New Frontiers in Neurotherapy for Multiple Sclerosis

New Frontiers in Neurotherapy for Multiple Sclerosis
Investigations • Innovation • Clinical Application New Frontiers in Neurotherapy for Multiple Sclerosis Focus on the Foundation Role of Immunomodulation for Long-Term Efficacy, Safety, Neuronal Preservation, and Disability Mitigation Program Chairman Bruce A. Cree, MD, PhD, MCR Assistant Professor of Neurology Department of Neurology University of California San Francisco Multiple Sclerosis Center San Francisco, California

Program Faculty ROHIT BAKSHI, MD, FAAN BRUCE A. CREE, MD, PhD, MCR
Assistant Professor of Neurology Department of Neurology University of California San Francisco Multiple Sclerosis Center San Francisco, California MARK J. TULLMAN, MD Director, Multiple Sclerosis Clinical Care Center The Neurological Institute of New York Columbia University Medical Center New York, New York ROHIT BAKSHI, MD, FAAN Associate Professor of Neurology & Radiology Director, Laboratory for Neuroimaging Research MS Center, Brigham & Women’s Hospital Harvard Medical School Boston, MA GUY J. BUCKLE, MD, MPH Director of MS Clinical Care Partners Multiple Sclerosis Center Brigham and Women’s Hospital Assistant Professor of Neurology Boston, Massachusetts

The Evidence for First Line Therapy with Immune-Modulating Agents
Investigations • Innovation • Clinical Application The Evidence for First Line Therapy with Immune-Modulating Agents From Mechanisms to Therapy—Landmark Trials, Long-Term Safety Data and Clinical Experience Program Chairman Bruce A. Cree, MD, PhD, MCR Assistant Professor of Neurology Department of Neurology University of California San Francisco Multiple Sclerosis Center San Francisco, California

Overview Mechanisms of action of first line therapies
Outcome measures in clinical trials Comparison of landmark trials Longitudinal studies: what do they tell us?

Goals of Treatment Reduce frequency of relapse
Slow progression of disability Reduce MRI activity Prevent morbidity from symptoms and provide palliative care Maintain adherence Provide long-term efficacy and safety

Immunopathogenesis of the MS Lesion
CD8 Ab+C9neo gdT MO Oligo NO Oi TNFa MMP Pl Virus B Histamine Proteases TNFa NAA, ATP NO O2 5-HT IFNg TNF Th17 Th2/ Th3 Treg IL-10 TGFb Glutamate B7 CD28 MCP-1 MIP-1a IP-10 RANTES CD4+CD25+ Th1 Th17 Microglia Mast Cell Astrocyte CD40 CD40L BBB VCAM-1 Mast Cell ICAM-1 VCAM-1 MMP-2/9 IL-4 IL-5 IL-6 IL-13 TGFb Treg Th2/ Th3 B Complement LFA-1 VLA-4 gdT Th1 Th17 Monocyte IFNg TNF IL-17 IL-23 IL-4 & IL-10 Granutocyte CD8 IL-12 B7 CD28 CD4 APC CD4 HLA APC TCR Thp Thp Myelin Ag Microbial Ag Figure courtesy of Dhib-Jalbut S, 2008 CD40 CD40L

Adapted from Yong VW. Neurology. 2002;59:802-808.
IFN-: Activity TH1+ Resting T cell MMP Activated (+) T cells BBB Blood CNS TNF-α IFN-γ IL-2 TH1 APC IFN-β Myelin protein Antigen Activity of IFN- IFN-β has the following effects at the BBB.1 It decreases production of matrix metalloproteinases (MMPs) by T cells. It reduces expression of several chemokine receptors. It affects adhesion of T cells onto the endothelium. It reduces influx of T cells into the CNS. It rapidly resolves Gd-enhanced MRI activity. Reference 1. Yong VW. Differential mechanisms of action of interferon- and glatiramer acetate in MS. Neurology. 2002;59: Adapted from Yong VW. Neurology. 2002;59:

Glatiramer Acetate: Activity
BBB Periphery CNS Macrophage Microglia Bystander suppression effect APC MHC GA TCR APC MHC CNS Ag TCR GA therapy IL-4 IL-10 BDNF TCR Anti-inflammatory cytokines Activity of Glatiramer Acetate On the left side, glatiramer acetate is activating Th1 cells to transition to Th2 cells, which cross the BBB into the CNS.1 Once in the CNS, these Th2 cells release cytokines, including IL-10 and TGF-β, which inhibit encephalogenic T cells and prevent neuronal damage. Ziemssen and colleagues have proposed that the efficacy of glatiramer acetate-activated Th2 cells may be related to their ability to produce BDNF, on the right side. BDNF is a potent neurotrophin contributing to neuronal survival and dendritic growth.1 The investigators demonstrated the presence of BDNF in glatiramer acetate-activated long-term T cell lines from human donors using reverse transcription PCR, ELISA, and staining techniques.1 Similar findings in an EAE model have been reported.2 BDNF receptors have been isolated near MS plaques and in reactive astrocytes of MS lesions, suggesting direct access to target tissues. In fact, BDNF has been immunolocalized in active MS lesions.1,3 References 1. Ziemssen T, Kumpfel T, Schneider H, Klinkert WE, Neuhaus O, Hohlfeld R. Secretion of brain-derived neurotrophic factor by glatiramer acetate-reactive T-helper cell lines: implications for multiple sclerosis therapy. J Neurol Sci. 2005;233: 2. Aharoni R, Eilam R, Domev H, Labunskay G, Sela M, Arnon R. The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc Natl Acad Sci U S A. 2005;102: 3. Stadelmann C, Kerschensteiner M, Misgeld T, Bruck W, Hohlfeld R, Lassmann H. BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain. 2002;125:75-85. + + Neurotrophins GA- specific T cell Neuroregeneration TH1 TH2 TH2 Adapted from Ziemssen T et al. J Neurol Sci. 2005;233:

Long-Term Disability Effect of Early Relapses
50 40 30 20 10 60 80 100 Time from onset of MS (years) Percent Pts DSS < 6 p < Low (0-1 attacks in 2 years) Intermediate (2-4 attacks in 2 years) High (> 5 in 2 years) Weinhenker B et al. Brain. 1989;112:1422

Development of Disability
Effect of Early Clinical Course Clinical Characteristic Significance* Number of Attacks, 1st 2 years p <0.001 Interval Between 1st 2 Attacks DSS at 2 years p < 0.001 DSS at 5 years * Controlled for age at onset, remitting at onset, cerebellar, cerebral Weinshenker B et al. Brain. 1991;114 ( Pt 2):

Relapses in MS Relapses are the most obvious evidence of inflammatory disease activity in RRMS Relapse frequency in typical untreated RRMS populations enables treatment effect to be rapidly assessable in a 12-month clinical study Total number of relapses during the study period Total in-study person-years

% Reduction in relapse rates
Effect on Annualized Relapse Rates: Summary of Phase III Trials – 2 years in-study 35 31% 8 MIU qod IFN beta-1b P=0.0001 29% 4.4 MIU tiw IFN beta-1a P<0.001 32% 8.8 MIU tiw IFN beta-1a P<0.0001 29% 20 mg qd glatiramer acetate P=0.055 30 25 20 % Reduction in relapse rates 18% 15 P=0.04 10 5 6 MIU qw IFN beta-1a N.B.: Results are from separate clinical trials Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655; IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277; Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701; PRISMS Study Group. Lancet. 1998;352:1498; Rebif package insert.

Is MS All About Relapses?
Hypothesis: if relapses cause long-term disability then patients with frequent relapses should be at higher risk for disability From the London Ontario natural history studies patients with frequent attacks are at highest risk for future ambulatory disability Assumption: modifying the relapse rate will influence long-term disability Weinshenker et al Brain 112:1419

Proportion of Placebo Groups with Clinical Activity
Relapses EDSS Progress IFNβ-1b (3 year) 86% 39% IFNβ-1a (QW) (2 year) 77% 35% IFNβ-1a (TIW) (2 year) 84% 38% Glatiramer acetate (2 year) 73% 25% Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655; IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277; Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701; PRISMS Study Group. Lancet. 1998;352:1498.

