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transcript
5/20/2014
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How do the Current DMT’s Affect the Altered Immune Response in MS
Scott Newsome, D.O.Assistant Professor of Neurology
Director, Neurology Outpatient Services Johns Hopkins University School of Medicine
Disclosures
• Consultant/Advisor: Biogen‐Idec, Genzyme
• Grant/Research Funding (paid directly to Institution): Biogen‐Idec, Novartis
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MS Subtypes
Relapsing‐remitting Secondary progressive
Primary progressive
Progressive relapsing
Time
Severity
Clinically isolated syndrome (CIS)
Relapsing-Remitting
Secondary Progressive
Preclinical
Time
Measures of brain volume
Relapses and impairment
MRI burden of disease
MRI activity
Axonal loss
Adapted from Goodkin DE. UCSF MS Curriculum. 1999.
Natural History of MS: Summary
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Immunopathogenesis of MS (2011)
Ab+C9neoRNOROSTNFMMP
Courtesy of Suhayl Dhib‐Jalbut, MD
B7
CD40 CD40L
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
IL-6 & IL1-ß
APC
IL‐23
IL‐17
TGFß
IL‐6
TregFoxp3
TregFoxp3
BAFFAPRILTACI
CD8p
EBV
FcR
CD8Reg
CCR6
CCL20
DC
Th0
Th17Th17
Th17
Neut
S1Pr
S1Pr
S1Pr
TLR
Non-selective Selective
Antigen-specificBroad-spectrumImmunosuppression
Strategies to block theImmune system’s attack
Toxicity Antigens unknownor multiple ones!
Slide courtesy of P. Calabresi
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FDA-approved therapies (Approval time period)
1995 2000 2005 2009 2010 2011
Extavia(IFNβ-1b)
Gilenya(fingolimod)
Tysabri
(natalizumab)Betaseron(IFNβ-1b)
Copaxone(glatiramer acetate)
Avonex(IFNβ-1a)
Rebif(IFNβ-1a)
Novantrone(mitoxantrone)
2012
Aubagio
(teriflunomide)
Tecfidera(dimethyl fumarate)
2013
Expanding Landscape of MS Therapeutics
Currently Approved MS Disease‐modifying TherapiesAgent Approval
YearRoute
IFNβ-1b (Betaseron) 1993 Subcutaneous injection every other day
IFNβ-1a (Avonex) 1996 Intramuscular injection every week
Glatiramer acetate (Copaxone) 1996 Subcutaneous injection daily
Mitoxantrone (Novantrone) 2000 Intravenous every 3 months
IFNβ-1a (Rebif) 2002 Subcutaneous 3 times per week
Natalizumab (Tysabri) 2004 Intravenous monthly
IFNβ-1b (Extavia) 2009 Subcutaneous every other day
Fingolimod (Gilenya) 2010 Oral daily
Teriflunomide (Aubagio) 2012 Oral daily
Dimethyl fumarate (Tecfidera) 2013 Oral twice a day
Glatiramer acetate (Copaxone) 2014 Subcutaneous 3 times per week
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Injectable Disease‐modifying Therapies
Interferon β
• Early findings MoA: reduce T‐cell activation/proliferation, reduce T‐cell secretion of matrix metalloproteinases, inhibit interferon gamma release, limit T‐cell migration across blood brain barrier, & reduce expression of HLA
• Recent findings MoA: interfere with antigen processing, reduce antigen presentation to T‐cells, & Th1/Th2 expression
Dhib-Jalbut S. Neurology. 2002 Apr 23;58(8 Suppl 4):S3-9.Lalive PH, et al. CNS Drugs. 2011 May;25(5):401-14.Mendes A, et al. Arq Neuropsiaquiatr. 2011;69(3):536-543
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Glatiramer acetate
• Early findings MoA: Th1 to Th2 shift & blocking MHC peptide antigen
• Recent findings MoA: CNS migration of Th2 cells, modify antibody production by plasma cells, regulates B‐cell properties, cytokine modulation, inhibits antigen presentation to T‐cells, & oligodendrocyte precursor cells (myelin repair)
Dhib-Jalbut S. Neurology. 2002 Apr 23;58(8 Suppl 4):S3-9.Lalive PH, et al. CNS Drugs. 2011 May;25(5):401-14.Mendes A, et al. Arq Neuropsiaquiatr. 2011;69(3):536-543
Injectable Disease‐modifying therapy efficacy
Initial Placebo controlled Pivotal Clinical Trials
Agent Relapses MRI activity12 week Disability Progression‐ EDSS
Multiple SclerosisCollabrative Research Group. Ann Neurol. 1996 Mar;39(3):285‐94.
IFNβ-1a (low dose)
ARR: ↓ 18%Gd+ lesions: ↓50%T2 lesions: no effect
↓ 37%
PRISMS. Lancet 1998; 352: 1498–504. IFNβ-1a
(high dose)ARR: ↓ 33%
Gd+ lesions: ↓84%T2 lesions: ↓78%
↓ 30%
IFNB Multiple Sclerosis Study Group. Neurology. 1993 Apr;43(4):655‐61. IFNβ-1b ARR: ↓ 34%
Gd+ lesions: ↓83%T2 lesions: ↓75%
Barely significant
Copolymer 1 Multiple Sclerosis Study Group. NEUROLOGY 1995;45: 1268‐1276.
