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The Evolving Landscape of MS Therapy
New Frontiers in Managed Care Pharmacy Practice
Emerging Challenges on the Therapeutic
Landscape of Multiple Sclerosis
The Managed Care Pharmacy and Medical
Director’s Perspective
Program Chairman
Douglas R. Jeffery, MD, PhD
Director, Multiple Sclerosis Center
Advance Neurology
Advance, NC
Welcome and Program Overview
CME-certified symposium jointly sponsored
by the University of Massachusetts Medical
School and CMEducation Resources, LLC
Commercial Support: Supported by an
independent educational grant from Teva
Neuroscience, Inc.
Faculty disclosures: Listed in program
syllabus
NOTE: Both trade and chemic names may
be used in this program to establish clarity,
and because many trials use acronyms that
employ the brand name. The use of brand
names should not be construed as
endorsements for these products.
Program Faculty
Program Chairman
Douglas R. Jeffery, MD, PhD
Director, Multiple Sclerosis Center
Advance Neurology
Advance, NC
Norman Kachuck, MD
Associate Professor of Neurology
Chief, Neuroimmunology Division,
Department of Neurology
Director, Multiple Sclerosis Comprehensive
Care Center and Research Group
Vice-Chair, Health Sciences IRB
University of Southern California Keck
School of Medicine
Los Angeles, California
Ronald J. DeBellis, PharmD, FCCP
Professor and Chairman
Department of Pharmacy Practice-Vermont
Campus
Albany College of Pharmacy and Health
Sciences
Colchester, VT
Jacquelyn Bainbridge, PharmD,
FCCP
Associate Professor
Department of Clinical
Pharmacy/Department of Neurology
University of Colorado Denver
Aurora, CO
Program Agenda and Format
8:00 AM — 8:20 AM
Welcome and Introduction
The Evolving and Complex Therapeutic Landscape
for Multiple Sclerosis: Achieving the Ideal Balance
Between Safety and Efficacy for Long-Term
Treatment In the Managed Care Setting
What Will Goals of MS Management in the Managed
Care Setting Be? How Should MCO Pharmacists, Medical
Directors, and Neurologists Respond?
Program Chairman
Douglas R. Jeffery, MD, PhD
Director, Multiple Sclerosis Center │ Advance Neurology │
Advance, NC
8:20 AM — 8:40 AM
Group Discussion: Discuss Emerging Concerns,
Challenges, and Strategic Needs for Optimizing
MS Care in the Managed Care Environment
Program Agenda and Format
8:40 AM — 9:05 AM
Trial-Based Evidence for First Line Therapy with
Immune- Modulating Agents (IMTs): From Mechanisms
to Therapy—Landmark Studies, Long-Term Safety Data,
and Clinical Experience with IMTs in the Managed Care
Environment
Current Foundations of MS Care in the Managed Care Setting:
What Has Worked? What Hasn’t? Where Is the Room for
Improvement?
Program Chairman
Douglas R. Jeffery, MD, PhD
Director, Multiple Sclerosis Center │ Advance Neurology │ Advance, NC
9:05 AM — 9:20 AM
Group Discussion: Discuss Current Strategies and MS
Treatment Paradigms Using IMT-Based Platforms for
Initial Therapy for MS in the Managed Care Setting
Program Agenda and Format
9:20 AM — 9:45 AM
The Emergence of Oral Immunosuppressive and
Other Agents for MS: What Do We Know (or Not
Know) About Their Safety and Efficacy?
Cautionary Notes for Managed Care Pharmacy and Medical
Directors, and MS Treaters in Managed Care: How Do We
Monitor Adverse Events, Risks for Infection, and Signals for
Malignancy Over the Long Term?
Norman Kachuck, MD
Associate Professor of Neurology │ Chief, Neuroimmunology Division,
Department of Neurology │ Director, Multiple Sclerosis
Comprehensive Care │ Center and Research Group │ Vice-Chair,
Health Sciences IRB │ University of Southern California Keck School
of Medicine │ Los Angeles, California
9:45 AM — 10:00 AM
Group Discussion: Discuss Complexity of Evolving
Agents for MS and Approaches to Making a RiskBenefit Analysis
Program Agenda and Format
10:00 AM — 10:20 AM
The Changing MS Therapeutic Landscape:
Perspectives of an MS-Focused Pharmacist—
How Will We Need to Adapt to and Analyze
the New Generation of MS Therapies?
How Will Pharmacy and Medical/Neurology
Program Directors Come Together to Make
Decisions About Long-Term Therapy for MS in the
Managed Care Setting?
Ronald J. DeBellis, PharmD, FCCP
Professor and Chairman │
Department of Pharmacy Practice-Vermont Campus │
Albany College of Pharmacy and Health Sciences │
Colchester, VT
10:20 AM — 10:40 AM
Group Discussion: The Near Future of MS
Care
Program Agenda and Format
10:40 AM — 11:00 AM
The Role of Comparative Effectiveness Guidelines,
Long Term Safety Considerations, and Monitoring
Costs for Evaluating Therapies for MS
Impact on Managed Care-Based Management for Improving
Health Outcomes and Providing Value for their Health
Plans—The Managed Care Medical and Pharmacy Director’s
Perspective
Jacquelyn Bainbridge, PharmD, FCCP
Associate Professor │ Department of Clinical │ Pharmacy/
Department of Neurology │ University of Colorado
Denver │ Aurora, CO
11:00 AM — 11:30 AM
Group Discussion: The Complexities, Challenges and
Solutions for Making Sense and Adapting to the
Emerging Landscape—and New Risk/Benefit
Equations—of Oral Agents for MS. Will Patient
Registries Be Required?
Format: We Want a Dialogue
PROGRAM FORMAT
Following each didactic presentation, we will call upon the
regional and local leaders in the managed care community—
pharmacy, medical and department of neurology directors
who are seated at the faculty table—to respond, analyze
and discuss how they and their colleague are responding to
these new challenges and dilemmas.
We thank them for coming and participating as adjunct
faculty members and educational leaders for this program.
The Group Discussions are key to helping us complete the
journey form “challenges” to real world “solutions.”
Epidemiology of Multiple Sclerosis
►
The most common chronic disease affecting the CNS in young adults
►
Approximately 400,000 cases in the United States
●
Estimates range from 250,000 to 500,000
►
The chances of developing MS are 1:1000 in the general population
►
Estimated 2.5 million cases worldwide
►
Highest incidence in Caucasians
►
Higher incidence in women (approximately 3:1)
►
MS strikes individuals between the ages 20-50, normally a time of
peak productivity
CNS = central nervous system.
Compston A, et al. Lancet. 2002;359(9313):1221-1231. Frohman EM. Med Clin N Am. 2003;87(4):
867-897. Hogancamp WE, et al. Mayo Clin Proc. 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
January 8, 2009. Lage MJ, et al. Work. 2006;27(2):143-151.
Age of Onset of Multiple Sclerosis
Distribution of Patients According to
the Decade of Life of MS Symptoms Onset
35
Patients (%)
30
25
20
15
10
5
0
0-10
11-20
21-30
31-40
Years
Cardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):727-730.
41-50
51-60
Clinical Manifestations of MS
►
Fatigue
►
Optic neuritis
►
Pain
►
Bladder dysfunction
►
Depression
►
Bowel dysfunction
►
Numbness/paresthesias
►
Cerebellar dysfunction
►
Cognitive dysfunction
►
Sexual dysfunction
►
Weakness
►
Gait abnormalities
►
Spasticity
►
Partial/complete
paralysis
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-knowabout-ms/symptoms/index.aspx. Accessed February 21, 2010.
Natural History of MS and Cost of MS
Pre-clinical
CIS
RRMS
SPMS
Atrophy and Axonal
Degradation
Predicted Cost
Early
Intervention*
MRI lesion
activity
*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.
US$ per Year
Clinical Threshold
Progression of Disability: EDSS
10.0 = Death due to MS
9.0–9.5 = Completely dependent
Increasing
disease
burden
8.0–8.5 = Confined to bed or chair
7.0–7.5 = Confined to wheelchair
6.0–6.5 = Walking assistance is needed
5.0–5.5 = Increasing limitation in ability to walk
4.0–4.5 = Disability is moderate
3.0–3.5 = Disability is mild to moderate
2.0–2.5 = Disability is minimal
1.0–1.5 = No disability
0 = Normal neurologic exam
EDSS = Expanded Disability Status Scale.
Kurtzke JF. Neurology. 1983;33:1444-1452.
Baseline Brain MRI Lesion Number
20-Year Clinical Status
Fisniku LK. Brain 2008;131:808-817.
Baseline Brain MRI Lesion Number
20-Year Clinical Status
Fisniku LK. Brain 2008;131:808-817.
Immunopathogenesis of the MS Lesion
gdT
Histamine
Proteases
TNFa
NAA, ATP
NO
O2
5-HT
CD8
Oligo
MO
Virus
B7 CD28
Th1
Th17
Microglia
Mast Cell
B
IFNg
TNF
Th17
Glutamate
Ab+C9neo
Pl
NO
Oi
TNFa
MMP
IL-10
TGFb
MCP-1
MIP-1a
IP-10
RANTES
Astrocyte
BBB
ICAM-1
MMP- VCAM-1
2/9
LFA-1
VLA-4
Th1
VCAM-1
Complement
gdT
Monocyte
Granutocyte
CD8
IFNg
TNF
IL-17
Th17
IL-4
IL-5
IL-6
IL-13
TGFb
B
IL-23
TCR
Thp
Treg
Th2/
Th3
IL-4 & IL-10
IL-12
CD4
Figure courtesy of Dhib-Jalbut S, 2008
Treg
CD4+CD25+
CD40 CD40L
Mast Cell
Th2/
Th3
B7 CD28
HLA
APC
CD4
Myelin Ag
Microbial Ag
Thp
APC
CD40 CD40L
Trends Across MS Clinical Trials
Annualized Relapse Rate (ARR)
Johnson
1995
Jacobs
1996
IFNβ-1b PRISMS-2 Kappos Polman
study
1998 TRANSFORMS 2006
group,1993
REGARD
2007
BEYOND
2007
BECOME
2007
CAMMS223
2008
3 years
HERMES
2008
48 weeks
FORTE
2008
1 year
CLARITY
2009
Goals of Treatment
►
Reduce frequency of relapse
►
Slow progression of disability
►
Reduce MRI activity
►
Prevent morbidity from symptoms and provide
palliative care
►
Maintain adherence
►
Provide long-term efficacy and safety
Existing and Emerging MS Therapies
2005
2006
2007
2010
2013
BG12
BG12
Cladribine
Cladribine
Rebif
Rebif
Fingolimod
Betaseron
Teriflunomide
Teriflunomide
Ampyra
Ampyra
Copaxone
Laquinimod
Laquinimod
Extavia
Extavia
Avonex
Novantrone
2012
Oral
Injectables
IV
2011
Ocrelizumab
Ocrelizumab
Tysabri
Tysabri
IV
Generic
Generic
Mitoxantrone
Mitoxantrone
(oncology)
(MS)
(oncology)
MS
Alemtuzumab
Alemtuzumab
Approved
In phase II
In phase III
Filed
The Evolving Landscape of MS Therapy
► New generation of multiple sclerosis therapies is
currently emerging
► Among them are four oral agents: dalfampridine,
laquinimod, cladribine, and fingolimod, that have been
or likely will be approved for managing patients with
MS
► Efficacy data for these new oral agents are impressive
and demonstrate that they have the potential to
replace or complement injectable treatment options
for MS
The Evolving Landscape of MS Therapy
► However, there are concerns relating to safety and
cost, especially for the immunosuppressive agents
► In addition, patients with MS have poor treatment
adherence to the current available therapies and it is
uncertain if the introduction of oral agents will
increase patient adherence
Analyzing Risk-to-Benefit Equation for
Established and Emerging Agents
Questions We Will Address Today
1. How has your organization decided to provide and
make decisions about MS care?
