The ExTINGUISH Trial of Inebilizumab in NMDAR Encephalitis

Summary

Determine the difference in the modified Rankin score at 16 weeks in participants with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis treated with "first-line" immunomodulatory therapies provided as standard-of-care, and either inebilizumab (investigational agent) or placebo.

Timeline

Start

2022-03-30

Primary completion

2028-09-30

Completion

2028-09-30

Publications

• Results Titulaer MJ, McCracken L, Gabilondo I, Armangue T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013 Feb;12(2):157-65. doi: 10.1016/S1474-4422(12)70310-1. Epub 2013 Jan 3.
• Results Gabilondo I, Saiz A, Galan L, Gonzalez V, Jadraque R, Sabater L, Sans A, Sempere A, Vela A, Villalobos F, Vinals M, Villoslada P, Graus F. Analysis of relapses in anti-NMDAR encephalitis. Neurology. 2011 Sep 6;77(10):996-9. doi: 10.1212/WNL.0b013e31822cfc6b. Epub 2011 Aug 24.
• Results Dalmau J, Tuzun E, Wu HY, Masjuan J, Rossi JE, Voloschin A, Baehring JM, Shimazaki H, Koide R, King D, Mason W, Sansing LH, Dichter MA, Rosenfeld MR, Lynch DR. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007 Jan;61(1):25-36. doi: 10.1002/ana.21050.
• Results Dubey D, Pittock SJ, Kelly CR, McKeon A, Lopez-Chiriboga AS, Lennon VA, Gadoth A, Smith CY, Bryant SC, Klein CJ, Aksamit AJ, Toledano M, Boeve BF, Tillema JM, Flanagan EP. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018 Jan;83(1):166-177. doi: 10.1002/ana.25131.
• Results Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008 Dec;7(12):1091-8. doi: 10.1016/S1474-4422(08)70224-2. Epub 2008 Oct 11.
• Results Gresa-Arribas N, Titulaer MJ, Torrents A, Aguilar E, McCracken L, Leypoldt F, Gleichman AJ, Balice-Gordon R, Rosenfeld MR, Lynch D, Graus F, Dalmau J. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014 Feb;13(2):167-77. doi: 10.1016/S1474-4422(13)70282-5. Epub 2013 Dec 18.
• Results Guasp M, Modena Y, Armangue T, Dalmau J, Graus F. Clinical features of seronegative, but CSF antibody-positive, anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflamm. 2020 Jan 3;7(2):e659. doi: 10.1212/NXI.0000000000000659. Print 2020 Mar.
• Results Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011 Jan;10(1):63-74. doi: 10.1016/S1474-4422(10)70253-2.
• Results Cree BAC, Bennett JL, Kim HJ, Weinshenker BG, Pittock SJ, Wingerchuk DM, Fujihara K, Paul F, Cutter GR, Marignier R, Green AJ, Aktas O, Hartung HP, Lublin FD, Drappa J, Barron G, Madani S, Ratchford JN, She D, Cimbora D, Katz E; N-MOmentum study investigators. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019 Oct 12;394(10206):1352-1363. doi: 10.1016/S0140-6736(19)31817-3. Epub 2019 Sep 5.
• Results Hara M, Martinez-Hernandez E, Arino H, Armangue T, Spatola M, Petit-Pedrol M, Saiz A, Rosenfeld MR, Graus F, Dalmau J. Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor. Neurology. 2018 Apr 17;90(16):e1386-e1394. doi: 10.1212/WNL.0000000000005329. Epub 2018 Mar 16.
• Results Warikoo N, Brunwasser SJ, Benz A, Shu HJ, Paul SM, Lewis M, Doherty J, Quirk M, Piccio L, Zorumski CF, Day GS, Mennerick S. Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis. J Neurosci. 2018 Mar 28;38(13):3218-3229. doi: 10.1523/JNEUROSCI.3377-17.2018. Epub 2018 Feb 23.
• Results Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, Parsons TD, Lynch DR, Dalmau J, Balice-Gordon RJ. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010 Apr 28;30(17):5866-75. doi: 10.1523/JNEUROSCI.0167-10.2010.
• Results Tuzun E, Zhou L, Baehring JM, Bannykh S, Rosenfeld MR, Dalmau J. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol. 2009 Dec;118(6):737-43. doi: 10.1007/s00401-009-0582-4.
