Transcript Practical Issues in Multiple Sclerosis: Advances in the

Emerging Therapies
for Multiple Sclerosis
Slide 1 of 26
Newly Identified Players in the
Pathophysiology of Multiple Sclerosis
Suhayl Dhib-Jalbut, MD
Professor and Chairman
Department of Neurology
UMDNJ-Robert Wood Johnson Medical School
New Brunswick, New Jersey
Slide 2 of 26
Pathogenesis of MS
Outline
• Genes
• Th17 cells
• B-cells
• CD8 and NK cells
• T-regulatory cells
• Mode of action of MS therapies
Slide 3 of 26
MS Lesions
Axonal Changes
Axonal Transection in MS Lesions
Trapp BD, et al. N Engl J Med. 1998;338:278. Copyright © [1998]. Massachusetts Medical Society.
All rights reserved.
Slide 4 of 26
Types of Cortical Lesions
Type I
Type II
Type III
Lesion in white
matter and cortex
Intracortical lesions
Lesions extending
into the cortex from
the pial surface
Peterson JW, et al. In: Multiple Sclerosis as a Neuronal Disease. Elsevier Academic Press, 2005.
165-184.
Graphic courtesy of Dr. Suhayl Dhib-Jalbut.
Slide 5 of 26
Disease Heterogeneity by Cellular
Pathology
Pattern I
Pattern II
Pattern III
Pattern IV
CD3 T-cells
+++
++
++
++
Plasma cells/Ab
++
+++
++
+
-
++
-
-
++
+
+
+++
Perivenous
Perivenous
Ill-defined
concentric
Perivenous
Oligodendrocytes
+++
+++
+
+
DNA fragment/apoptosis
+/-
+/-
++ (Apo)
-
Even
Even
++
++
-
-
~12%–16%
~53%–60%
~25%–30%
≤4%
Inflammation
Complement (C9neo)
Macrophages
Demyelination
Myelin loss
Remyelination
Relative prevalence (???)
MAG
Even
Abbreviation: MAG, myelin-associated glycoprotein.
With permission from Lucchinetti C, et al. Ann Neurol. 2000;47:707-717.
Slide 6 of 26
Homogeneity of Active Demyelinating
Lesions in Established MS
Complement, IgG, FcyR, and PLP
Co-Localize to Phagocytic Macrophages
With permission from Breij ECW, et al. Ann Neurol. 2008;63:16-25.
Slide 7 of 26
Multiple Sclerosis
An Immunogenetic Disease
Environmental Factors
Demographics/Epidemics
Microbial Agents
EBV
Vitamin D
Genetic Predisposition
• Twins studies
• HLA-DR2 (DRß1*1501)
(antigen presentation)
• IL-2Ra
• (regulatory T-cells)
• IL-7Ra
 (memory T-cells)
• ST8SIA1
Immune Dysregulation
Graphic courtesy of Dr. Suhayl Dhib-Jalbut.
MS
Slide 8 of 26
Pathogenic T-Cells
New Player: Th17
Slide 9 of 26
Helper T-Cell Differentiation
IL-12/STAT4
IL-4/STAT6
IL-6 + TGF-β
TH1
IFN-g
TH2
IL-4
IL-5
IL-10
IL-13
TH17
IL-17
Treg
TGF-β
Pro-inflammatory
Anti-inflammatory/
Allergy
Pro-inflammatory
IL-23
TGF-β
Graphic courtesy of Dr. Scott Zamvil.
Regulatory
Slide 10 of 26
IL-17 Expression in Acute and
Chronic Active MS Plaques
With permission from Tzartos JS, et al. Am J Pathol. 2008;172:146-155.
Slide 11 of 26
Immune Effects of IL-17 in MS
• Induces proinflammatory cytokines
• Induces chemokines
• Enhances dendritic cell maturation
• Promotes neutrophils function
Gold R, et al. Am J Pathol. 2008;172:8-10.
Slide 12 of 26
Pathogenic
B-Cells
Slide 13 of 26
MS Is Not Necessarily a Th1-Driven
Disease!
