1. The evolving landscape of MS
John Woolmore
Consultant Neurologist UHB
FIN14-C173. Date of preparation: September 2014

2. Plan Introduction Established therapies
Newer therapies, “on the horizon”
MOA, pivotal trials, other efficacy data, safety
NHS England
Conclusion and questions

3. Putative targets for MS therapies
Barten et al Drug Des Devel Ther. 2010;4: ; Linker et al, Trends Pharmacol Sci. 2008;29:558–

4. Established therapies
ABCR/BRACE
Tysabri
Gilenya
(mitoxantrone)

5. Newer therapies Lemtrada, Alemtuzumab, Campath
Tecfidera, Dimethyl fumarate, BG 12
Aubagio, Teriflunomide, (leflunomide)

6. On the horizon Daclizumab - anti IL-2 Ocrelizumab
Firategast alpha4beta1 integrin
Ofatumumab
BAF S1P1 and S1 P5
Anti Lingo BIIB033
Copaxone/glatriamer TIW
Plegridy 2 weekly IFN beta1a sub cut
(Laquinimod)

7. Daclizumab DECIDE - Presented 11/9/14 ECTRIMS 2014, Kappos et al
DAC HYP once monthly s/c vs IFNB1a
45% reduction in ARR
Relapse risk reduction rate 41%
T2 MRI rate 54% reduction, GAD 65%
6 month disability progression reduced by 27%
Treatment discontinuation 9% - cutaneous events main AEs

8. Sustained-Release Dimethyl Fumarate
Tecfidera
Sustained-Release Dimethyl Fumarate

9. Inflammatory response
Through Activation of Nrf2, DMF/MMF Activate Both Anti-Oxidant and Anti-Inflammatory Responses
Under normal conditions, Nrf2 is sequestered in the cytoplasm via Keap1 1
DMF/MMF
DMF/MMF cause Nrf2 to translocate to the nucleus (imitates physiological stress response) 2
Nrf2
Genes that code for proteins involved in ROS detoxification share a common promoter element, called the antioxidant response element (ARE).
ARE-mediated gene activation is coordinated by Nrf2, which upon exposure to electrophiles or ROS, translocates to the nucleus where it binds ARE and activates antioxidant enzyme gene transcription.
Activation of the Nrf2 pathway may lead to the promotion of cellular detoxification of free radicals, repair of damaged cellular proteins, and normalization of energy metabolism.
Keap1
Nrf2 activates intrinsic
defense mechanisms 3
Cytoplasm
Antioxidant response
Inflammatory response
Nucleus
Nrf2=nuclear factor (erythroid-derived 2)-like 2; Keap1=kelch-like ECH-associated protein. van Horssen J et al. Biochem Biophys Acta. 2011;1812: ; Linker RA et al. Brain. 2011;134: ; Scannevin R et al. J Pharmacol Exp Ther. 2012;341:

10. DEFINE: Proportion of Patients Relapsed (INEC-Confirmed)
0.6
0.5
0.4
0.3
0.2
0.1
HR (95% CI):
BID vs placebo=0.51 (0.40, 0.66); 49% risk reduction; P<0.0001
TID vs placebo=0.50 (0.39, 0.65); 50% risk reduction; P<0.0001
0.461
Probability of Relapse
Placebo (n=408)
DMF 240 mg BID (n=410)
DMF 240 mg TID (n=416) BL
Time on Study (weeks)
Number of Patients at Risk
Placebo
408
356
321
282
243
224
205
190
115
DMF BID
410
353
324
303
286
267
255
154
DMF TID
416
346
322
301
270
251
244
166
DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS; INEC=independent neurology evaluation committee; HR=hazard ration; CI=confidence interval; BID=twice daily; TID=3 times daily; BL=baseline; MS=multiple sclerosis. Gold R et al. Presented at ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands. S34.

11. DEFINE: Annualized Relapse Rate at 2 Years (Secondary Endpoint)
53%
reduction
vs placebo P<0.0001
48%
reduction
vs placebo
P<0.0001
0.364
0.189
0.172
*Annualized relapse rate calculated with negative binomial regression, adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age (<40 vs ≥40 years), region, and number of relapses in the 1 year prior to study entry. DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS; CI=confidence interval; BID=twice daily; TID=3 times daily; EDSS=Expanded Disability Status Scale; MS=multiple sclerosis.
Gold R et al. Presented at ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands. S34.

