Disease Modifying Therapies David Paling - Sheffield Rachel - - PowerPoint PPT Presentation
Disease Modifying Therapies David Paling - Sheffield Rachel Dorsey-Campbell - Imperial Timeline of treatments Timeline of treatments Lemtrada Cladribine Plegridy Tecfidera Ocrelizumab Aubagio Daclizumab Plegridy Betaferon Avonex
Disease Modifying Therapies
David Paling - Sheffield Rachel Dorsey-Campbell - Imperial
Timeline of treatments Timeline of treatments
Plegridy1994 2017
1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016
Betaferon Avonex Copaxone Mitoxantrone Tysabri Fingolimod Tecfidera Aubagio Lemtrada Plegridy Ocrelizumab Daclizumab Cladribine Decision on treatments
Decision on treatments
Pathology
Pathology of relapsing MS
Treatments
IFN Beta/ GA DMF
Teriflunomide
Alemtuzumab Cladribine Ocrelizumab AHSCT
Fingolimod Natalizumab
Mechanisms of action
Limits pyrimidine availability for rapid cell division
Teriflunomide Reduced proliferation Fingolimod Natalizumab
Lymph node BBB CNS S1P1
B T
α4- integrin Periphery
Anti-migratory Ocrelizumab
Alemtuzumab CD52 Lysis of mature B and T cells CD20
Cladribine Cell lysis AHSCT
B, B cell; BBB, blood–brain barrier; CNS, central nervous system; IFN, interferon; IL2, interleukin 2; nrf 2, nuclear factor)-like 2; S1P1, sphingosine-1-phosphate receptor 1; T, T cell; Th, T-helper cell
Adapted from: 1. Loleit V et al. Curr Pharm Biotechnol. 2014;15:276–96; 2. Scannevin R et al. J Pharmacol Exp Ther. 2012;341:274–84; 3. Chen H et al. J Clin Invest. 2014;124:2188–92. Heckler et al. Mol Neurobiol. 2013;48:737-56
IFNs Glatiramer acetate
Activation of IFN-response genes Modulation of Th1:Th2 balance Activation of nrf 2 responsive genes Dimethyl fumarate
Immuno Modulatory
Decision on treatments
Mode of administration
Decision on treatments
Hepatic Failure TTP Graves Disease Renal Failure 2006 2007
Apr Jun Aug Oct Dec Feb Apr
Start Betainterferon
May 1
Screening Blood Tests
Apr 1
Blood Test
Nov 2
Blood Test
May 1
2016 2017
Apr Jun Aug Oct Dec Feb Apr
Blood Pressure
Aug 1
Blood Pressure
Nov 1
Blood Pressure
Feb 1
Blood Pressure
May 1
Screening Blood Tests
Apr 1
14 Blood Tests in one year Start Teriflunamide
May 1
Monitoring Blood tests
– 1 monthly Natalizumab (although other MRI monitoring) – 6 monthly Ocrelizumab
– DMF, Beta interferons, Cladribine
– Alemtuzumab
– Teriflunamide
Monitoring
MS DMT monitoring burden
Admin Support
Decision on treatments
Pregnancy
Decision on treatments
Side effects
Side effects
Decision on treatments
PML
PML
5 10 15 20 25 30 Symptoms Asymptomatic
Mortality
Mortality
9 fold
PML
PML
Decision on treatments
Efficacy
Treatments for MS
BIFN GA Teriflunomide Fingolimod Natalizumab Ocrelizumab
Treatment burden
Fumarate (BG-12) Cladribine Alemtuzumab
AHSCT
Risk vs Benefit
Interferon Beta Copaxone Dimethyl Fumarate Teriflunamide Fingolimod Natalizumab Mitoxantrone 2 relapses in 2 years Restricted indication Natalizumab JCV+ Less effective More effective Less dangerous More dangerous All active MS Alemtuzumab Ocrelizumab Cladribine AHSCT
Decision on treatments
Induction vs escalation
Making treatment decision
Risk of MS Risk and burden of treatment Severity of relapses Associated neurological disability MRI disease activity Oligoclonal Bands Age Plans for pregnancy Method of Administration Frequency of administration Occupation Other medical conditions Poor mobility (ulcers / chest infections)
Evidence Base
20 40 60 80 100 120 140 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
Number of papers in PubMed per year for multiple sclerosis with drug name in the title
Glatiramer Acetate and Beta Interferon Natalizumab Fingolimod Di Methly Fumarate Alemtuzumab Cladribine
Evidence Base
Does not include Ocrelizumab, Siponimod, Posenimod, Ofatunumab
50 100 150 200 250 300 350 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
Number of papers in PubMed per year for multiple sclerosis with Beta Interferon, Glatiramer, Natalizumab, Fingolimod, Fumarate, or Cladribine in the title
Total
2016/17 Spend on DMTs
Courtesy of Prof Coles, Cambridge
£249,417,164
15 new schools 5000 physiotherapists 150 per MS centre
DMT algorithm
– 2 neurologists, MS nurse – Pharmacists, Radiology advice
Clinical Case 1
2016 2015 2014
Aug 2014 R ON VA 2/6 Aug 2015 Weakness left leg Level at T10 Oct 15: Sensory signs EDSS 2.0 Steroids Steroids MRI normal MRI lesions
Clinical case 1
Clinical Case 1
Case 2
2016 2015 2014 2017 2018
Aug 2014 R ON VA 2/6 Aug 2015 Weakness left leg Level at T10 Oct 15: Sensory signs EDSS 2.0 Dimethyl Fumarate Nov 16 Incoordination EDSS 2.0 Oct 16: Well EDSS 0 Steroids Steroids Steroids MRI normal MRI lesions MRI new lesions and contrast enhancing lesions
Case 2
Case 2
2016 2015 2014 2017 2018
Aug 2014 R ON VA 2/6 MRI normal Aug 2015 Weakness left leg Sexual dysfunction Oct 15: Sensory changes leg EDSS 2.0 Dimethyl Fumarate Nov 16 Incoordination EDSS 2.0 Oct 16: Well EDSS 0 Feb 17 Ocrelizumab EDSS 1.5 Steroids Steroids Steroids Ocrelizumab Aug 17 EDSS 0
Case 2
*
2 4 6 8 10 12 No relapses or new lesions Relapses without new lesions New lesions without relapses Relapses with new lesions
Odds ratios of relapses over three years based upon disease activity in the first year
Odds ratio of relapses in next 3 years
Rio et al. Multiple Sclerosis 2009;15:848
If that doesn’t work
Disease Modifying Therapies
David Paling - Sheffield Rachel Dorsey-Campbell - Imperial