Altered Immune Response in MS

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

MS Subtypes

Relapsing‐remitting       

Secondary progressive

Primary progressive 

Progressive relapsing 

Time

Sev

e

rity

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.

Immunopathogenesis of MS (2011)

Ab+C9neo RNO ROS TNF MMP Courtesy of Suhayl Dhib‐Jalbut, MD B7 CD40 CD40L CD28 Th1 Glutamate T CD8 CTL IFN TNF MMP-2/9 B Pl Oligo

BBB

MCP-1 MIP-1 P-10 RANTES Astrocyte B CD40L CD28 CD40

IL-4 & IL-10

CD4 APC Thp B7 IFN TNF LFA-1 Th1 VLA-4 ICAM-1 VCAM-1 IL-12 APC Thp CD4 Myelin Ag Microbial Ag HLA TCR Tr1 Th2 Th3 IL-4 IL-5 IL-10 IL-13 TGF- IL-10 TGF Treg Foxp3 CD4+CD25+ Tr1 Th2 Th3

IL-6 & IL1-ß

APC IL‐23 IL‐17 TGFß IL‐6 Treg Foxp3 Treg Foxp3 BAFF APRIL TACI CD8p

EBV

FcR CD8 Reg CCR6 CCL20 DC

Th0

Th17

Th17

Th17

Neut

S1Pr

S1Pr

S1Pr

TLR

Non-selective

Selective

Antigen-specific

Broad-spectrum

Immunosuppression

Strategies to block the

Immune system’s attack

Toxicity

Antigens unknown

or multiple ones!

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 Therapies

Agent

Approval

Year

Route

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

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

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 activity 12 week Disability 

Progression‐ EDSS Multiple Sclerosis Collabrative 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. Glatiramer acetate ARR: ↓ 29% Not adequately

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

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

Oral Disease‐modifying therapy efficacy

Initial Placebo  controlled Pivotal 

Clinical Trials 

Agent Relapses MRI activity 12 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

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/m

2

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 

Intravenous Disease‐modifying therapy efficacy

Initial Placebo  controlled Pivotal 

Clinical Trials 

Agent Relapses MRI activity 12 week Disability 

Progression‐ EDSS MIMS trial. Lancet  2002; 360: 2018–25. Mitoxantrone (12 mg/m2) ARR: ↓ 68% Gd+ lesions: + trend T2 lesions: ↓85% ↓43% AFFIRM. N Engl J Med.  2006;354(9):899‐910.

Agent Minor side effects Major side effects Pregnancy  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 Glatiramer acetate Injection‐site  reactions and  post‐injection  vasodilatory reaction Lipoatrophy, skin  necrosis, anaphylaxis B None required

Injectable Disease‐modifying therapy 

side effects/monitoring

Agent Minor side _effects Major side effects Pregnancy _category Monitoring

Fingolimod Lymphopenia (absolute lymphocyte  count >200),  transaminitis Bradycardia, heart block,  hypertension, risk of  infections (herpetic),  lymphopenia (absolute lymphocyte 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

Agent Minor side effects Major side effects Pregnancy  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, Tysabri antibodies (if clinically  warranted) Mitoxantrone Nausea, vomiting, hair thinning,  menstrual  irregularities  Cardiac toxicity, acute  myelogenous leukemia, 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

Emerging Therapies

for

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) Infusion yearly 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 every 6 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

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 pain

Care-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.