The Evolving Landscape of MS Therapy New Frontiers in Managed Care Pharmacy Practice Emerging Challenges on the Therapeutic Landscape of Multiple Sclerosis

The Evolving Landscape of MS The Evolving Landscape of MS TherapyTherapy

New Frontiers in Managed Care Pharmacy PracticeNew Frontiers in Managed Care Pharmacy Practice

Emerging Challenges Emerging Challenges on the on the Therapeutic Landscape Therapeutic Landscape ofof Multiple Multiple

SclerosisSclerosis

The Managed Care Pharmacy and Medical The Managed Care Pharmacy and Medical Director’s PerspectiveDirector’s Perspective

Program ChairmanProgram ChairmanDouglas R. Jeffery, MD, PhDDouglas R. Jeffery, MD, PhDDirector, Multiple Sclerosis CenterDirector, Multiple Sclerosis Center

Advance NeurologyAdvance NeurologyAdvance, NCAdvance, NC

CME-certified symposium CME-certified symposium jointly jointly sponsored by the University of sponsored by the University of Massachusetts Medical School and Massachusetts Medical School and CMEducation Resources, LLCCMEducation Resources, LLC

Commercial Support: Commercial Support: Supported by an Supported by an independent educational grant from independent educational grant from Teva Neuroscience, Inc.Teva Neuroscience, Inc.

Faculty disclosures: Faculty disclosures: Listed in program Listed in program syllabussyllabus

NOTENOTE: Both trade and chemic names : Both trade and chemic names may be used in this program to may be used in this program to establish clarity, and because many establish clarity, and because many trials use acronyms that employ the trials use acronyms that employ the brand name. The use of brand names brand name. The use of brand names should not be construed as should not be construed as endorsements for these products.endorsements for these products.

Welcome and Program Overview Welcome and Program Overview

Program FacultyProgram Faculty

Program ChairmanProgram ChairmanDouglas R. Jeffery, MD, PhDDouglas R. Jeffery, MD, PhDDirector, Multiple Sclerosis CenterDirector, Multiple Sclerosis CenterAdvance NeurologyAdvance NeurologyAdvance, NCAdvance, NC

Norman Kachuck, MDNorman Kachuck, MDAssociate Professor of NeurologyAssociate Professor of NeurologyChief, Neuroimmunology Division, Chief, Neuroimmunology Division, Department of Neurology Department of Neurology Director, Multiple Sclerosis Director, Multiple Sclerosis Comprehensive Care Center and Comprehensive Care Center and Research Group Research Group Vice-Chair, Health Sciences IRB Vice-Chair, Health Sciences IRB University of Southern California Keck University of Southern California Keck School of Medicine School of Medicine Los Angeles, California Los Angeles, California

Ronald J. DeBellis, PharmD, FCCPProfessor and ChairmanDepartment of Pharmacy Practice-Vermont CampusAlbany College of Pharmacy and Health SciencesColchester, VT Jacquelyn Bainbridge, Jacquelyn Bainbridge, PharmD, FCCPPharmD, FCCPAssociate ProfessorDepartment of Clinical Pharmacy/Department of NeurologyUniversity of Colorado DenverAurora, CO

Program Agenda and FormatProgram Agenda and Format 8:00 AM — 8:20 AM8:00 AM — 8:20 AMWelcome and IntroductionWelcome and IntroductionThe Evolving and Complex Therapeutic The Evolving and Complex Therapeutic Landscape for Multiple Sclerosis: Achieving Landscape for Multiple Sclerosis: Achieving the Ideal Balance Between Safety and the Ideal Balance Between Safety and Efficacy for Long-Term Treatment In the Efficacy for Long-Term Treatment In the Managed Care SettingManaged Care Setting What Will Goals of MS Management in the What Will Goals of MS Management in the Managed Care Setting Be? How Should MCO Managed Care Setting Be? How Should MCO Pharmacists, Medical Directors, and Neurologists Pharmacists, Medical Directors, and Neurologists Respond?Respond?

Program ChairmanProgram ChairmanDouglas R. Jeffery, MD, PhDDouglas R. Jeffery, MD, PhDDirector, Multiple Sclerosis Center Director, Multiple Sclerosis Center │ │ Advance Neurology Advance Neurology │ │ Advance, NCAdvance, NC

8:20 AM — 8:40 AM8:20 AM — 8:40 AMGroup Discussion: Discuss Emerging Group Discussion: Discuss Emerging Concerns, Challenges, and Strategic Needs Concerns, Challenges, and Strategic Needs for Optimizing MS Care in the Managed for Optimizing MS Care in the Managed Care EnvironmentCare Environment

Program Agenda and FormatProgram Agenda and Format 8:40 AM — 9:05 AM8:40 AM — 9:05 AMTrial-Based Evidence for First Line Therapy with Trial-Based Evidence for First Line Therapy with Immune- Modulating Agents (IMTs): From Immune- Modulating Agents (IMTs): From Mechanisms to Therapy—Landmark Studies, Mechanisms to Therapy—Landmark Studies, Long-Term Safety Data, and Clinical Experience Long-Term Safety Data, and Clinical Experience with IMTs in the Managed Care Environmentwith IMTs in the Managed Care Environment Current Foundations of MS Care in the Managed Care Current Foundations of MS Care in the Managed Care Setting: What Has Worked? What Hasn’t? Where Is the Setting: What Has Worked? What Hasn’t? Where Is the Room for Improvement?Room for Improvement?

Program ChairmanProgram ChairmanDouglas R. Jeffery, MD, PhDDouglas R. Jeffery, MD, PhDDirector, Multiple Sclerosis Center Director, Multiple Sclerosis Center │ │ Advance Neurology Advance Neurology │ │ Advance, NCAdvance, NC

9:05 AM — 9:20 AM9:05 AM — 9:20 AMGroup Discussion:Group Discussion: Discuss Current Strategies Discuss Current Strategies and MS Treatment Paradigms Using IMT-Based and MS Treatment Paradigms Using IMT-Based Platforms for Initial Therapy for MS in the Platforms for Initial Therapy for MS in the Managed Care SettingManaged Care Setting

Program Agenda and FormatProgram Agenda and Format

9:20 AM — 9:45 AM9:20 AM — 9:45 AMThe Emergence of Oral Immunosuppressive The Emergence of Oral Immunosuppressive and Other Agents for MS: What Do We Know and Other Agents for MS: What Do We Know (or Not Know) About Their Safety and Efficacy?(or Not Know) About Their Safety and Efficacy? Cautionary Notes for Managed Care Pharmacy and Cautionary Notes for Managed Care Pharmacy and Medical Directors, and MS Treaters in Managed Care: Medical Directors, and MS Treaters in Managed Care: How Do We Monitor Adverse Events, Risks for How Do We Monitor Adverse Events, Risks for Infection, and Signals for Malignancy Over the Long Infection, and Signals for Malignancy Over the Long Term?Term?

Norman Kachuck, MDNorman Kachuck, MDAssociate Professor of Neurology Associate Professor of Neurology │ │ Chief, Neuroimmunology Chief, Neuroimmunology Division, Division, Department of Neurology Department of Neurology │ │ Director, Multiple Sclerosis Director, Multiple Sclerosis Comprehensive Care Comprehensive Care │ │ Center and Research Group Center and Research Group │ │ Vice-Vice-Chair, Health Sciences IRB Chair, Health Sciences IRB │ │ University of Southern University of Southern California Keck School of Medicine California Keck School of Medicine │ │ Los Angeles, CaliforniaLos Angeles, California

9:45 AM — 10:00 AM9:45 AM — 10:00 AMGroup Discussion: Discuss Complexity of Group Discussion: Discuss Complexity of Evolving Agents for MS and Approaches to Evolving Agents for MS and Approaches to Making a Risk-Benefit AnalysisMaking a Risk-Benefit Analysis

Program Agenda and FormatProgram Agenda and Format

10:00 AM — 10:20 AM10:00 AM — 10:20 AMThe Changing MS Therapeutic The Changing MS Therapeutic Landscape: Perspectives of an MS-Landscape: Perspectives of an MS-Focused Pharmacist—How Will We Focused Pharmacist—How Will We Need to Adapt to and Analyze the New Need to Adapt to and Analyze the New Generation of MS Therapies?Generation of MS Therapies? How Will Pharmacy and Medical/Neurology How Will Pharmacy and Medical/Neurology Program Directors Come Together to Make Program Directors Come Together to Make Decisions About Long-Term Therapy for MS Decisions About Long-Term Therapy for MS in the Managed Care Setting?in the Managed Care Setting?

Ronald J. DeBellis, PharmD, FCCPRonald J. DeBellis, PharmD, FCCPProfessor and Chairman Professor and Chairman │ │ Department of Pharmacy Practice-Vermont Department of Pharmacy Practice-Vermont CampusCampus │ │ Albany College of Pharmacy and Health SciencesAlbany College of Pharmacy and Health Sciences │ │ Colchester, VTColchester, VT

10:20 AM — 10:40 AM10:20 AM — 10:40 AMGroup Discussion: The Near Future of Group Discussion: The Near Future of MS CareMS Care

Program Agenda and FormatProgram Agenda and Format10:40 AM — 11:00 AM10:40 AM — 11:00 AMThe Role of Comparative Effectiveness The Role of Comparative Effectiveness Guidelines, Long Term Safety Considerations, Guidelines, Long Term Safety Considerations, and Monitoring Costs for Evaluating Therapies and Monitoring Costs for Evaluating Therapies for MSfor MS Impact on Managed Care-Based Management for Impact on Managed Care-Based Management for Improving Health Outcomes and Providing Value for Improving Health Outcomes and Providing Value for their Health Plans—The Managed Care Medical and their Health Plans—The Managed Care Medical and Pharmacy Director’s PerspectivePharmacy Director’s Perspective

Jacquelyn Bainbridge, PharmD, FCCPJacquelyn Bainbridge, PharmD, FCCPAssociate Professor │ Department of Clinical │ Pharmacy/ Associate Professor │ Department of Clinical │ Pharmacy/ Department of Neurology │ University of Colorado Department of Neurology │ University of Colorado Denver │ Aurora, CODenver │ Aurora, CO

11:00 AM — 11:30 AM11:00 AM — 11:30 AMGroup Discussion: The Complexities, Group Discussion: The Complexities, Challenges and Solutions for Making Sense and Challenges and Solutions for Making Sense and Adapting to the Emerging Landscape—and Adapting to the Emerging Landscape—and New Risk/Benefit Equations—of Oral Agents for New Risk/Benefit Equations—of Oral Agents for MS. Will Patient Registries Be Required?MS. Will Patient Registries Be Required?

Format: We Want a Dialogue Format: We Want a Dialogue

PROGRAM FORMATPROGRAM FORMAT

Following each didactic presentation, we will call Following each didactic presentation, we will call upon the regional and local leaders in the managed upon the regional and local leaders in the managed care community—pharmacy, medical and care community—pharmacy, medical and department of neurology directors who are seated at department of neurology directors who are seated at the faculty table—to respond, analyze and discuss the faculty table—to respond, analyze and discuss how they and their colleague are responding to how they and their colleague are responding to these new challenges and dilemmas. these new challenges and dilemmas.

We thank them for coming and participating as We thank them for coming and participating as adjunct faculty members and educational leaders for adjunct faculty members and educational leaders for this program.this program.

The Group Discussions are key to helping us The Group Discussions are key to helping us complete the journey form “challenges” to real world complete the journey form “challenges” to real world “solutions.”“solutions.”

CNS = central nervous system.CNS = central nervous system.Compston A, et al. Compston A, et al. LancetLancet. 2002;359(9313):1221-1231. Frohman EM. . 2002;359(9313):1221-1231. Frohman EM. Med Clin N AmMed Clin N Am. 2003;87(4): . 2003;87(4): 867-897. Hogancamp WE, et al. 867-897. Hogancamp WE, et al. Mayo Clin Proc.Mayo Clin Proc. 1997;72(9):871-878. National Multiple Sclerosis Society. 1997;72(9):871-878. National Multiple Sclerosis Society. Who gets MS? http://www.nationalmssociety.org/about-multiple-sclerosis/who-gets-ms/index.aspx. Accessed Who gets MS? http://www.nationalmssociety.org/about-multiple-sclerosis/who-gets-ms/index.aspx. Accessed

January 8, 2009. January 8, 2009. Lage MJ, et al. Lage MJ, et al. WorkWork. 2006;27(2):143-151. 2006;27(2):143-151.

Epidemiology of Multiple SclerosisEpidemiology of Multiple Sclerosis

► The most common chronic disease affecting the CNS in The most common chronic disease affecting the CNS in young adults young adults

► Approximately 400,000 cases in the United StatesApproximately 400,000 cases in the United States● Estimates range from 250,000 to 500,000Estimates range from 250,000 to 500,000

► The chances of developing MS are 1:1000 in the general The chances of developing MS are 1:1000 in the general populationpopulation

► Estimated 2.5 million cases worldwideEstimated 2.5 million cases worldwide

► Highest incidence in Caucasians Highest incidence in Caucasians

► Higher incidence in women (approximately 3:1)Higher incidence in women (approximately 3:1)

► MS strikes individuals between the ages 20-50, normally a MS strikes individuals between the ages 20-50, normally a time of peak productivitytime of peak productivity

Age of Onset of Multiple SclerosisAge of Onset of Multiple Sclerosis

Cardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):727-730.

0

5

10

15

20

25

30

35

0-10 11-20 21-30 31-40 41-50 51-60

YearsYears

Pati

ents

(%

)Pati

ents

(%

)

Distribution of Patients According toDistribution of Patients According tothe Decade of Life of MS Symptoms Onsetthe Decade of Life of MS Symptoms Onset

National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/index.aspx. Accessed February 21, 2010.

Clinical Manifestations of MSClinical Manifestations of MS

► FatigueFatigue

► PainPain

► DepressionDepression

► Numbness/Numbness/paresthesiasparesthesias

► Cognitive dysfunctionCognitive dysfunction

► WeaknessWeakness

► SpasticitySpasticity

► Optic neuritisOptic neuritis

► Bladder dysfunctionBladder dysfunction

► Bowel dysfunctionBowel dysfunction

► Cerebellar Cerebellar dysfunctiondysfunction

► Sexual dysfunctionSexual dysfunction

► Gait abnormalitiesGait abnormalities

► Partial/complete Partial/complete paralysisparalysis

Natural History of MS and Cost of Natural History of MS and Cost of MSMS

*Curve is based on an estimation of the decrease in cost for early treatment of about 40% at each range of EDSS

Burks J. J Manag Care Med. 2008;12(1):26-31. [Exhibit 8].Comi G. Neurol Sci. 2006;27:S8-S12.Kobelt G, et al. Neurology. 2006;66(11):1696-1702.

CIS RRMS SPMSPre-clinical

Predicted Cost

Early Intervention*

MRI lesion activity

Clinical Threshold

Atrophy and Axonal Degradation

US

$ pe

r Y

ear

US

$ pe

r Y

ear

EDSS = Expanded Disability Status Scale. EDSS = Expanded Disability Status Scale. Kurtzke JF. Kurtzke JF. NeurologyNeurology. 1983;33:1444-1452.. 1983;33:1444-1452.

Progression of Disability: EDSSProgression of Disability: EDSS

8.0–8.5 = Confined to bed or chair8.0–8.5 = Confined to bed or chair

7.0–7.5 = Confined to wheelchair7.0–7.5 = Confined to wheelchair

6.0–6.5 = Walking assistance is needed6.0–6.5 = Walking assistance is needed

5.0–5.5 = Increasing limitation in ability to walk5.0–5.5 = Increasing limitation in ability to walk

4.0–4.5 = Disability is moderate4.0–4.5 = Disability is moderate

3.0–3.5 = Disability is mild to moderate3.0–3.5 = Disability is mild to moderate

2.0–2.5 = Disability is minimal2.0–2.5 = Disability is minimal

1.0–1.5 = No disability1.0–1.5 = No disability

0 = Normal neurologic exam0 = Normal neurologic exam

Increasing disease burden

10.0 = Death due to MS

9.0–9.5 = Completely dependent

Baseline Brain MRI Lesion NumberBaseline Brain MRI Lesion Number20-Year Clinical Status20-Year Clinical Status

Fisniku LK. Brain 2008;131:808-817.

Baseline Brain MRI Lesion NumberBaseline Brain MRI Lesion Number20-Year Clinical Status20-Year Clinical Status

Fisniku LK. Brain 2008;131:808-817.