How is Sustained Progression Measured?
Most clinical trials define progression by comparing the change in EDSS from baseline to study conclusion, and then confirm the change in EDSS at 3 or 6 months Does this measure of confirmed progression reflect permanent disability? If so, then confirmed changes in EDSS during the course of the trial should be sustained by the end of the study

Does Sustained Disability Measure Permanent Disability?
50% of patients with a 1 point change, confirmed at 3 months will improve to a lower EDSS 33% of patients with a 1 point change, confirmed at 6 months, will improve to a lower EDSS More stringent measures of change are harder to demonstrate in 2-year trials because relatively few MS patients will progress Conclusions: 6 months sustained EDSS change is more rigorous than a 3-month sustained change, but neither is a good predictor of long term disability Liu C & Blumhardt LD J Neurol Neurosurg Psychiatry. 2000;68:450-7.

Effect on Sustained Disability*: Summary of Phase III Trials
37% 40 29% 30% p=0.02 30 sustained disability progression (%) Reduction in 22% p<0.05 20 p=NS p<0.05 12% 10 p=NS 20 mg qd glatiramer acetate 8 MIU qod IFN beta-1b 6 MIU qw IFN beta-1a 4.4 MIU tiw IFN beta-1a 8.8 MIU tiw IFN beta-1a *1 EDSS point sustained for 6 months in 6 MIU qw phase III trial and for 3 months in all other phase III trials. Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655 IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277 Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701 PRISMS Study Group. Lancet. 1998;352:1498 1. Jacobs et al. Ann Neurol. 1996;39: IFNB MS Study Group. Neurology. 1993;43: Johnson et al. Neurology. 1995:45:1268. 4. PRISMS Study Group. Lancet. 1998;352:1498.

Summary Relapses and disability progression represent different but complimentary aspects of MS natural history Relapse rate reduction and the mean change in EDSS are the most sensitive clinical outcome measures in MS trials The generally accepted sustained change in EDSS measure is not a reliable marker of long term disability Phase III trials results showed: The interferons and glatiramer acetate modestly reduce the relapse rate IFN beta-1a has a statistically significant impact on sustained disability progression over two years IFN beta-1a and glatiramer acetate have a statistically significant impact on the mean EDSS over two year

Are direct comparator studies needed in MS or can we make valid conclusions from cross trial comparisons?

Cross Trial Comparisons Relative Efficacy (RR)
July 2006 Cross Trial Comparisons Relative Efficacy (RR) IFNβ-1a 30 µg qw IFNβ-1b, 250 µg qod IFN β-1a 44 µg tiw GA 20 mg qd Relapse rate (annualized) -18% -34% -32% -29% Relapse-Free (2 years) +42% +95% +100% +36% Progression free -37% -30% -12% New T2 Lesions -36% -83% -78% -38% Gd+ Lesions -42% - -88% -33% BOD - 4% -17% -15% -8% © Merck KGaA Darmstadt/Germany

The REGARD Trial Time to First Relapse (1o endpoint)
July 2006 The REGARD Trial Time to First Relapse (1o endpoint) 1.00 672 days (96 weeks) 0.75 IFNβ-1a GA Hazard ratio (95% CI): (0.74, 1.21) p = 0.643 Survival distribution function 0.50 0.25 0.00 100 200 300 400 500 600 700 Time to first relapse (days) © Merck KGaA Darmstadt/Germany

The BEYOND Trial Relapse Risk (1o Endpoint)
July 2006 No significant difference in relapse risk between any group Sensitivity Analysis (no major protocol violations, 100% of doses, post-hoc) Primary Analysis P-values (one-sided) P-values (one-sided) Interferon beta-1b vs. Interferon beta-1b 250 P=0.16 P=0.73 P=0.43 P=0.29 P=0.30 P=0.18 Interferon beta-1b 250 vs. Glatiramer acetate All three groups behaved very similarly regarding the primary outcome measure, the relapse risk. All point estimates for the hazard ratios are very close to 1 and the confidence intervals are wide, confirming that all treatments were similarly effective. All sensitivity analyses confirmed this result, see the example on the right hand side (that includes approx. two thirds of the events compared to the primary analysis). Based on these very robust results, the 500 mcg dose will not be filed for approval with health authorities. Background note: Due to the 1-sided nature of the p-values, any p-value <0.025 would be considered statistically significant. Interferon beta-1b 500 vs. Glatiramer acetate © Merck KGaA Darmstadt/Germany

What can be learned from long-term follow up studies?

Long-Term Follow Up Do long-term follow up studies adequately address medication safety? Do long-term studies adequately address longitudinal efficacy? Have methods of analysis for longitudinal studies been optimized?

Sources of Bias in LTFU Studies
July 2006 Sources of Bias in LTFU Studies Bias Impact Strategy Ascertainment Modified therapeutic effect dependent on characteristics of participating patients. F/U must be as complete as possible Directly compare baseline and on-RCT characteristics of those patients in LTF to those not in LTF Informed Therapeutic Decisions Inflated estimate of therapeutic benefit because patients doing well continue therapy whereas failing patients switch or stop therapy. MPR: Use percent of total possible time on therapy instead of absolute time to assess exposure. Treatment Selection Modified therapeutic effect dependent on patient selection characteristics. Propensity Scoring: Adjust for the propensity (i.e., likelihood) that a particular treatment will be selected based on available patient characteristics Multiple Testing Increased risk of Type 1 error from the use of multiple predictor variables and weighting schemes Create a single model and apply adjustments to p-values according to the number of predictors tested in the model. © Merck KGaA Darmstadt/Germany

Glatiramer Acetate 15 year LTFU
Ford C et al. Mult Scler. 2010;16:

July 2006 Glatiramer Acetate 15 year LTFU Time to reach confirmed Expanded Disability Status Scale 4, 6, and 8 for the mITT and Ongoing cohorts while they were on glatiramer acetate therapy. The mean disease duration at glatiramer acetate start for the mITT cohort was 8.3 years and for the Ongoing cohort was 8.4 years. Ford C et al. Mult Scler. 2010;16: © Merck KGaA Darmstadt/Germany

In a small cohort of patients followed for 15 years, glatiramer acetate was safe and well tolerated 65% of continuously treated patients did not progress to SPMS 41% of patients withdrawing from the study did so because of disease progression Propensity scores were used to try to adjust for differences between ongoing and withdrawing patients EDSS at baseline predicts EDSS at 15 years

IFN β-1a (QW) LTFU Disposition
Complete 2-year follow-up (n=172) Unascertained (n=36) Ascertained for ASSURANCE (n=136; 79%) Able to locate, Unable to contact (n=13) Unable to locate (n=23) Living (n=122; 90%) Deceased (n=14; 10%) ICF and question booklet completed LOCF Bermel R et al. Mult Scler Feb 18. [Epub ahead of print]

IFN β-1a QW LTFU Outcomes
Currently receiving IM IFN ß-1a (n=56) Not currently receiving IM IFN ß-1a (n=66) P=0.006 P=0.062 P=0.114 P=0.326 Patients, % Patients, % EDSS Milestone Bermel R et al. Mult Scler Feb 18. [Epub ahead of print]

IFN β-1a QW LTFU Conclusions
79% of eligible patients were located for the 15 year follow up At 15 years, patients currently on IFN β-1a had less progression in EDSS scores than patients not on IFN β-1a However, patients not currently on IFN β-1a had higher baseline EDSS scores suggesting more severe baseline MS Propensity scores were used to adjust for these differences Inferences with regard to association with lower EDSS and ongoing treatment were not made Bermel R et al. Mult Scler Feb 18. [Epub ahead of print]

Patients under regular medical care - no trial
July 2006 IFN β-1b LTFU Design Pivotal Study (n=372) IFNβ-1b 250 µg 124 56 Patients under regular medical care - no trial IFNβ-1b 50 µg 125 52 LTF Placebo 123 58 1988 1990 1993 2005 Cross-sectional investigation of: - clinical outcomes (disability, relapse rate) - imaging (brain and spinal MRI) - cognition and mood - QoL, resource use - lab parameter including NAb's and PgX Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3 © Merck KGaA Darmstadt/Germany

