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Welcome! Please remove the Pre-activity Survey located at the front of your syllabus packet. Please fill it out and pass forward prior to the beginning.

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Presentation on theme: "Welcome! Please remove the Pre-activity Survey located at the front of your syllabus packet. Please fill it out and pass forward prior to the beginning."— Presentation transcript:

1 Welcome! Please remove the Pre-activity Survey located at the front of your syllabus packet. Please fill it out and pass forward prior to the beginning of the lecture. It is important that you do this prior to the talk, as we will repeat these questions at the end of the program to gauge the effectiveness of the activity. These tests are not graded, but are used to build CME that suits your needs. Your participation is greatly appreciated.


3 Disclosures The relevant financial relationships reported by faculty that they or their spouse/partner have with commercial interests is located on page 5 of your syllabus The relevant financial relationships reported by the steering committee that they or their spouse/partner have with commercial interests is provided on page 5 of your syllabus The relevant financial relationships reported by the non- faculty content contributors and/or reviewers that they or their spouse/partner have with commercial interests is located on page 5 of your syllabus

4 Off-label Discussion Disclosure This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

5 Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Select the most appropriate DMD therapies that can be used to initiate treatment earlier in the disease course Develop individualized treatment plans to optimize adherence and improve outcomes in patients with MS Describe how emerging biomarkers and newer MRI measures to improve the accuracy of diagnosis and monitoring of MS disease activity

6 MS Immune Dysregulation Genetic Predisposition -Twins studies -HLA-DR2 (DRß1*1501) (antigen presentation) -IL-2Ra (regulatory T-cells) -IL-7Ra (memory T-cells) GWAS (>100 alleles) Environmental Factors Demographics/Epidemics Microbial Agents EBV Vitamin D Smoking Salt Multiple Sclerosis: An Immuno-genetic Disease Dhib-Jalbut S. 2013.

7 Inflammation Regeneration Inflammatory Processes Occurring Early in MS Lead to Demyelination and Axonal Loss Time Onset of Disease InflammationDemyelinationAxonal loss Compston A et al. Lancet. 2008;372:1502-1517. Kuhlmann T et al. Brain. 2002;125:2202-2212. Paolillo A et al. J Neurol. 2004;251:432-439. Trapp BD et al. Curr Opin Neurol. 1999;12:295-302. Immunopathogenesis of MS

8 Dublin Revision 2011 For DIS: At least one T2 lesion in two of the following locations: –Periventricular –Juxtacortical –Infratentorial –Spinal cord For DIT: Any new lesion on any follow-up scan after a baseline scan done anytime after onset of CIS DIS=Dissemination in space; DIT=Dissemination in time; CIS= Clinically isolated syndrome Polman et al. Ann Neurol. 2011;69:292-302. McHugh et al. Mult Scler. 2008;14:81-85.

9 Single Early MRI In CIS, a single MRI, even in first 3 months, with Gad enhancing lesion(s) and T2H has high specificity for development of CDMS CDMS = clinically definite MS Polman et al. Ann Neurol. 2011;69:292-302.

10 Radiologically Isolated Syndrome 5-year Risk for an Initial Clinical Event from a Multinational Cohort (RISC ) Retrospective analysis of 20 databases from 5 countries >430 patients (largest cohort examined to date) 5-year observed conversion rate to first clinical event: 34% In multivariate model, several factors significantly associated with conversion: – Age (younger > older) – Gender (M > F) – Presence of spinal cord lesions RISC = Radiologically Isolated Syndrome Consortium Okuda D et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract PL01.002.

11 RIS: Management Implications Potential for misdiagnosis High probability of benign MS “Wait and watch” approach may be best Future challenges: –How to identify high-risk RIS group –Standardized MRI –Combining MRI with other predictors –Population-based prospective study RIS = Radiologically Isolated Syndrome Okuda D et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract PL01.002.

12 — George Burns “I look to the future because that’s where I’m going to spend the rest of my life.”