• Results Matute C, Palma A, Serrano-Regal MP, Maudes E, Barman S, Sanchez-Gomez MV, Domercq M, Goebels N, Dalmau J. N-Methyl-D-Aspartate Receptor Antibodies in Autoimmune Encephalopathy Alter Oligodendrocyte Function. Ann Neurol. 2020 May;87(5):670-676. doi: 10.1002/ana.25699. Epub 2020 Feb 24.
• Results Planaguma J, Leypoldt F, Mannara F, Gutierrez-Cuesta J, Martin-Garcia E, Aguilar E, Titulaer MJ, Petit-Pedrol M, Jain A, Balice-Gordon R, Lakadamyali M, Graus F, Maldonado R, Dalmau J. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain. 2015 Jan;138(Pt 1):94-109. doi: 10.1093/brain/awu310. Epub 2014 Nov 11.
• Results Planaguma J, Haselmann H, Mannara F, Petit-Pedrol M, Grunewald B, Aguilar E, Ropke L, Martin-Garcia E, Titulaer MJ, Jercog P, Graus F, Maldonado R, Geis C, Dalmau J. Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticity. Ann Neurol. 2016 Sep;80(3):388-400. doi: 10.1002/ana.24721. Epub 2016 Aug 2.
• Results Malviya M, Barman S, Golombeck KS, Planaguma J, Mannara F, Strutz-Seebohm N, Wrzos C, Demir F, Baksmeier C, Steckel J, Falk KK, Gross CC, Kovac S, Bonte K, Johnen A, Wandinger KP, Martin-Garcia E, Becker AJ, Elger CE, Klocker N, Wiendl H, Meuth SG, Hartung HP, Seebohm G, Leypoldt F, Maldonado R, Stadelmann C, Dalmau J, Melzer N, Goebels N. NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody. Ann Clin Transl Neurol. 2017 Oct 3;4(11):768-783. doi: 10.1002/acn3.444. eCollection 2017 Nov.
• Results Jones BE, Tovar KR, Goehring A, Jalali-Yazdi F, Okada NJ, Gouaux E, Westbrook GL. Autoimmune receptor encephalitis in mice induced by active immunization with conformationally stabilized holoreceptors. Sci Transl Med. 2019 Jul 10;11(500):eaaw0044. doi: 10.1126/scitranslmed.aaw0044.
• Results Rubenstein JL, Combs D, Rosenberg J, Levy A, McDermott M, Damon L, Ignoffo R, Aldape K, Shen A, Lee D, Grillo-Lopez A, Shuman MA. Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood. 2003 Jan 15;101(2):466-8. doi: 10.1182/blood-2002-06-1636. Epub 2002 Sep 5.
• Results Muldoon LL, Soussain C, Jahnke K, Johanson C, Siegal T, Smith QR, Hall WA, Hynynen K, Senter PD, Peereboom DM, Neuwelt EA. Chemotherapy delivery issues in central nervous system malignancy: a reality check. J Clin Oncol. 2007 Jun 1;25(16):2295-305. doi: 10.1200/JCO.2006.09.9861.
• Results Mei HE, Frolich D, Giesecke C, Loddenkemper C, Reiter K, Schmidt S, Feist E, Daridon C, Tony HP, Radbruch A, Dorner T. Steady-state generation of mucosal IgA+ plasmablasts is not abrogated by B-cell depletion therapy with rituximab. Blood. 2010 Dec 9;116(24):5181-90. doi: 10.1182/blood-2010-01-266536. Epub 2010 Sep 9.
• Results Dale RC, Pillai S, Brilot F. Cerebrospinal fluid CD19(+) B-cell expansion in N-methyl-D-aspartate receptor encephalitis. Dev Med Child Neurol. 2013 Feb;55(2):191-193. doi: 10.1111/dmcn.12036. Epub 2012 Nov 14.
• Results Makuch M, Wilson R, Al-Diwani A, Varley J, Kienzler AK, Taylor J, Berretta A, Fowler D, Lennox B, Leite MI, Waters P, Irani SR. N-methyl-D-aspartate receptor antibody production from germinal center reactions: Therapeutic implications. Ann Neurol. 2018 Mar;83(3):553-561. doi: 10.1002/ana.25173.
• Results Chen D, Gallagher S, Monson NL, Herbst R, Wang Y. Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies. J Clin Med. 2016 Nov 24;5(12):107. doi: 10.3390/jcm5120107.
• Results Sanz I. Rationale for B cell targeting in SLE. Semin Immunopathol. 2014 May;36(3):365-75. doi: 10.1007/s00281-014-0430-z. Epub 2014 Apr 25.
• Results Halliley JL, Tipton CM, Liesveld J, Rosenberg AF, Darce J, Gregoretti IV, Popova L, Kaminiski D, Fucile CF, Albizua I, Kyu S, Chiang KY, Bradley KT, Burack R, Slifka M, Hammarlund E, Wu H, Zhao L, Walsh EE, Falsey AR, Randall TD, Cheung WC, Sanz I, Lee FE. Long-Lived Plasma Cells Are Contained within the CD19(-)CD38(hi)CD138(+) Subset in Human Bone Marrow. Immunity. 2015 Jul 21;43(1):132-45. doi: 10.1016/j.immuni.2015.06.016. Epub 2015 Jul 14.
