Transcript Slide 1

New Frontiers and
Landmark Practice Advances
Optimizing Neurotherapy for
Multiple Sclerosis and
Parkinson’s Disease
Applying Science, Expert Analysis, Guidelines, and
Landmark Trials to the Front Lines Patient Care
Program Chairman
C. Warren Olanow M.D., FRCPC
Henry P. and Georgette Goldschmidt Professor and
Chairman Emeritus, Department of Neurology
Professor, Department of Neuroscience
Director, Robert and John M. Bendheim Parkinson’s Disease Center
Mount Sinai School of Medicine
Welcome and Program Overview
CME-certified symposium jointly
sponsored by the University of
Massachusetts Medical School and
CMEducation Resources, LLC
Commercial Support: Sponsored by
an independent educational grant
from Teva Neuroscience, Inc.
Faculty disclosures: Listed in
program syllabus
Program Faculty
Program Chairman
C. Warren Olanow M.D., FRCPC
Henry P. and Georgette Goldschmidt
Professor and Chairman Emeritus,
Department of Neurology
Professor, Department of Neuroscience
Director, Robert and John M. Bendheim
Parkinson’s Disease Center
Mount Sinai School of Medicine
Douglas R. Jeffery, MD, PhD
Associate Professor
Department of Neurology
Wake Forest University Baptist Medical
Center
Winston-Salem, NC
Howard L. Zwibel, MD
Founding Medical Director, Emeritus
Neuroscience Consultants
Comprehensive Multiple Sclerosis
Center in affiliation with the National
Multiple Sclerosis Center Coral
Gables, Florida
Baptist Health Doctors Hospital MS Center
Coral Gables, FL
New Frontiers and
Landmark Practice Advances
Parkinson’s Disease and
Multiple Sclerosis
Two Diseases in Need of a Neuroprotective Therapy
Program Chairman
C. Warren Olanow M.D., FRCPC
Henry P. and Georgette Goldschmidt Professor and
Chairman Emeritus, Department of Neurology
Professor, Department of Neuroscience
Director, Robert and John M. Bendheim Parkinson’s Disease Center
Mount Sinai School of Medicine
Parkinson’s Disease and Multiple Sclerosis
►
Two important neurological disorders
●
●
►
Both have surrogate imaging markers
●
●
►
Primarily affect older individuals (PD)
Primarily affect younger individuals (MS)
FD-PET (PD)
MRI (MS)
Treatments are available for both diseases
●
●
Benefit symptoms (PD)
Reduce relapse rate (MS)
Parkinson’s Disease and Multiple Sclerosis
►
Both result in unacceptable disability for
many patients despite available treatments
►
Disease-modifying or neuroprotective
therapies are urgent priorities
►
Both offer many candidate diseasemodifying agents based on laboratory work
Parkinson’s Disease and Multiple Sclerosis
►
Development of a disease modifying
therapy in each condition would be
enhanced by:
●
●
●
►
Insight into the precise cause of the
disease
Better animal models
Better clinical trial designs with endpoints
reflecting the underlying disease process
Advances in these areas will be reviewed in
the current session
New Frontiers and
Landmark Practice Advances
Attempts to Obtain
Neuroprotection for Parkinson’s Disease
Program Chairman
C. Warren Olanow M.D., FRCPC
Henry P. and Georgette Goldschmidt Professor and
Chairman Emeritus, Department of Neurology
Professor, Department of Neuroscience
Director, Robert and John M. Bendheim Parkinson’s Disease Center
Mount Sinai School of Medicine
Current Therapies for PD
►
Primarily dopaminergic
►
Highly effective for the classic motor features
●
►
Do not satisfactorily control non-dopaminergic
features
●
►
Tremor, rigidity, bradykinesia
Gait dysfunction, freezing, postural instability,
falling, autonomic dysfunction, mood disorders,
sensory problems, cognitive impairment, dementia
Do not stop disease progression
The Sydney Long Term PD Study
►
149 PD patients were entered
►
52 survivors after 15 years
►
None were still employed
►
40% were in a nursing home
►
95% had levodopa-induced dyskinesia and
wearing off
►
Non-dopaminergic features (falling, dementia)
were the primary cause of disability and of
nursing home placement
Neuroprotective (Disease-Modifying)
Therapy For PD
A treatment intervention that slows,
stops or reverses disease progression
Neuroprotective Trials in PD
Negative Studies
Agent
Mechanism
Endpoint
Anti-oxidant
Time to L-dopa
Anti-glutamate
Time to L-dopa
Minocycline
Anti-Inflammatory
Δ UPDRS
Imunophilin
Trophic
Time to L-dopa
GDNF/Neurturin
Trophic factors
Δ UPDRS
TCH346
Anti-apoptotic
Time to L-dopa
CEP1347
Anti-apoptotic
Time to L-dopa
Cell replacement
Δ UPDRS/QOL
Vitamin E
Riluzole
DA Cell Transplant
Obstacles to Finding a Neuroprotective
Therapy for PD
►
We do not know the precise etiology or
pathogenesis of PD—we don’t know what to
target
►
We do not have a reliable animal model that
is progressive and reflects the
etiopathogeneis of PD
►
We do not have a good method for
determining the optimal dose to use in a
clinical trial
Neuroprotective Trials in PD
Positive Studies
Agent
Mechanism
Endpoint
Selegiline (DATATOP)
Anti-apoptotic
Time to L-dopa
Selegiline (SINDEPAR)
Anti-apoptotic
Wash Out
Co-Q10
Bio-energetic
Δ UPDRS
Creatine
Bio-energetic
Δ UPDRS
Ropinirole
Anti-apoptotic
Β-CIT-SPECT
Pramipexole
Anti-apoptotic
F-DOPA PET
Obstacles to Finding a Neuroprotective
Therapy for PD
We do not know the precise etiology or
pathogenesis of PD –we don’t know what to
target
► We do not have a reliable animal model that is
progressive and reflects the etiopathogeneis of
PD
► We do not have a good method for determining
the optimal dose to use in a clinical trial
► We do not have a clinical trial design that can
reliably detect a disease-modifying agent
►
Trial Designs for Neuroprotection in PD
►
Time to a milestone of disease progression
►
Washout design (change from untreated
baseline to final visit performed after drug
washout)
►
Change from baseline to final visit in UPDRS
score
►
Neuroimaging of surrogate biomarker of
dopaminergic function
Delayed Start Design
Period I
Placebo
Early Start
Early Start
Intervention
Delayed Start Design
Period I
Period II
Delayed
Start
Placebo
Early Start
Early Start
Intervention
Delayed Start
Intervention
Symptomatic
Effect
Delayed Start Design
Period I
Period II
Delayed
Start
Placebo
Early Start
Early study
Intervention
Delayed Start
Intervention
Possible
Disease Modifying
Effect
Delayed Start Study
Principal Statistical Analyses
Mean UPDRS change from baseline
Improvement
Worsening
I. Superiority of Early Start vs
Placebo (UPDRS Slope weeks 12 – 36)
II. Superiority of Early Start vs Delayed
Start (UPDRS change from baseline to week 72)
II
III
I
12
24
36
42
48
54
60
66
72
Week
III. Non-Inferiority of Early Start vs
Delayed Start (UPDRS slope weeks 48 – 72;)
Delayed Start (Placebo-Rasagiline)
Early Start (Rasagiline-Rasagiline)
Adapted from Olanow et al. Mov Disord. 2008.
Issues That Must Be Addressed in a
Delayed-Start Study
►
Duration of period 1 and period 2
●
●
●
Long enough for protective effect to occur
Long enough for full symptomatic effect to occur
Not so long that patients withdraw
►
Drop outs
►
Missing data
●
►
Need for sensitivity and imputation analyses
Sufficient numbers of visits to permit slope
analysis in period 1 and 2
The ADAGIO Study
ADAGIO Study Design
1 mg/day
1 mg/day
Untreated
PD patients
Placebo
2 mg/day
2 mg/day
Week
0
4
12
24
36-week (9-month)
Double Blind PlaceboControlled Phase
Olanow et al. Mov Disord. 2008
36 42 48 54 60 66 72
36-week (9-month)
Double Blind ActiveTreatment Phase
ADAGIO – Baseline Characteristics
Patients randomised (n)
Male patients (n, %)
1,176
718 (61.1%)
Age, years (mean, SD)
62.2 (9.6)
PD duration, months (mean, SD)
4.5 (4.6)
UPDRS-Total score (mean, SD)
Motor
ADL
20.4 (8.5)
14,2 (6.4)
5.2 (2.8)
Hoehn & Yahr score (mean, SD)
1.5 (0.5)
Olanow et al. Mov Disord 2008
Rasagiline 1mg: Early vs Delayed Start
Olanow et al. NEJM; 2009
Rasagiline 2mg: Early vs Delayed Start
Olanow et al. NEJM; 2009
The ADAGIO Study
Summary and Conclusions
►
Rasagiline 1 mg/day met all 3 primary outcomes of
the delayed start study
●
►
Is this a false positive?