13 Predicting the Course of MS Clinical features of onset bout –Motor worse than sensory –Polyregional worse than monosymptomatic –Early bladder involvement poor prognosis Incomplete recovery from initial attack Short interval between attacks

14 MRI and MS Prognosis Initial MRI –T2 lesion numbers –Median EDSS at 20 years = 6 for ≥10 T2 lesions –3 or 4 Barkhof criteria moderate correlation with EDSS at 5 years Fisniku LK. Brain. 2008;131:808-817.

15 Lawrence Peter “Yogi” Berra “The future ain’t what it used to be.”

16 Assessing Risk Patients need to be informed and involved in decision- making process Need to steer patients to a limited number of options based upon disease severity Patient risk tolerance to adverse events Patient disease tolerance to neurologic dysfunction

17 1 moderate/severe clinical relapse over 1 year 2 mild clinical relapses over 2 years 1-2 Gd enhancing brain lesions over 1 year 2 T2 lesions over 2 years A functionally significant worsening in cognition, ambulation, upper extremity function Need to account for time for medication to work optimally Follow-up MRI 6-12 months after treatment initiation Defining Breakthrough Disease

18 Existing and Emerging MS Therapies *In March 2011, the FDA did not approve cladribine and requested Merck KGaA provide an improved understanding of its safety risks and overall benefit-risk profile Phase III completed In Phase III Approved therapies 20092010 2011 2005 1995 2000 Gilenya ® (fingolimod) Aubagio ® (teriflunomide) Extavia ® (IFNβ-1b) Tysabri ® (natalizumab) Betaseron ® (IFNβ-1b) Copaxone ® (glatiramer acetate) Avonex ® (IFNβ-1a) Rebif ® (IFNβ-1a) Novantrone ® (mitoxantrone) Laquinimod Approval date Estimated launch date Cladribine* 2012 Daclizumab Ocrelizumab Ofatumumab Mastinib Ampyra ® (4-amino pyradine) Nuedexta ® (dextromethorphan/ quinidine) 2013 Lemtrada ® (alemtuzumab) Tecfidera ® (dimethyl fumarate) Plegridy ® (IFNβ-1a) 2014

19 ADVANCE Phase III Trial of PEGylated IFNb-1a in RRMS PegIFN has longer t1/2 and results in prolonged exposure (AUC, Cmax) than standard formulations Pts (n=1512) randomized to placebo, pegIFNb-1a 125 mcg q2wk, or q4wk ENDPOINT ( reduction compared with placebo at 1 year ) PEGIFNB-1A Q2WK PEGIFNB-1A Q4WK ARR35.6%*27.5%* Accrual of disability38%* T2 lesions67%*28%* Gd-enhancing T1 lesions86%*36%* Neutralizing Abs seen in <1% of patients in both IFN groups Adverse events similar to known IFN profile (ISRs, pyrexia, flu-like symptoms, hepatic enzyme elevations) ATTAIN: long-term extension study from ADVANCE ongoing * Statistically significant finding PEG=polyethylene glycol; AUC=area under the curve; ARR=annualized relapse rate; IFN=interferon; Abs=antibodies; ISRs=injection site reactions Calabresi P et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S31.006.

20 Glatiramer Acetate Low-frequency Administration (GALA): Phase III Study ARR = annualized relapse rate; SEM = standard error of mean Khan O et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S01.005. 34.4% reduction, P < 0.0001 Primary Endpoint: ARR ARR ± SEM Secondary Endpoint: Cum. No. of New/Enlarging T2 Lesions 34.7% reduction, P < 0.0001

21 Lymphocyte Trafficking Inhibition Implications for Multiple Sclerosis Therapy Reduced leukocyte infiltration and brain inflammation Leukocyte infiltration and brain inflammation Leukocyte Chemoattractant signal a4b1 (VLA-4) Blood Vessel Lumen Endothelial Cells Tissue VCAM-1 Leukocyte Chemoattractant Signal a4b1 (VLA-4) Blood Vessel Lumen Endothelial Cells TissueVCAM-1 O’Connor P. Expert Opin Biol Ther. 2007;7:123-136.

