Efficacy convenience of MS treatments. Xavier Montalban Department of Neurology-Neuroimmunology. ECF Baveno 2013

Transcription

1 Efficacy convenience of MS treatments Xavier Montalban Department of Neurology-Neuroimmunology ECF Baveno 2013

2 Disclaimer Dr. Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, GSK, Roche, Almirall, ECTRIMS, NMSS and MSIF.

3 What does patients and doctors consider? Efficacy Safety Convenience Tolerability Compliance

4 What does patients and doctors consider? Efficacy

5 DMDs (IFNs and GA) at different MS stages % reduction in ARR No clear effect on disability progression

6 Percentage of Patients Progressing Interferon beta - clinical studies Effect of IFN -1a IM on Disability over 2 Years P = 0.02 N = 301 Data Analyzed on ITT Basis (n=301) % 37% reduction in risk of progression 20 Placebo (N=143) 21.9% 10 IFN -1a IM (N=158) Weeks Jacobs et al. Ann Neurol. 1996;39:

7 Time to confirmed EDSS progression* 3 year results of the integrated data-set (BENEFIT) Confirmed EDSS Progression (%) 40 Log rank: p= Risk reduction of 40% over 3 years** (hazard ratio= 0.60) Delayed treatment 24% 10 Early IFNB-1b 16% 0 Year 1 Year 2 Year 3 Patients at risk n= n= * Main analysis without unscheduled visits ** by proportional hazards regression adjusted for T2-lesion volume

8 Early Is Better in Real Life Early treatment (<1 yr disease duration) n=2570 RRMS patients Mean follow-up: 4.5 yr Risk of not progressing Risk of not progressing 76.8% 57.4% Early treatment Delayed treatment 66.5% Early treatment Delayed treatment 40% Reduced risk of reaching EDSS 4.0 (HR=0.56) Reduced risk of reaching a EDSS progression (HR=0.63) Trojano M et al. Ann Neurol. 2007;66:

9 Proportion of patients who are still alive Time from Study Randomization to Death Early treatment with IFNβ-1b 50 µg was associated with a 47% reduction in the hazard ratio for all-cause mortality over 21 years compared with initial placebo treatment 100% 95% 90% IFNB-1b 50 µg Placebo 85% 80% 75% At risk: IFNB-1b 50 µg Placebo 70% 65% HR=0.535 (95% CI: ) 46.5% reduction in hazard ratio Log rank, P= Time (Years) Goodin et al. Neurology 2012

10 1000 CIS: Barcelona CIS inception cohort Mar Tintoré, Àlex Rovira, Jordi Río, Susana Otero, Georgina Arrambide, Carmen Tur, Manuel Comabella, Carlos Nos, Laura Negrotto, Ingrid Galán, Angela Vidal-Jordana, Joaquim Castilló, Filipe Palavra, Eva Simón, Raquel Mitjana, Cristina Auger, Jaume Sastre-Garriga, Xavier Montalban Centre d Esclerosi Múltiple de Catalunya (Cemcat) and MR Unit Departments of Neurology-Neuroimmunolgy and Radiology Hospital Universitari Vall d Hebron Universitat Autònoma de Barcelona ECTRIMS 2013

11 Patients and methods Inception cohort of patients with CIS started in 1995-ongoing Cemcat Department of Neuroimmunology Neurorehabilitation Unit Clinical session

12 Patients and methods Inclusion criteria: Age < 50 years Entry window: 3 months from disease onset Follow-up visits: Clinical assessment every three to six months: relapses and EDSS Radiological assessment: MRI at baseline, 3-6 m, 12 m and every 5 years OB IgG: agarose IEF+immunoblotting Remnant CSF and serum samples: stored at -80 C Informed consent

13 Results: CDMS multivariate Gender HR 1 ( ) Age cat HR 1.4 ( ) HR 1.7 ( ) HR 1.9 ( ) Topography HR 0.9 ( ) Oligoclonal bands HR 1.5 (1.1 2) Barkhof criteria HR 3.6 ( ) HR 6.6 ( ) Treatment HR 0.6 ( )

14 Results: EDSS3 multivariate Gender HR 0.7 ( ) Age cat HR 0.7 ( ) HR 0.6 ( ) HR 0.8 ( ) Topography HR 0.6 ( ) Oligoclonal bands HR 2.3 ( ) Barkhof criteria HR 0.8 ( ) HR 2.4 ( ) Treatment HR 0.5 ( )

15 Conclusions Early treatment decreases the risk of conversion to CDMS and accumulation of disability

16 Annualized Relapse Rate (95% CI) Natalizumab Annualized Relapse Rate P< Year % 0.78 P< % Placebo n=315 Natalizumab n= P< Year 0-1 Year % FDA per subject mean relapse rate at 2 years = 0.67 for placebo and 0.22 for natalizumab (67% reduction)

