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?

Silber; MSRT 2016

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• Some SP patients relapse when DMTs are withdrawn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

Silber; MSRT 2016

Silber; MSRT 2016

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

Silber; MSRT 2016

Disease progression

Silber; MSRT 2016

Silber; MSRT 2016

Ocrelizumab in PP MS

Silber; MSRT 2016

Silber; MSRT 2016

Silber; MSRT 2016

Silber; MSRT 2016

Dacluzimab: Mechanism of action

Silber; MSRT 2016

Silber; MSRT 2016

Silber; MSRT 2016

Silber; MSRT 2016

Silber; MSRT 2016

Silber; MSRT 2016

Silber; MSRT 2016

Silber; MSRT 2016

Silber; MSRT 2016

? 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

Silber; MSRT 2016

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