22 Natalizumab v Placebo Affirm Study Polman C et al. N Engl J Med. 2006;354:899-910. Annualized Relapse Rate (95% CI) 68% P <0.0001 Placebo n=315 0.81 Natalizumab n=627 0.26 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

23 Natalizumab Use in the Post-marketing Setting and PML Risk 224,718 patient-years of natalizumab exposure *As of October 22, 2012: 298 cases of natalizumab-associated PML have been reported; of these, 62 patients have died (22%) Vermersch P et al. Presented at ECTRIMS 2012; October 9-13, 2012; Lyon, France. [Abstract 173]. ≥ 36 Months ≥ 30 Months ≥ 24 Months ≥ 18 Months ≥ 12 Months Overall Exposure ≥ 42 Months ≥ 48 Months Patients 2.95 2.33 0.82 0.45 2.32 1.54 2.79 1.76 2.63 1.38 Number of infusions 0.11 0.02

24 Estimated Incidence of Natalizumab- associated PML Stratified by Risk Factors Natalizumab exposure No Prior IS UsePrior IS Use 1–24 months 0.7/1,000 patients1.8/1,000 patients 25–48 months 5.3/1,000 patients11.2/1,000 patients 49–72 months 6.1/1,000 patientsInsufficient data Sorenson P et al. Mult Scler. 2012;18:143-152. Anti-JCV Antibody Status Positive Prior IS Use? 0.1/1000 95% CI: 0.1-0.35 NoYes Negative

25 Anti-JCV Antibody Index Distribution in Anti-JCV Ab+ non-PML and pre-PML Patients with No Prior IS Use Plavina T et al. Use of anti-JC virus antibody index to further define risk of PML in anti-JCV antibody-positive TYSABRI-treated patients with MS. Platform presentation presented at 23 rd Annual Meeting of European Neurological Society, June 9, 2013; Barcelona, Spain.

26 Plavina T et al. Anti-JCV antibody index further defines PML risk in TYSABRI-treated MS patients. Poster presented at CMSC 27 th Annual Meeting, May 29-June 1 2013; Orlando, FL. PML Risk Estimates by Index Threshold in Anti-JCV Ab+ Patients with No Prior IS Use

27 S1P receptor FTY720 results in internalization of the S1P1 receptor This blocks lymphocyte egress from lymph nodes while sparing immune surveillance by circulating memory T cells LN Prevents T cell invasion of CNS FTY720 traps circulating lymphocytes in peripheral lymph nodes Fingolimod (FTY720): Mode of Action Cohen JA, Chun J. Ann Neurol.2011;69:759-777. T cell FTY720-P

28 Fingolimod Efficacy Kappos L et al. N Engl J Med. 2010;362:387-401. Cohen JA, et al. N Engl J Med. 2010;362:402-415. Adjusted Annualized Relapse Rate FREEDOMS TRANSFORMS

29 Managing Fingolimod Patients Prior to Treatment Initiation –Baseline CBC and hepatic panel –Ophthalmological examination –Cardiac status –Varicella immune status Rx Initiation: 6-hour observation b/o bradycardia On Treatment –CBC, hepatic panel –Ophthalmological exam at 3-4 months –Check BP

30 Recent Additions to Fingolimod Prescribing Information First Dosing Monitoring Observe signs and symptoms of bradycardia for at least 6 hrs after first dose with hourly pulse and blood pressure measurement Obtain ECG prior to dosing and at the end of the observation period Monitor AV block until resolution if heart rate <45 bpm, or a new onset 2 nd -degree or higher Pts at lowest post-dose heart rate at the end of observation period should be monitored until heart rate increases If symptomatic bradycardia, begin continuous ECG monitoring until symptoms have resolved If pharmacological intervention required for bradycardia, continue ECG monitoring overnight in a medical facility, and repeat 1 st -dose monitoring procedures for 2 nd dose Patients who may be less tolerant of fingolimod-induced bradycardia are at higher risk of serious rhythm disturbance, or with prolonged QTc interval at baseline, or at any time during the observation period, should be observed overnight with continuous ECG monitoring Patients who have stopped taking fingolimod for more than 14 days and re-initialize treatment are advised to again follow these updated recommendations

