Rituximab RITUXAN Multiple Sclerosis

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

6. 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 *In 1997- The first FDA approved monoclonal antibody for cancer therapy. Although, rituxan is not a true chemotherapy medication in the way that the word chemotherapy is used. It�s an antibody. *In 2006- FDA approval for use in combination with methotrexate for the treatment of Rheumatoid arthritis *Anecdotal reports are available for over 30 autoimmune diseases *Multiple Sclerosis - studies in progress *Other neurological diseases treated: Devic�s neuromyelitis optica, myasthenia gravis, several autoimmune peripheral neuropathies, inflammatory myopathies *In 1997- The first FDA approved monoclonal antibody for cancer therapy. Although, rituxan is not a true chemotherapy medication in the way that the word chemotherapy is used. It�s an antibody. *In 2006- FDA approval for use in combination with methotrexate for the treatment of Rheumatoid arthritis *Anecdotal reports are available for over 30 autoimmune diseases *Multiple Sclerosis - studies in progress *Other neurological diseases treated: Devic�s neuromyelitis optica, myasthenia gravis, several autoimmune peripheral neuropathies, inflammatory myopathies

7. 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

8. 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

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

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

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

12. T-cells in CSF depicting temporal decline after treatment with rituximab (1 patient) *But also the T-cells are decreased in the CSF*But also the T-cells are decreased in the CSF

13. 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 *48-week results from an open-label 72-week trial in RRMS by Dr. Amit Bar-Or (McGill U. in Montreal) *No placebo group *Other results: -significant reduction in gadolinium enhancing lesions noted at week 4 -re-dosing at 6 months appeared to further reduce gadolinium enhancing lesions -reduction in relapses from at least 1 per year to only a few for the entire study *48-week results from an open-label 72-week trial in RRMS by Dr. Amit Bar-Or (McGill U. in Montreal) *No placebo group *Other results: -significant reduction in gadolinium enhancing lesions noted at week 4 -re-dosing at 6 months appeared to further reduce gadolinium enhancing lesions -reduction in relapses from at least 1 per year to only a few for the entire study

14. 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 Anything that happened occurred around the times of the infusions.Anything that happened occurred around the times of the infusions.

15. 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 *A Phase II Randomized, Placebo-Controlled, Multicenter Trial of Rituximab in Adults with Relapsing Remitting MS. Hauser S. et al -AAN 2007 Abstract and Plenary Presentation ***Of note: the rituxan group had greater disease activity than the placebo group prior to treatment: Inflamed lesion count: 2.1 lesions vs. 0.3 lesions *A Phase II Randomized, Placebo-Controlled, Multicenter Trial of Rituximab in Adults with Relapsing Remitting MS. Hauser S. et al -AAN 2007 Abstract and Plenary Presentation ***Of note: the rituxan group had greater disease activity than the placebo group prior to treatment: Inflamed lesion count: 2.1 lesions vs. 0.3 lesions

16. MRI Results Relative Reduction of actively inflamed lesions: 91% ***Of note: the rituxan group had greater disease activity than the placebo group prior to treatment: inflamed lesion count: 2.1 lesions vs. 0.3 lesions ***Of note: the rituxan group had greater disease activity than the placebo group prior to treatment: inflamed lesion count: 2.1 lesions vs. 0.3 lesions

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

18. 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 *As this shows, the infusion reactions and incidence of infections were no greater with rituxan than with placebo. *As this shows, the infusion reactions and incidence of infections were no greater with rituxan than with placebo.

19. Phase II Trial Conclusion Fewer actively inflamed brain lesions on monthly MRI�s Reduced relapses 2 treatments had effects for at least 6 months 30% of patients developed antibodies to rituxan, but they did not appear to diminish the clinical effect and the B-cells were still depleted. No known increase in infusion reactions with antibodies to rituxan in MS patients. 30% of patients developed antibodies to rituxan, but they did not appear to diminish the clinical effect and the B-cells were still depleted. No known increase in infusion reactions with antibodies to rituxan in MS patients.

20. Administration Current MS trials: 2 dosages of 1 gram IV given 2 weeks apart Slow infusion: around 4 to 6 hours *Blood test are monitored for total B-cell count and white blood cell count *B-cells remain suppressed for at least 6 months, and sometimes up to 9 months or more *Blood tests to determine B-cell counts have not been correlated to clinical effects on MS *Duration of clinical benefit has not been accurately determined *Ideal time to repeat treatment has not been accurately established *Rituximab has rarely been associated with fatal infusion reactions (tumor lysis syndrome), PML, renal toxicity, + other adverse effects (in the treatment of other diseases than MS). *Another protocol gives rituxan based on body surface area and divides it over 4 weekly infusions � 375 mg/m2 each infusion. -This is the same dosing as rheumatoid arthritis dosing *Blood test are monitored for total B-cell count and white blood cell count *B-cells remain suppressed for at least 6 months, and sometimes up to 9 months or more *Blood tests to determine B-cell counts have not been correlated to clinical effects on MS *Duration of clinical benefit has not been accurately determined *Ideal time to repeat treatment has not been accurately established *Rituximab has rarely been associated with fatal infusion reactions (tumor lysis syndrome), PML, renal toxicity, + other adverse effects (in the treatment of other diseases than MS). *Another protocol gives rituxan based on body surface area and divides it over 4 weekly infusions � 375 mg/m2 each infusion. -This is the same dosing as rheumatoid arthritis dosing

21. 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 **I am just bringing this up because of the interest in PML with tysabri, but lupus and cancer are very different diseases than MS, and both predisposes to PML. **There is no reason to expect PML to occur in patients with MS who have been treated with rituxan. *In December, 2006: FDA announced 2 cases of PML in systemic lupus. *SLE is a disease that is significantly different than MS. SLE patients can have diminished immune systems from the disease as well as the treatment, whereas MS patients sometimes have diminished immune systems from the treatment.**I am just bringing this up because of the interest in PML with tysabri, but lupus and cancer are very different diseases than MS, and both predisposes to PML. **There is no reason to expect PML to occur in patients with MS who have been treated with rituxan. *In December, 2006: FDA announced 2 cases of PML in systemic lupus. *SLE is a disease that is significantly different than MS. SLE patients can have diminished immune systems from the disease as well as the treatment, whereas MS patients sometimes have diminished immune systems from the treatment.

22. 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 *Even if Rituxan works, it doesn�t mean it works purely by affecting B-cells or that the patients in whom it works possesses a type of MS caused by prominent B-cell pathology*Even if Rituxan works, it doesn�t mean it works purely by affecting B-cells or that the patients in whom it works possesses a type of MS caused by prominent B-cell pathology

23. 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 *Rituxan may be a �First Generation� anti-CD20 antibody 60-65% human & 35-40% mouse protein Increased allergic reactions In development: Ocrelizumab - 90-95% humanized anti-CD 20 Ofatumumab (or 2H7) - fully human anti-CD 20 �3rd Generation� anti-CD 20 antibody: bioengineered to enhance ability to destroy B-cells *Rituxan may be a �First Generation� anti-CD20 antibody 60-65% human & 35-40% mouse protein Increased allergic reactions In development: Ocrelizumab - 90-95% humanized anti-CD 20 Ofatumumab (or 2H7) - fully human anti-CD 20 �3rd Generation� anti-CD 20 antibody: bioengineered to enhance ability to destroy B-cells