Event Rates and Long-Term Efficacy
July 2006 Event Rates and Long-Term Efficacy Clinical and Radiological Endpoints Need to demonstrate that the short-term event-rates are correlated with long-term outcome. Need to demonstrate that the short-term event-rates contribute independently to predicting outcome. Need to demonstrate that therapies which reduce the event-rates, are also associated with improved long-term outcome. Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3 © Merck KGaA Darmstadt/Germany

IFN β-1b LTFU Adjusted OUtcome
July 2006 IFN β-1b LTFU Adjusted OUtcome Any Variable + Any Exposure Weighting – Any Negative Outcome 1 EDSS p<0.001 2 Exposure p<0.001 Low High Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3 © Merck KGaA Darmstadt/Germany

Event Rates and Long-Term Efficacy
Conclusions July 2006 The LTF study demonstrates that the short-term event-rate is correlated with long-term outcome. The LTF study also demonstrates that the short-term event-rate contributes independently to predicting long-term outcome. The LTF study provides convincing evidence that early initiation and sustained use of IFNβ-1b has a beneficial impact on long-term outcome in MS. The analysis strategy employed provides a methodological framework for mitigating bias in assessing long-term efficacy in other clinical trials having similar non-randomized data. © Merck KGaA Darmstadt/Germany

Conclusions Disease modifying therapy seems favorably effect the long-term course of MS Propensity score adjusted analysis and other statistical methods for controlling biases inherent in long term, unblinded studies are important statistical advances for interpreting these studies Once the MS community agrees on the relevant covariates, these methods can be used to sort out some of these issues without the cost (and ethical dilemmas) posed by long-term placebo-controlled trials.

Investigations • Innovation • Clinical Application
The Emergence of Immunosuppressive Agents for MS Safety, Efficacy, and Cautionary Notes— Patient Monitoring, Risks for Infection, and Mechanisms of Action Mark J. Tullman, MD Assistant Professor of Neurology Director, Multiple Sclerosis Clinical Care Center The Neurological Institute of New York Columbia University Medical Center New York, New York

Existing and Emerging MS Therapies
2005 2006 2007 2010 2011 2012 2013 Oral Injectables BG12 Caldribine BG12 Cladribine Rebif Rebif Fingolimod Betaseron Ampyra Ampyra Teriflunomide Teriflunomide Copaxone Extavia Extavia Laquinimod Laquinimod Avonex Ocrelizumab Ocrelizumab IV Novantrone Tysabri Tysabri IV Generic Mitoxantrone (oncology) MS Generic Mitoxantrone (oncology) (MS) Alemtuzumab Alemtuzumab Filed Approved In phase II In phase III

Efficacy in Recent Studies
Annualized relapse rate over 2 years 58-61% relapse-free over 2 years 79-81% without disability progression over 2 years 88.3% without disability progression over 96 weeks 91.3% without disability progression over 96 weeks 74% without disability progression over 3 years 75% without EDSS progression 5 years after CIS onset 13.3% reduction in MRI T2 lesion load over 3 years All in placebo, interferon, or glatiramer acetate-treated patients Kappos L, et al. Lancet Neurol 2009; 8: 987–97; Giovannoni G, et al. N Engl J Med. 2010;362: ; CAMMS223 Trial Investigators. NEJM 2008;359: ; Kappos L et al. N Engl J Med. 2006;355: ; Mikol et al. Lancet Neurol 2008; 7: 903–14

Prognostic Signs Favorable Outcome Worse Outcome Female Male
Younger age at onset Little disability 5 years after onset Optic neuritis as 1st attack Worse Outcome Male Older age at onset Frequent attacks Short interval between 1st 2 attacks Incomplete recovery from 1st attack Cerebellar involvement as 1st symptom Rapidly accumulating disability Progressive disease from onset

Baseline Brain MRI Lesion Number 20-Year Clinical Status
Fisniku LK. Brain 2008;131:

Disease Free State Proportion Free of Clinical and MRI Activity
Natalizumab Placebo Hardova E, et al. Lancet Neurol 2009;8:

Alemtuzumab Monoclonal humanized antibody directed against CD52 antigen CD52 antigen is a cell surface glycoprotein that is present on >95% of T lymphocytes, B lymphocytes, monocytes, and eosinophils Results in prolonged depletion of B cells, T cells, and monocytes Within an hour following a single 5- to 10-mg dose, lymphocytes and monocytes are no longer detectable in circulation FDA-approved for B-CLL Muraro P, et al. Neurotherapeutics. 2007;4: Coles A, et al. J Neurol. 2006;253:

Alemtuzumab 12 mg daily IV Alemtuzumab 24 mg daily IV
IFNβ-1a 44 mcg thw SC Alemtuzumab 12 mg daily IV 24 77 Alemtuzumab 24 mg daily IV 22 88 Month Month Month Month 36 CAMMS223 Trial Investigators. NEJM 2008;359:

Alemtuzumab CAMMS223: Co-Primary Endpoints (36 months)
CAMMS223 Trial Investigators. NEJM 2008;359:

Alemtuzumab CAMMS223: MRI Outcomes
Months P=0.04 P=0.03 n=75 P=0.04 n=91 n=60 n=87 P=0.16 n=96 n=80 n=100 n=96 n=91 Months P≤0.03 for both doses of alemtuzumab vs. IFN at m 0-12 and P=NS at m 0-36 CAMMS223 Trial Investigators. N Engl J Med. 2008;359:

Alemtuzumab CAMMS223: Safety
Principal AEs associated with alemtuzumab included: Infusion reactions Mild-to-moderate infections Autoimmunity Immune thrombocytopenia in 6 of 216 patients (2.8%) including one death Thyroid disorders (28% vs. 3% for IFNβ-1a) 1 case of Goodpasture’s syndrome CAMMS223 Trial Investigators. N Engl J Med. 2008;359:

Alemtuzumab CAMMS223: Safety
Infections, % IFN ß-1a (n=107) Alem mg (n=108) Alem mg (n=108) Upper resp. infection* 27.1 44.4 50.9 Lower resp. infection* 1.9 11.1 13.9 Herpes simplex 2.8 8.3 Herpes zoster 0.9 5.6 Meningitis** 1.8 * P<0.001 alemtuzumab vs. IFN ** Listeria or viral meningitis CAMMS223 Trial Investigators. N Engl J Med. 2008;359:

Alemtuzumab: Effects on the Immune System
B cells returned to normal within 3-6 months Median recovery time for CD4+ T cells > 100 cells/µL = 3 months 6-9 months for CD4+ T cells > 200 cells/µL Median recovery time to baseline levels of CD4+ T cells = 61 months Thompson S, et al. J Clin Immunol 2010;30:99–105. Coles A, et al. J Neurol. 2006;253:

Cladribine Synthetic purine nucleoside analogue prodrug
Accumulates and is incorporated into the DNA of lymphocytes as a result of a high ratio of deoxycytidinekinaseto 5' nucleotidase activity Selectively induces apoptosis in dividing and non-dividing lymphocytes Sustained reduction in lymphocyte subtypes (CD4+ T cells, CD8+ T cells and B cells Relatively transient effects on other immune cells such as neutrophils and monocytes Reduces levels of pro-inflammatory chemokines Crosses the blood brain barrier - CSF concentration = 25% of plasma (patients with no BBB compromise) FDA-approved for hairy cell leukemia Carson et al. Blood 1983;62:737–43; 2Beutler et al. Proc Natl Acad Sci USA 1996;93:1716–20. Rice et al.Neurology 2000;54:1145–55. Szczucinski et al. Acta Neurol Scand 2007;115:137–46Bartosik-Psujek et al. Acta Neurol Scand 2004;109:390–2. Liliemark.ClinPharmacokinet1997;32:120–3. 51

Cladribine 3.50 mg/kg total dose; 4 courses (n = 433)
X X X X X X Placebo (n = 437) 1326 patients X X X X X X Cladribine 3.50 mg/kg total dose; 4 courses (n = 433) X X X X X X Cladribine 5.25 mg/kg total dose; 6 courses (n = 456) –4 5 9 13 16 24 36 44 48 52 60 72 84 96 Time (weeks) MRI Neurological examination Dosing: 4-5 day courses at month 1 and 2 (3.50 mg/kg) or months 1-4 (5.25 mg/kg) and additional monthly courses beginning at week 48 Giovannoni G, et al. N Engl J Med. 2010;362: 52

