Sequencing of Disease Modifying Treatments in

Multiple SclerosisMS TRUST CONFERENCE

Beaumont Estate06/11/2016

Benefit of Early Treatment

Shared Decision Making

ABN Guidelines• Eligible patients will normally be ambulant.

• All patients with active RRMS should be considered expeditiously for treatment.

• The currently licensed DMTs divide broadly into two categories.

• Drugs of moderate efficacy ( category 1)

• beta interferons ( Including pegylated)• Glatiramer acetate• Teriflunomide• Dimethyl fumarate• fingolimod

The currently licensed DMTs divide broadly into two categories.

Drugs of moderate efficacy ( category 1)• Beta-interferons ( Including pegylated)• Glatiramer acetate• Teriflunomide• Dimethyl fumarate• Fingolimod

Drugs of high efficacy• Alemtuzemab• Natalizumab

Induction versus Escalation( Maintenance)

Prevailing practice escalation.(Maintenance) Treatment starts with a “first line”agent.Changes are made based upon• Tolerability• Safety• Efficacy

• 32 year old woman, single mother of daughter three.

• Nursery manager.• PMHx asthma, hyperhidrosis.• Presentation Sept 2015 ascending

numbness both legs up to waist.• April 2016 Right facial numbness tingling

lips and dropping right eye.• June 2016 admission with spasticity of

legs.

• JCV positive.• Given information about treatment options

while IP.• 5 days oral methylprednisolone.• OP clinic August 2016.• Had developed new left facial sensory

changes over previous 3 weeks with feeling of pressure in her spine.

• Treatment choice??

INDUCTION

Tolerability changes• Limited by license.

• If no evidence of poor efficacy ( clinical / MRI) No problem to change between platform therapies.

• Changes between Avonex/ Plegridy, Dimethyl fumarate to Teriflunomide.

• Dependent on preference. Oral/ Injectable, plans for pregnancy etc.

What constitutes efficacy failure?

NEDA (no evidence of disease activity)

• (i) no relapses; • (ii) no disability progression and • (iii) no MRI activity (new or enlarging T2

lesions or Gd-enhancing lesions).  

How do we assess this?

• Patient report of relapses.• Rebaselining with MRI scan after

commencement of treatment.• Annual MRI monitoring.

• NEDA4• NEDA5

Efficacy Failure

• DMF• Fingolimod• Natalizumab• Clinical trials ie Ocrelizumab• Potentially

Daclizumab/Cladribine/Rituximab

PwMS and Clinician preferences

• Level of MS activity.• Oral versus Infusion (versus Injectable).• Life style.• Reliability of PwMS to attend for required monitoring.• Adherence.• Level of MS activity.• JCV status.• PwMS understanding of risk/benefit.• Pregnancy.• Cost.

JB male aged 41,Financial adviser married one child 6 months.

Initial presentation 06/11/2011 with confusion, visual blurring and unsteadiness, sensory changes in feet.

OE ACE 71/100

CSF 40 WC paired OCBs.

Diagnosis on basis of Clinical and MRI – ADEM

Treated with 3 days IVMP.

Improvement discharged 30/11/2011

Represents 06/12/2011 with slurred speech, poor balance

bilateral ptosis.

• 3 days IVIg no improvement.• Worsening with increased confusion, ataxia, L

UMN facial weakness and weak left arm and leg.• 16/12/2011 Admitted ITU.• Further deterioration –improved left sided

weakness but now right arm and leg weakness and aphasia.

• Develops bilateral PEs, treated with IVIg.• Further deterioration with complex

opthalmoplegia.• PLEX.• First treatment with Natalizumab Jan 2012.

• JCV negative.Commenced on natalizumab Jan 2012.

• Complete resolution of signs and symptoms.• Returned to work.• Monitored with annual MRI scans and 6 monthly JCV.• Late 2014 first time JCV Positive –no titre• March 2015 JCV positive titre 2.49• Repeated May2015 JCV positive titre 3.19.• Expressed extreme anxiety regarding risk of PML.• Wishing to consider stopping or changing to another

treatment.

