A GROWING BODY OF STUDIES FROM AROUND THE WORLD HAS GIVEN US AN OUTCOME WE HAVE NOT BEEN ACCUSTOMED TO THINK ABOUT – SURVIVAL IN MS OR CHANGES IN LIFE EXPECTANCY FOR MS PATIENTS. SEVERAL STUDIES AND EVIDENCE FROM LARGE PATIENT REGISTRIES HAVE CONSISTENTLY SHOWN THAT LIFE EXPECTANCY FOR MS PATIENTS IS SHORTENED BY 7 TO 14 YEARS COMPARED WITH THAT OF THE OVERALL POPULATION. [i][ii],[iii],[iv] THE STANDARDIZED MORTALITIY RATIO IS THE RATIO BETWEEN THE SURVIVAL OF MS PATIENTS COMPARED TO SURVIVAL IN THE GENERAL POPULATION – THIS RATIO IN MS IS WIDELY ACCEPTED TO BE APPROXIMATELY THREE ACROSS MANY STUDIES. THIS MEANS THERE IS A THREE FOLD INCREASE OF THE PROPORTION OF MS PATIENTS DYING DURING THEIR LIFESPAN, COMPARED TO THE UNDERLYING POPULATION. [WE WILL ANIMATE THIS WITH SMR AS BARS IN THE GRAPH, LIGHTEN THE BLUE HUE ON THE 95% CI BARS PLEASE] < COMMENT PLEASE ADJUST REFERENCE NUMBERING><USE EACH REFERENCE NUMBER ONLY ONCE THAN REPEAT IF NEEDED THROUGHPOUT THIS DOCUMENT> [i] Torkildsen NG, Lie SA, Aarseth JH, Nyland H, Myhr KM. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler 2008;14:1191–1198 [ii] Brønnum-Hansen H, Koch-Henriksen N, Stenager E. Trends in survival and cause of death in Danish patients with multiple sclerosis. Brain 2004;127:844 – 850 [iii] Wallin MT, Page WF, Kurtzke JF. Epidemiology of multiple sclerosis in US veterans. VIII. Long-term survival after onset of multiple sclerosis. Brain 2000;123:1677–1687 [iv] Ernst FR, Pocoski J, Cutter G, Kaufman D, Golub H, Knappertz V. Multiple sclerosis-related in-hospital characteristics: principle diagnoses associated with admission and death. Poster P-173; ECTRIMS, Gothenburg, Sweden; October 13–16, 2010
The current theoretical model regarding effects of treatment postulates that the early intervention at the time of diagnosis is likely to result in slower accumulation of disability, compared to disability accumulation in patients who receive treatment later in the course of disease or in patients who do not receive treatment at all.
Why a new anti-spastic? This extract from an Editorial in the June edition of Nature Medicine sums up our pitch. “ To ease the pain, Winter was prescribed baclofen, the leading drug used to treat spinal cord injury–associated spasticity. The medication, however, came with side effects, including excessive drowsiness, which meant that Winter had to strike a delicate balance between controlling her spasms and being mobile. Because of the downside to baclofen, a derivative of gamma-aminobutyric acid (GABA), researchers have been on the lookout for alternatives to it for decades.” We think we VSN16R is this alternative.
MS Update 2012
MS Update Gavin GiovannoniBarts and The London School of Medicine and Dentistry
Survival in MSers is shortened by 8 to 12 years Survival Probability of Norwegian Patients with RRMS (Hordaland County, Western Norway, 1953–2003) 100 General Population 90 RRMS 95% CI 80 70 Survival (%) 60 50 40 30 20 10 0 0 5 10 15 20 25 30 35 40 45 50 Years After Onset 30 35 40 45 50 55 60 65 70 75 80 RRMS=relapsing-remitting MS. Approximate Patient AgeAdapted from Torkildsen NG et al. Mult Scler. 2008;14:1191-1198.