• No benefit from anti-CD4+ mAb treatment
(phase II)
• No benefit from anti-IL12p40 (phase II x 2)
• Uncertain benefit from CD4+ T-cell vaccine trials
including APL (disease worsened), anti-CD4v
vaccine, and recent MBP peptide/CD4+ (phase
II trials in SPMS)
• CTLA4-Ig first phase II modest benefit
Slide 14 of 26
B-Cell Depletion with Rituximab in
Relapsing-Remitting MS
• 48-week phase II study of 104 MS patients comparing
1000 mg IV rituximab with placebo
• Endpoint was number of gadolinium-enhancing lesions
on MRI at weeks 12, 16, 20, and 24
• Rituximab significantly reduced the number of
gadolinium-enhancing lesions and the number of new
lesions
• Rituximab significantly reduced the relapse rate at week
24 (14.5% vs 34.5%) and week 48 (20.3% vs 40.0%)
• Results imply B-cell involvement in relapsing-remitting
MS
Hauser SL, et al. N Engl J Med. 2008;358:676-688.
Slide 15 of 26
Relapsing-Remitting MS
Rituximab Versus Placebo
Hauser SL, et al. N Engl J Med. 2008;358:676-688. Copyright © [2008]. Massachusetts
Medical Society. All rights reserved.
Slide 16 of 26
The B-Cell
Old Player, New Position on the Team
McFarland HF, et al. N Engl J Med. 2008;358:664-665. Copyright © [2008].
Massachusetts Medical Society. All rights reserved.
Slide 17 of 26
How the CNS Fosters B-Cells in MS
• The CNS contains molecules that regulate B-cell homing
and survival
• B-cell differentiation normally occurs in secondary
lymphoid organs in response to antigen
– In some neuroinflammatory diseases, this process is
replicated in the CNS
• Chronic inflammation can induce formation of ectopic
lymphoid follicles in the meninges of MS patients
– May represent major source of B-cells and plasma
cells that accumulate in MS lesions
Slide 18 of 26
Uccelli A, et al. Trends Immunol. 2005;26:254-259.
T-Regulatory Cells (Tregs)
Slide 19 of 26
CD4+CD25+ Tregs in MS
• Have reduced suppressive function in MS
• Occur with no difference in frequency
between MS and healthy controls
• Blocking IL-10, TGF- does not cause loss
of suppressor function
Viglietta V, et al. J Exp Med. 2004;199:971-979.
Slide 20 of 26
10.0
Mean GA-R
CD4+ CD25+FoxP3+
7.5
5.0
2.5
0.0
Pre-Rx 3mo
6mo
12mo 24mo
% Gated in CD4+ Cells
% Gated in CD4+ Cells
Induction of CD4+CD25+FOXP3+ Tregs
During Glatiramer Acetate Treatment
Mean GA-HR/NR
CD4 + CD25+FoxP3+
10.0
7.5
5.0
2.5
0.0
Pre-Rx 3mo
6mo
12mo 24mo
Abbreviations: GA-R, glatiramer acetate-responder; GA-HR/NR, glatiramer acetate –
hypo-responder/non-responder.
With permission from Dhib-Jalbut S, et al. 23rd Congress of ECTRIMS, 12th Conference
of Rehabilitation in MS; October 11-14, 2007; Abstract ID 52136.
Slide 21 of 26
Modulation of Tregs by Therapy in MS
With permission from Saresella M, et al. FASEB. 2008;22:3500-3508.
Slide 22 of 26
CD8+ T-Cells in MS
• CD8 T-cells are a prevalent cell type in MS
lesions
• In vitro tissue culture and in vivo animal models
demonstrate both suppressive and pathogenic
roles for the CD8 T-cells
• CD8 T-cells can transect axons, induce
oligodendrocyte death, and promote vascular
permeability, all of which are observed in MS
lesions
• Conversely, CD8+ T-cells exhibit regulatory
activity directed at suppression of effector CD4+
T-cells
Slide 23 of 26
Natural Killer Cells
• NK cells are a subset of bone marrow–derived
lymphocytes distinct from B and T lineage
• Innate response to kill microbe-infected cells and
activate macrophages via IL-12 mediated pathways
• NK cells express CD16 (FcRIII), which binds to IgG
opsonized cells and is lytic by ADCC-like mechanism
• In autoimmunity, NK cells may play opposing roles—
they function as both regulators and inducers of disease
relative to cytokine environment and cell:cell contact
• IL-15 appears to play pivotal role in the differentiation of
NK cells from their progenitors, the maintenance of their
survival, and their activation
Abbreviations: ADCC, antibody-dependent cell-meditated cytotoxicity; NK, natural killer.
