Advanced medicine conference. Monday 20 Tuesday 21 June 2016

Transcription

1 Advanced medicine conference Monday 20 Tuesday 21 June 2016

2 Relapsing Multiple Sclerosis: new and emerging treatments Jeremy Chataway Queen Square MS Centre National Hospital for Neurology and Neurosurgery, Queen Square, London

3 A 23 year old woman, works as a teacher, 10 days ago she developed blurred and painful vision in her right eye. 1 year ago she was very unbalanced for about a month [put down to viral labyrinthitis]

4

5 The task=45 years long-term condition MS Onset 30ys SPMS onset 45-50yrs Death 75years

6 Some approaches Go in hard early Reduce established progression

7 Looking under the MS bonnet

8 The success of RRMS Natalizumab Alemtuzumab Fumarate (BG-12) Fingolimod BIFN GA Teriflunomide Escalation Treatment burden

9 The Armamentarium Armamentarium 2013 Glatiramer Acetate Interferon beta Options Fingolimod Natalizumab

10 The Future Armamentarium? Armamentarium 2016 Glatiramer Acetate Teriflunomide Fingolimod Tecfidera Options Natalizumab Alemtuzumab Interferon beta

11 What have we got? Group 1 (35%) binfs, Copaxone, Teriflunomide[aubagio] Group 2 (50%) Fingolimod [glenyia], Fumarate [tecfidera] Group 3 (70-80%) Natalizumab [tysabri], Alemtuzumab [lemtrada]

12 Health warning Differences in study design make it hard to compare efficacy Safety and tolerability easier to compare

13 Group 1

14 binf and Copaxone binf and GA reduce relapses by approx. 30% Betaferon: IFNB-1b MS Study Group. Neurology 1993 Avonex: Jacobs et al. Ann Neurol 1996 Rebif: PRISMS Lancet 1998 Copaxone: Johnson et al. Neurology 1995 Adapted from Rudge P. The Lancet 1999

15 Teriflunomide Active metabolite of leflunomide Pyrimidine synthesis inhibitor with immunomodulatory and immunoregulatory properties Phase 3 studies TEMSO vs placebo Tower vs placebo TOPIC in CIS TENERE vs IFNB

16 TEMSO and TOWER relapse rate Teriflunomide 14 mg od vs placebo TEMSO 32% reduction in ARR 1 TOWER - 36% reduction in ARR 2 1 O Connor P et al NEJM Data presented at ECTRIMS 2012

17 Teriflunomide safety / tolerability TEMSO GI side effects Liver inflammation Alopecia Pregnancy!

18 Group 2

19 Fingolimod FREEDOMS ARR reduced by 54 60% compared to placebo TRANSFORMS ARR reduced by 38 52% compared to IFN-B FREEDOMS Fingolimod 0.5mg reduced probability of progression compared to placebo (18% vs 24%). FREEDOMS Disease activity freedom in 33% patients on Fingolimod 0.5mg 1 1 Kappos et al 2011 AAN

20 Fingolimod safety Side effect Significance Screening considerations 1 st dose bradyarrhythmia Rarely symptomatic Requires cardiac monitor May require overnight admission. Liver inflammation Stop drug if ALT >5x ULN Can re-try Lymphopenia Macular oedema Stop drug if lymphocytes <0.2x10 9 /L Can re-try 0.4% patients in trials Excluded if significant cardiovascular dx or heart block (2 nd / 3 rd degree) Excluded if significant liver disease Excluded if active infection Screen pre-drug if diabetes or uveitis 11 deaths 7 unexplained, 4 cardiac 1 case PML

21 Dimethyl fumarate=bg-12=tecfidera Activates the nrf-2 signaling pathway Reduces cytotoxic effects of oxidative stress May influence immune responses by modulating proinflammatory pathways.

22 BG-12 Phase 3 trials DEFINE 1 Proportion of patients with relapse by 2 years BG-12 27% vs placebo 46% Hazard ratio 0.51 ( ) Reduction in ARR by 50% vs placebo CONFIRM 2 Reduction in ARR by 44% compared to placebo (GA - 29%) 1 Gold R et al, NEJM Fox R et al, NEJM 2012

23 BG-12 Phase 3 trials DEFINE Disability progression BG-12 reduction in relative risk by 38%. Disability unaffected in CONFIRM

24 DEFINE BG-12 safety / tolerability Lymphocytes reduced by 30% 4% patients lymphocytes <0.5 x10 9 /L ALT increase >3x ULN in 6%

25 BG-12 tolerability Flushing GI side effects DEFINE - Majority of flushing and GI side effects reported in first month CONFIRM 6% discontinued due to flushing or GI side effects in bd gp.