Rasagiline 2 mg/day failed to meet all primary
outcomes of the delayed start study
●
Is this a false negative?
ADAGIO – Clinical Significance of
Positive Result with Rasagiline 1 mg
►
UPDRS difference of 1.7 units
►
38% reduction in rate of decline of
UPDRS score
►
Reflects only 9 months of active
treatment
ADAGIO Trial
Clinical Significance
►
Delayed-start study designed to determine if a
study intervention has benefits that cannot be
accounted for by symptomatic effects alone
►
Long-term studies are required to assess effect
of drug on cumulative disability
●
●
●
Extension study
Long-term simple study
Endpoints that include measures of motor and nonmotor function - UPDRS gait, cognitive function, and
quality of life
New Dimensions and
Landmark Practice Advances
The Evidence for First Line Therapy in MS
with Immune-Modulating Agents (IMTs)
From Mechanisms to Therapy-Landmark Trials, LongTerm Safety Data, and Clinical Experience
Howard L. Zwibel, MD
Founding Medical Director, Emeritus | Neuroscience
Consultants | Comprehensive Multiple Sclerosis Center
in affiliation with the National Multiple Sclerosis Center
Coral Gables, Florida | Baptist Health Doctors Hospital
MS Center | Coral Gables, FL
New Dimensions and
Landmark Practice Advances
The Evidence for First Line Therapy in MS
with Immune-Modulating Agents (IMTs)
From Mechanisms to Therapy-Landmark Trials, LongTerm Safety Data, and Clinical Experience
NOTE: Both trade and chemic names are
used in the presentation 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.
MS: Immune Dysfunction
Proinflammatory
immune cells
Proinflammatory
cytokines
Antigen-presenting cell
Blood-brain barrier
T cells
1. Ziemssen T. J Neurol. 2005;252:V/38-V/45. 2. Yong VW, et al. Neurology. 2007;68:S32-S37. 3. DhibJalbut S. Neurology. 2007;68:S13-S21. 4. Tzartos JS, et al. Am J Pathol. 2008;172:146-155.
Diagnosis of MS
Based on
modifications to
McDonald Criteria
CSF = cerebrospinal fluid
Polman CH, et al. Ann Neurol. 2005;58:840-846.
Compston A, Coles A. Lancet. 2008;372:15021517. Figure 1.
Differentiating MS Lesions Using MRI
A
B
Note:
Scans are not from
the same patient.
T2 with
FLAIR
T2
C
T1
Precontrast
Black Holes
FLAIR = Fluid Attenuated Inversion Recovery
Slide courtesy of JS Wolinsky.
D
T1 Post-Gd
Contrast
Active Inflammation
Clinically Isolated Syndrome (CIS)
►
►
Clinical episode consistent with demyelination
● Characterized by MRI and lab data
● Patient may or may not develop clinically definite MS (CDMS)
Features of CIS suggestive of a first MS attack include:
● Appropriate age; female gender
● Abnormal brain MRI
● Optic neuritis
• Typically unilateral, retrobulbar, and painful
● Brainstem/cerebellar dysfunction
• Most commonly ocular motor syndromes (INO, nystagmus),
ataxia, dysarthria, sensory or motor signs
● Myelitis
• Partial sensory more common than partial motor
• Bowel and bladder dysfunction common
INO: Internuclear ophthalmoparesis
Frohman, et al. Neurology. 2003;61:602-611.
Clinically Isolated Syndrome (CIS)
► The challenge for physician is to determine the likelihood
that person experiencing this type of demyelinating event
is going to experience a second demyelinating event in
the future, thereby meeting the criteria for a definite
diagnosis of MS.
► When the CIS is accompanied by MRI-detected brain
lesions consistent with those seen in MS, there is a high
risk of a second neurologic event and diagnosis of
clinically definite MS within several years.
► Individuals who experience CIS with no evidence of MRIdetected lesions are at relatively low risk of developing
MS.
National MS Society. Clinically isolated syndrome. http://www.nationalmssociety.org/about-multiplesclerosis/diagnosing-ms/cis/index.aspx. Accessed 12/08.
CIS: MRI Lesions at Baseline Associated with
Development of CDMS Over Next 20 Years
82%
85%
81%
21%
(n = 34)
Fisniku LK, et al. Brain. 2008;131:808-817.
(n = 22)
(n = 20)
(n = 31)
CIS or First Demyelinating Event:
Phase III, Placebo-Controlled Studies
Acronym
Full name
Primary
Endpoint(s)
Status
PreCISe
Study to Evaluate the Effect of Early
Glatiramer Acetate (GA, Copaxone®)
Treatment in Delaying the Conversion to
CDMS of Subjects Presenting with a CIS
Time to clinically
definite MS (CDMS)
Completed
BENEFIT
Betaferon® (IFNb-1b) in Newly Emerging MS
for Initial Treatment
Time to CDMS
Time to McDonald MS
Completed
CHAMPS
Controlled High-Risk Subjects (IFNb-1a)
Avonex® Multiple Sclerosis Prevention Study
Probability of
developing CDMS
Changes in MRI
Completed
ETOMS
Early Treatment of MS Study (IFNb-1a)
Conversion to CDMS
Completed
REFLEX
Rebif® (IFNb-1a) FLEXible Dosing in Early MS
Time to conversion to
MS (McDonald criteria)
Ongoing
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.
Comi G, et al. Lancet. 2009;Published online 10/7/09, DOI:10.1016/50140-6736(09)61259-9.
Kappos L, et al. Neurology. 2006;67(7):1242-1249.
Jacobs LD, et al. N Engl J Med. 2000;343(13):898-904.
Comi G, et al. Lancet. 2001;357:1576-1582.
Completed CIS Clinical Trials:
Demographics and Key Results
PreCISe
(GA)
BENEFIT
(IFNb-1b SC)
CHAMPS
(IFNb-1a IM)
ETOMS
(IFNb-1a SC)
3 yrs (stopped
early)
2 yrs
3 yrs (stopped
early)
2 yrs
Patients (N)
481
468
383
308
Patient age
31 ± 7 yrs
30 yrs
33 ± 7 yrs
28 ± 6 yrs
EDSS (mean)
NA
1.5
NA
1.17 ± 1.2
% Reduction
in CDMS Risk
45%
50%
44%
39%
0.0005
< 0.0001
0.002
0.047
Parameter
Duration
P-value
NA = not available
EDSS= expanded disability status score
Comi G, et al. Lancet. 2009;Published online 10/7/09, DOI:10.1016/50140-6736(09)61259-9.
Kappos L, et al. Neurology. 2006;67(7):1242-1249.
Jacobs LD, et al. N Engl J Med. 2000;343(13):898-904.
Comi G, et al. Lancet. 2001;357:1576-1582.
BENEFIT 5-Year Extension Data:
Early Versus Delayed IFNβ-1b
57%
46%
HR 0.63, 95% Cl 0.48–0.83; P = 0.003
Kappos L, et al. Lancet. 2009; published online September 11, 2009
DOI:1016/S1474-4422(09)70237-6
37%
reduction in
risk of
developing
CDMS
CDMS = clinically
definite multiple
sclerosis
CHAMPIONS (CHAMPS Open-label
Extension): Early Versus Delayed IFNβ-1a
Incidence of CDMS by Treatment Group: 10-year extension data
Delayed Treatment (n = 190)
Immediate Treatment (n = 193)
Univariate HR (95% CI) = 0.64 (0.47–0.86), P = 0.003
Adjusted HR (95% CI) = 0.60 (0.44–0.81), P < 0.001
Kinkel RP, et al. Presented at the 25th Congress of the European Committee
for Treatment and Research in Multiple Sclerosis (ECTRIMS), Düsseldorf,
Germany, September 9-12, 2009. Poster # 446.
40%
reduction in
risk of
developing
CDMS
►
“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.”
National Clinical Advisory Board of the National Multiple Sclerosis Society (2007).
http://www.nationalmssociety.org/about-multiple-sclerosis/treatments/download.aspx?id=8. Accessed 01/14/09.
Summary
►Early treatment of CIS with DMTs (GA, IFNβ
formulations) delays progression to CDMS
►Early treatment of CIS or MS
• Reduces rate of relapses
• Delays the development of disability
• May reduce the overall cost of care
Current MS Therapies
Immunosuppressants or Immunomodulators?
►
►
Generally considered to be immunomodulators
●
Glatiramer acetate [GA] injection
●
IFNβ products
●
Natalizumab (?)
