Bayer Pharmaceuticals Corporation Research Articles

What We Know About Creativity

<b>Objective:</b> We sought to establish the reliability and validity of a novel composite cognitive endpoint for monitoring improvement in memory and processing speed in future drug trials. <b>Background</b> Approximately 50% of all patients with Multiple Sclerosis have clinically significant symptoms of cognitive impairment that impact their ability to work and interfere with the quality of their home life and leisure activities. FDA officials have approved composite cognitive endpoints for the study of drug interventions for Alzheimer9s (ADAS-COG) and Schizophrenia (MATRICS), but not MS. <b>Design/Methods:</b> We administered the Selective Reminding Test (SRT), Brief Visuospatial Memory Test, Revised, PASAT, and SDMT to 60 MS patients at 4 centers twice over a 45 day timespan. These measures were chosen based on their known sensitivity to MS cognitive symptoms, the availability of alternate forms and known cross-cultural utility. Norm-referenced data was used to study the test-retest reliability of each measure. A composite measure for use as an endpoint in a drug trial was constructed based on factor structure. <b>Results:</b> Test-retest reliability for individual subtests ranged from r = .62 for the SRT delayed recall trial to .88 for the SDMT. A general composite representative of performance across measures had reliability of .91. Processing Speed and Memory composite indices were r =.89 and r =.86, respectively with modest practice effects. Secondary Progressive patients performed approximately .8 standard deviations below Relapsing-Remitting patients, with the two populations demonstrating cognitive impairment with frequencies 77% and 39%, respectively. Cognitive impairment correlated reasonably well (r = .40) with Informant reports on the Multiple Sclerosis Neuropsychological Questionnaire. <b>Conclusions:</b> The novel composite endpoint is a reliable, repeatable measure of general cognitive functioning that is sensitive to cognitive impairment in both Secondary Progressive and Relapsing –Remitting MS patients. Supported by: Biogen-Idec. <b>Disclosure:</b> Dr. DeLuca has received personal compensation for activities with Kessler Foundation Research Center and Biogen Idec.Dr. DeLuca has received research support from Biogen Idec. Dr. Foley has received personal compensation for activities with Biogen Idec. Dr. Foley has received research support from Bayer Pharmaceuticals. Dr. Benedict has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Serono, Inc., Novartis, Merck &amp; Co., Inc. and Pfizer Inc as speaker, consultant and/or member on advisory panel. Dr. Benedict has received research support from Memen Pharmaceuticals, Shire Pharmaceuticals and Biogen Idec. Dr. Caruso has received personal compensation for activities with Biogen Idec as a consultant. Dr. Caruso has received research support from Biogen Idec. Dr. Erlanger has received personal compensation for activities with Biogen Idec as a consultant. Dr. Erlanger has received research support from Biogen Idec. Dr. Kaushik has received personal compensation for activities with Panmedix as a research coordinator. Dr. Kaushik has received research support from Biogen-Idec.

Clinical Outcomes and Cause of Death for Interferon Beta-1b Versus Placebo, 21 Years Following Randomization (P04.129)

Objective: To evaluate the effect of IFNB-1b 250 µg (Betaseron®/Betaferon®) on long-term clinical outcomes in patients with MS at 21 yrs after the start of randomized treatment and identify the cause of death in patients who died. Background The 21-Year Long-Term Follow-Up (21-Y LTF) study identified the vital status of 98.4% (366/372) patients who participated in the pivotal IFNB-1b trial conducted between 1988 and 1993. Design/Methods: Originally, 372 patients were randomized to receive IFNB-1b 50 µg (n=125), IFNB-1b 250 µg (n=124), or placebo (n=123) every other day. Patients remained on randomized treatment during the trial for a median of 3.8 yrs (maximum 5.1 yrs), before licensed treatment became available. Clinical status of alive patients was assessed with a questionnaire, including a validated phone-based EDSS. Among patients who died, the cause of death and MS-relationship was determined by an adjudication committee masked to treatment assignment. Results: Original randomization to IFNB-1b 250 µg showed significant reduction (46.8%) in the risk of death over the 21-Y LTF period compared with placebo (log-rank, p=0.0173); the hazard ratio was 0.532. Clinical outcomes at 21-Y LTF were similar across the treatment arms. The categorical cause of death has been determined for 82.7% of deceased patients. Of the 67 assessed causes of death, 10 were CV disease/stroke, 6 cancer, 17 pulmonary infections, 11 accidental death/suicide, 21 MS, 1 multisystem dysfunction and 1 GI bleed. 78.3% of deaths were MS-related. Conclusions: With near-complete patient ascertainment (98.4%), an initial randomized control trial design, and the longest period of follow-up for a treatment-exposed MS population, these data provide insight into both the effects of IFNB-1b on survival/mortality in patients with MS and long-term clinical outcomes. The difference in mortality between placebo and active treatment appears to be MS-related. Also, cause of death due to pulmonary infections was more frequent in placebo compared to active treatment. Supported by: Bayer HealthCare Pharmaceuticals, Inc. Disclosure: Dr. Reder has received personal compensation from Abbott Laboratories, Immunoscience, Parsippany, NJ, American Medical Association, Astra Merck, Athena Neurosciences, Aventis Pharma, and Bayer.Dr. Reder has received personal compensation in an editorial capacity for Medlink/Neurobase electronic journal. Dr. Goodin has received personal compensation for activities with Merck Serono, Novartis, Berlex Laboratories, Bayer Pharmaceuticals Corporation, Biogen Idec, Schering AG and Teva Neuroscience as speaker, consultant and participant in clinical trials. Dr. Goodin has received research support from Novartis. Dr. Ebers has received personal compensation for activities with Bayer HealthCare Pharmaceuticals as a consultant. Dr. Cutter has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Cleveland Clinic, Daiichi Pharmaceutical Corporation, GlaxoSmithKline, Inc., Genmab Biopharmaceuticals, Eli Lilly & Company, Medivation, Modigenetech, Ono Pharmaceutical, PTC Therapeutics, Teva Neuroscience, Vivus, University of Pennsylvania, NHLBI, NINDS, NMSS, Alexion, Bayhill Therapeutics, Bayer Pharmaceuticals Corporation, Celgene, Novartis, Consortium of MS Centers, Genzyme Corporation, Klein-Buendel Incorporated, Nuron Biotech, Peptimmune, Somnus Pharmaceuticals, Sandoz, University of Texas Southwestern and Visioneering Technologies, Inc. Dr. Cutter has received compensation for serving on the board of Pythagoras, INC. Dr. Cutter has received research support from various pharmaceutical corporations. Dr. Kremenchutzky has received personal compensation for activities with MS Society of Canada, the End MS Research and Training Network, the Research Scientific Foundation of the MS Society of Canada, and the Canadian Institute of Health Research, Bayer Pharmaceuticals, Biogen Idec, Serono, Inc., Genzyme Corporation, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience as a speaker, researcher and/or consultant. Dr. Kremenchutzky has received research support from MS Society of Canada, Bayer Pharmaceuticals Corporation, Biogen Idec, Serono, Inc., Teva Neuroscience, Genetech, Inc., and Novartis. Dr. Oger has received personal compensation for activities with Aspreva, Sanofi-Aventis Pharmaceuticals, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec, EMD Serono, Genentech, Inc., Schering, Talecris, and Teva Neuroscience. Dr. Oger has received research support to his University to use Biacore to evaluate neutralizing antibodies to interferon. Dr. Langdon has received personal compensation for activities with Bayer Schering Pharma, AG/Bayer HealthCare Pharmaceuticals, Biogen, Hoffman La Roche, Merck Serono, Novartis, Sanofi-Aventis and Serono Symposia.Dr. Langdon has received research support from Bayer HealthCare, Merck Serono and Novartis. Mr. Rametta has received personal compensation for activities with Bayer Health Care Pharmaceuticals as an employee. Dr. Beckmann has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Knappertz has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee.