31 Teriflunomide A Selective Dihydro-orotate Dehydrogenase Inhibitor A newly approved oral disease- modifier for relapsing forms of MS (RMS) Blocks de novo pyrimidine synthesis, reducing T- and B-cell proliferation and function in response to autoantigens Preserves replication and function of cells (e.g. haemopoietic cells, memory T-cells) living on the existing pyrimidine pool (salvage pathway) DHO-DH, dihydro-orotate dehydrogenase; Blasting lymphocyte De novo pathway DHO-DH Pyrimidine pools Salvage pathway CTP-, UTP-sugarsNucleotidesCDP lipids Glycoproteins, GlycolipidsRNA, DNAPhospholipids Cell-cell contact Adhesion and diapedesis Proliferation Ig secretion Cell membranes Second messengers Non- lymphoid cells Resting lymphocyte Teriflunomide Miller A et al. Clinical and MRI outcomes from a Phase III trial (TEMSO) of oral teriflunomide in multiple sclerosis with relapses. Presented at AAN Annual Meeting, April 9-16, 2011, Honolulu, HI.

32 Teriflunomide for RRMS (Phase III TEMSO Study) Key Clinical Outcomes RRR: 31.2% P =0.0002 RRR: 31.5% P =0.0005 RRR = relative risk reduction O’Connor P et all. N Engl J Med. 2011;365:1293-1303. 23.7% P =0.0835 29.8% P =0.0279 21.7 Annualized Relapse Rate EDSS 12 Week Sustained Change Teriflunomide 27.3

33 Teriflunomide Phase III TOWER Study Efficacy OutcomePlacebo Teri 7 mg Teri 14 mg ARR (primary endpoint) Reduction vs placebo 0.5010.389* 22.3% 0.319* 36.3% 12-week confirmed disability progression HR vs placebo 0.9550.685* Mean EDSS change (baseline to week 48)0.0890.042-0.05* *Statistically significant vs placebo. Miller A et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S01.004.

34 TOWER: Treatment-Emergent AEs Preferred term, % Placebo (n = 385) Teriflunomide 7 mg (n = 409) Teriflunomide 14 mg (n = 371) Headache Leading to discontinuation 10.9 0.3 14.7 0 12.4 0 Increased ALT Leading to discontinuation 8.3 1.6 11.2 2.9 14.0 2.4 Alopecia (hair thinning) Leading to discontinuation 4.4 0.3 10.3 0 13.5 1.6 Diarrhea Leading to discontinuation 7.3 0.3 12.0 1.0 11.1 0.8 Nausea Leading to discontinuation 8.8 0 8.3 0 10.2 0.8 Neutropenia Leading to discontinuation 2.9 0 7.1 1.0 9.4 2.2 ALT = alanine aminotransferase Miller A et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S01.004.

35 Teriflunomide Counseling and Start-up Pregnancy Category X At Baseline: CBC with diff, LFTs, TB testing Monthly x 6 months: AST/ALT Every 6 months: CBC with diff, LFTs

36 Proposed Mechanisms: Dimethyl Fumarate An oral formulation of dimethyl fumarate Inhibits the expression of adhesion molecules and proinflammatory cytokines Induces a Th1 to Th2 shift Decreases circulating T cells Activates the Nrf2 pathway >30 years of use of fumaric acids in the treatment of psoriasis (both topical and oral) Kappos L et al. Lancet. 2008;372:1463-1472. Gold R et al. N Engl J Med. 2012;367:1098-107. Gasperini C et al. Expert Opin Emerg Drugs. 2008;13:465-477.