Uses of these immunomodulators
●
●
GA and IFNβ products are first-line therapies for the
long-term treatment of CIS and RRMS
Natalizumab for patients who are unresponsive or who
cannot tolerate first-line DMTs, first-line use in very active
RRMS
Chan A, et al. J Neuron. 2008;255(suppl 6):22-27.
Glatiramer Acetate
►
Dose: 20 mg sc daily (pre-filled syringes)
►
Pregnancy Category: B
►
Drug Interactions: None noted in clinical
trials
►
Laboratory monitoring: None needed
►
Adverse events: Injection site reaction,
immediate post-injection reaction
Presumed MOA of Glatiramer Acetate:
Immunomodulation
Proinflammatory
immune cells
Proinflammatory
cytokines
Regulatory T-cell types
Anti-inflammatory
cytokines
Antigen-presenting cell
Neurotrophic factors
T cells
Blood-brain barrier
●
●
●
Weber MS, et al. Neurotherapeutics. 2007;4:647-653.
Aharoni R, et al. Proc Natl Acad Sci U S A. 2008;105:1135811363.
Induces a population of regulatory
T-cell types (Th2,Treg)
Anti-inflammatory cytokines and
neurotrophic factors are released
May prevent nerve damage and
lead to remyelination*
* It is not known if these effects play an important role in the observed
clinical activity of COPAXONE® in MS. T cells derived from MS patients
receiving therapy with COPAXONE® have been shown to produce
neurotrophic factors, including brain-derived neurotrophic factor, and to
prevent nerve damage and enhance in situ remyelination and repair in
animal models.
Interferons
Avonex®, Betaseron®, Rebif®
►
Doses:
●
●
●
Avonex ® : 30 mcg IM once weekly
Betaseron ® : 250 mcg SC every other day
Rebif ® : 22 mcg, or 44 mcg, SC TIW
►
Pregnancy Category: C
►
Drug Interactions: Possible with hepatically active
drugs
►
Laboratory monitoring: CBC, LFT, thyroid
►
Adverse events: Flu-like symptoms, injection site
reaction, depression, hepatic injury
Presumed MOA of IFNβ:
Immunomodulation
Proinflamatory
immune cells
Proinflammatory
cytokines
Eliminated
immune cell
T cells
Antigen-presenting cell
Blood-brain barrier
●
●
Betaseron® prescribing information. Bayer HealthCare Pharmaceuticals Inc.
Reduces proinflammatory
cytokine levels
Reduces lymphocyte
trafficking into the central
nervous system (CNS)
Monoclonal Antibody
Natalizumab
►
Dose:
●
300 mg iv infusion monthly
►
Pregnancy Category: C
►
Drug Interactions: Immunosuppressants,
corticosteroids
►
Safety Issues:
●
●
●
●
●
Progressive Multifocal Leukoencephalopathy (PML)
Hypersensitivity Reaction / NAbs
Melanoma / Other Cancers
Liver Injury
Reactivation of Latent Viruses
Presumed MOA of Natalizumab:
Reduction of Cell Trafficking
Proinflammatory
immune cells
Proinflammatory
cytokines
Antigen-presenting
cells
Blood-brain barrier
T cells
●
●
Tysabri® (natalizumab) prescribing information. Biogen Idec Inc.
Inhibits the α4-mediated
adhesion of leukocytes to
vascular cell adhesion
molecule-1
Strongly reduces
proinflammatory cell
recruitment to the CNS
Head to Head Clinical Trials
Head to Head Clinical Studies
EVidence of Interferon Dose-response:
European North American
Comparative Efficacy
(The EVIDENCE Trial)
Results : Primary Endpoint
Proportion Relapse Free at 64 Weeks
% Relapse Free
56.3%
Panitch H, et.al. J Neurol Sci. 2005;239:67-74.
P = 0.023
48.2%
Results : Mean T2 Active Lesions at 64 Weeks
Secondary Endpoint
1.4
Mean T2 Lesions
P < 0.001
0.9
Panitch H, et.al. J Neurol Sci. 2005;239:67-74.
Head to Head Clinical Studies
REbif® vs. Glatiramer Acetate
in Relapsing MS Disease
(The REGARD Study)
Phase IV Multicenter, Open Label, Randomized Study
of Rebif® 44 µg Administered Three Times Per Week
by Subcutaneous Injection Compared with Copaxone® 20
mg Administered Daily by Subcutaneous Injection in the
Treatment of RRMS
Time to First Relapse
Survival distribution function
(Primary Endpoint)
672 days
(96 weeks)
IFNβ-1a
Hazard ratio (95% CI):
0.943 (0.74, 1.21)
GA
p = 0.643
Time to first relapse (days)
Adapted from an analyst report by Bernstein Research, October 15, 2007.
Head to Head Clinical Studies
Betaseron Efficacy Yielding
Outcomes of a New Dose
(The BEYOND Study)
Annualized Relapse Rate 1 Year
Before and During Treatment
2.0
IFNβ-1b
500 ug
IFNβ-1b
250 ug
GA
1.5
1.0
-79% -78% -79%
0.5
*No significant differences
0
Before
During
Comi G. Presented at: The European Charcot Foundation Symposium 2007; Nov 29 – Dec 1, 2007;
Fiuggi, Italy.
Head to Head Clinical Studies
BEtaseron® vs. COpaxone® in
MS with Triple-Dose Gadolinium
and 3-T MRI Endpoints
(The BECOME Study)
The BECOME Study
►
Study Design
●
●
●
●
●
Investigator-initiated study (single site)
N = 75
RRMS (61) and CIS (14) patients
Triple dose Gd with 40 min post-injection delay
3-Tesla MRI
• “This protocol is optimized to detect enhancement…”
●
►
Sponsored by Berlex/Schering AG
Primary Outcome Measure
●
The mean number of combined active lesions (CALs) per scan
• CALs were defined as Gd-enhancing lesions + new
T2/FLAIR lesions unassociated with enhancement
Wolansky L, et al. Presented at: 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis;
September 27-30, 2006; Madrid, Spain.
BECOME: Summary
►
Primary Outcome (CAL Count)
●
►
No significant differences on the following secondary outcomes
●
●
●
►
“The primary outcome of the BECOME study demonstrates that
IFNβ-1b and GA have similar efficacy and onset of action for
suppression of blood–brain barrier (BBB) breakdown in MS”
New enhancing lesions
Black Holes (acute hypointensities and persistent black holes)
Clinical: ARR, sustained disability progression, cognitive function
It is difficult to generalize from one set of cohorts, however, the
implication of the BECOME trial is that “the superiority of IFNβ1b over GA for reducing the incidence of active inflammation in
MS may have been overestimated”
Wolansky L, et al. Presented at: 23rd Congress of the European Committee for Treatment and Research in Multiple
Sclerosis; October 11-14, 2007; Prague, Czech Republic. Cheriyan J, et al. Presented at: 132nd Annual Meeting, American
Neurological Association; October 7-10, 2007; Washington, D.C. Cadavid D, et al. Presented at: 23rd Congress of the
European Committee for Treatment and Research in Multiple Sclerosis; October 11-14, 2007; Prague, Czech Republic.
% Reduction in ARR vs Baseline
Trends Across Clinical Trials:
% Reduction in ARR – ~2 Years
100
85
79
80
60
71
69
GA
Rebif 44
REGARD
2007
REGARD
2007
79
78
GA
Betaseron
84
86
GA
Betaseron
59
51
44
42
40
20
0
GA
Johnson
1995
Avonex Betaseron Rebif 44
Jacobs
1996
IFNβ-1b study PRISMS-2
group,1993
1998
FTY720
Tysabri
Kappos
Polman
ECTRIMS 2006,
2006
NEJM 2006
BEYOND
2007
BEYOND
2007
BECOME
2007
BECOME
2007
Trends Across Clinical Trials:
Annualized Relapse Rate – ~2 Years
Annualized Relapse Rate – 2-yrs
1.00
0.84
0.87
0.80
0.67
0.60
0.59
0.40
0.20
0.29
0.30
GA
Rebif 44
0.34
0.35
0.32
0.28
0.23
0.20
0.00
GA
Johnson
1995
Avonex
Bet aseron
Jacobs IFNB-1b study
1996
group,1993
Rebif 44
FTY720
PRISMS-2
Kappos
1998
ECTRIMS 2006
Tysabri
Polman
2006
REGARD
2007
REGARD
2007
GA
BEYOND
2007
Bet aseron
BEYOND
2007
GA
BECOME
2007
Bet aseron
BECOME
2007
Long Term IMT Data
Long-term Study Design in RRMS
Copaxone® (glatiramer acetate injection)20,21
N=251 in original pivotal trial; 19 placebo patients of 251 in pivotal trial did not enter
open-label extension, and 1 patient received 1 dose of COPAXONE® and never returned for
evaluation. Therefore, 231 patients were included in the mITT analysis. The Ongoing cohort
included 108 patients at 10 years and 100 patients at 15 years.
