Soliris Medical Policy Prior Authorization Program Summary

Soliris Medical Policy Prior Authorization Program Summary Precertification/Prior Authorization may be required under certain plans. Please verify each member s benefits. OBJECTIVE The intent of the Soliris medical drug criteria is to appropriately select patients for therapy according to product labeling and/or clinical guidelines and/or clinical studies and to verify appropriate FDA labeled dosing for specified indications. The criteria will direct its use to the FDA approved and/or clinically supported indications. Criteria require that patients do not have any FDA labeled contraindications to use with the requested agent. The program will approve the requested agent for doses within FDA labeling. Doses above FDA labeling will be approved when the prescriber has submitted documentation in support of therapy with a higher dose for the intended diagnosis. Target Drugs Soliris (eculizumab) Initial Evaluation Soliris (eculizumab) will be approved when ALL of the following are met: 1. The patient does NOT have any FDA labeled contraindications to the requested agent 2. ONE of the a. The patient has been immunized with a meningococcal vaccine at least prior to administering the first dose of eculizumab b. The prescriber has provided documentation indicating the risks of delaying eculizumab therapy outweigh the risks of developing a meningococcal infection 3. ONE of the a. The patient has a diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) and ALL of the i. The prescriber has submitted documentation showing flow cytometric confirmation of at least 10% PNH cells ii. The agent is being prescribed by a specialist in the area of practice related to the iii. The prescriber has submitted documented pretreatment baseline levels for one or more of the following (required for renewal): 1. Hemoglobin level that is less than or equal to 7 g/dl, or the individual has symptoms of anemia and the hemoglobin is less than or equal to 9 g/dl 2. Serum lactate dehydrogenase (LDH) that is greater than 1.5 times the upper limit of normal 3. Packed RBC transfusion requirement b. The patient has a diagnosis of atypical hemolytic uremic syndrome (ahus) and ALL of the AL_CS_Soliris_PA_MDC_ProgSum_0717 Page 1 of 6

i. Shigatoxin-related HUS has been ruled out ii. The agent is being prescribed by a specialist in the area of practice related to the iii. The prescriber has submitted documented pretreatment baseline levels for one or more of the following (required for renewal): 1. Platelet count 2. Serum lactate dehydrogenase (LDH) 3. Plasma exchange/infusion requirement 4. Serum creatinine/egfr 4. ONE of the a. The dose is within the FDA labeled dose b. The dose requested is greater than the maximum dose recommended in FDA labeling, and the prescriber has submitted documentation in support of therapy with a higher dose for the intended diagnosis which has been reviewed and approved Length of Approval: 6 months Renewal Evaluation Soliris (eculizumab) will be approved when ALL of the following are met: 1. The patient does NOT have any FDA labeled contraindications to the requested agent 2. ONE of the a. The patient has been immunized with a meningococcal vaccine at least prior to administering the first dose of eculizumab and revaccinated according to current medical guidelines for vaccine use b. The prescriber has provided documentation indicating the risks of delaying eculizumab therapy outweigh the risks of developing a meningococcal infection 3. ONE of the a. The patient has a diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) and BOTH of the i. The agent is being prescribed by a specialist in the area of practice related to the ii. The prescriber has submitted documentation supporting one or more of the 1. Stabilization/improvement in hemoglobin level from pretreatment baseline 2. Decrease in serum lactate dehydrogenase (LDH) from pretreatment baseline 3. Decrease in packed RBC transfusion requirement from pretreatment baseline b. The patient has a diagnosis of atypical hemolytic uremic syndrome (ahus) and ALL of the i. Shiga toxin-related HUS has been ruled out ii. The agent is being prescribed by a specialist in the area of practice related to the AL_CS_Soliris_PA_MDC_ProgSum_0717 Page 2 of 6

iii. The prescriber has submitted documentation supporting one or more of the 1. Increased platelet count from pretreatment baseline 2. Decrease in serum lactate dehydrogenase (LDH) from pretreatment baseline 3. Decrease in plasma exchange/infusion requirement from pretreatment baseline 4. Stabilization/improvement in serum creatinine/egfr from pretreatment baseline 4. ONE of the a. The dose is within the FDA labeled dose b. The dose requested is greater than the maximum dose recommended in FDA labeling, and the prescriber has submitted documentation in support of therapy with a higher dose for the intended diagnosis which has been reviewed and approved Length of Approval: 12 months Agent Soliris (eculizumab) Contraindication(s) Patients with unresolved serious Neisseria meningitidis infection. Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying Soliris treatment outweigh the risks of developing a meningococcal infection. Blue Cross and Blue Shield of Alabama does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. Blue Cross and Blue Shield of Alabama administers benefits based on the members' contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination. This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment. This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and preprocedure review) in Blue Cross and Blue Shield s administration of plan contracts. Blue Cross and Blue Shield of Alabama is an independent licensee of the Blue Cross and Blue Shield Association. BLUE CROSS, BLUE SHIELD and the Cross and Shield symbols are registered trademarks of the Blue Cross and Blue Shield Association. Prime Therapeutics LLC is an independent limited liability company providing pharmacy benefit management services. AL_CS_Soliris_PA_MDC_ProgSum_0717 Page 3 of 6