2. Who makes these decisions? A formulary
committee? Department of Pharmacy? Neurologists
and MS Specialists? A consensus among many
stakeholders?
3. Are all MS drugs available in your managed care
organization? Or have you made restrictions and/or
prioritized agents? And if so, how and why?
The Evolving Landscape of MS Therapy
4. Do you employ a formalized pathway for MS care in
your MCO? For first-line treatment? Second line
treatment? Or are these decisions left to the
treating physicians?
5. What is the patient's role in determining the initial
MS therapy offered to them? Is it a dialogue? If so,
what is the shape of the dialogue? If not, how is
the decision made?
The Evolving Landscape of MS Therapy
MISSION STATEMENT
The purpose of this “Challenges and Solutions” Workshop
is to discuss possible approaches for evaluating the riskbenefit-cost profiles of these new oral agents; to compare
them against established IMTs and each other; to evaluate
the implications for long-term safety monitoring and
pharmacovigilance that will be required, especially for
immunosuppressive agents; how placement of these oral
agents on managed care organization (MCO) formularies
may also influence and/or modify use of established IMTs;
and what impact this landscape change might have on
clinical outcomes of MS patients managed in MCOs.
Investigations • Innovation • Clinical Application
The Evidence for First Line Therapy
with Immune-Modulating Agents
Landmark Trials, Perils and Pitfalls of CrossTrial Comparisons, and What can be Learned
from Long Term Studies
Program Chairman
Douglas R. Jeffery, MD, PhD
Director, Multiple Sclerosis Center
Advance Neurology
Advance, NC
Overview of Presentation
►
Mechanisms of action of IMTs
►
Outcome measures in clinical trials
►
Comparison of landmark trials
►
Longitudinal studies: what do they tell us?
►
Price of MS versus cost of treatment
The Evolving Landscape of MS Therapy
Mechanisms of
Action
IFN-b: Activity
Blood
BBB
CNS
MMP
IFN-β
TH1+
Myelin
protein
Antigen
TH1+
APC
Resting
T cell
Activated (+)
T cells
TH1+
TH1
APC
MMP
IL-2
TNF-α
TH1+
IFN-γ
IFN-β
Adapted from Yong VW. Neurology. 2002;59:802-808.
Glatiramer Acetate: Activity
BBB
Periphery
CNS
APC
TCR
GA therapy
Macrophage
MHC
GA
TCR
Microglia
Bystander
suppression
effect
MHC
CNS Ag
TCR
IL-4
IL-10
+
+
Anti-inflammatory
cytokines
BDNF
Neurotrophins
GAspecific
T cell
TH1
TH2
Adapted from Ziemssen T et al. J Neurol Sci. 2005;233:109-112.
TH2
Neuroregeneration
Fingolimod: modulates S1P1 receptors
S1P receptor
Prevents T cell
invasion of CNS
T cell
FTY720-P
FTY720 results in internalisation
of the S1P1 receptor
This blocks lymphocyte egress
from lymph nodes while sparing
immune surveillance by
circulating memory T cells
LN
FTY720 traps
circulating
lymphocytes
in peripheral
lymph nodes
Laquinimod Induced Immunomodulation
on the Molecular Level
Overexpression/downregulation
Long-Term Disability
Effect of Early Relapses
Percent Pts DSS < 6
100
Low (0-1 attacks in 2 years)
Intermediate (2-4 attacks in 2 years)
High (> 5 in 2 years)
80
60
40
p < 0.0001
20
0
0
10
20
30
40
Time from onset of MS (years)
Weinhenker B et al. Brain. 1989;112:1422
50
Relapses in Multiple Sclerosis
►
Relapses are the most obvious evidence of
inflammatory disease activity in RRMS
►
Relapse frequency in typical untreated RRMS
populations enables treatment effect to be rapidly
assessable in a 12-month clinical study
Total number of relapses during the study period
Total in-study person-years
FREEDOMS
Primary Endpoint: Annualized Relapse Rate
0.4
Annualized relapse rate
0.40
p<0.001
0.3
54%
reduction
p<0.001
60%
reduction
0.2
0.18
0.16
Fingolimod 0.5 mg
(n=425)
Fingolimod 1.25 mg
(n=429)
0.1
0
Placebo
(n=418)
ARR was consistently reduced in both treatment-naïve patients and
patients previously treated with DMT (p<0.01 for all comparisons)
ITT population
Negative binomial regression model adjusted for treatment group, country, number of relapses in
previous two years and baseline Expanded Disability Status Scale
ARR, annualized relapse rate; DMT, disease-modifying therapy
Effect on Annualized Relapse Rates:
Summary of Phase III Trials – 2 years in-study
% Reduction in relapse rates
70
60%
60
P<.0001
50
40
30
31%
29%
P<.0001
P=.0001
18%
20
32%
P<.001
29%
P=.055
P=.04
10
0
250 µg qod
IFN β-1b
30 µg qw
IFN β-1a
22 µg tiw
IFN β-1a
44 µg tiw
IFN β-1a
20 mg qd
glatiramer
acetate
0.5 mg qd
fingolimod
N.B.: Results are from separate clinical trials
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; Rebif package insert.
Kappos et al. N Engl J Med 2010;362:387-401; Gilenya package insert.
Relapses Can Result in
Residual Long-Term Disability
Net Change in EDSS Score from before a Relapse to after a Relapse*
100
42.4% increase 0.5 or more
Number of Subjects
86
80
28.1% increase 1 or more
60
40
32
33
20
20
1
3
-3.5
-2.5
7
4
14
8
8
5
1
2
3.5
4.0
0
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
42% of patients had a residual deficit ≥0.5 point
28% had a residual deficit ≥1.0 point
*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.
Medical Costs Per Relapse
$243
$1847
$12,870
Low-Intensity Episode
Initial Contact
Moderate-Intensity Episode
Initial Contact
High-Intensity Episode
Initial Contact
Usual care physician
Usual care physician
Usual care physician
ED
ED
IV Methylprednisolone
Hospital day case
Hospital Admission
Post Discharge Services
Home administration
Outpatient follow-up
Symptom-Related Medications
Rehabilitation
Home healthcare
Skilled nursing
Nursing home
Hospital readmissions
Follow-Up Office Visits
Symptom-Related Medications
Follow-Up Office Visits
Consults
Therapists
ED = emergency department; IV = intravenous.
O’Brien J, et al. BMC Health Serv Res. 2003;3(1):17-28.
Economic Implications
►
Annual cost of MS in the United States is estimated at
approximately $13.6 billion (in 1994 dollars)
►
Total lifetime direct and indirect costs per patient are estimated
at approximately $2.4 million (in 1994 dollars)
►
Mean annual direct and indirect costs per patient total an
estimated $47,215 (in 2004 dollars)
►
Mean direct healthcare costs incurred by insured patients with
MS are 2 to 3 times higher than those without MS
►
Direct correlation between cost (direct and indirect) and severity
of disease has been well-established
►
Therapeutics that modify MS activity and severity can result in
both clinical and economic benefits
Whetton-Goldstein K, et al. Mult Scler. 1998;4(5):419-425. Pope GC, et al. Neurology. 2002;58(1):37-43.
Kobelt G, et al. Neurology. 2006;66(11):1696-1702. Patwardhan MB, et al. Mult Scler. 2005;11(2):232-239.
O’Brien JA, et al. J Neurosurg Psychiatry. 2006;77:918-926.
Is MS All About Relapses?
►
Hypothesis: if relapses cause long-term
disability then patients with frequent relapses
should be at higher risk for disability
►
From the London Ontario natural history
studies patients with frequent attacks are at
highest risk for future ambulatory disability
►
Assumption: modifying the relapse rate will
influence long-term disability
Weinshenker et al. 1989 Brain 112:1419
Proportion of Placebo Groups
with Clinical Activity
Relapses
EDSS
Progress
IFNβ-1b (3 year)
86%
39%
IFNβ-1a (QW) (2 year)
77%
35%
IFNβ-1a (TIW) (2 year)
84%
38%
Glatiramer acetate (2 year)
73%
25%
Fingolimod (2 year)
54%
24%
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.
How is Sustained Progression
Measured?
►
Most clinical trials define progression by
demonstrating a 1 point change in the EDSS,
and then confirming the change in 3 or 6
months
►
Does this measure of confirmed progression
reflect permanent disability?
►
If so, then confirmed changes in EDSS during
the course of the trial should be sustained by
the end of the study
Reduction in
sustained disability
progression (%)
Effect on Sustained Disability*:
Summary of Phase III Trials
40
37%
35
P=.02
30
25
29%
P=NS
37%
6 mon
30%
P=.02
30%
P<.05
P=.02
22%
P<.05
20
12%
15
P=NS
10
5
0
250 µg qod
IFN β-1b
30 µg qw
IFN β-1a
22 µg tiw
IFN β-1a
44 µg tiw
IFN β-1a
20 mg qd
glatiramer
acetate
0.5 mg qd
fingolimod
*1 EDSS point sustained for 3 months in IFN β-1b, IFN β-1a tiw, GA trials and
fingolimod phase III trials. 1 EDSS point sustained for 6 months in IFN β-a qw and
fingolimod phase III trials.
