantitative Myasthenia Gravis (QMG) score: A score for evaluating disease severity used to monitor the individual over time and to evaluate the response to interventions. Parameters include: 1) double vision on lateral gaze; 2) ptosis on upward gaze; 3) weakness of facial muscles; 4) swallowing water; 5) speech after counting aloud; 6) ability to keep right arm outstretched; 7) ability to keep left arm outstretched; 8) vital capacity as percent of predicted; 9) right hand grip strength; 10) left hand grip strength; 11) ability to keep head lifted when lying supine; 12) ability to keep the right leg outstretched; and, 13) ability to keep the left leg outstretched. Each item is scored from 0 (normal) to 3 (significant), with a total score equal to the sum of points for all 13 applicable parameters (minimum score: 0; maximum score: 39). The higher the score, the greater the disease severity.

Thrombocytopenia: A reduced level of circulating platelets, which are cell fragments that normally assist with blood clotting. In individuals with aHUS, fewer platelets are available in the bloodstream because a large number of platelets are used to make abnormal clots.

Thrombotic microangiopathy (TMA): The formation of blood clots (thrombi) in small blood vessels (arterioles and capillaries), as occurs in thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremia syndrome (aHUS).

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

J1300

Injection, eculizumab, 10 mg

 

 

ICD-10 Diagnosis

 

 

 

Including, but not limited to, the following and any associated symptoms or complications:

 

D59.3

Hemolytic-uremic syndrome [when specified as aHUS]

 

D59.5

Paroxysmal nocturnal hemoglobinuria [Marchiafava-Micheli]

 

G70.00-G70.01

Myasthenia gravis

 

When services are Investigational and Not Medically Necessary:
For the procedure code listed above when criteria are not met and for the following diagnosis codes; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

ICD-10 Diagnosis

 

 

Including, but not limited to the following:

D68.61

Antiphospholipid syndrome

G36.0

Neuromyelitis optica [Devic]

H35.3110-H35.3194

Nonexudative age-related macular degeneration

M31.1

Thrombotic microangiopathy (thrombotic thrombocytopenic purpura)

M32.0-M32.9

Systemic lupus erythematosus (SLE)

O14.20-O14.25

HELLP syndrome

References

Peer Reviewed Publications:

  1. Ardissino G, Testa S, Possenti I, et al. 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. 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. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol. 2012; 7(5):748-756.
  4. Brodsky RA. Stem cell transplantation for paroxysmal nocturnal hemoglobinuria. Haematologica. 2010; 95(6):855-856.
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  20. Hillmen P, Elebute M, Kelly R, et al. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. Am J Hematol. 2010; 85(8):553-559.
  21. Hillmen P, Hall C, Marsh JC, et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004; 350(6):552-559.
  22. Hillmen P, Muus P, Duhrsen U, et al. Effect of complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007; 110(12):4123-4128.
  23. Hillmen P, Muus P, Roth A, et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013; 162(1):62-73.
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  26. Howard JF Jr, Freimer M, O'Brien F, et al. QMG and MG-ADL correlations: study of eculizumab treatment of myasthenia gravis. Muscle Nerve. 2017a; 56(2):328-330.
  27. Howard JF Jr, Utsugisawa K, Benatar M, et al. 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. 2017b Oct 20. [Epub ahead of print].
  28. Kanakura Y, Ohyashiki K, Shichishima T, et al. Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS clinical trial. Int J Hematol. 2011; 93(1):36-46.
  29. Kelly R, Arnold L, Richards S, et al. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J Haematol. 2010; 149(3):446-450.
  30. Kelly RJ, Hochsmann B, Szer J, et al. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2015; 373(11):1032-1039.
  31. Kocak B, Arpali E, Demiralp E, et al. Eculizumab for salvage treatment of refractory antibody-mediated rejection in kidney transplant patients: case reports. Transplant Proc. 2013; 45(3):1022-1025.
  32. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, et al. Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med. 2011; 364(26):2561-2563.
  33. Lee JW, Jang JH, Kim JS, et al. Clinical signs and symptoms associated with increased risk for thrombosis in patients with paroxysmal nocturnal hemoglobinuria from a Korean Registry. Int J Hematol. 2013; 97(6):749-757.
  34. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013; 368(23):2169-2181.
  35. Licht C, Greenbaum LA, Muus P, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int. 2015; 87(5):1061-1073.
  36. Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011; 6:60.
  37. Lonze BE, Zachary AA, Magro CM, et al. Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. Am J Transplant. 2014; 14(2):459-465.
  38. McCaughan JA, O’Rouke DM, Courtney AE. Recurrent dense deposit disease after renal transplantation: an emerging role for complimentary therapies. Am J Transplant. 2012; 12(4):1046-1051.
  39. Nishimura J, Kanakura Y, Ware RE, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore). 2004; 83(3):193-207.
  40. Noris M, Caprioli J, Bresin E, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010; 5(10):1844-1859.
  41. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009; 361(17):1676-1687.
  42. Oosterveld MJ, Garrelfs MR, Hoppe B, et al. Eculizumab in pediatric dense deposit disease. Clin J Am Soc Nephrol. 2015; 10(10):1773-1782.
  43. Orandi BJ, Zachary AA, Dagher NN, et al. Eculizumab and splenectomy as salvage therapy for severe antibody-mediated rejection after HLA-incompatible kidney transplantation. Transplantation. 2014; 98(8):857-863.
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Government Agency, Medical Society, and Other Authoritative Publications:

  1. Centers for Disease Control (CDC) and Prevention. Immunization Schedules (2017). Available at: http://www.cdc.gov/vaccines/schedules/. Accessed on November 1, 2017.
  2. Eculizumab Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised January 2, 2014. Accessed on November 1, 2017.
  3. Loirat C, Fakhouri F, Ariceta G, et al; HUS International. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2016; 31(1):15-39.
  4. Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016; 87(4):419-425.
  5. Scully M, Hunt BJ, Benjamin S, et al; British Committee for Standards in Haematology. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012; 158(3):323-335.
  6. Soliris [Product Information]. Alexion Pharmaceutical, Inc., Cheshire, CT; October 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125166s422lbl.pdf. Accessed on November 1, 2017.
  7. U.S. National Institutes of Health (NIH). ClinicalTrials.gov. ECU-MG-302: an extension trial of ECU-MG-301 to evaluate the safety and efficacy of eculizumab in refractory generalized myasthenia gravis. NLM Identifier: NCT02301624. Last updated August 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02301624. Accessed on November 1, 2017.
Websites for Additional Information
  1. U.S. National Library of Medicine (National Institutes of Health). Genetics Home Reference. Genetics Conditions. Available at: http://ghr.nlm.nih.gov/BrowseConditions. Accessed on November 1, 2017.
    • Atypical hemolytic uremic syndrome
    • Paroxysmal nocturnal hemoglobinuria
Index

Atypical Hemolytic Uremic Syndrome (aHUS)
Paroxysmal Nocturnal Hemoglobinuria (PNH)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Revised

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review. Added MN criteria for FDA expanded approval of eculizumab to treat adults with generalized myasthenia gravis. Removed myasthenia gravis from the INV and NMN statement. Updated Description, Rationale, Background, Definitions, Coding, References, and Websites for Additional Information sections.

Revised

11/01/2017

Hematology/Oncology Subcommittee review. Administrative edits to the Position Statements (removed abbreviations). The document header wording updated from “Current Effective Date” to “Publish Date.”

Revised

11/03/2016

MPTAC review.

Revised

11/02/2016

Hematology/Oncology Subcommittee review. Updated formatting in Position Statement section. Added specific sections to the MN indications for PNH and aHUS. Updated Rationale, Background, References, and Websites for Additional Information sections.

 

10/01/2016

Updated Coding section with 10/01/2016 ICD-10-CM diagnosis code changes.

Revised

11/05/2015

MPTAC review.

Revised

11/04/2015

Hematology/Oncology Subcommittee review. Format changes and clarifications to the medically necessary statement for PNH (initiation of therapy). Revised the medically necessary statement for initiation of PNH therapy, removing  from A. 1. a) “at least 10%...” and from A, 1. b)  “greater than 50% of...”. Addition of a second medically necessary statement for continuation of eculizumab therapy in an individual with documented PNH who is currently receiving treatment with eculizumab. Updated Rationale, References, and Websites for Additional Information sections. Removed ICD-9 codes from Coding section.

Revised

05/07/2015

MPTAC review.

Revised

05/06/2015

Hematology/Oncology Subcommittee review. Medically necessary criterion for LDH levels revised to state: “Lactate dehydrogenase (LDH) is greater than 1.5 times the upper limit of normal.” Clarified the investigational and not medically necessary statement. Updated Description, Rationale, Background, References, and Websites for Additional Information sections. Other format changes throughout document.

Revised

05/15/2014

MPTAC review.

Revised

05/14/2014

Hematology/Oncology Subcommittee review. Clarified medically necessary statement for eculizumab for PNH and updated investigational and not medically necessary statement. Updated Rationale, Background, References, and Websites for Additional Information sections.

Revised

05/09/2013

MPTAC review.

Revised

05/08/2013

Hematology/Oncology Subcommittee review. Revised medically necessary criteria for PNH: 1) removed transfusion requirements and that MAVE occur while on therapeutic anticoagulation therapy, and 2) added criterion requiring that LDH be greater than 1,000 U/L. Revised medically necessary statement for aHUS, adding criteria for: 1) an initial 6-week trial, 2) evaluation of ADAMTS 13 status, and 3) continuation of therapy following the initial 6-week trial. Clarified investigational and not medically necessary statement. Updated Rationale, Background, Definitions, References, and Websites for Additional Information.

Revised

11/08/2012

MPTAC review.

Revised

11/07/2012

Hematology/Oncology Subcommittee review. Updated Position Statement with a Note and cross reference to the Rationale. Revised medically necessary criterion for PNH and aHUS. Updated Rationale, Background, References, and Websites for Additional Information.

New

08/09/2012

MPTAC review. Initial document development.