FDA APPROVED INDICATIONS DOSAGE 1 Agent(s) 1 Indication Dosing Soliris (eculizumab) # The treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. The treatment of patients with atypical hemolytic uremic syndrome (ahus) to inhibit complementmediated thrombotic microangiopathy. Administered as an intravenous infusion. PNH Soliris therapy consists of: 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every thereafter. Soliris should be administered at the recommended dosage regimen time points, or within two days of these time points. Administered as an intravenous infusion. ahus For patients 18 years of age and older, Soliris therapy consists of: 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, then 1200 mg every thereafter. For patients less than 18 years of age, administer Soliris based upon body weight, according to the following schedule: Patient Body Weight Induction Maintenance 40 kg and over 900 mg weekly x 4 doses 1200 mg at week 5; then 1200 mg every 30 kg to less than 40 kg 600 mg weekly x 2 doses 900 mg at week 3; then 900 mg every 20 kg to less than 30 kg 600 mg weekly x 2 doses 600 mg at week 3; then 600 mg every 300 mg at week 2; 10 kg to less than then 300 mg every 20 kg 600 mg weekly x 1 dose 300 mg at week 2; 5 kg to less than then 300 mg every 10 kg 300 mg weekly x 1 dose 3 weeks Soliris should be administered at the recommended dosage regimen time points, or within two days of these time points. # Limitation of Use Soliris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS) CLINICAL RATIONALE Soliris, a complement inhibitor, is a formulation of eculizumab which is a recombinant humanized monoclonal IgG2/4κ antibody produced by murine myeloma cell culture and purified by standard bioprocess technology. Eculizumab contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kda. 1 Paroxysmal Nocturnal Hemoglobinuria (PNH) Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by complement mediated hemolysis resulting in anemia, hemoglobinuria, and complications related to presence of free hemoglobin. Patients with PNH have a median survival of ten years after diagnosis. 2 Flow cytometry to AL_CS_Soliris_PA_MDC_ProgSum_0717 Page 4 of 6

