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Review
. 2025 Apr 22;104(8):e213487.
doi: 10.1212/WNL.0000000000213487. Epub 2025 Mar 27.

The Clinical Trial Landscape in Autoimmune Encephalitis: Challenges and Opportunities

Hesham Abboud  1   2 , Stacey L Clardy  3   4 , Divyanshu Dubey  5 , Jonathan Wickel  6 , Gregory Scott Day  7 , Christian Geis  6 , Jeffrey M Gelfand  8 , Sarosh R Irani  7 , Soon-Tae Lee  9 , Maarten J Titulaer  10
Affiliations
Review

The Clinical Trial Landscape in Autoimmune Encephalitis: Challenges and Opportunities

Hesham Abboud et al. Neurology. .

Abstract

Autoimmune encephalitis (AE) is an important cause of neurologic morbidity and mortality. Treatment algorithms are primarily based on observational studies, retrospective series, and expert opinion. Despite clinical improvement with empiric therapy, recovery is often incomplete with a substantial burden of residual neurologic deficits and recurring symptoms. There is a pressing need for higher quality evidence-based therapies. However, designing and conducting clinical trials for patients with rare diseases such as AE has specific challenges, including slow recruitment, suboptimal outcome measures, and inclusivity vs exclusivity of the various disease subtypes. The anticipated knowledge gained from AE clinical trials emphasizes the need to overcome these challenges and support the development of the next generation of clinical trials. Yet, given these challenges, alternative approaches may be required. In this article, we review past and present clinical trials in AE with a focus on studies enrolling patients with neural surface antibodies. We discuss the potential challenges and opportunities inherent to clinical trials in rare diseases and provide an outlook for the field.

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Conflict of interest statement

H. Abboud is a steering committee member of CIELO; serves as a consultant and/or speaker for Biogen, Genentech, BMS, Horizon/Amgen, Alexion, UCB, and TG Therapeutics; has served as a consultant and/or advisory board member for Cycle Pharma, Alpine Pharma, and Axonics; received honoraria from Neurology Live; receives research support (paid to institution) from Genentech, BMS, Novartis, Sanofi-Genzyme, UCB, COREVITA, and the Guthy-Jackson Charitable Foundation; has served as an assistant editor for the Neurology® journal and is on the Neurology® editorial board; and receives royalties from UpToDate. S.L. Clardy is the principal investigator of EXTINGUISH, which receives support from National Institute of Neurological Disorders and Stroke (U01NS120901) and Amgen Pharmaceuticals; additional sources of support include the Western Institute for Veteran Research, the Siegel Rare Neuroimmune Association, the Immune Deficiency Foundation, Viela Bio/Horizon, Alexion/AstraZeneca, the Barbara Gural Steinmetz Foundation, and Sumaira Foundation for NMO; she has served on consulting/scientific advisory boards for Alexion, VielaBio/Horizon, and Genentech/Roche, is on the medical Advisory Board of the Sumaira Foundation for NMO (unpaid); and is the section editor of the Neurology® Podcast and Neurology Minute, and is on the editorial board of Neurology® Neuroimmunology and Neuroinflammation. D. Dubey is the principal investigator of LEGIONE and has been on clinical advisory boards for UCB, Argenx and Arialys; all compensation for consulting activities is paid directly to Mayo Clinic; he is a named inventor on filed patent that relates to KLHL11 as marker of autoimmunity and germ cell tumor; has patents pending for LUZP4-IgG, cavin-4-IgG and SKOR2-IgG as markers of neurologic autoimmunity; and has received funding from the DOD (CA210208 & PR220430), the David J. Tomassoni ALS Research Grant Program, and UCB. J. Wickel is a steering committee member of GENERATE-BOOST and has received research support from Ionis Pharmaceuticals. G.S. Day is a project PI for the ExTINGUISH Trial, which receives support from National Institute of Neurological Disorders and Stroke (U01NS120901) and Amgen Pharmaceuticals; he also receives support from NIH/NIA (U01AG057195, U01NS120901, U19AG032438); serves as a consultant for Arialys Therapeutics and Parabon Nanolabs Inc. and as a topic editor (Dementia) for DynaMed (EBSCO); has developed educational materials for Continuing Education Inc. and Ionis Pharmaceutical; and owns stock in ANI pharmaceuticals; additionally, his institution has received in-kind contributions for radiotracer precursors for tau-PET neuroimaging in studies of memory and aging (via Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly). C. Geis is the principal investigator of GENERATE-BOOST and serves as a consultant and/or advisory board member and speaker for Alexion, Roche, Argenx, and Sobi. J.M. Gelfand chairs the trial steering committee for CIELO and receives research support to his institution from Hoffman LaRoche; he also receives research support to his institution from Vigil Neurosciences and personal compensation for consulting for Arialys and Ventyx Bio. S.R. Irani is a steering committee member of LEGIONE and CIELO; and has received honoraria/research support from UCB, Immunovant, MedImmun, Roche, Janssen, Cerebral Therapeutics, ADC Therapeutics, BioHaven Therapeutics, CSL Behring, and ONO Pharma. S.-T. Lee is a steering committee member of CIELO, serves as an advisory board member for Argenx and Advanced Neural Technologies, and receives research support to his institution from Hoffman LaRoche and Celltrion. M.J. Titulaer is co-principal investigator of the ExTINGUISH study; is a steering committee member of LEGIONE; has filed a patent on behalf of the Erasmus MC for methods for typing neurologic disorders and cancer, and devices for use therein; and has received research funds for serving on scientific advisory boards for Horizon Therapeutics/Amgen and Argenx, for consultation at Guidepoint Global LLC, and for consultation at UCB; has received an unrestricted research grant from Euroimmune AG, and from CSL Behring; and receives royalties from UpToDate. Go to Neurology.org/N for full disclosures.

References

    1. Dubey D, Pittock SJ, Kelly CR, et al. . Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018;83(1):166-177. doi:10.1002/ana.25131 - DOI - PMC - PubMed
    1. Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012;54(7):899-904. doi:10.1093/cid/cir1038 - DOI - PMC - PubMed
    1. Rosenfeld MR, Dalmau J. Paraneoplastic neurologic syndromes. Neurol Clin. 2018;36(3):675-685. doi:10.1016/j.ncl.2018.04.015 - DOI - PubMed
    1. Abboud H, Briggs F, Buerki R, et al. . Residual symptoms and long-term outcomes after all-cause autoimmune encephalitis in adults. J Neurol Sci. 2022;434:120124. doi:10.1016/j.jns.2021.120124 - DOI - PubMed
    1. Guasp M, Rosa-Justicia M, Muñoz-Lopetegi A, et al. ; Spanish anti-NMDAR Encephalitis Study Group. Clinical characterisation of patients in the post-acute stage of anti-NMDA receptor encephalitis: a prospective cohort study and comparison with patients with schizophrenia spectrum disorders. Lancet Neurol. 2022;21(10):899-910. doi:10.1016/S1474-4422(22)00299-X - DOI - PubMed

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