CLARITY: Clinical Outcomes
0.33 ( ) 0.14* ( ) 0.15* 57.6% 54.5% Annualized relapse rate (95% CI) Odds Ratio (95% CI) 2.43 ( ) Percent of relapse-free patients at 98 weeks Odds Ratio (95% CI) 2.53 ( ) 78.9* 79.7* 60.9 Placebo (n = 437) Cladribine 3.50 mg/kg (n = 433) Cladribine 5.25 mg/kg (n = 456) * P < 0.001 Giovannoni G, et al. N Engl J Med. 2010;362:

CLARITY: Clinical Outcomes
25 Time to Confirmed EDSS Progression Placebo HR vs Placebo (95% CI) 20 Cladribine 3.50 mg/kg ( ); P = 0.02 Cladribine 5.25 mg/kg ( ); P = 0.03 15 Proportion with confirmed 3-month EDSS progression (%) 10 5 12 24 36 48 60 72 84 96 Weeks Placebo 3.50 mg 5.25 mg Giovannoni G, et al. N Engl J Med. 2010;362:

mean ± SE lesions/patient/scan T1 Gadolinium-Enhancing Lesions
CLARITY: MRI Outcomes 87.9% mean ± SE lesions/patient/scan 0.91 85.7% T1 Gadolinium-Enhancing Lesions Active T2-Weighted Lesions Combined Unique Lesions 1.72 0.43 0.38 74.4% 77.9% 1.43 0.38 0.33 73.4% 76.9% 0.12 0.11 Placebo (n = 437) Cladribine 3.50 mg/kg (n = 433) Cladribine 5.25 mg/kg (n = 456) All P < 0.001 Giovannoni G, et al. N Engl J Med. 2010;362:

CLARITY: Safety and Tolerability
Preferred term, n (%) patients Placebo (n = 435) Cladribine 3.5 mg/kg (n = 430) Cladribine 5.25 mg/kg (n = 454) Cladribine overall (n = 884) Herpes zoster 8 (1.9) 11 (2.4) 19 (2.1) Herpes zoster oticus 1 (0.2) 1 (0.1) Varicella 2 (0.2) Any infection or infestation 188 (42.5) 205 (47.7) 222 (48.9) 427 (48.3) Deaths 2 (0.5) 2 (0.4) 4 (0.5) 20 patients had 21 zoster events in the cladribine groups All 21 cases were self-limiting and dermatomal; no cases were disseminated 3.2% of patients developing grade 3 or 4 lymphopenia at any time during the study developed zoster versus 1.8% of those that did not 70% of patients with zoster had normal lymphocyte count or lesser grade lymphopenia at the approximate time zoster developed Deaths - Placebo: Hemorrhagic CVA, suicide; cladribine 3.5 mg/kg: acute MI, pancreatic carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardio-respiratory arrest Giovannoni G, et al. N Engl J Med. 2010;362:

CLARITY: Safety and Tolerability
Malignancies Preferred term, n (%) Placebo (n = 435) Cladribine 3.5 mg/kg (n = 430) Cladribine 5.25 mg/kg (n = 454) Cladribine overall (n = 884) During Study Melanoma 1(0.2) Ovarian 1 (0.1) Pancreatic 1 (0.2) Cervix During post-study surveillance Choriocarcinoma Giovannoni G, et al. N Engl J Med. 2010;362:

CLARITY: Effects on Lymphocyte Subsets
Maximum Effects on CD4 and CD 19 Counts* Weeks Weeks 48-96 mg/kg mg/kg mg/kg mg/kg CD4 (week) Cells/µL CD19 (week) 16 391 9 18 209 14 72 275 52 27 207 31 Add Reference *Median values Rieckmann P, et al. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, Poster #816.

Fingolimod (FTY720) Sphingosine-1-phosphate (S1P) receptor modulator
Sequesters circulating lymphocytes into secondary lymphoid organs Peripheral reduction of CD3+, CD4+, CD8+, CD45RA+ (naive T cells), CD45RO+ (memory T cells) and CD19+ cells No effect on lymphocyte induction, proliferation, or memory function May inhibit the production of IL-17 S1P receptors located within the CNS Fingolimod or deletion of S1P1 from neural cells reduces astrogliosis in EAE 1. Brown B, et al. Ann Pharmacother. 2007;41: Kappos L, et al. N Engl J Med. 2006;355: Mullershausen F, et al. Presented at: ECTRIMS; October 11-14, 2007; Prague, Czech Republic. 4. Miron VE, et al. Presented at: ECTRIMS; October 11-14, 2007; Prague, Czech Republic. 5. Barske C, et al. Presented at: ECTRIMS; October 11-14, 2007; Prague, Czech Republic.

Oral fingolimod 0.50 mg once daily (n = 425)
MRI Oral fingolimod 1.25 mg once daily (n = 429) Placebo once daily (n = 418) Randomization Month Month Month 24 1272 patients (1:1:1) Clinic visits Kappos L, et al. N Engl J Med. 2010;362: 60

FREEDOMS: Primary Efficacy Endpoint
Annualized Relapse Rate at 24 months -54% vs Placebo p < 0.001 -60% vs Placebo p < 0.001 β Placebo (n = 431) Fingolimod 0.5 mg (n = 429) Fingolimod 1.25 mg (n = 420) Kappos L, et al. N Engl J Med. 2010;362:

FREEDOMS: Disability Data
FTY mg (17%)† Days on study 5 10 15 20 25 30 Placebo (24%) FTY mg (18%)* Percent with 3-month confirmed EDSS progression FTY mg vs placebo HR 0.70 P = 0.02 in time to disability Progression FTY mg vs placebo HR 0.68 * P = 0.03 vs placebo † P = 0.01 vs placebo Number at Risk FTY mg FTY mg Placebo Kappos L, et al. N Engl J Med. 2010;362:

FREEDOMS: MRI Endpoints
T2 and Gadolinium-Enhancing Lesions at 24 Months -82% P<0.001 -74% P<0.001 Kappos L, et al. N Engl J Med. 2010;362:

FREEDOMS: Brain Volume
P≤0.03 for both doses of fingolimod vs. placebo at all time points Kappos L, et al. N Engl J Med. 2010;362:

Randomization Month 6 Month 12 Ongoing
Optional extension phase Oral fingolimod 0.5 mg once daily and matching weekly placebo injection IM Oral fingolimod 1.25 mg once daily and matching weekly placebo injection IM IFNβ-1a 30 µg IM once weekly and matching daily oral placebo capsule Assessments MRI EDSS Clinical visit Randomization Month 6 Month 12 Ongoing Cohen J, et al. N Engl J Med. 2010;362:

TRANSFORMS: Primary Efficacy Endpoint
Annualized Relapse Rate at 12 months -52% vs IFNβ-1a, p < 0.001 -38% vs IFNβ-1a, p < 0.001 β IFNβ-1a 30 µg IM once weekly (n = 431) Oral fingolimod 0.5 mg (n = 429) Oral fingolimod 1.25 mg (n = 420) Cohen J, et al. N Engl J Med. 2010;362:

TRANSFORMS: MRI Endpoints
T2 and Gadolinium-Enhancing Lesions at 12 Months -35% vs. IFNß-1a P=0.004 -55% vs. IFNß-1a P<0.001 -42% vs. IFNß-1a P<0.001 -73% vs. IFNß-1a P<0.001 Cohen J, et al. N Engl J Med. 2010;362:

TRANSFORMS: Brain Volume
P < 0.001 Cohen J, et al. N Engl J Med. 2010;362:

Fingolimod: Safety Transient reduction in heart rate on initiation of treatment Elevated blood pressure ↑mean systolic BP (1.9 and 3.6 mm Hg for 0.5 mg and 1.25 mg, respectively) and diastolic BP (0.7 and 2.1 mm HG for 0.5 and 1.25 mg, respectively) Elevated liver enzymes ↑LFTs ≥ 3 x ULN 8% for FTY mg, 10% for FTY mg, 1.2% for placebo, 2% for IFNß-1a Macular edema FREEDOMS - 7 cases in the 1.25 mg dose group (1.6%) and none in the 0.5 mg dose group TRANSFORMS – 6 cases (4 in the 1.25 mg dose group (1%) and 2 in the 0.5 mg dose group (0.5%)) Kappos L, et al. N Engl J Med. 2010;362: Cohen J, et al. N Engl J Med. 2010;362:

Malignancies and Herpes Infections
Fingolimod: Safety Malignancies and Herpes Infections AE, n (%) FTY mg (n = 854) FTY mg (n = 849) Placebo (n = 418) IFNß-1a (n = 431) Skin Cancers Basal cell carcinoma 7(0.8) 3(0.4) 3(0.7) 1(0.2) Melanoma 1(0.1) Bowen’s Disease 1 (0.1) Infections Herpes infections 46(5.4) 48(5.7) 33(7.9) 12(2.8) Kappos L, et al. N Engl J Med. 2010;362: Cohen J, et al. N Engl J Med. 2010;362:

Fingolimod: Safety Two fatal infections in patients treated with FTY mg Herpes encephalitis primary disseminated varicella Hemorrhagic encephalitis in a patient treated with FTY mg Posterior reversible encephalopathy syndrome in a patient treated with 5 mg in the phase 2 study Cohen J, et al. N Engl J Med. 2010;362: ; Kappos L et al. N Engl J Med. 2006;355: ; Leypoldt F, et al. LK. Neurology 2009;72:

FTY720 1.25 mg (n = 16) Normal range Treatment duration (yrs),
mean ± SEM 1.9 ± 0.2 - Lymphocyte count (x 109/L), 0.4 ± 0.1 CD4 T cell count (cells/µL), 78 ± 5.6 CD8 T cell count (cells/µL), 149 ± 7.4 Mehling M, et al. Neurology 2008;71:1261–1267

[PD5.006] Prolonged Reduction in Circulating Lymphocytes after Discontinuation of FTY720 (Fingolimod): Possible Relationship to Duration of Therapy Mark R. Keezer, Yves Lapierre, Igor Shames, David Haegert, Amit Bar-Or, Jack Antel, Montreal, QC, Canada CONCLUSIONS/RELEVANCE: Peripheral lymphocyte counts remained depressed beyond the currently expected time period in 2 patients following cessation of long-term FTY720 therapy. Regional lymph node architecture was preserved in the one available patient. Exploration of larger datasets will determine the true incidence of prolonged lymphopenia and whether time to recovery of circulating lymphocytes may provide a potential biomarker for guiding continued therapy. Category - MS and Related Diseases - Clinical Science Presented at the AAN Annual Meeting 2010.

Emerging Therapies: Trading Efficacy for Safety
? Impaired immune surveillance and opportunistic infections Viral and other infections ? Malignancies Long-lasting effects Autoimmunity Teratogenicity Rare, but serious infusion reactions The Unknown

Natalizumab and the Risk of PML

Evaluated in 4 randomized, double-blind, placebo-controlled trials
Humanized monoclonal antibody directed against CD11a affecting T-lymphocyte activation, migration, and reactivation Evaluated in 4 randomized, double-blind, placebo-controlled trials FDA-approved for psoriasis in 2003 At the time of approval, 2764 patients had been treated 218 treated for ≥ 1 year Nijsten T, et al. Arch Dermatol 2009;145:

October 2008: Label update to include PML February 2009:
FDA issued a Public Health Advisory and changed the label to include a “black box” warning for PML At the time, 48,000 patients treated with efalizumab, but only 14,000 for > 1 year, 5,100 for > 2 years, and 1,900 for > 3 years EMEA recommends suspension of marketing Health Canada suspends marketing April 2009: Genentech announced plans for a voluntary withdrawal from the U.S. market Nijsten T, et al. Arch Dermatol 2009;145:

Treatment Decisions: Considering Benefits and Risks
Benefits Risks Meaningful impact Disease Course MRI ? Better than ABCR ? Window of opportunity Convenience Short-term safety Long-term safety Pharmacovigilance Post-approval studies Pregnancy issues

New Frontiers in Neurotherapy
The Long Haul: Optimizing Long-Term Functional Status and Financial Outcomes in RRMS with Immunomodulation Therapy What Do The Trials Teach Us? Guy J. Buckle, MD, MPH Director of MS Clinical Care Partners Multiple Sclerosis Center Brigham and Women’s Hospital Assistant Professor of Neurology Harvard Medical School Boston, Massachusetts

Epidemiology of MS The most common chronic disease affecting the CNS in young adults Approximately 400,000 cases in the United States Estimates range from 250,000 to 500,000 The chances of developing MS are 1:1000 in the general population Estimated 2.5 million cases worldwide Highest incidence in Caucasians Higher incidence in women (approximately 3:1) MS strikes individuals between the ages 20-50, normally a time of peak productivity According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72: The National MS Society Information Sourcebook. Available at: Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. CNS = central nervous system. Compston A, et al. Lancet. 2002;359(9313): Frohman EM. Med Clin N Am. 2003;87(4): Hogancamp WE, et al. Mayo Clin Proc. 1997;72(9): National Multiple Sclerosis Society. Who gets MS? Accessed January 8, Lage MJ, et al. Work. 2006;27(2):

Potential Triggers for MS
Infectious Agent Genetic Predisposition Environmental Factors MS is believed to result from of an abnormal immunologic response to an infectious agent and/or unknown environmental factors in people who have a genetic predisposition to MS.1 Besides geography, researchers have concentrated on two other broad areas of inquiry: genetics and infectious agents (bacteria and viruses). Genetics: Numerous studies show that genetics play a role in the development of MS, but are not the sole cause of the disease. Roughly 1%-4% of MS patients will have a first-degree relative, a parent, a sibling, or an aunt or uncle, who also has MS.2 The identical twin of a person with MS has a 1 in 3 chance of developing MS.2 Although these facts are not considered conclusive proof of familial inheritance of MS, they do tell doctors that genetic factors definitely contribute to the risk of developing MS. Infectious agents: There is the possibility that a single germ or combination of germs may increase a person’s risk of developing MS. The viruses that cause measles and herpes, and chlamydia have been considered possible culprits; however, to date, no specific agent has ever been conclusively proven to be the sole cause of MS.2 Miller, et al. Immunopathogenesis. In: Continuum: Lifelong Learning in Neurology. Multiple Sclerosis (Part A) What is MS? Available at: http;//mscenter.ucsf.edu/fag.htm. Accessed Abnormal Immunologic Response MS Cardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):

Clinical Manifestations
Fatigue Pain Depression Numbness/paresthesias Cognitive dysfunction Weakness Spasticity Optic neuritis Bladder dysfunction Bowel dysfunction Cerebellar dysfunction Sexual dysfunction Gait abnormalities Partial/complete paralysis National Multiple Sclerosis Society. Accessed February 21, 2010.

Age of Onset of MS Distribution of Patients According to
the Decade of Life of MS Symptoms Onset 35 30 25 20 Patients (%) 15 10 5 0-10 11-20 21-30 31-40 41-50 51-60 Years Cardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):

Progression of Disability: EDSS
10.0 = Death due to MS 9.0–9.5 = Completely dependent Increasing disease burden 8.0–8.5 = Confined to bed or chair 7.0–7.5 = Confined to wheelchair 6.0–6.5 = Walking assistance is needed 5.0–5.5 = Increasing limitation in ability to walk 4.0–4.5 = Disability is moderate All trials in RRMS have received approvals from the FDA based on relapse rates—just counting the number of relapses—and/or disability as measured by the Kurtzke EDSS scale. Scores range from 0 to 10. Scores from 0 to 4.5 are based on the neurologic exam and reflect a person who is ambulatory Rating 5 to 9.5 are defined by impact on ambulation. Critique: weighted too heavily on gait In higher ranges, it is relatively insensitive to clinical changes that do not impair gait. The most widely used assessment of impact on MS is the Kurtzke Expanded Disability Status Scale (EDSS). The Disability Status Scale (DSS) was published in 1955 and later revised and expanded to the EDSS in 1983 To measure the EDSS score, a standard neurologic exam is used to evaluate functional system abnormalities involving thee: pyramidal, cerebellar, brain stem, sensory, bladder and bowel, visual, and mental. Functional system scores vary from 0 (normal function) to 7 or 8 (complete dysfunction). These assignments determine the EDSS score in half-steps from 0 (normal neurologic function) to 10 (death from MS). For example, and EDSS score of 1.5 means there is no disability, but minimal changes are evident in more than one functional system. An EDSS score of 4.0 to 4.5 means disability is moderate. The patient can only walk 330 to 550 yards without assistance or rest. 3.0–3.5 = Disability is mild to moderate 2.0–2.5 = Disability is minimal 1.0–1.5 = No disability 0 = Normal neurologic exam EDSS = Expanded Disability Status Scale. Kurtzke JF. Neurology. 1983;33:

Natural History of MS and Cost of MS
CIS RRMS SPMS Pre-clinical Predicted Cost Early Intervention* MRI lesion activity Clinical Threshold Atrophy and Axonal Degradation US$ per Year It is estimated that for every attack symptomatic enough for a patient to seek care, there are perhaps 10 attacks that can be documented on MRI scans; thus sub-clinical damage is ongoing. The latter phase of MS is characterized by increasing disability (as measured by EDSS scores) as the process of irreversible nerve damage continues. As neurodegeneration progresses, the disease becomes increasingly more difficult to treat. As MS progresses and the level of disability increases, both the direct and indirect costs of care will increase. The objective of early treatment is to lessen the development of disability, and thereby reduce the overall cost of care. *Curve is based on an estimation of the decrease in cost for early treatment of about 40% at each range of EDSS Burks J. J Manag Care Med. 2008;12(1): [Exhibit 8]. Comi G. Neurol Sci. 2006;27:S8-S12. Kobelt G, et al. Neurology. 2006;66(11):

Early Relapses Affect Long-term Disability
100 Low (0-1 attacks in 2 years) Intermediate (2-4 attacks in 2 years) High (≥5 in 2 years) 80 60 Patients (%) 40 20 10 20 30 40 50 Time from Onset of MS (years) Actuarial analysis of disability—percentage of patients not having reached EDSS 6: difference between the groups is significant (P < .0001). Weinshenker BG, et al. Brain. 1989;112:

Relapses Can Result in Residual Long-Term Disability
Net Change in EDSS Score from before a Relapse to after a Relapse* 100 86 42.4% increase 0.5 or more 80 28.1% increase 1 or more 60 Number of Subjects 40 32 33 20 20 14 7 8 8 3 4 5 1 1 2 -3.5 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.5 4.0 42% of patients had a residual deficit ≥0.5 point 28% had a residual deficit ≥1.0 point *In 224 placebo patients from the NMSS task force on clinical outcome assessment. EDSS = Expanded Disability Status Scale; NMSS = National Multiple Sclerosis Society. Lublin FD, et al. Neurology. 2003;61:

Long-term Study Design in RRMS
Copaxone® (glatiramer acetate injection)20,21 N=251 in original pivotal trial; 19 placebo patients of 251 in pivotal trial did not enter open-label extension, and 1 patient received 1 dose of COPAXONE® and never returned for evaluation. Therefore, 231 patients were included in the mITT analysis. The Ongoing cohort included 108 patients at 10 years and 100 patients at 15 years. Avonex® (IFNβ-1a)9,23 Avonex®: N=301; 158 Avonex®, 143 placebo; subset (85 Avonex®, 87 placebo) followed for 2 years. 15-year retrospective follow-up: n=116; 15-year follow-up consisted of a questionnaire at year 15. Betaseron® (IFNβ-1b)24,25 Betaseron®: N=372; 125 Betaseron® 1.6 MIU, 124 Betaseron® 8 MIU, 123 placebo. 16-year retrospective follow-up: n=328 identified patients (35 of these were deceased but included in the study as identified patients). LTFU data were obtained in an observational study consisting of a single-visit assessment or report at 16 years. At LTFU, 182/260 patients were not taking Betaseron®. Rebif® (IFNβ-1a)26 N=560; 184 Rebif® 44 mcg, 189 Rebif® 22 mcg, 187 placebo; at end of year 2, 172 placebo patients randomized to 22 mcg (n=84) or 44 mcg (n=87); and double-blind study was continued to year 4. LTFU data were obtained in an observational study consisting of a single-visit assessment 7-8 years after enrollment. Tysabri® (natalizumab)27 N=942; Tysabri® 300 mg (n=627) or placebo (n=315). Up to 15 years 2 yrs 15 years 5 yrs 16 years 4 yrs 7-8 years 3 yrs Key Prospective study design Retrospective follow-up 9. Jacobs LD, et al. Ann Neurol. 1996;39: Ford C, et al. WCTRIMS Abstract P Ford CC, et al. Mult Scler. 2006;12: 23. Bermel RA, et al. WCTRIMS Abstract P IFNβ Study Group. Neurology. 1995;45: Ebers G, et al. AAN P 26. Kappos L, et al. Neurology. 2006;67: O’Connor PW, et al. AAN P

Data Supporting Long-Term Use of DMT
Disease Duration (Years) Percentage Reaching EDSS 4 Percentage Reaching EDSS 6 GA 15-year LTFU >18.5 38% 18% High-dose IFN-1a PRISMS 8 ~13 26.8% 20% IFN-1b 16 Year(> 80) ~20 Not reported ~45% Low-dose IFN-1a 15-year 14.3 64% 32% Ryan M, et al. J Manag Care Pharm. 2009;15(1)(Suppl S-b):S1-S17.

Scope of QoL Three important domains in life Physical functioning
Psychosocial functioning Symptom-related phenomenon

The Two Faces of Multiple Sclerosis
MS Relapse Progression MRI Symptoms Mobility Employment Depression Fatigue Cognition

Mobility and HRQOL Improvement in strength and mobility can lead to improved social interaction and emotional behavior Improved fitness in MS is associated with improved HRQOL Physical activity is indirectly associated with improved depression, fatigue, pain, in individuals with MS HRQOL = Health-related quality of life. Petajan JH, et al. Ann Neurol. 1996;39(4): Motl R,W et al. Psychol Health Med. 2009;14(1)

Multiple Sclerosis MS <5 Years MS >15 Years First Rank (%)
40 35 MS <5 Years 30 MS >15 Years 25 First Rank (%) 20 15 10 5 Walking Power and Coordination of Hands Normal Skin Sensations Lack of Pain Bladder Control Bowel Control Visual Function Awakefulness and Alertness Thinking and Memory Speech Swallowing Mood sexuality Heesen C, et al. Mult Scler. 2008;14(7):

Walking Impairment and Quality of Life
64% of patients report difficulty walking Impairment worsens with increasing EDSS severity Percent Among Patients who Reported Walking Impairment Johanesson et al. J Neurol. 2007;254:

Trends Across MS Clinical Trials Annualized Relapse Rate (ARR)
Johnson 1995 Polman 2006 REGARD 2007 BECOME Kappos TRANSFORMS Jacobs 1996 IFNβ-1b study group,1993 PRISMS-2 1998 BEYOND CAMMS223 2008 3 years HERMES 48 weeks FORTE 1 year CLARITY 2009

Cost of MS Relapse Reducing relapses is key to reducing costs
The number of relapses is a significant predictor of total cost Cost of treating a relapse is difficult to calculate Includes initial care, acute treatment costs, post-discharge services, daily cost of outpatient medications In one study, using 2002 dollars, costs ranged from $243 to $12,870, depending on level of management needed Cost estimates do not differentiate between the different forms of MS Morrow TJ. J Neurol Sci. 2007;256(supp 1):S39-S44. Grudzinski AN, et al. J Manag Care Pharm. 2000;6:19-24. O’Brien JA, et al. BMC Health Serv Res. 2003;3:17-29. 96

Medical Costs Per Relapse
$243 $1847 $12,870 Low-Intensity Episode Moderate-Intensity Episode High-Intensity Episode Initial Contact Initial Contact Initial Contact Usual care physician Usual care physician Usual care physician ED ED Symptom-Related Medications IV Methylprednisolone Hospital Admission Hospital day case Post Discharge Services Home administration Outpatient follow-up Rehabilitation Home healthcare Skilled nursing Nursing home Hospital readmissions Follow-Up Office Visits Symptom-Related Medications Follow-Up Office Visits Consults Therapists ED = emergency department; IV = intravenous. O’Brien J, et al. BMC Health Serv Res. 2003;3(1):17-28.

