The ExTINGUISH Trial of Inebilizumab in NMDAR Encephalitis

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.

N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis, with prevalence exceeding herpes encephalitis in industrialized nations. Typically, the disease affects patients age 10-50 causing prominent psychiatric symptoms, altered consciousness, seizures, movement disorders and life-threatening dysautonomia. Intensive care, including cardiorespiratory support is required in 75% of cases. The diagnosis is confirmed by detection of IgG autoantibodies against central nervous system NMDAR in the cerebrospinal fluid. Despite the severity of the illness, NMDAR encephalitis is a treatable neurological disease, with retrospective case series establishing the benefit of off-label intravenous steroids and immunoglobulins. These treatments are presumed to work through effects on IgG NMDAR autoantibody levels in the CSF, although prospective data informing predictors of treatment responses are limited. Even with prompt treatment, \~50% of patients remain disabled, requiring prolonged hospital admissions. Various off-label therapies have been proposed as "second-line" treatments in NMDAR encephalitis. The majority of second-line treatments target circulating B-cells with various degrees of blood brain penetrance and efficacy, and poor consensus on the timing, dose and route of delivery of candidate agents. High-quality evidence is needed to inform the treatment of NMDAR encephalitis. Inebilizumab is a promising therapeutic monoclonal antibody for the treatment of NMDAR encephalitis. This humanized monoclonal antibody against the B-cell surface antigen CD19 was recently shown to be safe and efficacious in the treatment of neuromyelitis optica spectrum disorder-another antibody-mediated disorder of the central nervous system. Compared to other off label B-cell depleting therapies, such as rituximab, inebilizumab not only depletes CD20+ B-cells, but also CD20- plasmablasts and plasma cells, resulting in robust and sustained suppression of B-cell expression. The ExTINGUISH Trial will randomize 116 participants with moderate-to-severe NMDAR encephalitis to receive either inebilizumab or placebo in addition to first-line therapies. Patient outcomes will be ascertained at standard intervals using the modified Rankin scale and accepted safety measures (primary outcomes at 16 weeks), together with comprehensive validated neuropsychological tests, bedside cognitive screening tools, quality of life/ functional indices, and outcome prediction measures. Clinical data will be combined with quantitative measures of NMDAR autoantibody titers and cytokines implicated in B-cell activation and antibody production within the intrathecal compartment to identify treatment responders, inform the biologic contributors to outcomes, and evaluate for biomarkers that may serve as early predictors of favorable outcomes in future clinical trials in NMDAR encephalitis. The ExTINGUISH Trial will prospectively study an optimized B-cell depletion therapy to promote better long-term outcomes in NMDAR encephalitis, to determine more meaningful cognitive endpoints, and to identify better biologic biomarkers to predict outcome.

Eligibility Criteria:
Inclusion Criteria

1. Diagnosis of NMDAR encephalitis, defined by both a and b:

   1. A subacute onset of change in mental status consistent with autoimmune encephalitis,
   2. A positive cell-based assay for anti-NMDA receptor IgG antibody in the CSF confirmed in study-specified laboratories.
2. Participants, ≥ 12 years of age at the time of informed consent. Participants under 18 years of age must weigh ≥40 kilograms.
3. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act \[HIPAA\] in the United States of America \[USA\], European Union \[EU\] Data Privacy Directive in the EU) obtained from the participant/legal representative prior to performing any protocol-related procedures, including screening evaluations.
4. Non-sterilized participants who are sexually active with a partner capable of becoming pregnant must use a condom with spermicide from Day 1 through to the end of the study and must agree to continue using such precautions for at least 6 months after the final dose of IP. A recommendation will be made that the partners (capable of becoming pregnant) of study participants (capable of getting their partner pregnant) should use a highly effective method of contraception other than a physical method.

   Participants of childbearing potential who are sexually active with a non-sterilized partner capable of getting their partner pregnant must agree to use a highly effective method of contraception beginning at screening or upon discharge from hospitalization/inpatient rehabilitation (for participants who were incapacitated at the time of screening), and to continue precautions for 12 months after the final dose of IP.
   1. Participants of childbearing potential are defined as those who are not surgically sterile (e.g., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who are not postmenopausal (per ICH M3 (R2) 11.2: defined as 12 months with no menses without an alternative medical cause).
   2. A highly effective method of contraception is defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Periodic abstinence, the rhythm method, and the withdrawal method do not qualify as "highly effective" or acceptable methods of contraception for study purposes. Acceptable methods of contraception are listed in the table below:

      Physical Methods Hormonal Methods e

      • Intrauterine device (IUD)