• Results Mei HE, Wirries I, Frolich D, Brisslert M, Giesecke C, Grun JR, Alexander T, Schmidt S, Luda K, Kuhl AA, Engelmann R, Durr M, Scheel T, Bokarewa M, Perka C, Radbruch A, Dorner T. A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. Blood. 2015 Mar 12;125(11):1739-48. doi: 10.1182/blood-2014-02-555169. Epub 2015 Jan 8.
• Results Schuh E, Berer K, Mulazzani M, Feil K, Meinl I, Lahm H, Krane M, Lange R, Pfannes K, Subklewe M, Gurkov R, Bradl M, Hohlfeld R, Kumpfel T, Meinl E, Krumbholz M. Features of Human CD3+CD20+ T Cells. J Immunol. 2016 Aug 15;197(4):1111-7. doi: 10.4049/jimmunol.1600089. Epub 2016 Jul 13.
• Results Herbst R, Wang Y, Gallagher S, Mittereder N, Kuta E, Damschroder M, Woods R, Rowe DC, Cheng L, Cook K, Evans K, Sims GP, Pfarr DS, Bowen MA, Dall'Acqua W, Shlomchik M, Tedder TF, Kiener P, Jallal B, Wu H, Coyle AJ. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther. 2010 Oct;335(1):213-22. doi: 10.1124/jpet.110.168062. Epub 2010 Jul 6.
• Results Agius MA, Klodowska-Duda G, Maciejowski M, Potemkowski A, Li J, Patra K, Wesley J, Madani S, Barron G, Katz E, Flor A. Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study. Mult Scler. 2019 Feb;25(2):235-245. doi: 10.1177/1352458517740641. Epub 2017 Nov 16.
• Results Schiopu E, Chatterjee S, Hsu V, Flor A, Cimbora D, Patra K, Yao W, Li J, Streicher K, McKeever K, White B, Katz E, Drappa J, Sweeny S, Herbst R. Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: a phase I, randomized, placebo-controlled, escalating single-dose study. Arthritis Res Ther. 2016 Jun 7;18(1):131. doi: 10.1186/s13075-016-1021-2.
• Results Streicher K, Sridhar S, Kuziora M, Morehouse CA, Higgs BW, Sebastian Y, Groves CJ, Pilataxi F, Brohawn PZ, Herbst R, Ranade K. Baseline Plasma Cell Gene Signature Predicts Improvement in Systemic Sclerosis Skin Scores Following Treatment With Inebilizumab (MEDI-551) and Correlates With Disease Activity in Systemic Lupus Erythematosus and Chronic Obstructive Pulmonary Disease. Arthritis Rheumatol. 2018 Dec;70(12):2087-2095. doi: 10.1002/art.40656. Epub 2018 Oct 22.
• Results Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x.
• Results Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a Frontal Assessment Battery at bedside. Neurology. 2000 Dec 12;55(11):1621-6. doi: 10.1212/wnl.55.11.1621.
• Results Balu R, McCracken L, Lancaster E, Graus F, Dalmau J, Titulaer MJ. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology. 2019 Jan 15;92(3):e244-e252. doi: 10.1212/WNL.0000000000006783. Epub 2018 Dec 21.
• Results Lim JA, Lee ST, Moon J, Jun JS, Kim TJ, Shin YW, Abdullah S, Byun JI, Sunwoo JS, Kim KT, Yang TW, Lee WJ, Moon HJ, Kim DW, Lim BC, Cho YW, Yang TH, Kim HJ, Kim YS, Koo YS, Park B, Jung KH, Kim M, Park KI, Jung KY, Chu K, Lee SK. Development of the clinical assessment scale in autoimmune encephalitis. Ann Neurol. 2019 Mar;85(3):352-358. doi: 10.1002/ana.25421. Epub 2019 Feb 10.
• Results Lund FE, Garvy BA, Randall TD, Harris DP. Regulatory roles for cytokine-producing B cells in infection and autoimmune disease. Curr Dir Autoimmun. 2005;8:25-54. doi: 10.1159/000082086.
• Results Lund FE. Cytokine-producing B lymphocytes-key regulators of immunity. Curr Opin Immunol. 2008 Jun;20(3):332-8. doi: 10.1016/j.coi.2008.03.003. Epub 2008 Apr 15.
• Results Kothur K, Wienholt L, Mohammad SS, Tantsis EM, Pillai S, Britton PN, Jones CA, Angiti RR, Barnes EH, Schlub T, Bandodkar S, Brilot F, Dale RC. Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis. PLoS One. 2016 Aug 30;11(8):e0161656. doi: 10.1371/journal.pone.0161656. eCollection 2016.

Drugs

Indications