Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis

Autoimmune encephalitis is characterized by autoantibodies against neuronal surface antigens like the NMDA (N-methyl-D-aspartate) receptor or LGI1 (Leucin-rich glioma inactivated protein 1). So far, no specific therapy exists for this disease. Actual treatment includes combination therapies aiming for a reduction of pathogenic antibodies and containing the autoimmune process. In first line, patients are treated with plasmapheresis and cortisone. In second line, Rituximab and/or cyclophosphamide are administered. The response to these treatments are, however, often delayed and insufficient.

Therefore, we need a specific therapy aiming at the antibody-producing plasma cells.

Bortezomib is a proteasome inhibitor which interferes with NF-kB (nuclear factor kB) and the ubiquitin proteasome signaling pathway. Bortezomib acts preferably on cells with high protein synthesis - like plasma cells - and induces cell death in these cells. Bortezomib is used since more than a decade in chemotherapy of the multiple myeloma. Additionally, it is reported for systemic autoimmune diseases like lupus erythematodes that bortezomib leads to a depletion of plasma cells and therefore reduces the number of pathogenic antibodies and improves clinical outcome. The therapeutic potential of bortezomib for NMDAR encephalitis is described in a first case series with 5 patients.

• Bortezomib (Drug): 1 to 3 cycles Bortezomib with 1,3mg/m2 body surface s.c. + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)
• Placebo (Drug), also known as isotonic NaCl solution: 1 to 3 cycles placebo (NaCl solution) s.c. + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)

Primary outcomes

• modified Rankin-Score (mRS) [17 weeks after first administration of the study drug]: modified Rankin-Score from 0 = no symptoms to 6 = death

Secondary outcomes

• modified Rankin-Score (mRS) [3, 6, 9 and 13 weeks after first administration of the study drug; GCS Score also 17 weeks after first administration of the study drug]: modified Rankin-Score from 0 = no symptoms to 6 = death
• Length of in-hospital stay / length of ICU stay [until 17 weeks after first administration of the study drug]: Number of days in hospital or on ICU for each patient from first administration of the study drug until 17 weeks after first administration of the study drug
• Immune response [at study start and 17 weeks after first administration of the study drug]: Antibody titer (in serum and liquor) and cellular immune response (FACS analysis of liquor)
• neurocognitive function assessed by Montreal Cognitive Assessment [at study start and 17 weeks after first administration of the study medication]: total score of the Montreal Cognitive Assessment (MoCA) (0 to max. 30 points = best possible result)
• neurocognitive function assessed by Mini-Mental Status Test [at study start and 17 weeks after first administration of the study medication]: total score of the Mini-Mental Status Test (MMST) (0 to max 30 points = best possible result)
• neurocognitive function assessed by Rey Auditory Verbal Learning Test [at study start and 17 weeks after first administration of the study medication]: total score of the Rey Auditory Verbal Learning Test (RAVLT) (memory performance assessed by 3 word lists which are read to the patient and should be recalled and repeated by the patient; different proceeding for the 3 word lists)
• neurocognitive function assessed by Neuropsychiatric Inventory Questionnaire [at study start and 17 weeks after first administration of the study medication]: total score of the Neuropsychiatric Inventory Questionnaire (NPI) (0 = best score to max 36 (patient) or 60 (caregiver)
• safety of Bortezomib regarding polyneuropathy, increase of liver enzymes and secondary infections [until 17 weeks after first administration of the study drug]: number of polyneuropathy cases, number of increased liver enzymes, number of secondary infections
• safety of Bortezomib regarding polyneuropathy [until 17 weeks after first administration of the study drug]: number of polyneuropathy cases
• safety of Bortezomib regarding increase of liver enzymes [until 17 weeks after first administration of the study drug]: number of increased liver enzyme values
• Secondary infections due to Bortezomib [until 17 weeks after first administration of the study drug]: number of secondary infections
• Hematotoxicity events due to Bortezomib [until 17 weeks after first administration of the study drug]: number of hematotoxicity events
• Gastrointestinal toxicity due to Bortezomib [until 17 weeks after first administration of the study drug]: number of gastrointestinal toxicity events
• total Glasgow Coma Scale (GCS) [3, 6, 9, 13 and 17 weeks after first administration of the study drug]: GCS from 3 to 15 points (sum of 3 subscores eye response (1 to 4 points), motor response (1 to 6 points), verbal response (1 to 5 points); highest score = best score; 1= worst score)
• Destruction marker UCH-L1 (Ubiquitin carboxy-terminal hydrolase L1) in serum and liquor [at baseline visit and 17 weeks after first administration of the study drug]: Analysis of destruction marker UCH-L1 in serum and liquor
• Destruction marker Neurofilament light chain (in serum and liquor) [at baseline visit and 17 weeks after first administration of the study drug]: Analysis of destruction marker Neurofilament light chain in serum and liquor
• Destruction markers GFAP (glial fibrillary acidic protein) in serum and liquor [at baseline visit and 17 weeks after first administration of the study drug]: Analysis of destruction marker GFAP in serum and liquor
• Destruction marker TAU proteins in serum and liquor [at baseline visit and 17 weeks after first administration of the study drug]: Analysis of destruction marker TAU in serum and liquor

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Clinically diagnosed severe autoimmune encephalitis (defined as mRS ≥ 3) with autoantibodies to neuronal surface proteins in cerebrospinal fluid and / or serum
* Pretreatment with rituximab
* Age ≥18 years
* signed informed consent
* Women of childbearing potential (up to 2 years after menopause): negative pregnancy test

Exclusion Criteria:

* pregnancy/breast-feeding
* acute infiltrative pulmonary and pericardial disease
* malignant tumor under current chemotherapy
* Simultaneous participation in another intervention study
* Previous participation in this study
* Known hypersensitivity to an ingredient of the investigational product
* Continued therapy with glucocorticoids / rituximab during the study duration (last dose must be administered before the first dose of the investigational product)

• Results publication: Wickel J, Chung HY, Platzer S, Lehmann T, Pruss H, Leypoldt F, Gunther A, Scherag A, Geis C; GENERATE Study Group. Generate-Boost: study protocol for a prospective, multicenter, randomized controlled, double-blinded phase II trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis. Trials. 2020 Jul 8;21(1):625. doi: 10.1186/s13063-020-04516-7. PMID 32641101

• Christian Geis, Prof., Study director, University Hospital Jena

NIH grants: 2019