Medical Policy. MP Eculizumab (Soliris) Related Policies None. Last Review: 01/24/2019 Effective Date: 04/25/2019 Section: Prescription Drug

Transcription

1 Medical Policy Last Review: 01/24/2019 Effective Date: 04/25/2019 Section: Prescription Drug Related Policies None DISCLAIMER Our medical policies are designed for informational purposes only and are not an authorization, explanation of benefits or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. POLICY Due to the specialized nature of this treatment and risks associated with this disease, prescriptions for this agent must be ordered by a specialist in hematology/oncology. therapy may be considered medically necessary for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis and thrombosis when all of the following criteria are met: Documented diagnosis of PNH (flow cytometric confirmation of at least 10% PNH type III red cells and platelet counts of at least 30,000/microliter prior to initiation of eculizumab treatment; and Member is either transfusion dependent (i.e., has at least 2 transfusions in the 12 months prior, one of which in the 3 prior months prior to initiation of eculizumab due to documented hemoglobin less than 7 g/dl in persons without anemic symptoms or less than 9 g/dl in persons with symptoms from anemia), or member has a documented history of major adverse vascular event from thromboembolism while on therapeutic anticoagulation therapy; and Member has been vaccinated against meningococcal infection (at least 2 weeks prior to eculizumab treatment, if not previously vaccinated). Recurrent use of eculizumab (Soliris) therapy is not medically necessary for the treatment of PNH to reduce hemolysis when transfusion requirements are not significantly reduced. Recurrent use of eculizumab (Soliris) therapy is not medically necessary for the treatment of PNH to reduce thrombosis when thromboembolism events persist despite treatment. Reauthorization of eculizumab (Soliris) therapy may be considered medically necessary for the treatment of serious hemolysis after eculizumab (Soliris) discontinuation. Eculizumab may be considered medically necessary for the treatment of Atypical Hemolytic Uremic Syndrome for an initial 6-week trial 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

2 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. 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). Eculizumab (Solaris) therapy is considered investigational when the criteria are not met and for all other indications not specifically mentioned above, including, but not limited to BACKGROUND antibody-mediated rejection in organ transplantation Guillain-Barré syndrome systemic lupus Erythematosus Myasthenia Gravis antineutrophil cytoplasmic autoantibody vasculitis antiphospholipid antibody syndrome dense deposit disease or C3 nephropathy hemolysis elevated liver enzymes and low platelets syndrome in preeclampsia hemolytic cold agglutinin disease neuromyelitis optica nonexudative (dry) age-related macular degeneration Shiga toxin E. coli-related hemolytic uremic syndrome thrombotic thrombocytopenic purpura is a humanized monoclonal IgG antibody that selectively binds to complement protein C5 on the surface of human red blood cells. The high affinity bond protects against complement-mediated red blood cell hemolysis. Eculizumab antibody is FDA approved to treat patients with Atypical hemolytic uremic syndrome (ahus), generalized myasthenia Gravis (considered investigational in this policy due to lack of clinical evidence showing efficacy), and Paroxysmal Nocturnal Hemoglobinuria (PNH), which is an illness attributed to intravascular complement-mediated hemolysis. Treatment with eculizumab reduces hemolysis as a result of a high affinity bond with the red blood cell complement protein C5. The bond prevents enzymatic cleavage of C5 into C5a and C5b. This in turn prevents the generation of C5b-9. It is C5b-9, which causes intravascular red blood cell hemolysis. With sufficient hemolysis, a patient may develop hemolytic anemia, hypercoagulation, thrombosis, and bone marrow failure. Some patients are treated with repeated transfusions and/or anticoagulation. Progression to myelodysplasia, aplastic anemia, and acute leukemia can also occur. PNH is a form of hemolytic anemia secondary to a somatic mutation. A mutation of the X-linked phosphatidylinositol glycan class A (PIGA) gene, results in the absence of a protective protein. Without the glycosylphosphatidylinositol-linked protein, increased complement-mediated hemolysis occurs. The proportion of affected cells varies among patients. Original Policy Date: November 2011 Page: 2