17 Proportion With Sustained Progression Natalizumab Progression of Disability 0.4 Hazard Ratio (HR)=0.58 (95% CI: 0.43, 0.77) 0.3 P= Placebo 29% 42% Natalizumab 17% Weeks

18 Mean Number of Gd+ Lesions Natalizumab Number of Gd-enhancing lesions P< Placebo n=315 Natalizumab n= % 92% At Year 1 At Year 2

19 Freedoms (phase III trial): Primary Endpoint Annualized Relapse Rate Kappos L et al. NEJM 2010

20 Annualized relapse rate TRANSFORMS (phase III trial): Primary Outcome - Annualized Relapse Rate % vs IFNβ-1a p < % vs IFNβ-1a p = IFNβ-1a IM (n = 431) Fingolimod 0.5 mg (n = 429) Fingolimod 1.25 mg (n = 420) Intent-to-treat population Negative binomial regression model adjusted for treatment group, country, baseline number of relapses in previous 2 years and baseline Expanded Disability Status Scale as covariates; confirmed relapses; p = for fingolimod 0.5 vs 1.25 mg IFNβ-1a IM, interferon β-1a intramuscularly Cohen J et al. NEJM 2010

21 FREEDOMS and TRANSFORMS clinical outcomes: improvement relative to control Outcome FREEDOMS 2-year placebo control TRANSFORMS 1-year IFNβ-1a, IM control ARR ( ) 54%*** 52%*** Time to relapse, HR ( ) 52%*** 48%*** Proportion relapse-free ( ) 49%*** 18%*** Time to disability progression, 3 month, HR ( ) 30%* 29% Time to disability progression, 6 month, HR ( ) MSFC mean difference, z-score ( ) 37%** * 0.02* Data shown are for fingolimod 0.5 mg; *p 0.05; **p 0.01; ***p ARR, annualised relapse rate; HR, hazard ratio; IFN, interferon; IM, intramuscular; MSFC, Multiple Sclerosis functional composite

22 Mean (SD) lesion number Mean (SD) lesion number FREEDOMS: inflammatory disease activity Number of new/enlarging T 2 lesions, Months 0 to 24 Number of T 1 Gd+ lesions at Month 24 p< p< p< (13.2) p< % (2.4) 8 2 % 2 0 Placebo (n = 339) 2.5 (7.2) Fingolimod 0.5 mg (n = 370) 2.5 (5.5) Fingolimod 1.25 mg (n = 337 ) Placebo (n = 332) 0.2 (0.8) Fingolimod 0.5 mg (n = 369) 0.2 (1.1) Fingolimod 1.25 mg (n = 343 ) Gd+, gadolinium-enhanced; SD, standard deviation Kappos L et al. N Engl J Med 2010

23 Clinical trials forthcoming drugs Drug Trial n T2 Gd Relapses Progression BG-12 BID (vs placebo) BG-12 BID (vs placebo, GA) Teriflunomide (7-14mg vs placebo) Teriflunomide (7-14mg vs placebo) Laquinimod (vs placebo) Laquinimod (vs placebo, IFN) Alemtuzumab (vs IFN Beta 1a) Alemtuzumab (vs IFN Beta 1a) DEFINE % -90% -53% -38% CONFIRM % -74% -44% ns TEMSO % -80% -31% -30% TOWER % -31.5% ALLEGRO % -37% -23% -49% BRAVO % ns ns -40% CAREMS-I % -63% -54% ns CAREMS-II % -61% -49% -42%

24 Annualized relapse rates observed in the 26 MS trials against the publication year The size of the bubble indicates the size of the trial and is proportional to the sample size. The solid line shows the model values of the negative binomial regression and the dashed lines indicate 95% confidence intervals. 24 Nicholas et al, Mult Scler. 2011;17:

25 Atrophy Brain atrophy occurs at a faster rate in people with MS than in healthy controls Brain atrophy correlates with and predicts disability Some drugs have shown positive effects on global atrophy When included in a multivariate model, relapses and PBVC remained as independent contributors to the treatment effect on disability progression

26 Clinical trials - atrophy results licensed drugs (<2013) TRIAL Form Drug Reported results ETOMS CIS IFN Positive BENEFIT CIS IFN Negative CHAMPS CIS IFN Not reported PRECISE CIS GA Negative Pivotal Betaferon RRMS IFN Not reported PRISMS RRMS IFN Not reported Pivotal Avonex RRMS IFN Negative Eu-Can Copaxone RRMS GA Positive* AFFIRM RRMS NTZ Negative FREEDOMS I & II RRMS FTY Positive TRANSFORMS RRMS FTY Positive EUSPMS SPMS IFN Negative IMPACT SPMS IFN Not reported SPECTRIMS SPMS IFN Not reported PROMISE PPMS GA Negative Barcelona DBPC PPMS IFN Negative London DBPC PPMS IFN Negative *Reanalysis