Slide 24 of 26
Loss of Natural Killer (NK) Functional
Activity During Clinical Relapse
• Nine RRMS patients matched in age, sex, and NK
responder status with controls
• No significant difference in average NK cell functional
activity in the two groups
• Four clinical relapses in RRMS patients associated with
novel NK valleys in functional activity
– Observed in RRMS patients but not controls
– Preceded onset of clinical attacks
– Of greater depth and duration than cyclical valleys seen in
controls and RRMS patients
– Suggests that RRMS patients are at greater risk for relapse
during novel valleys in NK functional activity
Slide 25 of 26
Immunopathogenesis of MS
FcR
CD8
CTL
CD8
CTL
gdT
Oligo
CD8
Reg
Glutamate
Ne
ut
IL-17
Treg
17
FOXP3
CD40 CD40L
Treg
IL-23
Th
17
B7 CD28
LFA-1
IL-6
B
CD4+CD25+
Graphic courtesy of Dr. Suhayl Dhib-Jalbut.
IL-4
IL-5
IL-10
IL-13
TGF-
Tr1
Th2
Th3
IL-4 & IL-10
Foxp3
Thp
CD40 CD40L
VLA-4
Th1
IFNg
TNF
Treg
TGFß
CD4
APC
MMP-2/9
BAFF
APRIL
TACI
VCAM-1
Foxp3
IL-6 & TGF-ß
BBB
Astrocyte
ICAM-1
T
h17
Tr1
Th2
Th3
MCP-1
MIP-1a
IP-10
RANTES
Th1
IL-17
CD8p
IL-10
TGF
B7 CD28
Th
EBV
B
IFNg
TNF
Ab+C9neo
Pl
NO
Oi
TNFa
MMP
IL-12
CD4
TCR
Thp
B7 CD28
HLA
APC
APC
Myelin Ag
Microbial Ag
CD4
Slide 26 of 26
Thp
CD40 CD40L
Immunopathogenesis of the MS Lesion
gdT
CD8
Oligo
MO
Pl
NO
Memantine
Riluzole
Minocycline
IFNg
TNFa
Glutamate
B7 CD28
Microglia
BBB
CD40
Minocycline
VCAM-1
IFN-ß
B
IL-10
TGF
MCP-1
MIP-1a
IP-10
RANTES
Th1/Th17
Mitoxantrone
Alemtuzumab
Fingolimod
Laquinimod
Teriflunomide
Cladribine
Rapamycin
Daclizumab
K-Channel
Blockers
Ab+C
GA
B
CD40L
Steroids
MMP-2/9
VLA-4
Th1
Th17
IL-6/TGFß
B
Rituximab
Graphic courtesy of Dr. Suhayl Dhib-Jalbut.
