1. Switching Therapy in Multiple Sclerosis: Evidence & Challenges
Presenter: Dr Divya
Moderator: Prof R Bhatia
2016

2. Table of contents Case Scenario
Measures of disease activity and progression
When to switch therapy?
What are the options?
Evidence and challenges
Take home message

3. PATIENT PRESENTATION 37 YEAR OLD HOUSE WIFE , Mrs S D

4. Patient Presentation (cont)
Mrs S D
Mrs S D
What will be the next step??
Switch to a DMT ?? Which one?? What is the evidence ??

5. Neuro degeneration and
Changing the course of multiple sclerosis: the need for early
treatment optimization
RELAPSE
Focal
Damage
Inflammation
Disability
Progression
Diffuse
Neuro degeneration and
Brain volume loss
clinical course of MS consists of two
major phases: one early, inflammatory phase and one later, progressive,
inflammatory-independent phase. The widely used first-line therapies beta-interferon (IFN ß) and
glatiramer acetate (GA) have only demonstrated partial efficacy in
the treatment of MS . Considering the
early window of opportunity to influence the accumulation of ir-
reversible long-term damage (Leray et al., 2010; Freedman, 2011),
early switching to a high-efficacy therapy that targets both focal
and diffuse pathology may impact favorably on long-term outcomes
(Bermel et al., 2013; Río et al., 2009).
T. Ziemssen et al. / Multiple Sclerosis and Related Disorders 4 (2015) 460–469
DMT

12. ⩾ 1 relapse with incomplete remission
Criteria that should be considered for the evaluation of clinically relevant and measurable NEDA in patients with relapsing remitting MS that should be considered for treatment adjustment (modified from Gold et al. [2012])
Disability progression
Depending on the individual patient situation, even slight impairments represent a significant impairment in the working ability and quality of life
The EDSS value should categorically be kept under 3 for as long as possible
However, the EDSS is not sensitive enough particularly in its lower ranges
Fatigue and cognitive parameters are not considered enough in the EDSS
MRI parameters
The decision on treatment change should not be based solely on MRI findings
The detection of multiple new or enlarged T2 lesions or gadolineum-enhancing inflammatory lesions can, however, serve as an additional criterion
Relapse activity
The occurrence of one of the following events during therapy should in most cases result in a therapeutic change:
⩾ 1 relapse with incomplete remission
⩾ 1 severe relapse with necessity of escalating acute therapy [ultra high steroid treatment (i.e. 2 g/day for 5 days) or plasma exchange]
⩾ 2 clinically objectified relapses without residual symptoms in 1 year
whenever possible, with evidence of a correspondingly localized lesion in the MRI
there
is no clear definition of treatment failure and no
standardized method of how to follow patients
with MS in order to detect clinical worsening and
disease activity in everyday practice. Although the
crude definition of NEDA including relapse,
EDSS, and MRI parameter represents a good
starting point, this does not completely reflect the
need in clinical practice. In particular, in the low
EDSS ranges, slight clinical worsening and neuropsychological
aspects are not taken into consideration. Neuropsychological
aspects as well as individual working ability and
quality of life should also be included. A switch
should be performed ‘in due time’ in any case,
particularly in order to extend the time in the
lower EDSS range (up to 3), since progression
may be more difficult to stop thereafter
M Stangel, IK Penner et alTherapeutic Advances in Neurological Disorders 8(1).

13. The multi factorial model: the domains of disease activity and their rating to assess disease progression (MSDM points)
The interpretation of the total MSDM score may help in decision making for the optimization of immunomodulatory treatments

15. RISK FACTORS & CLINICAL COURSE IN OUR PATIENT
Debra’s Risk Factors

16. 2009
Debra’s 2009 FLAIR MRI
2010

17. Rationale for Switching
MS involves diverse damage mechanisms
MS is heterogenous
No DMT cures MS
Variability in how well a treatment is tolerated
MS generally results in disability
DMT efficacy may differ
Switching to a theoretically more effective agent is logical for breakthrough disease activity
Data are limited because there have been so few randomized prospective head-to-head trials

