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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?. Trade name = Rituxan Monoclonal antibody Suppresses the immune system Targets & depletes B-cells from the blood

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Rituximab (RITUXAN) & Multiple Sclerosis

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  1. Rituximab (RITUXAN) & Multiple Sclerosis Dr. Andrew Sylvester Attending Neurologist, IMSMP Assistant Clinical Scientist, MSRCNY

  2. 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

  3. 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

  4. B-cell Functions

  5. 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

  6. 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

  7. 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

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

  9. Rituximab also affects T-cells • At 24 weeks after treatment: • B-cells: reduced by 90% in CSF • T-cells: reduced over 50% in CSF

  10. B-cells in CSF depicting temporal decline after treatment with rituximab (1 patient)

  11. T-cells in CSF depicting temporal decline after treatment with rituximab (1 patient)

  12. 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

  13. 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

  14. 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

  15. MRI Results • Relative Reduction of actively inflamed lesions: 91%

  16. Relapse Data • Relapse Rate: reduced by 58% • Relapse-free patients: Increased by 58% • Rituximab = 86% • Placebo = 66%

  17. 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

  18. Phase II Trial Conclusion • Fewer actively inflamed brain lesions on monthly MRI’s • Reduced relapses • 2 treatments had effects for at least 6 months

  19. Administration • Current MS trials: 2 dosages of 1 gram IV given 2 weeks apart • Slow infusion: around 4 to 6 hours

  20. 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

  21. 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

  22. 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

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