Glatirameracetate
ARR: ↓ 29%Not adequatelyassessed
Not significant
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Oral Disease‐modifying Therapies
Fingolimod
• Sphingosine 1‐phosphate receptor (S1PR) modulator; S1P1, S1P3, S1P4, S1P5 receptors
• MoA: Functionally antagonizes S1PR blocking lymphocyte egress from secondary lymphoid organs to the peripheral blood circulation
• Oral medication given daily
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Teriflunomide
• Active metabolite of Leflunomide
• MoA: mimics DNA building blocks (pyrimidine); interferes with DNA synthesis and inhibits dihydro‐orotate dehydrogenase
=> cytostatic to proliferating B & T cells
=> reduces T‐cell proliferation, activation, & production of cytokines
=> interferes with the interaction between T‐cells & antigen‐presenting cells
• Oral medication adminstered daily (7mg or 14mg)
Dimethyl fumarate
• MoA: changes balance of Th1 to Th2 & activates Nrf2 transcriptional pathway (oxidative, metabolic & inflammatory stress)
• Oral medication given twice a day
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Oral Disease‐modifying therapy efficacy
Initial Placebo controlled Pivotal Clinical Trials
Agent Relapses MRI activity12 week Disability Progression‐ EDSS
FREEDOMS. N Engl J Med 2010;362:387‐401. Fingolimod ARR: ↓ 54%
Gd+ lesions: ↓82%T2 lesions: ↓74%
↓ 32%
TEMSO. N Engl J Med 2011;365:1293‐303.
Teriflunomide(14mg)
ARR: ↓ 32%Gd+ lesions: ↓80%Lesion volume: ↓67%
↓ 30%
DEFINE. N Engl J Med 2012;367:1098‐107.
Dimethyl fumarate
ARR: ↓ 53%Gd+ lesions: ↓90%T2 lesions: ↓85%
↓ 38%
Intravenous Disease‐modifying therapies
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Mitoxantrone
• Mainly used to treat leukemia and prostate cancer
• MoA: DNA topoisomerase II inhibitor; suppresses proliferation of T cells, B cells, and macrophages
• Lifetime dose of 140mg/m2
Natalizumab
• First drug developed in the class of selective adhesion molecule inhibitors
• MoA: Humanized monoclonal antibody against alpha‐4 (α4) integrin
• α4‐integrin is required for WBC to move into organs
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Intravenous Disease‐modifying therapy efficacy
Initial Placebo controlled Pivotal Clinical Trials
Agent Relapses MRI activity12 week Disability Progression‐ EDSS
MIMS trial. Lancet 2002; 360: 2018–25.
Mitoxantrone(12 mg/m2)
ARR: ↓ 68% Gd+ lesions: + trendT2 lesions: ↓85%
↓43%
AFFIRM. N Engl J Med. 2006;354(9):899‐910.
Natalizumab ARR: ↓ 68%Gd+ lesions: ↓92%T2 lesions: ↓83%
↓42%
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Agent Minor side effects Major side effectsPregnancy category
Monitoring
IFNβ‐1a (low dose)
Flu‐like symptoms, headache, transaminitis, depression
Suicidal ideation, anaphylaxis, hepatic injury, blood dyscrasias, seizures, autoimmune hepatitis
C
CBC with differential, LFTs, TFTs, interferon neutralizing antibodies (if clinically warranted)
IFNβ‐1a (high dose)
Same as above and injection‐site reactions
Same as above and skin necrosis C
Same as above
IFNβ‐1b Same as above Same as above
C
Same as above
Glatirameracetate
Injection‐site reactions and post‐injection vasodilatoryreaction
Lipoatrophy, skin necrosis, anaphylaxis
B
None required
Injectable Disease‐modifying therapy side effects/monitoring
AgentMinor side effects
Major side effectsPregnancy category
Monitoring
Fingolimod Lymphopenia(absolutelymphocyte count >200), transaminitis
Bradycardia, heart block, hypertension, risk of infections (herpetic), lymphopenia (absolutelymphocyte count <200), transaminitis, macular edema, skin cancer, reactive airway, PRES
C
1st dose cardiac monitoring, eye and skin exams, CBC with differential, LFTs, VZV IgG prior to starting medication, PFTs (if clinically indicated)
Teriflunomide Diarrhea, nausea, hair thinning
Transaminitis, lymphopenia, teratogenic(men & women), latent tuberculosis, neuropathy, hypertension
X
CBC with differential, LFTs (monthly for first 6 months), PPD prior to starting, wash out (if needed)
Dimethyl fumarate
Flushing, gastrointestinal distress
Transaminitis, leukopenia
C
CBC with differential, LFTs
Oral Disease‐modifying therapy side effects/monitoring
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Agent Minor side effects Major side effectsPregnancy category
Monitoring