      • Intrauterine hormone-releasing system, also known as drug-eluting IUD a

      • Bilateral tubal occlusion

      • Vasectomized partner b

      • Sexual abstinence c • Combined (estrogen and progestogen-containing hormonal contraception)
      * Oral (combined pill)
      * Injectable
      * Transdermal (patch)
      * Progestogen-only hormonal contraception associated with inhibition of ovulation d
      * Implantable
      * Intravaginal a This is also considered to be a hormonal method. b With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate).

      c Sexual abstinence is considered to be a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the participant.

      d Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action (minipill) is not accepted as a highly effective method.

      e These methods are only considered highly effective and therefore acceptable when used in conjunction with a barrier method (i.e., diaphragm with spermicide, sponge with spermicide, cervical cap with spermicide, condoms, spermicide alone.)
5. Willing to forgo other immunomodulatory therapies (investigational or otherwise) for NMDAR encephalitis during the study.
6. Participant must have received at least 3 days of methylprednisolone 1000 mg IV or equivalent corticosteroid within 90 days prior to randomization (Day 1). In addition, participants must have received EITHER of the following treatments within 90 days before randomization.

   1. IVIg, at a dose range between 1.2 and 2 g/kg
   2. Plasma exchange or plasmapheresis, (defined as 5 to 6 exchanges).

   NOTE: These treatments may be provided during the screening period but must be completed prior to randomization. Participants who receive methylprednisolone and BOTH IVIg and plasma exchange are not excluded from participating in the trial, however, this treatment course with both IVIg and plasma exchange is not encouraged, and enrollment and randomization should not be delayed in order to complete additional first line treatments.
7. Modified Rankin Score of ≥3 at the screening visit, indicating at least moderate disability. The baseline mRS must be confirmed by Site Investigators at screening and confirmed / adjudicated before randomization.
8. Ability and willingness to attend study visits and complete the study. \*All inclusion criteria must be met during the screening period, prior to randomization, except where noted.

Exclusion Criteria

Any of the following excludes an individual from participation in the study:

1. Any condition that, in the opinion of the Investigator, would interfere with the evaluation or administration of the IP, interpretation of participant safety or study results, or would make participation in the study an unacceptable risk. This specifically includes recent history (last 5 years) of herpes simplex virus encephalitis or known central nervous system demyelinating disease (e.g., multiple sclerosis).
2. Presence of an active or chronic infection that is serious in the opinion of the Investigator.
3. History of solid organ or cell-based transplantation.

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1. Concurrent/previous enrollment in another clinical study involving an investigational treatment within 4 weeks or 5 published half-lives of the investigational treatment, whichever is longer, prior to randomization.
2. Lactating or pregnant individuals, or individuals who intend to become pregnant anytime from study enrollment to 12 months following last dose of investigational agent.
3. Known history of allergy or reaction to any component of the investigational agent formulation or history of anaphylaxis following any biologic therapy.
4. Receipt of the following at any time prior to randomization:

   a. Alemtuzumab b. Total lymphoid irradiation c. Bone marrow transplant d. T-cell vaccination therapy
5. Receipt of any biologic B cell-depleting therapy (e.g., rituximab, ocrelizumab, obinutuzumab, ofatumumab, inebilizumab) in the 6 months prior to screening. Receipt of such a B cell-depleting agent in the period 6-12 months prior to screening is exclusionary unless B cell counts have returned to ≥ age-based LLN by central laboratory. For EU participants, B cell counts at screening will be determined by the laboratories of the participating sites. Receipt of non-depleting B cell-directed therapy (e.g., belimumab), abatacept, or other biologic immunomodulatory agent within 6 months prior screening.
6. Treatment at therapeutic doses/durations with any of the following within 3 months prior to randomization

   a. Natalizumab (Tysabri®) b. Cyclosporine c. Methotrexate d. Mitoxantrone e. Cyclophosphamide\* f. Azathioprine g. Mycophenolate mofetil