21-year long-term follow-up of IFNb-1b study time from study randomization to deathEarly treatment (3 years) with IFNb-1b was associated with a 47% reduction in the risk of dying over 21 years compared with initial placebo treatment IFNB-1b 250 µg Placebo HR=0.532 (95% CI: 0.314–0.902) 46.8% reduction in hazard ratio Log rank, P=0.0173 At risk: IFNB-1b 250 µg 124 124 121 118 104 Placebo 123 120 117 109 88 Source: Poster Goodin et al AAN 2011
Relapsing MS Placebo 1. Delay attacks / onset of MS 2. Reduce number of attacks 3. Reduce severity of attacks 4. Reduce disability 5. Delay onset of SPMS ActiveDisability 6 months 12 months 6 months 24 months Time
Treat early Treatment at diagnosis Intervention at diagnosisDisability Time Disease Onset
Long-term follow-up 16 years % Risk Relative to Low Exposure IFN-beta exposure 80% vs. 20% Any Negative EDSS=6 SPMS WheelchairSource: Poster Goodin et al AAN 2011
Annualized Relapse Rate at 2 Years(Secondary Endpoint) 53% 48% 0.6 reduction reduction vs. placebo vs. placebo 0.5 P<0.0001 P<0.0001 0.364 0.4 0.3 0.189 % C A R 0.172 5 9 * ) ( I 0.2 0.1 0 Placebo BG-12 BID BG-12 TID (n=408) (n=410) (n=416)*ARR calculated with negative binomial regression, adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age (<40 vs≥40), region, and number of relapses in the 1 year prior to study entry. 22
PRIMARY ENDPOINT: ANNUALIZED RELAPSE RATE* 0.4 21% 29% Reduction Reduction P=0.03 P=0.002 Annualized Relapse Rate* 0.3 0.2 0.37 0.29 0.27 0.1 0 Placebo Laquinimod 0.6 mg IM IFN-β-1a 30 mcg (Avonex®)*Adjusted for baseline EDSS, number of relapses in 2-year pre-study, country, baseline T2 lesion volume and GdE-T1 status at baselinescan.Vollmer T, et al. Presented at: 5th Joint Triennial Congress of the European and Americas Committee for Treatment and Research in MultipleSclerosis. October 19-22, 2011. Amsterdam, NL. Abstract 148. Multiple Sclerosis. 2011;17:S507. 27
Efficacy and safety of ocrelizumab in patients with relapsing-remitting multiple sclerosis Results of a Phase II, randomised, placebo-controlled, multicentre trial Ludwig Kappos, University Hospital, Basel, Switzerland David Li, University of British Columbia, Vancouver, Canada Peter A Calabresi, Johns Hopkins University, Baltimore, MD, USA Paul O’Connor, University of Toronto, Toronto, ON, Canada Amit Bar-Or, McGill University, Montreal, Canada Frederik Barkhof, VU Medical Center, Amsterdam, The Netherlands Ming Yin, Genentech Inc, South San Francisco, CA, USA David Leppert, F Hoffmann-La Roche Ltd, Basel, Switzerland Robert Glanzman, F Hoffmann-La Roche Ltd, Nutley, NJ, USA Jeroen Tinbergen, F Hoffmann-La Roche Ltd, Basel, Switzerland Stephen L Hauser, UCSF, San Francisco, CA, USA ECTRIMS, 13–16 OCTOBER 2010, GÖTEBURG, SWEDEN
A Randomized, Double-Blind, Placebo-controlledStudy to Evaluate the Safety and Efficacy ofDaclizumab HYP Monotherapy in Relapsing RemittingMultiple Sclerosis: Primary Results of theSELECT TrialGavin Giovannoni1, Ralf Gold,2 Krzysztof Selmaj,3 Eva Havrdova,4Xavier Montalban,5 Ernst-Wilhelm Radue,6 Dusan Stefoski,7 RandyRobinson,8 Katherine Riester,9 Jacob Elkins,9 Gilmore O’Neill91 Queen Mary University of London, Barts and The London School of Medicine andDentistry, UK2St. Josef-Hospital/Ruhr-University Bochum, Bochum, Germany;3 Medical University of Lodz, Lodz, Poland;4Charles University in Prague, Prague,Czech Republic; 5Hospital Vall dHebron University, Barcelona, Spain; 6UniversityHospital Basel, Basel, Switzerland. 7Rush University Medical Center, Chicago, IL.USA; 8Abbott Biotherapeutics, Redwood City, CA, USA; 9Biogen Idec, Cambridge,MA, USA Confidential