CD4
IL-4
IL-5
IL-6
IL-13
TGF
Th2/
Th3
Tr1
IL-4 & IL-10
IL-12
Thp
Foxp3
Plasmaphoresis Statins, E2
Antegren
VLA-4
IFNg
TNFa
VCAM-1
Th2/
Th3
Tr1
B7 CD28
APC
APC
Thp
Slide 27 of 26
CD4
CD40 CD40L
Emerging Treatment Strategies for MS
Fred D. Lublin, MD
Saunders Family Professor of Neurology
The Corinne Goldsmith Dickinson Center for Multiple Sclerosis
Mount Sinai School of Medicine
New York, New York
Tracy M. DeAngelis, MD
Assistant Professor of Neurology
The Corinne Goldsmith Dickinson Center for Multiple Sclerosis
Mount Sinai School of Medicine
New York, New York
Slide 28 of 26
Where We Are Now…
FDA-approved disease modifying agents
• Interferon beta
– Interferon beta-1b (Betaseron®) 250 mcg qod
– Interferon beta-1a (Rebif®) 44 mcg SC TIW
– Interferon beta-1a (Avonex®) 30 mcg IM weekly
• Glatiramer acetate (Copaxone®)
– 20 mg SC qd
• Mitoxantrone (Novantrone®)
– 12 mg/m2 q3mo: lifetime max, 144 mg/m2
• Natalizumab (Tysabri®)
– 300 mg IV monthly infusion
Slide 29 of 26
Limitations of Current Therapies
• All are only partially effective
• All are injectable or IV and have side effects
• Risks vs benefits
– Existing therapies have advantage of long-term safety data
• Difficulty predicting therapeutic response
• Expensive
• Goal: Individualized, more effective, safe
medication(s) that are easier to administer and,
ideally, less expensive
Slide 30 of 26
Future Directions of MS Therapies
• Disease modification
– Building on existing therapies
– New immunotherapies
– Neuroprotection
– Remyelination and repair
• Symptomatic therapies
• Biomarkers of therapeutic response
Slide 31 of 26
Building on Current Therapies
• Early initiation of therapy
– Treating after clinically isolated syndrome
– BENEFIT, PRECISE, ETOMS, CHAMPS
• Combination therapies
• Double dosing
– GA 40mg – double dose glatiramer acetate
– BEYOND trial – double dose interferon beta-1b
• Reformulations
• Induction therapies
– ie, mitoxantrone, followed by disease-modifying agents,
interferon or glatiramer acetate
Slide 32 of 26
Combination Therapies
• Approach used in other diseases
– Rheumatologic disorders, cancers, HIV
– Ideal combination – synergistic, nonantagonistic
• Combination disease-modifying agents (DMA):
Combi-Rx Trial
– NIH multicenter study coordinated at Mount Sinai
 Interferon beta-1a + glatiramer acetate vs interferon beta-1a alone
vs glatiramer acetate alone
 Fully enrolled, 1008 patients
• Combination: DMA + chemotherapeutic agents
• Combination: DMA + steroids
Slide 33 of 26
Novel Therapies in Testing
• Parenteral (IV) drugs in phase II/III
– Monoclonal antibodies:
rituximab/ocrelizumab, alemtuzumab,
daclizumab
• Oral Drugs in phase III
– Fingolimod, cladribine, teriflunomide,
fumarate, laquinimod
• Symptomatic therapies
– Fampridine (4-AP), nerispirdine
Slide 34 of 26
Rituximab
•
Mechanism of action
–
–
•
Dosing
–
•
Chimeric human/murine mAb to CD20
Depletes circulating B-cells
2 doses given 2 weeks apart IV: 1 g on days 1 and 151
Side effects
–
Infusion reactions, infections, hepatitis B reactivation, cases of progressive multifocal
leukoencephalopathy in systemic lupus erythematosus/cancer population
Approved by FDA for lymphomas, rheumatoid arthritis
•
•
HERMES phase II study for RRMS1
Randomized, 48 weeks, 104 patients with RRMS
–
–
Rituximab 1 g IV vs placebo on days 1 and 15
91% decrease in mean total Gd+ lesions

–
Relapses at 24 weeks

•
•
Rituximab 0.5 ± 2.0; placebo 5.5 ± 15 (P <.0001)
Rituximab 14.5% vs placebo 34.3% (P = .02)
Neuromyelitis optica/Devic’s open-label study2
OLYMPUS trial phase II/III in PPMS – ineffective3
1. Hauser S, et al. N Engl J Med. 2008;358:676-688.
2. Cree BA, et al. Neurology. 2005;64:1270-1272.
3. Hawker KS, et al. Mult Scler. 2008;14:S299. Abstr 78.
Slide 35 of 26
Alemtuzumab
• Mechanism of action
– Anti-CD52 mAb to receptor on surface of T- and B-cells
 FDA approved for chronic lymphocytic leukemia
• Dosing
– Given IV for 3-5 days once yearly (produces rapid decrease in WBCs)1
• Alemtuzumab CAMSS223 Phase II trial 1
– 334 early RRMS patients randomized to alemtuzumab vs interferon
beta-1a
 2-year follow-up results
– Alemtuzumab group: 75% reduction in relapse rate vs interferon beta1a
– Significant reduction of risk of sustained disability
 3-year follow-up
– Maintained 71% and 74% reduction in risk of sustained disability and
relapse rate, respectively, vs interferon beta-1a
 2 phase III trials (CARE-MS, CARE-MS2) now enrolling
• Serious adverse events
– Infusion reactions
– Idiopathic thrombocytopenic purpura (3%): total of 6 cases – 1st case
Slide 36 of 26
was
1. Coles, AJ. N
Englfatal
J Med. 2008;359:1786-1801.