Avonex® (IFNβ-1a)9,23
Avonex®: N=301; 158 Avonex®, 143 placebo; subset (85 Avonex®, 87 placebo) followed for 2
years.
15-year retrospective follow-up: n=116; 15-year follow-up consisted of a questionnaire at year
15.
Up to
2
Tysabri® (natalizumab)27
N=942; Tysabri® 300 mg (n=627) or placebo (n=315).
years
5
Betaseron®: N=372; 125 Betaseron® 1.6 MIU, 124 Betaseron® 8 MIU, 123 placebo.
16-year retrospective follow-up: n=328 identified patients (35 of these were deceased but
included in the study as identified patients). LTFU data were obtained in an observational
study consisting of a single-visit assessment or report at 16 years. At LTFU, 182/260 patients
were not taking Betaseron®.
N=560; 184 Rebif® 44 mcg, 189 Rebif® 22 mcg, 187 placebo; at end of year 2, 172 placebo
patients randomized to 22 mcg (n=84) or 44 mcg (n=87); and double-blind study was
continued to year 4.
LTFU data were obtained in an observational study consisting of a single-visit assessment 7-8
years after enrollment.
15
yrs
Betaseron® (IFNβ-1b)24,25
Rebif® (IFNβ-1a)26
15 years
16
yrs
4
yrs
3
yrs
years
7-8
years
Key
Prospective study design
Retrospective follow-up
9. Jacobs LD, et al. Ann Neurol. 1996;39:285-294. 20. Ford C, et al. WCTRIMS 2008. Abstract P44.
21. Ford CC, et al. Mult Scler. 2006;12:309-320.
23. Bermel RA, et al. WCTRIMS 2008. Abstract P14. 24. IFNβ Study Group. Neurology.
1995;45:1277-1285. 25. Ebers G, et al. AAN 2006. P01.079.
26. Kappos L, et al. Neurology. 2006;67:944-953. 27. O’Connor PW, et al. AAN 2007. P06.082.
Pivotal Trial and Extension-Phase
Study Design
2008
EDSS assessment
3
6
Ongoing 6-month
assessments
• 15-year analysis for Ongoing cohort
• Mean disease duration: 22 years
9 12 15 18 21 24 27 30 33 36
13.6 years
glatiramer acetate
injection
mITT†‡
(n=232)
8.6 years
placebo
4.8 years
Double-blind,
placebo-controlled phase
0
Open-label extension phase
35*
60
120+
180
Months
*Due to staggered enrollment, the duration of the trial was 35 months in order to obtain 2-year results for all participants.
The mean time on treatment was 30 months.
†19 placebo patients of 251 in original pivotal trial chose not to enter open-label extension.
‡1 patient in the Withdrawn without long-term follow-up (LTFU) cohort withdrew before an on-treatment neurologic evaluation;
therefore, 231 patients were included in the efficacy evaluable modified intent-to-treat (mITT) cohort.
29. Johnson KP, et al. Neurology. 1995;45:1268-1276. 51. Ford C, et al. WCTRIMS 2008. Abstract P44. 52. Ford CC, et al. Mult Scler. 2006;12:309-320.
56. Johnson KP, et al. Neurology. 1998;50:701-708.
Yearly Relapse Rate While on GA
Mean Relapse Rate
1.25
1
0.75
0.5
0.25
0
*
1
2
3
4
5
6
7
8
9
10
Year
# of
pts†:
232
231
208 196
175
163
149
143
11
12
†
138
125
64
57
51
*ARR in the 2 years before GA start
†After year 9, mITT data included only those of patients randomized to GA in the double-blind phase of the study. Crossovers from
placebo group had not yet received GA
Ford CC, et al. Mult Scler. 2006;12:309-320.
Demonstrated Long-term Benefits
EDSS levels at 15-year follow-up
100
Patients (%)
80
60
40
38%
18%
20
0
EDSS of 4 or higher
EDSS of 6 or higher
3%
EDSS of 8 or higher
After an average of 22 years with RRMS and a mean of 14 years of COPAXONE ® (glatiramer acetate injection)
therapy, the majority of patients still in the study had not reached EDSS 4, 6, or 8
The labeling for COPAXONE® does not include an indication for slowing progression of disability.
Ford C, et al. WCTRIMS 2008. Abstract P44.
ASSURANCE
►
15-year long-term follow-up of pivotal IM
IFNβ1a relapsing trial (MSCRG)
●
●
Involved 2-year completers
Open label, retrospective, patient reported
►
N=136 (of 172) participated
►
46% currently on IM IFNβ1a (median
duration 13.3 years)
Rudick et al. MS 11:626, 2005
ASSURANCE
►
Those on IM IFNβ1a showed
●
●
●
●
●
↓ Mean EDSS change (2.3 vs. 3.3, p=0.011)
↓ EDSS 4 (64% vs. 83%, p=0.06)
↓ EDSS 6 (32% vs. 62%, p=0.008)
↓ EDSS 7 (9% vs. 33%, p=0.008)
Better physical score on SF36 (p<0.0001), greater
independence (p=0.0019; p=0.031)
Rudick et al. MS 11:626, 2005
16 Year Follow-Up
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
Goodin et al., Multiple Sclerosis; 2008: 14 (Suppl 1), P52
LTF
2005
16-Year LTF: Patient Disposition
in the Intent-to-Treat Population
Proportion of Patients
16.3%
7.2%
13.6%
11.4%
4.8%
10.5%
Deceased
84.7%
Not found
79.2%
Alive
72.4%
Placebo
n = 123
Ebers G. Presented at ECTRIMS 2006, Madrid, Spain.
INFB-1b
50 µg
n = 125
IFNB-1b
250 µg
n = 124
16-Year LTF: Other Findings
►
The most important predictors for better long-term outcomes
from the IFNB-1b 16-year LTF study were
●
●
Low EDSS (<2) at study entry
High exposure to IFNB-1b
• The risk of any negative outcome* was reduced by 60% with high
compared to low exposure
►
Safety and tolerability
●
●
No new or unexpected side effects
Flu-like symptoms , injection site reactions and NAbs continued
at a low level
*EDSS 6; SPMS; EDSS 6/SPMS, Wheelchair
Goodin et al. Multiple Sclerosis; 2008: 14 (Suppl 1), P52
PRISMS Long Term Follow-up
►
►
8-year follow-up of PRISMS SC IFNβ1a pivotal
relapsing trial
382 of 560 subjects (68.2%) evaluated
● 275 (72%) still receiving IFNβ1a
●
►
Subjects initially randomized to 44mcg showed best
EDSS, relapse rate, T2 burden of disease at 8 years
-no brain atrophy difference
19.7% progressed to SPMS
Neurology 2006;67:944
Natalizumab Monotherapy Trial: ARR
0.81†
0.73‡
68% reduction*
68% reduction*
0.26†
0.23‡
*P<0.001.
†Preplanned interim analysis.
‡Final analysis.
Polman CH et al. N Engl J Med. 2006;354:899-910.
Natalizumab Monotherapy Trial:
Time to Sustained Progression
Proportion of Patients with Sustained
Progression of Disability
0.4
Placebo
Natalizumab
0.3
P<0.001.
0.2
0.1
0
0
12
24
36
48
60
72
84
96
Weeks
Adapted with permission from Polman CH et al. N Engl J Med. 2006;354:899-910.
108
120
Natalizumab:
AFFIRM Gd-Enhancing Lesions
P<0.001 between groups for
all time intervals.
92%
92%
Miller DH et al. Neurology. 2007;68:1390-1401.
92%
Natalizumab: AFFIRM T2 Lesions
P<0.0001
83%
Miller DH et al. Neurology. 2007;68:1390-1401.