27 Clinical trials atrophy results forthcoming drugs Drug Trial n T2 Gd Relapses Progression Atrophy reduction BG-12 BID (vs placebo) BG-12 BID (vs placebo, GA) DEFINE % -90% -53% -38% -30% CONFIRM % -74% -44% ns -21% (ns) Teriflunomide (7-14mg vs placebo) TEMSO % -80% -31% -30% BPF, GM (ns) WM 164% (p=0.002) Teriflunomide (7-14mg vs placebo) Laquinimod (vs placebo) Laquinimod (vs placebo, IFN) Alemtuzumab (vs IFN Beta 1a) Alemtuzumab (vs IFN Beta 1a) TOWER % -31.5% ALLEGRO % -37% -23% -49% -33% BRAVO % ns ns -40% -27% CAREMS-I % -63% -54% ns -42% CAREMS-II % -61% -49% -42% -23%

28 What does patients and doctors consider? Efficacy Safety

29 What does patients and doctors consider? Efficacy Safety Convenience

30 Convenience Convenient procedures are those intended to increase ease in accessibility, save resources (such as time, effort and energy) and decrease frustration. Convenience is a relative concept, and depends on context

31 PATIENTS and DOCTORS MAY CONSIDER: CONVENIENCE

32 Injection anxiety or phobia Prevalence rates of injection-related anxiety significant enough to prevent selfinjection may be as high as 50% for some types of injections (Mohr et. al., 2001)

33 PATIENTS and DOCTORS MAY CONSIDER: CONVENIENCE Increase compliance Apparently more convenient that s.c. Lost of working days

34 PATIENTS and DOCTORS MAY CONSIDER: CONVENIENCE Much more convenient In theory, less compliance

35 Patients May Prefer Oral, Rather Than Injectable, Treatments in Chronic Disease??? In a survey of patient preference for a new oral or injectable medication for type 2 diabetes, the majority of respondents preferred the oral treatment option 2402 patients responded to the survey. Significantly more patients preferred the oral treatment option in each scenario (p<0.001) Dibonaventura MD et al. Patient Prefer Adherence 2010;4:

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37 PATIENTS and DOCTORS MAY CONSIDER: CONVENIENCE Complexity of treatment: Safety controls by other specialists and other tests Lost of working days

38 What does patients and doctors consider? Efficacy Safety Convenience Tolerability Compliance

39 Definitions of Adherence and Persistence Adherence (or compliance*) 1 The extent to which patients take medications as prescribed (i.e. the correct dose at the correct times) Persistence 2 The extent to which patients continue taking medications over time Adherence can be measured 1 Directly, using blood serum or urine levels of the drug or its metabolite(s) Indirectly, using patient self-reports, pill counts, or prescription claims * Adherence is preferred to compliance because it recognises the therapeutic alliance between the patient and the physician * Adherence is preferred to compliance because it recognises the therapeutic alliance between the patient and the physician 1. Osterberg L et al. N Engl J Med 2005;353: ; 2. Cramer JA et al. Value Health 2008;11:44 47.

40 The Global Adherence Project (GAP): Reasons for Non-adherence Injection/tolerability factors Patient factors Other 32% of patients: at least one injectionrelated reason 84% of patients: other various reasons Patients may report more than one reason N=2648. Devonshire V et al. Eur J Neurol 2011;18:69 77

41 Respect for their choice

42 Respect for their choice

43

44 Kasper et al. Eur J Neurol 2008 The DA consisted of a comprehensive evidence-based MS patient information booklet about immunotherapy options and an interactive worksheet

45 Kasper et al. Eur J Neurol 2008 Treatment choices: no differences were found between groups.

46 Kasper et al. Eur J Neurol 2008 Providing patients with balanced information may not be sufficient to alter the decision-making process

47 Estimated PML incidence stratified by the three risk factors of anti-jcv antibody serostatus, prior immunosuppressant use, and natalizumab treatment duration Tur et al. MSJ 2012

48 Classification of patients treated with natalizumab according to their risk of developing PML (CEM-Cat Jul 2011) 100% 100% 100% 76% 40% Patients who continue treatment after being informed of the JCV test results Tur et al. MSJ 2012

49 Shared decision making Patient Experiences Values and Preferences SDM INTERACTION Family, Society Clinician Treatment Options Potential benefits, harms, outcomes Shared decision making combines the measurement of patient preferences with evidence-based practice

50 OTHER ASPECTS: PATIENTS OPINION, MEDIA, SOCIAL NETWORKS

51 DMF s uptake in the first week of launch in US

52 COST

53 Key Points The field of MS therapy is changing rapidly Newer therapies may supplant currently available DMDs mainly in new patients The newer therapies will have both known and unforeseen complications Future treatment options will be far more complex than those currently available to us Budgetary constraints will play a major role in the decision making process

54 MRI