Slide 1 of 26 Emerging Therapies for Multiple Sclerosis.
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Transcript of Slide 1 of 26 Emerging Therapies for Multiple Sclerosis.
Slide 1 of 26
Emerging Therapiesfor Multiple Sclerosis
Slide 2 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 SchoolNew Brunswick, New Jersey
Slide 3 of 26
Pathogenesis of MSOutline
• Genes
• Th17 cells
• B-cells
• CD8 and NK cells
• T-regulatory cells
• Mode of action of MS therapies
Slide 4 of 26
MS LesionsAxonal 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 5 of 26
Types of Cortical Lesions
Peterson JW, et al. In: Multiple Sclerosis as a Neuronal Disease. Elsevier Academic Press, 2005.165-184.
Type ILesion in white
matter and cortex
Type IIIntracortical lesions
Type IIILesions extending
into the cortex from the pial surface
Graphic courtesy of Dr. Suhayl Dhib-Jalbut.Graphic courtesy of Dr. Suhayl Dhib-Jalbut.
Slide 6 of 26
Disease Heterogeneity by Cellular Pathology
Pattern I Pattern II Pattern III Pattern IV
Inflammation
CD3 T-cells +++ ++ ++ ++
Plasma cells/Ab ++ +++ ++ +
Complement (C9neo) - ++ - -
Macrophages ++ + + +++
Demyelination Perivenous Perivenous Ill-definedconcentric
Perivenous
Oligodendrocytes +++ +++ + +
DNA fragment/apoptosis +/- +/- ++ (Apo) -
Myelin loss Even Even MAG Even
Remyelination ++ ++ - -
Relative prevalence (???) ~12%–16% ~53%–60% ~25%–30% ≤4%
With permission from Lucchinetti C, et al. Ann Neurol. 2000;47:707-717.
Abbreviation: MAG, myelin-associated glycoprotein.
Slide 7 of 26
Homogeneity of Active Demyelinating Lesions in Established MS
Complement, IgG, FcyR, and PLPCo-Localize to Phagocytic Macrophages
With permission from Breij ECW, et al. Ann Neurol. 2008;63:16-25.
Slide 8 of 26
Multiple SclerosisAn Immunogenetic Disease
MS
Immune Dysregulation
Genetic Predisposition• Twins studies
• HLA-DR2 (DRß1*1501)(antigen presentation)
• IL-2R• (regulatory T-cells)
• IL-7R memory T-cells)
• ST8SIA1
Environmental FactorsDemographics/Epidemics
Microbial AgentsEBV
Vitamin D
Graphic courtesy of Dr. Suhayl Dhib-Jalbut.
Slide 9 of 26
Pathogenic T-Cells
New Player: Th17
Slide 10 of 26
Helper T-Cell Differentiation
TH0
IL-12/STAT4 IFN- Pro-inflammatoryTH1
TH2
IL-4
IL-5
IL-10
IL-13
Anti-inflammatory/
Allergy
IL-4/STAT6
IL-23
IL-17 Pro-inflammatoryTH17IL-6 + TGF-β
TGF-β RegulatoryTreg
TGF-β
TH0
Graphic courtesy of Dr. Scott Zamvil.
Slide 11 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 12 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 13 of 26
Pathogenic B-Cells
Slide 14 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 15 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 16 of 26Hauser SL, et al. N Engl J Med. 2008;358:676-688. Copyright © [2008]. Massachusetts Medical Society. All rights reserved.
Relapsing-Remitting MSRituximab Versus Placebo
Slide 17 of 26
The B-CellOld 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 18 of 26
Uccelli A, et al. Trends Immunol. 2005;26:254-259.
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 19 of 26
T-Regulatory Cells (Tregs)
Slide 20 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 21 of 26
Induction of CD4+CD25+FOXP3+ Tregs During Glatiramer Acetate Treatment
0.0
2.5
5.0
7.5
10.0 CD4+CD25+FoxP3+
Mean GA-R
Pre-Rx 3mo 6mo 12mo 24mo
% G
ate
d i
n C
D4+
Ce
lls
0.0
2.5
5.0
7.5
10.0CD4+CD25+FoxP3+
Mean GA-HR/NR
Pre-Rx 3mo 6mo 12mo 24mo% G
ate
d i
n C
D4+
Ce
lls
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.
Abbreviations: GA-R, glatiramer acetate-responder; GA-HR/NR, glatiramer acetate – hypo-responder/non-responder.Abbreviations: GA-R, glatiramer acetate-responder; GA-HR/NR, glatiramer acetate – hypo-responder/non-responder.
Slide 22 of 26
Modulation of Tregs by Therapy in MS
With permission from Saresella M, et al. FASEB. 2008;22:3500-3508.
Slide 23 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 24 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 25 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 26 of 26
Immunopathogenesis of MS
Ab+C9neoNOOiTNFMMP
Graphic courtesy of Dr. Suhayl Dhib-Jalbut.
B7
CD40MicrogliaCD40L
CD28
Th1
Glutamate
TCD8CTL
IFNTNF
MMP-2/9
B
PlOligo
BBB
MCP-1MIP-1P-10RANTES
Astrocyte
B
CD40L
CD28
CD40
IL-4 & IL-10
CD4APCThp
B7
IFNTNFLFA-1
Th1VLA-4
ICAM-1VCAM-1
IL-12
APC
Thp
CD4
Myelin AgMicrobial Ag
HLATCR
Tr1Th2Th3
IL-4IL-5IL-10IL-13TGF-
IL-10TGF
TregFoxp3
CD4+CD25+
Tr1Th2Th3
CD40L
CD28
CD40
IL-6 & TGF-ß
CD4APCThp
B7
Th17
Th17
Th17
Th17
Th17
Th17
IL-23IL-17
TGFß
IL-6
TregFOXP3
TregFoxp3
BAFFAPRILTACI
CD8CTL
CD8p
NeutNeut
IL-17
EBV
FcR
CD8Reg
Slide 27 of 26
Immunopathogenesis of the MS Lesion
Th2/Th3Tr1
MO
IL-4IL-5IL-6IL-13TGF
B
IL-12
APCThp
CD4CD40LCD40
IL-4 & IL-10
CD4APC
ThpCD28B7
Th2/Th3Tr1B7
CD40
MicrogliaCD40L
CD28
Th1/Th17
B
Glutamate
T CD8
MMP-2/9VCAM-1 VCAM-1
IFNTNF
IL-10TGF
Ab+CPl
IFNTNF
NO
VLA-4 VLA-4Th1Th17
Oligo
BBB
MCP-1MIP-1P-10RANTES B
IFN-ß
Rituximab
GA
Minocycline Statins, E2
Minocycline
Plasmaphoresis
MitoxantroneAlemtuzumabFingolimodLaquinimodTeriflunomideCladribineRapamycinDaclizumab
MemantineRiluzole
Antegren
Foxp3
IL-6/TGFß
Steroids
K-ChannelBlockers
Graphic courtesy of Dr. Suhayl Dhib-Jalbut.Graphic courtesy of Dr. Suhayl Dhib-Jalbut.
Slide 28 of 26
Emerging Treatment Strategies for MS
Fred D. Lublin, MD
Saunders Family Professor of NeurologyThe Corinne Goldsmith Dickinson Center for Multiple Sclerosis
Mount Sinai School of MedicineNew York, New York
Tracy M. DeAngelis, MD
Assistant Professor of Neurology The Corinne Goldsmith Dickinson Center for Multiple Sclerosis
Mount Sinai School of MedicineNew York, New York
Slide 29 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 30 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 31 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 32 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 33 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 34 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 35 of 26
Rituximab• Mechanism of action
– Chimeric human/murine mAb to CD20
– Depletes circulating B-cells
• Dosing– 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 Rituximab 0.5 ± 2.0; placebo 5.5 ± 15 (P <.0001)
– Relapses at 24 weeks 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 36 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 beta-1a– 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 was fatal– Grave’s disease – autoimmune thyroiditis (20%)
1. Coles, AJ. N Engl J Med. 2008;359:1786-1801.
Slide 37 of 26
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 38 of 26
FingolimodMechanism 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 39 of 26
Fingolimod
TRANSFORMS (phase 3) AAN 2009 update: primary endpoint reached
Outcome IFN beta-1aFingolimod (0.5 mg/d)
Fingolimod (1.25 mg/d)
ARR .33 .16 .20
% reduction vs IFN beta-1a
52% 38%
P value 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 40 of 26
Fingolimod
FREEDOMS (phase 3)Primary endpoint reached
Outcome PlaceboFingolimod
(0.5 mg/d)
Fingolimod (1.25 mg/d)
ARR .40 .18 .16
% reduction vs placebo
54% 60%
P value P <.001 P <.001Graphic courtesy of Dr. Fred Lublin.
Slide 41 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 42 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 43 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)– Trend towards lower relapse rate in high-dose group
• Phase III trial ongoing2-year trial in clinically isolated syndrome enrolling
1. O’Connor PW, et al. Neurology. 2006;66:894-900.
Slide 44 of 26
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 45 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 46 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 47 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 seizures1. 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 48 of 26
Future Directions
• Therapeutic research
• Genetic studies
• New MRI metrics
• Proteomics/genomics – biomarker fingerprints
• Neuroprotection strategies
• Regeneration and repair
Slide 49 of 26
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