TregTh2/Th3

MO

IL-4IL-5IL-6

IL-13TGF

B

HistamineProteases

TNFNAA, ATP

NOO2

5-HT

Mast Cell

IL-12

APC

Thp

CD4

CD40LCD40

IL-4 & IL-10

CD4APCThp

CD28B7

Th2/Th3

B7

CD40

MicrogliaCD40L

CD28

Th1Th17

B

Glutamate

TCD8

MMP-2/9

VCAM-1ICAM-1 VCAM-1

IFNTNFIL-17

IL-10TGF

Ab+C9neo

CD8

Mast Cell

T

Granutocyte

Complement

Monocyte

Pl

Figure courtesy of Dhib-Jalbut S, 2008

Immunopathogenesis of the MS LesionImmunopathogenesis of the MS Lesion

IFNTNFTh17

NOOi

TNFaMMP

LFA-1VLA-4Th1

Th17

Oligo

BBB

MCP-1MIP-1P-10

RANTES

Astrocyte

IL-23

Treg

CD4+CD25+

Myelin AgMicrobial Ag

HLA

Virus

TCR

Trends Across MS Clinical TrialsTrends Across MS Clinical TrialsAnnualized Relapse Rate (ARR)Annualized Relapse Rate (ARR)

Johnson1995

Polman2006

REGARD2007

BECOME2007

KapposTRANSFORMS

Jacobs1996

IFNββ-1b study

group,1993

PRISMS-21998

BEYOND2007

CAMMS2232008

3 years

HERMES2008

48 weeks

FORTE20081 year

CLARITY2009

Goals of TreatmentGoals of Treatment

► Reduce frequency of relapseReduce frequency of relapse

► Slow progression of disabilitySlow progression of disability

► Reduce MRI activityReduce MRI activity

► Prevent morbidity from symptoms and Prevent morbidity from symptoms and provide palliative careprovide palliative care

► Maintain adherenceMaintain adherence

► Provide long-term efficacy and safety Provide long-term efficacy and safety

Existing and Emerging MS TherapiesExisting and Emerging MS Therapies

20052005 2011201120062006 20072007 20102010 20122012 20132013

Injectables

IV

Generic Mitoxantrone (oncology) (MS)


TysabriTysabri

Rebif

Filed

Approved In phase II

In phase III

Cladribine

AmpyraAmpyra

BG12

Teriflunomide

Laquinimod

Ocrelizumab

IV

Alemtuzumab

Oral

ExtaviaExtavia

Rebif

Betaseron

Copaxone

Avonex

Novantrone

Ampyra

Extavia

Tysabri

BG12Cladribine

Fingolimod

OcrelizumabOcrelizumab

TeriflunomideTeriflunomide

LaquinimodLaquinimod

AlemtuzumabAlemtuzumab

GenericMitoxantrone

(oncology) MS


► New generation of multiple sclerosis therapies New generation of multiple sclerosis therapies is currently emergingis currently emerging

► Among them are four oral agents: Among them are four oral agents: dalfampridine, laquinimod, cladribine, and dalfampridine, laquinimod, cladribine, and fingolimod, that have been or likely will be fingolimod, that have been or likely will be approved for managing patients with MSapproved for managing patients with MS

► Efficacy data for these new oral agents are Efficacy data for these new oral agents are impressive and demonstrate that they have the impressive and demonstrate that they have the potential to replace or complement injectable potential to replace or complement injectable treatment options for MStreatment options for MS


►However, there are concerns relating to safety However, there are concerns relating to safety and cost, especially for the immunosuppressive and cost, especially for the immunosuppressive agentsagents

►In addition, patients with MS have poor In addition, patients with MS have poor treatment adherence to the current available treatment adherence to the current available therapies and it is uncertain if the introduction of therapies and it is uncertain if the introduction of oral agents will increase patient adherenceoral agents will increase patient adherence

Analyzing Risk-to-Benefit Equation forAnalyzing Risk-to-Benefit Equation forEstablished and Emerging AgentsEstablished and Emerging Agents

Questions We Will Address Today Questions We Will Address Today

1.1. How has your organization decided to How has your organization decided to provide and make decisions about MS care?provide and make decisions about MS care?

2.2. Who makes these decisions? A formulary Who makes these decisions? A formulary committee? Department of Pharmacy? committee? Department of Pharmacy? Neurologists and MS Specialists? A Neurologists and MS Specialists? A consensus among many stakeholders?consensus among many stakeholders?

3.3. Are all MS drugs available in your managed Are all MS drugs available in your managed care organization? Or have you made care organization? Or have you made restrictions and/or prioritized agents? And if restrictions and/or prioritized agents? And if so, how and why?so, how and why?


4.4.Do you employ a formalized pathway for MS Do you employ a formalized pathway for MS care in your MCO? For first-line treatment? care in your MCO? For first-line treatment? Second line treatment? Or are these decisions Second line treatment? Or are these decisions left to the treating physicians?left to the treating physicians?

5.5.What is the patient's role in determining the What is the patient's role in determining the initial MS therapy offered to them? Is it a initial MS therapy offered to them? Is it a dialogue? If so, what is the shape of the dialogue? If so, what is the shape of the dialogue? If not, how is the decision made? dialogue? If not, how is the decision made?


MISSION STATEMENTMISSION STATEMENT The purpose of this “Challenges and Solutions” The purpose of this “Challenges and Solutions” Workshop is to discuss possible approaches for Workshop is to discuss possible approaches for evaluating the risk-benefit-cost profiles of these new evaluating the risk-benefit-cost profiles of these new oral agents; to compare them against established oral agents; to compare them against established IMTs and each other; to evaluate the implications for IMTs and each other; to evaluate the implications for long-term safety monitoring and pharmacovigilance long-term safety monitoring and pharmacovigilance that will be required, especially for that will be required, especially for immunosuppressive agents; how placement of these immunosuppressive agents; how placement of these oral agents on managed care organization (MCO) oral agents on managed care organization (MCO) formularies may also influence and/or modify use of formularies may also influence and/or modify use of established IMTs; and what impact this landscape established IMTs; and what impact this landscape change might have on clinical outcomes of MS change might have on clinical outcomes of MS patients managed in MCOs.patients managed in MCOs.

The Evidence for First Line The Evidence for First Line Therapy with Immune-Therapy with Immune-

Modulating AgentsModulating AgentsLandmark Trials, Perils and Pitfalls of Landmark Trials, Perils and Pitfalls of

Cross-Trial Comparisons, and What can Cross-Trial Comparisons, and What can be Learned from Long Term Studiesbe Learned from Long Term Studies

Investigations • Innovation • Clinical ApplicationInvestigations • Innovation • Clinical Application

Program ChairmanProgram ChairmanDouglas R. Jeffery, MD, PhDDouglas R. Jeffery, MD, PhDDirector, Multiple Sclerosis CenterDirector, Multiple Sclerosis Center

Advance NeurologyAdvance NeurologyAdvance, NCAdvance, NC

Overview of PresentationOverview of Presentation

► Mechanisms of action of IMTsMechanisms of action of IMTs

► Outcome measures in clinical trialsOutcome measures in clinical trials

► Comparison of landmark trialsComparison of landmark trials

► Longitudinal studies: what do they tell Longitudinal studies: what do they tell us?us?

► Price of MS versus cost of treatmentPrice of MS versus cost of treatment

Mechanisms of Mechanisms of ActionAction


IFN-IFN-: Activity: Activity

TH1+

RestingT cell

MMP

Activated (+)T cells

TH1+

TH1+

MMP

BBBBlood CNS

TNF-α IFN-γ

IL-2

TH1APC APC

IFN-β

IFN-β

MyelinproteinAntigen

TH1+

Adapted from Yong VW. Adapted from Yong VW. NeurologyNeurology. 2002;59:802-808.. 2002;59:802-808.

Glatiramer Acetate: ActivityGlatiramer Acetate: Activity

Adapted from Ziemssen T et al. J Neurol Sci. 2005;233:109-112.Adapted from Ziemssen T et al. J Neurol Sci. 2005;233:109-112.

BBB

GA-specificT cell

APC

GA

ther

apy

TH1 TH2

APC

Microglia

MHC

CNS Ag

TCR

Macrophage

Periphery CNS

TH2

MHC

GA

TCR

Neuroregeneration

Bystandersuppression

effect

Anti-inflammatory cytokines

Neurotrophins+ +

TCRIL-4

IL-10

BDNF

Fingolimod: modulates S1P1 Fingolimod: modulates S1P1 receptorsreceptors

T cell FTY720-P

S1P receptor

FTY720 results in internalisation

of the S1P1 receptor

This blocks lymphocyte egress from lymph nodes while sparing

immune surveillance by circulating memory T cells

Prevents T cell invasion of CNS

LN

FTY720 traps circulating lymphocytes in peripheral lymph nodes

Laquinimod Induced Immunomodulation Laquinimod Induced Immunomodulation on the Molecular Level on the Molecular Level

Overexpression/downregulation

Low (0-1 attacks in 2 years)Low (0-1 attacks in 2 years)

Intermediate (2-4 attacks in 2 years)Intermediate (2-4 attacks in 2 years)

High (High (>> 5 in 2 years) 5 in 2 years)

Weinhenker B et al. Brain. 1989;112:1422Weinhenker B et al. Brain. 1989;112:1422

Long-Term DisabilityLong-Term DisabilityEffect of Early RelapsesEffect of Early Relapses

50504040303020201010

2020

00

00

4040

6060

8080

100100

Time from onset of MS (years)Time from onset of MS (years)

Per

cent

Pts

DS

S <

6P

erce

nt P

ts D

SS

< 6

p < 0.0001p < 0.0001

Relapses in Multiple SclerosisRelapses in Multiple Sclerosis

► Relapses are the most obvious evidence of Relapses are the most obvious evidence of inflammatory disease activity in RRMS inflammatory disease activity in RRMS

► Relapse frequency in typical untreated Relapse frequency in typical untreated RRMS populations enables treatment effect RRMS populations enables treatment effect to be rapidly assessable in a 12-month to be rapidly assessable in a 12-month clinical studyclinical study

Total number of relapses during the study periodTotal in-study person-years

ITT populationNegative binomial regression model adjusted for treatment group, country, number of relapses in previous two years and baseline Expanded Disability Status ScaleARR, annualized relapse rate; DMT, disease-modifying therapy

0.160.160.180.18

0.400.40

0

0.1

0.2

0.3

0.4

Ann

ualiz

ed r

elap

se r

ate

Placebo (n=418)

Fingolimod 0.5 mg(n=425)

Fingolimod 1.25 mg(n=429)

ARR was consistently reduced in both treatment-naïve patients and patients previously treated with DMT (p<0.01 for all comparisons)

p<0.001p<0.001

54% reduction

60% reduction

FREEDOMSFREEDOMS

Primary Endpoint: Annualized Relapse RatePrimary Endpoint: Annualized Relapse Rate

Effect on Annualized Relapse Rates: Effect on Annualized Relapse Rates: Summary of Phase III Trials – 2 years in-studySummary of Phase III Trials – 2 years in-study

% R

educ

tion

in r

elap

se r

ates

% R

educ

tion

in r

elap

se r

ates

N.B.: Results are from separate clinical trialsJacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655; IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277; Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701; PRISMS Study Group. Lancet. 1998;352:1498; Rebif package insert.Kappos et al. N Engl J Med 2010;362:387-401; Gilenya package insert.

31%

18%

29% 29%32%

60%

P=.0001

P=.04

P<.001P<.0001

P=.055

P<.0001

*In 224 placebo patients from the NMSS task force on clinical outcome assessment. EDSS = Expanded Disability Status Scale; NMSS = National Multiple Sclerosis Society.Lublin FD, et al. Neurology. 2003;61:1528-1532.

Relapses Can Result inRelapses Can Result inResidual Long-Term DisabilityResidual Long-Term Disability

Net Change in EDSS Score from before a Relapse to after a Relapse*Net Change in EDSS Score from before a Relapse to after a Relapse*

42% of patients had a residual deficit ≥0.5 point% of patients had a residual deficit ≥0.5 point28% had a residual deficit ≥1.0 point28% had a residual deficit ≥1.0 point

42.4% increase 0.5 or more

28.1% increase 1 or more

Nu

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er o

f S

ub

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s

1 37 4

8

20

86

32 33

148 5

1 20

20

40

60

80

100

-3.5 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.5 4.0

Medical Costs Per RelapseMedical Costs Per Relapse

ED = emergency department; IV = intravenous.O’Brien J, et al. BMC Health Serv Res. 2003;3(1):17-28.

TherapistsTherapistsConsultsConsults

Follow-Up Office VisitsFollow-Up Office VisitsSymptom-Related MedicationsSymptom-Related MedicationsFollow-Up Office VisitsFollow-Up Office Visits

Hospital readmissionsHospital readmissions

Nursing homeNursing home

Skilled nursingSkilled nursing

Home healthcareHome healthcare

RehabilitationRehabilitation

Outpatient follow-upOutpatient follow-upHome administrationHome administration

Post Discharge ServicesPost Discharge ServicesHospital day caseHospital day case

Hospital AdmissionHospital AdmissionIV MethylprednisoloneIV MethylprednisoloneSymptom-Related MedicationsSymptom-Related MedicationsEDEDEDED

Usual care physicianUsual care physicianUsual care physicianUsual care physicianUsual care physicianUsual care physician

Initial ContactInitial ContactInitial ContactInitial ContactInitial ContactInitial ContactHigh-Intensity EpisodeHigh-Intensity EpisodeModerate-Intensity EpisodeModerate-Intensity EpisodeLow-Intensity EpisodeLow-Intensity Episode

$12,870$1847$243

Whetton-Goldstein K, et al. Whetton-Goldstein K, et al. Mult Scler. Mult Scler. 1998;4(5):419-425. Pope GC, et al. 1998;4(5):419-425. Pope GC, et al. NeurologyNeurology. 2002;58(1):37-43. . 2002;58(1):37-43. Kobelt G, et al. Kobelt G, et al. Neurology. Neurology. 2006;66(11):1696-1702. Patwardhan MB, et al. 2006;66(11):1696-1702. Patwardhan MB, et al. Mult Scler. Mult Scler. 2005;11(2):232-239. 2005;11(2):232-239. O’Brien JA, et al. O’Brien JA, et al. J Neurosurg Psychiatry. J Neurosurg Psychiatry. 2006;77:918-926.2006;77:918-926.

Economic ImplicationsEconomic Implications

► Annual cost of MS in the United States is estimated at Annual cost of MS in the United States is estimated at approximately $13.6 billion (in 1994 dollars)approximately $13.6 billion (in 1994 dollars)

► Total lifetime direct and indirect costs per patient are Total lifetime direct and indirect costs per patient are estimated at approximately $2.4 million (in 1994 dollars)estimated at approximately $2.4 million (in 1994 dollars)

► Mean annual direct and indirect costs per patient total Mean annual direct and indirect costs per patient total an estimated $47,215 (in 2004 dollars)an estimated $47,215 (in 2004 dollars)

► Mean direct healthcare costs incurred by insured Mean direct healthcare costs incurred by insured patients with MS are 2 to 3 times higher than those patients with MS are 2 to 3 times higher than those without MSwithout MS

► Direct correlation between cost (direct and indirect) and Direct correlation between cost (direct and indirect) and severity of disease has been well-establishedseverity of disease has been well-established

► Therapeutics that modify MS activity and severity can Therapeutics that modify MS activity and severity can result in both clinical and economic benefitsresult in both clinical and economic benefits

Is MS All About Relapses? Is MS All About Relapses?

► Hypothesis: if relapses cause long-term Hypothesis: if relapses cause long-term disability then patients with frequent disability then patients with frequent relapses should be at higher risk for relapses should be at higher risk for disabilitydisability

► From the London Ontario natural history From the London Ontario natural history studies patients with frequent attacks studies patients with frequent attacks are at highest risk for future ambulatory are at highest risk for future ambulatory disabilitydisability

► Assumption: modifying the relapse rate Assumption: modifying the relapse rate will influence long-term disabilitywill influence long-term disability

Weinshenker et al. 1989 Brain 112:1419Weinshenker et al. 1989 Brain 112:1419

Proportion of Placebo Groups Proportion of Placebo Groups with Clinical Activity with Clinical Activity

Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655; IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277; Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701; PRISMS Study Group. Lancet. 1998;352:1498.

RelapsesRelapses EDSS EDSS ProgressProgress

IFNβ-1b (3 year) 86%86% 39%39%

IFNβ-1a (QW) (2 year) 77%77% 35%35%

IFNβ-1a (TIW) (2 year) 84%84% 38%38%

Glatiramer acetate (2 year) 73%73% 25%25%

Fingolimod (2 year) 54%54% 24%24%

How is Sustained Progression How is Sustained Progression Measured?Measured?

► Most clinical trials define progression by Most clinical trials define progression by demonstrating a 1 point change in the demonstrating a 1 point change in the EDSS, and then EDSS, and then confirmingconfirming the change in the change in 3 or 6 months3 or 6 months

► Does this measure of confirmed Does this measure of confirmed progression reflect permanent disability?progression reflect permanent disability?

► If so, then confirmed changes in EDSS If so, then confirmed changes in EDSS during the course of the trial should be during the course of the trial should be sustainedsustained by the end of the study by the end of the study

Effect on Sustained Disability*: Effect on Sustained Disability*: Summary of Phase III TrialsSummary of Phase III Trials

**1 EDSS point sustained for 1 EDSS point sustained for 3 months 3 months in IFN β-1b, IFN β-1a tiw, GA trials and in IFN β-1b, IFN β-1a tiw, GA trials and fingolimod phase III trials. fingolimod phase III trials. 1 EDSS point sustained for 1 EDSS point sustained for 6 months 6 months in IFN β-a qw and in IFN β-a qw and fingolimod fingolimod phase III trials.phase III trials.

Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701PRISMS Study Group. Lancet. 1998;352:1498Kappos et al. N Engl J Med 2010;362:387-401; Gilenya package insert.

Reduct

ion in

R

educt

ion in

su

stain

ed d

isabili

ty

sust

ain

ed d

isabili

ty

pro

gre

ssio

n (

%)

pro

gre

ssio

n (

%) 29%

37%

22%

30%

12%

30%

P=NS

P=.02

P<.05

P<.05

P=NS

P=.02

SummarySummary

► Disability progression in clinical trials with RRMS Disability progression in clinical trials with RRMS patients is for the primarily related to disability from patients is for the primarily related to disability from relapsesrelapses

► Relapse rate reduction and the mean change in Relapse rate reduction and the mean change in EDSS are the most sensitive clinical outcome EDSS are the most sensitive clinical outcome measures in MS trialsmeasures in MS trials

► The generally accepted sustained change in EDSS The generally accepted sustained change in EDSS measure is not a reliable marker of long term measure is not a reliable marker of long term disability disability

► Phase III trials results showed:Phase III trials results showed: The interferons, glatiramer acetate and fingolimod reduce the The interferons, glatiramer acetate and fingolimod reduce the

relapse raterelapse rate IFN beta-1a and fingolimod have statistically significant effects on IFN beta-1a and fingolimod have statistically significant effects on

sustained change in EDSS measure over two yearssustained change in EDSS measure over two years IFN beta-1a, glatiramer acetate and fingolimod have statistically IFN beta-1a, glatiramer acetate and fingolimod have statistically

significant impacts on the mean change in EDSS over two yearssignificant impacts on the mean change in EDSS over two years

Are direct comparator studies Are direct comparator studies needed in MS or can we make needed in MS or can we make

valid conclusions from cross trial valid conclusions from cross trial comparisons?comparisons?


