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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.