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

1. Sequencing of Disease
Modifying Treatments in
Multiple Sclerosis
MS TRUST CONFERENCE
Beaumont Estate
06/11/2016

2. Benefit of Early Treatment

9. Shared Decision Making

10. 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

11. 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

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

13. • 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.

17. • 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??

18. INDUCTION

19. 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.

21. 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).

22. How do we assess this?
• Patient report of relapses.
• Rebaselining with MRI scan after
commencement of treatment.
• Annual MRI monitoring.
• NEDA4
• NEDA5

25. Efficacy Failure
• DMF
• Fingolimod
• Natalizumab
• Clinical trials ie Ocrelizumab
• Potentially
Daclizumab/Cladribine/Rituximab

26. 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.

30. 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.

31. Diagnosis on basis of Clinical and MRI – ADEM
Treated with 3 days IVMP.
Improvement discharged 30/11/2011

32. Represents 06/12/2011 with slurred speech, poor balance
bilateral ptosis.

33. • 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.

34. • 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.

35. What is his risk of PML?

36. • 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.

38. • 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.

40. • 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.

42. 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.

43. Why still Natalizumab?

45. RESTORE
( Natalizumab treatment interruption)

48. • 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

49. Fingolimod after Natalizumab and the risk
of 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

53. 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

55. Other potential reasons to consider
a switch.
• Neutralizing antibody.
• Pregnancy.

57. • 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.

58. MRI 02/05/2010

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

63. • 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

64. • 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

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

70. • JCV negative.
• What would you do next?

72. 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.

73. Thank you.