Cross Trial ComparisonsCross Trial ComparisonsRelative Efficacy (RR)Relative Efficacy (RR)

IFNIFNββ-1a-1a30 30 µµgg qwqw

IFNIFNββ-1b, -1b, 250 250 µµgg

qodqod

IFN IFN ββ-1a -1a 44 44 µµgg

tiwtiw

GA GA 20 mg20 mg

qdqd

Fingolimod 0.5 Fingolimod 0.5 mg qdmg qd

Relapse rate (annualized) -18%-18% -34%-34% -32%-32% -29%-29% -60%-60%

Relapse-Free (2 years) +42%+42% +95%+95% +100%+100% +36%+36% +52%+52%

Progression free -37%-37% -29%-29% -30%-30% -12%-12% -30% / -37%-30% / -37%

New T2 Lesions -36%-36% -83%-83% -78%-78% -38%-38% -75%-75%

Gd+ Lesions -42%-42% -- -88%-88% -33%-33% -82%-82%

Predict: Predict: IFNIFNββ-1a tiw will be superior to GA for relapse free outcome-1a tiw will be superior to GA for relapse free outcome

672 days (96 weeks)

IFNβ-1a tiw

GA

Time to first relapse (days)Time to first relapse (days)

Hazard ratio (95% CI): 0.943 (0.74, 1.21) p = 0.643

0 100 200 300 400 500 600 700

0.00

0.25

0.50

0.75

1.00

Sur

viva

l dis

trib

utio

n fu

nctio

nS

urvi

val d

istr

ibut

ion

func

tion

The REGARD TrialThe REGARD TrialTime to First Relapse (1Time to First Relapse (1oo endpoint) endpoint)

Head to Head Studies and Head to Head Studies and Cross Trial ComparisonsCross Trial Comparisons

► Head to head studies of glatiramer acetate and Head to head studies of glatiramer acetate and interferon interferon ββ underscore the problem with cross trial underscore the problem with cross trial comparisonscomparisons

► Differences in patients enrolled in different studies Differences in patients enrolled in different studies heavily influence disease activity observed during heavily influence disease activity observed during trialstrials

► Differences in definitions of relapses (confirmed Differences in definitions of relapses (confirmed versus non-confirmed) and disability measures (3 versus non-confirmed) and disability measures (3 month versus 6 month sustained change versus month versus 6 month sustained change versus mean change in EDSS) may be different between mean change in EDSS) may be different between studies further complicating cross trial comparisonsstudies further complicating cross trial comparisons

► Relative efficacy is best measured by well-designed Relative efficacy is best measured by well-designed head to head trialshead to head trials

What can be learned from What can be learned from long-term follow up studies?long-term follow up studies?


Long-Term Follow UpLong-Term Follow Up

► Do long-term follow up studies Do long-term follow up studies adequately address medication safety?adequately address medication safety?

► Do long-term studies adequately Do long-term studies adequately address longitudinal efficacy?address longitudinal efficacy?

► Have methods of analysis for Have methods of analysis for longitudinal studies been optimized?longitudinal studies been optimized?

BiasBias ImpactImpact StrategyStrategy

AscertainmentModified therapeutic effect dependent Modified therapeutic effect dependent on characteristics of participating on characteristics of participating patients.patients.

F/U must be as complete as possible F/U must be as complete as possible Directly compare baseline and on-Directly compare baseline and on-RCT characteristics of those patients RCT characteristics of those patients in LTF to those not in LTFin LTF to those not in LTF

InformedTherapeutic

Decisions

Inflated estimate of therapeutic benefit Inflated estimate of therapeutic benefit because patients doing well continue because patients doing well continue therapy whereas failing patients therapy whereas failing patients switch or stop therapy.switch or stop therapy.

MPR: Use percent of total possible MPR: Use percent of total possible time on therapy instead of absolute time on therapy instead of absolute time to assess exposure.time to assess exposure.

Treatment Selection

Modified therapeutic effect dependent Modified therapeutic effect dependent on patient selection characteristics.on patient selection characteristics.

Propensity Scoring: Adjust for the Propensity Scoring: Adjust for the propensity (i.e., likelihood) that a propensity (i.e., likelihood) that a particular treatment will be selected particular treatment will be selected based on available patient based on available patient characteristicscharacteristics

Multiple TestingIncreased risk of Type 1 error from the Increased risk of Type 1 error from the use of multiple predictor variables and use of multiple predictor variables and weighting schemesweighting schemes

Create a single model and apply Create a single model and apply adjustments to p-values according to adjustments to p-values according to the number of predictors tested in the the number of predictors tested in the model.model.

Sources of Bias in LTFU StudiesSources of Bias in LTFU Studies

Glatiramer Acetate 15 year LTFUGlatiramer Acetate 15 year LTFU

Ford C et al. Mult Scler. 2010;16:342-50. Ford C et al. Mult Scler. 2010;16:342-50.


Ford C et al. Mult Scler. 2010;16:342-50. Ford C et al. Mult Scler. 2010;16:342-50.


► In a small cohort of patients (N=100) In a small cohort of patients (N=100) followed for 15 years, glatiramer acetate followed for 15 years, glatiramer acetate was safe and well toleratedwas safe and well tolerated

► 65% of continuously treated patients did 65% of continuously treated patients did not progress to SPMSnot progress to SPMS

► 41% of patients withdrawing from the 41% of patients withdrawing from the study did so because of disease study did so because of disease progressionprogression● Propensity scores were used to try to adjust Propensity scores were used to try to adjust

for differences between ongoing and for differences between ongoing and withdrawing patientswithdrawing patients

► EDSS at baseline predicts EDSS at 15 EDSS at baseline predicts EDSS at 15 yearsyears

124124

125125

123123

5252

5858

5656IFNβ-1b 250 µg

IFNβ-1b 50 µg

Placebo

1988 1993

Pivotal Study (n=372)Pivotal Study (n=372)

LTF

2005

Cross-sectional investigation of:- clinical outcomes (disability, relapse rate)- imaging (brain and spinal MRI)- cognition and mood- QoL, resource use- lab parameter including NAb's and PgX

Patients under regular medical care - no trial

1990

IFN IFN ββ-1b LTFU Design-1b LTFU Design

Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666Ebers G et al. presented at AAN, October 2006: M-3Ebers G et al. presented at AAN, October 2006: M-3

IFN IFN ββ-1b LTFU Adjusted Outcome-1b LTFU Adjusted Outcome

Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666Ebers G et al. presented at AAN, October 2006: M-3Ebers G et al. presented at AAN, October 2006: M-3

► LTFU of IFN LTFU of IFN β-1b showed that β-1b showed that patients with a baseline EDSS patients with a baseline EDSS score ≤ 2 were more likely to have score ≤ 2 were more likely to have lower disability at 15 year follow up lower disability at 15 year follow up than patients with baseline EDSS than patients with baseline EDSS scores > 2 regardless of treatmentscores > 2 regardless of treatment

► For patients with baseline EDSS For patients with baseline EDSS score > 2, the duration of exposure score > 2, the duration of exposure to treatment with IFN β-1b to treatment with IFN β-1b influenced the long term outcome.influenced the long term outcome.

► Patients with longer duration of Patients with longer duration of treatment had less disability than treatment had less disability than patients with shorter duration of patients with shorter duration of treatmenttreatment

Any Variable + Any Exposure Weighting – Any Negative Outcome

EDSSp<0.001

1

Exposurep<0.001

2

HighLow

► Disease modifying therapy seems to favorably effect the Disease modifying therapy seems to favorably effect the long-term course of MSlong-term course of MS

► Propensity score adjusted analysis and other statistical Propensity score adjusted analysis and other statistical methods for controlling biases inherent in long term, open methods for controlling biases inherent in long term, open label studies are important statistical advances for label studies are important statistical advances for interpreting these studiesinterpreting these studies

► These methods can provide complimentary information These methods can provide complimentary information about the long term effects of treatment without the cost about the long term effects of treatment without the cost (and ethical dilemmas) posed by long-term placebo-(and ethical dilemmas) posed by long-term placebo-controlled trialscontrolled trials

ConclusionsConclusions

Price of MS versus Price of MS versus Cost of Care. Cost of Care.

Is Treatment Worth It?Is Treatment Worth It?


DMT = disease-modifying therapy.Kobelt G, et al. Neurology. 2006;66(11):1696-1702.

MS Cost DriversMS Cost Drivers

Sick Leave/Reduced Working Time (10%)

Early Retirement (34%)

Hospital Inpatient Care (3%)

Ambulatory Care (4%)

Tests (2%)

Other Drugs (6%)

Services (2%)

Adaptations (5%)

DMTs (22%)

Informal Care (12%)

Cost of CareCost of Care

Cost and functionalityCost and functionality

Adapted from: Kobelt G, Berg J, Atherly D et al. Neurology. 2006; 66:1696–1702.Adapted from: Kobelt G, Berg J, Atherly D et al. Neurology. 2006; 66:1696–1702.

* 2004 US Dollars Non-Drug Costs

EDSS ScoreEDSS Score

Approximate Mean Annual Cost*Approximate Mean Annual Cost*

MedicalMedicalUnpaid Unpaid

CaregiveCaregiver Timer Time

Lost Lost Work Work TimeTime

TotalTotal

MildEDSS 0 - 3.5

$3,106$3,106 $932$932 $9,938$9,938 $13,976$13,976

ModerateEDSS 4.0 - 6.0

$5,100$5,100 $3,188$3,188 $22,950$22,950 $31,238$31,238

SevereEDSS 6.5 - 9.5

$12,524$12,524 $12,524$12,524 $21,291$21,291 $46,339$46,339

AWP = average wholesale price.Prescott JD, et al. J Manag Care Pharm. 2007;13(1):44-52. CuraScript 2008 Specialty Drug Trend Report. April 2009. Red Book Update. Vol. 30(1). January 2010.

DMT-Associated CostsDMT-Associated Costs

► Approximately 65% of annual direct per patient Approximately 65% of annual direct per patient healthcare costs in MS are attributable to drug therapyhealthcare costs in MS are attributable to drug therapy

► MS drugs represent 20.2% of specialty drug MS drugs represent 20.2% of specialty drug expenditures within managed care plansexpenditures within managed care plans

► National trend in MS drug expenditures was +18.3% in National trend in MS drug expenditures was +18.3% in 20082008

● 23.5% increase in manufacturer pricing was primary driver 23.5% increase in manufacturer pricing was primary driver of trendof trendAgentAgent DosageDosage AWP/dayAWP/day AWP/yearAWP/year

Interferon beta-1b 0.25 mg SC every other 0.25 mg SC every other dayday $105.41$105.41 $38,475$38,475

Interferon beta-1a IM 30 mcg IM once weekly30 mcg IM once weekly $98.66$98.66 $36,010$36,010

Interferon beta-1a SC 44 mcg SC 3 times 44 mcg SC 3 times weeklyweekly $106.20$106.20 $38,761$38,761

Glatiramer acetate 20 mg SC daily20 mg SC daily $110.10$110.10 $40,187$40,187

Fingolimod 0.5 mg PO daily0.5 mg PO daily $131.51$131.51 $48,000$48,000

Recent Analyses of the Economic Recent Analyses of the Economic Impact of MS TreatmentImpact of MS Treatment

► In an analysis of an employer medical, drug and disability In an analysis of an employer medical, drug and disability claims database:claims database:● Baseline MS-related medical costs were higher for treated vs Baseline MS-related medical costs were higher for treated vs

untreated employees ($2520 vs $1012,untreated employees ($2520 vs $1012,PP < 0.0001) < 0.0001)● Risk-adjusted total annual medical costs ($4,393 vs $6,187) Risk-adjusted total annual medical costs ($4,393 vs $6,187)

and indirect costs ($2,252 vs $3,053) were significantly and indirect costs ($2,252 vs $3,053) were significantly lower (lower (PP < 0.0001) for treated vs untreated employees with < 0.0001) for treated vs untreated employees with MSMS

● Study limitation: lack of clinical detail on MS severityStudy limitation: lack of clinical detail on MS severity

► Early use of DMTs in patients with CIS that delayed Early use of DMTs in patients with CIS that delayed conversion to CDMS provided a conversion to CDMS provided a positivepositive incremental cost-incremental cost-effectiveness ratio (ICER) per patient-year compared with effectiveness ratio (ICER) per patient-year compared with no treatment (Euros 2,574.94)no treatment (Euros 2,574.94)

Birnbaum HG, et al. Curr Med Res Opin. 2009;25(4):869-877.Lazzaro C, et al. Neurol Sci. 2009;30:21-31.

Fewer days absent from work from 1999–2002 for individuals with MS treated with GA (n = 28), INF-1a (n = 74), or INF-1b (n = 16) compared to untreated individuals with MS (n = 166) Lage MJ, et al. Work. 2006;27(2):143-151.

Effect of Immunomodulatory Effect of Immunomodulatory Therapy on Employment Loss TimeTherapy on Employment Loss Time

-20-20

-10-10

00

1010

2020

3030

4040

5050

6060

Short-termDisability

WorkersComp

AnyReason

Few

er D

ays

Ab

sen

tF

ewer

Day

s A

bse

nt

(P = .003)

(P = .71)

(P = .09)

(P = .04)

(P = .18)(P = .47)

(P = .03)

(P = .33)

(P = .39)

INFbeta-1a

INFbeta-1b

GA

National Clinical Advisory Board of the National MS Society. MS Disease Management Consensus Statement. 2007. http://www.nationalmssociety.org. Accessed February 10, 2010.

MS Consensus GuidelinesMS Consensus Guidelines

► National MS Society Expert Consensus Statement National MS Society Expert Consensus Statement (2007)(2007)

● Initiate therapy as soon as possible following diagnosis of Initiate therapy as soon as possible following diagnosis of active-relapsing disease with an interferon beta agent or active-relapsing disease with an interferon beta agent or glatiramer acetateglatiramer acetate

● Drug therapy should also be considered in patients with Drug therapy should also be considered in patients with first attack at high risk of MSfirst attack at high risk of MS

● Access to medications should not be limited by age, level Access to medications should not be limited by age, level of disability, or frequency of relapsesof disability, or frequency of relapses

● Continue treatment indefinitely unless lack of benefit, Continue treatment indefinitely unless lack of benefit, intolerant adverse effects, or better treatment becomes intolerant adverse effects, or better treatment becomes availableavailable

● Ensure adequate accessibility of all FDA-approved drugs Ensure adequate accessibility of all FDA-approved drugs for MSfor MS

● Change treatments only for medically appropriate Change treatments only for medically appropriate reasonsreasons

ConclusionConclusion

► MS is a chronic, debilitating, and progressive diseaseMS is a chronic, debilitating, and progressive disease

► Economic implications are significant and appear Economic implications are significant and appear directly correlated with disease severitydirectly correlated with disease severity

► Although costly, long-term data and expert Although costly, long-term data and expert consensus support the primary role of DMT in consensus support the primary role of DMT in managing disease progressionmanaging disease progression

► Optimal therapeutic benefit with DMT hinges strongly Optimal therapeutic benefit with DMT hinges strongly on multidimensional support from the healthcare on multidimensional support from the healthcare systemsystem

► Patient education and careful monitoring are key Patient education and careful monitoring are key factors driving success in MS therapyfactors driving success in MS therapy

Questions to ConsiderQuestions to Consider

1.1. How do you anticipate responding to the new How do you anticipate responding to the new MS treatment landscape that will include high MS treatment landscape that will include high cost, oral therapies that require monitoring cost, oral therapies that require monitoring measures?measures?

2.2. How, depending on the risk-to- benefit ratio, How, depending on the risk-to- benefit ratio, will managed care pharmacy and medical will managed care pharmacy and medical directors respond to a new landscape for MS directors respond to a new landscape for MS as oral agents with potentially less favorable as oral agents with potentially less favorable side effect profiles become available?side effect profiles become available?


3.3. Given these considerations, in the absence of Given these considerations, in the absence of long-term data, how do you get to the long-term data, how do you get to the bottom of a benefit-risk-cost decision for new bottom of a benefit-risk-cost decision for new MS therapies in the managed care setting? MS therapies in the managed care setting? How will that play out?How will that play out?

4.4. What incentives are there, if any, for altering What incentives are there, if any, for altering the current approach to initial therapy for MS, the current approach to initial therapy for MS, in which IMTs have demonstrated long-term in which IMTs have demonstrated long-term safety and efficacy?safety and efficacy?

5.5. How will Obamacare influence MS treatment How will Obamacare influence MS treatment decisions?decisions?

The Next Generation of Immune-The Next Generation of Immune-Modulating Therapies for MSModulating Therapies for MS

What do we know (and not know) What do we know (and not know) about their safety and efficacyabout their safety and efficacy

How will their usefulness be established?How will their usefulness be established?

Investigations • Innovation • Clinical ApplicationInvestigations • Innovation • Clinical Application

Norman Kachuck, MDNorman Kachuck, MDAssociate Professor of NeurologyAssociate Professor of Neurology

Chief, Neuroimmunology Division, Chief, Neuroimmunology Division, Department of Neurology Department of Neurology

Director, Multiple Sclerosis Comprehensive Care Center and Research Director, Multiple Sclerosis Comprehensive Care Center and Research Group Group

Vice-Chair, Health Sciences IRB Vice-Chair, Health Sciences IRB University of Southern California Keck School of Medicine University of Southern California Keck School of Medicine

Los Angeles, CaliforniaLos Angeles, California

Existing and Emerging MS TherapiesExisting and Emerging MS Therapies

20052005 2011201120062006 20072007 20102010 20122012 20132013

Injectables

IV



TysabriTysabri

Rebif

Filed

Approved In phase II

In phase III

Cladribine

AmpyraAmpyra

BG12

Teriflunomide

Laquinimod

Ocrelizumab

IV

Alemtuzumab

Oral

ExtaviaExtavia

Rebif

Betaseron

Copaxone

Avonex

Novantrone

Ampyra

Extavia

Tysabri

BG12Cladribine

Fingolimod

Ocrelizumab

TeriflunomideTeriflunomide

LaquinimodLaquinimod

AlemtuzumabAlemtuzumab

GenericMitoxantrone

(oncology) MS

What We Do Not KnowWhat We Do Not Know

► What initiates MS?What initiates MS?► Can we identify the different pathogenetic Can we identify the different pathogenetic

mechanisms in different individuals?mechanisms in different individuals?► Which occurs first: Myelin breakdown or Which occurs first: Myelin breakdown or

oligodendrocyte destruction?oligodendrocyte destruction?► What are the mechanisms of axonal What are the mechanisms of axonal

injury/loss?injury/loss?► What mediates regeneration of What mediates regeneration of

axons/myelinating elementsaxons/myelinating elements► Why does repair ultimately fail?Why does repair ultimately fail?

Implications of the Paradigm ShiftImplications of the Paradigm Shift

► Homogeneity of lesion type in an individualHomogeneity of lesion type in an individual► Heterogeneity in the phenotype of disease Heterogeneity in the phenotype of disease

across individuals across individuals ► Variable response to a given intervention Variable response to a given intervention

due to this heterogeneitydue to this heterogeneity► Likely need to create combinations of Likely need to create combinations of

therapies based on an individual’s diseasetherapies based on an individual’s disease► Biomarkers and noninvasive metrics Biomarkers and noninvasive metrics

are critical to evaluate, target, and are critical to evaluate, target, and follow disease and its injury and follow disease and its injury and repair response to treatmentrepair response to treatment

Bielekova B, Martin R. Brain. 2004;127;1463-1478.

What We Do Not KnowWhat We Do Not Know

► How can we optimize therapy for a How can we optimize therapy for a given patient using this information?given patient using this information?

► How do we optimize therapy for a How do we optimize therapy for a heterogeneous MS population under heterogeneous MS population under managed care, using this informationmanaged care, using this information

► How do we keep such decisions How do we keep such decisions rational, evidence-based, AND rational, evidence-based, AND ETHICAL?ETHICAL?

► And when we can’t know with And when we can’t know with certainty, how do we communicate certainty, how do we communicate and act on that uncertainty?and act on that uncertainty?

Therapies Reviewed TodayTherapies Reviewed Today

► Alemtuzumab (Campath®)Alemtuzumab (Campath®)

► Cladribine (Leustatin®, Cladribine (Leustatin®,

Movecto®)Movecto®)

► Fingolimod (Gilenya®)Fingolimod (Gilenya®)

Alemtuzumab (Campath®)Alemtuzumab (Campath®)

► Monoclonal humanized antibody directed Monoclonal humanized antibody directed against CD52 antigenagainst CD52 antigen

● CD52 antigen is a cell surface glycoprotein that CD52 antigen is a cell surface glycoprotein that is present on >95% of T lymphocytes, B is present on >95% of T lymphocytes, B lymphocytes, monocytes, and eosinophilslymphocytes, monocytes, and eosinophils

● Results in prolonged depletion of B cells, T cells, Results in prolonged depletion of B cells, T cells, and monocytesand monocytes

► Within an hour following a single 5- to 10-mg Within an hour following a single 5- to 10-mg dose, lymphocytes and monocytes are no dose, lymphocytes and monocytes are no longer detectable in circulationlonger detectable in circulation

► FDA-approved for B-CLLFDA-approved for B-CLLMuraro P, et al. Neurotherapeutics. 2007;4:676-692. Coles A, et al. J Neurol. 2006;253:98-108.Muraro P, et al. Neurotherapeutics. 2007;4:676-692. Coles A, et al. J Neurol. 2006;253:98-108.

CAMMS223 Trial Investigators. NEJM 2008;359:1786-1801.CAMMS223 Trial Investigators. NEJM 2008;359:1786-1801.

Month 0 Month 12Month 0 Month 12 Month 24 Month 24 Month 36 Month 36

107107 95 80 95 80 6666

108108 105 104 105 104 9292

108108 102 101 102 101 92922424

7777

2222

8888

IFNIFNββ-1a-1a44 mcg thw SC44 mcg thw SC

AlemtuzumabAlemtuzumab12 mg daily IV12 mg daily IV

AlemtuzumabAlemtuzumab24 mg daily IV24 mg daily IV

Alemtuzumab CAMMS223: Co-Alemtuzumab CAMMS223: Co-Primary Endpoints (36 months)Primary Endpoints (36 months)

CAMMS223 Trial Investigators. NEJM 2008;359:1786-1801.CAMMS223 Trial Investigators. NEJM 2008;359:1786-1801.

Alemtuzumab CAMMS223: Alemtuzumab CAMMS223: MRI OutcomesMRI Outcomes

CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801.

P≤0.03 for both doses of alemtuzumab vs. IFN at m 0-12 and 0-24. P=NS at m 0-36

Months 0-12 0-24 0-36

n=91

n=96

n=100

n=75

n=96n=91

n=60

n=80

n=87

P=0.16

P=0.04

P=0.04

P=0.03

Months 0-36 12-36

Alemtuzumab CAMMS223: SafetyAlemtuzumab CAMMS223: Safety

► Principal AEs associated with alemtuzumab Principal AEs associated with alemtuzumab

included:included:

● Infusion reactionsInfusion reactions

● Mild-to-moderate infectionsMild-to-moderate infections

● AutoimmunityAutoimmunity• Immune thrombocytopenia in 6 of 216 patients Immune thrombocytopenia in 6 of 216 patients

(2.8%)(2.8%) including one deathincluding one death

• Thyroid disorders (28% vs. 3% for IFNThyroid disorders (28% vs. 3% for IFNββ-1a)-1a)

• 1 case of Goodpasture’s syndrome1 case of Goodpasture’s syndrome

CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801. CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801.

Alemtuzumab CAMMS223: SafetyAlemtuzumab CAMMS223: Safety

Infections, %IFN ß-1a(n=107)

Alem 12 mg

(n=108)

Alem 24 mg

(n=108)

Upper resp. infection* 27.1 44.4 50.9

Lower resp. infection* 1.9 11.1 13.9

Herpes simplex 2.8 8.3 8.3

Herpes zoster 0.9 1.9 5.6

Meningitis** 0 0 1.8

* P<0.001 alemtuzumab vs. IFN ** Listeria or viral meningitis

CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801. CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801.

Alemtuzumab: Alemtuzumab: Effects on the Immune SystemEffects on the Immune System

► B cells returned to B cells returned to normal within 3-6 normal within 3-6 monthsmonths

► Median recovery time Median recovery time for CD4+ T cells > for CD4+ T cells > 100 cells/100 cells/µL = 3 µL = 3 monthsmonths

► 6-9 months for CD4+ 6-9 months for CD4+ T cells > 200 cells/T cells > 200 cells/µLµL

► Median recovery time Median recovery time to baseline levels of to baseline levels of CD4+ T cells = 61 CD4+ T cells = 61 monthsmonths

Thompson S, et al. J Clin Immunol 2010;30:99–105. Coles A, et al. J Neurol. 2006;253:98-108.Thompson S, et al. J Clin Immunol 2010;30:99–105. Coles A, et al. J Neurol. 2006;253:98-108.

Alemtuzumab long term efficacy at 5 years – Alemtuzumab long term efficacy at 5 years – ECTRIMS 2010ECTRIMS 2010

► 68% Alem in follow-68% Alem in follow-upup

► ARRARR● months 0-60 = months 0-60 =

0.110.11● Months 36-60 = Months 36-60 =

0.140.14

► SAD @ 60 = .13SAD @ 60 = .13► Mean EDSS -0.30Mean EDSS -0.30

► 42% IFNB-1a follow-42% IFNB-1a follow-upup

► ARR ARR ● Months 0-60 = .35Months 0-60 = .35● Months 36-60= .28Months 36-60= .28

► SAD @ 60 = .38SAD @ 60 = .38► Mean EDSS +0.46Mean EDSS +0.46

ARR=annualized relapse rate; SAD-sustained accumulation of disability

Alemtuzumab – Current Status (CARE-MS Alemtuzumab – Current Status (CARE-MS I/II) Phase III Studies in ProgressI/II) Phase III Studies in Progress

► CAMMS323 - Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study One

► Randomized, Rater- and Randomized, Rater- and Dose-Blinded Study Dose-Blinded Study Comparing 2 Annual Cycles Comparing 2 Annual Cycles of IV 12 mg and 24 mg of IV 12 mg and 24 mg Alemtuzumab to 3x Weekly Alemtuzumab to 3x Weekly SC Interferon Beta-1a SC Interferon Beta-1a (Rebif®) in Relapsing-(Rebif®) in Relapsing-Remitting Multiple Sclerosis Remitting Multiple Sclerosis Patients Who Have Relapsed Patients Who Have Relapsed on Therapyon Therapy

► Enrollment: 840 Study Start Enrollment: 840 Study Start Date: October 2007 Date: October 2007 Estimated Study Completion Estimated Study Completion Date: September 2011Date: September 2011

► CAMMS32400507 - Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study Two

► Randomized, Rater-Blinded Randomized, Rater-Blinded Study Comparing Two Study Comparing Two Annual Cycles of Annual Cycles of Intravenous Alemtuzumab to Intravenous Alemtuzumab to Three-Times Weekly Three-Times Weekly Subcutaneous Interferon Subcutaneous Interferon Beta-1a (Rebif®) in Beta-1a (Rebif®) in Treatment-Naïve Patients Treatment-Naïve Patients With Relapsing-Remitting With Relapsing-Remitting Multiple SclerosisMultiple Sclerosis

► Enrollment: 581 Study Start Enrollment: 581 Study Start Date: September 2007 Date: September 2007 Estimated Study Completion Estimated Study Completion Date: May 2011Date: May 2011

Source: Clinicaltrials.gov

http://www.genzymeclinicalresearch.com/clinicaltrials/trialdetailresults.asp?nct=NCT00530348








Cladribine (Leustatin)Cladribine (Leustatin)

► Synthetic purine nucleoside analogue prodrugSynthetic purine nucleoside analogue prodrug► Accumulates and is incorporated into the DNA of lymphocytes as Accumulates and is incorporated into the DNA of lymphocytes as

a result of a high ratio of deoxycytidinekinaseto 5' nucleotidase a result of a high ratio of deoxycytidinekinaseto 5' nucleotidase activityactivity

► Selectively induces apoptosis in dividing and non-dividing Selectively induces apoptosis in dividing and non-dividing lymphocyteslymphocytes

► Sustained reduction in lymphocyte subtypes (CD4+ T cells, CD8+ Sustained reduction in lymphocyte subtypes (CD4+ T cells, CD8+ T cells and B cellsT cells and B cells

► Relatively transient effects on other immune cells such as Relatively transient effects on other immune cells such as neutrophils and monocytesneutrophils and monocytes

► Reduces levels of pro-inflammatory chemokinesReduces levels of pro-inflammatory chemokines► Crosses the blood brain barrier - CSF concentration = 25% of Crosses the blood brain barrier - CSF concentration = 25% of

plasma (patients with no BBB compromise)plasma (patients with no BBB compromise)► FDA-approved for hairy cell leukemiaFDA-approved for hairy cell leukemia

Carson et al. Blood 1983;62:737–43; 2Beutler et al. Proc Natl Acad Sci USA 1996;93:1716–20. Rice et al.Neurology 2000;54:1145–55. Szczucinski et al. Acta Neurol Scand 2007;115:137–46Bartosik-Psujek et al. Acta Neurol Scand 2004;109:390–2. Liliemark.ClinPharmacokinet1997;32:120–3.

Dosing: 4-5 day courses at month 1 and 2 (3.50 mg/kg) or months 1-4 (5.25 mg/kg) and 2 additional monthly courses beginning at week 48

1326 patients

Placebo (n = 437)

Cladribine 3.50 mg/kg total dose; 4 courses (n = 433)

Cladribine 5.25 mg/kg total dose; 6 courses (n = 456)

48 96 Time (weeks) 0 60 72 84362413

MRI

Neurological examination

–4

X X X X

X X X X

95 16

X X X X

X X

44 52

X X

X X

Giovannoni G, et al. N Engl J Med. 2010;362:416-426.

CLARITY: Clinical OutcomesCLARITY: Clinical Outcomes

* P < 0.001

0.33 (0.29-0.38)

0.14* (0.12-0.17)

0.15*(0.12-0.17)

57.6%

54.5%

An

nu

aliz

ed r

elap

se

rate

(9

5% C

I)

60.9

79.7*

78.9*

Odds Ratio (95% CI)2.43 (1.81-3.27)

Odds Ratio (95% CI)2.53 (1.87-3.43)

Per

cen

t o

f re

lap

se-f

ree

pa

tie

nts

at

98 w

eeks

Placebo (n = 437)

Cladribine 3.50 mg/kg (n = 433)



CLARITY: Clinical OutcomesCLARITY: Clinical Outcomes

Placebo 437 424 399 373 355 333 315 304 3043.50 mg 433 424 407 389 379 364 355 347 3475.25 mg 456 447 425 404 388 375 363 350 350

Placebo

Cladribine 3.50 mg/kg 0.67 (0.48-0.93); P = 0.02

Cladribine 5.25 mg/kg 0.69 (0.49-0.96); P = 0.03

0 12 24 36 48 60 72 84 96

0

5

10

15

20

25

HR vs Placebo (95% CI)

Weeks

Pro

po

rtio

n w

ith

co

nfi

rme

d 3

-mo

nth

E

DS

S p

rog

ress

ion

(%

)

Time to Confirmed EDSS Progression


CLARITY: MRI OutcomesCLARITY: MRI Outcomes

0.12 0.11

All P < 0.001

87.9%

me

an

± S

E l

es

ion

s/p

ati

en

t/s

ca

n

0.91

85.7%

T1 Gadolinium-T1 Gadolinium-Enhancing LesionsEnhancing Lesions Active T2-Weighted LesionsActive T2-Weighted Lesions

1.43

0.38 0.33

73.4%

76.9%

1.72

0.43 0.38

74.4%

77.9%Combined Unique LesionsCombined Unique Lesions

Placebo (n = 437)




CLARITY: Safety and TolerabilityCLARITY: Safety and Tolerability

Preferred term, n (%) patientsPreferred term, n (%) patients PlaceboPlacebo(n = 435)(n = 435)

CladribineCladribine3.5 mg/kg3.5 mg/kg(n = 430)(n = 430)


CladribineCladribineoveralloverall

(n = 884)(n = 884)

Herpes zoster 0 8 (1.9) 11 (2.4) 19 (2.1)

Herpes zoster oticus 0 0 1 (0.2) 1 (0.1)

Varicella 1 (0.2) 1 (0.2) 1 (0.2) 2 (0.2)

Any infection or infestation 188 (42.5) 205 (47.7) 222 (48.9) 427 (48.3)

Deaths 2 (0.5) 2 (0.5) 2 (0.4) 4 (0.5)

► 20 patients had 21 zoster events in the cladribine groups20 patients had 21 zoster events in the cladribine groups► All 21 cases were self-limiting and dermatomal; no cases were disseminatedAll 21 cases were self-limiting and dermatomal; no cases were disseminated► 3.2% of patients developing grade 3 or 4 lymphopenia at any time during the study 3.2% of patients developing grade 3 or 4 lymphopenia at any time during the study

developed zoster versus 1.8% of those that did notdeveloped zoster versus 1.8% of those that did not► 70% of patients with zoster had normal lymphocyte count or lesser grade lymphopenia 70% of patients with zoster had normal lymphocyte count or lesser grade lymphopenia

at the approximate time zoster developedat the approximate time zoster developed► Deaths - Placebo: Hemorrhagic CVA, suicide; cladribine 3.5 mg/kg: acute MI, pancreatic Deaths - Placebo: Hemorrhagic CVA, suicide; cladribine 3.5 mg/kg: acute MI, pancreatic

carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardio-carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardio-respiratory arrestrespiratory arrest


CLARITY: Safety and TolerabilityCLARITY: Safety and Tolerability

Preferred term, n (%)Preferred term, n (%) PlaceboPlacebo(n = 435)(n = 435)



CladribineCladribineoveralloverall

(n = 884)(n = 884)

During StudyDuring Study

MelanomaMelanoma 00 1(0.2)1(0.2) 00 1(0.2)1(0.2)

OvarianOvarian 00 1(0.2)1(0.2) 00 1 (0.1)1 (0.1)

PancreaticPancreatic 00 1 (0.2)1 (0.2) 00 1 (0.1)1 (0.1)

CervixCervix 00 00 1(0.2)1(0.2) 1(0.2)1(0.2)

During post-study During post-study surveillancesurveillance

ChoriocarcinomaChoriocarcinoma 00 00 1(0.2)1(0.2) 1(0.2)1(0.2)

MalignanciesMalignancies


CLARITY: Effects on Lymphocyte SubsetsCLARITY: Effects on Lymphocyte Subsets

Maximum Effects on CD4 and CD 19 Counts*Maximum Effects on CD4 and CD 19 Counts*

Weeks 0-48 Weeks 48-96Weeks 0-48 Weeks 48-96

3.5 5.25 3.5 5.253.5 5.25 3.5 5.25

mg/kg mg/kg mg/kg mg/kgmg/kg mg/kg mg/kg mg/kg

CD4 (week)CD4 (week)

Cells/µLCells/µL

CD19 (week)CD19 (week)

Cells/µLCells/µL

1616

391391

99

1818

1616

209209

1616

1414

7272

275275

5252

2727

7272

207207

5252

3131Add Reference

*Median values

Rieckmann P, et al. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, 2009. Poster #816.

Cladribine – Current StatusCladribine – Current Status

► Approved in Approved in Australia and Australia and Russia (Movectro®)Russia (Movectro®)

► Applications Applications pending elsewherepending elsewhere

•9/24/2010 Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) says no •FDA application granted Priority Review

Fingolimod (FTY720) (Gilenya®) Fingolimod (FTY720) (Gilenya®)

1. Brown B, et al. Ann Pharmacother. 2007;41:1660-1668. 2. Kappos L, et al. N Engl J Med. 2006;355:1124-1140. 3. Mullershausen F, et al. Presented at: ECTRIMS; October 11-14, 2007; Prague, Czech Republic. 4. Miron VE, et al. Presented at: ECTRIMS; October 11-14, 2007; Prague, Czech Republic. 5. Barske C, et al. Presented at: ECTRIMS; October 11-14, 2007; Prague, Czech Republic.

