Rapid and Sustained Long-Term Efficacy and Safety of Canakinumab in Patients With Cryopyrin-Associated Periodic Syndrome Ages Five Years and Younger

Paul A Brogan, Michael Hofer, Jasmin B Kuemmerle-Deschner, Isabelle Koné-Paut, Joachim Roesler, Tilmann Kallinich, Gerd Horneff, Inmaculada Calvo Penadés, Belén Sevilla-Perez, Laurence Goffin, Bernard R Lauwerys, Helen J Lachmann, Yosef Uziel, Xiaoling Wei, Ronald M Laxer, Paul A Brogan, Michael Hofer, Jasmin B Kuemmerle-Deschner, Isabelle Koné-Paut, Joachim Roesler, Tilmann Kallinich, Gerd Horneff, Inmaculada Calvo Penadés, Belén Sevilla-Perez, Laurence Goffin, Bernard R Lauwerys, Helen J Lachmann, Yosef Uziel, Xiaoling Wei, Ronald M Laxer

Abstract

Objective: To assess long-term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin-associated periodic syndrome (CAPS).

Methods: CAPS patients (ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal-onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open-label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C-reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization.

Results: Of the 17 patients enrolled, 12 (71%) had Muckle-Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as "absent" at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy.

Conclusion: Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non-live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long-term use of canakinumab for CAPS in children ≤5 years of age.

Trial registration: ClinicalTrials.gov NCT01302860 NCT01576367.

© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Figures

Figure 1
Figure 1
Canakinumab dosing at baseline, the end of the core study, and the end of the extension study (final dose) in patients with familial cold autoinflammatory syndrome (FCAS), Muckle‐Wells syndrome (MWS), and neonatal‐onset multisystem inflammatory disease (NOMID). Doses are rounded up to the nearest whole number. Values in the >4 mg/kg category at the end of the core study and for the final dose are the median (range). See Supplementary Table 1, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.41004/abstract for exact doses in individual patients.
Figure 2
Figure 2
Percentage of patients with a complete response to treatment in the entire study period (152 weeks). A, Kaplan‐Meier estimate of the time to first response. Complete response was defined as physician global assessment of autoinflammatory disease activity as less than or equal to “minimal” (on a 5‐point scale of absent, minimal, mild, moderate, and severe) and assessment of skin disease as less than or equal to “minimal” (on a 5‐point scale of absent, minimal, mild, moderate, and severe) and serologic response indicated by serum C‐reactive protein (CRP) <15 mg/liter or serum amyloid A protein (SAA) <10 mg/liter. B, Kaplan‐Meier estimate of the time to first relapse. Relapse was defined for complete responders as a physician global assessment of autoinflammatory disease greater than “minimal,” or physician global assessment greater than or equal to “minimal” and assessment of skin disease greater than “minimal,”and serum CRP >30 mg/liter or SAA >30 mg/liter.
Figure 3
Figure 3
Physician global assessment of autoinflammatory disease in patients with cryopyrin‐associated periodic syndrome. Values are the percentage of patients in each category at the indicated week. EOS = end of study.