12. Integrated Safety Analysis: Common Adverse Events (≥10% in Any Group)
Event, n (%)
Placebo
(n=836)
DMF bid
(n=769)
DMF tid
(n=823)
Any adverse event
769 (92)
733 (95)
767 (93)
Flushing
39 (5)
265 (34)
240 (29)
MS relapse
360 (43)
221 (29)
211 (26)
Nasopharyngitis
169 (20)
170 (22)
179 (22)
Headache
137 (16)
133 (17)
138 (17)
Diarrhea
86 (10)
107 (14)
136 (17)
Urinary tract infection
96 (11)
95 (12)
Upper respiratory tract infection
88 (11)
99 (13)
101 (12)
Nausea
72 (9)
93 (12)
115 (14)
Fatigue
91 (11)
94 (12)
103 (13)
Back pain
92 (11)
84 (10)
Abdominal pain upper
47 (6)
76 (10)
94 (11)
Proteinuria*
59 (7)
67 (9)
85 (10)
Indicates ≥3% higher incidence in either dimethyl fumarate group vs placebo.
DMF 240mg BID is the licensed dose , 240mg BID and 240mg TID DMF doses were assessed for safety and efficacy in DEFINE and CONFIRM.
The overall incidence of any GI event was 31%, 40%, and 43% in the placebo, dimethyl fumarate bid, and dimethyl fumarate tid groups, respectively; *no notable differences in levels of BUN and creatinine, urine β2-microglobulin, and urine microalbumin were observed across treatment groups with monitoring every 4 weeks.GI=gastrointestinal; BUN=blood urea nitrogen.
Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.

13. 4% discontinuation for GI events in DMF BID group
Integrated Safety Analysis: Events Leading to Study Drug Discontinuation (≥1% in Any Group)
Event, n (%)
Placebo
(n=836)
DMF bid
(n=769)
DMF tid
(n=823)
Discontinued study drug due to adverse event
94 (11)
109 (14)
117 (14)
MS relapse
48 (6)
11 (1)
13 (2)
Flushing
1 (<1)
24 (3)
GI events
Diarrhea
Nausea
Vomiting
Abdominal pain, upper
Abdominal pain
2 (<1)
7 (<1)
6 (<1)
8 (1)
5 (<1)
15 (2)
14 (2)
12 (1)
10 (1)
9 (1)
4% discontinuation for GI events in DMF BID group
GI=gastrointestinal.
DMF 240mg BID is the licensed dose , 240mg BID and 240mg TID DMF doses were assessed for safety and efficacy in DEFINE and CONFIRM. Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.

14. Natalizumab

15. AFFIRM: Annualized Relapse Rate Overall Population
68% reduction in annualized relapse rate vs placebo
Placebo n=315
Natalizumab n=627
1.0
0.78
0.9
68% reduction
vs placebo
P<0.001
70% reduction
vs placebo
P<0.001
0.73
66% reduction
vs placebo
P<0.001
0.67
0.8
0.7
0.6
Annualized Relapse Rate (95% CI)
0.5
0.4
0.27
0.23
0.20
0.3
0.2
0.1
Years 0–2
Year 0–1
Years 1–2
CI=confidence interval. Polman CH et al. N Engl J Med. 2006;354: 5

16. AFFIRM: Risk of Disability Progression Overall Population
3-Month Sustained*
Placebo 29%
Natalizumab 17%
0.1
0.2
0.3
0.4 12 24 36 48 60 72 84 96
108
120
Number of Patients at Risk
Placebo
Natalizumab
315
296
283
264
248
240
229
216
208
200
627
601
582
567
546
525
517
503
490
478
199
473
Proportion with Sustained Progression
42% risk reduction HR=0.58 P<0.001
Week
6-Month Sustained†
0.1
0.2
0.3
0.4
Week 12 24 36 48 60 72 84 96
108
120
Proportion with Sustained Progression
Natalizumab 11%
Placebo 23%
Number of Patients at Risk
Placebo
Natalizumab
315
298
287
269
253
246
237
225
216
211
627
611
594
581
559
540
532
521
509
503
502
54% risk reduction HR=0.46 P<0.001
*Primary endpoint; †prespecified sensitivity analysis. HR=hazard ratio.
Polman CH et al. N Engl J Med. 2006;354:
•Updated Sept 2012 6