► Sphingosine-1-phosphate (S1P) receptor modulatorSphingosine-1-phosphate (S1P) receptor modulator (S1PR1 and 5 > 2,3,4)(S1PR1 and 5 > 2,3,4)

► Sequesters circulating lymphocytes into secondary Sequesters circulating lymphocytes into secondary lymphoid organslymphoid organs

● Peripheral reduction of CD3+, CD4+, CD8+, CD45RA+ (naive T Peripheral reduction of CD3+, CD4+, CD8+, CD45RA+ (naive T cells), CD45RO+ (memory T cells) and CD19+ cellscells), CD45RO+ (memory T cells) and CD19+ cells

● No effect on lymphocyte induction, proliferation, No effect on lymphocyte induction, proliferation, or memory functionor memory function

► May inhibit the production of IL-17May inhibit the production of IL-17► Crosses BBB, and S1P receptors shown to function Crosses BBB, and S1P receptors shown to function

within the CNS, but unknown clinical relevancewithin the CNS, but unknown clinical relevance● Fingolimod or deletion of S1P1 from neural cells reduces Fingolimod or deletion of S1P1 from neural cells reduces

astrogliosis in EAE and can stimulate OPC maturationastrogliosis in EAE and can stimulate OPC maturation

1272 patients(1:1:1)

Clinic visits

Oral fingolimod 0.50 mg once daily (n = 425)

MRI

Oral fingolimod 1.25 mg once daily (n = 429)

Placebo once daily (n = 418)

Randomization Month 6 Month 12 Month 24

Kappos L, et al. N Engl J Med. 2010;362:387-401.

FREEDOMS: Primary Efficacy FREEDOMS: Primary Efficacy EndpointEndpoint

Annualized Relapse Rate at 24 monthsAnnualized Relapse Rate at 24 months

PlaceboPlacebo(n = 431)(n = 431)

FingolimodFingolimod0.5 mg0.5 mg

(n = 429)(n = 429)

FingolimodFingolimod1.25 mg1.25 mg(n = 420)(n = 420)

-54% vs Placebop < 0.001

-60% vs Placebop < 0.001


FREEDOMS: Disability DataFREEDOMS: Disability Data

Number at RiskFTY720 1.25 mg 429 401 373 356 344 332 322 305 165FTY720 0.50 mg 425 416 388 370 354 340 332 321 152Placebo 418 391 371 341 320 308 290 279 143

FTY720 1.25 mg (17%)†

Days on studyDays on study

90 180 270 360 450 540 630 720

5

10

15

20

25

30

Placebo (24%)

FTY720 0.50 mg (18%)*

Per

cen

t w

ith

3-m

on

th c

on

firm

ed

Per

cen

t w

ith

3-m

on

th c

on

firm

ed

ED

SS

pro

gre

ssio

nE

DS

S p

rog

ress

ion

FTY720 0.50 mg vs placebo HR 0.70P = 0.02 in time to disability Progression

FTY720 1.25 mg vs placebo HR 0.68P = 0.02 in time to disability Progression

* P = 0.03 vs placebo† P = 0.01 vs placebo


0

FREEDOMS: MRI EndpointsFREEDOMS: MRI Endpoints

T2 and Gadolinium-Enhancing Lesions at 24 MonthsT2 and Gadolinium-Enhancing Lesions at 24 Months

-82% P<0.001-74% P<0.001

Kappos L, et al. N Engl J Med. 2010;362:387-401.Kappos L, et al. N Engl J Med. 2010;362:387-401.

FREEDOMS: Brain VolumeFREEDOMS: Brain Volume

P≤0.03 for both doses of fingolimodvs. placebo at all time points

Kappos L, et al. N Engl J Med. 2010;362:387-401.Kappos L, et al. N Engl J Med. 2010;362:387-401.

Randomization Month 6 Month 12 Ongoing

Oral fingolimod 0.5 mg once daily and matchingweekly placebo injection IM

Optional extensionphase

Oral fingolimod 1.25 mg once daily and matchingweekly placebo injection IM

IFNβ-1a 30 µg IM once weekly andmatching daily oral placebo capsule Assessments

MRI

EDSS

Clinical visit

Cohen J, et al. N Engl J Med. 2010;362:412-415.

TRANSFORMS: TRANSFORMS: Primary Efficacy EndpointPrimary Efficacy Endpoint

Annualized Relapse Rate at 12 monthsAnnualized Relapse Rate at 12 months

IFNIFNββ-1a 30 µg IM-1a 30 µg IMonce weeklyonce weekly

(n = 431)(n = 431)

Oral fingolimodOral fingolimod0.5 mg0.5 mg

(n = 429)(n = 429)

Oral fingolimodOral fingolimod1.25 mg1.25 mg(n = 420)(n = 420)

-52% vs IFNβ-1a,p < 0.001

-38% vs IFNβ-1a,p < 0.001


TRANSFORMS: MRI EndpointsTRANSFORMS: MRI Endpoints

T2 and Gadolinium-Enhancing Lesions at 12 MonthsT2 and Gadolinium-Enhancing Lesions at 12 Months

Cohen J, et al. N Engl J Med. 2010;362:412-415.Cohen J, et al. N Engl J Med. 2010;362:412-415.

-42% vs. IFNß-1aP<0.001

-35% vs. IFNß-1aP=0.004

-55% vs. IFNß-1aP<0.001

-73% vs.IFNß-1a P<0.001

TRANSFORMS: Brain VolumeTRANSFORMS: Brain Volume

P < 0.001


Gilenya®: SafetyGilenya®: Safety

► Transient reduction in heart rate on initiation of Transient reduction in heart rate on initiation of treatmenttreatment

► Elevated blood pressureElevated blood pressure● ↑↑mean systolic BP (mean systolic BP (1.9 and 3.6 mm Hg for 0.5 1.9 and 3.6 mm Hg for 0.5

mg and 1.25 mg, respectively) and diastolic BP mg and 1.25 mg, respectively) and diastolic BP (0.7 and 2.1 mm HG for 0.5 and 1.25 mg, (0.7 and 2.1 mm HG for 0.5 and 1.25 mg, respectively)respectively)

► Elevated liver enzymesElevated liver enzymes● ↑↑LFTs ≥ 3 x ULN 8% for FTY720 0.5 mg, 10% for LFTs ≥ 3 x ULN 8% for FTY720 0.5 mg, 10% for

FTY720 1.25 mg, 1.2% for placebo, 2% for IFNß-FTY720 1.25 mg, 1.2% for placebo, 2% for IFNß-1a1a

► Macular edemaMacular edema● FREEDOMS - 7 cases in the 1.25 mg dose group FREEDOMS - 7 cases in the 1.25 mg dose group

(1.6%) and none in the 0.5 mg dose group(1.6%) and none in the 0.5 mg dose group● TRANSFORMS – 6 cases (4 in the 1.25 mg dose TRANSFORMS – 6 cases (4 in the 1.25 mg dose

group (1%) and 2 in the 0.5 mg dose group group (1%) and 2 in the 0.5 mg dose group (0.5%))(0.5%))

Kappos L, et al. N Engl J Med. 2010;362:387-401. Cohen J, et al. N Engl J Med. 2010;362:412-415.

Fingolimod (Fingolimod (Gilenya®)Gilenya®): Safety: Safety

AE, n (%)AE, n (%)

FTY720 FTY720 0.5 mg 0.5 mg (n = 854)(n = 854)

FTY720FTY7201.25 mg1.25 mg(n = 849)(n = 849)

PlaceboPlacebo(n = 418)(n = 418)

IFNß-1aIFNß-1a(n = 431)(n = 431)

Skin Cancers

Basal cell carcinoma 7(0.8)7(0.8) 3(0.4)3(0.4) 3(0.7)3(0.7) 1(0.2)1(0.2)

Melanoma 3(0.4)3(0.4) 1(0.1)1(0.1) 1(0.2)1(0.2) 00

Bowen’s Disease 1 (0.1)1 (0.1) 00 00 00

Infections

Herpes infections 46(5.4)46(5.4) 48(5.7)48(5.7) 33(7.9)33(7.9) 12(2.8)12(2.8)

Malignancies and Herpes InfectionsMalignancies and Herpes Infections

Kappos L, et al. N Engl J Med. 2010;362:387-401. Cohen J, et al. N Engl J Med. 2010;362:412-415.

Fingolimod (Gilenya®): SafetyFingolimod (Gilenya®): Safety

► Two fatal infections in patients treated Two fatal infections in patients treated with FTY720 1.25 mg with FTY720 1.25 mg ● Herpes encephalitis Herpes encephalitis ● primary disseminated varicellaprimary disseminated varicella

► Hemorrhagic encephalitis in a patient Hemorrhagic encephalitis in a patient treated with FTY720 1.25 mgtreated with FTY720 1.25 mg

► Posterior reversible encephalopathy Posterior reversible encephalopathy syndrome in a patient treated with 5 mg syndrome in a patient treated with 5 mg in the phase 2 studyin the phase 2 study

Cohen J, et al. N Engl J Med. 2010;362:412-415; Kappos L et al. Cohen J, et al. N Engl J Med. 2010;362:412-415; Kappos L et al. N Engl J Med. 2006;355:1124-40; N Engl J Med. 2006;355:1124-40; Leypoldt F, et al. LK. Neurology 2009;72:1022-24. Leypoldt F, et al. LK. Neurology 2009;72:1022-24.

Normal range Normal range

Treatment duration (yrs), Treatment duration (yrs), mean ± SEMmean ± SEM 1.9 ± 0.21.9 ± 0.2 --

Lymphocyte count (x 10Lymphocyte count (x 1099/L), /L), mean ± SEMmean ± SEM 0.4 ± 0.10.4 ± 0.1 0.9-3.30.9-3.3

CD4 T cell count (cells/µL), CD4 T cell count (cells/µL), mean ± SEMmean ± SEM 78 ± 5.678 ± 5.6 700-1100700-1100

CD8 T cell count (cells/µL), CD8 T cell count (cells/µL), mean ± SEMmean ± SEM 149 ± 7.4149 ± 7.4 500-900500-900

FTY720 1.25 mg (n = 16)FTY720 1.25 mg (n = 16)

Mehling M, et al. Neurology 2008;71:1261–1267

Gilenya®: Current StatusGilenya®: Current Status

► Sept 22, 2010 FDA approval, indicated for Sept 22, 2010 FDA approval, indicated for the treatment of patients with relapsing the treatment of patients with relapsing forms of multiple sclerosis to reduce the forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to frequency of clinical exacerbations and to delay the accumulation of physical delay the accumulation of physical disability.disability.

► Recommended dose: 0.5 mg orally once Recommended dose: 0.5 mg orally once daily, with or without fooddaily, with or without food

► REMS includes outreach letters, with REMS includes outreach letters, with recommendations for 6 hour initiation recommendations for 6 hour initiation observation period, monitoring for observation period, monitoring for infections, ophthalmologic, dermatologic infections, ophthalmologic, dermatologic and hepatic toxicity; NO REGISTRY or and hepatic toxicity; NO REGISTRY or restricted distribution processrestricted distribution process

Emerging Therapies:Emerging Therapies:Trading Efficacy for SafetyTrading Efficacy for Safety

► ? Impaired ? Impaired immune immune surveillance and surveillance and opportunistic opportunistic infectionsinfections

► Viral and other Viral and other infectionsinfections

► ? Malignancies? Malignancies► Long-lasting Long-lasting

effectseffects

► AutoimmunityAutoimmunity► TeratogenicityTeratogenicity► Rare, but serious Rare, but serious

infusion reactionsinfusion reactions► The UnknownThe Unknown

Natalizumab and the Risk of PMLNatalizumab and the Risk of PML

112

Changing therapy optionsChanging therapy options5-195-19

5. MS treatment side effects. 6. Company news; F.D.A. approves a multiple sclerosis drug. 7. Biotechnology medications move closer to the market. 8. Serono's

rebif(R) receives FDA approval. 9. Immunex gets FDA OK. 10. Multiple sclerosis (relapsing-remitting): emerging therapies that offer improved convenience will not unseat current drugs. Decision Base 2009. 11. Giovannoni G, et al. 2009 ECTRIMS. Abstract P470. 12. Cohen J, et al. 2009 ECTRIMS. Abstract P456. 13. Study results: multiple sclerosis patients have significant and sustained reduction in disability and risk of relapse on alemtuzumab versus approved therapy. 14. Clinicaltrials.gov Web site. ALLEGRO study. 15. Clinicaltrials.gov Web site. BRAVO study. 16. Biogen Idec showcases more than 70 data presentations at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis [news release]. 17. Study of teriflunomide in reducing the frequency of relapses and accumulation of disability in patients with multiple sclerosis (TEMSO). 18. Novantrone® (mitoxantrone). National Multiple Sclerosis Society Web site. 19. Tysabri® prescribing information. Biogen Idec Inc.

Phase III completed In Phase IIIApproved therapies

2009 2010 201120051995 2000

Gilenya® (fingolimod)

Cladribine

Campath®

(alemtuzumab)

Fumarate(BG-12)

Teriflunomide

Extavia®

(IFNβ-1b)

Tysabri® (natalizumab)

Betaseron®

(IFNβ-1b)

Copaxone®

(glatiramer acetate)

Avonex® (IFNβ-1a)

Rebif ®

(IFNβ-1a)

Novantrone® (mitoxantrone)

Laquinimod

Approval date Estimated launch date

Rituximab/Ocrilizumab

Meaningful impactMeaningful impact

Disease CourseDisease Course

MRIMRI

? Better than ABCR? Better than ABCR

? Window of opportunity? Window of opportunity

ConvenienceConvenience

Benefits RisksBenefits Risks

Treatment Decisions: Treatment Decisions: Considering Benefits and RisksConsidering Benefits and Risks

Short-term safetyShort-term safety

Long-term safetyLong-term safety

PharmacovigilancePharmacovigilance

Post-approval studiesPost-approval studies

Pregnancy issuesPregnancy issues

114

What therapy characteristic will be the What therapy characteristic will be the key driver for future therapy decisions?key driver for future therapy decisions?

Efficacy

Safety

Tolerability

Other Considerations

115

How will patient characteristics, risk aversion How will patient characteristics, risk aversion and cost play a role in our therapy decisions?and cost play a role in our therapy decisions?

Demographics:AgeGenderGenetic load

Present disabilityDisease Prognosis

Risk ToleranceRisk Aversion

Other Considerations: Price of Rx and care, Resource utilizationDelivery process

116

Multiple situations are encompassed Multiple situations are encompassed by by

the term “suboptimal response”the term “suboptimal response”1-51-5

EfficacyRelapsesNew lesionsBrain atrophyWorsening EDSSNeutralizing antibodies

TolerabilityComplianceImmediate postinjection reaction (IPIR)Injection-site reactions (ISRs)Flu-like symptomsDepression

SafetyClinically recognizable organ toxicityOpportunistic infectionAbnormal laboratory values

Other ConsiderationsFatigueWorsening cognition

1. Cohen BA, et al. Neurology. 2004;63:S33-S40.2. Freedman MS, et al. Can J Neurol Sci. 2004;31:157-168.3. National Multiple Sclerosis Society Expert Opinion Paper. 2004.4. International Working Group for Treatment Optimization in MS. Eur J Neurol. 2004;11:43-47.5. Coyle PK. J Neurol. 2008;255(suppl 1):44-50.

117

What is our ethical approach to prescribing What is our ethical approach to prescribing therapies with better efficacy but therapies with better efficacy but risks? risks?

Suitable for all patients?

Only for heavily treatment-experienced

patients?

Only for those with worsening disease?

Choose other established therapy?

For patients who request therapy?

My Take Home Points on MS My Take Home Points on MS TherapyTherapy

► Diagnose High Risk Presumptive and Diagnose High Risk Presumptive and Definite MS earlyDefinite MS early

► Treat early as aggressively as seems Treat early as aggressively as seems reasonable, to interrupt inflammatory reasonable, to interrupt inflammatory cascade and possible secondary cascade and possible secondary degenerationdegeneration

► Consider how to predict disease course Consider how to predict disease course using accurate surrogate markersusing accurate surrogate markers

► Make risk tolerance/aversion decisions on Make risk tolerance/aversion decisions on therapy on a patient by patient basistherapy on a patient by patient basis

► Involve patients in clinical research as ableInvolve patients in clinical research as able


1.1. How will new molecular mechanisms of action How will new molecular mechanisms of action and comparative analysis of injectable and new and comparative analysis of injectable and new oral MS agents under investigation and/or in the oral MS agents under investigation and/or in the FDA approval process; and, based on the FDA approval process; and, based on the reported risks, unknowns, safety signals, and reported risks, unknowns, safety signals, and therapeutic efficacy of such agents, affect MS therapeutic efficacy of such agents, affect MS treatment pathways in the MC setting?treatment pathways in the MC setting?

2.2. What are the potential risks and cautionary What are the potential risks and cautionary notes-medico-legal and otherwise-of embarking notes-medico-legal and otherwise-of embarking on a course of therapy with unknown safety risks on a course of therapy with unknown safety risks and lack of comparative studies, especially when and lack of comparative studies, especially when a safe platform therapy is already established a safe platform therapy is already established and available?and available?


3.3. Who will actually make the risk-benefit decisions? Who will actually make the risk-benefit decisions? Pharmacist? Formulary committee? Physician? Pharmacist? Formulary committee? Physician? Patient advocacy groups?Patient advocacy groups?

4.4. Will managed care organizations need to set up Will managed care organizations need to set up their own registries? And how will Phase 4 data their own registries? And how will Phase 4 data be communicated?be communicated?

5.5. In the absence of risk-stratification criteria, which In the absence of risk-stratification criteria, which are lacking for MS, how will MCO pharmacists and are lacking for MS, how will MCO pharmacists and physicians select patients for new therapies?physicians select patients for new therapies?

The Changing MS Therapeutic The Changing MS Therapeutic Landscape: Perspectives of an MS-Landscape: Perspectives of an MS-

Focused PharmacistFocused Pharmacist

How Will We Need to Adapt to and Analyze How Will We Need to Adapt to and Analyze the New Generation of MS Therapies?the New Generation of MS Therapies?

