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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 l.jpg

Rituximab (RITUXAN) & Multiple Sclerosis

Dr. Andrew Sylvester

Attending Neurologist, IMSMP

Assistant Clinical Scientist, MSRCNY


What is rituximab l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
    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 l.jpg
    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 l.jpg
    B-cells & T-cells Interact

    • This interaction has profound effects on the functioning of both B-cells & T-cells


    Rituximab also affects t cells l.jpg
    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 l.jpg
    Phase I: Safety and Tolerability with rituximab (1 patient)

    • 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 l.jpg
    Side Effects in Phase I trial: with rituximab (1 patient)

    • 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 l.jpg
    Phase 2 Study: with rituximab (1 patient)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 l.jpg
    MRI Results with rituximab (1 patient)

    • Relative Reduction of actively inflamed lesions:

      91%


    Relapse data l.jpg
    Relapse Data with rituximab (1 patient)

    • Relapse Rate: reduced by 58%

    • Relapse-free patients:

      Increased by 58%

      • Rituximab = 86%

      • Placebo = 66%


    Phase ii side effects l.jpg
    Phase II Side Effects with rituximab (1 patient)

    • 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 l.jpg
    Phase II Trial Conclusion with rituximab (1 patient)

    • Fewer actively inflamed brain lesions on monthly MRI’s

    • Reduced relapses

    • 2 treatments had effects for at least 6 months


    Administration l.jpg
    Administration with rituximab (1 patient)

    • 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 l.jpg
    Progressive Multifocal Leukoencephalopathy (PML) & Rituximab with rituximab (1 patient)

    • 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


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    Concluding Remarks: with rituximab (1 patient)

    • 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 l.jpg
    Future Directions: with rituximab (1 patient)

    • 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


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