Natalizumab (Tysabri) Humanized, MAb Against α 4 subunit of α 4 β 1 Integrin Complementarity-Determining Regions (CDRs) Multiple Sclerosis Treatment Update CDR grafted from murine Ab Human IgG 4 framework Retains full potency Human IgG 4 Framework Natalizumab Trial (AFFIRM) 2-Year Outcomes Placebo n315 Natalizumab n627 Natalizumab Trial (AFFIRM) Disability Progression 0.73 p0.0001 68% 0.23 1.2 p0.0001 92% 0.1 11.0 p0.0001 83% 1.9 Probability of Sustained Progression 0.4 0.3 0.2 0.1 0.0 12-Week Sustained Hazard ratio0.58 P0.001 Placebo 29% Natalizumab 17% 0 12 24 36 48 60 72 84 96 108 120 Week Probability of Sustained Progression 0.4 0.3 0.2 0.1 0.0 24-Week Sustained Hazard ratio0.46 P0.001 Placebo 23% Natalizumab 11% 0 12 24 36 48 60 72 84 96 108 120 Week Relapse Rate Gd+ Lesions New T2 Lesions Polman CH, et al. N Engl J Med. 2006;354:899-910. 1
Trial Phase II, RRMS AFFIRM, RRMS SENTINEL, RRMS Natalizumab Trials MS Clinical Activity MRI Activity Clinical Severity MRI Severity Significantly Improved (p0.01) Marginally Improved (p0.01-0.05) ns not improved Natalizumab Current Status 22,000 MS patients using Natalizumab world-wide 6,600 > 1 year RR-MS patients not adequately controlled on standard therapy, or tolerating standard therapy No new PML Hypersensitivity ( 2%) Hepatotoxicity 16 cases Two cases of malignant melanoma just reported The RERD Trial Study patients Relapsing Remitting MS Compared: IFNβ-1a 44 µg, s.c., tiw vs. 20 mg, s.c., qd 18 60 years of age 1 attack within the prior 12 months Clinically stable in the prior 4 weeks EDSS score of 0 5.5 n 764 Primary Time to first relapse Secondary The RERD Trial Main Study Endpoints Mean number of T2 active (new or enlarging) lesions per patient per scan Mean number of T1 gadolinium (Gd)-enhancing lesions per patient per scan Tertiary Combined unique active (CUA) lesions (new T1-Gd+/new or enlarging T2) Clinical Relapse rate Proportion relapse-free 3 month 1-point confirmed EDSS progression 2
The RERD Trial Time to First Relapse (1 o endpoint) The RERD Trial Other Outcomes 1.00 672 days (96 weeks) Survival distribution function 0.75 0.50 0.25 IFN beta-1a IFNβ-1a 432 495 Hazard ratio (95% CI): 0.943 (0.74, 1.21) p 0.643 No significant difference in the hazard rates for time to EDSS progression (6 months sustained 1-point progression) The 3-month outcome was the pre-specified tertiary endpoint but patients were only seen once every 6 months No unexpected safety issues with either therapy 0 120 240 360 480 600 30 th percentile: number of days to first attack 0.00 0 100 200 300 400 500 600 700 Time to first relapse (days) Mikol DD, et al. ECTRIMS 2007. Abstract 119. 8 The RERD Trial Gd+ lesions (2 o endpoint) The Regard Trial Summary: Efficacy and Tolerability 0.5 *Mean number Gd+ lesions 0.4 0.3 0.2 0.1 0 Mean* (SE) Treatment Difference -0.2 (0.1); p 0.001 There was no clinical efficacy difference between Rebif 44 µg over in this patient population There was an advantage of Rebif 44 µg over Copaxone on some MRI activity measures The safety and tolerability of both Rebif 44 µg and 20 mg was again demonstrated IFN beta-1a (n 230) (n 230) *Mean number per patient per scan CI confidence interval; glatiramer acetate; SE standard error. 3