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
Kappos et al. N Engl J Med 2010;362:387-401; Gilenya package insert.
Summary
► Disability progression in clinical trials with RRMS patients is
for the primarily related to disability from relapses
► Relapse rate reduction and the mean change in EDSS are
the most sensitive clinical outcome measures in MS trials
► The generally accepted sustained change in EDSS measure
is not a reliable marker of long term disability
► Phase III trials results showed:

The interferons, glatiramer acetate and fingolimod reduce the relapse rate

IFN beta-1a and fingolimod have statistically significant effects on sustained
change in EDSS measure over two years

IFN beta-1a, glatiramer acetate and fingolimod have statistically significant
impacts on the mean change in EDSS over two years
The Evolving Landscape of MS Therapy
Are direct comparator studies
needed in MS or can we make valid
conclusions from cross trial
comparisons?
Cross Trial Comparisons
Relative Efficacy (RR)
IFNβ-1a
30 µg
qw
IFNβ-1b,
250 µg
qod
IFN β-1a
44 µg
tiw
GA
20 mg
qd
Fingolimod 0.5
mg qd
Relapse rate
(annualized)
-18%
-34%
-32%
-29%
-60%
Relapse-Free (2 years)
+42%
+95%
+100%
+36%
+52%
Progression free
-37%
-29%
-30%
-12%
-30% / -37%
New T2 Lesions
-36%
-83%
-78%
-38%
-75%
Gd+ Lesions
-42%
-
-88%
-33%
-82%
Predict: IFNβ-1a tiw will be superior to GA for relapse free outcome
The REGARD Trial
Time to First Relapse (1o endpoint)
Survival distribution function
1.00
672 days
(96 weeks)
IFNβ-1a tiw
0.75
GA
Hazard ratio (95% CI):
0.943 (0.74, 1.21)
p = 0.643
0.50
0.25
0.00
0
100
200
300
400
500
Time to first relapse (days)
600
700
Head to Head Studies and
Cross Trial Comparisons
►
Head to head studies of glatiramer acetate and interferon
β underscore the problem with cross trial comparisons
►
Differences in patients enrolled in different studies heavily
influence disease activity observed during trials
►
Differences in definitions of relapses (confirmed versus
non-confirmed) and disability measures (3 month versus 6
month sustained change versus mean change in EDSS)
may be different between studies further complicating
cross trial comparisons
►
Relative efficacy is best measured by well-designed head
to head trials
The Evolving Landscape of MS Therapy
What can be learned from
long-term follow up studies?
Long-Term Follow Up
►
Do long-term follow up studies adequately
address medication safety?
►
Do long-term studies adequately address
longitudinal efficacy?
►
Have methods of analysis for longitudinal
studies been optimized?
Sources of Bias in LTFU Studies
Bias
Impact
Strategy
Ascertainment
Modified therapeutic effect dependent
on characteristics of participating
patients.
F/U must be as complete as possible
Directly compare baseline and onRCT characteristics of those patients
in LTF to those not in LTF
Informed
Therapeutic
Decisions
Inflated estimate of therapeutic benefit
because patients doing well continue
therapy whereas failing patients switch
or stop therapy.
MPR: Use percent of total possible
time on therapy instead of absolute
time to assess exposure.
Treatment
Selection
Modified therapeutic effect dependent
on patient selection characteristics.
Propensity Scoring: Adjust for the
propensity (i.e., likelihood) that a
particular treatment will be selected
based on available patient
characteristics
Multiple Testing
Increased risk of Type 1 error from the
use of multiple predictor variables and
weighting schemes
Create a single model and apply
adjustments to p-values according to
the number of predictors tested in the
model.
Glatiramer Acetate 15 year LTFU
Ford C et al. Mult Scler. 2010;16:342-50.
Glatiramer Acetate 15 year LTFU
Ford C et al. Mult Scler. 2010;16:342-50.
Glatiramer Acetate 15 year LTFU
►
In a small cohort of patients (N=100) followed
for 15 years, glatiramer acetate was safe and
well tolerated
►
65% of continuously treated patients did not
progress to SPMS
►
41% of patients withdrawing from the study did
so because of disease progression
●
►
Propensity scores were used to try to adjust for
differences between ongoing and withdrawing
patients
EDSS at baseline predicts EDSS at 15 years
IFN β-1b LTFU Design
Pivotal Study (n=372)
IFNβ-1b 250 µg
124
56
IFNβ-1b 50 µg
125
52
Placebo
123
58
1988 1990
Patients under regular medical care no trial
1993
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
Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666
Ebers G et al. presented at AAN, October 2006: M-3
LTF
2005
IFN β-1b LTFU Adjusted Outcome
►
►
►
LTFU of IFN β-1b showed that patients
with a baseline EDSS score ≤ 2 were
more likely to have lower disability at 15
year follow up than patients with
baseline EDSS scores > 2 regardless
of treatment
Any Variable + Any Exposure Weighting – Any
Negative Outcome
For patients with baseline EDSS score >
2, the duration of exposure to treatment
with IFN β-1b influenced the long term
outcome.
Patients with longer duration of
treatment had less disability than
patients with shorter duration of
treatment
Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666
Ebers G et al. presented at AAN, October 2006: M-3
1
EDSS
p<0.001
2
Exposure
p<0.001
Low
High
Conclusions
► Disease modifying therapy seems to favorably effect the
long-term course of MS
► Propensity score adjusted analysis and other statistical
methods for controlling biases inherent in long term, open
label studies are important statistical advances for
interpreting these studies
► These methods can provide complimentary information
about the long term effects of treatment without the cost
(and ethical dilemmas) posed by long-term placebocontrolled trials
The Evolving Landscape of MS Therapy
Price of MS versus
Cost of Care.
Is Treatment Worth It?
MS Cost Drivers
Informal Care (12%)
Sick Leave/Reduced Working Time (10%)
Adaptations (5%)
Services (2%)
Other Drugs (6%)
Early Retirement (34%)
DMTs (22%)
Tests (2%)
Ambulatory Care (4%)
DMT = disease-modifying therapy.
Kobelt G, et al. Neurology. 2006;66(11):1696-1702.
Hospital Inpatient Care (3%)
Cost of Care
Cost and functionality
Approximate Mean Annual Cost*
EDSS Score
Medical
Unpaid
Caregiver
Time
Lost Work
Time
Total
Mild
$3,106
$932
$9,938
$13,976
Moderate
$5,100
$3,188
$22,950
$31,238
Severe
$12,524
$12,524
$21,291
$46,339
EDSS 0 - 3.5
EDSS 4.0 - 6.0
EDSS 6.5 - 9.5
* 2004 US Dollars Non-Drug Costs
Adapted from: Kobelt G, Berg J, Atherly D et al. Neurology. 2006; 66:1696–1702.
DMT-Associated Costs
►
Approximately 65% of annual direct per patient healthcare costs
in MS are attributable to drug therapy
►
MS drugs represent 20.2% of specialty drug expenditures within
managed care plans
►
National trend in MS drug expenditures was +18.3% in 2008
23.5% increase in manufacturer pricing was primary driver of trend
●
Agent
Dosage
AWP/day
AWP/year
Interferon beta-1b
0.25 mg SC every other day
$105.41
$38,475
Interferon beta-1a IM
30 mcg IM once weekly
$98.66
$36,010
Interferon beta-1a SC
44 mcg SC 3 times weekly
$106.20
$38,761
Glatiramer acetate
20 mg SC daily
$110.10
$40,187
Fingolimod
0.5 mg PO daily
$131.51
$48,000
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.
Recent Analyses of the Economic
Impact of MS Treatment
►
In an analysis of an employer medical, drug and disability claims
database:
●
●
●
►
Baseline MS-related medical costs were higher for treated vs
untreated employees ($2520 vs $1012,P < 0.0001)
Risk-adjusted total annual medical costs ($4,393 vs $6,187) and
indirect costs ($2,252 vs $3,053) were significantly lower (P <
0.0001) for treated vs untreated employees with MS
Study limitation: lack of clinical detail on MS severity
Early use of DMTs in patients with CIS that delayed conversion to
CDMS provided a positive incremental cost-effectiveness ratio
(ICER) per patient-year compared with 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.
Effect of Immunomodulatory Therapy
on Employment Loss Time
60
(P = .003)
Fewer Days Absent
50
GA
INFbeta-1a
INFbeta-1b
40
(P = .04)
30
20
10
(P = .03)
(P = .18)
(P = .47)
(P = .09)
(P = .71)
(P = .33)
(P = .39)
0
-10
Short-term
Disability
Workers
Comp
Any
Reason
-20
Fewer days absent from work from 1999–2002 for individuals with MS treated with GA (n = 28), INFb1a (n = 74), or INFb-1b (n = 16) compared to untreated individuals with MS (n = 166)
Lage MJ, et al. Work. 2006;27(2):143-151.
MS Consensus Guidelines
►
National MS Society Expert Consensus Statement (2007)
●
●
●
●
●
●
Initiate therapy as soon as possible following diagnosis of activerelapsing disease with an interferon beta agent or glatiramer
acetate
Drug therapy should also be considered in patients with first
attack at high risk of MS
Access to medications should not be limited by age, level of
disability, or frequency of relapses
Continue treatment indefinitely unless lack of benefit, intolerant
adverse effects, or better treatment becomes available
Ensure adequate accessibility of all FDA-approved drugs for MS
Change treatments only for medically appropriate reasons
National Clinical Advisory Board of the National MS Society. MS Disease Management Consensus
Statement. 2007. http://www.nationalmssociety.org. Accessed February 10, 2010.
Conclusion
►
MS is a chronic, debilitating, and progressive disease
►
Economic implications are significant and appear directly
correlated with disease severity
►
Although costly, long-term data and expert consensus
support the primary role of DMT in managing disease
progression
►
Optimal therapeutic benefit with DMT hinges strongly on
multidimensional support from the healthcare system
►
Patient education and careful monitoring are key factors
driving success in MS therapy
Questions to Consider
1. How do you anticipate responding to the new MS
treatment landscape that will include high cost, oral
therapies that require monitoring measures?