Summary
GA and interferons
►
Efficacy data documented from initial event to long-term
►
GA long-term data is prospective
►
Interferon data long-term is retrospective
►
No long-term safety signalling with GA or interferons
Natalizumab
►
Efficacy data short term
►
Safety signalling for development of PML
New Dimensions and
Landmark Practice Advances
The Evolution of
Chemotherapeutic Agents in the
Treatment of Multiple Sclerosis
Douglas R. Jeffery, MD, PhD
Associate Professor
Department of Neurology
Wake Forest University Baptist Medical Center
Winston-Salem, NC
“Chemotherapeutic”
►
Nonspecific cytotoxic agents that kill cells via a
mechanism that involves impairment of cell
division
►
Usually mediated by an effect on DNA or RNA
synthesis
►
Through this mechanism such agents kill T-cells,
B-cells, and macrophages thus impairing an
immune response against a wide variety of
stimuli
►
Immunosuppressive agents that also increase
the risk of infection through the nonspecific
suppression of immune function
The Search for a Treatment
►
Early on there were no treatments for MS
►
Other disciplines (rheumatology) adopted the
use of chemotherapeutic agents to treat
autoimmune diseases
►
MS thought by many to be autoimmune in
nature
►
Investigators in the MS field considered the use
of these agents
►
Early study designs were flawed and some
doubted the effectiveness of these agents
Benefits vs. Risk of
Chemotherapuetuc Agents
►
Chemotherapies are nonspecific
immunosuppressive agents
►
Many have well known and very serious side
effects
●
●
●
●
►
Immunosuppression
Infection
Hepatoxicity
Secondary malignancy
In the absence of other effective treatments
the benefits outweighed the risks in those with
worsening disability
Agents that have Been Studied in MS
►
Azathioprine
►
Methotrexate
►
Cyclophosphamide
►
Mycophenylate
►
Mitoxantrone
►
Cladribine
►
Cyclosporine
Azathioprine
►
Earliest studies date back to 1971
►
Small poorly controlled trials suggested a modest
effect on relapses
►
Later controlled trials confirmed an effect on
relapse rate but not disability progression
►
Cochrane meta analysis suggested an effect on
relapse rate
►
Odds ratio of remaining relapse free on
azathioprine was 1.51 at yr 1, 2.04 at yr 2, and
1.97 at yr 3
Yudkin et. al. 1991
Azathioprine
►
Used widely in Europe prior to the introduction of
IFNβs
►
Less popular in the modern era of
immunomodulatory therapy
►
Studied and used widely as a combination
therapy in those with a suboptimal response to
IFNβs and galtiramer acatete (GLAT)
►
Use as a monotherapy felt to be suboptimal
given potential for longterm toxicity
Azathioprine in Multiple Sclerosis
►
354 patients randomized to azathioprine vs. placebo
►
Double blinded, 3 yr duration
►
At 3 yrs mean EDSS decreased 0.80 in the placebo
and 0.62 in the treated group
►
At 3yrs the placebo group had an average of 2,5
relapse while the azathioprine group had an
average of 2.2 relapses (ns)
►
Results showed a very small benefit
►
Could not be recommended for most patients with
MS
Lancet. 1988; 23:179-183
Effect of Azathioprine on MRI Metrics
►
14 patients with at least three gd(+) lesions within 6
months
►
Azathioprine dosed up to 3mg/kg daily depending on
lymphocyte counts
►
Evaluation for six months before treatment and six months
of treatment
►
Reduction of greater than 50% observed in 12 of 14
patients
►
Reduction of greater than 50% or more in new T2 lesions
►
Azathioprine reduced new MS brain lesions
Massacesi, et. al. 2005
Toxicity of Azathioprine
►
Bone marrow suppression
●
●
●
Leukopenia
Lymphopenia
Thrombocytopenia
►
Increased risk of infection
►
Hepatotoxicity
►
Malignancy risk increased with duration of exposure
●
Solid organ tumors, myelodysplastic syndromes,
epitheliomas, skin cancer
La Mantia 2007, Confravreux 1996
Cyclophosphamide
►
Early studies suggested a possible effect in
secondarily progressive MS and rapidly
progressive MS
►
Conflicting results of several trials led to
controversy as to whether it was effective at all
►
Some believed it was highly effective and others
felt it to be ineffective and dangerous
►
Both were right. It depended on whether the
extent of the inflammatory process present
Hauser et. al.
Weiner et. al. 1993
Northeast Cooperative MS Treatment Group
►
Randomized
●
●
Standard vs modified induction
Induction only vs induction + maintenance
IV CTX (700 mg/m2) bimonthly
►
Induction
●
●
►
IV CTX (600 mg/m2) days 1, 2, 4, 6, 8
IV ACTH for 14 days
Maintenance
●
Weiner et. al. 1993
IV CTX (700 mg/m2) bimonthly
NE Cooperative Study
Percentage Stable/Improved on DSS
Months on Study
6
12
18
24
30
36
Induct (20)
75%
56%
46%
24%
17%
15%
Boosters (127)
71%
55%
48%
38%
27%
20%
P value
0.76
0.71
0.61
0.04
0.04
0.14
NE Cooperative Study
Months on Study, with Maintenance
6
12
18
24
30
36
Younger (<41)
81%
62%
57%
42%
40%
28%
Older (>41)
60%
47%
40%
34%
14%
21%
P value
0.02
0.13
0.10
0.18
0.01
0.05
Cytoxan
►
Factors effecting response to therapy
●
●
●
●
●
Younger age
Rapidly progressive course
Relapses in the year before therapy
<2yrs in the progressive phase
Enhancing lesions on T1+Gd
Canadian Cooperative Trial
►
CP-MS
►
EDSS 4.0-6.5 and increase >1.0 step prior 1
year
►
Randomized
●
●
●
►
IVCTX + prednisone
PlEx + POCTX + prednisone
Sham PlEx + placebo po meds
Blinded examining neurologist
Lancet 337:441, 1991
55
57
56
Canadian Cooperative Trial
►
Randomized, placebo-controlled
►
Clin-def, CP MS
►
EDSS 4.0-6.5
►
Worsening on EDSS >1.0 steps prior 12M
►
Non-blinded monitoring neurologist
►
Blinded examining neurologist
Lancet 337:441, 1991
Canadian Cooperative Trial
►
CTX group (n=55)
●
●
►
PlEx group (n=57)
●
●
●
►
IV CTX 1 gm QOD until WBC<4.5 up to 9 gm
Prednisone 40 mg qD x 10 then taper over 6 d
PlEx qW for 20 wk
PO CTX 1.5-2.0 mg/kg/d for 22 wk
Prednisone 20 mg QOD
Placebo group (n=56)
●
Sham PlEx, PO CTX placebo, Prednisone placebo
Lancet 337:441, 1991
Canadian Cooperative Trial
Results
No significant differences in:
►
Rate of failure (increase in EDSS >1.0
sustained for 6 months)
►
Proportions improved, stable, worse at
each visit up to 36 months
►
Mean change in EDSS
Lancet 337:441, 1991
Canadian Cooperative Trial
Results
►
Proportion of treatment failures
●
●
●
►
CTX
PlEx
Plac
35%
32%
29%
Mean time to treatment failure (months)
●
●
●
Lancet 337:441, 1991
CTX
PlEx
Plac
24.8 + 7.6
29.3 + 10.9
20.6 + 9.5
Canadian Cooperative Trial
Results
M12 vs. baseline
Improved
Stable
Worse
IVCTX
3 (6%)
38 (79%)
7 (15%)
PIEx
4 (8%)
39 (81%)
5 (10%)
Placebo
1 (2%)
35 (73%)
12 (25%)
CTX vs placebo p=0.295
Lancet 337:441, 1991
Canadian Cooperative Trial
Results
M24 vs. baseline
Improved
Stable
Worse
IVCTX
2 (6%)
13 (42%)
16 (52%)
PIEx
1 (3%)
25 (81%)
5 (16%)
0
20 (67%)
10 (33%)
Placebo
CTX vs placebo p=0.088
Lancet 337:441, 1991
Canadian Cooperative Trial
Results
M36 vs. baseline
Improved
Stable
Worse
IVCTX
2 (4%)
24 (44%)
28 (52%)
PIEx
1 (2%)
34 (59%)
22 (39%)
Placebo
1 (2%)
32 (59%)
21 (39%)
CTX vs placebo p=0.290
Lancet 337:441, 1991
Kaiser Study
►
CP-MS (EDSS 3.0-8.0)
►
Increased EDSS or AI >1 step prior 1
year
►
Randomized
●
●
►
IV CTX
Placebo
Single-blind
Likosky WH et al. JNNP 54:1055, 1991
22
20
Kaiser Study
Results
EDSS Stable or
Improved*
CTX
Placebo
12 Months
14/22 (64%)
14/20 (70%)
24 Months
9/19 (47%)
9/17 (53%)
* based on EDSS change of >1.0 step
Likosky WH et al. JNNP 54:1055, 1991
Kaiser Study
Results
Mean DEDSS
Placebo-CTX
(95% CI)
Month
CTX
Placebo
0 to 12
0.50
0.53
0.03 (-0.60 to
0.65)
0 to 18
0.38
0.73
0.35 (-0.40 to
1.10)
0 to 24
0.58
0.97
0.39 (-0.45 to