Long-Term Safety and Efficacy and Association between Baseline Treatment History and Postbaseline Relapses in Multiple Sclerosis Patients Treated with Natalizumab in the TYSABRI(R) Observational Program (TOP) (P04.134)

Objective: Evaluate long-term safety, efficacy, and associations between baseline treatment history and postbaseline annualized relapse rate (ARR) in multiple sclerosis (MS) patients treated with natalizumab. Background The ongoing natalizumab (TYSABRI®) Observational Program (TOP) study is an open-label, multinational, observational study assessing long-term outcomes in relapsing-remitting MS patients in the postmarketing setting in Europe, Australia, and Canada. Design/Methods: As of June 2011, 3484 patients from 15 countries were enrolled. Incidence of serious adverse events (SAEs) was analyzed. ARR and Expanded Disability Status Scale (EDSS) scores were assessed. Associations between baseline therapy and postbaseline ARR were analyzed using negative binomial regression for 5 baseline groups: therapy naive (n=337), interferon (IFN) only (n=1626), glatiramer acetate (GA) only (n=288), switched between GA and IFN in either order (n=595), or immunosuppressant (IS) use (n=487). Results: - 53]) natalizumab infusions. Overall, 5.1% of patients experienced ≥1 SAE; infections (1.1%) and hypersensitivity reactions (0.7%) were most frequent. Seven cases of progressive multifocal leukoencephalopathy (PML) occurred after 35, 29, 28, 26, 24, 24, and 12 natalizumab infusions. Three of them were previously exposed to mitoxantrone. Overall, the mean EDSS score was 3.5 at baseline and 3.4 after 3 years. ARR was significantly decreased regardless of baseline treatment history; mean ARR decreased (n=3458) from baseline (1.98) to postbaseline (0.28; P Conclusions: The overall incidence and type of SAEs reported in TOP are consistent with natalizumab9s known safety profile. EDSS scores were stable and ARR was significantly reduced after 3 years of natalizumab therapy. ARRs were lowest in therapy-naive patients and highest in patients with prior IS. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Disclosure: Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Belachew has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Merck Serono as a consultant. Dr. Belachew has received research support from Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Butzkueven has received personal compensation for activities with Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., National Health and Medical Research Council, and National MS Society. Dr. Butzkueven has received personal compensation in an editorial capacity for Multiple Sclerosis International Federation and Multiple Sclerosis. Dr Butzkueven has received research support from Biogen Idec, Merck Serono, and Novartis. Dr. Pellegrini has received personal compensation for activities with Biogen Idec as a consultant. Dr. Trojano has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Sanofi-Aventis Pharmaceuticals, Inc. as a consultant and/or speaker. Dr. Trojano has received research support from Merck & Co., Inc. Dr. Wiendl has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Wiendl has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Medac, Merck-Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Hotermans has received personal compensation for activities with Biogen Idec as an employee.Dr. Hotermans holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hotermans was involved as an investigator.

Assessment of Baseline Characteristics, Treatment Efficacy, and Serious Adverse Events among Natalizumab-Treated MS Patients without Prior Treatment (P06.172)

Objective: Evaluate geographic region, enrollment time, baseline characteristics, postbaseline efficacy, and safety in natalizumab-treated multiple sclerosis (MS) patients with and without prior treatment. Background The ongoing natalizumab (TYSABRI®) Observational Program (TOP) assesses long-term outcomes in natalizumab-treated patients with relapsing-remitting MS in Europe, Australia, and Canada. Design/Methods: Baseline characteristics of treatment-naive and previously treated patients were compared. The association between prior treatment status and postbaseline annualized relapse rates (ARRs) was examined using a negative binomial regression model. Time to improvement on the Expanded Disability Status Scale (EDSS) was analyzed using a Cox proportional hazards model. Serious adverse events (SAEs) were compared using a Pearson chi-square or Fisher exact test. Results: As of June 1, 2011, 337 of 3484 natalizumab-treated patients (10%) had been treatment naive before natalizumab treatment. Proportions of treatment-naive patients varied significantly by country (Slovakia, 0%; Great Britain, 36%) and time since enrollment (0–12 months, 12%; 13–24 months, 7%; >24 months, 9%). Baseline differences between treatment-naive and previously treated patients included mean age (35.8 vs 37.6 years), median disease duration (1.9 vs 7.8 years), and median EDSS score (3.0 vs 3.5) (all P ≤0.013). Treatment-naive patients had a lower postbaseline ARR (0.18 vs 0.26; P =0.002) and were more likely to show improvement in EDSS at 3 years (HR [95% confidence interval]=1.59 [1.14–2.22]; P =0.007). Treatment-naive and previously treated groups did not significantly differ in incidence of SAEs (4.2% vs 5.2%; P =0.340), infection-related SAEs (0.9% vs 1.2%; P =0.640), or progressive multifocal leukoencephalopathy (0.0% vs 0.2%; P =1.00). Conclusions: Treatment-naive patients were younger than previously treated patients, had shorter disease duration and lower baseline EDSS, were more likely to show EDSS improvement, and differed significantly in geographic distribution and enrollment time. While relapses decreased in both groups, postbaseline ARR was significantly lower in treatment-naive patient, whereas SAE incidence was similar. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Disclosure: Dr. Butzkueven has received personal compensation for activities with Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., National Health and Medical Research Council, and National MS Society. Dr. Butzkueven has received personal compensation in an editorial capacity for Multiple Sclerosis International Federation and Multiple Sclerosis. Dr Butzkueven has received research support from Biogen Idec, Merck Serono, and Novartis. Dr. Belachew has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Merck Serono as a consultant. Dr. Belachew has received research support from Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Pellegrini has received personal compensation for activities with Biogen Idec as a consultant. Dr. Trojano has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Sanofi-Aventis Pharmaceuticals, Inc. as a consultant and/or speaker. Dr. Trojano has received research support from Merck & Co., Inc. Dr. Wiendl has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Wiendl has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Medac, Merck-Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Hotermans has received personal compensation for activities with Biogen Idec as an employee.Dr. Hotermans holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hotermans was involved as an investigator.