Annualized Relapse Rate 0.50 0.46 0.45 54% 50% Annualized relapse rate 0.40 reduction, reduction, P<0.0001 P=0.0002 0.35 0.30 0.25 0.23 0.21 0.20 0.15 0.10 0.05 0.00 Placebo DAC HYP DAC HYP (n=196) 150 mg 300 mg (n=201) (n=203) Estimated from a negative binomial regression model adjusted for number of relapses in 1-year period prior to study entry, baseline EDSS (≤2.5 vs. >2.5), and age (≤35 vs. >35)34 Confidential
Natalizumab 81% reduction in annualised relapse rate vs. placebo over 2 years (p < 0.001) 64% reduction in the risk of disability progression, sustained for 24 weeks, as assessed over 2 years (p =0.008) AFFIRM Highly Active* 1 (n= 148 for TYSABRI, 61 for PBO) *Patients with ³ 2 relapses and ³ 1 Gd+ lesion in year prior to entry 1. Natalizumab SmPC
Natalizumab PML risk stratification tool Anti-JC virus antibody status Mitoxantrone Negative Positive Azathioprine Methotrexate Prior immunosuppressant use Cyclophosphamide Mycophenolate Cladribine Rituximab Etc. No Yes Natalizumab treatment Natalizumab treatment >2 Years >2 Years Yes No Yes No Lowest Highest Relative PML Risk< 1 in 10,000 1 in 1887 1 in 256 1 in 668 1 in 94
Progressive MS Placebo 1. Reduce rate of disability progression ActiveDisability 12 months 24 months 36 months Time
Compared to relapsing MS Placebo 1. Delay attacks / onset of MS 2. Reduce number of attacks 3. Reduce severity of attacks 4. Reduce disability 5. Delay onset of SPMS ActiveDisability 6 months 12 months 6 months 24 months Time
1 Delayed Progression 2 Stabilised Progression3 Improved Function 4 Recovered Function
WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS? 3 2 1 48www.ms-res.org
Placebo tablet 280 MS’ers Year 1 Year 2 Year 3560 MS’ers 280 MS’ers Active tablet
Placebo ActiveDisability Year 1 Year 2 Year 3 Time
Placebo ActiveDisability Year 1 Year 2 Year 3 Time
~300 MS’ersYear 1 Year 2 Year 6 Year 7 Year 3 Year 4 Year 5 ~600 MS’ers 300 MS’ers Recruitment Trial Data analysis ? Registration 7 years
Spinal fluid neurofilament levels Spinal fluidneurofilament levels Disability (EDSS) and 3 years Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Axonal damage in relapsing MS is markedly reduced by natalizumab = Gunnarsson et al. Ann Neurol 2010; Epub.
30 MS’ers placebo tablet 6 months 6 months 6 months 6 months60 MS’ers 30 MS’ers active tablet LP1 LP2 LP3 Recruitment Trial Data analysis 2 years
New paradigm 600 MS’ers for 7 years 60 MS’ers for 2 years3 LPs = 10x as many trials in a ⅓ of the time
Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial Goodman et al. Lancet 2009; 373: 732–38.
Conclusions• Current first-line therapies are only moderately effective • Safe, but are associated with troublesome side effects and poor adherence• Escalation therapies (Natalizumab) • More effective but serious adverse effects • JCV testing optimises risk:benefit• A healthy drug pipeline • 3 oral agents look to emerge from the pipeline • Alemtuzumab, daclizumab and anti-CD20 most exciting of the parenteral therapies in phase 2/3• Symptomatic treatments • Sativex • Fampridine• Patient factors – risk assessment tools, education and a focus on wellness• Neuroprotection – several phase 2 trials currently been undertaken with oral agents
Questionsemail@example.comProf. Gavin GiovannoniDepartment of NeurologyRoyal London HospitalWhitechapel, London E1 1BB