2. How, depending on the risk-to- benefit ratio, will
managed care pharmacy and medical directors
respond to a new landscape for MS as oral agents
with potentially less favorable side effect profiles
become available?
Questions to Consider
3. Given these considerations, in the absence of longterm data, how do you get to the bottom of a
benefit-risk-cost decision for new MS therapies in
the managed care setting? How will that play out?
4. What incentives are there, if any, for altering the
current approach to initial therapy for MS, in
which IMTs have demonstrated long-term safety
and efficacy?
5. How will Obamacare influence MS treatment
decisions?
Investigations • Innovation • Clinical Application
The Next Generation of Immune-Modulating
Therapies for MS
What do we know (and not know)
about their safety and efficacy
How will their usefulness be established?
Norman Kachuck, MD
Associate Professor of Neurology
Chief, Neuroimmunology Division,
Department of Neurology
Director, Multiple Sclerosis Comprehensive Care Center and Research Group
Vice-Chair, Health Sciences IRB
University of Southern California Keck School of Medicine
Los Angeles, California
Existing and Emerging MS Therapies
2005
2006
2007
2010
2013
BG12
BG12
Cladribine
Cladribine
Rebif
Rebif
Fingolimod
Betaseron
Teriflunomide
Teriflunomide
Ampyra
Ampyra
Copaxone
Laquinimod
Laquinimod
Extavia
Extavia
Avonex
Novantrone
2012
Oral
Injectables
IV
2011
Ocrelizumab
Ocrelizumab
Tysabri
Tysabri
IV
Generic
Generic
Mitoxantrone
Mitoxantrone
(oncology)
(MS)
(oncology)
MS
Alemtuzumab
Alemtuzumab
Approved
In phase II
In phase III
Filed
What We Do Not Know
►
What initiates MS?
►
Can we identify the different pathogenetic
mechanisms in different individuals?
►
Which occurs first: Myelin breakdown or
oligodendrocyte destruction?
►
What are the mechanisms of axonal injury/loss?
►
What mediates regeneration of
axons/myelinating elements
►
Why does repair ultimately fail?
Implications of the Paradigm Shift
►
Homogeneity of lesion type in an individual
►
Heterogeneity in the phenotype of disease
across individuals
►
Variable response to a given intervention due to
this heterogeneity
►
Likely need to create combinations of therapies
based on an individual’s disease
►
Biomarkers and noninvasive metrics are
critical to evaluate, target, and follow
disease and its injury and repair response
to treatment
Bielekova B, Martin R. Brain. 2004;127;1463-1478.
What We Do Not Know
► How
can we optimize therapy for a given
patient using this information?
► How
do we optimize therapy for a
heterogeneous MS population under
managed care, using this information
► How
do we keep such decisions rational,
evidence-based, AND ETHICAL?
► And
when we can’t know with certainty,
how do we communicate and act on that
uncertainty?
Therapies Reviewed Today
► Alemtuzumab
► Cladribine
(Campath®)
(Leustatin®, Movecto®)
► Fingolimod
(Gilenya®)
Alemtuzumab (Campath®)
►
Monoclonal humanized antibody directed against
CD52 antigen
●
●
CD52 antigen is a cell surface glycoprotein that is
present on >95% of T lymphocytes, B lymphocytes,
monocytes, and eosinophils
Results in prolonged depletion of B cells, T cells, and
monocytes
►
Within an hour following a single 5- to 10-mg dose,
lymphocytes and monocytes are no longer detectable
in circulation
►
FDA-approved for B-CLL
Muraro P, et al. Neurotherapeutics. 2007;4:676-692. Coles A, et al. J Neurol. 2006;253:98-108.
IFNβ-1a
44 mcg thw SC 107
95
Alemtuzumab
12 mg daily IV 108
66
80
24
102
92
101
77
Alemtuzumab
24 mg daily IV 108
22
105
92
104
88
Month 0
Month 12
CAMMS223 Trial Investigators. NEJM 2008;359:1786-1801.
Month 24
Month 36
Alemtuzumab CAMMS223: Co-Primary
Endpoints (36 months)
CAMMS223 Trial Investigators. NEJM 2008;359:1786-1801.
Alemtuzumab CAMMS223:
MRI Outcomes
Months 0-12
0-24
0-36
P=0.04
P=0.03
n=75
P=0.04
n=91
n=60
n=96
n=87
P=0.16
n=80
n=100
n=91
n=96
P≤0.03 for both doses of
alemtuzumab vs. IFN at
m 0-12 and 0-24. P=NS
at m 0-36
Months 0-36
CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801.
12-36
Alemtuzumab CAMMS223: Safety
►
Principal AEs associated with alemtuzumab included:
●
Infusion reactions
●
Mild-to-moderate infections
●
Autoimmunity
• Immune thrombocytopenia in 6 of 216 patients (2.8%)
including one death
• Thyroid disorders (28% vs. 3% for IFNβ-1a)
• 1 case of Goodpasture’s syndrome
CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801.
Alemtuzumab CAMMS223: Safety
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
0
0
1.8
Infections, %
Meningitis**
* P<0.001 alemtuzumab vs. IFN
** Listeria or viral meningitis
CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801.
Alemtuzumab:
Effects on the Immune System
►
B cells returned to
normal within 3-6
months
►
Median recovery time for
CD4+ T cells > 100
cells/µL = 3 months
►
6-9 months for CD4+ T
cells > 200 cells/µL
►
Median recovery time to
baseline levels of CD4+
T cells = 61 months
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 –
ECTRIMS 2010
►
68% Alem in follow-up
►
42% IFNB-1a follow-up
►
ARR
►
ARR
●
●
months 0-60 = 0.11
Months 36-60 = 0.14
●
●
Months 0-60 = .35
Months 36-60= .28
►
SAD @ 60 = .13
►
SAD @ 60 = .38
►
Mean EDSS -0.30
►
Mean EDSS +0.46
ARR=annualized relapse rate; SAD-sustained accumulation of
disability
Alemtuzumab – Current Status (CARE-MS
I/II) Phase III Studies in Progress
►
CAMMS323 - Comparison of
Alemtuzumab and Rebif®
Efficacy in Multiple Sclerosis,
Study One
►
Randomized, Rater- and DoseBlinded Study Comparing 2
Annual Cycles of IV 12 mg and
24 mg Alemtuzumab to 3x
Weekly SC Interferon Beta-1a
(Rebif®) in Relapsing-Remitting
Multiple Sclerosis Patients Who
Have Relapsed on Therapy
►
Enrollment: 840 Study Start
Date: October 2007 Estimated
Study Completion Date:
September 2011
Source: Clinicaltrials.gov
►
CAMMS32400507 Comparison of Alemtuzumab
and Rebif® Efficacy in
Multiple Sclerosis, Study Two
►
Randomized, Rater-Blinded
Study Comparing Two Annual
Cycles of Intravenous
Alemtuzumab to Three-Times
Weekly Subcutaneous Interferon
Beta-1a (Rebif®) in TreatmentNaïve Patients With RelapsingRemitting Multiple Sclerosis
►
Enrollment: 581 Study Start
Date: September 2007
Estimated Study Completion
Date: May 2011
Cladribine (Leustatin)
►
►
►
►
►
►
►
►
Synthetic purine nucleoside analogue prodrug
Accumulates and is incorporated into the DNA of lymphocytes as a result
of a high ratio of deoxycytidinekinaseto 5' nucleotidase activity
Selectively induces apoptosis in dividing and non-dividing lymphocytes
Sustained reduction in lymphocyte subtypes (CD4+ T cells, CD8+ T cells
and B cells
Relatively transient effects on other immune cells such as neutrophils and
monocytes
Reduces levels of pro-inflammatory chemokines
Crosses the blood brain barrier - CSF concentration = 25% of plasma
(patients with no BBB compromise)
FDA-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.
XXXX
XX
Placebo (n = 437)
1326
patients
XXXX
XX
Cladribine 3.50 mg/kg total dose; 4 courses (n = 433)
XXXX
XX
Cladribine 5.25 mg/kg total dose; 6 courses (n = 456)
–4
0 5 9
13 16
24
36
44 48 52
60
72
84
96 Time (weeks)
MRI
Neurological
examination
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
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
CLARITY: Clinical Outcomes
Annualized relapse rate (95% CI)
57.6%
0.33
(0.29-0.38)
0.14*
0.15*
(0.12-0.17) (0.12-0.17)
* P < 0.001
Percent of relapse-free patients at
98 weeks
54.5%
Placebo (n = 437)
Cladribine 3.50 mg/kg (n = 433)
Cladribine 5.25 mg/kg (n = 456)
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
Odds Ratio (95% CI)
2.43 (1.81-3.27)
Odds Ratio (95% CI)
2.53 (1.87-3.43)
79.7*
60.9
78.9*
CLARITY: Clinical Outcomes
Proportion with confirmed 3-month
EDSS progression (%)
25
Time to Confirmed EDSS Progression
20
Placebo
HR vs Placebo (95% CI)
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
15
10
5
0
0
12
24
36
48
60
72
333
364
375
315
355
363
84
96
Weeks
Placebo
3.50 mg
5.25 mg
437
433
456
424
424
447
399
407
425
373
389
404
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
355
379
388
304
347
350
304
347
350
CLARITY: MRI Outcomes
T1 GadoliniumEnhancing Lesions
Active T2-Weighted Lesions
Combined Unique Lesions
77.9%
76.9%
74.4%
mean ± SE lesions/patient/scan
73.4%
87.9%
1.72
1.43
85.7%
0.91
0.38
0.33
0.43
0.12
All P < 0.001
0.11
Placebo (n = 437)
Cladribine 3.50 mg/kg (n = 433)
Cladribine 5.25 mg/kg (n = 456)
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
0.38
CLARITY: Safety and Tolerability
Placebo
(n = 435)
Cladribine
3.5 mg/kg
(n = 430)
Cladribine
5.25 mg/kg
(n = 454)
Cladribine
overall
(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)
1 (0.2)
1 (0.2)
1 (0.2)
2 (0.2)
188 (42.5)
205 (47.7)
222 (48.9)
427 (48.3)
2 (0.5)
2 (0.5)
2 (0.4)
4 (0.5)
Preferred term, n (%) patients
Varicella
Any infection or infestation
Deaths
►
►
►
►
►
20 patients had 21 zoster events in the cladribine groups
All 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 developed
zoster versus 1.8% of those that did not
70% of patients with zoster had normal lymphocyte count or lesser grade lymphopenia at the
approximate time zoster developed
Deaths - Placebo: Hemorrhagic CVA, suicide; cladribine 3.5 mg/kg: acute MI, pancreatic carcinoma;
cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardio-respiratory arrest
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
CLARITY: Safety and Tolerability
Malignancies
Placebo
(n = 435)
Cladribine
3.5 mg/kg
(n = 430)
Cladribine
5.25 mg/kg
(n = 454)
Cladribine
overall
(n = 884)
Melanoma
0
1(0.2)
0
1(0.2)
Ovarian
0
1(0.2)
0
1 (0.1)
Pancreatic
0
1 (0.2)
0
1 (0.1)
Cervix
0
0
1(0.2)
1(0.2)
0
0
1(0.2)
1(0.2)
Preferred term, n (%)
During Study
During post-study
surveillance
Choriocarcinoma
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
CLARITY: Effects on Lymphocyte Subsets
Maximum Effects on CD4 and CD 19 Counts*
Weeks 0-48
Weeks 48-96
3.5
5.25
3.5
mg/kg mg/kg mg/kg
Add Reference
CD4 (week)
Cells/µL
CD19 (week)
Cells/µL
16
391
9
18
16
209
16
14
72
275
52
27
5.25
mg/kg
72
207
52
31
*Median values
Rieckmann P, et al. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, 2009. Poster #816.