1.23)
Likosky WH et al. JNNP 54:1055, 1991
Spectrum of Disease Activity
►
Early inflammatory process with frequent
relapse and “apparent” progression may appear
“progressive”
►
Usually accompanied by numerous enhancing
lesions and rapidly increasing T2 lesion burden
►
Late stage secondary progression related to a
poorly understood degenerative process
►
Infrequent enhancing lesions and little evidence
of progression on MRI
►
These forms of disease differ in their response
to treatment
Natural History of MS
Measures of brain volume
Relapses and impairment
MRI burden of disease
MRI activity
Preclinical
Secondary-progressive
Relapsing-remitting
Time
Reconciliation of Early Studies on the Use of
Cyclophosphamide and Mitoxantrone in MS
►
Many early studies probably included patients with very
active inflammation that led to the appearance of
progressive disease
►
The reality was that the dynamics of disease in these
patients was characterized by active inflammation
►
The Canadian cooperative trial and the Kaiser trial
probably included a greater proportion of patients with
primary progressive MS and true secondary progression
►
CPM was effective in those with an active inflammatory
component but not in those with slowly progressive
degeneration observed in true secondary progression
Cyclophosphamide
Potential Adverse Effects
Acute:
Chronic:
Nausea / malaise
Infertility
Alopecia
Pulmonary fibrosis
Hemorrhagic cystitis
Myocarditis
Myelosuppression
Malignancy
Infection
Mitoxantrone
►
An anthracenedione related to dauxorubicin
with potent immunosuppressive effects
►
Intercalates DNA and blocks the synthesis of
RNA
►
Inhibits topoisomerase
►
Potent effects on B-cell and T-cell function
►
Inhibits both passive and active EAE
Clinical Trials of Mitoxantrone in MS
►
Early trials produced slightly conflicting results
and employed dose regimens that differed
considerably
►
This may have been due to the patient
populations studied
►
What emerged was a marked reduction in
relapse rate and a reduction in enhancing lesion
frequency
►
Suggesting that MITX might be useful in rapidly
progressive forms of MS characterized by active
inflammatory disease
Methylprednisolone and Mitoxantrone in
MS (MP+M): Trial Design
Randomized Treatment
Triage
M1
M2
M3
M4
M5
M6
M5
M6
Mitoxantrone 20 mg/mo IV +
Methylprednisolone 1 g/mo IV
M -2
M -1
M0
M1
M2
M3
M4
Methylprednisolone 1 g/mo IV
MP+M: Lower Incidence of
New MRI Lesions
Percentage of Patients Developing New Gd-Enhancing Lesions
MP (N = 21)
100
MP+M (N = 21)
*
Patients (%)
80
*P = .009
†P = .030
‡P = .033
§P = .001
†
‡
§
60
40
86%
Reduction
20
0
-1
Edan et al. 1997.
0
1
2
3
Months
4
5
6
MP+M: Slower Progression of
Neurologic Disability
Confirmed EDSS 1-Point Variation* Between
Patient Inclusion and End of Study
P<.01
Patients
(%)
(N = 12)
(N = 12)
(N = 8)
(N = 6)
(N = 3)
(N = 1)
*EDSS changes from 6.0-6.5 and from 6.5-7.0 were considered equivalent to 1-point change. The
1-point variation was measured for 2 months running at the end of the study.
Edan et al. 1997.
Mitoxantrone and IVMP in RPMS
Relapse Assessment
IVMP
(n=21)
Mito +
IVMP
(n=21)
P-value
Baseline annualized
relapse rate
2.9
3.1
NS
On study annualized
relapse rate
3.0
0.7
0.003
7 (33%)
14 (67%)
0.031
Patients free of relapses
on study
Edan G et al. J Neurol Neurosurg Psychiatry. 1997;62:112-118.
MP+M: Conclusions
► Addition
of mitoxantrone to
methylprednisolone significantly
●
●
●
Reduced new MRI lesions
Slowed the progression of neurologic disability
Reduced relapse rate
Edan et al. 1997.
Mitoxantrone in Multiple Sclerosis
(MIMS): Study Design
►
2-year, double-blind, multicenter, placebo
controlled
►
194 patients, 18-55 years, EDSS 3-6
►
Treatment arms
●
●
●
Mitoxantrone 5 mg/m2, IV, q3mo
Mitoxantrone 12 mg/m2, IV, q3mo
Placebo
MIMS Design
R
A
N
D
O
M
I
Z
E
Placebo
Mitoxantrone 5 mg/m2
Mitoxantrone 12 mg/m2
Rx every 3 months x 24 months
Follow up at Month 36
Hartung, H.P. et al. The Lancet 2002. v360 2018-2025
MIMS Study
Inclusion and Exclusion Criteria
Inclusion Criteria
►
►
►
►
►
Age 18 to 55
Definite MS (Poser’s
criteria)
Secondary progressive or
remitting progressive MS
(worsening RRMS)
EDSS progression
1 point in preceding
18 months
Baseline EDSS from
3.0-6.0
Exclusion Criteria
►
►
►
►
►
►
Hartung, H.P. et al. The Lancet 2002. v360 2018-2025
Benign or primary
progressive MS
Relapse or treatment
with corticosteroids in
preceding
8 weeks
Prior treatment with
NOVANTRONE®
Immunosuppressive therapy
in preceding 9 months
Cardiac risk factors
Major medical illness
MIMS Baseline Demographics* (1)
Placebo
Mitox 5
Mitox 12
(n=64)
(n=64)
(n=60)
Male/Female (%)
52/48
39/61
53/47
Mean age (years)
40
40
40
Remittent progressive (%)
45
58
47
Secondary progressive (%)
55
42
53
Type of MS
* No significant differences between the 3 groups
Hartung, H.P. et al. The Lancet 2002. v360 2018-2025
Mitoxantrone Efficacy at 2 Years:
Primary Efficacy Variables
Placebo
(n=64)
Mitoxantrone
12 mg/m2
(n=60)
Multivariate primary efficacy
criterion
P-value
Mitoxantrone
12 mg/m2 vs.
Placebo
<0.0001
EDSS change (mean)
0.23
-0.13
0.0194
Mean no. of treated relapses
1.20
0.40
0.0002
Time to first treated relapse
(median months)
14.2
NR
0.0004
SNS change (mean)
0.77
-1.07
0.0269
NR=not reached within 24 months.
Hartung, H.P. et al. The Lancet 2002. v360 2018-2025
Changes in EDSS
(m24 - Baseline)
Mean Change in EDSS
p = 0.0194 †
†
Placebo vs. Mitoxantrone 12 mg/m2
Hartung, H.P. et al. The Lancet 2002. v360 2018-2025
EDSS >1.0 Point Deterioration
from Baseline
% of patients
(N=16)
p = 0.036 †
(N=5)
†
Placebo vs. Mitoxantrone 12 mg/m2
Hartung, H.P. et al. The Lancet 2002. v360 2018-2025
Time to First Treated Relapse
Placebo
Mitox 12
1.00
0.75
Mitox 12mg not reached
0.50
Placebo =14.19
m.
0.25
p=0.0004†
0.00
0
†
3
6
9
Placebo vs. Mitoxantrone 12 mg/m2
Hartung, H.P. et al. The Lancet 2002. v360 2018-2025
12
Months
15
18
21
24
MIMS: Patients With
New Gd-Enhancing Lesions (N = 110)
19%
(N = 7)
P = .02 at Month 24
Placebo
Mitoxantrone 12 mg/m2
16%
(N = 5)
Patients (%)
12%
(N = 4)
(N = 0)
0%
Month
Significantly Reduced the Change in the
Number of T2-Weighted Lesions vs Placebo
Mean Change in
Number of
T2-Weighted
Lesions at 24
Months
85%
reduction
Mitoxantrone
12 mg/m2
(n=28)
Placebo
(n=32)
Potential Adverse Effects of
Mitoxantrone
►
Acute
● Alopecia
● Myelosupression
● Infection
● Nausea/vomiting
● Malaise
● Discoloration of sclera
● Arrhythmia
►
Chronic
● Cardiac toxicity
● Malignancy
● Amenorrhea
● Infertility
● Fetal malformation
Mitoxantrone
►
Approved by the FDA for worsening RR
MS, SP MS with relapse, and PR MS
►
Recognized as a rescue therapy
►
More dangerous than A,B,C,R
►
Useful in those failing conventional therapy
or with aggressive disease from the outset
The “Evolution”
►
Much has changed since the advent of
mitoxantrone
►
Our understanding of the disease process and
the importance of the inflammatory process
has grown substantially
►
Not much has changed regarding the profiles
of the chemotherapeutic agents used and
being developed
►
Cladribine is a perfect example
Cladrbine
Synthetic purine analogue product
(adenosine analogue)
Deoxycytidine kinase
(phosphorylation)
Affect cellular metabolism, induce DNA damage and
apoptosis in dividing and non dividing cells
Reduction of CD4 and CD8 T cells, B cells but also other immune
cells such as neutrophils and monocytes
Background
►
Approved by FDA for:
●
●
Hairy cells leukemia
Malignant lymphoma
►
A few phase 1 and 2 studies have
been conducted in MS with cladribine
iv or s/c.