detect populations of glycophosphatidylinositol (GPI) anchor deficient cells is firmly established as the method of choice for diagnosis and monitoring PNH. 4,5 The safety and efficacy of Soliris were evaluated in a randomized, double-blind, placebo-controlled 26 week study evaluated eculizumab in the treatment of PNH (n=87). 1 PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either Soliris (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the hemoglobin concentration (the "set-point") which would define each patient s hemoglobin stabilization and transfusion outcomes. The hemoglobin set-point was less than or equal to 9 g/dl in patients with symptoms and was less than or equal to 7 g/dl in patients without symptoms. Primary endpoints were stabilization of hemoglobin above level required for transfusion and number of packed red blood cells transfused during the study period. Secondary efficacy measures included hemolysis, change in level of fatigue as measured by FACIT-fatigue score, and proportion of patients with transfusion independence. Stabilization of hemoglobin levels occurred in 49% of eculizumab treated patients compared to zero in the placebo group (p<0.001). The median number of packed red blood cells infused was zero in the eculizumab group compared to ten in the placebo group (p<0.001).transfusion independence was achieved by 51% of patients treated with eculizumab compared to zero for placebo (p<0.001). Fatigue scores were improved with eculizumab (+6.4 points) versus placebo (-4 points) (p<0.001). Hemolysis was also reduced with eculizumab therapy compared to placebo (p<0.001). 1 Study 2 was a 52 week, open label study involving 97 patients with PNH. The primary endpoint of the study was reduction in hemolysis as measured by lactic dehydrogenase area under the curve (LDH AUC). Secondary endpoints included fatigue and change in hemolysis from baseline. A mean decrease in LDH AUC of 667,000 U/L x day from baseline was achieved by patients treated with eculizumab (p<0.001). Significant reductions occurred regardless of prior transfusion requirements. Eculizumab improved fatigue in patients as measured by a mean change in the FACIT score of 12.2 (p<0.001). LDH was reduced from a median of 2051 U/L at baseline to 269 U/L at week 52 with eculizumab therapy (p<0.001). 1 Atypical Hemolytic-Uremic Syndrome (ahus) Atypical hemolytic-uremic syndrome (ahus) is a genetic, chronic, and progressive inflammatory disease caused by defects in regulation of the complement system. Patients have a risk of systemic clinical complications of thrombotic microangiopathy (TMA), including damage to multiple organ systems. 1,3 The efficacy of eculizumab in ahus patients was evaluated in 3 single-arm studies (two prospective and 1 retrospective). In all three trials the endpoints evaluated include platelet count change from baseline, hematologic normalization (maintenance of normal platelet counts and LDH levels for at least 4 weeks), complete TMA response (hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of 4 weeks), TMA-event free status (absence for at least 1 of a decrease in platelet count of >25% from baseline, plasma exchange or plasma infusion and new dialysis requirement), and daily TMA intervention rate (number of plasma exchange or plasma infusion interventions (PE/PI) and the number of new dialysis required per patient per day). 1,3 Study 1 enrolled 17 patients with ahus resistant to PE/PI. Patients were treated for a minimum of 26 weeks (mean was 38 weeks). Eculizumab reduced signs of complement-mediated TMA activity shown by an increase from 109 ± 32 x10 9 /L at baseline to 169 ± 72x10 9 /L by one week with the effect maintained through 26 weeks. Study 2 enrolled 20 patients with ahus sensitive to PE/PI who were treated with eculizumab for a minimum of 26 weeks (mean was 40 weeks). Eculizumab reduced signs of complement mediated TMA in this study as well. Platelet counts were maintained at normal levels despite elimination of PE/PI. The mean platelet count was 229 ± 78x10 9 /L at baseline and 233 ± 69x10 9 /L at week 26. The retrospective study 3 of 19 pediatric patients was conducted for a mean duration range of 16 to 38 weeks depending on age range. Efficacy results were consistent with results of Study 1 and 2. Eculizumab reduced signs of complement-mediated TMA shown by an increase in mean platelet AL_CS_Soliris_PA_MDC_ProgSum_0717 Page 5 of 6

count of 171 ± 83x10 9 /L at baseline to 233 ± 109x10 9 /L one week after therapy. The effect was maintained through 26 weeks. Mean platelet count at week 26 was 254 ± 79x10 9 /L. Safety Eculizumab has a boxed warning of increased risk to meningococcal infections. Two patients developed serious meningococcal infections during clinical trials, both had been vaccinated. All patients without a history for meningococcal vaccination should receive the vaccine at least two weeks prior to receiving the first dose of eculizumab. 1 The most common adverse events reported include headache, nasopharyngitis, back pain, and nausea. Headache and back pain occurred more frequently in the eculizumab group compared to placebo. Serious adverse events were reported by 16% of patients during clinical studies. The most common serious adverse events were viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). 1 References 1. Soliris prescribing information. Alexion Pharmaceuticals, Inc. December 2015. 2. Parker C, Omine M, Richards Sm et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005; 106(12):3699-3709. 3. Legendre CM, Licht C, Muus P, et al. Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic-Uremic Syndrome. NEJM 2013; 368 (23): 2169-81. 4. Borowitz MJ, Craig FE, DiGiuseppe JA, et al; Guidelines for the Diagnosis and Monitoring of Paroxysmal Nocturnal Hemoglobinuria and Related Disorders by Flow Cytometry. Cytometry Part B. 2010;78B:211-230. 5. Sahin F, Meltem Akay O, Ayer M et al. Pesg PNH diagnosis, follow-up and treatment guidelines. Am J Blood Res. 2016; 6(2): 19-27. Blue Cross and Blue Shield of Alabama does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. Blue Cross and Blue Shield of Alabama administers benefits based on the members' contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination. This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment. This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and preprocedure review) in Blue Cross and Blue Shield s administration of plan contracts. Blue Cross and Blue Shield of Alabama is an independent licensee of the Blue Cross and Blue Shield Association. BLUE CROSS, BLUE SHIELD and the Cross and Shield symbols are registered trademarks of the Blue Cross and Blue Shield Association. Prime Therapeutics LLC is an independent limited liability company providing pharmacy benefit management services. AL_CS_Soliris_PA_MDC_ProgSum_0717 Page 6 of 6