Cladribine – Current Status
►
Approved in Australia
and Russia
(Movectro®)
►
Applications pending
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®)
►
Sphingosine-1-phosphate (S1P) receptor modulator (S1PR1
and 5 > 2,3,4)
►
Sequesters circulating lymphocytes into secondary lymphoid
organs
●
●
Peripheral reduction of CD3+, CD4+, CD8+, CD45RA+ (naive T cells),
CD45RO+ (memory T cells) and CD19+ cells
No effect on lymphocyte induction, proliferation,
or memory function
►
May inhibit the production of IL-17
►
Crosses BBB, and S1P receptors shown to function within
the CNS, but unknown clinical relevance
●
Fingolimod or deletion of S1P1 from neural cells reduces astrogliosis
in EAE and can stimulate OPC maturation
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.
Oral fingolimod 0.50 mg once daily (n = 425)
1272
patients
(1:1:1)
Oral fingolimod 1.25 mg once daily (n = 429)
Placebo once daily (n = 418)
Randomization
Month 6
Month 12
Month 24
MRI
Clinic visits
Kappos L, et al. N Engl J Med. 2010;362:387-401.
FREEDOMS: Primary Efficacy Endpoint
Annualized Relapse Rate at 24 months
Placebo
(n = 431)
Kappos L, et al. N Engl J Med. 2010;362:387-401.
-54% vs Placebo
p < 0.001
-60% vs Placebo
p < 0.001
Fingolimod
0.5 mg
(n = 429)
Fingolimod
1.25 mg
(n = 420)
Percent with 3-month confirmed
EDSS progression
FREEDOMS: Disability Data
30
FTY720 0.50 mg vs placebo HR 0.70
P = 0.02 in time to disability
Progression
Placebo (24%)
25
20
FTY720 1.25 mg vs placebo HR 0.68
P = 0.02 in time to disability
Progression
FTY720 0.50 mg (18%)*
15
FTY720 1.25 mg (17%)†
10
* P = 0.03 vs placebo
† P = 0.01 vs placebo
5
0
90
Number at Risk
FTY720 1.25 mg 429
FTY720 0.50 mg 425
Placebo
418
180
270
360
450
540
630
720
322
332
290
305
321
279
165
152
143
Days on study
401
416
391
373
388
371
356
370
341
Kappos L, et al. N Engl J Med. 2010;362:387-401.
344
354
320
332
340
308
FREEDOMS: MRI Endpoints
T2 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.
FREEDOMS: Brain Volume
P≤0.03 for both doses of fingolimod
vs. placebo at all time points
Kappos L, et al. N Engl J Med. 2010;362:387-401.
Optional
extension
phase
Oral fingolimod 0.5 mg once daily and matching
weekly placebo injection IM
Oral fingolimod 1.25 mg once daily and matching
weekly placebo injection IM
IFNβ-1a 30 µg IM once weekly and
matching daily oral placebo capsule
Assessments
MRI
EDSS
Clinical visit
Randomization
Month 6
Cohen J, et al. N Engl J Med. 2010;362:412-415.
Month 12
Ongoing
TRANSFORMS:
Primary Efficacy Endpoint
Annualized Relapse Rate at 12 months
IFNβ-1a 30 µg IM
once weekly
(n = 431)
Cohen J, et al. N Engl J Med. 2010;362:412-415.
-52% vs IFNβ-1a,
p < 0.001
-38% vs IFNβ-1a,
p < 0.001
Oral fingolimod
0.5 mg
(n = 429)
Oral fingolimod
1.25 mg
(n = 420)
TRANSFORMS: MRI Endpoints
T2 and Gadolinium-Enhancing Lesions at 12 Months
-35% vs. IFNß-1a
P=0.004
-42% vs. IFNß-1a
P<0.001
-55% vs. IFNß-1a
P<0.001
-73% vs.
IFNß-1a
P<0.001
Cohen J, et al. N Engl J Med. 2010;362:412-415.
TRANSFORMS: Brain Volume
P < 0.001
Cohen J, et al. N Engl J Med. 2010;362:412-415.
Gilenya®: Safety
►
Transient reduction in heart rate on initiation of
treatment
►
Elevated blood pressure
●
►
Elevated liver enzymes
●
►
↑mean systolic BP (1.9 and 3.6 mm Hg for 0.5 mg and
1.25 mg, respectively) and diastolic BP (0.7 and 2.1
mm HG for 0.5 and 1.25 mg, respectively)
↑LFTs ≥ 3 x ULN 8% for FTY720 0.5 mg, 10% for
FTY720 1.25 mg, 1.2% for placebo, 2% for IFNß-1a
Macular edema
●
●
FREEDOMS - 7 cases in the 1.25 mg dose group
(1.6%) and none in the 0.5 mg dose group
TRANSFORMS – 6 cases (4 in the 1.25 mg dose group
(1%) and 2 in the 0.5 mg dose group (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 (Gilenya®): Safety
Malignancies and Herpes Infections
FTY720
0.5 mg
FTY720
1.25 mg
Placebo
IFNß-1a
(n = 854)
(n = 849)
(n = 418)
(n = 431)
Basal cell carcinoma
7(0.8)
3(0.4)
3(0.7)
1(0.2)
Melanoma
3(0.4)
1(0.1)
1(0.2)
0
Bowen’s Disease
1 (0.1)
0
0
0
46(5.4)
48(5.7)
33(7.9)
12(2.8)
AE, n (%)
Skin Cancers
Infections
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®): Safety
►
Two fatal infections in patients treated with
FTY720 1.25 mg
●
Herpes encephalitis
●
primary disseminated varicella
►
Hemorrhagic encephalitis in a patient treated
with FTY720 1.25 mg
►
Posterior reversible encephalopathy syndrome
in a patient treated with 5 mg in the phase 2
study
Cohen J, et al. N Engl J Med. 2010;362:412-415; Kappos L et al. N Engl J Med. 2006;355:1124-40;
Leypoldt F, et al. LK. Neurology 2009;72:1022-24.
FTY720 1.25 mg (n = 16)
Normal range
Treatment duration (yrs),
mean ± SEM
1.9 ± 0.2
-
Lymphocyte count (x 109/L),
mean ± SEM
0.4 ± 0.1
0.9-3.3
CD4 T cell count (cells/µL),
mean ± SEM
78 ± 5.6
700-1100
CD8 T cell count (cells/µL),
mean ± SEM
149 ± 7.4
500-900
Mehling M, et al. Neurology 2008;71:1261–1267
Gilenya®: Current Status
►
Sept 22, 2010 FDA approval, indicated for the
treatment of patients with relapsing forms of
multiple sclerosis to reduce the frequency of
clinical exacerbations and to delay the
accumulation of physical disability.
►
Recommended dose: 0.5 mg orally once daily,
with or without food
►
REMS includes outreach letters, with
recommendations for 6 hour initiation observation
period, monitoring for infections, ophthalmologic,
dermatologic and hepatic toxicity; NO REGISTRY
or restricted distribution process
Emerging Therapies:
Trading Efficacy for Safety
►
? Impaired immune
surveillance and
opportunistic
infections
►
Viral and other
infections
►
? Malignancies
►
Long-lasting effects
►
Autoimmunity
►
Teratogenicity
►
Rare, but serious
infusion reactions
►
The Unknown
Natalizumab and the Risk of PML
Changing therapy options5-19
Betaseron®
Tysabri®
(IFNβ-1b)
(natalizumab)
Rituximab/Ocriliz
umab
Campath®
Avonex®
Extavia®
(IFNβ-1a)
(IFNβ-1b)
(alemtuzumab)
Laquinimod
Copaxone®
(glatiramer acetate)
Cladribine
Novantrone®
(BG-12)
(mitoxantrone)
Gilenya®
(fingolimod)
Rebif ®
(IFNβ-1a)
1995
2000
2005
Approval date
Approved therapies
Fumarate
2009
Teriflunomide
2010
2011
Estimated launch date
Phase III completed
In Phase III
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.
112
Treatment Decisions:
Considering Benefits and Risks
Benefits
Risks
Meaningful impact
Short-term safety
Disease Course
Long-term safety
MRI
Pharmacovigilance
? Better than ABCR
Post-approval studies
? Window of opportunity
Pregnancy issues
Convenience
What therapy characteristic will be the
key driver for future therapy decisions?
114
Efficacy
Tolerability
Safety
Other
Considerations
How will patient characteristics, risk aversion
and cost play a role in our therapy decisions?
Demographics:
Age
Gender
Genetic load
Present disability
Disease Prognosis
115
Risk Tolerance
Risk Aversion
Other
Considerations:
Price of Rx and
care,
Resource
utilization
Delivery process
Multiple situations are encompassed by
the term “suboptimal response”
1-5
Efficacy
Relapses
New lesions
Brain atrophy
Worsening EDSS
Neutralizing antibodies
Tolerability
Compliance
Immediate postinjection
reaction (IPIR)
Injection-site reactions (ISRs)
Flu-like symptoms
Depression
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.