►
Pregnancy category D
The FDA has a categorization of drug risks to the fetus that runs from:
"Category A" (safest) to "Category X" (known danger--do not use!)
Category A
Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no
evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.
Category B
Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled
studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other
than a decrease in fertility) that was not confirmed in controlled studies in women in the first
trimester (and there is no evidence of a risk in later trimesters).
Category C
Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal
or other) and there are no controlled studies in women, or studies in women and animals are not
available. Drugs should be given only if the potential benefit justifies the potential risk to the
fetus.
Category D
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may
be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a
serious disease for which safer drugs cannot be used or are ineffective).
Category X
Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence
of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant
women clearly outweighs any possible benefit. The drug is contraindicated in women who are or
may become pregnant.
CLARITY - Treatment Regimen
►
Annual short-course treatment
●
●
Each course = 1–2 tablets (10 mg) daily for 4 or 5 consecutive
days per month
Courses given for 2 or 4 consecutive months in Year 1 and
for 2 consecutive months in Year 2
First 48 weeks
XXXX
Second 48 weeks
XX
Placebo
Screening
1326
randomized
(1:1:1)
••
XX
••
Cladribine tables: 4 courses, total dose 3.5 mg/kg
••••
••
X
Placebo
course
•
Cladribine
course
Cladribine tables: 6 courses, total dose 5.25 mg/kg
Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA;
April 30, 2009.
Primary Outcome
Reduction in Relapse Rates (ITT)
Annualized relapse rate
54.5% reduction (P < 0.001)
57.6% reduction
(P < 0.001)
0.4
0.33
0.3
0.2
0.14
0.15
Cladribine
3.5 mg/kg
(n = 433)
Cladribine
5.25 mg/kg
(n = 456)
0.1
0
Placebo
(n = 437)
ITT = intent-to-treat population; error bars indicate upper limit of 95% confidence interval.
Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.
Secondary Outcome
Reduction in Disability Progression (ITT)
Hazard ratio vs placebo (95% CI)*
Proportion with 3-month
confirmed EDSS progression (%)
Placebo
Cladribine 3.5 mg/kg
0.67 (0.48, 0.93); P = 0.018
Cladribine 5.25 mg/kg 0.69 (0.49, 0.96); P = 0.026
Number of patients at risk:
Placebo
437
424
3.5 mg/kg
433
424
5.25 mg/kg
456
447
33%
31%
Relative
reduction
399
407
425
373
389
404
355
379
388
333
364
375
315
355
363
304
347
350
304
347
350
Time to sustained change for  3 months in EDSS of  1 point (or  1.5 point if baseline EDSS was 0, or  0.5 point if baseline EDSS was 5);
CI = confidence interval; *Cox proportional hazards model.
Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.
Secondary Outcome
Improvement in MRI Parameters (ITT)
Placebo
Cladribine 3.5 mg/kg
–87.9%*
Cladribine 5.25 mg/kg
–76.9%*
–77.9%*
Mean ± SE lesions/patient/scan
2.00
–86.8%*
–74.6%*
–73.4%*
1.72
1.50
1.43
*P < 0.001
*P < 0.001
*P < 0.001
1.00
0.91
0.50
0.12
0.11
0.38
0.33
0.43
0.38
0
T1 Gd+
lesions
Active T2
lesions
Combined unique
lesions
SE = standard error.
Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.
Secondary Outcome
Safety Overview
Placebo
Cladribine
3.5 mg/kg
(n = 435)
(n = 430)
Any treatment-emergent AE
73.3
80.7
83.9
82.4
AEs leading to discontinuation
2.1
3.5
7.9
5.8
AEs leading to withdrawal
1.1
1.2
2.0
1.6
Serious AEs
6.4
8.4
9.0
8.7
0.5
(n = 2)
0.5
(n = 2)
0.4
(n = 2)
0.4
(n = 2)
Patients with AE (%)
Deaths*
Cladribine Cladribine
5.25 mg/kg
overall
(n = 454)
(n = 884)
*Placebo: hemorrhagic cerebrovascular accident, suicide; cladribine 3.5 mg/kg: acute myocardial
infarction, pancreatic carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then
cardiorespiratory arrest.
AEs = adverse events
Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting;
Seattle, USA; April 30, 2009.
Cladribine
Depletion of Lymphocyte Subpopulations in Phase 3 Trial in SPMS and PPMS
CD4+ (helper T cells)
CD8+ (cytotoxic T cells)
CD19+ (B cells)
Placebo
Cladribine 0.7 mg/kg
Cladribine 2.1 mg/kg
CD19+/CD56+ (natural killer cells)
Guarnaccia JB, et al. Presented at: WCTRIMS; September 17-20, 2008; Montreal, Canada. [P55].
Cladribine: Effect after 3-5 years on Naïve
(CD45RA+) and Memory (CD45RO+) - CD4+ Tcells
Hairy Cell Leukemia
patients were treated with
Cladribine (1 mg/kg c.i.
for 7 days)
At 3-5 years post dose,
there was a decrease in
CD4+/CD45RA+ cells
while CD4+CD45RO+
cells slightly increased
These findings may
suggest that
CD4+/CD45RA+ cells are
more sensitive than
CD4+/CD45RO+ to the
toxic effect of cladribine
Raspadori D, et al. Leukemia. 1999;13:1254-1257.
Subject with Resolved Grade 3 and 4 Toxicity
Hematology (resolved = returning to Grade 1 or 0)
►
►
App. 50% of Grade 3 and 4 lymphopenia resolved on study; median duration ~ 24 wks
Almost all other Grade 3 and 4 toxicities resolved on study
Laboratory
test
Haemoglobin
WBC
Neutrophils
Lymphocyte
Statistics
Cladribine 5.25 Cladribine 3.5
mg/kg (n=454) mg/kg (n=430)
n (%)
n (%)
Mean duration (SD) (weeks)
Median duration (weeks)
Min;Max duration (weeks)
0 (1 total)
Mean duration (SD) (weeks)
Median duration (weeks)
Min;Max duration (weeks)
Placebo
(n=435)
n (%)
3 (5 total)
2 (3 total)
17.5 (6.8)
18.1
10.4;24.0
13.0 (8.3)
13.0
7.1;18.9
8 (10 total)
6 (6 total)
2 (2 total)
11.8 (10.3)
9.0
1.4;29.1
3.7 (1.9)
3.4
1.6;6.0
2.8 (0.9)
2.8
2.1;3.4
Mean duration (SD) (weeks)
Median duration (weeks)
Min;Max duration (weeks)
17 (17 total)
12 (12 total)
17 (18 total)
8.1 (9.6)
5.9
1.1;42.1
5.2 (3.8)
4.9
1.0;12.1
4.8 (3.1)
4.3
1.1;12.1
Mean duration (SD) (weeks)
Median duration (weeks)
Min;Max duration (weeks)
108 (203 total)
52 (110 total)
2 (2 total)
29.4 (20.8)
24.1
2.9;88.0
25.4 (19.8)
23.4
0.9;92.7
4.6 (0.6)
4.6
4.1;5.0
PS. Sorenson, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 10, 2009; Poster 472.
Adverse Events of Special Interest
Herpes Zoster
Preferred term,
n (%) patients
Placebo
(n=435)
Herpes zoster
0
Herpes zoster oticus
0
Varicella
►
1 (0.2)
Cladribine
3.5 mg/kg
(n=430)
Cladribine
5.25 mg/kg
(n=454)
Cladribine
overall
(n=884)
8 (1.9)
11 (2.4)
19 (2.1)
1 (0.2)
1 (0.1)
1 (0.2)
2 (0.2)
0
1 (0.2)
Herpes zoster was reported more frequently with cladribine tablets
than placebo
●
20 patients had 21 zoster events in the cladribine tablets groups
●
All 21 cases were self-limiting and dermatomal
S. Cook, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 11, 2009.
Adverse Events of Special Interest
Malignancies
Placebo
(n = 435)
Cladribine
3.5 mg/kg
(n = 430)
Cervix carcinoma Stage 0
0
0
0.2 (1)
0.1 (1)
Malignant melanoma
0
0.2 (1)
0
0.1 (1)
Ovarian cancer
0
0.2 (1)
0
0.1 (1)
Pancreatic cancer,
metastatic
0
0.2 (1)
0
0.1 (1)
0
0
0.2 (1)
0.1 (1)
Preferred term, % (n)
Cladribine Cladribine
5.25 mg/kg
overall
(n = 454)
(n = 884)
During study
During post-study surveillance
Choriocarcinoma
Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.