Ronald J. DeBellis, Pharm.D., FCCPRonald J. DeBellis, Pharm.D., FCCPProfessor and ChairProfessor and Chair

Department of Pharmacy PracticeDepartment of Pharmacy PracticeAlbany College of Pharmacy and Albany College of Pharmacy and

Health Sciences-VermontHealth Sciences-Vermont

The Evolving Landscape of MS TherapyThe Evolving Landscape of MS Therapy

Changing DirectionsChanging Directions

► Oral AgentsOral Agents► Pharmacist Advanced Provision of Pharmacist Advanced Provision of

CareCare► EducationEducation► CostCost► AdherenceAdherence

Oral Agents for Multiple SclerosisOral Agents for Multiple Sclerosis

FDA data accessed 10/14/10

Oral AgentOral Agent Mechanism of Mechanism of ActionAction StatusStatus Expected DosingExpected Dosing

Dalfampridine

Potassium Potassium channel channel blockerblocker

Approved for use by Approved for use by the FDAthe FDA

10.0 mg twice 10.0 mg twice dailydaily

Laquinimod ImmunomdulatImmunomdulatoror

Granted fast-track Granted fast-track review by FDAreview by FDA 0.6 mg daily0.6 mg daily

Cladribine

Purine Purine nucleoside nucleoside analogue analogue prodrugprodrug

FDA issued a FDA issued a refuse-to-file letter refuse-to-file letter for the New Drug for the New Drug Application due to Application due to reports of patients reports of patients developing solid developing solid

malignanciesmalignancies

1 (0.2)1 (0.2)

Fingolimod

Partial Partial sphingosine 1-sphingosine 1-

phosphate-phosphate-receptor receptor agonistagonist

Approved for use by Approved for use by FDAFDA 0.5 mg daily0.5 mg daily

Considerations as Therapy Shifts Considerations as Therapy Shifts from Injectable to Oral Agentsfrom Injectable to Oral Agents

► AdherenceAdherence● Pharmacists will play a larger role in that time spent with Pharmacists will play a larger role in that time spent with

patients in clinic will decrease due to less need to teach patients in clinic will decrease due to less need to teach patients how to injectpatients how to inject

● May be an initial increase in adherence since May be an initial increase in adherence since medications will be easier to takemedications will be easier to take• May eventually result in a decrease in adherence as May eventually result in a decrease in adherence as

undesirable side effects may emergeundesirable side effects may emerge● Increased amount of follow-up and coaching by Increased amount of follow-up and coaching by

pharmacists (particularly where high cost/high stakes pharmacists (particularly where high cost/high stakes therapy is involved)therapy is involved)• Seek Continuing Education in Motivational Seek Continuing Education in Motivational

Interviewing over the telephoneInterviewing over the telephone• Consider setting up follow-up schedule with MS Consider setting up follow-up schedule with MS

patientspatients• Schedule and provide detailed counseling sessions for Schedule and provide detailed counseling sessions for

patients when they come for prescription pick uppatients when they come for prescription pick up• Keep note to fax to MD after each visit to utilize team Keep note to fax to MD after each visit to utilize team

approach to care of patients with MSapproach to care of patients with MS● Utilize SWOT analysis to achieve realistic approach to MS Utilize SWOT analysis to achieve realistic approach to MS

patient care in a pharmacy settingpatient care in a pharmacy setting

Oral Agents and Managed CareOral Agents and Managed Care

► 4 oral agents on the horizon4 oral agents on the horizon● Dalfampridine, laquinimod, cladribine, fingolimodDalfampridine, laquinimod, cladribine, fingolimod

► Discontinuation rates with current therapies as high as Discontinuation rates with current therapies as high as 46%46%

● Lack of efficacy (perceived and real)Lack of efficacy (perceived and real)● Adverse drug reactionAdverse drug reaction● Cost to the patientCost to the patient● Injection anxietyInjection anxiety

► Oral agents and adherenceOral agents and adherence● Better tolerated physically and psychologicallyBetter tolerated physically and psychologically● Pts prefer receiving oral or inhaled medicationsPts prefer receiving oral or inhaled medications● Majority of patients did not perceive oral meds Majority of patients did not perceive oral meds

interfering with lifeinterfering with life• Minority of patients did not take oral meds and Minority of patients did not take oral meds and

perceive them less effective than injectable perceive them less effective than injectable medicationsmedications

Fallowfield L, Atkins L, Catt S, et al. Ann Oncol 2006;17:205-210. Halfdanarson TR, et al.Curr Oncol Rep. 2010;12(4):247-252.; Lipsy RJ et al. J Manag Care Pharm. 2009;15(9-a)(Suppl):S2-S15

Oral Agents and Managed CareOral Agents and Managed Care

► Trends/ConsiderationsTrends/Considerations● Oral medications will require less out-of Oral medications will require less out-of

pocket expenses for members compared pocket expenses for members compared with current injectable medicationswith current injectable medications

● Preliminary results indicate that oral Preliminary results indicate that oral medications are as effective as, or possibly medications are as effective as, or possibly more effective than, current injectable more effective than, current injectable formulationsformulations

● Patients newly diagnosed with MS may Patients newly diagnosed with MS may prefer oral agents when they become prefer oral agents when they become availableavailable

● Data presented regarding oral therapy is Data presented regarding oral therapy is trending to being significantly positive in trending to being significantly positive in the short time from 2009-2010the short time from 2009-2010Fallowfield L, Atkins L, Catt S, et al. Ann Oncol 2006;17:205-210. Halfdanarson TR, et al.Curr Oncol Rep. 2010;12(4):247-252.; Lipsy RJ

et al. J Manag Care Pharm. 2009;15(9-a)(Suppl):S2-S15




Collaborative Drug Therapy Collaborative Drug Therapy ManagementManagement

CDTMCDTM

Attributes of State and Federal Regulations Attributes of State and Federal Regulations Governing Collaborative PracticeGoverning Collaborative Practice

2001-2002 ACCP Task Force on Collaborative Drug Therapy Management. Collaborative Drug Therapy Management by Pharmacists 2003. Pharmacotherapy 2003;23:1210-1225.

PharmacovigilancePharmacovigilance

PharmacovigilencePharmacovigilence

► The science and activities relating to the The science and activities relating to the detection, assessment, understanding and detection, assessment, understanding and prevention of adverse effects or any other prevention of adverse effects or any other possible drug-related problem (WHO)possible drug-related problem (WHO) In recent history, the role of the pharmacist has In recent history, the role of the pharmacist has

been to dispense drugs prescribed by a been to dispense drugs prescribed by a physician and ensure drugs met required physician and ensure drugs met required standardsstandards

In healthcare today, the pharmacist’s role has In healthcare today, the pharmacist’s role has changed to acting as a consultant on changed to acting as a consultant on pharmacotherapy, including over the counter pharmacotherapy, including over the counter productsproducts

WHO. The Importance of Pharmacovigilence, Safety Monitoring of Medical Products. Geneva: WHO; 2002; van Grootheest AC, de Jong-van den Berg LTW. The role of hospital and community pharmacists in pharmacovigilance. Research in Social and Administrative Pharmacy 2005;1:126-33.

Percentage of Professional ADR Reports Percentage of Professional ADR Reports Originating from Pharmacists by CountryOriginating from Pharmacists by Country

CountryCountry %%Hospital Hospital

PharmacistsPharmacistsCommunity Community PharmacistsPharmacists

Canada 88.3 + -

USA 68 + -

Australia 40.3 + +

Netherlands 40.2 - +

Japan 39 ? +

Spain 25.9 + +

“+” Indicates that it is primarily pharmacists from this setting who originate reports“-” Indicates that pharmacists do not typically originate the reports“+” indicates that some but infrequent reports originate from pharmacists practicing in this setting“?” indicates unknown data

Van Grootheest AC, de Jong-van den Berg LTW. The role of hospital and community pharmacists in pharmacovigilance. Social and Administrative Pharmacy 2005;1:126-133.

Medication Therapy Medication Therapy Management in the Management in the

MS Patient MS Patient

MTMMTM

Medication Therapy Management in Pharmacy Practice: Core Elements of an MTM Service Model Version 2.0. American Pharmacists Association and National Association of Chain Drug Stores Foundation, 2008.

Criteria for Identifying Individuals for Criteria for Identifying Individuals for MTM ServicesMTM Services

American College of Clinical Pharmacy 2006 Clinical Practice Affairs Committee. Medication therapy management services: application of the core elements in ambulatory settings.

► Referral from other health care providersReferral from other health care providers► More than one prescriberMore than one prescriber► Patients on four or more chronic medicationsPatients on four or more chronic medications► Patients with at least once chronic disease requiring Patients with at least once chronic disease requiring

pharmacotherapypharmacotherapy► Patients taking a medication with a narrow therapeutic index (e.g. Patients taking a medication with a narrow therapeutic index (e.g.

warfarin, phenytoin, theophylline)warfarin, phenytoin, theophylline)► Lab values outside the normal range that could be improved with Lab values outside the normal range that could be improved with

medication therapymedication therapy► Non-adherence for more than 3 monthsNon-adherence for more than 3 months► Patients requiring intensive communication die to literacy and/or Patients requiring intensive communication die to literacy and/or

cultural issuescultural issues► Total monthly cost of medication in excess of $200Total monthly cost of medication in excess of $200► Patients discharged from a hospital or skilled nursing facility within Patients discharged from a hospital or skilled nursing facility within

14 days with new medications14 days with new medications► Over-utilization or under-utilization of medicationsOver-utilization or under-utilization of medications► Routinely non-adherent with medication regimensRoutinely non-adherent with medication regimens► Lack of understanding regarding medication useLack of understanding regarding medication use► Patients confronted with financial barriersPatients confronted with financial barriers

Documentation Elements for the Patient Documentation Elements for the Patient Record in an MTM EncounterRecord in an MTM Encounter

Medication Therapy Management in Pharmacy Practice: Core Elements of an MTM Service Model Version 2.0. American Pharmacists Association and National Association of Chain Drug Stores Foundation, 2008.

Studies Demonstrating Improved Economic and Studies Demonstrating Improved Economic and Clinical Outcomes with Pharmacists’ Interventions or Clinical Outcomes with Pharmacists’ Interventions or

ServicesServices

Chisolm-Burns MA, et al. Economic effects of pharmacists on health outcomes in the United States: a systematic review. AJHP 2010;67:1624-34.




Educational Opportunities for Pharmacist/ Educational Opportunities for Pharmacist/ Allied Health Involvement in MS TherapyAllied Health Involvement in MS Therapy

Ross AP. Neurology 2008;71(suppl 3):s21-s23.

Optimal MS Manageme

nt

DiseaseModification

SupportSystem

Symptom Management

ClinicalFindings

MRIFindings

Wellness

Considerations-EducationConsiderations-Education

► EducationEducation● Increased pharmacist education about MS diseaseIncreased pharmacist education about MS disease

• Access to quick reference with therapeutic optionsAccess to quick reference with therapeutic options• Counseling tips and FAQ’s to address from MS patientsCounseling tips and FAQ’s to address from MS patients• Promote web sites and contact information for pharmacists to “chat” with Promote web sites and contact information for pharmacists to “chat” with

MS pharmacy specialists in order to better care for their patientsMS pharmacy specialists in order to better care for their patients

● Provide templates and programs specific for pharmacists to Provide templates and programs specific for pharmacists to have a greater knowledge base than the patient (knowing have a greater knowledge base than the patient (knowing from previous information that MS patients are “smarter” the from previous information that MS patients are “smarter” the average patientaverage patient

• How to manage side effects of medicationsHow to manage side effects of medications• Use of alternative therapies to control and manage disease stateUse of alternative therapies to control and manage disease state• Role of alternatives in treating neurologic diseasesRole of alternatives in treating neurologic diseases

● Use of Motivational Interviewing skills to enhance and foster Use of Motivational Interviewing skills to enhance and foster long-term use of medications in chronic diseaseslong-term use of medications in chronic diseases

• Provide continuous professional development or certification in Provide continuous professional development or certification in motivational interviewing as part of patient caremotivational interviewing as part of patient care

• Address specific counseling opportunities and barriers in patient s with Address specific counseling opportunities and barriers in patient s with chronic neurological disease to colleges of medicine, pharmacy and chronic neurological disease to colleges of medicine, pharmacy and nursingnursing




Total Average Annual MS CostTotal Average Annual MS Costby Insurance Type and Payer (2004)by Insurance Type and Payer (2004)

Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52

Total Average Annual MS Cost by Presence Total Average Annual MS Cost by Presence of Selected Comorbid Conditions (2004)of Selected Comorbid Conditions (2004)


MS Component Costs—MS Component Costs—Overall Population (2004)Overall Population (2004)


Average Total Annual MS Cost by Disease-Average Total Annual MS Cost by Disease-Modifying Drug Utilization (2004)Modifying Drug Utilization (2004)


Newer Biologic Treatments in MSNewer Biologic Treatments in MS

► Payers are demanding more information on the overall Payers are demanding more information on the overall value of these therapies in making coverage decisionsvalue of these therapies in making coverage decisions

● Starting a biologic for the treatment of RA or MS was Starting a biologic for the treatment of RA or MS was associated with lower use of some types of medical services associated with lower use of some types of medical services within 2 to 3 years of initiationwithin 2 to 3 years of initiation

● Although biologics may reduce other types of service use, the Although biologics may reduce other types of service use, the savings do not come close to offsetting the full cost of these savings do not come close to offsetting the full cost of these drugsdrugs

● Health plans may rightly focus on making sure only patients Health plans may rightly focus on making sure only patients who will most benefit from biologics receive them. But once who will most benefit from biologics receive them. But once such patients are identified, it makes little sense to limit such patients are identified, it makes little sense to limit coveragecoverage

► Considerations/SpeculationsConsiderations/Speculations● Consider newer oral therapies for treatment for potentially Consider newer oral therapies for treatment for potentially

lower overall cost to both patients and MCO’slower overall cost to both patients and MCO’s

Joyce GF, et al. Am J Manag Care 2008;14(12):821-82

Considerations - CostsConsiderations - Costs

► CostsCosts● Utilize adherence and education strategies Utilize adherence and education strategies

to contain costs associated with diseaseto contain costs associated with disease• Shift and reduce costs from acute therapy and Shift and reduce costs from acute therapy and

health degeneration to medication health degeneration to medication management, adherence and educationmanagement, adherence and education

• Conduct continual research to demonstrate the Conduct continual research to demonstrate the value of adherence and education in cost value of adherence and education in cost reductionreduction

• Promote the concept of the “disseminated” Promote the concept of the “disseminated” healthcare team working to achieve adherence healthcare team working to achieve adherence and educationand education




AdherenceAdherence

► The term adherence is preferred over The term adherence is preferred over compliance due to authoritative and compliance due to authoritative and paternalistic connotations of the latterpaternalistic connotations of the latter Adherence: the extent to which a person’s Adherence: the extent to which a person’s

behavior–taking medication, following diet behavior–taking medication, following diet guidelines, or enacting lifestyle changes—guidelines, or enacting lifestyle changes—corresponds with recommendations from a corresponds with recommendations from a health care providerhealth care provider

Persistence and performance quality are also Persistence and performance quality are also associated with adherenceassociated with adherence

► Non adherence rates with DMT’s average 25% Non adherence rates with DMT’s average 25% (13-46%) (13-46%)

– Similar to DMSimilar to DM

Klauer T, Zettl UK. Compliance, adherence and the treatment of multiple sclerosis. J Neurol 2008;255 (suppl 6):87-92

Adherent vs. Non-adherent BehaviorAdherent vs. Non-adherent Behavior

AdherentAdherent

► Utilization and Utilization and consequent maintenance consequent maintenance of therapyof therapy

► Keep treatment and Keep treatment and aftercare appointmentsaftercare appointments

► Take drugs correctlyTake drugs correctly

► Active change to health Active change to health lifestylelifestyle

► Complete treatment-Complete treatment-related homeworkrelated homework

► Reduce risk behaviorsReduce risk behaviors

Non-adherentNon-adherent

• Complete refusal of Complete refusal of therapytherapy

• Refusal of specific Refusal of specific treatment optionstreatment options

• Arbitrary or unintended Arbitrary or unintended modification of modification of prescriptionsprescriptions

– Intentional non-adherenceIntentional non-adherence


Motivations for Non-AdherenceMotivations for Non-Adherence

• Most severe demands of IMT posed on Most severe demands of IMT posed on patientspatients– Injectable medications, frequently IM or SQ for Injectable medications, frequently IM or SQ for

months or yearsmonths or years– Benefits of IMT will not be positively experienced Benefits of IMT will not be positively experienced

by patients and outweighed by side effectsby patients and outweighed by side effects• Flu-like symptomsFlu-like symptoms• FlushingFlushing• Chest painChest pain• PalpitationsPalpitations• DyspneaDyspnea• Pain on injectionPain on injection


Effects of Non-Adherence Effects of Non-Adherence on Treatment Prevalenceon Treatment Prevalence

Brandes DW, et al. A review of disease-modifying therapies for MS: maximizing adherence and miminizing adverse events. Current Medical Research and Opinion 2009;25:77-92.

Reasons for Discontinuing Reasons for Discontinuing MS MedicationsMS Medications

Lipsy R. Will the newer oral MS agents be welcomed by managed care organizations? Am J Manag Care 2010;16:S227-S223.

Poor Compliance Associated with Higher Poor Compliance Associated with Higher Out-of-Pocket Expenses with MS DrugsOut-of-Pocket Expenses with MS Drugs

Gleason PP, et al. J Manag Care Pharm. 2009;15(8):648-658.

Motivational Interviewing as Early Motivational Interviewing as Early Vocational Intervention in MSVocational Intervention in MS

► 90% of people with MS have a history of employment, only 20-90% of people with MS have a history of employment, only 20-30% will be employed 5-15 years from diagnosis30% will be employed 5-15 years from diagnosis

► Many people with MS do not participate in interventions designed Many people with MS do not participate in interventions designed to preserve employment until they experience a work-related to preserve employment until they experience a work-related crisis because of fatigue, concern about disclosure, or preference crisis because of fatigue, concern about disclosure, or preference to not anticipate future problemsto not anticipate future problems

► MI is a brief, client centered, directive counseling approach that MI is a brief, client centered, directive counseling approach that enhances intrinsic motivation to change by exploring and enhances intrinsic motivation to change by exploring and resolving ambivalenceresolving ambivalence

► U. of Washington MS Rehabilitation Research and Training Center U. of Washington MS Rehabilitation Research and Training Center is providing brief telephone MI sessions to individuals with MS to is providing brief telephone MI sessions to individuals with MS to explore costs, benefits, and ambivalence of study participants explore costs, benefits, and ambivalence of study participants toward making accommodations at work in efforts to stay toward making accommodations at work in efforts to stay employed through the progression of the diseaseemployed through the progression of the disease

Hunter C, Johnson K , Fraser R. Motivational Interviewing as Early Vocational Intervention in MS (P09). 21 st Annual Meeting of the Consortium for Multiple Sclerosis Centers, 2007 Washington, DC.