116
Safety
Clinically recognizable organ
toxicity
Opportunistic infection
Abnormal laboratory values
Other
Considerations
Fatigue
Worsening cognition
What is our ethical approach to prescribing
therapies with better efficacy but  risks?
Suitable for all patients?
For patients who
request therapy?
Choose other
established therapy?
117
Only for heavily
treatment-experienced
patients?
Only for those with
worsening disease?
My Take Home Points on MS
Therapy
►
Diagnose High Risk Presumptive and Definite MS
early
►
Treat early as aggressively as seems reasonable,
to interrupt inflammatory cascade and possible
secondary degeneration
►
Consider how to predict disease course using
accurate surrogate markers
►
Make risk tolerance/aversion decisions on
therapy on a patient by patient basis
►
Involve patients in clinical research as able
Questions to Consider
1. How will new molecular mechanisms of action and
comparative analysis of injectable and new oral MS
agents under investigation and/or in the FDA approval
process; and, based on the reported risks, unknowns,
safety signals, and therapeutic efficacy of such agents,
affect MS treatment pathways in the MC setting?
2. What are the potential risks and cautionary notesmedico-legal and otherwise-of embarking on a course of
therapy with unknown safety risks and lack of
comparative studies, especially when a safe platform
therapy is already established and available?
Questions to Consider
3. Who will actually make the risk-benefit decisions?
Pharmacist? Formulary committee? Physician? Patient
advocacy groups?
4. Will managed care organizations need to set up their
own registries? And how will Phase 4 data be
communicated?
5. In the absence of risk-stratification criteria, which are
lacking for MS, how will MCO pharmacists and
physicians select patients for new therapies?
The Evolving Landscape of MS Therapy
The Changing MS Therapeutic
Landscape: Perspectives of an MSFocused Pharmacist
How Will We Need to Adapt to and Analyze the
New Generation of MS Therapies?
Ronald J. DeBellis, Pharm.D., FCCP
Professor and Chair
Department of Pharmacy Practice
Albany College of Pharmacy and
Health Sciences-Vermont
Changing Directions
►
Oral Agents
►
Pharmacist Advanced Provision of
Care
►
Education
►
Cost
►
Adherence
Oral Agents for Multiple Sclerosis
Oral Agent
Mechanism of
Action
Status
Expected Dosing
Dalfampridine
Potassium
channel blocker
Approved for use by
the FDA
10.0 mg twice daily
Immunomdulator
Granted fast-track
review by FDA
0.6 mg daily
Cladribine
Purine nucleoside
analogue prodrug
FDA issued a refuseto-file letter for the
New Drug Application
due to reports of
patients developing
solid malignancies
1 (0.2)
Fingolimod
Partial
sphingosine 1phosphatereceptor agonist
Approved for use by
FDA
0.5 mg daily
Laquinimod
FDA data accessed 10/14/10
Considerations as Therapy Shifts from
Injectable to Oral Agents
►
Adherence
●
●
Pharmacists will play a larger role in that time spent with patients
in clinic will decrease due to less need to teach patients how to
inject
May be an initial increase in adherence since medications will be
easier to take
• May eventually result in a decrease in adherence as
undesirable side effects may emerge
●
Increased amount of follow-up and coaching by pharmacists
(particularly where high cost/high stakes therapy is involved)
• Seek Continuing Education in Motivational Interviewing over
the telephone
• Consider setting up follow-up schedule with MS patients
• Schedule and provide detailed counseling sessions for patients
when they come for prescription pick up
• Keep note to fax to MD after each visit to utilize team
approach to care of patients with MS
●
Utilize SWOT analysis to achieve realistic approach to MS patient
care in a pharmacy setting
Oral Agents and Managed Care
►
4 oral agents on the horizon
●
►
Discontinuation rates with current therapies as high as 46%
●
●
●
●
►
Dalfampridine, laquinimod, cladribine, fingolimod
Lack of efficacy (perceived and real)
Adverse drug reaction
Cost to the patient
Injection anxiety
Oral agents and adherence
●
●
●
Better tolerated physically and psychologically
Pts prefer receiving oral or inhaled medications
Majority of patients did not perceive oral meds interfering with
life
• Minority of patients did not take oral meds and perceive them
less effective than injectable medications
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 Care
►
Trends/Considerations
●
●
●
●
Oral medications will require less out-of pocket
expenses for members compared with current
injectable medications
Preliminary results indicate that oral medications
are as effective as, or possibly more effective
than, current injectable formulations
Patients newly diagnosed with MS may prefer
oral agents when they become available
Data presented regarding oral therapy is trending
to being significantly positive in the short time
from 2009-2010
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
Changing Directions
►
Oral Agents
►
Pharmacist Advanced Provision of
Care
►
Education
►
Cost
►
Adherence
Collaborative Drug Therapy
Management
CDTM
Attributes of State and Federal Regulations
Governing Collaborative Practice
2001-2002 ACCP Task Force on Collaborative Drug Therapy Management. Collaborative Drug Therapy Management by Pharmacists 2003.
Pharmacotherapy 2003;23:1210-1225.
Pharmacovigilance
Pharmacovigilence
► The science and activities relating to the detection,
assessment, understanding and prevention of
adverse effects or any other possible drug-related
problem (WHO)
 In recent history, the role of the pharmacist has been
to dispense drugs prescribed by a physician and ensure
drugs met required standards
 In healthcare today, the pharmacist’s role has changed
to acting as a consultant on pharmacotherapy,
including over the counter products
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
Originating from Pharmacists by Country
Country
%
Hospital
Pharmacists
Community
Pharmacists
Canada
88.3
+
-
68
+
-
Australia
40.3
+
+
Netherlands
40.2
-
+
Japan
39
?
+
Spain
25.9
+
+
USA
“+” 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
Management in the
MS Patient
MTM
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
MTM Services
►
►
►
►
►
►
►
►
►
►
►
►
►
►
Referral from other health care providers
More than one prescriber
Patients on four or more chronic medications
Patients with at least once chronic disease requiring pharmacotherapy
Patients taking a medication with a narrow therapeutic index (e.g. warfarin,
phenytoin, theophylline)
Lab values outside the normal range that could be improved with medication
therapy
Non-adherence for more than 3 months
Patients requiring intensive communication die to literacy and/or cultural
issues
Total monthly cost of medication in excess of $200
Patients discharged from a hospital or skilled nursing facility within 14 days
with new medications
Over-utilization or under-utilization of medications
Routinely non-adherent with medication regimens
Lack of understanding regarding medication use
Patients confronted with financial barriers
American College of Clinical Pharmacy 2006 Clinical Practice Affairs Committee. Medication therapy management services: application of the core
elements in ambulatory settings.
Documentation Elements for the Patient
Record 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 Clinical
Outcomes with Pharmacists’ Interventions or 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.
Changing Directions
►
Oral Agents
►
Pharmacist Advanced Provision of
Care
►
Education
►
Cost
►
Adherence
Educational Opportunities for Pharmacist/
Allied Health Involvement in MS Therapy
Disease
Modification
Symptom
Management
Optimal MS
Management
Clinical
Findings
Ross AP. Neurology 2008;71(suppl 3):s21-s23.
Support
System
Wellness
MRI
Findings
Considerations-Education
►
Education
● Increased pharmacist education about MS disease
• Access to quick reference with therapeutic options
• Counseling tips and FAQ’s to address from MS patients
• Promote web sites and contact information for pharmacists to “chat” with MS
pharmacy specialists in order to better care for their patients
●
Provide templates and programs specific for pharmacists to have a
greater knowledge base than the patient (knowing from previous
information that MS patients are “smarter” the average patient
• How to manage side effects of medications
• Use of alternative therapies to control and manage disease state
• Role of alternatives in treating neurologic diseases
●
Use of Motivational Interviewing skills to enhance and foster long-term
use of medications in chronic diseases
• Provide continuous professional development or certification in motivational
interviewing as part of patient care
• Address specific counseling opportunities and barriers in patient s with chronic
neurological disease to colleges of medicine, pharmacy and nursing
Changing Directions
►
Oral Agents
►
Pharmacist Advanced Provision of
Care
►
Education
►
Cost
►
Adherence
Total Average Annual MS Cost
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
of Selected Comorbid Conditions (2004)
Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52
MS Component Costs—
Overall Population (2004)
Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52
Average Total Annual MS Cost by DiseaseModifying Drug Utilization (2004)
Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52
Newer Biologic Treatments in MS
►
Payers are demanding more information on the overall value
of these therapies in making coverage decisions
●
●
●
►
Starting a biologic for the treatment of RA or MS was associated with
lower use of some types of medical services within 2 to 3 years of
initiation
Although biologics may reduce other types of service use, the savings
do not come close to offsetting the full cost of these drugs
Health plans may rightly focus on making sure only patients who will
most benefit from biologics receive them. But once such patients are
identified, it makes little sense to limit coverage
Considerations/Speculations
●
Consider newer oral therapies for treatment for potentially lower overall
cost to both patients and MCO’s
Joyce GF, et al. Am J Manag Care 2008;14(12):821-82
Considerations - Costs
►
Costs
●
Utilize adherence and education strategies to
contain costs associated with disease
• Shift and reduce costs from acute therapy and health
degeneration to medication management, adherence
and education
• Conduct continual research to demonstrate the value
of adherence and education in cost reduction
• Promote the concept of the “disseminated” healthcare
team working to achieve adherence and education
Changing Directions
►
Oral Agents
►
Pharmacist Advanced Provision of
Care
►
Education
►
Cost
►
Adherence
Adherence
► The term adherence is preferred over compliance
due to authoritative and paternalistic connotations of
the latter


Adherence: the extent to which a person’s behavior–
taking medication, following diet guidelines, or
enacting lifestyle changes—corresponds with
recommendations from a health care provider
Persistence and performance quality are also
associated with adherence
► Non adherence rates with DMT’s average 25% (1346%)
–
Similar 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 Behavior
Adherent
Non-adherent
► Utilization and consequent
maintenance of therapy
• Complete refusal of therapy
► Keep treatment and
aftercare appointments
► Take drugs correctly
► Active change to health
lifestyle
• Refusal of specific treatment
options
• Arbitrary or unintended
modification of prescriptions
–
Intentional non-adherence
► Complete treatment-related
homework
► Reduce risk behaviors
Klauer T, Zettl UK. Compliance, adherence and the treatment of multiple sclerosis. J Neurol 2008;255 (suppl 6):87-92
Motivations for Non-Adherence
•
Most severe demands of IMT posed on patients
–
–
Injectable medications, frequently IM or SQ for months
or years
Benefits of IMT will not be positively experienced by
patients and outweighed by side effects
•
•
•
•
•
•
Flu-like symptoms
Flushing
Chest pain
Palpitations
Dyspnea
Pain on injection
Klauer T, Zettl UK. Compliance, adherence and the treatment of multiple sclerosis. J Neurol 2008;255 (suppl 6):87-92
Effects of Non-Adherence
on 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
MS 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
Out-of-Pocket Expenses with MS Drugs
Gleason PP, et al. J Manag Care Pharm. 2009;15(8):648-658.
