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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
A Dilemma and Clinical Decision Update
for the Managed Care Physician
Program Chairman
Bruce A. Cree, MD, PhD, MCR
Assistant Professor of Neurology
Department of Neurology
University of California
San Francisco Multiple Sclerosis Center
San Francisco, California
Program Faculty
Bruce A. Cree, MD, PhD, MCR
Assistant Professor of Neurology
Department of Neurology
University of California
San Francisco Multiple Sclerosis Center
San Francisco, California
Brian Steingo, MD
Medical Director
Neurologic Associates Research
Fort Lauderdale MS Center
Pompano Beach, FL
The Evolving Landscape of MS Therapy
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
Program Chairman
Bruce A. Cree, MD, PhD, MCR
Assistant Professor of Neurology
Department of Neurology
University of California
San Francisco Multiple Sclerosis Center
San Francisco, California
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?
Questions We Will Address Today
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?
Investigations • Innovation • Clinical Application
A New Era of Oral Therapy
for Multiple Sclerosis
The Good, The Bad, The Uncertain—
Cautionary Notes for Managed Care Physicians
Program Chairman
Bruce A. Cree, MD, PhD, MCR
Assistant Professor of Neurology
Department of Neurology
University of California
San Francisco Multiple Sclerosis Center
San Francisco, California
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
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
Does Sustained Disability Measure
Permanent Disability?
►
50% of patients with a 1 point change, confirmed at 3
months will improve to a lower EDSS
►
33% of patients with a 1 point change, confirmed at 6
months, will improve to a lower EDSS
►
More stringent measures of change are harder to
demonstrate in 2-year trials because relatively few MS
patients will progress
►
Conclusions: 6 months sustained EDSS change is
more rigorous than a 3-month sustained change, but
neither is a good predictor of long term disability
Liu C & Blumhardt LD J Neurol Neurosurg Psychiatry. 2000;68:450-7.
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
Redefining the Long-Term
Benefit-to-Risk Equation for Therapy
of Multiple Sclerosis
Implications for the Managed Care Setting
Brian Steingo, MD
Medical Director
Neurologic Associates Research
Fort Lauderdale MS Center
Pompano Beach, FL
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
Trends Across Clinical Trials
Annualized Relapse Rate (ARR)
1
0.7
0.6
0.87
0.67
FTY720
Avonex
NTZ
Betaseron
Campath®
Rebif
Rituximab
0.59
0.5
0.4
0.3
0.29
0.35
0.36
0.37
0.32
0.28
0.27
0.16
0.2
0.1
Johnson Jacobs
1995
1996
IFNβ-1b PRISMS-2 Kappos
study
1998
TRANSgroup,
FORMS
1993
Polman
2006
REGARD
2007
BEYOND
2007
BECOME
2007
CAMMS223
2008
3 years
HERMES
2008
48 weeks
GA
Rituximab
Rebif
Campath
Betaseron
GA
Betaseron
GA
Rebif 44
GA
NTZ
FTY-720
Rebif 44
Betaseron
0.10
Avonex
0
0.30
0.34
0.23
GA
ARR (2 Years)
0.9
0.8
0.84
GA
FORTE
2008
1 year
Alemtuzumab
►
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=96
n=91
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.
Cladribine
►
►
►
►
►
►
►
►
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
84
96
333
364
375
315
355
363
304
347
350
304
347
350
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
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.
Fingolimod (FTY720)
►
Sphingosine-1-phosphate (S1P) receptor modulator
►
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
►
S1P receptors located within the CNS
●
Fingolimod or deletion of S1P1 from neural cells reduces astrogliosis
in EAE
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.
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.
Fingolimod: 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: 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: 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
Laquinimod
A novel synthetic compound
Route of administration – oral
► Primary Indication – Relapsing remitting
multiple sclerosis; two phase III studies
ongoing
► Additional Indications – Crohn’s Disease; SLE
Phase IIb - Laquinimod
Effect on T1 Gd Enhancing Lesions
Median
Mean
60% reduction
P=0.01
Mean Number of Cumulative Gd
Enhancing Lesions (week 12-36)
Median Number of Cumulative Gd
Enhancing Lesions (week 12-36)
51% reduction
P < 0.0001
PBO
LQ 0.3mg
LQ 0.6mg
* Adjusted means
Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:2085-92.
PBO
LQ 0.3mg
LQ 0.6mg
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
Conclusions
► An oral, once-daily dose of laquinimod 0.6mg
has shown:

A robust, consistent and early effect on MRI activity in
RRMS patients

A trend in reducing the number of relapses

A trend in slowing the progression of brain atrophy
► Laquinimod 0.6mg is safe and tolerable
Phase IIb Laquinimod Study
Safety
► No deaths
► No effect on vital signs
► No effect on ECG
► No specific pattern of adverse events
Elevations to Potentially
Clinically Significant Levels
Liver Enzyme Elevation:
• All cases are reversible
• Most normalized while on laquinimod
Placebo
(n=102)
0.3mg
(n=98)
0.6mg
(n=106)
• No signs of liver damage/failure
ALT (x3)
2 (1.9%)
2 (2.0%)
8 (7.5%)
• No concomitant bilirubinemia
AST (x3)
3 (2.9%)
1 (0.9%)
1 (0.9%)
Bilirubin (x2)
3 (2.9%)
0
0
Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:2085-92.
Laquinimod Does Not Cause
Immunosuppression
► It does not affect viability or proliferation of
human PBMCs
► It does not affect the ability of animals to
mount cellular or humoral immune responses
► It does not affect graft survival
► No clinical signs of opportunistic infections
Laquinimod is an Immunomodulator
► Modulation of cytokine profile
► Reduction of leukocyte infiltration
► Down regulation of inflammatory genes
► Down regulation of MHC class II expression
► Effects on dendritic cells (DC) compartment
Laquinimod MoA In Multiple Sclerosis
Summary
► Laquinimod is an immunomodulator with both
anti-inflammatory & neuroprotective properties:
 Shifts the cytokine balance towards a Th2/Th3
profile
 Reduces immune cell infiltration into the CNS
 Induces myelin and axonal preservation
Oral Laquinimod for RRMS
Phase III Program
Completed enrollment of
~1100 RRMS patients
ORAL LAQUINIMOD 0.6 MG
ALLEGRO
24 MONTHS OF TREATMENT
OPEN LABEL
EXTENSION
ORAL MATCHING PLACEBO
Completed enrollment of
~1300 RRMS patients
ORAL LAQUINIMOD 0.6 MG
BRAVO
AVONEX® 30MCG/WEEK
24 MONTHS OF TREATMENT
ORAL MATCHING PLACEBO
OPEN LABEL
EXTENSION
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
►
Humanized monoclonal antibody directed against CD11a
affecting T-lymphocyte activation, migration, and
reactivation
►
Evaluated in 4 randomized, double-blind, placebocontrolled trials
►
FDA-approved for psoriasis in 2003
●
●
At the time of approval, 2764 patients had been treated
218 treated for ≥ 1 year
Nijsten T, et al. Arch Dermatol 2009;145:1037-39.
►
►
October 2008: Label update to include PML
February 2009:
• FDA issued a Public Health Advisory and changed the label to
include a “black box” warning for PML
– At the time, 48,000 patients treated with efalizumab, but only
14,000 for > 1 year, 5,100 for > 2 years, and 1,900 for > 3 years
• EMEA recommends suspension of marketing
• Health Canada suspends marketing
►
April 2009: Genentech announced plans for a voluntary
withdrawal from the U.S. market
Nijsten T, et al. Arch Dermatol 2009;145:1037-39.
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
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?