Patient Compliance Improves Through Patient Compliance Improves Through “Motivational Interviewing”“Motivational Interviewing”

► Patient often resist the advice of health care Patient often resist the advice of health care providers and thus neglect what is in their best providers and thus neglect what is in their best interestsinterests

► Attempts to persuade patients when they are not Attempts to persuade patients when they are not ready to changeready to change A patient may quit taking medication because they feel A patient may quit taking medication because they feel

no improvementno improvement Determine motivation and increase probability that Determine motivation and increase probability that

they will make good decisionsthey will make good decisions

► Software available to aid Pharmacists in MISoftware available to aid Pharmacists in MI 8.7% of pts receiving advice from counselors without 8.7% of pts receiving advice from counselors without

using software quit taking medicationsusing software quit taking medications 1.2% of pts quit taking medications when software was 1.2% of pts quit taking medications when software was

usedused

http://www.sciencedaily.com/releases/2007/07/070721194716.htm Accessed 10/4/2010

Physical Activity for Depression in People Physical Activity for Depression in People Aging with Multiple Sclerosis and Spinal Cord Aging with Multiple Sclerosis and Spinal Cord

InjuryInjury

► Ongoing study at University of Washington Ongoing study at University of Washington currently recruiting, completion date March 2012currently recruiting, completion date March 2012

► PurposePurpose– Lack of physical activity has been positively correlated Lack of physical activity has been positively correlated

with higher levels of depressionwith higher levels of depression– Longitudinal data and treatment trials suggest that Longitudinal data and treatment trials suggest that

increased physical activity is related to improved moodincreased physical activity is related to improved mood– Condition: MS; Intervention: Behavioral (Motivational Condition: MS; Intervention: Behavioral (Motivational

InterviewingInterviewing))

http://clinicaltrials.gov/ct2/show/NCT00947232, accessed 10/4/2010

Physical Activity for Depression in People Physical Activity for Depression in People Aging with Multiple Sclerosis and Spinal Cord Aging with Multiple Sclerosis and Spinal Cord

InjuryInjury

► RandomizationRandomization– Motivational Interviewing: experimentalMotivational Interviewing: experimental

• Motivational interviewing for people aging with MS or Motivational interviewing for people aging with MS or spinal cord injury to increase physical activity and spinal cord injury to increase physical activity and decrease depressiondecrease depression

– Behavioral: motivational interviewingBehavioral: motivational interviewing• Motivational interviewing, a proven counseling method Motivational interviewing, a proven counseling method

that centers on individual goals and motivations, to that centers on individual goals and motivations, to increase exercise and decrease depressionincrease exercise and decrease depression

http://clinicaltrials.gov/ct2/show/NCT00947232, accessed 10/4/2010

Strategies to Enhance Adherence to Strategies to Enhance Adherence to DMT’sDMT’s


Establishing a therapeutic relationship

Managingpatient

expectations

Educating patient and

family

Managing adverse

events

Addressing patient

concerns

Increased adherenc

e to treatmen

t

Sample Questions Providing Alternative Sample Questions Providing Alternative Views for Patients with Injection AnxietyViews for Patients with Injection Anxiety


► If you could inject <1 min/Week, with minimal If you could inject <1 min/Week, with minimal anxiety, would it be a burden?anxiety, would it be a burden?

► While the injections may result in side effects in While the injections may result in side effects in the first months, what are your goals for the next the first months, what are your goals for the next 10 years10 years

► If you were walking in the desert and had If you were walking in the desert and had antivenin with you and a rattlesnake bit you, antivenin with you and a rattlesnake bit you, would you self-inject?would you self-inject?

Male vs. Female MS CharacteristicsMale vs. Female MS Characteristics

► Female patients have greater self-reported symptom Female patients have greater self-reported symptom awareness and more positive perceptions of ability to awareness and more positive perceptions of ability to manage therapymanage therapy

► 80% of a mailed surveys of commercially insured MS 80% of a mailed surveys of commercially insured MS patients were femalepatients were female

● Majority of whom had RRMSMajority of whom had RRMS● 68% of whom were on glatiramir acetate or interferon beta-1a68% of whom were on glatiramir acetate or interferon beta-1a● Females more often perceived that DMM made a difference Females more often perceived that DMM made a difference

and were more aware of treatment optionsand were more aware of treatment options

► Considerations/SpeculationsConsiderations/Speculations● Male patients would be a sizeable target for beginning MS Male patients would be a sizeable target for beginning MS

therapytherapy● Male patients need consistent reminders of importance of Male patients need consistent reminders of importance of

therapy as well as treatment optionstherapy as well as treatment options

Vlahiotis A, et al. J Manag Care Pharm 2010;16:206-16.

Kaplan-Meier Hazards for Probability for Kaplan-Meier Hazards for Probability for Medication ContinuanceMedication Continuance

Daugherty KK, et al. Factors leading patients to discontinue multiple sclerosis therapies. J Am Pharm Assoc 2005;45:371-375.

Determinants of AdherenceDeterminants of Adherence

► Missing treatment effects or undesirable side Missing treatment effects or undesirable side effects explain only medium amounts of variance effects explain only medium amounts of variance in adherencein adherence– Disease characteristicsDisease characteristics– Patient variablesPatient variables– Quality of patient therapist relationshipQuality of patient therapist relationship– Treatment settingTreatment setting– Influences from social environmentInfluences from social environment

Mohr DC, et al. Injectable medication for the treatment of multiple sclerosis: The influence of self-efficacy expectations and injection anxiety on the adherence and ability to self inject. Ann Behav Med 2001;23:125-132.

Determinants of AdherenceDeterminants of Adherence

• Adherence most strongly threatened by disorders that Adherence most strongly threatened by disorders that specifically and directly interfere with medication specifically and directly interfere with medication applicationapplication

– Injection phobiaInjection phobia– Treatment of diabetes mellitusTreatment of diabetes mellitus– DepressionDepression

• Non-adherence has been regarded as a risk for Non-adherence has been regarded as a risk for patient morbidity and mortality and has an patient morbidity and mortality and has an unnecessary economical burden for the health care unnecessary economical burden for the health care systemsystem

Mohr DC, et al. Injectable medication for the treatment of multiple sclerosis: The influence of self-efficacy expectations and injection anxiety on the adherence and ability to self inject. Ann Behav Med 2001;23:125-132.

► The Society recognizes that the factors that enter The Society recognizes that the factors that enter into a decision to treat are complex and best into a decision to treat are complex and best analyzed by the individual patient’s neurologist.analyzed by the individual patient’s neurologist.

► Initiation of treatment with an interferon beta Initiation of treatment with an interferon beta medication or glatiramer acetate should be medication or glatiramer acetate should be considered as soon as possible following a considered as soon as possible following a definite diagnosis of MS with active, relapsing definite diagnosis of MS with active, relapsing disease, and may also be considered for selected disease, and may also be considered for selected patients with a first attack who are at high risk of patients with a first attack who are at high risk of MS.*MS.*

Expert Opinion Paper, National Multiple Sclerosis Society, 2007

Recommendations—National Multiple Sclerosis Society 2007Recommendations—National Multiple Sclerosis Society 2007

Disease Management Consensus StatementDisease Management Consensus Statement

Disease Management Consensus StatementDisease Management Consensus Statement

► Natalizumab is generally recommended by the Natalizumab is generally recommended by the Food and Drug Administration (FDA) for patients Food and Drug Administration (FDA) for patients who have had an inadequate response to, or are who have had an inadequate response to, or are unable to tolerate, other multiple sclerosis unable to tolerate, other multiple sclerosis therapies.therapies.

► Treatment with mitoxantrone may be considered Treatment with mitoxantrone may be considered for selected relapsing patients with worsening for selected relapsing patients with worsening disease or patients with secondary-progressive disease or patients with secondary-progressive multiple sclerosis who are worsening, whether or multiple sclerosis who are worsening, whether or not relapses are occurring.not relapses are occurring.


Recommendations—National Multiple Sclerosis Society 2007Recommendations—National Multiple Sclerosis Society 2007

Recommendations ContinuedRecommendations Continued

► Patients’ access to medication should not be Patients’ access to medication should not be limited by the frequency of relapses, age, or level limited by the frequency of relapses, age, or level of disability.of disability.

► Treatment is not to be stopped while insurers Treatment is not to be stopped while insurers evaluate for continuing coverage of treatment, as evaluate for continuing coverage of treatment, as this would put patients at increased risk for this would put patients at increased risk for recurrent disease activity.recurrent disease activity.

► Therapy is to be continued indefinitely, except for Therapy is to be continued indefinitely, except for the following circumstances: there is clear lack of the following circumstances: there is clear lack of benefit; there are intolerable side effects; better benefit; there are intolerable side effects; better therapy becomes available.therapy becomes available.


Recommendations ContinuedRecommendations Continued

► All of these FDA-approved agents should be All of these FDA-approved agents should be included in formularies and covered by third included in formularies and covered by third party payers so that physicians and patients can party payers so that physicians and patients can determine the most appropriate agent on an determine the most appropriate agent on an individual basis; failure to do so is unethical and individual basis; failure to do so is unethical and discriminatory.discriminatory.

► Movement from one disease-modifying Movement from one disease-modifying medication to another should occur only for medication to another should occur only for medically appropriate reasons.medically appropriate reasons.

► None of the therapies has been approved for use None of the therapies has been approved for use by women who are trying to become pregnant, by women who are trying to become pregnant, are pregnant, or are nursing mothers.are pregnant, or are nursing mothers.Expert Opinion Paper, National Multiple Sclerosis Society, 2007

Dose, Route, Frequency and Common Dose, Route, Frequency and Common Adverse Effects of Medications Used in MS Adverse Effects of Medications Used in MS

TreatmentTreatment

Daugherty KK, et al. Factors leading patients to discontinue multiple sclerosis therapies. J Am Pharm Assoc 2005;45:371-375.

MedicatioMedicationn

DoseDose RouteRoute FrequencFrequencyy

Common Common Adverse EventsAdverse Events

Interferon beta-1a

30 micrograms

IntramuscularOnce

weekly

Injection site reactions,

inflammation, fever, myalgia, chills

Interferon beta-1a

44 micrograms

SubcutaneousThree times

per week



Interferon beta-1b

0.25 milligrams

SubcutaneousEvery other

day



Glatiramer acetate

20 milligrams Subcutaneous Once daily

Local injection site reactions and transient, self-limited, facial

flushing and chest tightness

Direct and Indirect Costs that Should be Direct and Indirect Costs that Should be Considered in Direct Patient Care ServicesConsidered in Direct Patient Care Services

Chisolm-Burns MA, et al. Economic effects of pharmacists on health outcomes in the United States: a systematic review. AJHP 2010;67:1624-34.


1. 1. How likely is the approval of new MS therapies—How likely is the approval of new MS therapies—including both oral and injectable agents—including both oral and injectable agents—change the risk- to-benefit analyses for long-term change the risk- to-benefit analyses for long-term MS treatments and influence management MS treatments and influence management decisions for MS in the managed care setting?decisions for MS in the managed care setting?

2. 2. How do you anticipate responding to the new MS How do you anticipate responding to the new MS treatment landscape that will include high cost, treatment landscape that will include high cost, oral therapies that require pharmacovigilance oral therapies that require pharmacovigilance measures?measures?

3. 3. In the absence of precise guideline from U.S. In the absence of precise guideline from U.S. FDA, how will your organization decide to tier FDA, how will your organization decide to tier first-line and second-line therapies?first-line and second-line therapies?

4. 4. Specifically, to what extent has cost of therapy Specifically, to what extent has cost of therapy influenced decision-making at your MCO? And influenced decision-making at your MCO? And how will it influence therapy moving forward?how will it influence therapy moving forward?

5. 5. How will your organization respond to pricing How will your organization respond to pricing issues for MS? For example, fingolimod is priced at issues for MS? For example, fingolimod is priced at $48,000 one year of treatment? How will that $48,000 one year of treatment? How will that influence your MS treatment decisions when safe and influence your MS treatment decisions when safe and effective therapies currently cost from $32,000 to effective therapies currently cost from $32,000 to $40,000?$40,000?

6. 6. How will you respond to additional demands for How will you respond to additional demands for safety monitoring for new agents, such as fingolimod safety monitoring for new agents, such as fingolimod and other immunosuppressives? What are these and other immunosuppressives? What are these monitoring dimensions?monitoring dimensions?


The Role of Comparative The Role of Comparative Effectiveness, Long Term Safety Effectiveness, Long Term Safety Considerations, and Monitoring Considerations, and Monitoring

Costs for Evaluating Therapies for Costs for Evaluating Therapies for MSMS

The Evolving Landscape of MS TherapyThe Evolving Landscape of MS Therapy

Jacquelyn Bainbridge, PharmD, FCCPJacquelyn Bainbridge, PharmD, FCCPProfessor

Department of Clinical Pharmacy/Department of Neurology

University of Colorado DenverAurora, CO

To Treat or Not to Treat?To Treat or Not to Treat?

► Does early treatment of patients with CIS delay the Does early treatment of patients with CIS delay the development of a second clinical event (CDMS development of a second clinical event (CDMS diagnosis)?diagnosis)?

► Four randomized, placebo-controlled, phase III trials Four randomized, placebo-controlled, phase III trials have addressed that questionhave addressed that question

● PreCISePreCISe: Study to Evaluate the Effect of Early Glatiramer : Study to Evaluate the Effect of Early Glatiramer Acetate Treatment in Delaying the Conversion to CDMS of Acetate Treatment in Delaying the Conversion to CDMS of Subjects Presenting with CIS Subjects Presenting with CIS

● BENEFITBENEFIT: Betaseron: Betaseron®® (SC IFN (SC IFNββ-1b) in Newly Emerging MS for -1b) in Newly Emerging MS for Initial TreatmentInitial Treatment

● CHAMPSCHAMPS: Controlled High-Risk Subjects (IM IFN: Controlled High-Risk Subjects (IM IFNββ-1a) Avenox-1a) Avenox®® Multiple Sclerosis PreventionMultiple Sclerosis Prevention

● ETOMSETOMS: Early Treatment of MS: Early Treatment of MS

► One additional ongoing studyOne additional ongoing study● REFLEXREFLEX: Rebif: Rebif®® (SC IFN (SC IFNββ-1a) FLEXible Dosing in Early MS-1a) FLEXible Dosing in Early MS

IFN = interferon; IM = intramuscular; SC = subcutaneous.

Clinically Isolated Syndrome (CIS)Clinically Isolated Syndrome (CIS)

► CIS: single, symptomatic neurologic CIS: single, symptomatic neurologic episode consistent with MS, first attackepisode consistent with MS, first attack● Common symptoms: optic neuritis, ocular Common symptoms: optic neuritis, ocular

motor syndromes, ataxia, dysarthria, sensory motor syndromes, ataxia, dysarthria, sensory or motor signs, partial myelitis, and bladder or or motor signs, partial myelitis, and bladder or bowel dysfunctionbowel dysfunction

● Patient may already have lesions on MRIPatient may already have lesions on MRI

► Clinically definite MS (CDMS): second Clinically definite MS (CDMS): second attack consistent with MSattack consistent with MS

CIS = clinically isolated syndrome; MRI = magnetic resonance imaging; MS = multiple sclerosis.

Prognosis in CISPrognosis in CISRate of Conversion to CDMSRate of Conversion to CDMS

0

20

40

60

80

100

5 10 15

0 Lesions

1–3 Lesions

4–10 Lesions

>10 Lesions

YearsYears

% C

on

vert

ing

to C

DM

S%

Con

vert

ing

to C

DM

S

Baseline Measure

Adapted with permission from Brex et al. N Engl J Med. 2002;346:158-164.

TreatmentTreatment

► All of the clinical trials in patients with CIS All of the clinical trials in patients with CIS showed statistically significant reductions showed statistically significant reductions (39%(39%––50%) in risk of developing CDMS when 50%) in risk of developing CDMS when early treatment was initiated. early treatment was initiated.

► All of the clinical trials showed a delay in All of the clinical trials showed a delay in physical disability and a significant reduction physical disability and a significant reduction in either the number and/or volume of brain in either the number and/or volume of brain lesions.lesions.

MS Prognosis Without TherapyMS Prognosis Without Therapy

► 1010––20% have “benign MS” 20% have “benign MS” ● Rare attacks, little disabilityRare attacks, little disability● Post-hoc determinationPost-hoc determination

► About 5% have “malignant MS”About 5% have “malignant MS”• Rapid accumulation of disabilityRapid accumulation of disability• Wheelchair-bound in 5 years, bed bound in 10 Wheelchair-bound in 5 years, bed bound in 10

yearsyears

► Most are between these extremesMost are between these extremes

► Newer data suggests overall better prognosis Newer data suggests overall better prognosis

Economic Impact of Multiple Economic Impact of Multiple Sclerosis Sclerosis

► Impact in the work place (MS vs non-MS)Impact in the work place (MS vs non-MS)● Higher percentage of employees claiming short- or Higher percentage of employees claiming short- or

long-term disability (21.4% vs 5.2%) (long-term disability (21.4% vs 5.2%) (P P <.0001)<.0001)11

● More disability days per year (29.8 vs 4.5) (More disability days per year (29.8 vs 4.5) (P P <.0001)<.0001)11

● Average annual costs for disability $3868 vs $414 Average annual costs for disability $3868 vs $414 US US ((PP <.0001) <.0001)11

1. Ivanova JI, et al. Pharmacoecomonics. 2009;27:681-691

Key Parameters in MS Management: Key Parameters in MS Management: DisabilityDisability

Expanded Disability Status Scale = Rating system used by neurologists and clinical trial investigators to follow the progression of disability in MS

Patient Disability Classification0 0.5

1.01.5 2.0 2.5 3.0

3.54.0 4.5 5.0 5.5

6.0 6.57.57.0

8.5

Normal neurologic exam

Minimal disability

Increased limitation in walking ability

Need for walking assistance

Restriction to wheelchair

Helpless bed patient

Death

Kurtzke. Neurology. 1983;33:1444-1452.