Motivational Interviewing as Early
Vocational Intervention in MS
► 90% of people with MS have a history of employment, only 20-30% will
be employed 5-15 years from diagnosis
► Many people with MS do not participate in interventions designed to
preserve employment until they experience a work-related crisis because
of fatigue, concern about disclosure, or preference to not anticipate future
problems
► MI is a brief, client centered, directive counseling approach that enhances
intrinsic motivation to change by exploring and resolving ambivalence
► U. of Washington MS Rehabilitation Research and Training Center is
providing brief telephone MI sessions to individuals with MS to explore
costs, benefits, and ambivalence of study participants toward making
accommodations at work in efforts to stay employed through the
progression of the disease
Hunter C, Johnson K , Fraser R. Motivational Interviewing as Early Vocational Intervention in MS (P09). 21st Annual Meeting of the Consortium for
Multiple Sclerosis Centers, 2007 Washington, DC.
Patient Compliance Improves Through
“Motivational Interviewing”
► Patient often resist the advice of health care providers and
thus neglect what is in their best interests
► Attempts to persuade patients when they are not ready to
change


A patient may quit taking medication because they feel no
improvement
Determine motivation and increase probability that they will
make good decisions
► Software available to aid Pharmacists in MI


8.7% of pts receiving advice from counselors without using
software quit taking medications
1.2% of pts quit taking medications when software was used
http://www.sciencedaily.com/releases/2007/07/070721194716.htm Accessed 10/4/2010
Physical Activity for Depression in People Aging
with Multiple Sclerosis and Spinal Cord Injury
► Ongoing study at University of Washington currently
recruiting, completion date March 2012
► Purpose
–
–
–
Lack of physical activity has been positively correlated with higher
levels of depression
Longitudinal data and treatment trials suggest that increased
physical activity is related to improved mood
Condition: MS; Intervention: Behavioral (Motivational
Interviewing)
http://clinicaltrials.gov/ct2/show/NCT00947232, accessed 10/4/2010
Physical Activity for Depression in People Aging
with Multiple Sclerosis and Spinal Cord Injury
► Randomization
–
Motivational Interviewing: experimental
• Motivational interviewing for people aging with MS or spinal
cord injury to increase physical activity and decrease
depression
–
Behavioral: motivational interviewing
• Motivational interviewing, a proven counseling method that
centers on individual goals and motivations, to increase
exercise and decrease depression
http://clinicaltrials.gov/ct2/show/NCT00947232, accessed 10/4/2010
Strategies to Enhance Adherence to DMT’s
Establishing a
therapeutic
relationship
Managing
patient
expectations
Educating
patient and
family
Increased
adherence
to
treatment
Managing
adverse
events
Addressing
patient
concerns
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.
Sample Questions Providing Alternative
Views for Patients with Injection Anxiety
► If you could inject <1 min/Week, with minimal anxiety,
would it be a burden?
► While the injections may result in side effects in the first
months, what are your goals for the next 10 years
► If you were walking in the desert and had antivenin
with you and a rattlesnake bit you, would you selfinject?
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.
Male vs. Female MS Characteristics
►
Female patients have greater self-reported symptom
awareness and more positive perceptions of ability to manage
therapy
►
80% of a mailed surveys of commercially insured MS patients
were female
●
●
●
►
Majority of whom had RRMS
68% of whom were on glatiramir acetate or interferon beta-1a
Females more often perceived that DMM made a difference and were
more aware of treatment options
Considerations/Speculations
●
●
Male patients would be a sizeable target for beginning MS therapy
Male patients need consistent reminders of importance of therapy as
well as treatment options
Vlahiotis A, et al. J Manag Care Pharm 2010;16:206-16.
Kaplan-Meier Hazards for Probability for
Medication Continuance
Daugherty KK, et al. Factors leading patients to discontinue multiple sclerosis therapies. J Am Pharm Assoc 2005;45:371-375.
Determinants of Adherence
► Missing treatment effects or undesirable side effects
explain only medium amounts of variance in adherence
–
–
–
–
–
Disease characteristics
Patient variables
Quality of patient therapist relationship
Treatment setting
Influences 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 Adherence
•
Adherence most strongly threatened by disorders that
specifically and directly interfere with medication application
–
–
–
•
Injection phobia
Treatment of diabetes mellitus
Depression
Non-adherence has been regarded as a risk for patient
morbidity and mortality and has an unnecessary economical
burden for the health care system
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.
Disease Management Consensus Statement
Recommendations—National Multiple Sclerosis Society 2007
► The Society recognizes that the factors that enter into a
decision to treat are complex and best analyzed by the
individual patient’s neurologist.
► Initiation of treatment with an interferon beta
medication or glatiramer acetate should be considered
as soon as possible following a definite diagnosis of MS
with active, relapsing disease, and may also be
considered for selected patients with a first attack who
are at high risk of MS.*
Expert Opinion Paper, National Multiple Sclerosis Society, 2007
Disease Management Consensus Statement
Recommendations—National Multiple Sclerosis Society 2007
► Natalizumab is generally recommended by the Food and
Drug Administration (FDA) for patients who have had an
inadequate response to, or are unable to tolerate, other
multiple sclerosis therapies.
► Treatment with mitoxantrone may be considered for
selected relapsing patients with worsening disease or
patients with secondary-progressive multiple sclerosis
who are worsening, whether or not relapses are
occurring.
Expert Opinion Paper, National Multiple Sclerosis Society, 2007
Recommendations Continued
► Patients’ access to medication should not be limited by
the frequency of relapses, age, or level of disability.
► Treatment is not to be stopped while insurers evaluate
for continuing coverage of treatment, as this would put
patients at increased risk for recurrent disease activity.
► Therapy is to be continued indefinitely, except for the
following circumstances: there is clear lack of benefit;
there are intolerable side effects; better therapy
becomes available.
Expert Opinion Paper, National Multiple Sclerosis Society, 2007
Recommendations Continued
► All of these FDA-approved agents should be included in
formularies and covered by third party payers so that
physicians and patients can determine the most
appropriate agent on an individual basis; failure to do so
is unethical and discriminatory.
► Movement from one disease-modifying medication to
another should occur only for medically appropriate
reasons.
► None of the therapies has been approved for use by
women who are trying to become pregnant, are
pregnant, or are nursing mothers.
Expert Opinion Paper, National Multiple Sclerosis Society, 2007
Dose, Route, Frequency and Common Adverse
Effects of Medications Used in MS Treatment
Medication
Interferon
beta-1a
Interferon
beta-1a
Interferon
beta-1b
Glatiramer
acetate
Dose
30 micrograms
44 micrograms
0.25 milligrams
20 milligrams
Frequency
Common Adverse
Events
Intramuscular
Once weekly
Injection site reactions,
inflammation, fever,
myalgia, chills
Subcutaneous
Three times
per week
Injection site reactions,
inflammation, fever,
myalgia, chills
Subcutaneous
Every other
day
Injection site reactions,
inflammation, fever,
myalgia, chills
Once daily
Local injection site
reactions and transient,
self-limited, facial
flushing and chest
tightness
Route
Subcutaneous
Daugherty KK, et al. Factors leading patients to discontinue multiple sclerosis therapies. J Am Pharm Assoc 2005;45:371-375.
Direct and Indirect Costs that Should be
Considered 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.
Questions to Consider
1. How likely is the approval of new MS therapies—
including both oral and injectable agents—change the
risk- to-benefit analyses for long-term MS treatments
and influence management decisions for MS in the
managed care setting?
2. How do you anticipate responding to the new MS
treatment landscape that will include high cost, oral
therapies that require pharmacovigilance measures?
3. In the absence of precise guideline from U.S. FDA, how
will your organization decide to tier first-line and
second-line therapies?
4. Specifically, to what extent has cost of therapy
influenced decision-making at your MCO? And how will
it influence therapy moving forward?
Questions to Consider
5. How will your organization respond to pricing issues for MS?
For example, fingolimod is priced at $48,000 one year of
treatment? How will that influence your MS treatment
decisions when safe and effective therapies currently cost
from $32,000 to $40,000?
6. How will you respond to additional demands for safety
monitoring for new agents, such as fingolimod and other
immunosuppressives? What are these monitoring
dimensions?
The Evolving Landscape of MS Therapy
The Role of Comparative Effectiveness,
Long Term Safety Considerations, and
Monitoring Costs for Evaluating
Therapies for MS
Jacquelyn Bainbridge, PharmD, FCCP
Professor
Department of Clinical
Pharmacy/Department of Neurology
University of Colorado Denver
Aurora, CO
To Treat or Not to Treat?
►
Does early treatment of patients with CIS delay the
development of a second clinical event (CDMS diagnosis)?
►
Four randomized, placebo-controlled, phase III trials have
addressed that question
●
●
●
●
►
PreCISe: Study to Evaluate the Effect of Early Glatiramer Acetate
Treatment in Delaying the Conversion to CDMS of Subjects Presenting
with CIS
BENEFIT: Betaseron® (SC IFNβ-1b) in Newly Emerging MS for Initial
Treatment
CHAMPS: Controlled High-Risk Subjects (IM IFNβ-1a) Avenox® Multiple
Sclerosis Prevention
ETOMS: Early Treatment of MS
One additional ongoing study
●
REFLEX: Rebif® (SC IFNβ-1a) FLEXible Dosing in Early MS
IFN = interferon; IM = intramuscular; SC = subcutaneous.