The BEYOND Trial Study Design Phase III, randomized, multi-center study Double-blind Betaseron 250 µg Rater-blinded Betaseron 500 µg Rater-blinded Copaxone 20 mg 2,244 patients randomized from 198 sites in 26 countries, 2,220 at SoT Yearly MRIs: central, blinded evaluation Treatment duration: at least 2 years Treatment-naïve RRMS patients (Diagnosis McDonald 2001) Enrollment completed end of June 2005 Last patient last visit on August 8, 2007 Primary The BEYOND Trial Main Study Endpoints Relapse Risk (Hazard ratio for time to recurrent relapses) Supportive Relapse-Related Outcomes Secondary Relapse Rate, Time to 1 st relapse, Proportion relapse-free Time to confirmed EDSS progression MRI Black holes Other Endpoints Yearly MRI measures: Burden of disease, atrophy, new T2 lesions NAbs MSFC QoL The BEYOND Trial Relapse Risk (1 o Endpoint) The BEYOND Trial Other Outcomes No significant difference in Relapse Risk between any group Betaseron 500 vs. Betaseron 250 Betaseron 250 vs. Copaxone Betaseron 500 vs. Copaxone P-values (one-sided) P0.16 P0.73 P0.43 Primary Analysis Sensitivity Analysis (no major protocol violations, 100% of doses, post-hoc) P-values (one-sided) P0.29 P0.30 P0.18 Supportive relapse-based outcomes and most of the other MRI outcome measures also show no differences between the three treatment groups. No difference in EDSS progression between groups 0.5 1.0 1.5 0.5 1.0 1.5 hazard ratio estimate (± 95% CI) hazard ratio estimate (± 95% CI) 4
The BEYOND Trial Volume of T2 Lesions The BEYOND Trial Number of New T2 Lesions - 32% ; p 0.001-23% ; p 0.001 20-43% ; p 0.001 8-25% ; p 0.017 Change in T2 Lesion Volume 15 10 5 11.9 9.9% 17.3% Mean New T2 Lesions 6 4 2 4.9 4.8 6.4 0 500 µg 250 µg 20mg 0 500 µg 250 µg 20mg The BEYOND Trial Efficacy, Tolerability and Adherence The BEYOND and RERD Trials Summary There was no clinical efficacy advantage of 500 µg over 250 µg or of either dose over in this patient population There was an advantage of 250 and 500 µg over on some MRI measures of activity and severity The safety and tolerability of 250 µg and was again demonstrated. Effects Attack Rate EDSS Progression MRI Activity MRI Severity Side Effects Flu Like Sx Injection Site Reactions LFT Abnormalities Depression IFNβ-1a 44µg 250µg 20mg 5
AFFIRM, BEYOND, and RERD Trials Relapse Rates (Before and After Rx) Several Clinical Trials Baseline Demographics 2 Year Prior to Rx After Rx Year of Study Start BEYOND (n2244) 2003 AFFIRM (n942) 2001 RERD (n764) 2004 Pivotal (n372) 1988 1.6 Age (mean) 35.7 36.0 36.7 35.5 Annual Attack Rate 1.2 0.8 0.4-85% -79% -70% Mean Disease Duration (years) Mean relapses in prior year EDSS 2.0 (% patients) EDSS (mean) 5.3 1.6 31% 2.3 5.2 1.5 34% 2.3 6.2 na 33% 2.4 8.0 na 18% 2.9 0 AFFIRM BEYOND RERD Gd-enhancement (%) Number of Gd+ lesions (mean) 47% 2.2 49% 2.2 41% 1.6 na na Event Rates in MS Clinical Trials Summary of the On-Drug Experience Future MS Therapies Currently Being Tested 1 0.8 0.6 0.4 0.2 0 0.87 0.84 0.77 0.67 0.59 0.54 0.23 COP 1 MSCRG PRISMS OWIMS EVIDENCE AFFIRM 0.34 0.085 By Date of Study End 0.34 0.35 0.34 0.3 0.29 CAMPATH R CAMPATH RERD R RERD BEYOND HD BEYOND LD BEYOND Oral Therapies FTY-720, Fingolimod Teriflunomide Fumarate, BG-12 Laquinimod Cladribine Riluzole VLA4-inhibitors (many) Infusions Alemtuzumab (Campath) Anti-CD20 rituximab, ocrelizumab Daclizumab (Zenapax) Anti-IL12 MBP8298 TCR vaccine 1992-2001 2002-2007 6
Rituximab Trial Anti-CD20 MAb Rituximab Trial in RRMS Phase II Study Design Screen (4 wks) Treatment period (48 wks) Rituximab is a genetically engineered chimeric (mouse-human) monoclonal antibody that targets CD20-positive B lymphocytes CD20 is expressed on B and pre-b lymphocytes but not on stem cells or plasma cells MRI Week -4 0 2 4 12 16 20 24 28 36 48 Long duration of action FDA approval for B-cell lymphoma (1997) and RA (2006) Rituximab/ Placebo Infusion Wk 4 MRI to evaluate safety Primary Endpoint Total number of Gd-enhancing lesions at Wks 12, 16, 20, and 24 Secondary Endpoints Proportion of patients relapsing Wks 0-24 New Gd-enhancing lesions T2 lesion volume changes B/L-Wk 24 Rituximab Trial Gd+ Lesions Rituximab Trial in RRMS % Relapsing 24 Weeks Placebo (n35) Rituximab (n69) p-value (n104) Proportion with Relapses 12 (34.3%) 10 (14.5%) 0.0238 48 Weeks Placebo (n35) Rituximab (n69) p-value (n104) Proportion with Relapses 14 (40.0)% 14 (20.3%) 0.0370 Mean New Gd+ Lesions by Week 7