Relapse Outcomes with Alemtuzumab vs. Rebif(R) in Treatment-Naive Relapsing-Remitting Multiple Sclerosis (CARE-MS I): Secondary and Tertiary Endpoints (PD5.004)

Objective: Compare alemtuzumab and subcutaneous interferon beta-1a (IFNB-1a) on relapse outcomes from a phase 3 trial in patients with relapsing-remitting multiple sclerosis (RRMS). Background Over 2 years, alemtuzumab reduced the rate of relapse by 55% compared with IFNB-1a (p Design/Methods: CARE-MS I was a 2-year, randomized, rater-blinded, global trial comparing the efficacy and safety of alemtuzumab to subcutaneous IFNB-1a in active, treatment-naive RRMS patients. Alemtuzumab treatment was 12mg/day intravenously for 5 days at study start and 3 days one year later. IFNB-1a treatment was 44mcg SC 3-times weekly for 24 months. Relapse rate was a co-primary endpoint. Relapse events were required to last at least 48 hours, required objective signs on exam as assessed by blinded raters, and were adjudicated by an independent relapse adjudication committee. Results: Annualized relapse rate was 0.18 (95% CI: 0.13, 0.23) for alemtuzumab-treated patients compared with 0.39 (95% CI: 0.29, 0.53) for IFNB-1a-treated patients (55% reduction, p Conclusions: Alemtuzumab significantly reduces relapses in RRMS patients compared with high-dose, high-frequency IFNB-1a. These results suggest the potential for alemtuzumab to be a meaningful addition to treatment options for RRMS, if approved. Supported by: Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals. Disclosure: Dr. Fox has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, EMD Serono, Genzyme Corporation, Novartis, Opexa Therapeutics, Pfizer Inc, and Teva Neuroscience. Dr. Fox has received personal compensation in an editorial capacity for Neura. Dr. Fox has received research support from Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, Novartis, Ono Pharmaceutical, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Brinar has nothing to disclose. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Coles has received personal compensation for activities with Genzyme Corporation, GlaxoSmithKline, Inc., and Merck Serono as a consultant and/or speaker. Dr. Coles has received research support from Genzyme Corportation. Dr. Confavruex has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavruex has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Stojanovic has nothing to disclose. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neurosciences, GlaxoSmithKline, Nasvax, Xenoport and Genzyme Corporation as consulting and/or speaking activities. Dr. Weiner has received research support from Merck Serono. Dr. Lake has received personal compensation for activities with Genzyme as an employee. Dr. Margolin has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Panzara has received personal compensation for activities with Biogen Idec as an employee.Dr. Panzara holds stock and/or stock options in Biogen Idec. Dr. Compston has received personal compensation for activities with Genzyme Corporation as a speaker. Dr. Compston has received research support from Genzyme Corporation.

Teriflunomide Increases the Proportion of Patients Free from Disease Activity in the TEMSO Phase III Study (PD5.007)

Objective: To determine the effect of teriflunomide in reducing the risk of a composite endpoint of disease activity in patients with relapsing forms of MS (RMS) over a 2-year period in TEMSO (NCT00134563). Background Teriflunomide is a novel oral disease-modifying therapy in development for the treatment of RMS. Teriflunomide reduced the annualized relapse rate, the risk of 12-week confirmed disability progression and MRI activity in a dose-dependent fashion in TEMSO. Design/Methods: TEMSO randomized 1088 RMS patients (mean age: 38 years; mean Expanded Disability Status Scale [EDSS] score: ≤5.5; mean number of relapses within past 2 years: 2.2) to placebo (N=363), teriflunomide, 7 mg (N=366) or 14 mg (N=359), once-daily for 108 weeks. This post hoc analysis evaluated time to disease activity (clinical relapse, 12-week sustained disability progression, or new unique active lesions (new T1 gadolinium-enhancing and new/enlarged T2 lesions) using a log-rank test with treatment group as the test variable and region and baseline EDSS strata as stratification factors. Hazard ratios for teriflunomide versus placebo were estimated using a Cox regression model. Results: Both teriflunomide doses reduced the risk of disease activity compared with placebo (p=0.0002 and p=0.0293, for 14 mg and 7 mg respectively). A total of 82 [22.9%], 67 [18.4%] and 52 [14.3%] patients remained disease free for teriflunomide 14 mg, 7 mg and placebo, respectively. Hazard ratios (95% confidence intervals) were 0.726 (0.617, 0.855) for 14 mg and 0.834 (0.711, 0.978) for 7 mg versus placebo. The respective proportions of patients free from clinical disease were 189 (52.8%), 180 (49.3%) and 156 (43.0%), and from new MRI activity were 144 (40.2%), 117 (32.1%) and 89 (24.5%). Conclusions: Teriflunomide treatment led to nearly twice as many patients being free from all measured clinical and MRI disease activity, with a trend, as in the core study, favoring the 14 mg dose. Supported by: sanofi-aventis. Disclosure: Dr. Freedman has received personal compensation for activities with Bayer Healthcare, Genzyme Corporation, EMD Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Freedman has received research support from Genzyme Corporation and Bayer Healthcare. Dr. O9Connor has received personal compensation for activities with Abbott Labratories, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceuticals Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals as a consultant. Dr. O9Connor has received research support from Abbott Labratories, Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceutical Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals. Dr. Wolinsky has received personal compensation for activities with Astellas, Bayer Pharmaceuticals Corporation, Bayer Multiple Sclerosis Council, Celgene Corporation, Eli Lilly & Company, Roche Diagnostics Corporation, Novartis, Sanofi-Aventis Pharmaceuticals and Teva Neuroscience as consultant and participant on monitoring and advisory boards. Dr. Wolinsky has received (royalty or license fee or contractual rights) payments from University of Texas Health Science Center at Houston. Dr. Wolinsky has received research support from Sanofi-Aventis Pharmaceuticals, Inc. Dr. Confavruex has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavruex has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Olsson has received personal compensation for activities with Biogen Idec, Merck & Co., Inc., Sanofi-Aventis Pharmaceuticals, Inc., Novartis, and Bayer Healthcare. Dr. Olsson has received research support from Biogen Idec, Merck & Co., Inc., Sanofi-Aventis Pharmaceuticals, Inc., Novartis and Bayer Healthcare. Dr. Truffinet has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc. Dr. Dukovic has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals as an employee. Dr. Miller has received personal compensation for activities with Acordia Therapeutics, Avanir, Biogen Idec, Chelsea Therapeutics, EMD Serono, GlaxoSmithKline, La-Ser, Merck Serono, Novartis, Nuron BiotechONO, Pfizer, Sanofi-Aventis, and Teva Neuroscience. Dr. Miller has received personal compensation in an editorial capacity for Continuum and Real Living with Multiple Sclerosis. Dr. Miller has received research support from Acorda, Biogen Idec, Genentech, Genzyme, Novartis, Roche, Sanofi-Aventis, and Teva Neuroscience.