18. When to Switch General indications for changing therapy
CNS Drugs
April 2013, Volume 27, Issue 4, pp
When to Switch
General indications for changing therapy
Intolerable side effects
Category
Examples
Adverse reactions
Injection site reaction, infusion reaction, infections
Persistent symptoms
Flu-like symptoms, headache, nausea
Significant and persistent laboratory abnormality
Increased liver enzymes, low WBC
Detection of antibodies
JC virus antibody positivity
Pertinent for natalizumab use
Persistent neutralizing antibodies
Pertinent for natalizumab and IFNβ (high titer antibodies)
Unacceptable breakthrough activity
Clinical activity
Relapses, disability, cognitive status, transition to progressive disease
Neuroimaging activity
Brain MRI, spinal cord MRI abnormalities

19. SUMMARY OF MS THERAPY

20. Unapproved: off-label
CNS Drugs
April 2013, Volume 27, Issue 4, pp
Unapproved: off-label
 Intravenous immunoglobulin
Gammagard, Gamunex, Privigen, Octagam, Carimune, Gamaplex, Flebogamma, Hizentra
IV or SC
Episodic
 Plasma exchange/plasmapheresis
Plasma exchange/plasmapheresis IV
 Anti-CD20 monoclonal
Rituximab/Rituxan (chimeric), Ofatumumab/Arzerra (human)
 Anti-CD25 monoclonal
Daclizumab/Zenapax
 Anti-CD52 monoclonalc
Alemtuzumab/Lemtrada, Campath
Annually
Ocrelizumab (humanized)
 Laquinimod (quinoline 3- carboximide)
Laquinimod PO
Daily
 Azathioprine (purine antimetabolite)
Imuran PO
Daily
 Cladribine (purine antimetabolite)
Cladribine, Leustatin (IV)
SC, IV
Episodic
 Cyclophosphamide (alkylating agent)
Cytoxan, Cyrevia IV
Episodic; single high dose course over four days
 Methotrexate (antifolate antimetabolite)
Rheumatrex, Trexall
PO, intrathecal, IV
Weekly (PO), episodic
 Mycophenolate (purine antimetabolite)
Cellcept, Myfortic
 Glucocorticoids
Prednisone/Deltasone, Methylprednisolone/Solume drol, Dexamethasone/Decadron
IV or PO

21. NZ
TREATMENT LADDER AZ
MITO GA
TERI
DMF
IFNB
FINGO
DMF

22. RECOMMENDATIONS FOR PATIENTS WITH SUBOPTIMAL THERAPEUTIC RESPONSES
Increasing the Frequency of IFN-beta Therapy
Switching From IFN to GA in Patients With Suboptimal Response
Switching From IFN or GA to Natalizumab Therapy
Switching From IFN or GA to Chemotherapeutic Agents
Oral Fingolimod/ BG12
Combination therapy

23. Increasing the Frequency of IFN-beta Therapy
Randomized, comparative study of interferon β-1a treatment regimens in MS: The EVIDENCE Trial
Randomized, controlled, multicenter trial
Compared the efficacy and safety of IFNbeta-1a (Rebif) 44 mcg s/c thrice weekly & IFNbeta-1a (Avonex) 30 mcg IM once weekly
677 patients with RRMS, at least 2 exacerbations of MS in the prior 2 years, and EDSS scores of 0–5.5
The primary endpoint: The proportion of patients who were relapse free at 24 weeks
MRI endpoint: Number of active lesions per patient per scan at 24 weeks
74.9% (254/339) of patients receiving IFNbeta-1a 44 mcg tiw remained relapse free compared with 63.3% (214/338) of those given 30 mcg qw
Injection-site reactions were more frequent with 44 micro g tiw (83% vs 28%, p < 0.001), as were asymptomatic abnormalities of liver enzymes (18% vs 9%, p = 0.002) and altered leukocyte counts (11% vs 5%, p = 0.003) compared with the 30 micro g qw dosage
Neurology. 2002 Nov 26;59(10):

24. Randomized, comparative study of interferon β-1a treatment regimens in MS: The EVIDENCE Trial
The odds ratio for remaining relapse free: 1.9 (95% CI, 1.3 to 2.6; p = ) at 24 weeks and 1.5 (95% CI, 1.1 to 2.1; p = 0.009) at 48 weeks
Patients receiving 44 micro g tiw had fewer active MRI lesions (p < at 24 and 48 weeks) at 48 weeks
Neutralizing antibodies: 25% of 44 mcg tiw p and 2% of patients receiving 30 mcg qw
IFNbeta-1a 44 mcg s/c tiw was more effective than IFNbeta-1a 30 mcg IM qw on all primary and secondary outcomes investigated after 24 and 48 weeks of treatment
 . However, the difference was primarily seen for the first 24 weeks, whereas during the subsequent 24 weeks, the relapse rate was similar for the 2 groups, suggesting a possible faster clinical induction of IFN activity with the higher frequency dosing during the initial 24-week period. Similarly, the disability measures were not different at the end of the 1-year study period
Neurology. 2002 Nov 26;59(10):

25. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomized multicenter study (INCOMIN)
49 (51%) of IFN beta-1b remained relapse-free compared with 33 (36%) given IFN beta-1a relative risk of relapse 0.76; 95% CI ; p=0.03)
42 (55%) compared with 19 (26%)remained free from new T2 lesions at MRI (relative risk of new T2 lesion 0.6; ; p<0.0003)
In both groups, the differences between the two treatments increased during the second year
High-dose interferon beta-1b administered every other day is more effective than interferon beta-1a given once a week
2-year, prospective, randomised, multicentre study
Compared the clinical & MRI benefits of on-alternate-day IFN beta-1b 250 mcg with once-weekly interferon beta-1a 30 mcg
188 patients with relapsing-remitting MS 
IFN beta-1b (n=96), IFN beta-1a (n=92)
Primary outcome measures: Proportion of patients free from relapses & Patients free from new proton density/T2 lesions at MRI assessment
unblinded patients and examiners, limit the conclusions that can be drawn.
Lancet. 2002 Apr 27;359(9316):

26. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis (INCOMIN Trial) II: analysis of MRI responses to treatment and correlation with Nab
Development of MRI active lesions is strongly reduced by EOD-IFNbeta-1b (1 3/76, 17%) t compared with OW-IFNbeta-1a (25/73, 34%), (P = 0.014)
NAb frequency over two-year follow-up: 22/65 (33.8%) in the EOD IFNbeta-1b arm, 4/62 (6.5%) in the OW IFNbeta-1a arm
Logistic regression: NAb status did not affect the risk of MRI activity
Mult Scler. 2006 Feb;12(1):72-6.

27. Quality Assessment in Multiple Sclerosis Therapy (QUASIMS): a comparison of interferon beta therapies for relapsing-remitting multiple sclerosis
Of 4754 patients, 3991 (84%) received IFN-beta as initial therapy
No significant differences among IFN-beta products when used as initial or follow-up therapy on almost all outcome variables
Relapse rate was consistently higher and percentage of relapse-free patients consistently lower for all products used as follow-up versus initial therapy
These results call into question the benefit of switching between IFN-beta preparations/dosing regimens
Large, observational, retrospective, controlled cohort study
Conducted by chart review
Compared the effectiveness and tolerability of available IFN beta preparations for patients of RRMS
Enrolled patients had received one of the four available IFN beta preparations/dosing regimens for >or= 2 years
Outcomes at 1 and 2 years : Change from baseline EDSS score, percentage of progression-free patients (< 1.0 EDSS point), annualized relapse rate (RR), percentage of relapse-free patients, and reasons for therapy change
J Neurol. 2007 Jan;254(1): Epub 2007 Feb 1.

28. Switching From IFN to GA in Patients With Suboptimal Response
Clinical course after change of immuno modulating therapy in relapsing-remitting multiple sclerosis
Switching From IFN to GA in Patients With Suboptimal Response
Population: 85 consecutive RRMS patients who received weekly IFN beta-1a 6 MU i.m. for at least 18 months
Baseline ARR for the 2 years prior to initiating therapy with IFN beta-1a was obtained from charts
Treatment duration 18 to 24 months (mean 19.7 months)
Treatment with IFN beta-1a reduced the mean ARR from 1.41 to 1.23 (P=0.005)
All 85 patients were then switched to glatiramer acetate (GA) 20 mg s.c. daily 
Prospectively followed up for months (mean 37.5 months)
Treatment with GA reduced the mean ARR from 1.23 to 0.53 (P=0.0001)
In patients who were switched because of lack of efficacy (n=62), the mean ARR was reduced from 1.32 on IFN beta-1a to 0.52 on GA (P=0.0001)
In patients who switched because of persistent toxicity (n=23), the mean ARR was reduced from 0.61 on IFN beta-1a to 0.47 on GA (P, non-significant)
Clinical observations such as relapse rate and tolerability may be used as criteria for switching DMT in clinical practice
Eur J Neurol.  2006; 13(5):471-4 (ISSN: )

29. Efficacy of treatment of MS with IFN-1b or glatiramer acetate by monthly brain MRI in the BECOME study
Secondary outcomes : Number of new lesions and clinical exacerbations over 2 years
The primary outcome showed similar median (75th percentile) CAL per patient per scan for months 1–12, 0.63 (2.76) for IFN- 1b, and 0.58 (2.45) for GA (p 0.58)
There were no differences in new lesion or clinical relapses for 2 years
Conclusion: Patients with relapsing multiple sclerosis randomized to interferon beta 1b or glatiramer acetate showed similar MRI and clinical activity
Objective: To compare the efficacy of IFN-1b and GA for suppression of MS disease activity as evidenced on frequent brain MRI
75 patients with relapsing-remitting MS or clinically isolated syndromes
Randomization to standard doses of IFN-1b or GA and followed by monthly brain MRI for up to 2 years
Primary outcome: Number of combined active lesions (CAL) per patient per scan during the first year, which included all enhancing lesions and nonenhancing new T2/FLAIR lesions
There are no published MRI studies comparing interferon beta 1b (IFN
-1b) and glatiramer acetate (GA) for treatment of relapsing multiple sclerosis (MS).
Recent MRI data have suggested that GA and IFN-beta have a similar impact on contrast-enhancing lesion activity after 1 year of therapy.[35] The Betaseron vs Copaxone in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (BECOME) is the first head-to-head, randomized, prospective study comparing IFN-beta-1b and GA by MRI parameters in relapsing MS.
D. Cadavid, MD et al. NEUROLOGY · APRIL 2009

30. Switching From IFN or GA to Natalizumab Therapy
Natalizumab reduced the rate of clinical relapse at one year by 68 percent
(P<0.001)
83 percent reduction in the accumulation of new or enlarging hyperintense
lesions, as detected by T2-weighted MRI over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001)
92 percent fewer lesions in the natalizumab group than in the placebo group at both one and two years (P<0.001)
Natalizumab reduced the risk of the sustained progression of disability and the rate
of clinical relapse in patients with relapsing multiple sclerosis
942 patients
Randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years
The primary end points: Rate of clinical relapse at one year and the rate of sustained progression of disability (EDSS) at 2 years
Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent CI, 0.43 to 0.77; P<0.001)
he adverse events that were significantly more frequent
in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21
percent, P = 0.048) and allergic reaction (9 percent vs. 4 percent, P = 0.012). Hypersensitivity
reactions of
any
kind
occurred in
25 patients
receiving
natalizumab (4
percent),
and
serious
hypersensitivity
8 patients (1
percent)

31. Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon ß-1a IM: Subgroup analyses of TRANSFORMS
Compared with interferon ß-1a intramuscular, fingolimod 0.5 mg significantly reduced annualized relapse rate in patients who were treatment naive, received prior interferon-ß treatment, discontinued prior disease-modifying therapy for unsatisfactory therapeutic effect, or had prior disease-modifying therapy duration of > 1year(Pr0.05, all comparisons)
Similar trends were observed in patients with prior glatiramer acetate treatment
Significant reductions were also seen with fingolimod 1.25 mg for treatment-naive and prior interferon-ß-treated patients
Conclusions: This analysis demonstrates superiority of fingolimod over interferon ß-1a intramuscular regardless of prior (interferon-ß) treatment and prior treatment efficacy and duration
TRANSFORMS: 12-month, phase 3, multicenter, randomized, double-blind, , active-controlled trial, with optional extension
Post-hoc analysis of phase 3 TRANSFORMS data compared Annualized relapse rate and safety of once-daily oral fingolimod 0.5 mg, 1.25 mg, or once weekly interferon ß-1a 30 µg intramuscular for 12 months in 1292 patients with RRMS according to prior disease-modifying therapy, reason for prior disease-modifying therapy discontinuation and prior disease-modifying therapy duration
B.O. Khatri et al. Subgroup analyses of the TRANSFORMS study

32. Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis (DEFINE)
Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg BD, BG-12 at a dose of 240 mg TDS, or placebo
The primary end point: Proportion of patients who had a relapse by 2 years
Other end points : annualized relapse rate, the time to confirmed progression of disability, and findings on MRI
Proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 BD and 26% with BG-12 TDS vs. 46% with placebo, P <.001 for both comparisons)
The annualized relapse rate at 2 years : in the BD BG-12 group and 0.19 in the TDS BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P <.001)
Randomized, double-blind, placebo-controlled phase 3 study
Population:
Diagnosis of RRMS according to the McDonald criteria, Age of 18 to 55 years,
A baseline score of 0 to 5.0 on EDSS
Disease activity as evidenced by at least one clinically documented relapse within 12 months before randomization or a brain MRI obtained within 6 weeks before randomization, that showed at least one gadolinium enhancing lesion
n engl j med 367;12 nejm.org september 20, 2012

33. BG-12 significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T2- weighted hyperintense lesions
The estimated proportion of patients with confirmed progression of disability: 16% in the BG-12 group (BD), 18% in BG-12 group, (TDS) and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P=0.005) and 34% with BG-12 thrice daily (P=0.01)
In patients with relapsing–remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI.
n engl j med 367;12 nejm.org september 20, 2012

34. As compared with placebo, twice daily BG-12, thrice-daily BG-12, and
Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant
As compared with placebo, twice daily BG-12, thrice-daily BG-12, and
Glatiramer acetate significantly reduced new or enlarging T2 W hyper intense lesions and new T1 W hypo intense lesions
In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for ARR (thrice-daily BG-12), new or enlarging T2 W hyper intense lesions (both BG-12 doses), and new T1 W hypo intense lesions (thrice-daily BG-12)
Phase 3, randomized study (CONFIRM study)
Investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing–remitting multiple sclerosis
Active agent, glatiramer acetate included as a reference comparator
The primary end point: annualized relapse rate over a period of 2 years
The study was not designed to test the superiority or non inferiority of BG-12 versus glatiramer acetate
At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12
(0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo
(0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%,
P<0.001; glatiramer acetate, 29%, P = 0.01).

35. Prospective longitudinal observational study
Population: 114 patients of RRMS who failed first line mono therapy , atleast one relapse in last year, EDSS <6
Switch after 3 years, if criteria for treatment failure met: Inadequate efficacy/adverse effects
Every 3 months, patients underwent a full neurological examination
Outcome was compared between the 3-year Before Switch and After Switch treatment periods
Primary outcome measure: annualized relapse rate , Secondary outcome: Proportion of relapse-free patients and the median change in EDSS
Patients were required
to present either two or more relapses per year, a
sustained progression of disability defined as a change
from baseline EDSS score of ‡1 point sustained for at
least 6 months, or continued disease activity visible on
MRI. The adverse events criterion was defined as the
occurrence of either abnormalities in liver enzymes or
white blood cell counts, fever, weakness or fatigue
persisting for more than 24 h post-injection. All relapses were confirmed
within 7 days of symptom onset. A relapse was defined
as new symptoms or worsening of previous symptoms
lasting at least 48 h, characterized by an increase of at
least half a step on the EDSS, an increase of at least two
points on one of the seven functional systems or an
increase of at least one point on two or more of the
functional systems.

37. Patients were switched either from low dose to high-dose interferon-b (IFNb; n = 31)
From from IFNb to glatiramer acetate (GA; n = 52) or mitoxantrone (n = 13), or from GA to IFNb (n = 16)
In 3 years after switching, annualized relapse rates fell by 57–78% according to the group
The proportion of relapse-free patients varied from 56% to 81%
Least improved in patients switching between INFb preparations
Median EDSS scores remained stable in all groups except the GA to IFNb switchers
Conclusion: Patients who fail first-line immunomodulatory therapy generally benefit from switching to another class of immuno modulatory therapy

38. Alemtuzumab for patients with RRMS after disease-modifying therapy: CARE MS II
2 year, rater-masked, randomized controlled phase 3 trial
Population: adults aged 18–55 years with RRMS and at least one relapse on interferon beta or GA
Randomly allocated in a 1:2:2 ratio
S/c IFN beta 1a 44 µg/d thrice a week: iv alemtuzumab 12 mg/d x 5 days at baseline & 3 days at 12months : iv alemtuzumab 24 mg/d
Co primary endpoints : Relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug
Lancet 2012; 380: 1829–39

39. 202 (87%) of 231 patients in IFN beta 1a and 426 (98%) of 436 patients in alemtuzumab 12 mg
104 (51%) patients in the IFN beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI0·39–0·65]; p<0·0001
94 (47%) patients in IFN beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001)
40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in alemtuzumab group (hazard ratio 0·58 [95% CI 0·38–0·87]; p=0·008)
For patients with first-line treatment-refractory RRMS, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability
For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions,334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostlymild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.

41. 95 patients had breakthrough disease on first-line therapy
Open-label retrospective cohort study of 993 patients seen at least four time at study centre
95 patients had breakthrough disease on first-line therapy
60 patients switched to natalizumab, 22 to immuno suppressants and 13 declined the switch [non-switchers]
Outcome: Relapse rate within and across groups before and after the switch
PLoS ONE |

42. Relapse rate in non-switchers did not decrease (6%, p = 0.87)
In the within-group analyses, the relapse rate decreased by 70% (95% CI 50,82%; p,0.001) in switchers to natalizumab and by 77% (95% CI 59,87%; p,0.001) in switchers to immuno suppressants
Relapse rate in non-switchers did not decrease (6%, p = 0.87)
Relative to the reduction among non-switchers, the relapse rate was reduced by 68% among natalizumab switchers (95% CI 19,87%; p = 0.017) and by 76% among the immunosuppressant switchers (95% CI 36,91%; p = 0.004)
PLoS ONE |

44. Back to Mrs S D
Post delivery she was started on Natalizumab after discussing the treatment options, efficacy and side effects
JC virus negative
Doing well on DMT

45. Washout Considerations
CNS Drugs
April 2013, Volume 27, Issue 4, pp
Washout Considerations
Specified time period between DMT switches when a patient is kept off therapy, to allow effects of the original DMT to dissipate
Switch to natalizumab in a patient who has been on an immunosuppressive DMT: Risk of PML!!!! wait till immune system recovers
But Active disease!!!! Rebound disease!!!! on stopping DMT
JC virus status: if negative no wash out beyond a few weeks, if positive wait till lymphopenia recovers
Natalizumab to Fingolimod: Jc virus positive: Exit MRI and wash out period of 4 to 8 weeks

46. Switch principles and suggestions
Document and evaluate all relapses on treatment
  - Face-to-face examination
  - MRI
Switches based on cognitive loss should be verified with formal testing and neuroimaging
Isolated worsening on the neurologic examination, or on brain MRI, should lead to closer monitoring rather than immediate switch
  - With silent brain MRI activity, reassess MRI in several months
• Don’t wait too long to switch
Minimize adherence issues, assess adherence with any breakthrough activity
Screen for disease activity, especially in the first 2 years on therapy
 - Consider monitoring/surveillance MRIs
Take into account prognostic factors to guide switch decisions
  - Switch poor prognosis quickly
  - Consider switch to second-line agent with poor prognosis

47. Thank you !!!

49. Progressive multifocal leukoencephalopathy and natalizumab (Tysabri)®
In more than 3,000 patients who had received natalizumab in trials (average treatment period 17.9 months), PML occurred only in three persons
– The disease occurred only in patients subjected to combination therapy with natalizumab plus Avonex® (n = 2) or following previous, partly overlapping, immunosuppressive pre-treatment under monotherapy
The calculated risk of contracting PML is thus calculated as approx. 1:1,000 following an average treatment period of just under 18 months
Multiple Sclerosis Therapy Consensus Group

50. FDA and EMEA notified healthcare professionals of reports of clinically significant liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, that occurred as early as six days after the first dose of Tysabri®
Natalizumab should be used as monotherapy only, in approved dosages and application intervals in immuno competent patients (normal differential blood count and exclusion of infection) and if therapy with recombinant IFN-ß (or glatiramer acetate) has failed
Multiple Sclerosis Therapy Consensus Group

51. There should be a therapy-free interval of at least 14 days before the first dose of natalizumab (Tysabri®) according to current expert opinion
Patients with RRMS not responding to immunosuppressive drugs can be switched to natalizumab (Tysabri®) after considering the risk-benefit ratio and only after at least a 3-month drug-free interval following azathioprine-equivalent drugs and after a much longer interval (up to 6 months) following mitoxantrone (expert opinion)
Multiple Sclerosis Therapy Consensus Group

52. Overview of evidence supporting the treatment positioning of the more recently approved DMT
Teriflunomide
(Sanofi-Aventis Groupe, 2014; Vermersch et al., 2014; O'Connor et al., 2011; Confavreux et al., 2014; Wolinsky et al., 2013; Olsson et al., 2014; Leist et al., 2014)
DMF
(Gold et al., 2012; Fox et al.,2012; Arnold et al., 2014; Milleret al., 2012; Gold et al., 2015;
Hutchinson et al., 2013; Hutchinson et al., 2013; Bar-Or et al., 2013; Tan and Koralnik, 2010; Multiple Sclerosis Society News, 2014; Biogen Idec, 2015)
For treatment-naive patients and mild/moderate disease activity
Mild to moderate efficacy
Homogenous efficacy on clinical disease activity across subgroups stratified by baseline demographics, clinical, and MRI characteristics
No proven efficacy vs. active comparator
No significant reduction in global BVL
High efficacy in newly diagnosed patients
More effective in treatment-naive
patients than in patients previously treated with >1 DMT
No provén efficacy vs. Active comparator
Inconsistent effect on BVL across
clinical trials

53. Fingolimod Natalizumab Alemtuzumab
(Novartis Pharma
GmbH, 2014; Calabresi et al., 2014; Cohen et al., 2010; Bergvall et al., 2014; Khatri et al., 2011; He et al., 2015; Ziemssen et al., 2014; Novartis International AG, 2014;
Havrdová et al., 2011
Natalizumab
(Biogen Idec, 2015; Biogen Idec Ltd, 2014; Polman et al.,2006; Rudick et al., 2006; Miller et al., 2007; Butzkueven et al., 2014; Río et al., 2012; Belachew et al., 2011; Castillo-Trivino et al., 2011; Prosperini et al., 2012, Putzki et al., 2010; Putzki et al., 2009; Putzkiet al., 2010; Bloomgren et al., 2012)
Alemtuzumab
(Genzyme Therapeutics Ltd, 2014; Cohen et al.,2012; Coles et al., 2012; Coles, 2013; Miller et al., 2014)
For patients with (highly) active disease (despite first-line treatment)
High efficacy in patients with disease activity despite prior DMT use
High efficacy in patients who switched from IFNs or GA to fingolimod
Proven efficacy against active comparator (IFN ß-1a IM)
Early and consistent effect on BVL
High efficacy in patients with suboptimal treatment response on IFN ß or GA
No provén efficacy vs. active
comparator
No early and consistent effect on BVL
High efficacy in patients with > 1 relapse on IFN ß or GA
Proven efficacy vs. active comparator (IFN ß-1a SC)
Effect on BVL vs. active comparator (IFN ß-1a SC)

54. Azathioprine for multiple sclerosis (Review)
Alternative to interferon beta for treating MS also because it is less expensive
Concerns about its safety, mainly a possible increased risk of malignancy, has limited its use
Objectives
To compare azathioprine versus placebo
To determine the effect of azathioprine on major clinical outcomes, i.e., disability progression and relapses in patients with MS
Selection criteria
All parallel group randomised controlled trials (RCTs) comparing azathioprine treatment of a least one year duration with placebo for patients with MS
Cohorts, case controls, case series and case reports to assess adverse effect
The Cochrane Library 2007, Issue 4

55. The five trials that met criteria included 698 patients
Data from 499 (71.5%) were available for analysis of relapse frequency at one year's, from 488 (70%) at two years' and from 415 (59.5%) at three years' follow-up
Azathioprine reduced the number of patients who had relapses during the first year of treatment (relative risk reduction [RRR] =20%; 95% CI = 5% to 33%), at two years' (RRR =23%; 95% CI = 12% to 33%) and three years' (RRR =18%; 95% CI = 7% to 27%) follow-up
Data from only three small trials with a total of 87 patients were available to calculate the number of patients who progressed during the first two to three years
There was a statistically significant benefit (RRR = 42%; 95% CI = 7% to 64%) of azathioprine therapy at three years' follow-up
Gastrointestinal disturbances, bone marrow suppression and hepatic toxicity were greater in the azathioprine group rather than in the placebo group; they were anticipated, and, by monitoring and dosage adjustment, were easily managed
Withdrawals due to adverse effects were few, occurring mostly during the first year of azathioprine treatment and mainly due to gastrointestinal intolerance (5%)
Data from the trials and from cohort and case controls studies available in the literature did not show an increase in risk of malignancy from azathioprin
A possible long-term risk of cancer from azathioprine may be related to a treatment duration above ten years and cumulative doses above 600 g