26 Group 3

27 Natalizumab: anti alpha-4 integrin humanized IgG4 Mab Natalizumab

28 Defining the template

29 Natalizumab AFFIRM trial - RRMS Natalizumab AFFIRM Reduced ARR by about 70% Reduced sustained disease progression by 42% Disease activity freedom at 2 years AFFIRM 37% (vs 6% placebo) 1 Post-marketing registries France BIONAT (n=793) 46% 2 Italy (n=285) - 63% 3 1 Havrdova et al, Lancet Neurol Outteryck et al, Eur J Neurol Sangalli et al, Neurol Sci 2011

30 05/10/15

31 30/10/15

32 09/11/15

33 16/11/15

34 23/11/15

35 23/11/15

36

37 PML

38 Alemtuzumab Profound depletion of mature lymphocytes Rapid reconstitution of B cells Mechanism of action in MS probably complex re-organisation of immune repertoire as the immune system reconstitutes. Anti-CD52 monoclonal Ab

39 Compelling results from Phase 2 study (CAMMS223) 1 Alemtuzumab reduced risk of sustained disability by 71% and reduced relapses by 74% compared to B-IFN1a Effect sustained up to 60 months 2 1 Coles AJ et al 2 Coles AJ et al Neurology 2012; 78 :

40 Alemtuzumab Phase 3 trials CARE MS 1 Alemtuzumab reduced risk of relapses by 55% compared to IFN-B1a 1 CARE MS 2 Alemtuzumab reduced risk of relapses by 49% compared to IFN-B1a 2 1 Cohen J et al, Lancet Coles A et al, Lancet 2012

41 Alemtuzumab Phase 3 trials CARE MS 1 No difference in disability progression between Alemtuzumab (8%) and B- IFN1a (11%) Disease activity freedom 39% vs 27% CARE MS 2 Disability progression reduced in Alemtuzumab (13%) and B-IFN1a (20%) Disease activity freedom 32% vs 14%

42 The downside of Alemtuzumab Infusion reactions pyrexia, headache, nausea, rash Infections cutaneous herpes, chest, urine Autoimmunity thyroid (Graves), ITP, renal Cossburn M et al

43 Assessment of treatment response Disease progression Disability Relapses MRI activity Focal inflammation (relapses / MRI lesions) Diffuse damage accumulation (neurodegeneration / failure of repair; disability / atrophy)

44 Parameters available Clinical Relapse count X Progression EDSS MSFC+ Cognition eg BICAMS MSIS29 MSWS MRI T2 number X Brain volume Emerging OCT Neurofilaments Cord MRI Grey matter

45 A patient with RRMS over 3 years (PD weighted) MAGNIMS consensus guidelines: Nature Rev Neurol 11;2015:

46 A patient with RRMS after 1 year (FLAIR) MAGNIMS consensus guidelines: Nature Rev Neurol 11;2015:

47 Summary During IFN therapy, only substantial increase in MRI lesions in 1y can predict poor treatment response Combination of both relapses and MRI is the best way to assess treatment response Integrated scoring systems incorporating clinical and MRI measures of disease activity could be useful for a personalized approach to treatment Scoring algorithms continue to evolve as data accumulates

48 NEDA-4 attainment 1. Bevan et al. Disease activity free status. JAMA Neurology Published online January 6, 2014 ; 2. Khatri et al. PD AAN2012

49 Past/Future Passe Laquinimod Mitoxantrone 2017 Daclizumab Ocrelizumab?Stem cells

50 Therapeutic Options: how do we balance it? Active MS Rapidly evolving severe RRMS Induction Natalizumab Alemtuzumab Fumarate (BG-12) Fingolimod BIFN GA Teriflunomide With induction agent? Escalation Treatment burden

51 The analysis process Disease severity Efficacy - reduces relapses [disability progression], MRI changes Disease activity freedom Adverse effects safety / tolerability Ease of administration injectable, oral, infusion frequency Availability NICE / NHS England

52 Revision Group 1 (35%): binfs, Copaxone: safe-injectables Teriflunomide: not for women-oral Group 2 (50%):oral Fingolimod -cardiac, Fumarate-GI Group 3 (70-80%) Natalizumab-PML, Alemtuzumabautoimmune/thyroid

53 For me in 2016? Group 1 (35%) binfs, Copaxone, Teriflunomide Group 2 (50%) Fingolimod, Fumarate Group 3 (70-80%) Natalizumab, Alemtuzumab

54 Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial For the MS-SMART Trialists London 2015 MS-SMART - Meeting 28th January

55 Interventions Amiloride 5 mg bd Riluzole 50mg bd Fluoxetine 20mg bd MS-SMART - Meeting 28th January

56 Centres 440 people SPMS UK Glasgow Edinburgh Newcastle Recruitment into the trial Started in Dec 2014 Liverpool Sheffield North Staffordshire Oxford Nottingham T T T T London 3 sites UCLH, Barts & the London, Imperial Truro T T Plymouth Brighton/Haywards H MS-SMART - Meeting 28th January

57 Recruitment to date MS-SMART - Meeting 28th January

58 Recruitment done!-results end

59 Remyelination miconazole/clobetasol

60 With many thanks