Efficacy and Safety Results from Comparison of Alemtuzumab and Rebif(R) Efficacy in Multiple Sclerosis I (CARE-MS I): A Phase 3 Study in Relapsing-Remitting Treatment-Naive Patients (S01.006)

Objective: Compare alemtuzumab and interferon beta-1a (IFNB-1a) on top-line clinical efficacy and safety outcomes in the phase 3 pivotal study: CARE-MS I. Background Alemtuzumab is an anti-CD52 humanized monoclonal antibody that alters the circulating lymphocyte pool. Design/Methods: CARE-MS I was a 2-year, randomized, rater-blinded, active-comparator, trial comparing alemtuzumab to IFNB-1a in active, treatment-naive relapsing-remitting MS (RRMS) patients. Alemtuzumab treatment was 12mg/day iv for 5 days at study start and 3 days one year later. IFNB-1a treatment was 44 mcg SC 3-times weekly for 24 months. Primary efficacy endpoints were relapse rate and time to 6-month sustained accumulation of disability (SAD). Results: 581 patients from 98 centers in 16 countries were randomized 2:1 to alemtuzumab or IFNB-1a. Mean age was 33; mean EDSS was 2; mean time since first episode was 2 years. Alemtuzumab reduced relapse rate by 55% compared to IFNB-1a (p Conclusions: Alemtuzumab significantly reduces the relapse rate in RRMS patients compared to an active comparator. Effect on disability accumulation was not significantly different, possibly due to the very low incidence of disability accumulation in the sample overall. The safety profile for alemtuzumab was consistent with previous studies. These results suggest the potential for alemtuzumab to be a meaningful addition to treatment options for RRMS, if approved. Supported by: Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals. Disclosure: Dr. Coles has received personal compensation for activities with Genzyme Corporation, GlaxoSmithKline, Inc., and Merck Serono as a consultant and/or speaker. Dr. Coles has received research support from Genzyme Corportation. Dr. Brinar has nothing to disclose. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Confavruex has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavruex has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Fox has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, EMD Serono, Genzyme Corporation, Novartis, Opexa Therapeutics, Pfizer Inc, and Teva Neuroscience. Dr. Fox has received personal compensation in an editorial capacity for Neura. Dr. Fox has received research support from Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, Novartis, Ono Pharmaceutical, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neurosciences, GlaxoSmithKline, Nasvax, Xenoport and Genzyme Corporation as consulting and/or speaking activities. Dr. Weiner has received research support from Merck Serono. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Stojanovic has nothing to disclose. Dr. Lake has received personal compensation for activities with Genzyme as an employee. Dr. Margolin has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Panzara has received personal compensation for activities with Biogen Idec as an employee.Dr. Panzara holds stock and/or stock options in Biogen Idec. Dr. Compston has received personal compensation for activities with Genzyme Corporation as a speaker. Dr. Compston has received research support from Genzyme Corporation.

BG-12 Increases the Proportion of Patients Free of Clinical and Radiologic Disease Activity in Relapsing-Remitting Multiple Sclerosis: Findings from the DEFINE Study (PD5.005)

Objective: To evaluate the impact of BG-12 (dimethyl fumarate) on the proportion of patients with relapsing-remitting multiple sclerosis (RRMS) who were free of clinical or magnetic resonance imaging (MRI) disease activity in the Phase 3 DEFINE study. Background DEFINE was a 2-year randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of BG-12 in patients with RRMS. In DEFINE, BG-12 significantly reduced clinical relapses, disability progression, and MRI measures of disease activity. Design/Methods: Patients aged 18-55 years with a diagnosis of RRMS and an Expanded Disability Status Scale (EDSS) score of 0.0-5.0 were included in the study. Patients were randomly assigned 1:1:1 to placebo, BG-12 240 mg twice daily (BID) or three times daily (TID). In the current analysis, absence of disease activity over 2 years was analyzed as follows: clinical (no relapses or EDSS progression), radiologic (no new or newly enlarging T2 lesions and gadolinium-enhancing lesions), and overall (no clinical and radiologic disease activity). Analyses of disease-free measures were performed on the MRI cohort using a chi-square test and logistic regression model. Results: The analysis included 469 patients with MRI measures. The proportion of disease-free patients over 2 years was significantly higher in both BG-12 treatment groups versus placebo: clinical (BID 63% and TID 59% vs placebo 39%; P P P Conclusions: Findings from this subset analysis of DEFINE indicate that BG-12 demonstrated a significant treatment effect on clinical, radiologic, and overall disease-free activity compared with placebo over 2 years in patients with RRMS. Supported by: Biogen Idec Inc. Disclosure: Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Sheikh has received personal compensation for activities with Biogen Idec as an employee. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Subcutaneous Interferon -1a in Children and Adolescents with Multiple Sclerosis: An International Retrospective Study of 307 Patients (P04.119)

Objective: To review the safety, tolerability, and efficacy of subcutaneous interferon β-1a (sc IFN β-1a) in children and adolescents with multiple sclerosis (MS). Background 3–10% of patients with MS present before 16 years; Design/Methods: A multi-regional retrospective cohort study of patients who received ≥1 injection of sc IFN β-1a for demyelinating events before age of 18 years. A patient9s 9observation period9 began with the first medical record available until “lost to follow-up” or 31 December 2009, whichever occurred first. Outcomes included safety medical events (MEs) and laboratory parameters occurring after treatment initiation; clinical attacks and Expanded Disability Status Scale (EDSS) scores were collected. Results: Data from 307 patients were analyzed; mean age at treatment initiation: 14.0 years, with 52 patients (16.9%) aged Conclusions: Most children ( Supported by: Merck Serono S.A. – Geneva, Switzerland, a branch of Merck Serono SA, Coinsins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany. Disclosure: Dr. Pohl has received personal compensation for activities with Bayer Schering, Merck Serono and Teva. Dr. Banwell has received personal compensation for activities with Merck-Serono, Biogen-IDEC, Bayer Pharmaceuticals Corporation, Genzyme Corporation and Teva Neuroscience as a speaker and or advisor. Dr. Ghezzi has received personal compensation for activities with Biogen Idec, Bayer Pharmaceuticals Corporation and Sanofi-Aventis Pharmaceuticals, Inc. as a speaker. Dr. Krupp has received personal compensation for activities with Teva Neuroscience, BiogenIdec, Serono, Inc., Bayer Pharmaceuticals Corporation, Guidepoint Global, Pfizer Inc, Axon Advisors, Sanofi-Aventis Pharmaceuticals, Inc., as a speaker, consultant and/or participant on an advisory board. Dr. Krupp has received (royalty or license fee or contractual rights) payments from Genzyme Corporation, Bristol-Myers Squibb Company, MedImmune, and Novartis. Dr. Krupp has received research support from Serono Inc. and Biogen Idec. Dr. Boyko has received personal compensation for activities with Novartis, Merck Serono, TEVA, Gensyme, Biogen Idec, Nicomed as a member of advisory boards, a speaker and a participant of clinical trials. Dr. Meinel has received personal compensation for activities with Novartis as an employee. Dr. Rocak has received personal compensation for activities with Merck Serono S.A. as an employee. Dr. Margaretha Stam Moraga has received personal compensation for activities with Merck Serono S.A. as an employee. Dr. Tenembaum has received personal compensation for activities with Genzyme Corporation, Bayer Pharmaceuticals Corporation, Teva Neuroscience, Merck Serono and Biogen Idec as a consultant and/or speaker. Dr. Tenembaum has received research support from Merck Serono.

