Ublituximab for Acute Neuromyelitis Optica (NMO) Relapses
Condition: Neuromyelitis Optica; Neuromyelitis Optica Spectrum Disorder
MeSH terms: Neuromyelitis Optica; Optic Neuritis
Intervention: Ublituximab
Intervention description: Monoclonal antibody that specifically binds to the trans-membrane antigen CD20, which induces immune response that causes lysis of B cells.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Transverse myelitis, optic neuritis, neuromyelitis optica

Summary:

      Ublituximab (also known as LFB-R603) is a monoclonal antibody that specifically binds to the
      trans-membrane antigen CD20. The binding induces immune response that causes lysis of B
      cells.

      The rationale for using ublituximab in neuromyelitis optica (NMO) and neuromyelitis optica
      spectrum disorder (NMOSD) is based on the known roles of B cells, antibody production and
      plasma cells in the pathophysiology of NMO. NMO is characterized by the presence of an
      anti-Aquaporin-4 (AQP4) antibody, which can only be produced by differentiation of B cells to
      plasma cells. Because these anti-AQP4 antibodies may be pathogenic, B cells recognizing AQP4
      may be directly involved in the disease process as well. B cells also play a role as potent
      antigen presenting cells in NMO. The strongest evidence of the importance of B cells in NMO
      comes from studies of B cell depletion, most commonly with anti-CD20 monoclonal antibody,
      rituximab (Rituxan®).

      Rituximab has been shown in five retrospective and two prospective studies to be effective in
      reducing NMO relapses up to 90% and achieving remission in up to 80% of patients solely by
      its action on CD20+ B cells, despite no change in plasma cell population and anti-AQP4
      antibody titers. These human trials strongly suggest a critical role for B cells in the
      pathophysiology of human disease. While typically used in the prevention of disease, B-cell
      depletion may be beneficial in the treatment of an acute relapse as well. Emerging evidence
      indicates that peripheral B cells are activated during a relapse and plasmablast production
      of anti-AQP4 antibodies spikes. B cells are also found within acute lesions of the spinal
      cord and optic nerve suggesting roles both in the blood and in the central nervous system
      during a relapse.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Able and willing to provide written informed consent.

          2. 18-100 years of age.

          3. New acute optic neuritis and/or transverse myelitis. A clinical event is defined as an
             episode of inflammation in the spinal cord and/or optic nerve leading to neurologic
             deficits on physical exam not attributable to another disease process.

          4. Confirmed or highly suspected diagnosis of NMO according to the 2006 revisions of the
             Wingerchuk diagnostic criteria for NMO (Wingerchuk, 2006), or AQP4 positive NMOSD.

          5. The B cell count must be normal (5-20% of total lymphocytes) in subjects who have not
             received another B cell depleting therapy in the past year. For those on B cell
             depleting therapy within the past year, a B cell count of at least 0.5% is necessary.

          6. A female subject is eligible to enter the trial if she is:

               -  Not pregnant or nursing;

               -  Of non-childbearing potential OR of child-bearing potential

          7. Subject has a negative serum pregnancy test at screening and agrees to one of the
             following:

               -  Complete abstinence from intercourse for the period from consent into the trial
                  until 6 months after the last dose of investigational product; or,

               -  Consistent and correct use of one of the following acceptable methods of birth
                  control for the period from consent into the trial until 6 months after the last
                  dose of investigational product:

                    -  Oral contraceptives

                    -  Injectable progesterone

                    -  Levonorgestrel implants

                    -  Estrogenic vaginal ring

                    -  Percutaneous contraceptive patches

                    -  Intrauterine device (IUD) or intrauterine system (IUS)

                    -  Male partner sterilization

                    -  Double barrier method

        Exclusion Criteria:

          1. Current evidence or known history of clinically significant infection including:

               -  Chronic or ongoing active infectious disease

               -  Previous serious opportunistic or atypical infections.

               -  Hepatitis B

               -  Tuberculosis (TB)

               -  HIV

          2. History of clinically significant central nervous system (CNS) trauma (e.g. spinal
             cord compression).

          3. Past or current history of medically significant adverse effects from:

               -  Corticosteroids

               -  Diphenhydramine

               -  Murine or mouse/human chimeric antibodies

          4. Past or current malignancy, except for

               -  Cervical carcinoma Stage 1B or less

               -  Non-invasive basal cell and squamous cell skin carcinoma

               -  Cancer diagnoses with a duration of complete response (remission) >5 years A
                  history of hematologic malignancy excludes a subject from participation,
                  regardless of response.

          5. Significant concurrent, uncontrolled medical condition including, but not limited to,
             cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency
             syndrome, pulmonary, cerebral, psychiatric, or neurological disease which could affect
             the subject's safety, impair the subject's reliable participation in the trial, impair
             the evaluation of endpoints, or necessitate the use of medication not allowed by the
             protocol, as determined by the PI of the trial.

          6. Use of an investigational drug or other experimental therapy for a condition other
             than NMO within 4 weeks, 5 pharmacokinetic half lives or duration of biological effect
             (whichever is longer) prior to screening.

          7. Current participation in any other interventional clinical trial. Participation in
             non-interventional trial requires approval of the protocol by investigator.

          8. Subjects who are concurrently receiving any other investigational agents, or have
             participated in an interventional clinical trial within the last 21 days, or subjects
             who have been vaccinated with a live vaccine < 2 months prior to trial inclusion.

          9. Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with ublituximab breastfeeding should be
             discontinued if the mother is treated with ublituximab.