Ilaris (canakinumab for subcutaneous [SC] injection Novartis)

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1 Ilaris (canakinumab for subcutaneous [SC] injection Novartis) Policy Number: Last Review: 8/2017 Origination: 7/2013 Next Review: 8/2018 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for Ilaris (canankinumab) when it is determined to be medically necessary because the following criteria are met. When Policy Topic is covered FDA-Approved Indications 1. Cryopyrin-Associated Periodic Syndromes (CAPS) (including Familial Cold Autoinflammatory Syndrome [FCAS], Muckle-Wells Syndrome [MWS], and Neonatal Onset Multisystem Inflammatory Disease [NOMID] or Chronic Infantile Neurological Cutaneous and Articular [CINCA] Syndrome). A. Initial Therapy. Approve for 3 months if the patient meets the following conditions (i and ii): i. Patient is 4 years of age; AND ii. Ilaris is prescribed by or in consultation with a rheumatologist, geneticist, allergist/immunologist, or dermatologist. B. Patients Currently Receiving Ilaris. Approve for 1 years if the patient has had a response, as determined by the prescriber. Ilaris is indicated for the treatment of MWS or FCAS in patients 4 years of age. 1 The usual dose is 150 mg in patients weighing > 40 kg or 2 mg/kg in those weighing 15 to 40 kg and is given every 8 weeks. In the published pivotal trial, only patients with a sustained complete response during the initial 8 weeks of the study were eligible for continuation in the trial. 6 A complete clinical response was observed in 71% of patients 1 week after starting therapy and in 97% of patients (34 out of 35 patients) by Week 8. A single-center observational study found that 9 out of 10 patients with CAPS (n = 8 [MWS]; n = 2 [CINCA]) improved following one dose of Ilaris; results were sustained at median followup of 21 months. 7 NOMID is the most severe form of the CAPS. Two patients in the published pivotal CAPS trial had both MWS and NOMID. 1,6 An open-label, multicenter, Phase III study evaluated the use of Ilaris in patients with all phenotypes of CAPS (n = 166) and included 32 patients with NOMID. 8 Of the Ilaris-naïve patients, 78% of patients (n = 85/109) achieved a complete response by Day 21 and an additional 23 patients achieved a partial response (e.g., decrease in C-reactive protein [CRP], serum amyloid A [SAA] levels, disease activity, and/or skin rash). For the entire study population, CRP and SAA normalized while on Ilaris, and by Week 8, 79% of patients had absent/mild disease and 21% of patients had mild to moderate disease. At baseline, four NOMID/CINCA patients reported abnormal neurological findings; following 2 years of treatment with Ilaris, one patient showed normalization of these findings. Resolution of macular edema was noted in one eye of a NOMID/CINCA patient, and improvement in blepharitis was recorded in another patient. It is notable that higher doses of Ilaris were required for NOMID/CINCA patients and patients 40 kg compared with other patients in the cohort. In an open-label Phase I/II study evaluating Ilaris in patients with NOMID (n = 7), no patients had full remission at Month 6 (primary endpoint), but four patients achieved inflammatory remission based on