Effect of Teriflunomide on Relapses with Sequelae and Relapse Leading to Hospitalization in a Population with Relapsing Forms of Multiple Sclerosis: Results from the TEMSO Study (S30.003)

Objective: To assess whether teriflunomide reduces the occurrence of relapses with sequelae and relapses leading to hospitalization. Background Incomplete recovery from relapses leads to some degree of disability. Teriflunomide is a novel oral disease-modifying therapy in development for the treatment of RMS. The TEriflunomide Multiple Sclerosis Oral (TEMSO) study showed that teriflunomide reduced the annualized relapse rate by over 30% (p Design/Methods: TEMSO was a 2-year, randomized, double-blind study that assessed the efficacy and safety of teriflunomide 7mg and 14mg in patients with relapsing forms of MS (RMS) (N=1088); a typical patient was 38 years old, had experienced MS symptoms for over 8 years and 2.2 relapses within the past 2 years. Relapse with sequelae (investigator-defined) and relapse leading to hospitalization were analyzed (post hoc) on the intention-to-treat population (N=1086). Annualized rates were derived using a Poisson model, with treatment, Expanded Disability Status Scale (EDSS) score strata at baseline and region as covariates. The risks of sequelae and of hospitalization per relapse were calculated as a raw percentage observed over the study and compared with a Chi-square test. Results: Teriflunomide reduced the annualized rate of relapses with sequelae by 25% (ns) with 7mg and 53% (p Conclusions: In addition to its efficacy on overall relapse rates, teriflunomide significantly reduced the occurrence of relapses leading to hospitalization. Teriflunomide 14mg also significantly reduced the occurrence of relapses with sequelae, the risks of sequelae and of hospitalization per relapse. These benefits may suggest an effect on relapse severity. Supported by: sanofi-aventis. Disclosure: Dr. Miller has received personal compensation for activities with Acordia Therapeutics, Avanir, Biogen Idec, Chelsea Therapeutics, EMD Serono, GlaxoSmithKline, La-Ser, Merck Serono, Novartis, Nuron BiotechONO, Pfizer, Sanofi-Aventis, and Teva Neuroscience. Dr. Miller has received personal compensation in an editorial capacity for Continuum and Real Living with Multiple Sclerosis. Dr. Miller has received research support from Acorda, Biogen Idec, Genentech, Genzyme, Novartis, Roche, Sanofi-Aventis, and Teva Neuroscience. Dr. Lublin has received personal compensation for activities with Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Novartis, Pfizer, Teva Neuroscience, Genmab, Medicinova, Actelion, Allozyne, Sanofi, Acorda, Questcor, Avanir, Roche, Celgene, Abbott, MorphoSys, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, and MedImmune as a consultant.Dr. Lublin has received personal compensation in an editorial capacity for Elsevier: Multiple Sclerosis and Related Diseases. Dr. O9Connor has received personal compensation for activities with Abbott Labratories, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceuticals Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals as a consultant. Dr. O9Connor has received research support from Abbott Labratories, Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceutical Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals. Dr. Wolinsky has received personal compensation for activities with Astellas, Bayer Pharmaceuticals Corporation, Bayer Multiple Sclerosis Council, Celgene Corporation, Eli Lilly & Company, Roche Diagnostics Corporation, Novartis, Sanofi-Aventis Pharmaceuticals and Teva Neuroscience as consultant and participant on monitoring and advisory boards. Dr. Wolinsky has received (royalty or license fee or contractual rights) payments from University of Texas Health Science Center at Houston. Dr. Wolinsky has received research support from Sanofi-Aventis Pharmaceuticals, Inc. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Freedman has received personal compensation for activities with Bayer Healthcare, Genzyme Corporation, EMD Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Freedman has received research support from Genzyme Corporation and Bayer Healthcare. Dr. Olsson has received personal compensation for activities with Biogen Idec, Merck & Co., Inc., Sanofi-Aventis Pharmaceuticals, Inc., Novartis, and Bayer Healthcare. Dr. Olsson has received research support from Biogen Idec, Merck & Co., Inc., Sanofi-Aventis Pharmaceuticals, Inc., Novartis and Bayer Healthcare. Ms. Dive-Pouletty has received personal compensation for activities with Sanofi-Aventis. Dr. Bego-Le-Bagousse has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc. as an employee. Dr. Confavruex has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavruex has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience.

Effect of BG-12 in Subgroups of Patients with Relapsing-Remitting Multiple Sclerosis: Findings from the DEFINE Study (P01.130)

Objective: To assess the efficacy of BG-12 in subgroups of patients from the Phase 3 DEFINE study. Background BG-12 is an experimental oral treatment for relapsing-remitting multiple sclerosis (RRMS) that may have anti-inflammatory and neuroprotective effects via the Nrf2 pathway. DEFINE, a randomized, double-blind, placebo-controlled, multicenter study evaluating BG-12 over 2 years in patients with RRMS, showed significant reductions in clinical relapses, accumulation of disability progression, and disease activity on magnetic resonance imaging scans. Design/Methods: Patients 18-55 years with RRMS (McDonald criteria) and an Expanded Disability Status Scale score of 0.0-5.0 were randomized to placebo, BG-12 240 mg twice daily (BID), or BG-12 240 mg three times daily (TID). Subgroup analyses were based on baseline demographic and disease characteristics, including age, relapses in year prior to study entry (≤1 versus ≥2 relapses), prior MS treatment (yes/no), baseline EDSS score (≤ or >2.0), and others. Effects of BG-12 on primary efficacy endpoint and secondary clinical endpoints at 2 years were evaluated. Results: Both doses of BG-12 demonstrated consistent benefits on relapse and disability progression across all subgroups over 2 years. For instance, in patients who had ≤1 relapse in the year prior to study entry, the hazard ratio (HR [95% CI]) for risk of relapse over 2 years was 0.52 [0.38-0.71] for BG-12 BID and 0.51 [0.37-0.70] for BG-12 TID, representing reductions relative to placebo of 48% and 49%, respectively, whereas in patients who had ≥2 relapses in the year prior to study entry, reductions were 49% (0.51 [0.34-0.77]) and 51% (0.49 [0.32-0.74]). Likewise, both BG-12 doses demonstrated positive benefits on annualized relapse rate and disability progression regardless of the number of relapse in the year prior to study entry. Conclusions: BG-12 treatment resulted in reduction of clinical activity across RRMS patients with varied demographic and disease subgroups. Supported by: Biogen Idec Inc. Disclosure: Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. O9Gorman has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received research support from Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Effect of BG-12 on Brain Atrophy and Lesions Volume: MRI Results from the DEFINE Study during First and Second Year of Treatment (IN3-2.002)

