Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing...
Transcript of Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing...
![Page 1: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/1.jpg)
Klaus Schmierer, PhD FRCP Blizard Institute, Barts and The London School of Medicine & Dentistry
Barts Health NHS Trust
Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy
![Page 2: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/2.jpg)
Disclosures
PI of trials sponsored by Novartis & Roche.
Involved in trials sponsored by Biogen, Genzyme, Teva and BIAL.
Speaking honoraria from, and/or in an advisory role for, Novartis,
Sanofi-Aventis, Merck-Serono and Merck Inc.
Grant support from HEFCE, Isaac Schapera Trust, National MS
Society (US), MS Society of Great Britain & Northern Ireland,
Novartis and Barts and The London Charity.
![Page 3: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/3.jpg)
The suggested TSA “For products with an anticipated profound effect on the immune system and thus potential serious safety [concerns] a two step procedure is foreseen:
1) Products should be evaluated in comparative superiority study in patients with insufficient responsive to first line treatment
2) If the safety profile is judged to be acceptable, efficacy studies may be extended to a broader multiple sclerosis population.”
![Page 4: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/4.jpg)
Why challenge the TSA?
Because we already have one in the UK!
And we don’t like it
![Page 5: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/5.jpg)
Key document
EMA (safety & efficacy) > NICE (cost-effectiveness) > CCG (funding)
![Page 6: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/6.jpg)
• Patients have unchanged or increased relapse rate or ongoing severe relapses compared with previous year despite Tx with β IFN
• Fingolimod is provided at discounted price as part of patient access scheme
Start criteria Fingolimod
2013
![Page 7: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/7.jpg)
Challenging the TSA
• Predicting disease course • Efficacy of DMT • Side effects/safety of DMT • Cost of DMT
![Page 8: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/8.jpg)
Challenging the TSA
• Predicting disease course • Efficacy of DMT • Side effects/safety of DMT • Cost of DMT
![Page 9: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/9.jpg)
Relapses and disease progression
Scalfari, et al. Brain 2010
Time from disease onset to DSS 6*
*Requires a walking aid to walk 100m
![Page 10: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/10.jpg)
JNNP 2010
![Page 11: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/11.jpg)
Brain atrophy occurs across all stages
De Stefano, et al. Neurology 2010
n= 963 pwMS
![Page 12: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/12.jpg)
![Page 13: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/13.jpg)
Carassiti D, et al. ECTRIMS 2013, P425
13.3 billion
19.8 billion
Total number of cortical neurons
![Page 14: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/14.jpg)
Six years after diagnosis no decline in overall cognitive function, however significant changes in divided attention (dual task) and information processing speed (SDMT).
n= 30 MS, n= 37 HC, FU= 6 years
![Page 15: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/15.jpg)
The paradigm shift: Treat early Early active therapy for people with MS, as practiced in rheumatology
Potent immunomodulatory agents for early treatment are desired
Immune system rebooters vs. reversible immunomodulators (β-IFN, GLAT, Natalizumab, Fingolimod, Dimethyl-Fumarate, Teriflunomide, …)
Evidence from monoclonal antibody therapy Relapsing SPMS Relapsing Remitting MS
Coles et al., J Neurol 2006
![Page 16: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/16.jpg)
Treat early
Natural course of disease
Later intervention
Later treatment
Treatment at diagnosis Intervention
at diagnosis
Time Disease onset
![Page 17: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/17.jpg)
Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-β1b trial
Goodin et al. Neurology 2012;78:1315-1322.
Onset > death
Randomization> death
![Page 18: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/18.jpg)
Scalfari, et al. Neurology 2013
![Page 19: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/19.jpg)
Challenging the TSA
• Predicting disease course • Efficacy of DMT • Side effects/safety of DMT • Cost of DMT
![Page 20: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/20.jpg)
Fingolimod vs. placebo (n=1272)
% w
ith 3
-mon
th c
onfir
med
ED
SS p
rogr
essi
on 25
20
15
10
5
0 0 12 24 36 48 60 72 84 96
Weeks on study
Cladribine 5.25 mg/kg
Cladribine 3.5 mg/kg
Cladribine 3.5 mg/kg vs. placebo, HR=0.67 p=0.018
Cladribine 5.25 mg/kg vs. placebo, HR=0.69 p=0.026
Placebo
Cladribine vs. placebo (n=1326)
0.33
0.14 0.15
Placebo (n=437)
Cladribine 3.5 mg/kg (n=433)
0.40
0.30
0.20
0.10
0.00
Cladribine 5.25 mg/kg (n=456)
-54.5% vs placebo P<0.001
-57.6% vs placebo P<0.001
Results of pivotal trials of oral drugs in relapsing MS
![Page 21: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/21.jpg)
Cohen, et al. Lancet 2012
Is there an assumption that DMTs currently available are sufficiently efficacious AND safe such that no further drugs are needed in the early stages of RMS?