8.09.0 9.5 10.0

Seven Approved Seven Approved Disease-Modifying TherapiesDisease-Modifying Therapies

First-line First-line therapiestherapies

Second-lineSecond-lineTherapy ?Therapy ?

Worsening/Worsening/progressive progressive diseasedisease

IM IFNβ-1a IM IFNβ-1a SC IFNβ-1aSC IFNβ-1aSC IFNβ-1bSC IFNβ-1bGlatiramer acetateGlatiramer acetateFingolimodFingolimod

NatalizumabNatalizumabOther first-lineOther first-line

MitoxantroneMitoxantrone

Graphic courtesy of Dr. Robert J. Lipsy. Abbreviations: IFNβ, interferon beta; IM, intramuscular; SC, subcutaneous.

FDA-Approved Therapies for MSFDA-Approved Therapies for MSParenteral Immunomodulators Parenteral Immunomodulators

Agents*Agents* IndicationsIndications Doses and Doses and AdministrationAdministration

Glatiramer acetate1 (Copaxone®)

CIS CIS RRMSRRMS

20 mg/d SC20 mg/d SC

Low-dose IFNβ-1a2 (Avonex®)

CISCISRRMSRRMS

30 mcg/wk IM 30 mcg/wk IM

High-dose IFNβ-1a3 (Rebif®)

RRMSRRMSCISCIS††

22 mcg or 44 mcg TIW 22 mcg or 44 mcg TIW SC SC

High-dose IFNβ-1b4,5 (Betaseron®, Extavia®)

CIS CIS RRMSRRMS

250 mcg QOD SC250 mcg QOD SC

*Trade names are included in this presentation to reduce confusion regarding medication formulations and in no way endorses the use of the product with the trade name.†Pending FDA approval (REFLEX trial).

1. Glatiramer acetate (Copaxone®). www.accessdata.fda.gov/drugsatfda_docs/label/2009/020622s057lbl.pdf. 2. Low-dose IFNβ-1a (Avonex®). www.accessdata.fda.gov/drugsatfda_docs/label/2007/103628s5115lbl.pdf.3. High-dose IFNβ-1a (Rebif®). www.accessdata.fda.gov/drugsatfda_docs/label/2005/103780s5062lbl.pdf. 4. High-dose IFNβ-1b (Betaseron®). www.accessdata.fda.gov/drugsatfda_docs/label/2003/103471s5032lbl.pdf.5. High-dose IFNβ-1b (Extavia®). www.accessdata.fda.gov/drugsatfda_docs/label/2009/125290s0000lbl.pdf.

FDA-Approved Therapies for MSFDA-Approved Therapies for MS Parenteral Immunosuppressive Parenteral Immunosuppressive

Agents*Agents* IndicationsIndications Doses and Doses and AdministrationAdministration

Natalizumab1 (Tysabri®) †

Relapsing forms of Relapsing forms of MSMS 300 mg q4wk IV300 mg q4wk IV

Mitoxantrone2

(Novantrone®)

††

SPMS, PRMS, SPMS, PRMS, Worsening RRMSWorsening RRMS

12 mg/m12 mg/m22 over 5–15 over 5–15 min q3mo IV infusionmin q3mo IV infusion

*Trade names are included in this presentation to reduce confusion regarding medication formulations and in no way endorses the use of the product with the trade name.†Currently used as 2nd-line therapy.††Only indicated for progressive and/or worsening disease; cumulative dose should not exceed 140 mg/m2.

1. Natalizumab (Tysabri®). www.accessdata.fda.gov/drugsatfda_docs/label/2008/125104s106lbl.pdf2. Mitoxantrone (Novantrone®). www.accessdata.fda.gov/drugsatfda_docs/label/2009/ 019297s030s031lbl.pdf

Newly Approved Oral MS TherapiesNewly Approved Oral MS Therapies

Disease-Modifying Disease-Modifying TherapyTherapy Mechanisms of ActionMechanisms of Action

Fingolimod (FTY720) Sphingosine-1P (S-1P) receptor agonist

Blocks lymphocyte migration

Symptomatic Symptomatic ManagementManagement Mechanisms of ActionMechanisms of Action

DalfampridineBlocks voltage-dependent K+ channels

May restore conduction in poorly myelinated nerve fibers

Safety Considerations: Fingolimod & Safety Considerations: Fingolimod & NatalizumabNatalizumab

► FingolimodFingolimod● Lymphopenia is common because the drug sequesters Lymphopenia is common because the drug sequesters

lymphocytes in peripheral lymph nodeslymphocytes in peripheral lymph nodes1,21,2

• Reversal of lymphopenia can take ~ 2 to 4 weeks after the Reversal of lymphopenia can take ~ 2 to 4 weeks after the end of dosing, depending on the doseend of dosing, depending on the dose33

● First dose problems within 6 hoursFirst dose problems within 6 hours• BradycardiaBradycardia11 • Second-degree Wenckebach atrioventricular blockSecond-degree Wenckebach atrioventricular block

● Infections and malignanciesInfections and malignancies● Overall the 3 most important monitoring parameters:Overall the 3 most important monitoring parameters:

• Heart rateHeart rate• Macular edemaMacular edema• Pulmonary function tests (decrease FEV1) Pulmonary function tests (decrease FEV1)

► NatalizumabNatalizumab● TOUCH program = Progressive multifocal TOUCH program = Progressive multifocal

leucoencephalopathy (PML) leucoencephalopathy (PML) ● Infusion reactionsInfusion reactions● When stopping Natalizumab bridging needs to occur to When stopping Natalizumab bridging needs to occur to

prevent immune reconstitution inflammatory syndrome prevent immune reconstitution inflammatory syndrome (IRIS)(IRIS)44

1Brown et al. Ann Pharmacother. 22007;41:1660-1668; 3Kappos et al. N Engl J Med. 2006;355:1124-1140. 4Robinson R. Neurology Today. 07 OCT 2010;10(19):1,21.

TOUCH = Tysabri Outreach Unified Commitment to Health

FEV1 = forced expiratory volume in 1 second.

Phase IIb Laquinimod Study Phase IIb Laquinimod Study

Phase IIb Laquinimod StudyPhase IIb Laquinimod StudyEffect on Annualized Relapse RateEffect on Annualized Relapse Rate

► LAQ/5062 Study was LAQ/5062 Study was not powered to detect not powered to detect a statistically a statistically significant effect on significant effect on relapse raterelapse rate

► Trend (p=0.0978) Trend (p=0.0978) toward reduction of toward reduction of annualized relapse annualized relapse raterate

Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:2085-92.

PBO LQ 0.3mg LQ 0.6mg

33%

Ann

ualiz

ed R

elap

se R

ate

Ann

ualiz

ed R

elap

se R

ate

Phase IIb Laquinimod StudyPhase IIb Laquinimod StudyG

d-T

1 L

esi

on

Cou

nt

0.3 mg 0.6 mg Placebo

Laquinimod 0.6mg Reduced MRI Lesion Counts Early during the Treatment Course

Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:2085-92.

Conclusions & SummaryConclusions & Summary

► Laquinimod showed a robust, Laquinimod showed a robust, reproducible, sustained and early effect on reproducible, sustained and early effect on MRI activityMRI activity

► Laquinimod 0.6mg is safe and tolerableLaquinimod 0.6mg is safe and tolerable Transitory elevations of liver enzymes, most in the Transitory elevations of liver enzymes, most in the

first 3 months of Txfirst 3 months of Tx No signs of immunosuppression following No signs of immunosuppression following

prolonged exposureprolonged exposure

► Current data suggest a favorable, Current data suggest a favorable, balanced benefit-to-risk ratio of balanced benefit-to-risk ratio of laquinimod as a potential treatment for laquinimod as a potential treatment for RRMS patientsRRMS patients

Which ABCR Drug Is Best?Which ABCR Drug Is Best?ININFFββ vs vs ININFFββ

EVIDENCE = Evidence of Interferon Dose-response: European North American Comparative Efficacy; INCOMIN = Independent Comparison of Interferon; BEYOND = Betaseron Efficacy Yielding Outcomes of A New Dose; IM = Intramuscular; INF = Interferon; SC = Subcutaneously.

1Durelli et al. Lancet . 2002;359:1453-1460; 2Panitch et al. Neurology 2002;59:1496-506; 3Clanet et al. Neurology 2002;59:1507-1517; 4Comi G. Presented at: American Academy of Neurology 60th Annual Meeting; April 16, 2008; Chicago, IL. Abstract: LBS.003.

Which ABCR Drug Is Best?Which ABCR Drug Is Best? IN INFFββ vs GA vs GA

BEYOND = Betaseron Efficacy Yielding Outcomes of a New Dose; REGARD = Rebif vs Glatiramer Acetate in Relapsing Multiple Sclerosis Disease; BECOME = Betaseron vs Copaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-T MRI Endpoints.

1. Information presented at American Academy of Neurology 60th Annual Meeting, Abstract LBS.003; 2. Mikol et al.Lancet Neurol. 2008:7:903-914; 3.Wolansky et al. Mult Scler. 2007;12(suppl2):S58. Poster 206.;4. Cadavid et al. Mult Scler. 2007;12(suppl2):S58. Poster 207. 4. Haas J, Firzlaff M. Eur J Neurol. 2005;12:425-431.

Which New Agent is Best?Which New Agent is Best?New Agent vs.New Agent vs. ININFFββ

SENTINEL

trial1

Natalizumab + INFβ-1a IM vs INFβ-1a IM : The combination group was significantly more effective. The risk of relapse was 50% lower with combination therapy. Combination therapy represented 83% reduction in the number of new T2-lesions and an 89% reduction with gadolinium-enhancing lesions.

TRANSFORMS

trial2

Fingolimod 0.5 mg or 1.25 mg vs INFβ-1a IM: Superior efficacy of fingolimod with respect to relapse and MRI outcomes. Fingolimod reduced the annualized relapse rate to a range of 0.16 to 0.20 as compared to 0.33 for the INFβ-1a = a relative reduction of 38%-52%SENTINEL= The Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing

Remitting Multiple SclerosisTRANSFORMS= Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis

1Rudick RA et al. Natalizumab plus Interferon Beta-1a for Relapsing Multiple Sclerosis. The New England Journal ofMedicine. 02 Mar 2006;354;911-23. 2Cohen JA et al. Oral Fingolimod or Intramuscular Interferon for RelapsingMultiple Sclerosis. The New England Journal of Medicine. 04 Feb 2010;362:402-15.

SENTINEL= The Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with RelapsingRemitting Multiple SclerosisTRANSFORMS= Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis

1Rudick RA et al. Natalizumab plus Interferon Beta-1a for Relapsing Multiple Sclerosis. The New England Journal ofMedicine. 02 Mar 2006;354;911-23. 2Cohen JA et al. Oral Fingolimod or Intramuscular Interferon for RelapsingMultiple Sclerosis. The New England Journal of Medicine. 04 Feb 2010;362:402-15.

First-line therapies

Consistent effect on relapses and MRIUnclear effect on long-term disability

Potential to further enhance efficacy and ease of use

Oral agents Cladribine Laquinimod

Teriflunomide Fumaric acid

Monoclonal antibodies

DaclizumabAlemtuzumab

RituximabOcrelizumab

Combination therapy

IFN-basedGA-based

Novel agents

Main emerging therapies and strategies

GAIFN

FingolimodNatalizumab

Tx-naive patients

MS Forum Modern Management Workshop, February 2006, Glasgow, Scotland. Available at: http://www.msforum.net/Site/Slide-Sets-And-CD-Roms/Abbreviations: GA, glatiramer acetate; IFN, interferon beta.

Emerging MS TherapiesEmerging MS Therapies

Patient Adherence to MS Patient Adherence to MS MedicationMedication

► MS poses unusual challenges to adherenceMS poses unusual challenges to adherence● Needle phobiaNeedle phobia● New daily routinesNew daily routines● Perceived lack of efficacyPerceived lack of efficacy

► According to adherence studiesAccording to adherence studies● Many patients display new or increased depression within Many patients display new or increased depression within

6 months of treatment initiation6 months of treatment initiation11

• Depressed patients displayed decreased adherenceDepressed patients displayed decreased adherence11

• Treating depression may prevent treatment discontinuationTreating depression may prevent treatment discontinuation11

► Most frequent cause of stopping treatment is Most frequent cause of stopping treatment is perceived lack of efficacyperceived lack of efficacy22

● Most treatment withdrawals occur within 1st year of Most treatment withdrawals occur within 1st year of treatmenttreatment22

► Side effects and tolerability issues can result in Side effects and tolerability issues can result in nonadherence or discontinuation of medicationsnonadherence or discontinuation of medications

1. Mohr DC, et al. Arch Neurol. 1997;54:531-533. 2. Clerico M, et al. J Neurol Sci. 2007;259:104-108.

AdherenceAdherence

► Between 17% and 40% of patients stop Between 17% and 40% of patients stop taking taking disease-modifying drugsdisease-modifying drugs within 1 within 1 year of initiationyear of initiation1-31-3

► MultifactorialMultifactorial● Perceived lack of efficacyPerceived lack of efficacy1,21,2

● Adverse effectsAdverse effects2,32,3

● DepressionDepression• Within 6 months of treatment initiation, 41% of Within 6 months of treatment initiation, 41% of

patients had new or increased depressionpatients had new or increased depression44

• Decreased adherence in patients with untreated Decreased adherence in patients with untreated depressiondepression44

1. Clerico M, et al. J Neurol Sci. 2007;259:104-108. 2. Rio J, et al. Mult Scler. 2005;11:306-309. 3. Daugherty KK, et al. J Am Pharm Assoc. 2005;45:371-375. 4. Mohr DC, et al. Arch Neurol. 1997;54:531-533.

Studies of Patient Adherence Studies of Patient Adherence to MS Medicationsto MS Medications

► Longitudinal, prospective study of 199 Longitudinal, prospective study of 199 patients with definite MSpatients with definite MS● Of 97 patients taking DMTOf 97 patients taking DMT

• 73% missed doses73% missed doses• 10% missed >10 doses in a 6-month period10% missed >10 doses in a 6-month period• 25% stopped DMT25% stopped DMT

● Missed doses were associated with alcohol Missed doses were associated with alcohol intakeintake

● History of missed doses predicted future missed History of missed doses predicted future missed dosesdoses

● Numerous and divergent factors influenced Numerous and divergent factors influenced missed doses and stopping DMTmissed doses and stopping DMT• Indicates need for multifaceted approach to improving Indicates need for multifaceted approach to improving

adherenceadherence

Tremlett H, et al. Pharmacoepidemiol Drug Saf. 2008;17:565-576.

Patients in United States Find it Patients in United States Find it Harder to Pay for CareHarder to Pay for Care

Patients stating that they often have difficulty payingPatients stating that they often have difficulty payingfor medications or other care costsfor medications or other care costs

Graphic courtesy of Dr. Robert J. Lipsy.The Commonwealth Health Fund 2009 International Healthy Policy Survey of Primary Care Doctors. Health Affairs. 5 November 2009.

Anti-TNF Prescription AbandonmentAnti-TNF Prescription Abandonment

As out-of-pocket expenses increase, treatment abandonment increases

With permission from Gleason PP, et al. J Manag Care Pharm. 2009;15:648-658.

Promoting Adherence to Therapeutic Promoting Adherence to Therapeutic Regimens in MSRegimens in MS

Establishing Realistic ExpectationsEstablishing Realistic Expectations

Therapies have been shown to reduce relapses, Therapies have been shown to reduce relapses, reduce MRI activity, and attenuate disease reduce MRI activity, and attenuate disease activityactivity

• Attenuated disease activity may lead to more Attenuated disease activity may lead to more patients retaining employmentpatients retaining employment

Patients with MS must also realize that DMTsPatients with MS must also realize that DMTs• Only work if patients take themOnly work if patients take them• Are not cures for MSAre not cures for MS• May not eliminate MS symptomsMay not eliminate MS symptoms• Do not completely eliminate future disease activityDo not completely eliminate future disease activity

Cerghet M, et al. 60th AAN; April 12-19, 2008; Chicago, IL. P05.073. Putzki N, et al. 60th AAN; April 12-19, 2008; Chicago, IL. P05.076.

Disease-Modifying TherapiesDisease-Modifying Therapies

► Relapse free at 1 year 51%–80%Relapse free at 1 year 51%–80%► Relative decrease in annual relapse rate 30%–Relative decrease in annual relapse rate 30%–

80%80%► Absolute annual relapse rate 0.15–0.7Absolute annual relapse rate 0.15–0.7► Relative decrease in sustained progression Relative decrease in sustained progression

31%–42%31%–42%► Absolute rate of disease progression Absolute rate of disease progression

9%–18%9%–18%► Workers with MS on a DMT and not on a DMTWorkers with MS on a DMT and not on a DMT11

● N=258 vs. N=322N=258 vs. N=322● Treatment with DMT = reduced medical and Treatment with DMT = reduced medical and

indirect costsindirect costsData courtesy of Dr. Robert J. Lipsy.1. Birnbaum et al Curr Med Res Opin. 2009;25(4):869-877.


1.1. How will pharmacoviligance programs for MS How will pharmacoviligance programs for MS therapies used in managed care settings will need therapies used in managed care settings will need to adapt and change when potentially new, to adapt and change when potentially new, immunosuppressive therapies with a variable immunosuppressive therapies with a variable range of adverse effects and toxicities become range of adverse effects and toxicities become available?available?

2.2. How, depending on the risk-to- benefit ratio and How, depending on the risk-to- benefit ratio and pharmacovigilance requirements for new therapies, pharmacovigilance requirements for new therapies, will managed care pharmacy and medical directors will managed care pharmacy and medical directors respond to a new landscape for MS as oral agents respond to a new landscape for MS as oral agents with potentially less favorable side effect profiles with potentially less favorable side effect profiles become available?become available?

3.3. What will be the role that electronic records and What will be the role that electronic records and meticulous documentation of MS treatment plans meticulous documentation of MS treatment plans play in the near future as multiple agents, with play in the near future as multiple agents, with potentially additive immunosuppressive properties, potentially additive immunosuppressive properties, become available for treating MS in the managed become available for treating MS in the managed care setting?care setting?

Documents

The Evolving Landscape of MS Therapy New Frontiers in Managed Care Pharmacy Practice Emerging Challenges on the Therapeutic Landscape of Multiple Sclerosis