Objective: To report results of BG-12 on tertiary magnetic resonance imaging (MRI)-related outcomes from the Phase 3 DEFINE study. Background BG-12 is an experimental oral treatment for relapsing-remitting multiple sclerosis (RRMS) that may have anti-inflammatory and neuroprotective effects via the Nrf2 pathway. DEFINE, a randomized, double-blind, placebo-controlled study evaluating BG-12 over 2 years in RRMS patients, showed significant reductions in clinical relapses, accumulation of disability progression, and number of lesions on brain MRI images. Design/Methods: Patients aged 18-55 years with RRMS (McDonald criteria) and EDSS score of 0.0-5.0 were enrolled. Patients were randomized 1:1:1 to placebo or BG-12 240 mg twice (BID) or three times daily (TID). A subset of patients from 76 sites had MRI scans at baseline, 24 weeks, 1 year, and 2 years. Tertiary endpoints included brain atrophy from 6 months to 2 years measured using the SIENA method and the volume of T2, gadolinium-enhancing (Gd+), and T1 hypointense lesions at 1 and 2 years. Results: The MRI intent-to-treat cohort comprised 540 patients. The median percent whole brain volume change from 6 months to 2 years was -0.660% in placebo compared with -0.460% and -0.550% in the BG-12 BID and TID groups, respectively, representing reductions of 30% (P=0.0214) and 17% (P=0.2478) versus placebo. Over 2 years, the median percent change of T2 hyperintense lesion volume from baseline was 20.1% with placebo versus -6.2% (P Conclusions: Results of the MRI analysis of the DEFINE study demonstrate reduced brain atrophy and lesion volume compared with placebo and supports BG-129s potential as an effective oral treatment for RRMS patients. Supported by: Biogen Idec Inc. Disclosure: Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received research support from Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

BAF312, a Selective Sphingosine-1-Phosphate Receptor Modulator Improves MRI and Clinical Outcomes in Relapsing-Remitting Multiple Sclerosis (RRMS) (S30.001)

Objective: To report relapse data and MRI findings from a double-blind, placebo-controlled, adaptive design phase II dose-finding study of BAF312 in patients with RRMS. Background BAF312, a next generation selective sphingosine-1-phosphate receptor (S1PR-1/5) modulator, significantly reduces MRI lesion activity in RRMS, and has demonstrated a 3-month dose-MRI response curve 1 . Here we report 6-month relapse data. Design/Methods: Patients were randomized to two sequential cohorts: Cohort 1 (n=188), received once-daily BAF312 10mg, 2mg, 0.5mg or placebo for 6mo; Cohort 2 (n=109), 1.25mg, 0.25mg (doses selected following Cohort 1 interim analysis) or placebo for 3mo. Brain MRI was performed monthly. Patients completing the core study were eligible for the extension study. Annualized relapse rate (ARR), calculated from confirmed relapses in 6mo, was analyzed post-hoc: Cohort 1 (6mo core data), Cohort 2 (3mo core plus 3mo extension data). Results: At 6mo, adjusted proportion of relapse-free patients (Cohort 1 only), was 84%, 92% and 77% for BAF312 10mg, 2mg and 0.5mg, respectively, vs 72% for placebo (p=0.014 for BAF312 2mg vs placebo). In the 6mo post-hoc analysis, ARR was lower with BAF312 10mg, 2mg, and 1.25mg (0.30, 0.20, 0.23, respectively) compared to BAF312 0.5mg, 0.25mg and placebo (0.61, 0.55, and 0.58, respectively). BAF312 three highest doses resulted in 48%-66% ARR reduction over placebo (p=0.044 for 2mg vs placebo). A significant dose-response relationship at 3mo was previously demonstrated (p=0.0001) 1 . The MRI dose-response curve estimated at 3mo indicated near-maximal efficacy at 2mg and submaximal efficacy at 0.5mg (∼50% reduction vs placebo). BAF312 reduced brain MRI lesion numbers up to 80% vs placebo. Most frequent adverse events were headache, bradycardia, dizziness and nasopharyngitis; highest in BAF312 10mg. Conclusions: BAF312 1.25-10mg reduces relapses in RRMS, correlating with MRI efficacy estimated from the 3mo dose-response curve. Overall safety and tolerability was favorable. Reference 1. Selmaj et al. ECTRIMS 2011. Supported by: Novartis-sponsored. Disclosure: Dr. Stuve has received personal compensation for activities with Teva Neuroscience, Novartis, Roche, Genzyme, EMD Serono, and Sanofi-Aventis. Dr. Stuve has received personal compensation in an editorial capacity for Archives of Neurology. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Li has received personal compensation for activities with Genzyme, Novartis and Nuron as a consultant.Dr. Li has receved research support from Angiotech, Bayer, Berlex-Schering, Bio-MS, Boehringer-Ingelheim, Centocor, Daiichi Sankyo, Genentech, Hoffmann-LaRoche, Merck-Serono, Perceptives, Schering-Plough, Teva Neurosciences,Sanofi-Aventis, Transition Therapeutics, and Novartis. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Hemmer has received personal compensation for activities with Hoffmann la Roche, Merck Serono, Biogen Idec, Novartis, Micromet and Bayer Pharmaceuticals Corporation as scientific advisor and speaker. Dr. Hemmer has received research support from Novartis, Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Freedman has received personal compensation for activities with Bayer Healthcare, Genzyme Corporation, EMD Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Freedman has received research support from Genzyme Corporation and Bayer Healthcare. Dr. Rieckmann has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Boehringer-Ingelheim, Novartis, Merck-Serono, TEVA, and Sanofi-Aventis as a speaker. Dr. Montalban has received personal compensation for activities with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Montalban has received research support from Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Zhang-Auberson has received personal compensation for activities with Novartis as an employee. Dr. Pohlmann has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Mercier has received personal compensation for activities with Novartis as an employee. Dr. Dahlke has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Wallstrom has received personal compensation for activities with Novartis as an employee. Dr. Wallstrom holds stock and/or stock options in Novartis.

RESTORE Study: Effects of a 24-Week Natalizumab Treatment Interruption on Immune Parameters and Multiple Sclerosis Magnetic Resonance Imaging Disease Activity (P06.168)

RESTORE Study: Effects of a 24-Week Natalizumab Treatment Interruption on Immune Parameters and Multiple Sclerosis Magnetic Resonance Imaging Disease Activity (P06.168)

Effects of BG-12 on Magnetization Transfer Ratio in Whole Brain and Normal-Appearing Brain Tissue: Findings from the DEFINE Study (S11.004)