Cladribine
Cladribine Summary
►
Efficacy is comparable to high dose IFN
►
Toxicity is considerable
●
●
●
●
●
●
Risk of malignancy
Long-term immunosuppression
Increased risk of herpes infections
Infertility
Fetal malformation
Graft vs. host
►
How long can it be used with CD-4 counts
markedly reduced
►
What do you do if patients are worsening?
Evolution?
►
There has been no evolution!
►
Chemotherapeutic agents remain nonselective,
broad spectrum cytotoxic agents that suppress the
immune system in a nonspecific fashion
►
They all have considerable risk of adverse events
that include secondary malignancy, infection,
infertility, fetal malformation, and other end organ
toxicity
►
Newer monoclonal antibodies and other innovative
therapies appear equally or more effective and
have manageable risk
Case Studies
Challenging Cases in the
Management of Multiple Sclerosis and
Parkinson’s Disease
Multiple Sclerosis Case #1
► 24-year-old female with diplopia on looking to the
right for a day or two – Austin ophthalmologist
found nothing unusual
► Back in Houston another ophthalmologist called it
‘some type of optic nerve inflammation’ and gave
her 5 days of oral steroids
► 2 weeks into symptoms seen by a pro who noted
skew deviation, marked asymmetric nystagmus
with torsion and jerk greater to the right, no INO,
no APD and normal VERs to go with complaints of
vertical diplopia and oscillopsia
UPIN 4804
06/06/08
UPIN 4804
06/06/08
Multiple Sclerosis Case #1
► 4 days later continued double vision on looking to
the right
► Extensive past history uncovered only one week
of nausea and vomiting about 4 months ago
attributed to food poisoning
► Nystagmus to right gaze of greater amplitude in
adducting eye with incomplete abduction of right
eye, remaining exam normal
► CSF with 10 lymphocytes, IgG index 1.15 and 3
OCBs
► Intravenous methylprednisolone course started
UPIN 4804
07/02/08
UPIN 4804
07/02/08
Multiple Sclerosis Case #1
The Issues
► The subject was born and raised outside of the
reach of the Scandinavian gene pool - is this
NMO, and how unusual is this?
► When you have CIS and can’t diagnose more
than suspect MS by McDonald’s or Swanton’s,
do you just treat, use Frohman?
► When asked about the familial risk of MS in the
company of the patients twin sister, what is the
best course?
Multiple Sclerosis Case #2
► 30-year-old Caucasian female presented initially
with right optic neuritis.
► Vision improved after high dose intravenous
methylprednisolone treatment
► T2-weighted MRI brain scan showed 2 areas of
abnormal signal in the periventricular and
subcortical white matter.
► No disease modifying therapy was started at that
time.
Multiple Sclerosis Case #2
► 1 year later- numbness and weakness of both legs, urinary
hesitancy, and increasing gait difficulties over several days.
► MRI cord -increased T2 signal at C8 with a corresponding
area of Gd enhancement on T1.
► MRI brain- one new periventricular white matter lesion
without enhancement in comparison to last year’s.
► Motor symptoms improved with high dose corticosteroid
therapy
► Residual numbness in the feet and bladder control
difficulties.
Multiple Sclerosis Case #2
► Given diagnosis of MS and therapy with once weekly
IM interferon beta was begun.
► 6 months later she complained of markedly increased
fatigue and “fuzzy thinking.”
► Brain MRI scan revealed several new T2 lesions in
both cerebral hemispheres and several new enhancing
lesions around the corpus callosum.
► Disease modifying therapy was changed to a high
dose subcutaneous interferon beta.
Multiple Sclerosis Case #2
► Over the next year, she had no new symptoms
and there were no new lesions seen on a repeat
MRI scan.
► After several months she complained of balance
difficulties, memory difficulties, and an increase in
fatigue.
► MRI scan showed additional Gd+ enhancing
lesions.
► A test for neutralizing antibody against interferon
beta (NAb) revealed a titer greater than 1:100.
Multiple Sclerosis Case #2
► The same interferon treatment was continued
but after several months she complained of
ongoing problems with memory.
► Several new enhancing lesions were again found
on MRI. A repeat NAb titer was unchanged.
Multiple Sclerosis Case #3
►
Student nurse falls hitting head on concrete
when obese patient she is transporting begins
to fall off litter. MRI shows pineal cyst.
►
18 months later, follow-up MRI shows
unchanged cyst but single periventricular nonenhancing white matter lesion.
►
Three yearly follow-ups show no new MRI
lesions, no symptoms and no neurologic
abnormalities.
Is it Multiple Sclerosis?
►
While hiking with physician husband on hot
afternoon, she notes numbness in left foot.
►
Spinal cord MRI shows enhancing lesion at
T17.
►
Is it MS?
►
Treatment recommendations?
Multiple Sclerosis Case #4
► 32-year-old healthy female post-doc
researcher who participated in an MRI study
as a volunteer.
► Subject has no family history of MS or
immune-mediated diseases. No personal
past medical history.
► No neurological symptoms except rare
migraine headaches and no signs on her
neurological exam.
Multiple Sclerosis Case #3
Research Brain MRI
Parkinson’s Disease Case #1
►
A 56-year-old male in good health presents with
slight, intermittent rest tremor of the left (nondominant) hand. Tremor worse with stress and
when he walks. Wife has noticed decreased arm
swing on the left.
►
He notes some stiffness on the left side and
some constipation. He states that symptoms are
only minimally bothersome and not interfering
with job or home life. The couple is troubled that
the condition will become apparent to coworkers
and interfere with career.
Parkinson’s Disease Case #1
►
►
►
►
Family History: No family history of Parkinson’s
disease
Medical History/Medications: Wife noticed that for
the past three years the patient moves about
during sleep.
No current medications
Examination: Reveals normal mental status and
eye movements. He has slight bradykinesia on
repetitive alternating movements in the left hand
and a slight rest tremor is noted.
Decision making: Making the diagnosis of PD; early
non-motor features of PD; when to initiate therapy
Parkinson’s Disease Case #2
►
58-year-old male in good health presents with
resting tremor of the right (dominant) hand
and difficulty with simple tasks such as
brushing teeth and combing hair. He works as
a desk clerk and has noticed significant
problems with writing. Also has trouble
buttoning and at times has trouble cutting
food.
►
Complains of fatigue, lack of motivation and
disinterest. He tends to fall asleep easily during
the day.
Parkinson’s Disease Case #2
►
►
►
►
Family History: Father died with Parkinson Disease
and a cousin diagnosed with Parkinson’s disease 2
years ago is responding well to levodopa
Medical History/Medications: No significant medical
or surgical history. No current medications
Examination: Bilateral bradykinesia and
asymmetric rest tremor right greater than left. Gait
is slow but there is no problem turning. Pull Test is
negative. Rest of the examination is normal
Decision making: Patient diagnosed with
Parkinson’s disease with some disability and he
wishes to start treatment.
Parkinson’s Disease Case #3
►
68-year-old woman with a 4-year history of Parkinson’s
disease. She initially presented with asymmetric tremor
involving the left hand. Subsequently, she progressed
to have tremor both sides and significant slowness
bilaterally. Was started on levodopa 3 years ago.
►
Currently takes carbidopa-levodopa 25/100 one tablet 4
times per day. She is experiencing return of tremor and
slowness and sweating and abdominal pain as the
medication is wearing off. During off periods, and in
the early morning hours and she has painful dystonia of
the left foot. She has abnormal movements while the
medication is working.
Parkinson’s Disease Case #3
►
►
►
►
Family History: no relatives with PD
Medical History: No significant medical or
surgical history
Medications: Amitriptyline 50 mg. q.h.s for
depression in addition to carbidopalevodopa
Decision making: treatment of motor
fluctuations, non-motor features of PD
Parkinson’s Disease Case #4
►
►
82-year-old woman has a history of Parkinson’s
disease for 12 years. She presented with shuffling
gait, masked facies, postural instability, and a pillrolling tremor of the right hand.
Initially responded well to carbidopa-levodopa.
Then she developed mild wearing off and
dyskinesia. Over the past two years she has been
experiencing visual hallucinations, paranoia, and
vivid dreams. She has become more forgetful and
gets lost easily around familiar places. She falls
frequently.
Parkinson’s Disease Case #4
►
►
►
►
Family History: 87-year-old sister diagnosed with
Alzheimer’s disease and Parkinson’s disease
Medical History: Mild stroke 3 years ago; has
minimal residual effects of right-sided weakness.
Medications: She takes 1 aspirin daily in addition
to carbidopa-levodopa
Decision making: management of advanced PD
motor and non-motor features