2 disease activity diary scores and normal CRP. 9 At Month 12 and 18, 100% of patients (n = 4/4 at Month 12 and n = 3/3 for Month 18) were in inflammatory remission. Median duration in the trial was 615 days (range, 232 to 749 days). Data are available in two other patients with NOMID treated with Ilaris with long-term moderate efficacy (per the physician s global assessment [PGA]) [exposure of 120 to 463 days] Systemic Juvenile Idiopathic Arthritis (SJIA). A. Initial Therapy. Approve for 3 months 11 (which is adequate for three doses) if the patient meets ALL of the following conditions (i, ii, and iii): i. Patient is 2 years of age; AND ii. Patient meets ONE of the following conditions (a, b, or c): a) Patient has tried at least TWO other biologics for SJIA (e.g., Actemra [tocilizumab infusion], Kineret, Orencia [abatacept infusion], tumor necrosis factor [TNF] inhibitors [e.g., Enbrel {etanercept injection}, Humira {adalimumab injection}, Remicade {infliximab infusion}); OR b) Patient has features of poor prognosis (e.g., arthritis of the hip, radiographic damage, 6-month duration of significant active systemic disease, defined by: fever, elevated inflammatory markers, or requirement for treatment with systemic glucocorticoids), as determined by the prescribing physician AND has tried Actemra or Kineret; OR c) Patient has features of SJIA with active systemic features with concerns of progression to macrophage activation syndrome (MAS), as determined by the prescribing physician, AND has tried Kineret. iii. Ilaris is prescribed by or in consultation with a rheumatologist. B. Patient is Currently Receiving Ilaris. Approve for 1 years if the patient has had a response (e.g., resolution of fevers; improvement in limitation of motion; less joint pain or tenderness; decreased duration of morning stiffness or fatigue; improved function or activities of daily living; reduced dosage of corticosteroids), as determined by the prescriber. The patient may not have a full response, but there should have been a recent or past response to Ilaris. Ilaris is indicated for the treatment of active SJIA in patients 2 years of age. 1 There are standardized treatment plans published for use of biologic disease-modifying antirheumatic drugs (DMARDs), including Actemra, Kineret, and Ilaris, for use in patients with SJIA For Ilaris, the recommendation is to assess at Week 1 or 2 and Month 1, and adjust other therapies (e.g., corticosteroids) if disease is unchanged or worsening. 11 Patients should be reassessed at Month 3, when patients with unchanged or worsening disease or patients whose steroid dose is > 50% of the starting dose should have an increase in prednisone plus either addition of methotrexate (MTX) OR change to Actemra. Note that when discontinuing Ilaris, patients should wait between 1 and 2 months after discontinuation before switching to a different biologic DMARD. Guidelines from the American College of Rheumatology (ACR) for the management of SJIA (2013) mention Ilaris as a treatment alternative, depending upon the manifestations of SJIA being treated. 13 While there are a number of other effective options for treating synovitis in patients with active SJIA, effective options for treatment of MAS is much more limited. Recommended options for treatment of MAS are limited and include Kineret, calcineurin inhibitors, and systemic corticosteroids (no preferential sequencing noted). The SJIA guidelines note that use of Ilaris is uncertain in MAS in some situations, such as for initial therapy in patients with a poor physician s assessment; however, MAS is a potentially life-threatening situation with limited treatment options. In Phase III studies evaluating Ilaris in patients with SJIA, 56% to 66% of patients had previously tried a biologic therapy. 14 At Day 15, 84% of patients receiving Ilaris (n = 36/43) had an adapted JIA ACR 30 response compared with 10% of patients receiving placebo (n = 4/41) [P < 0.001]. In SJIA, Ilaris is administered every 4 weeks. 1 The criteria for previous therapy are recommended based on the professional opinion of specialized physicians.