3 The gold standard test for the diagnosis of PNH is flow cytometry. A peripheral blood sample is used. In addition to detecting small clones, the flow cytometry also has the ability to establish clonal size. Important in the PNH patient population, the test results are not affected by blood transfusions. In the past, treatment of PNH has been in response to clinical manifestations of the hemolysis. The supportive options have included folic acid supplementation, hydration, anti-coagulation, and red blood cell transfusions. The recommended dose for eculizumab (Soliris) treatment is as follows: 600 mg every seven days for the first four weeks, followed by 900 mg for the fifth dose 7 days later, then 900 mg every 14 days thereafter. received accelerated U.S. Food and Drug Administration (FDA) approval in March (Dmytrijuk et al, 2008) Two clinical studies are cited in the prescribing information for PNH. Both studies used the recommended treatment schedule. The first study enrolled PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells, and at least 100,000 platelets/microliter. Hemoglobin set-points of equal to or less than 9 g/dl and 7 g/dl for patients with and without symptoms respectively were used. Patient who did not need a transfusion during the three month set-point observation period were excluded. A total of 87 patients were randomized to eculizumab (43) or placebo (44) and treated for 26 weeks. In the twelve months prior to randomization, packed RBC units transfused per patient (median (Q1,Q3)) by group were eculizumab 18 (12, 24) and placebo 17 (14, 25). Concomitant anticoagulants used by members of each group were eculizumab 24 (56%) and placebo 20 (46%). Patients with a history of thrombosis by group were eculizumab 9 (16 events) and placebo 8 (11 events). By week 26, the patients treated with eculizumab received fewer transfused packed RBC units per patient. Mean number of transfused units was 3 for the treated group and 7 for the placebo group, whereas median units (range) transfused was 0 (0-16) compared to 10 (2-21) respectively. Transfusion avoidance by group was eculizumab 51% and placebo 0%. One patient in the placebo group had a thrombotic event. (Hillmen et al, 2006; Alexion Pharma, 2007) The second study enrolled PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter. A total of 97 patients were treated with eculizumab in an open-label, nonplacebo controlled study for 52 weeks. Concomitant anticoagulants were used by 63% of the patients. There was a reduction in need for RBC transfusion. Two patients, of which one event was fatal, had thrombotic events. (Alexion Pharma, 2007) Hypercoagulation and thrombotic events are a known consequence for some patients with PNH. The risk of thrombosis seems to correlate to the PNH clonal size. The effect of eculizumab on the incidence of thrombotic events has not been answered by a prospective randomized study. Retrospective and observational data suggest a benefit with eculizumab treatment. Thromboembolism rate before treatment was approximately seven times greater per 100 patient years when compared to the thromboembolism rate while receiving treatment. (Hillmen et al, 2007) In another retrospective study, warfarin provided complete protection against thromboembolic events in PNH patients. (Hall, et al, 2003) The prescribing information warns that patients who discontinue treatment with eculizumab (Soliris) may be at increased risk for serous hemolysis. Patients who discontinue eculizumab (Soliris) treatment should be monitored for at least 8 weeks to detect serous hemolysis and other reactions. In contrast, Original Policy Date: November 2011 Page: 3

4 Parker (2009) and the Canadian Agency for Technology Assessment in Health note the theoretical possibility of a rebound effect, cases have not been identified. (Parker, 2009; CADTH, 2010) Eculizumab is contraindicated in persons with unresolved serious Neisseria meningitidis infections, and in persons who are not currently vaccinated against Neisseria. Safely and effectiveness have not been established in patients below the age of 18. A minority of persons with PNH have a disease severity similar to that required to qualify for the pivotal eculizumab studies. In the eculizumab manufacturer s submission to the National Health Service, it was anticipated that the drug would be used for the 15% of PHN patients that are most severely affected by the illness. (Alexion Pharma, 2008) In the absence of significant hemolysis or recurrent thrombosis, the use of eculizumab is not supported by the current medical literature and would not be considered to be the most appropriate treatment at this time. 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 Shigatoxin/EHEC positive test (stool culture and polymerase chain reaction for Shiga-toxins; serology for antilipopolysaccharides 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 Original Policy Date: November 2011 Page: 4

5 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) TMAevent 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 complementmediated 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 Original Policy Date: November 2011 Page: 5

6 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 autoantibody. 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 Myasthenia Gravis Complement is likely to have a role in refractory generalized myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis. The efficacy and 13, 14 safety of eculizumab was further assessed in this patient population in a phase 3 trial. Original Policy Date: November 2011 Page: 6

7 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 13, 14 (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 13, 14 is needed. REFERENCES 1. Dmytrijuk A, Robie-Suh K, Cohen MH, et al. FDA report: for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Oncologist. 2008;13(9): Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355(12): Alexion Pharma UK Ltd. Form B: Detailed appraisal information, Soliris. Surrey, UK: Alexion; November 21, 2008 (as cited in All Wales Medicines Strategy Group, 2009). 4. 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); Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2003;102(10): Alexion Pharmaceuticals, Inc. Soliris (eculizumab). Prescribing Information. Cheshire, CT: Alexion; March Available at: Accessed October 4, Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet. 2009;373: Canadian Agency for Drugs and Technologies in Health (CADTH). Eculizumab. (Soliris - Alexion Pharmaceuticals, Inc.). Indication: Paroxysmal nocturnal hemoglobinuria. CEDAC Final Recommendation. Common Drug Review. Ottawa, ON: CADTH; February 19, Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Coehn DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood Jun 23: 117 (25): 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): 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): Howard JF Jr, Barohn RJ, Cutter GR, et al. A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve. 2013; 48(1): 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): Original Policy Date: November 2011 Page: 7

8 CODES 14. Howard JF Jr, Utsugisawa K, Benatar M, et al. Safety and efficacy of eculizumab in antiacetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017b Oct 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): Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011; 6: 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): Code Number Description HCPCS J1300 Injection, eculizumab, 10mg ICD-10-CM D59.5 Paroxysmal nocturnal hemoglobinuria [Marchiafava-Micheli] D59.3 Hemolytic-uremic syndrome [when specified as ahus] POLICY HISTORY Date Action Reason 08/01/14 Replace policy Added reference 9; updated description to reflect the appropriateness of Solaris for significant hemolysis or recurrent thrombosis. 05/01/16 Replace policy Blue Cross of Idaho annual review, no change to policy. 06/01/17 Replace policy Blue Cross of Idaho annual review, no change to policy. 04/30/18 Update only Medical policy renumbered from to /27/18 Replace policy Blue Cross of Idaho annual review; no change to policy. 1/24/19 Replace policy Blue Cross of Idaho adopted the changes as noted, effective 04/25/2019. Policy statement updated with criteria for Medically Necessary treatment of Atypical Hemolytic Uremic Syndrome (ahus) Original Policy Date: November 2011 Page: 8