Economic Implications
Annual cost of MS in the United States is estimated at approximately $13.6 billion (in 1994 dollars) Total lifetime direct and indirect costs per patient are estimated at approximately $2.4 million (in 1994 dollars) Mean annual direct and indirect costs per patient total an estimated $47,215 (in 2004 dollars) Mean direct healthcare costs incurred by insured patients with MS are 2 to 3 times higher than those without MS Direct correlation between cost (direct and indirect) and severity of disease has been well-established Therapeutics that modify MS activity and severity can result in both clinical and economic benefits Whetton-Goldstein K, et al. Mult Scler. 1998;4(5): Pope GC, et al. Neurology. 2002;58(1): Kobelt G, et al. Neurology. 2006;66(11): Patwardhan MB, et al. Mult Scler. 2005;11(2): O’Brien JA, et al. J Neurosurg Psychiatry. 2006;77:

MS Cost Drivers Sick Leave/Reduced Working Time (10%)
Informal Care (12%) Adaptations (5%) Services (2%) Other Drugs (6%) Early Retirement (34%) DMTs (22%) Hospital Inpatient Care (3%) Tests (2%) Ambulatory Care (4%) DMT = disease-modifying therapy. Kobelt G, et al. Neurology. 2006;66(11):

Costs of MS by Disease Severity
Informal Care Indirect Costs Direct Costs 70,000 Other Drugs DMTs 60,000 50,000 Cost ($) 40,000 30,000 20,000 10,000 Mild EDSS <4.0 Moderate EDSS Severe EDSS >6.0 All Patients DMTs = disease-modifying therapies. Kobelt G, et al. Neurology. 2006;66(11):

Approximate Mean Annual Cost*
Cost of Care Cost and functionality EDSS Score Approximate Mean Annual Cost* Medical Unpaid Caregiver Time Lost Work Time Total Mild EDSS $3,106 $932 $9,938 $13,976 Moderate EDSS $5,100 $3,188 $22,950 $31,238 Severe EDSS $12,524 $21,291 $46,339 * US Dollars Non-Drug Costs Adapted from: Kobelt G, Berg J, Atherly D et al. Neurology. 2006; 66:1696–1702.

DMT-Associated Costs Agent
Approximately 65% of annual direct per patient healthcare costs in MS are attributable to drug therapy MS drugs represent 20.2% of specialty drug expenditures within managed care plans National trend in MS drug expenditures was +18.3% in 2008 23.5% increase in manufacturer pricing was primary driver of trend Comparative AWPs of DMT options: Agent Dosage AWP/day AWP/year Interferon beta-1b 0.25 mg SC every other day $105.41 $38,475 Interferon beta-1a IM 30 mcg IM once weekly $98.66 $36,010 Interferon beta-1a SC 44 mcg SC 3 times weekly $106.20 $38,761 Glatiramer acetate 20 mg SC daily $110.10 $40,187 AWP = average wholesale price. Prescott JD, et al. J Manag Care Pharm. 2007;13(1): CuraScript 2008 Specialty Drug Trend Report. April Red Book Update. Vol. 30(1). January 2010.

MS Consensus Guidelines
National MS Society Expert Consensus Statement (2007): Initiate therapy as soon as possible following diagnosis of active-relapsing disease with an interferon beta agent or glatiramer acetate Drug therapy should also be considered in patients with first attack at high risk of MS Access to medications should not be limited by age, level of disability, or frequency of relapses Continue treatment indefinitely unless lack of benefit, intolerant adverse effects, or better treatment becomes available Ensure adequate accessibility of all FDA-approved drugs for MS Change treatments only for medically appropriate reasons National Clinical Advisory Board of the National MS Society. MS Disease Management Consensus Statement Accessed February 10, 2010.

Factors Influencing Adherence with DMT in MS
70 60 50 40 30 20 10 Fatigue Other Financial Depression Headache Weakness Flu-Like* Skin Reaction Didn’t Refill Forgot to Take* Inj Site Tired of Shots Injection Anxiety** Didn’t Feel Like It Not Sure of Benefits Dosing Inconvenient Pregnant or Planning No One Available to Give † Total *P<.05 †P<.01. Treadaway K, et al. J Neurol. 2009;256(4):

Promoting Adherence to Therapeutic Regimens in MS
Starting Therapy Educate Make a plan with the patient Reconfirm goals Schedule proper follow-up Treat relapses appropriately Treat comorbid conditions Keep channels of communication open Establishing a therapeutic relationship Educating patient and family Increased adherence to treatment Managing patient expectations Managing adverse events Addressing patient concerns Brandes DW, et al. Curr Med Res Opin. 2009;25(1): Figure 2. 105

Optimizing Treatment Outcomes in MS Patients
Patient Education Is Essential Understanding disease Clinical implications Rationale for treatment Reviewing treatment options Setting realistic goals/expectations Potential adverse effects Ways to minimize and manage adverse effects Minimizing fear and anxiety Proper injection training Recognizing relapses Tracking and reporting symptoms/relapses/adverse effects Emphasizing importance of adherence to therapy Treadaway K, et al. J Neurol. 2009;256(4):

Challenges to Adherence
Cognition and physical limitations negatively impact adherence Up to half of patients reportedly discontinue because of an AE or a lack of efficacy Association of depression carried a 3-fold risk of nonadherence Third-party reimbursement challenges Formulary status Copays Adherence tends to decrease over time due to a variety of factors, such as “treatment fatigue,” loss of motivation, and complacency Rio J, et al. Mult Scler. 2005;11: Twork et al. Curr Med Res Opin. 2007;23(6): O’Rourke KE, et al. Mult Scler. 2005;11(1): Ross AP. Neurology. 2008;71(Suppl 3):S1-S2. DiMatteo MR, et al. Arch Intern Med. 2000;160:

Recent Analyses of the Economic Impact of MS Treatment
In an analysis of an employer medical, drug and disability claims database: Baseline MS-related medical costs were higher for treated vs untreated employees ($2520 vs $1012,P < ) Risk-adjusted total annual medical costs ($4,393 vs $6,187) and indirect costs ($2,252 vs $3,053) were significantly lower (P < ) for treated vs untreated employees with MS Study limitation: lack of clinical detail on MS severity Early use of DMTs in patients with CIS that delayed conversion to CDMS provided a positive incremental cost-effectiveness ratio (ICER) per patient-year compared with no treatment (Euros 2,574.94) Birnbaum HG, et al. Curr Med Res Opin. 2009;25(4): Lazzaro C, et al. Neurol Sci. 2009;30:21-31.

Rates of Unemployment in Individuals with MS
Study Country Duration of MS Since Onset (Years) Unemployment Rate Busche et al., 2003 Canada 14.8 (median) (range 1-47) Baseline: 49.9% 2.5 years later: 59.4% Jackson and Quaal, 1991 > 5 in 80% of patients 76%* Gronning et al., 1990 Norway 10 (mean) (range 1-33 years) 72% of those with definite MS O’Connor et al., 2005 U.K. Employed: 10 (mean) Unemployed: 15 (mean) 64% Beatty et al., 1995 U.S. 15.4 (mean) 60-66% Kornblith et al., 1986 13 (mean) 80%* LaRocca et al., 1982 77% *Proportion of individuals unemployed during the study who had been employed at some time during his or her lives. Dennett SL, et al. Value Health (3):

Effect of IMT and Other Factors on Employment Loss Time
Focus: factors that influence time missed from work among individuals with MS (N = 284) Records were examined for details of medical claims Multivariate regressions were performed, controlling for demographic characteristics, type of immunomodulatory medication, and overall severity of illness Looked at total number of days missed from work for any reason and specifically due to absenteeism, short-term disability, or workers compensation Results indicate that lost work time is affected by severity of illness and type of IMT Reference Lage MJ, Castelli-Haley J, Oleen-Burkey MA. Effect of immunomodulatory therapy and other factors on employment loss time in multiple sclerosis. Work. 2006;27: Lage MJ, et al. Work. 2006;27(2): /071401