   \*Cyclophosphamide is only permitted as rescue therapy to be administered as outlined in Section 5.4.1 no earlier than the week 6 visit.
7. Severe drug allergic history or anaphylaxis to two or more food products or medicines (including known sensitivity to acetaminophen/paracetamol, diphenhydramine (cetirizine in EU) or equivalent antihistamine, and methylprednisolone or equivalent glucocorticoid).
8. Known history of a primary immunodeficiency (congenital or acquired) or an underlying condition such as human immunodeficiency virus (HIV) infection or splenectomy that predisposes the participant to infection.
9. Active malignancy or history of malignancy that was active within the last 10 years, apart from ovarian or extra-ovarian teratoma (also known as a dermoid cyst) or germ cell tumor, or squamous cell carcinoma of the skin or basal cell carcinoma of the skin, that in the opinion of the Medical Safety Monitor (MSM) would preclude enrollment due to safety concerns. Squamous cell and basal cell carcinomas should be treated with documented success of curative therapy \> 3 months prior to randomization.
10. At screening (repeat testing may be conducted to confirm results within the same screening period, prior to randomization), any of the following:

    a. Total white blood count \<2,500 cells/mm3 (or \< 2.5 × 109/L) b. Total immunoglobulin \< 600 mg/dL (or 6 µmol/L; 400 mg/dL for participants \<18 years)\* c. Absolute neutrophil count \< 1200 cells/μL (or \< 1.2 × 109/L) d. CD4 T lymphocyte count \< 300 cells/µL (or \< 0.3 × 109/L)

    \*Baseline levels of IgG prior to first line treatments (methylprednisolone, plasmapheresis/plasma exchange) should be used to determine eligibility.
11. Active hepatitis B or C established with positive hepatitis B serology (hepatitis B surface antigen and core antigen) and/or positive hepatitis C PCR testing and confirmed by the MSM
12. Any live or attenuated vaccine within 4 weeks prior to Day 1 (administration of killed vaccines is acceptable).
13. Bacillus of Calmette and Guérin (BCG) vaccine within 1 year of enrollment.
14. History of alcohol or drug abuse that, in the opinion of the Investigator, might affect participant safety or compliance with visits or interfere with safety or other study assessments.
15. Recurrence of previously treated NMDAR encephalitis within the last 5 years, or suspicion of symptomatic untreated NMDAR encephalitis of greater than 3 months duration at the time of screening.
16. Evidence of active tuberculosis\* (TB) or being at high risk for TB based on:

    a. History of active TB or untreated/incompletely treated latent TB. Participants with a history of active or latent TB who have documentation of completion of treatment according to local guidelines may be enrolled.

    b. History of recent (≤ 12 weeks of screening) close contact with someone with active TB (close contact is defined as ≥ 4 hours/week OR living in the same household OR in a house where a person with active TB is a frequent visitor).

    c. Signs or symptoms that could represent active TB by medical history or physical examination.

    d. Positive, indeterminate, or invalid interferon-gamma release assay test result at screening, unless previously treated for TB. Participants with an indeterminate test result can repeat the test once, but if the repeat test is also indeterminate, the participant is excluded.

    e. Chest radiograph, chest computed tomography or MRI scan that suggests a possible diagnosis of TB or suggests that a work-up for TB should be considered; all participants must have had lung imaging with an acceptable reading within 6 months prior to consent, or during screening.
17. Active, clinically significant (CS) infection at the time of randomization (IP administration may be delayed until recovery, if within 14-day screening window, otherwise participant may be rescreened).

Exclusion criteria are applied at time of screening and are applicable throughout the study.

* Participants will undergo QuantiFERON®-TB Gold testing or equivalent TB testing during screening as standard of care. A positive result will not exclude patients from participation; thus, enrollment should not be delayed awaiting this result. If positive, an appropriate course of anti-TB treatment will need to be documented. If results are in indeterminate, participants may still be eligible for randomization if history is not suggestive of active / latent TB and a chest x-ray shows no evidence of active or latent TB.

1.1 Additional Eligibility Considerations

The following criteria are not necessarily exclusionary but require review from the MSM to determine if a participant should be excluded due to safety concerns:

1. At screening (out of range lab values may be reviewed with the MSM to determine whether a potential participant should be excluded for safety reasons; repeat testing may be conducted to confirm results within the same screening period, prior to randomization), any of the following:

   1. Aspartate transaminase (AST) \> 2.5 × age-based upper limit of normal (ULN)
   2. Alanine transaminase (ALT) \> 2.5 × age-based ULN
   3. Total bilirubin \> 1.5 × age-based ULN (unless due to Gilbert's syndrome)
   4. Platelet count \< 75,000/μL (or \< 75 × 109/L)
   5. Hemoglobin \< 8 g/dL (or \< 80 g/L or 5 mmol/L)
2. History of untreated hepatitis C infection. Participants who are considered cured following antiviral therapy with an HCV load below the limit of detection may be enrolled pending confirmation from the MSM that there are no safety concerns for inclusion.
3. Patients with coexistent autoantibodies should not immediately be excluded but should be reviewed with the MSM to determine eligibility.