Altered Immune Response in MS

Transcription

1 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 1

2 Clinically isolated syndrome (CIS) Relapsing remitting MS Subtypes Secondary progressive Severity Primary progressive Progressive relapsing Time Natural History of MS: Summary Measures of brain volume Relapses and impairment MRI burden of disease MRI activity Axonal loss Secondary Progressive Preclinical Relapsing-Remitting Time Adapted from Goodkin DE. UCSF MS Curriculum

3 Immunopathogenesis of MS (2011) Courtesy of Suhayl Dhib Jalbut, MD CD8p DC Th17 CD8 Reg Neut CD8 CTL Treg Foxp3 Oligo S1Pr Glutamate T IFN TNF B7 CD28 CD40 CD40L Th1 FcR RNO ROS TNF MMP MCP-1 MIP-1 P-10 RANTES B Pl EBV IL-10 TGF S1Pr Astrocyte Ab+C9neo Tr1 Th2 Th3 BBB CCL20 CCR6 APC IL 17 ICAM-1 VCAM-1 IL 23 Treg MMP-2/9 Th17 Foxp3 IFN LFA-1 TNF Th17 IL 6 VLA-4 Th1 IL-6 & IL1-ß Th0 TGFß Treg Foxp3 CD4+CD25+ S1Pr IL-12 CD4 HLA TCR Thp APC BAFF APRIL TACI B TLR APC Myelin Ag Microbial Ag IL-4 IL-5 IL-10 IL-13 TGF- Tr1 Th2 Th3 IL-4 & IL-10 B7 CD28 CD4 Thp CD40 CD40L Strategies to block the Immune system s attack Broad-spectrum Immunosuppression Non-selective Antigen-specific Selective Toxicity Antigens unknown or multiple ones! Slide courtesy of P. Calabresi 3

4 Expanding Landscape of MS Therapeutics Betaseron (IFNβ-1b) Tysabri (natalizumab) Avonex (IFNβ-1a) Copaxone (glatiramer acetate) Novantrone (mitoxantrone) Extavia (IFNβ-1b) Gilenya (fingolimod) Aubagio (teriflunomide) Tecfidera (dimethyl fumarate) Rebif (IFNβ-1a) FDA-approved therapies (Approval time period) Agent Currently Approved MS Disease modifying Therapies 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 Glatiramer acetate (Copaxone) 2014 Subcutaneous 3 times per week 4

5 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 Apr 23;58(8 Suppl 4):S3-9. Lalive PH, et al. CNS Drugs May;25(5): Mendes A, et al. Arq Neuropsiaquiatr. 2011;69(3):

6 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 Apr 23;58(8 Suppl 4):S3-9. Lalive PH, et al. CNS Drugs May;25(5): Mendes A, et al. Arq Neuropsiaquiatr. 2011;69(3): 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 Mar;39(3): IFNβ-1a (low dose) ARR: 18% Gd+ lesions: 50% T2 lesions: no effect 37% PRISMS. Lancet 1998; 352: IFNβ-1a (high dose) ARR: 33% Gd+ lesions: 84% T2 lesions: 78% 30% IFNB Multiple Sclerosis Study Group. Neurology Apr;43(4): IFNβ-1b ARR: 34% Gd+ lesions: 83% T2 lesions: 75% Barely significant Copolymer 1 Multiple Sclerosis Study Group. NEUROLOGY 1995;45: Glatiramer acetate ARR: 29% Not adequately assessed Not significant 6

7 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 7

8 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 8

9 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: Fingolimod ARR: 54% Gd+ lesions: 82% T2 lesions: 74% 32% TEMSO. N Engl J Med 2011;365: Teriflunomide (14mg) ARR: 32% Gd+ lesions: 80% Lesion volume: 67% 30% DEFINE. N Engl J Med 2012;367: Dimethyl fumarate ARR: 53% Gd+ lesions: 90% T2 lesions: 85% 38% Intravenous Disease modifying therapies 9

10 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 10

11 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: Mitoxantrone (12 mg/m2) ARR: 68% Gd+ lesions: + trend T2 lesions: 85% 43% AFFIRM. N Engl J Med. 2006;354(9): Natalizumab ARR: 68% Gd+ lesions: 92% T2 lesions: 83% 42% 11

12 Injectable Disease modifying therapy side effects/monitoring 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 Agent Fingolimod Oral Disease modifying therapy side effects/monitoring Minor side effects Lymphopenia (absolute lymphocyte count >200), transaminitis Major side effects Bradycardia, heart block, hypertension, risk of infections (herpetic), lymphopenia (absolute lymphocyte count <200), transaminitis, macular edema, skin cancer, reactive airway, PRES Pregnancy category C Monitoring 1 st 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 12

13 Intravenous 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 Many faces of side effects 13

14 Emerging Therapies for Multiple Sclerosis Late Stage Clinical Development of Emerging Disease modifying Therapies 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 14

15 Emerging Therapies: Increased Efficacy, Increased Risks Existing Drugs with proven efficacy and variable safety and new drugs additional concerns: 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. Comi G, et al. AAN April 2011; P05.288; Cohen BA, et al. Int J Clin Pract. 2007;61: ; Kappos L, et al. Lancet. 2008;372: ; Miller A, et al. AAN April 2011; S41.002; Wolinsky J, et al. AAN April 2011; S *This information represents expert faculty opinion. 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: 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: 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: 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): 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): 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): 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: