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Rituximab (RITUXAN) & Multiple Sclerosis . Dr. Andrew Sylvester Attending Neurologist, IMSMP Assistant Clinical Scientist, MSRCNY. What is Rituximab?. Trade name = Rituxan Monoclonal antibody Suppresses the immune system Targets & depletes B-cells from the blood

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rituximab rituxan multiple sclerosis

Rituximab (RITUXAN) & Multiple Sclerosis

Dr. Andrew Sylvester

Attending Neurologist, IMSMP

Assistant Clinical Scientist, MSRCNY

what is rituximab
What is Rituximab?
  • Trade name = Rituxan
  • Monoclonal antibody
  • Suppresses the immune system
  • Targets & depletes B-cells from the blood
  • A potential new therapy for MS
  • Not FDA approved at this time
backround definitions
Backround Definitions:
  • ANTIBODIES: proteins that identify and neutralize foreign particles (bacteria and viruses)
  • MONOCLONAL ANTIBODIES: a collection of antibodies that are identical & specific in their function
  • B-cells:
    • Become plasma cells which produce antibodies
    • Help regulate other cells of the immune system (including T-cells)
  • T-cells: the major regulators of the immune system and inflammatory processes
rituxan
Rituxan:
  • Collection of antibodies specifically designed to bind to and destroy B-cells
  • Clinical Uses:
      • Autoimmune disorders
      • B-cell cancers
        • non-Hodgkin’s lymphomas & leukemia
  • Over 500,000 patients and 1,000,000 exposures
  • 10 year track record
b cells abnormalities in ms
B-Cells abnormalities in MS
  • B-cells have a significant role in MS
  • A subset of MS patients have prominent B-cell involvement (clinical & pathological data)
  • In the laboratory: OLIGOCLONAL BANDS in cerebrospinal fluid are a hallmark of MS
    • Consists of antibodies
    • Produced by plasma cells (which come from B-cells) in the brain and spinal cord
primary mechanism of action of rituximab
Primary mechanism of action of Rituximab
  • Binds to a protein called CD-20 (located on the surface of B-cells)
  • Causes destruction of the B-cells
b cells t cells interact
B-cells & T-cells Interact
  • This interaction has profound effects on the functioning of both B-cells & T-cells
rituximab also affects t cells
Rituximab also affects T-cells
  • At 24 weeks after treatment:
  • B-cells: reduced by 90% in CSF
  • T-cells: reduced over 50% in CSF
phase i safety and tolerability
Phase I: Safety and Tolerability
  • 48 week results
  • 26 relapsing-remitting MS patients
  • Treatment protocol:
    • 2 dosages of 1 gram IV given 2 weeks apart
    • Repeated 6 months later
side effects in phase i trial
Side Effects in Phase I trial:
  • Infusion Reactions:
  • Headache, chills, or infusion site reactions
  • Rituxan = 78% Placebo = 40%
  • >95% - mild to moderate, easily managed
  • Most with the first infusion
  • Subsequent infusions had lower risk
  • 1 patient dropped out due to severe headache
phase 2 study rituximab in relapsing remitting ms
Phase 2 Study: Rituximab in Relapsing-Remitting MS
  • 48 weeks study of 104 patient
  • Patients had at least 1 relapse in past year
  • Dosage: 2 doses of rituximab over 2 weeks
  • Evaluated:
    • Number of actively inflamed (gadolinium-enhancing) lesions on 4 monthly brain MRI scans starting at month #3
    • Relapses
  • 6 month data released
mri results
MRI Results
  • Relative Reduction of actively inflamed lesions:

91%

relapse data
Relapse Data
  • Relapse Rate: reduced by 58%
  • Relapse-free patients:

Increased by 58%

    • Rituximab = 86%
    • Placebo = 66%
phase ii side effects
Phase II Side Effects
  • Infusion reaction:

Rituximab = 10% Placebo = 14%

    • None were serious
    • 97% of all adverse reaction
  • Infections:
    • Rituximab = 65%
    • Placebo = 63%
    • No significant difference
phase ii trial conclusion
Phase II Trial Conclusion
  • Fewer actively inflamed brain lesions on monthly MRI’s
  • Reduced relapses
  • 2 treatments had effects for at least 6 months
administration
Administration
  • Current MS trials:

2 dosages of 1 gram IV

given 2 weeks apart

  • Slow infusion: around 4 to 6 hours
progressive multifocal leukoencephalopathy pml rituximab
Progressive Multifocal Leukoencephalopathy (PML) & Rituximab
  • About 23 cases of PML in > 500,000 patients
    • All had either B-cell cancer or lupus
    • Both diseases pose increased susceptibility for PML
    • 3 cases in approximately 10,000 Lupus patients
    • All were taking rituximab in combination with chemotherapy
  • Risk in MS and other neurological diseases
    • Has never happened
concluding remarks
Concluding Remarks:
  • A potentially promising new therapy for MS
    • marked beneficial effect on RRMS in 6 month data
    • Unique mechanism of action
    • Benefited the majority (not a subset) of patients
    • Early data may put it on par with Tysabri
    • Study underway for Primary Progressive MS
  • Convenient dosing
  • Well-tolerated
  • 10-year history
future directions
Future Directions:
  • Complete adequate studies to achieve FDA approval
  • Identify which patients will respond best
  • Assess the long-term safety & efficacy
  • Establish the ideal dose and frequency
  • Assess the safety and efficacy of combination therapy
  • Development of new B-cell therapies with fewer side effects and stronger effect