What is his risk of PML?

• Some persisting doubt as to whether this was MS given aggressive presentation.

• • ? Multiphasic ADEM.

• Tysabri stopped after stable MRI June 2015.• Represented August 2015 with new symptoms.• “Visual Snow”. Vague description of visual

disurbances.• No focal signs.

• Given time scale decided this was MS reactivation.

• Restarted on Natalizumab.• MRI stabilised but increasing concern

about PML.• Discussion about changing treatment.• Decision to change to alemtuzemab with

fingolimod as bridging agent.

• Option 3• Further MRI with contrast.• LP. CSF negative for JCV PCR• Admitted for first dose monitoring

fingolimod 20/08/2016.• Represented 29/09/2016, confused

agititated, word finding difficulty and worsening of visual disturbance.

• Admitted.

Options now?

• IV methyl prednisolone.• Further LP and csf testing for JCV

negative at several institutions.• Brain Biopsy?• Urgent switch to Alemtuzemab?• Rituximab off label?• Decision back onto Natalizumab but with

very close surveillance.

Why still Natalizumab?

RESTORE ( Natalizumab treatment interruption)

• Disease recurred in large proportion of patients who discontinued Natalizumab treatment.

• Radiologic disease recurrence was more frequent in patients with high disease activity (relapses) prior to Natalizumab treatment than those with lower disease activity.

• MRI evidence notable from 12 weeks.• Clinical activity reported from 4-8 weeks

Fingolimod after Natalizumab and the riskof short-term relapse.

• 533 patients from MS base registry.• 10 months follow up.• 30% of patients with disease activity on

natalizumab relapsed within the first 6 months on fingolimod.

• Jokubatis et al, Neurology 2014:82:1204-1211

Natalizumab-Fingolimod• Timing remains an important issue.

• Currently no guidelines for the optimal period between natalizumab cessation and fingolimod start.

• Data suggest that a treatment gap of 2–4 months is an independent predictor of increased relapse risk on fingolimod vs no

treatment gap, whereas a treatment gap of 1 day to 2 months was not.

• This study suggests that a treatment gap of less than 2 months between prior treatment (including natalizumab) cessation and fingolimod commencement reduces the risk of disease reactivation.

Jokubatis et al, Neurology 2014:82:1204-1211

Other potential reasons to consider a switch.

• Neutralizing antibody.• Pregnancy.

• Case:• 42 year old man• Smoker 15-20 day.• Previous IV drug use.• Living with partner and young daughter.• Father has epilepsy. • Presented 02/04/2010 with numbness left

arm and hand. Couldn’t do up buttons.

MRI 02/05/2010

• MRI Scan October 2013 after presented with sensory symptoms in legs.

• KB 28 years old.• Feb 2016 2 weeks numbness R arm and

right foot. Numb right side of tongue. Poor balance and falls.

• OE reduced sensation Right arm, leg and face. Power normal. Plantars flexor.

• GP--- Possible SOL • Urgent referral MAU 19/02/2016.• CT brain. Normal

• Further history • Previously well, no regular medication.• 2 children aged 10 and 3.• No family history.• OE variable convergence spasm.• Positive Hoovers sign.• Sensory loss ( Midline) affecting right face,

arm and leg,variable right sided weakness.• Dx ? Functional. ? MS• MRI

• Diagnosis RRMS confirmed.• Treatment with dimethyl fumarate.• September 2016 new symptoms.• Repeat MRI three enhancing lesions.

• JCV negative.• What would you do next?

Conclusions.

• The disease modifying landscape is becoming more complex as new treatment options become available.

• We need to involve pwMS in decision making .• No accepted treatment algorithm in UK.• Currently no large evidence base to inform

switching between higher efficacy treatments.• Unmet need for treatment registry.• Treat aggressively early. NEDA.

Thank you.