– Grave’s disease – autoimmune thyroiditis (20%)
Daclizumab
•
Mechanism of action
– Anti-CD25 mAb targeting α chain of IL-2 receptor (IL-2Rα)
– Blocks the IL-2 “proinflammatory, ie, bad” cytokine receptor
– Prevents activation of sensitized T-cells
•
Dosing
– IV infusion every 2 weeks (high dose) or every 4 weeks (low dose)
Side effects – infections, cutaneous reactions
•
FDA approved for graft versus host disease/kidney transplant rejection
– CHOICE Trial – phase II results1
 Randomized double-blind controlled trial
 Add-on to interferon in 230 patients with RRMS
 3 arms: 2 doses of daclizumab and placebo added to interferon
– Results
 Decrease in new MRI lesions with higher dose vs interferon alone
 No significant difference in relapse rate
 5.2% with significant infections, none life-threatening
– SELECT: phase II trial of daclizumab monotherapy – Ongoing
1. Montalban X, et al. Mult Scler. 2007;13:S7-S273. Abstr 50.
Slide 37 of 26
Fingolimod
Mechanism of action: Sphingosine 1-phosphate receptor analog which
sequesters activated lymphocytes (T-cells) in lymph nodes preventing egress to
central nervous system
• Dosing: once-daily pill
• Fingolimod phase II trial results1
–
–
–
–
255 patients with RRMS followed for 6 mo
Arms: Placebo, 1.25 mg/d or 5 mg/d of fingolimod
43% (1.25 mg/d) and 61% (5 mg/d) decrease new MRI gad+ lesions
53% (5 mg/d) and 55% (1.25 mg/d) reduction in relapse rate
 77% fingolimod patients were relapse-free
•
Long-term (3-year) data from phase II2
– Of 173 RRMS patients receiving fingolimod for 3 y, 67% were relapse-free after
3 y, with an annual relapse rate of 0.2%
•
Recent safety concerns in phase III
– 2 cases of opportunistic infections:
– Herpes encephalitis (resulting in coma)
– Disseminated Varicella Zoster (fatal)
1. Kappos L, et al. N Engl J Med. 2006;355:1124-1140.
2. Kappos L, Radue E, O'Connor P, et al. Oral fingolimod (FTY720) inpatients with relapsing
multiple sclerosis: 3 year results from a phase II study extension. Mult Scler. 2008;14(suppl
1):S50.
Slide 38 of 26
Fingolimod
TRANSFORMS (phase 3)
AAN 2009 update: primary endpoint reached
Outcome
ARR
% reduction vs
IFN beta-1a
P value
IFN beta-1a
Fingolimod
(0.5 mg/d)
Fingolimod
(1.25 mg/d)
.33
.16
.20
52%
38%
P <.001
P <.001
Cohen J, et al. AAN 61st Annual Meeting; June 25-May 2, 2009. Oral presentation.
Graphic courtesy of Dr. Fred Lublin.
Slide 39 of 26
Fingolimod
FREEDOMS (phase 3)
Primary endpoint reached
Outcome
ARR
%
reduction
vs placebo
Placebo
.40
P value
Graphic courtesy of Dr. Fred Lublin.
(0.5 mg/d)
Fingolimo
d (1.25
.18
.16
54%
60%
P <.001
P <.001
Fingolimod
mg/d)