37 DMF: Integrated Efficacy Analysis of DEFINE and CONFIRM Endpoint (at 2 years) Placebo (n = 771) DMF BID (n = 769) Annualized relapse rate (ARR) Reduction vs placebo 0.37 0.19* 49% Proportion of patients relapsed HR vs placebo0.57* Time to 12-week confirmed disability progression HR vs placebo0.68* Time to 24-week confirmed disability progression HR vs placebo0.71* *Statistically significant vs placebo Fox RJ et al. Presented at AAN; March 16-23, 2013; San Diego, CA. Abstract P07.097.

38 Alemtuzumab MOA Targets CD52 antigen expressed on B and T lymphocytes FDA approved for leukemia Phase II study comparing Campath vs Rebif in 334 patients –12 mg/day for 5 days at month 0, 12, 24 –24 mg/day for 5 days at month 0, 12, 24 Three-year observation period with interim analyses

39 Alemtuzumab vs Interferon-B1a: Care-MS Phase III Studies CARE – MS1CARE – MS2 IFN-B1aAlemtuzumab (12mg) IFN-B1aAlemtuzumab (12mg) Ann. relapse rate0.390.180.520.26 Risk reduction54.9% ( P <0.0001)49.4% ( P <0.0001) Sustained disability (% pts)11821.112.7 Risk reduction30% ( P =0.22)42% ( P =0.0084) Δ EDSS from baseline- 0.14 0.24- 0.17 Net EDSS change0.41 ( P <0.0001) Cohen JA et al. Lancet. 2012;380:1819-1828. Coles AJ et al. Lancet. 2012;380: 1829-1839.

40 Extension Analysis of Care-MS Phase III Studies Fox E et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S41.001. CARE-MS ICARE-MS II ARR0.240.25 EDSS improvement 40%45% Received alemtuzumab re-tx* 18%20% *Criterion for re-treatment was 1 relapse or ≥ 2 new lesions on MRI

41 Safety Analysis of Care-MS Phase III Studies Autoimmune thyroid disorders 19.4% in extension; 29.9% total study Autoimmune thrombocytopenia (ITP):1.3%; nephropathy: 0.3% (n=3) Infections More common with alemtuzumab compared with IFN (Incl. URI, UTI, sinusitis, and mucocutaneous herpetic and fungal infections) −Acyclovir prophylaxis seemed to reduce the risk of herpetic infection −Infections highest in mos 1 and 13 (after each alem course), −No evidence that neutrophil or lymphocyte counts before a treatment course predicted infection risk Fox E et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S41.001. Wray S et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract P01.172.

42 Trials in Progressive MS Secondary Progressive MS –ASCEND: Natalizumab vs Placebo –Siponimod vs Placebo Primary Progressive MS –FREEDOMS: Fingolimod vs Placebo –ORATORIO: Ocrelizumab vs Placebo

43 Choice of Therapy Aggressive Disease? Yes No JCV AB Positive? JCV AB Negative NTZ ? Fingo DMF NTZ Pregnancy?Non-injection GA IFN GA Teri ?DMF ?Fingo ?NTZ INSURANCE Safest


45 Immunopathogenesis of MS Dhib-Jalbut S. 2013.


47 Defining Interferon ß Response Status in MS 15-year follow-up of pivotal MSCRG trial for weekly interferon 172 patients in placebo-controlled IFN-ß1a trial x 2 years In IFNb-1a group, disease activity predicted EDSS worsening: –Gadolinium-enhancing lesions (OR, 8.96; P <0.001) –Relapses (OR, 4.44; P =0.01) –New T2 lesions (OR, 2.90; P =0.08) Conclusion: New MRI activity during IFN-ß1a treatment correlates with suboptimal response Rudick RA et al. Ann Neurol. 2004;56:546-555. Bermel RA et al. Ann Neurol. 2013;73:95-103.