3 When Policy Topic is not covered Ilaris has not been shown to be effective, or there are limited or preliminary data or potential safety concerns that are not supportive of general approval for the following conditions. Rationale for noncoverage for these specific conditions is provided below. (Note: This is not an exhaustive list of Conditions Not Recommended for Approval.) 1. Concurrent Biologic Therapy. Ilaris should not be administered in combination with another biologic agent for an inflammatory condition (e.g., tumor necrosis factor [TNF] blocking agents [e.g., Cimzia {certolizumab pegol for SC injection}, Enbrel, Humira, Remicade, Simponi {golimumab for SC injection}, Simponi Aria {golimumab for IV infusion}], Kineret, or Arcalyst). 1 Ilaris has not been used in combination with TNF blocking agents. An increased incidence of serious infections has been associated with another IL-1 blocker, Kineret, when given in combination with TNF antagonists in patients with rheumatoid arthritis. Concomitant administration of Ilaris and other agents that block IL-1 or its receptors is not recommended. 2. Gout. Guidelines (American College of Rheumatology [ACR], 2012; multinational recommendations [2014]) do not mention Ilaris as an appropriate option for the management of gout Furthermore, a systematic and Cochrane review (2014) that evaluated the evidence of agents for gout, including IL-1 blockers, concluded that additional evidence is required prior to making a formal treatment recommendation for Ilaris. 17 The efficacy of Ilaris for treatment of acute flares and reduction of frequency of subsequent flares was evaluated in two identical Phase III trials. 18 Eligible patients were required to be intolerant or refractory to colchicine and/or NSAIDs. Patients were assigned to treatment with Ilaris 150 mg SC or triamcinolone 40 mg intramuscularly (IM) and followed for 12 weeks. The primary endpoints were the mean difference in patient assessment of gout pain from baseline to 72 hours post-dose (on a 0 to 100 mm visual analog scale [VAS]) and time to new gout flare. Using last observation carried forward (LOCF) analysis, the estimated difference on the VAS was significantly decreased with Ilaris compared to triamcinolone in both studies (-11.4 mm [P = 0.005], -9.8 mm [P = ]). Median time to first new gout flare could not be estimated in either study because 50% of the patients in each group had not flared within the 12-week controlled period of either study. However, Kaplan-Meier estimates of flare probability and a hazard ratio (HR) were calculated, and Ilaris was associated with a lower risk of gout flare (HR: 0.45 [P = ] and 0.32 [P = ] for the respective studies). Extension trials have demonstrated efficacy for a total of 24 weeks of treatment. A 24-week Phase II dose-ranging study compared Ilaris to colchicine for the prevention of flares in patients with gout (n = 432) initiating allopurinol therapy. 19 The study found that patients taking various doses of Ilaris (25, 50, 100, 200, 300 mg SC or 150 mg SC in divided doses) were significantly less likely to have flares of gout than patients taking 0.5 mg of colchicine daily (HR range, 0.28 to 0.36; P 0.05 for all comparisons). The percentages of patients with flares in the Ilaris treatment groups ranged from 15% to 27% compared with 44% of patients in the colchicine treatment group (P 0.05 for all comparisons). However, this study did not compare Ilaris to the maximum recommended dose of colchicine (0.6 mg twice daily) which may be used in clinical practice. When reviewed by the Arthritis Advisory Committee at the FDA, an unacceptable risk profile, including infection, cardiovascular and renal function risks, and pharmacokinetics in older patients were cited as safety concerns in the gout population Rheumatoid Arthritis. Ilaris has been studied for the treatment of rheumatoid arthritis In a 12-week, Phase II, placebo-controlled, double-blind, dose-finding study, 277 patients who had failed treatment with MTX were randomized to Ilaris or placebo. 22 The primary endpoint, the ACR 50 at Week 12, was statistically significantly higher for Ilaris 150 mg SC every 4 weeks compared with placebo (26.5% vs. 11.4%, respectively; P = 0.028). There was not a statistically significant difference in ACR 50 for the other Ilaris treatment groups compared with placebo (Ilaris 300 mg SC every 2 weeks; Ilaris 600 mg loading dose followed by 300 mg SC every 2 weeks). Further studies are needed.

4 4. Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available. Considerations Ilaris requires prior authorization through the Clinical Pharmacy Department. This Blue Cross and Blue Shield of Kansas City policy Statement was developed using available resources such as, but not limited to: Food and Drug Administration (FDA) approvals, Facts and Comparisons, National specialty guidelines, Local medical policies of other health plans, Medicare (CMS), Local providers. Description of Procedure or Service Ilaris is a human anti-interleukin-1β (IL-1β) monoclonal antibody that binds to human IL-1β and neutralizes its activity by blocking its interaction with IL-1 receptors. 1 It does not bind IL-1α or IL-1 receptor antagonist (IL-1ra). IL-1 cytokine signaling is important in the pathogenesis of Cryopyrin- Associated Periodic Syndromes (CAPS). Ilaris is indicated for the treatment of CAPS including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children aged 4 years and older and in systemic juvenile idiopathic arthritis (SJIA) in patients 2 years of age. Dosage in CAPS: In patients weighing > 40 kg, the dose is 150 mg. In those weighing 15 to 40 kg the dose is 2 mg/kg. In children who weigh 15 to 40 kg who have an inadequate response, the dose can be increased to 3 mg/kg. Ilaris is given every 8 weeks by subcutaneous (SC) injection. Dosage in SJIA: In SJIA, the recommended dose of Ilaris in patients with a body weight 7.5 kg is 4 mg/kg SC (to a maximum of 300 mg) administered every 4 weeks. Rationale CAPS is a rare inherited inflammatory disease associated with overproduction of IL-1. CAPS encompasses three rare genetic syndromes. FCAS, MWS, and neonatal onset multisystem inflammatory disorder (NOMID) are thought to be one condition along a spectrum of disease severity. 2-3 NOMID was previously known as chronic infantile neurological cutaneous and articular syndrome (CINCA). FCAS is the mildest phenotype and NOMID is the most severe. There are no reliable prevalence statistics for CAPS, but the estimated number of persons with CAPS in the U.S. is 200 to 500 persons. These three disorders may be associated with mutations in the CIAS-1 gene and have autosomal dominant inheritance. Mutations in the CIAS-1 gene, which encode a protein (cryopyrin), cause excess release of IL-1β and an inflammatory response. These autoinflammatory syndromes are characterized by episodes of inflammation and are distinct from autoimmune disorders. The inflammatory symptoms in these patients include atypical urticaria, rash that is worse in the evening, fever, chills, severe fatigue, arthralgia, and conjunctival erythema. Exacerbations or flares can be triggered by exposure to cold, stress, exercise, or other stimuli. Patients with NOMID may have sensorineural hearing impairment, increased intracranial pressure, and joint abnormalities. One-fourth of patients with MWS may develop systemic AA amyloidosis which usually presents with renal impairment and nephrotic syndrome; amyloidosis is less common in the other forms of CAPS. Arcalyst (rilonacept for SC injection) is approved for the treatment of CAPS. 4 Arcalyst, given once weekly by SC injection, was effective in the treatment of CAPS in patients with MWS (n = 3) and FCAS (n = 44). 4-5 Like Ilaris, Arcalyst is not indicated in patients with NOMID. Kineret (anakinra for SC injection), a recombinant nonglycosylated form of the naturally occurring IL-1Ra, is an IL-1 antagonist that is indicated for NOMID and for the treatment of rheumatoid arthritis. Kineret has also been used off-label to treat various other forms of CAPS. 2 Kineret is given by SC injection once daily. Treatment of CAPS with antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and immunosuppressants (e.g., azathioprine, cyclosporine, mycophenolate mofetil) is usually not effective.

5 References 1. Ilaris for subcutaneous injection [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; October Shinkai K, McCalmont TH, Leslie KS. Cryopyrin-associated periodic syndromes and autoinflammation. Clin Exp Dermatol. 2008;33: Ozen S, Hoffman HM, Frenkel J, et al. Familial Mediterranean Fever (FMF) and beyond: a new horizon. Fourth International Congress on the Systemic Autoinflammatory Diseases held in Bethesda, USA, 6-10 November Ann Rheum Dis. 2006;65(7): Arcalyst for injection [prescribing information]. Tarrytown, NY: Regeneron Pharmaceuticals Inc; September Hoffman HM, Throne ML, Amar NJ, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebocontrolled studies. Arthritis Rheum. 2008;58: Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al; Canakinumab in CAPS Study Group. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360: Russo RA, Melo-Gomes S, Lachmann HJ, et al. Efficacy and safety of canakinumab therapy in paediatric patients with cryopyrin-associated periodic syndrome: a single-centre, real-world experience. Rheumatology (Oxford). 2014;53(4): Kuemmerle-Deschner JB, Hachulla E, Cartwright R, et al. Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis. 2011;70(12): Sibley CH, Chioato A, Felix S, et al. A 24-month open-label study of canakinumab in neonatalonset multisystem inflammatory disease. Ann Rheum Dis. 2015;74(9): Kuemmerle-Deschner JB, Ramos E, Blank N, et al. Canakinumab (ACZ885, a fully human IgG1 anti-il-1β mab) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res Ther. 2011;13(1):R Kimura Y, Morgan DeWitt E, Beukelman T, et al. Adding Canakinumab to the Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans for Systemic Juvenile Idiopathic Arthritis: comment on the article by DeWitt et al. Arthritis Care Res (Hoboken). 2014;66(9): DeWitt EM, Kimura Y, Beukelman T, et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2012;64(7): Ringold S, Weiss PF, Beukelman T, et al update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013;65(10): Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25): Sivera F, Andrés M, Carmona L, et al. Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative. Ann Rheum Dis. 2014;73(2): Khanna D, Fitzgerald JD, Khanna PP, et al American College of Rheumatology Guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012;64: Wechalekar MD, Vinik O, Moi JH, et al. The efficacy and safety of treatments for acute gout: results from a series of systematic literature reviews including cochrane reviews on intraarticular glucocorticoids, colchicine, nonsteroidal antiinflammatory drugs, and interleukin-1 inhibitors. J Rheumatol Suppl. 2014;92: FDA Briefing Document. Supplemental BLA : Ilaris (canakinumab) for the following proposed indication: Ilaris is indicated for the treatment of gouty arthritis attacks. ILARIS has also been shown to extend the time to the next attack and reduce the frequency of subsequent attacks. June 21, Accessed on September 23, Available at:

6 ugsadvisorycommittee/ucm pdf 19. Schlesinger N, Mysler E, Lin HY, et al. Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study. Ann Rheum Dis. 2011;70(7): Lowry F. FDA panel says no to canakinumab for gout attacks. Medscape Medical News. June 21, Novartis. Efficacy, safety and tolerability of ACZ885 in patients with active rheumatoid arthritis. In; ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Accessed on September 23, Available from: NLM Identifier: NCT Alten R, Gomez-Reino J, Durez P, et al. Efficacy and safety of the human anti-il-1β monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, Phase II, dose-finding study. BMC Musculoskelet Disord. 2011;12:153. Other References Utilized: Kitley JL, Lachmann HJ, Pinto A, et al. Neurologic manifestations of the cryopyrin-associated periodic syndrome. Neurology. 2010;74(16): Ruperto N, Quartier P, Wulffraat N, et al. A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum. 2012;64(2): Rissanen A, Howard CP, Botha J, et al. Effect of anti-il-1β antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebocontrolled trial. Diabetes Obes Metab. 2012;14(12): Moran A, Bundy B, Becker DJ, et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013;381(9881): Sivera F, Wechalekar MD, Andrés M, et al. Interleukin-1 inhibitors for acute gout. Cochrane Database Syst Rev Sep 1;9:CD Koné-Paut I, Galeotti C. Current treatment recommendations and considerations for cryopyrinassociated periodic syndrome. Expert Rev Clin Immunol. 2015;11(10): Billing Coding/Physician Documentation Information J0638 Injection, canakinumab, 1mg (medical benefit) M04.1 M04.2 M08.0+ M08.1 M08.2+ M08.3 M08.4+ M08.8+ M08.9+ Periodic Fever Syndromes Cryopyrin-associated periodic syndromes Unspecified juvenile rheumatoid arthritis Juvenile ankylosing spondylitis Juvenile rheumatoid arthritis with systemic onset Juvenile rheumatoid polyarthritis (seronegative) Pauciarticular juvenile rheumatoid arthritis Other juvenile arthritis Juvenile arthritis, unspecified Additional Policy Key Words Policy Number:

7 Policy Implementation/Update Information 07/ / / / /2017 New Policy titled Ilaris (canakinumab) Updated SJIA criteria with new ACR guidelines Updated initial approvals to 3 months; updated references; no changes to policy statement Policy reviewed; no changes to policy statement Policy reviewed; no changes to policy statement State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.