DM seminar Dr Divya SR Neuro, AIIMS

1. 2016
Presenter: Dr Divya
Moderator: Prof R Bhatia

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. Mrs S D
Mrs S D
What will be the next step??
Switch to a DMT ?? Which one?? What is the
evidence ??

5. RELAPSE
Focal
Damage
Inflammation
Disability
Progression
Diffuse
Damage
Neuro
degeneration and
Brain volume loss
DMT
Changing the course of multiple sclerosis: the need for early
treatment optimization
T. Ziemssen et al. / Multiple
Sclerosis and Related Disorders 4
(2015) 460–469

12. 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])
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
M Stangel, IK Penner et alTherapeutic Advances in Neurological Disorders 8(1).
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

13. The multi factorial model: the domains of disease activity and their
rating to assess disease progression (MSDM points)

15. RISK FACTORS & CLINICAL COURSE IN OUR PATIENT

16. 2009
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.  General indications for changing therapy
When to Switch
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
CNS Drugs
April 2013, Volume 27, Issue 4, pp 239-247

19. SUMMARY OF MS THERAPY

20. Unapproved: off-label
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 PO Daily
Glucocorticoids
Prednisone/Deltasone,
Methylprednisolone/Solume
drol,
Dexamethasone/Decadron IV or PO Episodic
CNS Drugs
April 2013, Volume 27, Issue 4, pp 239-247
Intravenous immunoglobulin
Gammagard, Gamunex,
Privigen, Octagam,
Carimune, Gamaplex,
Flebogamma, Hizentra IV or SC Episodic
Plasma
exchange/plasmapheresis
Plasma
exchange/plasmapheresis IV Episodic
Anti-CD20 monoclonal
Rituximab/Rituxan
(chimeric),
Ofatumumab/Arzerra
(human) IV Episodic
Anti-CD25 monoclonal Daclizumab/Zenapax IV or SC Episodic
Anti-CD52 monoclonalc
Alemtuzumab/Lemtrada,
Campath IV Annually
Anti-CD20 monoclonal Ocrelizumab (humanized) IV Episodic
Laquinimod (quinoline 3-
carboximide) Laquinimod PO Daily

21. GA
TERI
DMF
IFNB
FIN
GO
DMF
NZ AZ
MIT
O
TREATMENT LADDER

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.  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
Neurology. 2002 Nov 26;59(10):1496-506
Increasing the Frequency of IFN-beta Therapy
Randomized, comparative study of interferon β-1a treatment
regimens in MS: The EVIDENCE Trial

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 =
0.0005) 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 <
0.001 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
Neurology. 2002 Nov 26;59(10):1496-506

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)
 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
Lancet. 2002 Apr 27;359(9316):1453-60
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 0.59-0.9; 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; 0.45-0.8; 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

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.  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
Quality Assessment in Multiple Sclerosis Therapy (QUASIMS): a
comparison of interferon beta therapies for relapsing-remitting multiple
sclerosis
J Neurol. 2007 Jan;254(1):67-77. Epub 2007 Feb 1.
• 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

28. 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
Clinical course after change of immuno modulating therapy in
relapsing-remitting multiple sclerosis
Eur J Neurol. 2006; 13(5):471-4 (ISSN: 1351-5101)
•Prospectively followed up for 36-42 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

29. Efficacy of treatment of MS with IFN-1b or glatiramer
acetate by monthly brain MRI in the BECOME study
 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
D. Cadavid, MD et al. NEUROLOGY · APRIL 2009
•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

30. Switching From IFN or GA to Natalizumab Therapy
 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)
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

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
 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
•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

32. Placebo-Controlled Phase 3 Study of Oral BG-12 for
Relapsing Multiple Sclerosis (DEFINE)
 Randomized, double-blind, placebo-controlled phase 3 study
 Population:
o Diagnosis of RRMS according to the McDonald criteria, Age of 18 to 55
years,
o A baseline score of 0 to 5.0 on EDSS
o 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
•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 : 0.17 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)

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)
n engl j med 367;12 nejm.org september 20, 2012

34.  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
•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)

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

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

41.  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 | www.plosone.org

42.  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 | www.plosone.org

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
 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
CNS Drugs
April 2013, Volume 27, Issue 4, pp 239-247

46. Switch principles and suggestions
 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
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

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

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

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

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
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
(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)
For patients with (highly)
active disease (despite first-
line treatment)
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. 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
•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
Azathioprine for multiple sclerosis (Review)
The Cochrane Library 2007, Issue 4
Objectives

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