Rituximab (RITUXAN) Rituximab (RITUXAN) & &

Multiple Sclerosis Multiple Sclerosis

Dr. Andrew SylvesterDr. Andrew SylvesterAttending Neurologist, IMSMPAttending Neurologist, IMSMP

Assistant Clinical Scientist, MSRCNYAssistant Clinical Scientist, MSRCNY

What is Rituximab?What is Rituximab?

Trade name = Trade name = RituxanRituxan Monoclonal antibodyMonoclonal antibody Suppresses the immune Suppresses the immune

systemsystem Targets & depletes B-cells Targets & depletes B-cells

from the bloodfrom the blood

A potential new therapy for MSA potential new therapy for MS Not FDA approved at this timeNot FDA approved at this time

Backround Definitions:Backround Definitions:

1.1. ANTIBODIES:ANTIBODIES: proteins that identify and proteins that identify and neutralize foreign particles (bacteria and neutralize foreign particles (bacteria and viruses)viruses)

2.2. MONOCLONAL ANTIBODIES:MONOCLONAL ANTIBODIES: a collection of a collection of antibodies that are identical & specific in their antibodies that are identical & specific in their function function

3.3. B-cells:B-cells: • Become plasma cells which produce Become plasma cells which produce

antibodiesantibodies• Help regulate other cells of the immune Help regulate other cells of the immune

system (including T-cells)system (including T-cells)4.4. T-cells:T-cells: the major regulators of the immune the major regulators of the immune

system and inflammatory processes system and inflammatory processes

B-cell Functions

Rituxan:Rituxan: Collection of antibodies specifically Collection of antibodies specifically

designed to bind to and destroy B-cells designed to bind to and destroy B-cells

Clinical Uses:Clinical Uses:Autoimmune disordersAutoimmune disordersB-cell cancers B-cell cancers

– non-Hodgkin’s lymphomas & leukemianon-Hodgkin’s lymphomas & leukemia

Over 500,000 patients and 1,000,000 Over 500,000 patients and 1,000,000 exposuresexposures

10 year track record10 year track record

B-Cells abnormalities in MSB-Cells abnormalities in MS

B-cells have a significant role in MSB-cells have a significant role in MS A subset of MS patients have A subset of MS patients have

prominent B-cell involvement prominent B-cell involvement (clinical & pathological data)(clinical & pathological data)

In the laboratory: In the laboratory: OLIGOCLONAL OLIGOCLONAL BANDSBANDS in cerebrospinal fluid are a in cerebrospinal fluid are a hallmark of MShallmark of MS– Consists of antibodiesConsists of antibodies– Produced by plasma cells (which come Produced by plasma cells (which come

from B-cells) in the brain and spinal cordfrom B-cells) in the brain and spinal cord

Primary mechanism of Primary mechanism of action of Rituximabaction of Rituximab

Binds to a protein Binds to a protein called called CD-20CD-20 (located on the (located on the surface of B-surface of B-cells)cells)

Causes Causes destruction of the destruction of the B-cellsB-cells

B-cells & T-cells B-cells & T-cells InteractInteract

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

Rituximab also affects T-Rituximab also affects T-cellscells

At 24 weeks after treatment:

B-cells: reduced by 90% in CSF T-cells: reduced over 50% in CSF

B-cells in CSF depicting temporal decline after treatment with rituximab (1

patient)B-cells

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B cells

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

T-cells

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T cells

Phase I: Safety and Phase I: Safety and TolerabilityTolerability

48 week results48 week results 26 relapsing-remitting MS patients26 relapsing-remitting MS patients

Treatment protocol:Treatment protocol: – 2 dosages of 1 gram IV given 2 2 dosages of 1 gram IV given 2

weeks apartweeks apart– Repeated 6 months laterRepeated 6 months later

Side Effects in Phase I Side Effects in Phase I trial:trial:

Infusion Reactions: Infusion Reactions: Headache, chills, or infusion site Headache, chills, or infusion site

reactionsreactions Rituxan = 78% Placebo = 40%Rituxan = 78% Placebo = 40%

>95% - mild to moderate, easily >95% - mild to moderate, easily managedmanaged

Most with the first infusion Most with the first infusion Subsequent infusions had lower riskSubsequent infusions had lower risk 1 patient dropped out due to severe 1 patient dropped out due to severe

headacheheadache

Phase 2 Study: Phase 2 Study: Rituximab in Relapsing-Remitting Rituximab in Relapsing-Remitting

MSMS 48 weeks study of 104 patient48 weeks study of 104 patient Patients had at least 1 relapse in past year Patients had at least 1 relapse in past year Dosage: 2 doses of rituximab over 2 weeks Dosage: 2 doses of rituximab over 2 weeks Evaluated: Evaluated:

– Number of actively inflamed (gadolinium-Number of actively inflamed (gadolinium-enhancing) lesions on 4 monthly brain MRI enhancing) lesions on 4 monthly brain MRI scans starting at month #3scans starting at month #3

– RelapsesRelapses 6 month data released6 month data released

MRI ResultsMRI Results

Relative Reduction of actively Relative Reduction of actively inflamed lesions:inflamed lesions:

91%91%PlaceboPlacebo

(35 patients)(35 patients)RituximabRituximab(69 patients)(69 patients)

Inflamed Inflamed Lesions Lesions

(mean)(mean) 5.55.5 0.50.5

Relapse DataRelapse Data Relapse Rate: reduced by Relapse Rate: reduced by

58%58%

Relapse-free patients: Increased by 58%

• Rituximab = 86%Rituximab = 86%• Placebo = 66%Placebo = 66%

Phase II Side EffectsPhase II Side Effects Infusion reaction:Infusion reaction:

Rituximab = 10% Placebo = 14%Rituximab = 10% Placebo = 14% – None were seriousNone were serious– 97% of all adverse reaction97% of all adverse reaction

Infections:Infections: – Rituximab = 65%Rituximab = 65%– Placebo = 63%Placebo = 63%– No significant differenceNo significant difference

Phase II Trial ConclusionPhase II Trial Conclusion

Fewer actively inflamed brain Fewer actively inflamed brain lesions on monthly MRI’s lesions on monthly MRI’s

Reduced relapsesReduced relapses 2 treatments had effects for 2 treatments had effects for

at least 6 monthsat least 6 months

AdministrationAdministration

Current MS trials:Current MS trials:

2 dosages of 1 gram IV 2 dosages of 1 gram IV

given 2 weeks apartgiven 2 weeks apart

Slow infusion: around 4 to 6 Slow infusion: around 4 to 6 hourshours

Progressive Multifocal Progressive Multifocal Leukoencephalopathy Leukoencephalopathy

(PML) & Rituximab(PML) & Rituximab About 23 cases of PML in > 500,000 patientsAbout 23 cases of PML in > 500,000 patients

– All had either B-cell cancer or lupusAll had either B-cell cancer or lupus– Both diseases pose increased susceptibility for Both diseases pose increased susceptibility for

PMLPML– 3 cases in approximately 10,000 Lupus patients3 cases in approximately 10,000 Lupus patients– All were taking rituximab in combination with All were taking rituximab in combination with

chemotherapychemotherapy

Risk in MS and other neurological diseasesRisk in MS and other neurological diseases– Has never happenedHas never happened

Concluding Remarks:Concluding Remarks:

A potentially promising new therapy for MSA potentially promising new therapy for MS– marked beneficial effect on RRMS in 6 month marked beneficial effect on RRMS in 6 month

datadata– Unique mechanism of actionUnique mechanism of action– Benefited the majority (not a subset) of Benefited the majority (not a subset) of

patientspatients– Early data may put it on par with TysabriEarly data may put it on par with Tysabri– Study underway for Primary Progressive MSStudy underway for Primary Progressive MS

Convenient dosingConvenient dosing Well-toleratedWell-tolerated 10-year history10-year history

Future Directions:Future Directions: Complete adequate studies to achieve Complete adequate studies to achieve

FDA approvalFDA approval Identify which patients will respond bestIdentify which patients will respond best Assess the long-term safety & efficacyAssess the long-term safety & efficacy Establish the ideal dose and frequencyEstablish the ideal dose and frequency Assess the safety and efficacy of Assess the safety and efficacy of

combination therapy combination therapy Development of new B-cell therapies Development of new B-cell therapies

with fewer side effects and stronger with fewer side effects and stronger effecteffect