Open Label Study of Safety and Tolerability of Rituximab in Neuromyelitis Optica, Recurrent Transverse Myelitis and Recurrent Bilateral Simultaneous Optic Neuritis
Rituximab is a genetically engineered, chimeric, murine/human monoclonal antibody directed
against the CD20 antigen found on the surface of normal and malignant pre-B and mature B
cells. The antibody is an IgG1 immunoglobulin containing murine light- and heavy chain
variable region sequences and human constant region sequences. Rituximab is composed of two
heavy chains of 451 amino acids and two light chains of 213 amino acids (based on cDNA
analysis) and has an approximate molecular mass of 145 kD. Rituximab has a binding affinity
for the CD20 antigen of ~8.0 nM.
Rituximab was developed by Biogen Idec and Genentech, Inc. It was approved by the FDA in
1997 for the treatment of relapsed or refractory low grade or follicular, CD20+, B-cell
non-Hodgkin's lymphoma (NHL).
Rituximab has also been studied in a variety of non-malignant autoimmune disorders where B
cells and auto antibodies appear to play a role in pathophysiology. Rituximab has been
reported to relieve signs and symptoms of rheumatoid arthritis , lupus , immune
thrombocytopenia , autoimmune anemia , autoimmune neuropathy , and paraneoplastic
opsoclonus/myoclonus .
A Phase II study (WA16291) has been completed in patients with rheumatoid arthritis (RA) .
A total of 161 patients were randomized to 4 treatment arms: Methotrexate, Rituximab alone,
Rituximab and Methotrexate, Rituximab and Cyclophosphamide. Two doses of Rituximab, 1 gm
each, were administered IV two weeks apart. Infusion reactions were observed in 36% of
patients during their first infusion of Rituximab compared to 30% for placebo . Four
Rituximab-treated patients developed serious infections, for a rate of 4.6 per 100 patient
years. For context, the rate of infections requiring hospital admission was 9.57 per 100
patient years in a community based epidemiologic study in RA.
We treated 8 patients with NMO with Rituximab and observed that Rituximab appears to be well
tolerated with 0/8 of the patients suffering serious adverse reactions that could be
directly related to Rituximab administration. Moreover, 7/8 patients experienced decrease
in neurological disability following treatment, suggesting that B-cell depletion may enhance
neurological recovery from attacks. 7/8 of the patients remained attack-free within a
period of 18 months of follow-up on average (range 3 to 12 months) following treatment. We
observed one attack following treatment in a single patient, whereas 14 attacks would have
been predicted by the pre-treatment attack rate (p=0.012, paired t test comparing pre- and
post-treatment attack rates). Nevertheless, the observed impact of treatment on recovery is
more than what would be expected from spontaneous recovery and deserves further
investigation. If B cells are essential for pathogenesis of recurrent attacks in NMO, B
cell depletion may induce sustained remission. We also observed in one case, a dramatic
recovery of electrophysiological conduction in the optic nerves (visual evoked potentials),
which implies that in this case, rituxan did not impair repair mechanisms, for example,
demyelination following the acute attack.
Interventional
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety and Tolerability of Rituximab in NMO (monitor for any AE during two years of follow up)
96 weeks
Yes
Bruce Cree, MD, PhD
Principal Investigator
MS Center , UCSF
United States: Institutional Review Board
H7620-25392-04
NCT00501748
January 2004
December 2010
Name | Location |
---|---|
UCSF MS Center , 350 Parnassus Ave , suite #908 | San Francisco, California 94117 |
The Neurological Institute of New York MS Center | Columbia University Medical Center 710 West 168th Street,, New York 10032 |