References

    1. Kuemmerle‐Deschner JB, Ramos E, Blank N, Roesler J, Felix SD, Jung T, 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:R34.
    1. Dodé C, Le Dû N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G, et al. New mutations of CIAS1 that are responsible for Muckle‐Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet 2002;70:1498–506.
    1. Gattorno M, Tassi S, Carta S, Delfino L, Ferlito F, Pelagatti MA, et al. Pattern of interleukin‐1β secretion in response to lipopolysaccharide and ATP before and after interleukin‐1 blockade in patients with CIAS1 mutations. Arthritis Rheum 2007;56:3138–48.
    1. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin‐like protein causes familial cold autoinflammatory syndrome and Muckle‐Wells syndrome. Nat Genet 2001;29:301–5.
    1. Miyamae T. Cryopyrin‐associated periodic syndromes: diagnosis and management. Paediatr Drugs 2012;14:109–17.
    1. Kone‐Paut I, Quartier P, Fain O, Grateau G, Pillet P, Le Blay P, et al. Real‐world experience and impact of canakinumab in cryopyrin‐associated periodic syndrome: results from a French observational study. Arthritis Care Res (Hoboken) 2017;69:903–11.
    1. Hoffman HM, Wanderer AA, Broide DH. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol 2001;108:615–20.
    1. Koné‐Paut I. Cryopyrine‐associated periodic syndrome: CAPS seen from adulthood. Rev Med Interne 2015;36:277–82.
    1. Muckle TJ, Well SM. Urticaria, deafness, and amyloidosis: a new heredo‐familial syndrome. Q J Med 1962;31:235–48.
    1. Kuemmerle‐Deschner JB. CAPS: pathogenesis, presentation and treatment of an autoinflammatory disease. Semin Immunopathol 2015;37:377–85.
    1. Kuemmerle‐Deschner JB, Koitschev A, Ummenhofer K, Hansmann S, Plontke SK, Koitschev C, et al. Hearing loss in Muckle‐Wells syndrome. Arthritis Rheum 2013;65:824–31.
    1. Sibley CH, Plass N, Snow J, Wiggs EA, Brewer CC, King KA, et al. Sustained response and prevention of damage progression in patients with neonatal‐onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three‐ and five‐year outcomes. Arthritis Rheum 2012;64:2375–86.
    1. Kanariou M, Tantou S, Varela I, Raptaki M, Petropoulou C, Nikas I, et al. Successful management of cryopyrin‐associated periodic syndrome with canakinumab in infancy. Pediatrics 2014;134:e1468–73.
    1. Paccaud Y, Berthet G, Von Scheven‐Gête A, Vaudaux B, Mivelaz Y, Hofer M, et al. Neonatal treatment of CINCA syndrome. Pediatr Rheumatol Online J 2014;12:52.
    1. Landmann EC, Walker UA. Pharmacological treatment options for cryopyrin‐associated periodic syndromes. Expert Rev Clin Pharmacol 2017;10:855–64.
    1. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin‐1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012;11:633–52.
    1. Koné‐Paut I, Galeotti C. Current treatment recommendations and considerations for cryopyrin‐associated periodic syndrome. Expert Rev Clin Immunol 2015;11:1083–92.
    1. Cantarini L, Lucherini OM, Cimaz R, Galeazzi M. Recurrent pericarditis caused by a rare mutation in the TNFRSF1A gene and with excellent response to anakinra treatment [letter]. Clin Exp Rheumatol 2010;28:802.
    1. Gattorno M, Pelagatti MA, Meini A, Obici L, Barcellona R, Federici S, et al. Persistent efficacy of anakinra in patients with tumor necrosis factor receptor–associated periodic syndrome. Arthritis Rheum 2008;58:1516–20.
    1. Kuemmerle‐Deschner JB, Haug I. Canakinumab in patients with cryopyrin‐associated periodic syndrome: an update for clinicians. Ther Adv Musculoskelet Dis 2013;5:315–29.
    1. Lachmann HJ, Kone‐Paut I, Kuemmerle‐Deschner JB, Leslie KS, Hachulla E, Quartier P, et al. Use of canakinumab in the cryopyrin‐associated periodic syndrome. N Engl J Med 2009;360:2416–25.
    1. Russo RA, Melo‐Gomes S, Lachmann HJ, Wynne K, Rajput K, Eleftheriou D, 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;53:665–70.
    1. Yokota S, Imagawa T, Nishikomori R, Takada H, Abrams K, Lheritier K, et al. Long‐term safety and efficacy of canakinumab in cryopyrin‐associated periodic syndrome: results from an open‐label, phase III pivotal study in Japanese patients. Clin Exp Rheumatol 2017;35 Suppl 108:19–26.
    1. Chioato A, Noseda E, Felix SD, Stevens M, Del Giudice G, Fitoussi S, et al. Influenza and meningococcal vaccinations are effective in healthy subjects treated with the interleukin‐1β‐blocking antibody canakinumab: results of an open‐label, parallel group, randomized, single‐center study. Clin Vaccine Immunol 2010;17:1952–7.
    1. Jaeger VK, Hoffman HM, van der Poll T, Tilson H, Seibert J, Speziale A, et al. Safety of vaccinations in patients with cryopyrin‐associated periodic syndromes: a prospective registry based study. Rheumatology (Oxford) 2017;56:1484–91.
    1. Imagawa T, Nishikomori R, Takada H, Takeshita S, Patel N, Kim D, et al. Safety and efficacy of canakinumab in Japanese patients with phenotypes of cryopyrin‐associated periodic syndrome as established in the first open‐label, phase‐3 pivotal study (24‐week results). Clin Exp Rheumatol 2013;31:302–9.
    1. Yu JR, Leslie KS. Cryopyrin‐associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep 2011;11:12–20.
    1. Ter Haar NM, Oswald M, Jeyaratnam J, Anton J, Barron KS, Brogan PA, et al. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis 2015;74:1636–44.
    1. Kuemmerle‐Deschner J, Blank N, Roesler J, Ramos E, Lachmann HJ, Hoyer JD, et al. Canakinumab (ACZ885), a new IL‐1β blocking monoclonal antibody, provides sustained remission in patients with cryopyrin associated periodic fever syndrome (CAPS): results of an open label phase II study [abstract]. Ann Rheum Dis 2009;68 Suppl 3:366.
    1. Mamoudjy N, Maurey H, Marie I, Koné‐Paut I, Deiva K. Neurological outcome of patients with cryopyrin‐associated periodic syndrome (CAPS). Orphanet J Rare Dis 2017;12:33.
    1. Rodriguez‐Smith J, Lin YC, Tsai WL, Kim H, Montealegre‐Sanchez G, Chapelle D, et al. Cerebrospinal fluid cytokines correlate with aseptic meningitis and blood–brain barrier function in neonatal‐onset multisystem inflammatory disease: central nervous system biomarkers in neonatal‐onset multisystem inflammatory disease correlate with central nervous system inflammation. Arthritis Rheumatol 2017;69:1325–36.
    1. Hoffman HM, Kuemmerle‐Deschner JB, Hawkins PN, van der Poll T, Walker UA, Speziale A, et al. Safety and efficacy of long‐term canakinumab therapy in patients with CAPS: final results from β‐confident registry [abstract]. Arthritis Rheumatol 2016;68 Suppl 10 URL: .
    1. Watanabe M, Nishikomori R, Fujimaki Y, Heike T, Ohara A, Saji T. Live‐attenuated vaccines in a cryopyrin‐associated periodic syndrome patient receiving canakinumab treatment during infancy. Clin Case Rep 2017;5:1750–5.

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