‘Imperfections’ of current DMTs
![Page 22: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/22.jpg)
Challenging the TSA
• Predicting disease course • Efficacy of DMT • Side effects/safety of DMT • Cost of DMT
![Page 23: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/23.jpg)
• Potentially fatal infections (natalizumab, fingolimod)
• Gastro-intestinal, flushing (DMF), PML (fumaderm)
• Hair loss, liver toxicity, teratogenecity, (teriflunomide)
• 20-30% secondary autoimmunity (alemtuzumab)
• Lymphopenia, ?malignancies
Adverse effects of highly effective DMTs
![Page 24: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/24.jpg)
n= 651 pwMS
Maximum acceptable annual risk (MAR)
![Page 25: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/25.jpg)
Discontinuation rates (β-IFN): 17% - 46%
Adherence to injectable DMTs
Pozilli C, et al. J Neurol Sci 2011; Halpern R, et al. Patient Prefer Adherence 2011
![Page 26: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/26.jpg)
Key document
![Page 27: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/27.jpg)
• ≥ 2 disabling relapses over past year • ≥ 1 Gd+ lesions or increase in T2 lesion
load compared to previous MRI unless comparator MRI unavailable or assessment of Gd enhancement unreliable as patient treated with steroids at time of scan
• Either no previous DMD or receiving β IFN
2013 Start criteria Natalizumab
![Page 28: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/28.jpg)
AAN guideline – natalizumab
…natalizumab be reserved for use in pwRRMS who have failed other therapies either through continued disease activity or medication intolerance, or who have a particularly aggressive initial disease course…
Goodin, et al. Neurology 2008
![Page 29: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/29.jpg)
• Patients have unchanged or increased relapse rate or ongoing severe relapses compared with previous year despite Tx with β IFN
• Fingolimod is provided at discounted price as part of patient access scheme
Start criteria Fingolimod
2013
![Page 30: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/30.jpg)
US practice – fingolimod
• Approved as 1st line Tx for pwRRMS • Option when Tx response is poor or
intolerable side effects on IFN or GA • particularly in pwRRMS seropositive for
JC virus
Hyland & Cohen, Neurol Clin Pract 2011
![Page 31: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/31.jpg)
Challenging the TSA
• Predicting disease course • Efficacy of DMT • Side effects/safety of DMT • Cost of DMT
![Page 32: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/32.jpg)
The cost of MS
MSIF: Global economic impact of multiple sclerosis, 2010.
![Page 33: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/33.jpg)
• Over 10,000 pwRMS in the UK are currently on disease modifying treatments (DMTs)
• Annual cost, including enabling activities such as employing MS nurses: >£50m
• Current annual cost of DMTs (drug only) in the UK: – Glatiramer acetate (Copaxone) £6,800 – Interferon β-1b (Betaferon) £7,200 – Interferon β-1a (Avonex) £8,500 – Interferon β-1a (Rebif) £10,500 – Natalizumab (Tysabri) £14,690 – Fingolimod (Gilenya) £19,162 (BNF)
The cost of MS
Raftery, BMJ 2010
![Page 34: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/34.jpg)
5,000–10,000 Screened
250 Enter Preclinical
Testing
5 Enter
Clinical Testing
1 Approved by
the FDA
16
14
12
10
8
6
4
2
0
Net Cost: $802 million invested over 15 years Source: DiMasi et al. 2003, Tufts
Years
Discovery: (2-10 years)
Phase I: 20-80 healthy volunteers to determine
safety & dosage
Phase III: 1000-5000 volunteers to monitor
adverse reactions to long-term use
Phase II: 100-300 volunteers to look for efficacy & side effects
FDA Review Approval Additional post-
market testing
Preclinical: laboratory & animal tests
Compound Success Rates by Stage
‘Big Pharma’ Model
![Page 35: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/35.jpg)
The business of MS
2018: $23Bill
2012: $13.7Bill
“ ”
![Page 36: Treatment guidelines for relapsing MS and the ‘two step … · Treatment guidelines for relapsing MS and the ‘two step approach’ for disease modifying therapy . ... Early active](https://reader034.fdocuments.us/reader034/viewer/2022052518/5f03dda07e708231d40b2653/html5/thumbnails/36.jpg)
Conclusions • All current DMTs work best when used early in pwRMS • New generation drugs are an improvement compared to
current DMTs, and adverse effects are manageable despite some of them having a “profound effect on the immune system and thus potential serious safety issues”
• Nevertheless – or precisely for that reason – the evidence is not in favour of a TSA for trials of new DMTs
• New drugs should rather be tested in head-to-head studies or multi-arm design trials (Chataway)
• Not only severe and/or longterm side effects should be considered, but also adverse effects with significant impact on the current life of pwRMS
• A TSA would delay development of new DMTs for pwMS and lead to a further rise in cost. Whilst this may cause some problems for ‘Big Pharma’ it would certainly destroy attempts at repurposing of potentially effective and yet affordable drugs