Objective: To report the BG-12 effects on magnetization transfer ratio (MTR) in the Phase 3 DEFINE study. Background Brain MTR measurements are considered to be sensitive to changes in myelin and axonal content, with increases reflecting higher concentrations of myelin and axons. DEFINE examined MTR changes with BG-12 treatment in the magnetic resonance imaging cohort. Design/Methods: DEFINE was a randomized, double-blind, placebo-controlled study evaluating BG-12 over 2 years in relapsing-remitting multiple sclerosis (RRMS). Patients aged 18-55 years with RRMS (McDonald criteria) and an Expanded Disability Status Scale score of 0.0-5.0 were randomized 1:1:1 to placebo or BG-12 240 mg twice (BID) or three times daily (TID). MTR was analyzed in whole brain (WB) and normal-appearing brain tissue (NABT) at baseline, 1, and 2 years. Results: MTR analysis included 392 patients. In WB, mean percentage change from baseline at 2 years in median MTR was -0.386% in the placebo group versus 0.129% ( P =0.0027) and 0.096% ( P =0.0051) with BID and TID, respectively, indicating significant increases relative to placebo. In NABT, mean percentage change from baseline at 2 years in median MTR was -0.392% with placebo versus 0.190% ( P =0.0006) and 0.115% ( P =0.0029) with BG-12 BID and TID, respectively. The post hoc analysis performed on patients with no new/enlarging T2 lesions (N=147) demonstrated decreased WB MTR with placebo (mean percentage change, -0.379%), but increased WB MTR with the BG-12 BID (mean percentage change, 0.286%; P =0.0293) and TID (mean percentage change, 0.170%; P =0.0538) groups at 2 years. Likewise, MTR in NABT decreased in the placebo group (mean percentage change, -0.312%) and increased in the BID (mean percentage change, 0.314%; P =0.0285) and TID (mean percentage change, 0.171%; P =0.0644) groups at 2 years. Conclusions: DEFINE MTR results demonstrate increased brain MTR in BG-12-treated patients, potentially reflecting protective effects leading to increased myelin and axonal content. Supported by: Biogen Idec Inc. Disclosure: Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Ms. Yang has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received research support from Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Effects of BG-12 on Quality of Life in Patients with Relapsing-Remitting Multiple Sclerosis: Findings from the DEFINE Study (P07.102)

Objective: To report the impact of BG-12 on patient quality of life (QoL) after 2 years9 treatment in the Phase 3 DEFINE study. Background In DEFINE, a randomized, double-blind, placebo-controlled, multicenter study that evaluated the efficacy and safety of BG-12 over 2 years in patients with relapsing-remitting multiple sclerosis (RRMS), BG-12 significantly reduced clinical relapses, disability progression, and magnetic resonance imaging measures of disease activity. Design/Methods: Patients aged 18-55 years with RRMS (McDonald criteria) and Expanded Disability Status Scale score of 0.0-5.0 were eligible for enrollment. Patients were randomized 1:1:1 to placebo or BG-12 240 mg twice (BID) or three times daily (TID). A Short Form (SF)-36 questionnaire measured patients9 health status and health-related QoL on 8 multi-item 100-point scales at baseline and 6, 12, and 24 months; higher scores indicated higher QoL. These scores were used to calculate the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Results: Overall, 1234 patients enrolled and received study treatment. At 2 years, patients reported higher mean SF-36 PCS scores with BG-12 BID (43.4) and TID (44.2) versus placebo (41.9; P Conclusions: Together with the significant effects on clinical measures (reduced relapse risk, annualized relapse rate, and disability progression), the demonstrated benefits on patient-reported health-related QoL further supports a potential role for BG-12 as a valuable oral treatment option in RRMS patients. Supported by: Biogen Idec Inc. Disclosure: Dr. Agarwal has received personal compensation for activities with Biogen Idec Inc as an employee. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Kong has received personal compensation for activities with Biogen Idec as an employee. Dr. Sheikh has received personal compensation for activities with Biogen Idec as an employee. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Efficacy and Safety Results from Comparison of Alemtuzumab and Rebif(R) Efficacy in Multiple Sclerosis II (CARE-MS II): A Phase 3 Study in Relapsing-Remitting Multiple Sclerosis Patients Who Relapsed on Prior Therapy (S01.004)

Objective: Evaluate the effect of alemtuzumab on relapse and disability versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis (RRMS) patients who have relapsed on prior therapy. Background Alemtuzumab was significantly more effective than SC IFNB-1a in two clinical trials with treatment-naive RRMS patients. Treatment options are limited for RRMS patients experiencing disease activity during therapy, and few controlled studies have been conducted to determine their appropriate management. Design/Methods: CARE-MS II is a 2-year rater-blinded trial with RRMS patients who have relapsed during prior therapy. Alemtuzumab treatment was 12 mg/day (or 24 mg/day in an exploratory cohort) by intravenous administration for 5 days at study start and 3 days one year later. IFNB-1a treatment was 44 mcg SC 3-times weekly throughout the study. Entry criteria included 18-55 years of age, MS symptom onset within 10 years, and Expanded Disability Status Scale (EDSS) score ≤5. Primary endpoints include relapses adjudicated by an independent panel and time to sustained accumulation of disability assessed by blinded evaluators. Results: 840 patients from 180 centers in 23 countries were randomized. Baseline characteristics (mean) were: age 35 years; disease duration 3.9 years; EDSS 2.7; with 1.6 and 2.7 relapses in 1 and 2 years prior to study entry, respectively. The most common prior MS therapies were interferon-beta (78.6%) or glatiramer acetate (32.5%); less than 5% of patients had received other prior MS therapy (some patients received more than one therapy). Conclusions: Database lock and study analysis will occur in late 2011. The principal efficacy and safety results will be presented. ®Rebif is a registered trademark of EMD Serono, Inc. Supported by: Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals. Disclosure: Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Twyman has received personal compensation for activities with Genzyme Corporation as a consultant, speaker and participant on advisory boards. Dr. Twyman has received research support from Genzyme Corporation. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Coles has received personal compensation for activities with Genzyme Corporation, GlaxoSmithKline, Inc., and Merck Serono as a consultant and/or speaker. Dr. Coles has received research support from Genzyme Corportation. Dr. Confavruex has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavruex has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Fox has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, EMD Serono, Genzyme Corporation, Novartis, Opexa Therapeutics, Pfizer Inc, and Teva Neuroscience. Dr. Fox has received personal compensation in an editorial capacity for Neura. Dr. Fox has received research support from Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, Novartis, Ono Pharmaceutical, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neurosciences, GlaxoSmithKline, Nasvax, Xenoport and Genzyme Corporation as consulting and/or speaking activities. Dr. Weiner has received research support from Merck Serono. Dr. Miller has received personal compensation for activities with Allergan, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Forest, Novartis, Sanofi Aventis, and Teva as a speaker. Dr. Miller has received research support from Allergan, Biogen Idec, Genzyme, Elan, Teva, Novartis, Ono, Sanofi Aventis, EMD Serono, and Roche-Genetech. Dr. Lake has received personal compensation for activities with Genzyme as an employee. Dr. Margolin has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Panzara has received personal compensation for activities with Biogen Idec as an employee.Dr. Panzara holds stock and/or stock options in Biogen Idec. Dr. Compston has received personal compensation for activities with Genzyme Corporation as a speaker. Dr. Compston has received research support from Genzyme Corporation.

