switching dmds and new pipeline therapies - dr eli silber
TRANSCRIPT
Switching DMDs and new pipeline therapies
Dr Eli SilberConsultant neurologistKings College Hospital
Silber; MSRT 2016
Outline• Where are we now
– Therapies• Uncertainties
– Induction v.s escalation v.s. rescue– Modelling outcomes– What is progressive disease, SP &PP– Risk reduction
• Why is there a need for new therapies?• When is there a need to switch?
Silber; MSRT 2016
A double edged sword
Safety
First line B InterferonCopaxone
Nil
Natalizumab JCV Pos
Alemtuzumab
Fingolimod
DMFNatalizumab JCV -ve
Teriflunomide
0% 30% 50% 70%Efficacy: Reduction in relapse rate
Silber; MSRT 2016
Choice of therapyDisease
Severity; RelapsesMRI Disability
PatientAttitude to riskWork/ lifestylePregnancy
Funding/ Guidance
Silber; MSRT 2016
Induction v.s. escalation v.s. rescue
Silber; MSRT 2016
How we decide who is going to do badly?
At onset• Gender/ age / race• Relapses
– Number– Site– Recovery?
• MRI– Lesion load/ T1
During therapy• Rio scores
– Clinical – MRI
Silber; MSRT 2016
Early attacks predict long term disability
Imperial study day September 2016
Rio & modified Rio scoreshelp to predict long term prognosis after
DMTs have been started
Silber; MSRT 2016
How useful and achievable is NEDA?
Silber; MSRT 2016
How you you define treatment failure?
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What do we mean by progressive disease?
Silber; MSRT 2016
1996 Classification of MS
Silber; MSRT 2016
2013 Classification: Relapsing disease
Silber; MSRT 2016
2013 Classification: Progressive disease
Silber; MSRT 2016
Progressive MS is dirty and complicated
• Some SP patients relapse when DMTs are withdrawn
• A minority of PP patients have a high lesion load and may respond to DMTs
• Progression is like middle age….obvious after some time but the transition is variable
• Many of my patients in a “grey area”
Silber; MSRT 2016
What to do with high JCV antibody positive natalizumab patients?
Close monitoring“step down” or “step
aside”• What drugs? • Fingolimod• What about DMF? • ? New agents such as
dacluzimab
Silber; MSRT 2016
Silber; MSRT 2016
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Silber; MSRT 2016
Adding to the spectrum
Safety
First line B InterferonCopaxone
Nil
Natalizumab JCV Pos
Alemtuzumab
HSCT
Fingolimod
DMFNatalizumab JCV -ve
Teriflunomide
0% 30%50% 70%
Ocreluzimab
Daclizumab
Cladribine
Silber; MSRT 2016
Silber; MSRT 2016
Silber; MSRT 2016
Ocrelizumab in RR MS
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Disease progression
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Ocrelizumab in PP MS
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Dacluzimab: Mechanism of action
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? Copy cat or improved• Ponesimod
– Selective SIP1 inhibitor – Shorter half life thus more rapid immune
reconstitution– More selective- Fewer cardiac effects
• Ofatunimab– Fully human monoclonal v.s. CD20– Licensed in CLL
Silber; MSRT 2016
Opicunimab: Anti-LINGO
EDSST25F Walk9RPTPASAT
Silber; MSRT 2016
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Going back to the drawing board: Cladribine
Oracle MS: Cladribine reduces the risks of converting to CDMS
Silber; MSRT 2016
Cladribine vs. placebo in RR MS
Silber; MSRT 2016
HSCT: Magic bullet or snake oil
• Three types of stem cells– Regeneration- experimental (Mesenchymal)– Reconstitution post immune ablation (HSCT)– The charlatans
Silber; MSRT 2016
Silber; MSRT 2016
Silber; MSRT 2016
Silber; MSRT 2016
HSCT at King’s College Hospital• 30 transplants completed at KCH (with further 8 awaiting)
• Detailed audit ongoing of transplant process with short/long term outcomes
Year Number of transplants
2012 42013 32014 32015 92016 11
Gender N (%)
Female 16 (53.3)Male 14 (46.7)
MS type N (%)
RRMS 18 (60)SPMS 10 (33.3)PPMS 2 (6.7)
Average age at transplant (range)
Overall 41.2 (22-60)Female 38.3 (29-60)Male 43.8 (22-49)
Silber; MSRT 2016
The bastards
Silber; MSRT 2016
Thank you: LEJOG 2016