Slide 40 of 26
Cladribine
• Mechanism of action
– Purine analog that semi-selectively blocks
lymphocyte and monocyte development
• Dosing
– Oral medication given for 5 consecutive days for
2 cycles
• Side effects
– Injection site reactions, neutropenia, muscle
weakness
Slide 41 of 26
Cladribine
• CLARITY phase III trial results1,2
– 58% reduction in annualized relapse rate
– 2.5-fold better odds of remaining relapse-free
– ~30% relative reduction in risk of disability progression
• May be first oral MS disease-modifying drug to be
FDA approved
• ORACLE: ORAL CLadribine in Early MS—a phase III
2-year, randomized, double-blind, placebo-controlled
study of conversion to clinically definite MS in CIS
patients
1. Vermersch P, et al. 19th Meeting of the European Neurological Society; June 20-24, 2009. Poster 700.
2. Giovannoni G, et al. 19th Meeting of the European Neurological Society; June 20-24, 2009.
Slide 42 of 26
Teriflunomide
• Mechanism of action
– Inhibits pyrimidine (DNA) synthesis in T-cells resulting
in destruction of immune cells
• Dosing
– Once-daily pill
• Side effects
– Well tolerated, adverse effects frequency similar to
placebo
• Results of phase II trial1: 36 weeks in 179
patients
– Teriflunomide (high dose and low dose) vs placebo
– Significant (>61%) decrease in new MRI lesions in
both doses
– Decrease in disease progression (in high dose) Slide 43 of 26
1. O’Connor PW, et al. Neurology. 2006;66:894-900.
– Trend towards lower relapse rate in high-dose group
Fumarate
•
Mechanism of action
– Oral formulation of dimethyl fumarate may exert a combination of
anti-inflammatory and neuroprotective effects
•
•
Dosing – thrice-daily pill
Side effects
– Hot flashes, GI events, nasopharyngitis, no effect on QTc
•
Results of phase II trial1
– 257 RRMS patients
– Placebo vs 120 mg (once daily), 360 mg (3 divided doses), 720 mg (3 divided
doses) for 24 weeks
– MRI outcomes
 Significant 69% decrease in Gd+ lesions with highest dose and 48% decrease in
new/enlarging T2 lesions
– Clinical outcomes
 32% decrease in relapse rate
 Not significant compared with placebo
•
2 phase III trials under way comparing fumarate with placebo and glatiramer
acetate
1. Kappos L, et al. Lancet. 2008;372:1463-1472.
Slide 44 of 26
Laquinimod
• Mechanism of action
– Immunomodulator that normalizes Th1:Th2 ratio
– Promotes regulation/suppression of inflammation
– Decreases number of infiltrating inflammatory cells
into CNS
• Dosing
– Oral once-daily dose
• Side effects
– Liver toxicity, transient rise in inflammation in
bloodstream
Slide 45 of 26
Laquinimod
• Phase IIa trial results1
– 209 patients enrolled
– Treatment arms: placebo, 0.1 mg/d, 0.3 mg/d for 24 weeks
– Significant decrease (44%) in new MRI lesions in high-dose
group
– No difference in relapse rate or progression
• Phase IIb trial results2
–
–
–
–
306 patients enrolled
Treatment arms: placebo, 0.3 mg/d, 0.6 mg/d for 36 weeks
Significant decrease (40%) in new MRI lesions in 0.6 mg/d group
Trend toward fewer relapses and greater time to first relapse in
0.6 mg/d group
• 2 phase III trials – 1 currently recruiting
1. Polman C, et al. Neurology. 2005;64:987-991.
2. Comi G, et al. Lancet. 2008;371:2085-2092.
Slide 46 of 26
Symptomatic Therapies
• Fampridine (4-aminopyridine)
– Mechanism: K+ channel blockade
 Enhances axonal conduction
 Side effects: seizures
– 2 recent phase III trials1,2
 Significant improvement 25% in walking speed in responders after
14 weeks: 34.8% compared with 8.3%1
 Submitted to the FDA for review
• Nerispirdine – currently enrolling
– Activated Na+ channel blockade in addition to K+ channel
blockade, which may decrease risk of seizures
1. Goodman AD, et al. Lancet. 2009;373:732-738.
2. Goodman, AD, Scwid SR, Brown TR, et al, for Fampridine MS-F204 Investigators.
Sustained-release fampridine consistently improves walking speed and leg strength in
multiple sclerosis: a phase 3 trial. Mult Scler. 2008;14:S295-S298.
Slide 47 of 26
Future Directions
• Therapeutic research
• Genetic studies
• New MRI metrics
• Proteomics/genomics – biomarker
fingerprints
• Neuroprotection strategies
• Regeneration and repair
Slide 48 of 26
Thank you for participating
in this webcast
Please remember to take the posttest
Slide 49 of 26