Clinically Isolated Syndrome (CIS)
►
CIS: single, symptomatic neurologic episode
consistent with MS, first attack
●
●
►
Common symptoms: optic neuritis, ocular motor
syndromes, ataxia, dysarthria, sensory or motor
signs, partial myelitis, and bladder or bowel
dysfunction
Patient may already have lesions on MRI
Clinically definite MS (CDMS): second attack
consistent with MS
CIS = clinically isolated syndrome; MRI = magnetic resonance imaging; MS = multiple sclerosis.
Prognosis in CIS
Rate of Conversion to CDMS
% Converting to CDMS
100
80
Baseline Measure
0 Lesions
1–3 Lesions
4–10 Lesions
>10 Lesions
60
40
20
0
5
10
Years
Adapted with permission from Brex et al. N Engl J Med. 2002;346:158-164.
15
Treatment
►
All of the clinical trials in patients with CIS showed
statistically significant reductions (39%–50%) in
risk of developing CDMS when early treatment was
initiated.
►
All of the clinical trials showed a delay in physical
disability and a significant reduction in either the
number and/or volume of brain lesions.
MS Prognosis Without Therapy
►
10–20% have “benign MS”
●
●
Rare attacks, little disability
Post-hoc determination
►
About 5% have “malignant MS”
• Rapid accumulation of disability
• Wheelchair-bound in 5 years, bed bound in 10 years
►
Most are between these extremes
►
Newer data suggests overall better prognosis
Economic Impact of Multiple Sclerosis
►
Impact in the work place (MS vs non-MS)
●
●
●
Higher percentage of employees claiming short- or
long-term disability (21.4% vs 5.2%) (P <.0001)1
More disability days per year (29.8 vs 4.5) (P <.0001)1
Average annual costs for disability $3868 vs $414 US
(P <.0001)1
1. Ivanova JI, et al. Pharmacoecomonics. 2009;27:681-691
Key Parameters in MS Management:
Disability
Death
Normal
neurologic
exam
Increased
limitation in
walking
ability
Minimal
disability
Need for
walking
assistance
6.0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
6.5
7.0
Helpless
bed patient
Restriction to
wheelchair
7.5
8.0
8.5
9.0
9.5 10.0
5.5
Patient Disability Classification
Expanded Disability Status Scale = Rating system used by neurologists and
clinical trial investigators to follow the progression of disability in MS
Kurtzke. Neurology. 1983;33:1444-1452.
Seven Approved
Disease-Modifying Therapies
First-line
therapies
IM IFNβ-1a
SC IFNβ-1a
SC IFNβ-1b
Glatiramer acetate
Fingolimod
Second-line
Therapy ?
Natalizumab
Other first-line
Worsening/
progressive
disease
Mitoxantrone
Graphic courtesy of Dr. Robert J. Lipsy.
Abbreviations: IFNβ, interferon beta; IM, intramuscular; SC, subcutaneous.
FDA-Approved Therapies for MS
Parenteral Immunomodulators
Agents*
Indications
Doses and
Administration
Glatiramer acetate1
(Copaxone®)
CIS
RRMS
20 mg/d SC
Low-dose IFNβ-1a2
(Avonex®)
CIS
RRMS
30 mcg/wk IM
High-dose IFNβ-1a3
(Rebif®)
RRMS
CIS†
22 mcg or 44 mcg TIW SC
High-dose IFNβ-1b4,5
(Betaseron®, Extavia®)
CIS
RRMS
250 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 MS
Parenteral Immunosuppressive
Agents*
Natalizumab1
(Tysabri®) †
Mitoxantrone2
(Novantrone®) ††
Indications
Doses and Administration
Relapsing forms of MS
300 mg q4wk IV
SPMS, PRMS,
Worsening RRMS
12 mg/m2 over 5–15 min
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.pdf
2. Mitoxantrone (Novantrone®). www.accessdata.fda.gov/drugsatfda_docs/label/2009/
019297s030s031lbl.pdf
Newly Approved Oral MS Therapies
Disease-Modifying Therapy
Fingolimod (FTY720)
Mechanisms of Action
Sphingosine-1P (S-1P) receptor
agonist
Blocks lymphocyte migration
Symptomatic Management
Dalfampridine
Mechanisms of Action
Blocks voltage-dependent
K+ channels
May restore conduction in poorly
myelinated nerve fibers
Safety Considerations: Fingolimod &
Natalizumab
►
Fingolimod
●
Lymphopenia is common because the drug sequesters lymphocytes in
peripheral lymph nodes1,2
• Reversal of lymphopenia can take ~ 2 to 4 weeks after the end of
dosing, depending on the dose3
First dose problems within 6 hours
• Bradycardia1
• Second-degree Wenckebach atrioventricular block
●
Infections and malignancies
●
Overall the 3 most important monitoring parameters:
• Heart rate
• Macular edema
• Pulmonary function tests (decrease FEV1)
Natalizumab
●
TOUCH program = Progressive multifocal leucoencephalopathy (PML)
●
Infusion reactions
●
When stopping Natalizumab bridging needs to occur to prevent
immune reconstitution inflammatory syndrome (IRIS)4
●
►
TOUCH = Tysabri Outreach Unified Commitment to Health
FEV1 = forced expiratory volume in 1 second.
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.
Phase IIb Laquinimod Study
Phase IIb Laquinimod Study
Effect on Annualized Relapse Rate
Annualized Relapse Rate
33%
► LAQ/5062 Study was not
powered to detect a
statistically significant
effect on relapse rate
► Trend (p=0.0978) toward
reduction of annualized
relapse rate
PBO
LQ 0.3mg
LQ 0.6mg
Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:2085-92.
Phase IIb Laquinimod Study
Gd-T1 Lesion
Count
Laquinimod 0.6mg Reduced MRI Lesion Counts Early
during the Treatment Course
0.3 mg
Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:2085-92.
0.6 mg
Placebo
Conclusions & Summary
►
►
Laquinimod showed a robust, reproducible,
sustained and early effect on MRI activity
Laquinimod 0.6mg is safe and tolerable


►
Transitory elevations of liver enzymes, most in the first 3
months of Tx
No signs of immunosuppression following prolonged
exposure
Current data suggest a favorable, balanced
benefit-to-risk ratio of laquinimod as a potential
treatment for RRMS patients
Which ABCR Drug Is Best?
INFβ vs INFβ
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?
INFβ 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?
New Agent vs. INFβ
SENTINEL
trial1
TRANSFORMS
trial2
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.
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 Sclerosis
TRANSFORMS= 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 of
Medicine. 02 Mar 2006;354;911-23. 2Cohen JA et al. Oral Fingolimod or Intramuscular Interferon for Relapsing
Multiple Sclerosis. The New England Journal of Medicine. 04 Feb 2010;362:402-15.
Emerging MS Therapies
Tx-naive
patients
GA
IFNb
First-line therapies
Fingolimod
Natalizumab
Consistent effect on relapses and MRI
Unclear effect on long-term disability
Potential to further enhance efficacy and ease of
use
Main emerging therapies and strategies
Oral agents
Cladribine
Laquinimod
Teriflunomide
Fumaric acid
Monoclonal antibodies
Daclizumab
Alemtuzumab
Rituximab
Ocrelizumab
Combination therapy
IFNb-based
GA-based
Novel agents
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; IFNb, interferon beta.
Patient Adherence to MS
Medication
►
MS poses unusual challenges to adherence
●
●
●
►
Needle phobia
New daily routines
Perceived lack of efficacy
According to adherence studies
●
Many patients display new or increased depression within
6 months of treatment initiation1
•
•
►
Most frequent cause of stopping treatment is perceived
lack of efficacy2
●
►
Depressed patients displayed decreased adherence1
Treating depression may prevent treatment discontinuation1
Most treatment withdrawals occur within 1st year of treatment2
Side effects and tolerability issues can result in
nonadherence 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.
Adherence
Between 17% and 40% of patients stop taking
disease-modifying drugs within 1 year of
initiation1-3
► Multifactorial
►
●
●
●
Perceived lack of efficacy1,2
Adverse effects2,3
Depression
Within 6 months of treatment initiation, 41% of patients had
new or increased depression4
• Decreased adherence in patients with untreated depression4
•
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
to MS Medications
►
Longitudinal, prospective study of 199 patients
with definite MS
●
●
●
●
Of 97 patients taking DMT
• 73% missed doses
• 10% missed >10 doses in a 6-month period
• 25% stopped DMT
Missed doses were associated with alcohol intake
History of missed doses predicted future missed doses
Numerous and divergent factors influenced missed
doses and stopping DMT
• Indicates need for multifaceted approach to improving
adherence
Tremlett H, et al. Pharmacoepidemiol Drug Saf. 2008;17:565-576.
Patients in United States Find it Harder
to Pay for Care
Patients stating that they often have difficulty paying
for 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 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
Regimens in MS
Establishing Realistic Expectations

Therapies have been shown to reduce relapses,
reduce MRI activity, and attenuate disease activity
•

Attenuated disease activity may lead to more patients
retaining employment
Patients with MS must also realize that DMTs
•
•
•
•
Only work if patients take them
Are not cures for MS
May not eliminate MS symptoms
Do 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 Therapies
►
Relapse free at 1 year 51%–80%
►
Relative decrease in annual relapse rate 30%–80%
►
Absolute annual relapse rate 0.15–0.7
►
Relative decrease in sustained progression 31%–42%
►
Absolute rate of disease progression
9%–18%
►
Workers with MS on a DMT and not on a DMT1
● N=258 vs. N=322
● Treatment with DMT = reduced medical and
indirect costs
Data courtesy of Dr. Robert J. Lipsy.1. Birnbaum et al Curr Med Res Opin. 2009;25(4):869-877.
Questions to Consider
1. How will pharmacoviligance programs for MS therapies
used in managed care settings will need to adapt and
change when potentially new, immunosuppressive
therapies with a variable range of adverse effects and
toxicities become available?
2. How, depending on the risk-to- benefit ratio and
pharmacovigilance requirements for new therapies, will
managed care pharmacy and medical directors respond to
a new landscape for MS as oral agents with potentially
less favorable side effect profiles become available?
3. What will be the role that electronic records and
meticulous documentation of MS treatment plans play in
the near future as multiple agents, with potentially
additive immunosuppressive properties, become available
for treating MS in the managed care setting?