48 Prosperini L, Pozzilli C. Mult Scler J. 2013;2013:756564. MRI as a Surrogate of Future Disease Activity 370 patients underwent MRI at baseline and 1 year after beginning IFN Followed for relapse or disability progression in years 1-4 At year 1: ≥1 Gd enhancing lesion or ≥2 T2 lesions had same risk for worsening disease in years 1-4 and for a clinical relapse within the first year MRI activity after starting IFN has similar implication as a relapse

49 Potential IFN-β Serum Biomarkers RespondersNon-responders Increase in IL-10IL-17F levels>200pg/ml Reduction in Th1 cytokinesHigh baseline IFN-β levels Increased in neurotrophic factors Increased monocytes IFN-I secretion in response to TLR NAB Increase PSTAT1 and IFNR1 on monocytes at baseline Dhib-Jalbut S et al. J Neuroimmunology. 2013;254:131-140. Comabella M et al. Brain. 2009;132:3353-3365.

50 Clinical Response to IFN-β Key Points Relapses are reduced by one-third Response is heterogeneous No validated laboratory biomarkers Persistent active MRI lesions at 6 mos predicts clinical activity Persistent high titer neutralizing Ab could be a reason to switch therapy Killestein J, Polman CH. Nat Rev Neurol. 2011;7:221-228.


52 Weber MS et al. Nat Med. 2007;13:935-943. Th0 GA HLA-Class II T-cell Receptor APC/type-2 Dendritic cells IL-4 Th2 Treg IL-10 TGFB IL-12 TNF Glatiramer Acetate Binds to HLA Class II on Antigen Presenting Cells and Induces Type-2 APCs

53 Response by Haplotype Dhib-Jalbut S et al. MSARD. 2013;2:340-348.

54 DR and DQ Haplotypes Predictors of Clinical Response to GA PROGNOSTIC PROFILE HAPLOTYPESNR / R (%R) Poor prognostic profile DR15 - DQ6 absent DR17 - DQ2 present 10 / 2 (16.7%) Neutral prognostic profile DR15 – DQ6 present & DR17 – DQ2 present DR15 – DQ6 absent & DR17 – DQ2 absent 17 / 11 (39.5%) Good prognostic profile DR15 – DQ6 present DR17 - DQ2 absent 7 / 17 (70.8%) Dhib-Jalbut S et al. MSARD. 2013;2:340-348.

55 Caspase-1 GA-RESPONDERS GA NON- RESPONDERS IL4/IFNg IL-18 FOXP3+ IL-17 DQ2 DR17 DQ2 DR17 Summary of Potential GA-Biomarkers DR15 DQ6 Dhib-Jalbut S. Presented at: ECTRIMS 2010. IL-10 BDNF

56 Black Holes


58 Defer G et al. J Neurol Sci. 2012;314:138-142.


60 L-Selectin and Risk of PML in Natalizumab-treated MS Patients Schwab N et al. Neurology. 2013;81:865-871.

61 Serum IL-21 and Autoimmunity Jones JL et al. J Clin Invest. 2009;119:2052-2061.

62 Choosing Therapies—Biomarkers Antibodies to aquaporin-4 Immune markers –IL-17 and response to IFN –Alemtuzumab autoimmunity: serum IL-21 –Daclizumab: CD56 Bright Genetics/genomics (HLA): Response to GA Neutralizing antibodies (NAB) (IFN-B, natalizumab) JC virus exposure (natalizumab)

63 Neuroprotection – how to recognize, measure, Rx Pathologic-based phenotyping will be increasingly important for treating progressive disease, informed (targeted) repair Biomarkers Measures of improvement Future Issues

64 Patient Resource Tools The National Multiple Sclerosis Society – –An online resource of patient information The American Academy of Neurology − −Understanding Multiple Sclerosis (located mid-page) −Available as a downloadable PDF or printed copies can be ordered by contacting Missy Render (

65 Participant CME Evaluation Please remove the Post-activity Survey and Evaluation from the back of your packet If you are not seeking credit, we ask that you fill out the information pertaining to your degree and specialty, as well as the few questions in the Post-activity Survey measuring the knowledge and competence you have garnered from this program. In order to receive CME credit, please complete the Evaluation Form, as well, and return to onsite staff. Your participation will help shape future CME activities. Thank You!

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