Therapeutic Mechanism of Action (MOAs) in MS: Targeting T- and B-cells to Reset the Immune System

Learning Objectives

• Explore emergent concepts in the management of MS, focusing on targeting T- and B-cells including:
  • Risks associated with continuous immunosuppression
  • Action on the inflammatory activity in the CNS compartment
• Review the benefit/risk strategies in selecting therapy for MS patients while assessing treatment regimens that carry acceptable or diminished risk of disease progression
• Identify strategies that simplify patient dosing and side effects to:
  • Increase treatment compliance
  • Improve patients’ quality of life
  • Slow disease progression

Treatment: Immunomodulation Type

Treatment: General Immunosuppression Type

Treatment: Immune-selective Intervention – Blockade Type

Treatment: Immune-selective Intervention – Depleting Type

Variation in the Human Immune System is Largely Driven by Non-heritable Influences

Variation in the Human Immune System is Largely Driven by Non-heritable Influences

• 77% dominated by non-heritable influences
• 58% almost completely determined by external factors
• Parameters become more variable with age - suggesting cumulative influence of environmental exposure
• Individualizing treatments becomes more and more necessary

MS Immunomodulatory Treatments

Of the 4 compounds in routine MS treatment, each induced unique constellations of immune deviations, which offers perspectives to the challenge of personalized medicine.

CNS-Compartmentalized Inflammatory Injury Plays a Key Role in MS

Is there a need for a MS therapy with evidence of direct action on the inflammatory activity in the CNS compartment?

Risks Associated with Prolonged or Continuous Immunosuppression

T cells and B cells play critical roles in MS, and therapies targeting lymphocytes have a clinical effect ¹

Phase 3 Trials of DMDs in Progressive MS

When inflammation is compartmentalized in the CNS, drugs that cannot cross the blood–brain barrier have no significant effect on the disease course ¹

The Crucial Role of B-Cells in MS 

B cells and the Brain

Involvement of B Cells in the Pathogenesis of Multiple Sclerosis

B Cells Play Key Functional Roles in MS

B Cells Express Different Surface Markers  Throughout Development

Reduction in Pre-specified Pooled Analysis of Confirmed Disability Progression (CDP) at 12 and 24 Weeks with IFN Β-1a

Actions of Four Key MS Medications

• Alemtuzmab
• Daclizumab
• Ocrelizumab
• Cladribine

Alemtuzumab: A Humanized Monoclonal Antibody Approved for Treatment of Patients with Active RRMS

• A humanized monoclonal antibody that selectively targets CD52, a protein abundant on the surface of B and T lymphocytes1
• Novel dosing regimen: administered 12 mg/day via intravenous (IV) infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later2,3
• Approved for adult patients with relapsing-remitting MS (RRMS) with active disease defined by clinical or imaging features4
• First approved - EU in 20135*

Daclizumab (CD25) blockade induces a shift of IL-2 signalling from activated T-cells to CD56-bright NK cells

Ocrelizumab in RMS Superior Efficacy, Similar Safety to Rebif 

Cladribine

Cladribine was designed by adding 1 chlorine atom to deoxyadenosine, making it largely resistant to degradation by ADA

Cladribine Enters Cells to be Activated and Exerts Its Effect

Cladribine works by a 4-step mechanism:

• Cladribine enters cell via nucleoside transporter
• Accumulates intracellularly due to ADA resistance
• Cladribine is activated by specific kinases
• Activated Cladribine induces selective lymphocyte reduction

Cladribine Selectivity for Lymphocytes is Due to Preferential Intracellular Activation in B and T Cells

Treatment With Cladribine Tablets Leads to Specific, Discontinuous Reduction in Lymphocyte Counts

Arrows show cladribine tablet dosing. aReductions in absolute lymphocyte counts (lymphopenia) were graded according to the Common Terminology Criteria for Adverse Events: 1, <lower limit of normal to 800/mm3; 2, <800 to 500/mm3; 3, <500 to 200/mm3; 4, <200/mm3.bLymphocyte count data were not available for all patients at every observation. cCentral laboratory reference range. Error bars represent 5–95 percentile range for cell counts at each time point. AE, adverse event; BL, baseline; LA, last assessment; MoA, mechanism of action. Figure reproduced with permission from Giovannoni G et al. N Engl J Med 2010;362:416–26 (supplementary). Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

Significant Reduction in Annualized Relapse Rate vs Placebo Over 2 Years (Primary Endpoint)

A relapse was defined as an increase of 2 points in at least one functional system of the EDSS or an increase of 1 point in at least two functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for at least 24 hours and to have been preceded by at least 30 days of clinical stability or improvement. RR, relative reduction. Intent-to-treat population. Figure reproduced with permission from Giovannoni G et al. N Engl J Med 2010;362:416–26. Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

Significant Delay in Time to 3-month Confirmed Disability Progression

^aThe hazard ratio, 95% CI and p-values were estimated using Cox proportional hazards model with fixed effects for treatment group and region. Intent-to-treat population CI, confidence interval; RR, risk reduction.
Giovannoni G et al. N Engl J Med 2010;362:416–26 

Summary

• In general MS DMTs modify the course of MS by
  • immunomodulation
  • generalised immunosuppression
  • reduced trafficking of T & B cells into the CNS
  • immunodepletion
• Some DMTs may act within the CNS
• Recently licensed and emerging DMTs include:
  • Oral cladribine (purine nucleoside analogue)
  • Alemtuzumab (anti-CD52)
  • Daclizumab (anti-CD25)
  • Ocrelizumab (anti-CD20)

This resource is supported by an educational grant from Merck KGaA, Darmstadt, Germany.