Natalizumab Headaches, joint pain, fatigue, wearing off phenomenon
Progressive multifocal leukoencephalopathy, infusion reaction, Herpes Zoster, other infections C
CBC with differential, LFT’s,serum JCV antibody (Q6 months), MRI, Tysabriantibodies (if clinically warranted)
Mitoxantrone Nausea, vomiting,hair thinning, menstrual irregularities
Cardiac toxicity, acute myelogenousleukemia, infections, infertility, liver dysfunction D
CBC with differential, LFT’s, ECG, Echo/MUGA scan (even after therapy completed), lifetime dose 140 mg/m2
Intravenous Disease‐modifying therapy side effects/monitoring
Many faces of side effects
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Emerging Therapiesfor
Multiple Sclerosis
Agent Mechanism(s) of Action Side effects Route Monitoring
Alemtuzumab(anti‐CD52, pan leukocyte marker)
Tagets against CD52+ cells (present on mature lymphocytes); depletes B and T cells
Infusion reactions,autoimmune thyroid disease, ITP, Goodpastures, infections (HSV, VZV)
Infusionyearly
Monthly CBC with differential, LFTs, TFTs
Daclizumab(anti‐CD25, IL‐2 receptor alpha)
Targets against the alpha subunit of the IL‐2 receptor on T cells; reduces T‐cell activation/proliferation and expands CD56 bright cells that inhibit T‐cell survival
Transaminitis, autoimmune hepatitis, lymphadenopathy,rash, alopecia universalis
Subcutaneous injection monthly
Exact monitoring to be determined;LFTs, CBC with differential
Ocrelizumab(anti‐CD20, B cells)
Fully humanized monoclonal antibody targeted against CD20 B cells
Infusion reactions,lymphopenia, infections
Infusion every6 months
CD19/CD20 B cell counts
PEG‐INF (Interferon beta‐1a with polyethylene glycol)
Same as other interferon products
Injection‐site reactions, flu‐like side effects
Subcutaneous injection
twice a month
Similar to other interferon products
Late Stage Clinical Development of Emerging Disease‐modifying Therapies
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Emerging Therapies:Increased Efficacy, Increased Risks
Serious Safety Concerns*
• Immune surveillance
• Infections
• Malignancies
• Long‐lasting and irreversible effects
• Autoimmunity
• Teratogenicity
• Rare but serious infusion reactions
• The unknown
Manageable Safety Concerns*
• Bradycardia
• Blood pressure elevations
• Reactive airway disease
• Liver function abnormalities
• Flushing
• GI discomfort
• Arthralgias
• Back/limb painCare-MS. http://care-ms.com/carems-program.aspx;
Comi G, et al. AAN April 2011; P05.288;Cohen BA, et al. Int J Clin Pract. 2007;61:1922-30;
Kappos L, et al. Lancet. 2008;372:1463-72;Miller A, et al. AAN April 2011; S41.002;
Wolinsky J, et al. AAN April 2011; S41.003. *This information represents expert faculty opinion.
Existing Drugs with proven efficacy and variable safety and new drugs additional concerns:
Additional References
• Cohen JA, Coles AJ, Arnold DL et al. (2012). Alemtuzumab versus interferon beta 1a as first‐line treatment for patients with relapsing‐remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 380: 1819–1828.
• Coles AJ, Twyman CL, Arnold DL et al. (2012). Alemtuzumab for patients with relapsing multiple sclerosis after disease modifying therapy: a randomised controlled phase 3 trial. Lancet 380: 1829–1839.
• Gold R, Giovannoni G, Selmaj K et al. (2013). Daclizumab high‐yield process in relapsing‐remitting multiple sclerosis (SELECT): a randomised, double‐blind, placebo controlled trial. Lancet 381: 2167–2175.
• Giovannoni G, Gold R, Selmaj K, et al. (2014). Daclizumab high‐yield process in relapsing‐remitting multiple sclerosis (SELECTION): a multicentre, randomised, double‐blind extension trial. Lancet Neurol May;13(5):472‐81.
• Oh J, Saidha S, Cortese I, et al. (2014). Daclizumab‐induced adverse events in multiple organ systems in multiple sclerosis. Neurology Mar 18;82(11):984‐8.
• Kappos L, Li D, Calabresi PA, et al. (2011). Ocrelizumab in relapsing‐remitting multiple sclerosis: a phase 2, randomised, placebo‐controlled, multicentre trial. Lancet Nov 19;378(9805):1779‐87.
• Calabresi PA, Kieseier B, Arnold D, et al. Clinical Efficacy and Safety of Peginterferon Beta‐1a in Relapsing Multiple Sclerosis: Data from the Pivotal Phase 3 ADVANCE Study. Lancet Neurol; In press.
• O'Connor PW, Oh J. Disease‐modifying agents in multiple sclerosis. Handb Clin Neurol. 2014;122:465‐501.