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1 Toronto Neurology Update Multiple Sclerosis A Review Liesly Lee MSc, MD, FRCPC Associate Professor of Medicine (Neurology) Sunnybrook HSC University of Toronto October, 2015 Declaration of Conflicts of Interests n Have served on advisory boards, received honoraria, conducted clinical trials with and received research funding from: u Allergan u Biogen Canada u Serono Canada u Teva Neurosciences u Schering (Berlex) u BioMS u Bayer Canada u Novartis, Canada u Sanofi-Aventis u Genzyme, Canada 1

2 Learning Objectives n Recognize the clinical features of multiple sclerosis n Review the evolving treatment options in multiple sclerosis n Recognize medical complications of MS and how to treat n Review community resources available for MS patients MS n The most common seriously disabling disease n 35,000 Canadians n prevalence rates of 1 in 1000 in North America 2

3 Potential Triggers for Multiple Sclerosis Genetic predisposition Infectious agent Abnormal immunologic response Environmental factors MS Gilden et al. Lancet Neurol. 2005;4:195; Noseworthy et al. N Engl J Med. 2000;343:938. 3

4 Disease Course in MS Demographics (N = 3019) Primaryprogressive 10% Progressiverelapsing 5% Secondary-progressive 30% Relapsing-remitting 55% Jacobs et al. Mult Scler. 1999;5:

5 Multiple Sclerosis - Signs n Optic nerve -decreased visual acuity -colour desaturation -RAPD -pale disc n Brainstem -INO; dysconjugate EOM s -nystagmus -pseudo-bulbar (dysarthria) 5

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8 Multiple Sclerosis - Signs n Motor Findings (UMN) -spasticity -weakness -hyperreflexia -extensor plantars -absent abdominal reflexes Multiple Sclerosis - Signs n Sensory -increased vibration sense (esp. legs) -pseudo-athetosis -sensory level (transverse myelitis) n Coordination -dysmetria -cerebellar tremor/rubral tremor 8

9 Multiple Sclerosis - Signs n Gait -spastic -wide-based (difficulty with tandem) n Cognition -dementia -pathological crying -depression 9

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12 Implications n Ability to make diagnosis of clinically definite multiple sclerosis in a patient with one relapse n NB: needs to have MRI brain with Gad completed +/- MRI spine Multiple Sclerosis - Natural History n 50% of patients develop secondary progression after 10 years n 90% of patients develop secondary progression after 25 years n 50% of patients become dependent on an assistive device after 15 years n Only 10% patients accumulate minimal disability or in benign state Weinshenker BG, Brain,

13 Phase III trials in R-R MS n Beta-interferon 1-b (Betaseron) 1993 n Beta-interferon 1-a (Avonex) 1996 n Beta-interferon 1-a (Rebif) 1998 n Glatiramer Acetate (Copaxone) 1995 n Natalizumab (Tysabri) 2007 n Fingolimod (Gilenya) 2011 n BG-12 (Tecfidera) n Teriflunomide (Aubagio) 2013 n Alemtuzumab (Lemtrada) % reduced attack frequency p< IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:

14 Cumulative percent progressing Interferon beta-1a time to increased disability by!!1.0 EDSS steps Time to sustained progression (weeks) Adapted from: Jacobs LD et al. Ann Neurol. 1996;39: % 21.9% Placebo Interferon beta-1a p = % reduction Burden of Disease with MRI 6 months 12 months 18 months 24 months 12 MIU 6 MIU Placebo PRISMS Study Group, Lancet 1998;353:

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16 Glatiramer Acetate n Local skin reactions n Idiosyncratic chest tightness sensations n Blood work not required n Costs about $ /year 16

17 SAM Inhibitors: Implications for MS Therapy Natalizumab 17

18 Annualized Relapse Rate Pre-specified Primary Endpoint Annualized Relapse Rate (95% CI) P< % Placebo Natalizumab n=315 n=627 American Academy of Neurology, April 2005 Natalizumab PML Incidence Estimates by Treatment Duration Incidence per 1000 patients Clinical Trials* Post Marketing >=12 Infusions >= 18 Infusions *Yousry TA, et al. N Engl J Med. 2006;354: Observed clinical trial rate in patients who received a mean of 17.9 monthly doses of natalizumab. The post-marketing rate is calculated as the number of PML cases since reintroduction in patients that have had at least 1 dose of natalizumab. Incidence estimates by treatment duration are calculated based on TYSABRI exposure through June 30, 2011 and 145 confirmed cases as of July 5, The incidence for each time period is calculated as the number of PML cases divided by the number of patients exposed to TYSABRI (e.g. for 24 infusions all PML cases diagnosed with exposure of 24 infusions or more divided by the total number of patients exposed to at least 24 infusions). Biogen Idec, data on file >=24 Infusions >=30 Infusions >=36 Infusions >= 42 Infusions

19 TRANSFORMS (phase III study) Primary endpoint: annualized relapse rate % vs IFNβ-1a p < % vs IFNβ-1a p < Annualized relapse rate IFNβ-1a IM (n = 431) Fingolimod 0.5 mg (n = 429) Fingolimod 1.25 mg (n = 420) Modified intention-to-treat population: all patients who underwent randomization and received one dose of a study drug Negative binomial regression model adjusted for study group, country, baseline number of relapses in previous 2 years and baseline disability score. p = 0.16 for fingolimod 0.5 mg vs 1.25 mg 19

20 Fingolimod revised first-dose monitoring guidance Jan 23, 2012 GIL_12_003 l Scientific Internal Use Only 40 20

21 BG-12 (Tecfidera) Annualized Relapse Rate* (95% CI) Annualized Relapse Rate at 2 Years 0.36 DEFINE 53% reduction vs placebo p < % reduction vs placebo p < Annualized Relapse Rate* (95% CI) CONFIRM 44% reduction vs placebo p < % reduction vs placebo p < % reduction vs placebo p= Placebo (n=408) BG-12 DMF BID (n=410) BG-12 DMF TID (n=416) 0 Placebo (n=363) BG-12 DMF BID (n=359) BG-12 DMF TID (n=345) GA (n=350) *Annualized relapse rate (ARR) calculated with negative binomial regression, with pre-specified adjustment for baseline EDSS score ( 2.0 vs > 2.0), baseline age (< 40 vs 40 years), region, and number of relapses in the 1 year prior to study entry; data after switch to alternative MS therapy were excluded; CI=confidence interval Gold R et al. N Engl J Med 2012; 367: ; Fox R et al. N Engl J Med 2012; 367:

22 Global Flushing Severity Scale Duration of Flushing and GI Events A. Flushing events as measured by Global Flushing Severity Scale (GFSS: 0-10) All groups, n= Upper Limit of Mild Flushing Day 1 Day 2 Day 3 Day 4 Day 5 Last Dose Pbo Pbo +ASA 240 mg BID 240 mg BID +ASA Pbo=placebo Sheikh S et al. Safety, tolerability and PK of BG 12 administered with and without aspirin: key findings from a randomized, double blind, placebo-controlled trial in healthy volunteers Neurology 2012 (suppl) B. Duration of abdominal pain, nausea/ vomiting and diarrhea events reported in the first 3 months of DMF BID treatment Events (%) > 1-2 Diarrhea (n=73 b ) Nausea/vomiting (n=108 b ) Abdominal pain a (n=110 b ) Median duration: Diarrhea = 8 days Nausea/vomiting = 8 days Abdominal pain = 9.5 days > 2-3 > 3-4 > 4-5 > 5-8 > 8-12 Duration (weeks) > a Includes abdominal pain upper; b number of patients with known start and end dates for the event Meltzer L, et al. AAN 2013 Teriflunomide: Introduction Leflunomide Teriflunomide (A , HMR1726) Teriflunomide is the active metabolite of leflunomide and is responsible for the activity of leflunomide in vivo 1 Leflunomide is indicated for the treatment of active rheumatoid arthritis (RA) in adults 2,3 Once daily, oral administration May be taken with or without food 1. Claussen M, Korn T. Clin Immunol. 2012;142:49-56; 2. Arava (leflunomide) Prescribing Information. sanofi-aventis, 2012; 3. Arava (leflunomide) Summary of Product Characteristics, sanofi-aventis, 2013; 4. Aubagio (teriflunomide) Prescribing Information or Product Information for Respective Countries; 5. Wang L, et al. Eur J Neurol. 2011;18(Suppl 2):

23 TEMSO: Hair Thinning Outcomes of patients who developed hair thinning during the TEMSO study (Week 108) Time course of probability of hair thinning Placebo (n=360) 100 Teriflunomide 7 mg (n=368) Total AEs of hair thinning (%) Placebo (n=360) Teriflunomide 7 mg (n=368) Teriflunomide 14 mg (n=358) Teriflunomide 14 mg (n=358) Highest probability Lessened risk over time Recovered without sequelae Recovered with sequelae Ongoing Worsening in intensity Unknown n In most cases, hair thinning occurred early in treatment (within 6 months), was mild to moderate, transient, and recovered without sequelae n The probability of onset of hair thinning reduces over time n 0.5% of patients in the teriflunomide 7-mg group and 1.4% in the teriflunomide 14-mg group discontinued treatment due to hair thinning AE=adverse event Data on file CONFIDENTIAL. Third line treatment n Alemtuzumab (Lemtrada). 23

24 Alemtuzumab a monoclonal antibody is Thought to Rebalance the Immune System in RRMS Alemtuzumab s exact mechanism of action is not fully elucidated 1. Fox EJ. Expert Rev Neurother. 2010;10(12): ; 2. Jones JL, et al. Brain. 2010;133(pt 8): ; 3. Cox AL, et al. Eur J Immunol. 2005;35(11): ; 4. Data on file. Cambridge, MA: Genzyme/sanofi. Laboratory Monitoring Lab Measurement Rationale Timing CBC with differential ITP Prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion Thyroid function tests, such as TSH level Thyroid disorders Prior to initiation of treatment and at quarterly intervals thereafter until 48 months after the last infusion Serum creatinine Nephropathies* Prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion Urinalysis with urine cell counts Nephropathies* Quarterly intervals until 48 months after the last infusion *Including anti-gbm disease. 24

25 What would I do.escalation First Line n Interferon n Glatiramer Acetate n Teriflunomide n BG-12 Second Line n Fingolimod n Natalizumab Third Line n Alemtuzumab n Clinical Trial/ chemotherapy n Stem cell 25

26 New Developments n Minocycline 100mg BID (Clinically Isolated Syndrome) u 6 month conversion to MS absolute risk reduction by 27.4% (NNT of 4) u Early or concomitant treatment? n Ocrelizumab (Primary Progressive MS) Symptomatic management n Fatigue amantadine, modafinil; Fampyra n Spasticity benzodiazepine, baclofen; tizanidine, dantrolene, Botulinum toxin n Bladder frequency oxybutynin, tolterodine, flavoxate, vasopressin, mirabegron 26

27 Symptomatic management n Paroxysmal Dystonia anti-convulsants n Tremor primidone, propranolol, DBS n Depression anti-depressants n Chronic Pain/Neuropathic Pain gabapentin, tricyclic, Cymbalta, cannibinoids For acute relapses n Solumedrol 1.0g IV for 3-5 days, followed by oral taper n Prednisone 500mg po BID for 3-5 days no taper.. n Rule out underlying infection first (ie UTI).. 27

28 Resources for the family physician n CCAC. (OT, PT, SW, PSW) n Toronto Rehab Institute torontorehab n Bridgepoint index.asp# n West Park Health Care Centre: n MS Society: (support groups, education, local resources) Conclusions n Our understanding of the pathophysiology of MS has evolved n Expanding treatment options of MS potentially progressive types as well? n Improved symptomatic management options 28