Rituximab Trial in RRMS T2 Lesion Volume Rituximab in NMO Trial Inclusion Criteria T2 Lesion Volume Change from Baseline to Week 24**, mm 3 Mean ± SD 436 ± 1358-163 ± 1188 T2 Lesion Volume Change from Baseline to Week 36**, mm 3 Mean ± SD Placebo (n35) 417 ± 1305 Rituximab (n68) -175 ± 1188 p-value 0.0077 0.0041 1. Criteria for Neuromyelitis Optica: a) ATM and ON occurring within 30 days of each other followed by a second attack > 3 months later b) ATM followed by ON > 3 months later c) ON followed by ATM > 3 months later 2. Criteria for patients at high risk for Neuromyelitis Optica: a) recurrent idiopathic ATM with >3 months between attacks b) recurrent bilateral simultaneous ON with >3 months between attacks. 3. Subjects should also have no clinical evidence of disease outside the optic nerve or spinal cord. Study Status: Still Enrolling Riluzole Trial Phase II Study Riluzole Trial Phase II Study Riluzole modulates kainate and NMDA receptors: Inactivation of voltage-dependant Na + channels on glutamatergic terminals Inhibition of pre-synaptic release of glutamate Noncompetitive blockade of post-synaptic NMDA channels Activation of G protein-dependant pathway Induces astrocyte-derived neurotrophic factors that promote survival of motor neurons MRI: Study Drug: Months: - 4 Screen 0 3 6 12 24 Primary Secondary Riluzole / placebo treatment period (104 weeks) IFNβ-1a (Avonex) treatment period (92 weeks) Endpoint Efficacy Outcome Measures Progression of atrophy (SIENA) (n40) Progression of gray matter and white matter atrophy (SIENAX) Changes on EDSS, MSFC, MFIS, cognitive testing, MSQLI Changes in T1 and T2 lesion volume Change in glutamate and NAA 8
Riluzole Trial Inclusion Criteria RR or CIS within one year of onset 18-55 years At least 2 silent T2 on brain and spinal cord MRI No IFNB exposure Copaxone discontinued for 3 months No corticosteroids/exacerbation previous 8 weeks Patient willing to begin Avonex at month 3 Normal LFT ( 2 x ULN) Study Status: Still Enrolling Sphingosine 1-phosphate (S1P) receptor modulator FTY720 LN FTY-720 (Fingolimod) Mode of Action FTY720: traps circulating lymphocytes in peripheral LN prevents T-cell invasion of CNS T cell S1P receptor FTY720-P internalizes S1P 1, blocks lymphocyte egress from LN while sparing immune surveillance by peripheral memory T cells FTY-720 (Fingolomod) Trial Entry Criteria MBP8298 Trial in SPMS Inclusion Criteria Patients with RRMS (2005 revised McDonald criteria) 18 through 55 years of age 1 documented relapse during the previous year or 2 documented relapses during prior 2 years EDSS score of 0-5.5 No relapse or steroid treatment within prior 30 days. Age: 18-65 years of age SPMS, with progression and HLA DR 2 and/or 4 positive Absence of relapse in the prior 3 months EDSS: 3.0 6.5 Pyramidal or Cerebellar FSS 2 Study Still Enrolling Study Status: Still Enrolling 9
New Therapy Update Conclusions There are many new and, more importantly, potentially really exciting therapies coming into the MS therapeutic armamentarium. However, we must be wary of forming hasty conclusions from crosstrial comparisons of new therapies vs. old. The populations of study may be very different. We must also remember to be cautious with regard to our opinion about the safety of new agents. Long-term safety is never guaranteed by short-term trials. Perhaps, our experience with the safety of IFNβ and over time was just blind-luck. 10