1) There are two broad categories of disease modifying treatments (DMTs) for multiple sclerosis - drugs of moderate efficacy including beta interferons, glatiramer acetate, teriflunomide, and dimethyl fumarate, and drugs of high efficacy including alemtuzumab and natalizumab. 2) The prevailing practice is treatment escalation, starting with a first-line drug and changing treatments based on tolerability, safety, and efficacy. No relapses, disability progression, or MRI activity (NEDA) indicates treatment success. 3) There is no accepted treatment algorithm in the UK. Involving patients in decision making is important as the treatment landscape becomes more complex

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.