Effect of Immunomodulatory Therapy on Employment Loss Time
60 (P = .003) 50 GA INFbeta-1a 40 INFbeta-1b (P = .04) 30 (P = .09) Fewer Days Absent (P = .03) (P = .18) 20 (P = .47) (P = .71) 10 (P = .33) (P = .39) Database contained records on workplace absence, short-term disability, and worker’s compensation data for 6 Fortune 200 company employees with MS. The total days absent of untreated MS patients over the study period (3 years) gave the baseline values for comparison. Treatment usually (with the exception of short term disability with INFbeta-1b) led to fewer days absent than was seen with the untreated patients. Results: (Compared to untreated patients with MS): Glatiramer acetate short-term disability (18.24 fewer days, P<0.03) worker’s compensation (29.50 fewer days, P<0.04) any reason (53.70 fewer days, P<0.003) Interferon beta-1a short-term disability (5.37 fewer days, P<0.33) worker’s compensation (13.27 fewer days, P<0.18) any reason (20.73 fewer days, P<0.09) Interferon beta-1b short-term disability (8.77 fewer days, P<0.39) worker’s compensation (13.07 fewer days, P<0.47) any reason (8.28 fewer days, P<0.71) Reference Lage MJ, Castelli-Haley J, Oleen-Burkey MA. Effect of immunomodulatory therapy and other factors on employment loss time in multiple sclerosis. Work. 2006;27: Abstract. The factors that influence time missed from work among individuals diagnosed with multiple sclerosis were the focus of this study. Records of individuals who were employed and diagnosed with multiple sclerosis between the years 1999 and 2002 (N = 284) were examined for details pertaining to their medical claims. Multivariate regressions, controlling for demographic characteristics, type of immunomodulatory medication, and overall severity of illness, were used in the examination of the total number of days missed from work for any reason and those missed due to absenteeism, short-term disability, or worker’s compensation. Results indicate that lost work time is affected by severity of illness, and type of immunomodulatory therapy. Comparing individuals treated with the specific immunomodulator glatiramer acetate, interferon beta-1a (intramuscular), or interferon beta-1b, to those who did not receive multiple sclerosis medications of this type; only glatiramer acetate was associated with significantly fewer days missed from work for short term disability (18.24 fewer days,P <0.03), worker’s compensation (29.50 fewer days,P <0.04) or any reason (53.70 fewer days,P <0.003). -10 Short-term Disability Workers Comp Any Reason -20 Fewer days absent from work from 1999–2002 for individuals with MS treated with GA (n = 28), INFb-1a (n = 74), or INFb-1b (n = 16) compared to untreated individuals with MS (n = 166) Lage MJ, et al. Work. 2006;27(2): /071401

Specialty Pharmacy Overview
Key Disease States Managed by a Specialty Pharmacy MS, RA, Hep C, hGH, Oral Oncolytics The number of patients utilizing Specialty Pharmacies continues to increase Currently estimated to be 40% - 50% of MS patients

SP Value Proposition Compliance & Adherence Patient Education
Typically 15% - 20% higher than retail* Patient Education Specially trained on rare diseases and therapies Collaborate with manufacturers and MS Specialists to assist with training Patient Monitoring Efficacy Side effects Co-Morbid Conditions *2008 IMS Report

SP Value Proposition Data Tracking and Monitoring Compliance/Adherence
Efficacy Baseline Relapses EDSS Side Effects Flu like symptoms Injection site reactions Co-Morbidities Asthma, Hypertension, diabetes Symptom Management Fatigue, Bladder Depression Appropriate and timely interventions

Therapy OPtimization in MS (TOP MS)
An Outcomes Study of disease management (DM) for MS based in Specialty Pharmacies who have demonstrated commitment to DM: Therapy Adherence and Compliance Disease Characteristics Relapses Disability Progression Quality of Life Work / Usual Activity Productivity

Therapy OPtimization in MS (TOP MS)
Brief Outline: 3 Specialty Pharmacies ~3,000 patients followed for 2 years Patient-specific clinical reports to physicians De-identified data collected in a research-quality database will be available to address outcomes research questions

Study Population Subjects who are treated with glatiramer acetate or interferon (IFN)-β and receive their therapy from a Specialty Pharmacy: Copaxone® Avonex® Betaseron® Rebif® Extavia®

Study Objective To demonstrate the benefits of compliance and adherence to MS therapy with patient outcomes: Relapses Disability progression Quality of life Work and usual activities productivity

Advocacy Assist patients with resources and support
Assist patients with navigation of health care system and insurance coverage Speak with third-party payors to advocate for coverage for all DMTs Become involved with advocacy organizations IOMSN CMSC NMSS MSAA MSF Educational activities for professionals and patients Development of written materials Working at organizational level for FDA approvals, third-party reimbursement IOMSN = International Organization of MS Nurses; CMSC = Consortium of MS Centers; NMSS = National MS Society; MSAA = MS Association of America.

Conclusion MS is a chronic, debilitating, and progressive disease
Economic implications are significant and appear directly correlated with disease severity Although costly, long-term data and expert consensus support the primary role of DMT in managing disease progression Optimal therapeutic benefit with DMT hinges strongly on multidimensional support from the healthcare system Patient education and careful monitoring are key factors driving success in MS therapy

Challenging Cases in the Management of Multiple Sclerosis
Case Studies Challenging Cases in the Management of Multiple Sclerosis

Multiple Sclerosis Case #1
24-year-old female with diplopia on looking to the right for a day or two – Austin ophthalmologist found nothing unusual Back in Houston another ophthalmologist called it ‘some type of optic nerve inflammation’ and gave her 5 days of oral steroids 2 weeks into symptoms seen by a pro who noted skew deviation, marked asymmetric nystagmus with torsion and jerk greater to the right, no INO, no APD and normal VERs to go with complaints of vertical diplopia and oscillopsia

UPIN 4804 06/06/08

4 days later continued double vision on looking to the right Extensive past history uncovered only one week of nausea and vomiting about 4 months ago attributed to food poisoning Nystagmus to right gaze of greater amplitude in adducting eye with incomplete abduction of right eye, remaining exam normal CSF with 10 lymphocytes, IgG index 1.15 and 3 OCBs Intravenous methylprednisolone course started

UPIN 4804 07/02/08

Multiple Sclerosis Case #1 The Issues
The subject was born and raised outside of the reach of the Scandinavian gene pool - is this NMO, and how unusual is this? When you have CIS and can’t diagnose more than suspect MS by McDonald’s or Swanton’s, do you just treat, use Frohman? When asked about the familial risk of MS in the company of the patients twin sister, what is the best course?

30-year-old Caucasian female presented initially with right optic neuritis. Vision improved after high dose intravenous methylprednisolone treatment T2-weighted MRI brain scan showed 2 areas of abnormal signal in the periventricular and subcortical white matter. No disease modifying therapy was started at that time.

1 year later- numbness and weakness of both legs, urinary hesitancy, and increasing gait difficulties over several days. MRI cord -increased T2 signal at C8 with a corresponding area of Gd enhancement on T1. MRI brain- one new periventricular white matter lesion without enhancement in comparison to last year’s. Motor symptoms improved with high dose corticosteroid therapy Residual numbness in the feet and bladder control difficulties.

Given diagnosis of MS and therapy with once weekly IM interferon beta was begun. 6 months later she complained of markedly increased fatigue and “fuzzy thinking.” Brain MRI scan revealed several new T2 lesions in both cerebral hemispheres and several new enhancing lesions around the corpus callosum. Disease modifying therapy was changed to a high dose subcutaneous interferon beta.

Over the next year, she had no new symptoms and there were no new lesions seen on a repeat MRI scan. After several months she complained of balance difficulties, memory difficulties, and an increase in fatigue. MRI scan showed additional Gd+ enhancing lesions. A test for neutralizing antibody against interferon beta (NAb) revealed a titer greater than 1:100.

The same interferon treatment was continued but after several months she complained of ongoing problems with memory. Several new enhancing lesions were again found on MRI. A repeat NAb titer was unchanged.

Student nurse falls hitting head on concrete when obese patient she is transporting begins to fall off litter. MRI shows pineal cyst. 18 months later, follow-up MRI shows unchanged cyst but single periventricular non- enhancing white matter lesion. Three yearly follow-ups show no new MRI lesions, no symptoms and no neurologic abnormalities.

Is it Multiple Sclerosis?
While hiking with physician husband on hot afternoon, she notes numbness in left foot. Spinal cord MRI shows enhancing lesion at T17. Is it MS? Treatment recommendations?

New Frontiers in Neurotherapy for Multiple Sclerosis

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