Long-Term (7-Year) Data from a Phase 2 Extension Study of Fingolimod in Relapsing Multiple Sclerosis (P01.129)

Objective: To report long-term outcomes and safety of fingolimod in relapsing multiple sclerosis (RMS) patients participating in a phase 2 study. Background After the 6-month (M) placebo controlled study in which fingolimod (1.25mg and 5mg dose groups) significantly reduced MRI and relapse activity compared to placebo all patients were invited to continue on fingolimod. The final analysis after 7 years is presented. Design/Methods: In the extension, placebo patients were re-randomized to fingolimod 1.25mg or 5mg (placebo/fingolimod group); fingolimod patients (1.25 or 5mg) continued with their core phase dose (fingolimod group). After the M24 visit, all patients received open-label, 1.25mg fingolimod and between M24-M60 were converted to 0.5mg. Results: Of 281 initially randomized patients 122 (43.4%) completed up to 7 years on study (core and extension). The overall ARR for the fingolimod group was 0.16 and for placebo/fingolimod 0.21. By study completion, 55-66% of fingolimod and 44% of placebo/fingolimod patients were relapse-free. The KM estimate of the proportion of patients who were free from 6-month confirmed disability progression ranged from 53-70% for both groups. At the end of study, 83% of all remaining patients were free of gadolinium-enhanced lesions. No increase in T2 lesion volume was observed. No chronic effects of fingolimod treatment were observed on heart rate or atrioventricular conduction. No cases of confirmed macular edema were observed. Twelve cases of skin malignancies have been reported (majority within the first 3 years): 5, basal cell carcinoma; 4, squamous cell carcinoma; 3, malignant melanoma. Conclusions: Long-term (>7 years) fingolimod treatment was associated with sustained low MRI and clinical disease activity in those remaining on therapy and was well tolerated with no new safety concerns arising with long-term dosing. Supported by: Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Antel has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Biogen Idec, Novartis, Serono, Inc., Genzyme Corporation, Teva Neuroscience, and GlaxoSmithKline. Dr. Antel has received personal compensation in an editorial capacity for Multiple Sclerosis. Dr. Antel has received research support from Novartis. Dr. Montalban has received personal compensation for activities with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Montalban has received research support from Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. O9Connor has received personal compensation for activities with Abbott Labratories, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceuticals Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals as a consultant. Dr. O9Connor has received research support from Abbott Labratories, Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceutical Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals. Dr. De Vera has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Cremer has received personal compensation for activities with Novartis. Dr. Sfikas has received personal compensation for activities with Novartis as an employee. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations.

Mortality in Multiple Sclerosis in the United States (MIMS-US): A Retrospective, Cohort Study of Survival and Mortality Trends (P06.195)

Objective: To assess survival and all-cause mortality among MS patients in a large US database and a MS patient registry compared to a non-MS population. Background Although MS is a generally well-characterized condition, survival and cause of mortality data within US populations is limited. Design/Methods: 28,845 MS and 86,129 non-MS patients were selected from a large US claims database affiliated with i3. Inclusion in the MS cohort required ≥2 ICD-9-340 codes ≥30 days apart, or a combination of 1 ICD-9-340 and ≥1 disease modifying treatment (DMT) code, all with ≥3 consecutive months of database reporting. Inclusion in the non-MS cohort required absence of ICD-9-340 and DMT codes throughout the database reporting. Non-MS patients were matched based on age at index year (year subjects first identified as having MS), sex, and residence region at index year. From NARCOMS (a US volunteer-based MS registry), 34,777 MS participants were selected. Patients9 vital status was achieved by matching their information to the National Death Index (NDI) and the Social Security Administration Death Master File. Analyses focused on overall mortality rates and survival patterns since birth within and among populations. Results: In the i3-affiliated database, a K-M survival analysis showed that participants with MS had a significant survival disadvantage compared to non-MS controls (p Conclusions: Patients with MS have a significant survival disadvantage compared to non-MS populations and have mortality rates 2- to 3-fold higher than those without MS. Supported by: Bayer HealthCare Pharmaceuticals, Inc. Disclosure: Ms. Reshef has received personal compensation for activities with Bayer HealthCare Pharmaceuticals as an employee. Dr. Cutter has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Cleveland Clinic, Daiichi Pharmaceutical Corporation, GlaxoSmithKline, Inc., Genmab Biopharmaceuticals, Eli Lilly & Company, Medivation, Modigenetech, Ono Pharmaceutical, PTC Therapeutics, Teva Neuroscience, Vivus, University of Pennsylvania, NHLBI, NINDS, NMSS, Alexion, Bayhill Therapeutics, Bayer Pharmaceuticals Corporation, Celgene, Novartis, Consortium of MS Centers, Genzyme Corporation, Klein-Buendel Incorporated, Nuron Biotech, Peptimmune, Somnus Pharmaceuticals, Sandoz, University of Texas Southwestern and Visioneering Technologies, Inc. Dr. Cutter has received compensation for serving on the board of Pythagoras, INC. Dr. Cutter has received research support from various pharmaceutical corporations. Dr. Golub has received personal compensation for activities with Bayer Pharmaceuticals Corporation. Dr. Brueckner has received personal compensation for activities with Bayer HealthCare Pharmaceuticals as an employee. Dr. Knappertz has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee.

Fatigue Severity Patterns Differ across Geographical Regions and Ethnic Groups in Patients with Clinically Isolated Syndrome and Early Multiple Sclerosis: First Results from the BEGIN Study (P04.105)

Objective: To evaluate fatigue severity patterns across different regions and ethnic groups in patients with clinically isolated syndrome (CIS) and early relapsing remitting multiple sclerosis (RRMS). Background The Betaferon® treatment and Exercise data Gathering IN early MS (BEGIN) study is a prospective, international, multicentre, observational study over a period of 2 years, assessing self-rated fatigue, depression, health-related quality of life (HRQoL), and physical activity in patients with CIS and early RRMS treated with interferon beta-1b (IFNB-1b). Design/Methods: A total of 770 patients (mean age: 36.2 (SD 9.96); 68.7% female; median time since first clinical event 10.5 months (IQR 17); mean EDSS at baseline: 2.0 (SD 1.91)) were assessed on fatigue by the Fatigue Scale of Motor and Cognitive Functions (FSMC), a recently developed and linguistically validated instrument for MS related fatigue. Ethic groups were distributed as follows: Caucasian: 583, Black: 10; Hispanic: 98; Asian: 43; other: 36. Sub-analyses were performed to evaluate whether fatigue scoring was geographically different. Sample distribution was as follows: Northern Europe (NE) and Northern America (NA): 58; Southern Europe (SE): 231; Eastern Europe (EE): 64; Western Europe (WE): 126; Asia (A): 40; Western Asia (WA): 74; Oceania (O): 74; Latin America (LA): 103. Results: In the total population 32% were classified as having no fatigue, 14% mild, 15% moderate, and 32% severe fatigue. The proportion of patients with severe fatigue was unexpectedly high with regard to the short disease duration. Further analyses revealed highest proportions of fatigue severity (around 40%) in NE and NA, A and O compared to SE, EE, WE, WA and LA. Conclusions: This first exploratory inspection of the data indicates that self-perceived ratings of fatigue differ between regions and ethnic groups. These results are of high relevance when applying patient reported outcomes in multi-centre trials. Supported by: Bayer Pharma AG. Disclosure: Dr. Penner has received personal compensation for activities with Actelion, Bayer-Schering, Biogen Nordic, Merck Serono, Roche, and Teva Aventis.Dr. Penner has received research support from Bayer Schering. Dr. Wicklein has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Beckmann has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Daumer has nothing to disclose. Dr. Hagstromer has nothing to disclose. Dr. Sjostrom has nothing to disclose. Dr. Tintore-Subirana has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Merck Serono, Biogen-Idec, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, and Novartis as a consultant and/or speaker.