17. Natalizumab: long-term efficacy data from STRATA1 Annualized Relapse Rate
STRATA is an ongoing, open-label, multinational study to evaluate the long-term safety and efficacy of natalizumab in RRMS patients who completed the feeder studies AFFIRM, SENTINEL and GLANCE.
Rudick, et al. ECTRIMS 2013; P593.

18. Natalizumab PML Incidence Estimates by
Treatment Epoch
Calculations based on exposure through 31st May 2014 and 472 confirmed cases as of 4th June 2014
Biogen Idec, data on file.

19. Anti-JCV Antibody Status 0.1/1000 95% CI 0.01-0.35 No Yes
Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration*
Anti-JCV
Antibody Status
Negative
Positive
Prior IS Use No
Yes
Natalizumab
Exposure
No Prior IS Use
Prior IS Use
1–24 months
0.7/ % CI
1.8/ % CI
25–48 months
5.3/ % CI
11.2/ % CI
49–72 months
6.1/1000
95% CI
Insufficient data
0.1/ % CI
Data beyond 4 years of treatment are limited. There are insufficient data to adequately determine PML risk in anti-JCV antibody positive patients with prior IS use and >48 months of natalizumab exposure.
*Based on natalizumab exposure and 343 confirmed PML cases as of 5th March Prior IS data in overall natalizumab-treated patients based on proportion of patients with IS use prior to natalizumab therapy in TYGRIS as of May 2011; and prior IS data in PML patients as of 5th March The analysis assumes that 55% of natalizumab-treated MS patients were anti-JCV antibody positive and that all PML patients test positive for anti-JCV antibodies prior to the onset and diagnosis of PML. The estimate of PML incidence in anti-JCV antibody negative patients is based on the assumption that all patients received at least 1 dose of natalizumab . Assuming that all patients received at least 18 doses of natalizumab, the estimate of PML incidence in anti-JCV antibody negative patients was generally consistent (0.16/1000; 95% CI 0.02–0.56).
Biogen Idec, data on file.

20. Teriflunomide

25. Alemtuzumab

26. Relapse Reduction: in RRMS and SPMS Patients
Relapse Rates in RRMS Cohort
Graph shows episodes reported in RRMS cohort (n=22) before and after treatment with 2 coursesa of alemtuzumab at Months 0 and 12 (red lines)
Relapse frequency significantly reduced in RRMS cohort (p<0.0001)
2.21/patient/yr before treatment vs /patient/yr after treatment
91% reduction
Similar results were seen in the SPMS cohort
The relapse rate fell from 0.7/patient/yr to 0.01/patient/yr (p<0.001; data not shown), which translates to a 98.5% reduction
-42
-36
-30
-24
-18
-12 -6 6 12 18 24 30 36 42 48 1 2
Relapses per 3-month Period, n
MS.US.PO – external/reactive
Months
Before Alemtuzumab Treatment
After Alemtuzumab Treatment
a Course=3 or 5 daily 20-mg intravenous administrations.
Coles AJ et al. J Neurol 2006;253:

27. Change in EDSS: in RRMS and SPMS Patients
MS.US.PO – external/reactive
1 year after alemtuzumab treatment, 33/36 SPMS patients had maintained their pre-treatment EDSS values
However, this proportion decreased with time and this cohort showed an overall worsening of disability
Note: Gradients above the equator represent increasing disability and below the equator represent reducing disability.
Coles AJ et al. J Neurol 2006;253:

33. Fingolimod in MS: efficacy from Phase III studies
RELAPSES
LESIONS†
DISABILITY PROGRESSION
BRAIN VOLUME LOSS
-82%*** (Gd+)
-74%*** (T2)
-30%* (3-mo conf.)
-37%* (6-mo conf.)
-70%*** (Gd+)
-17%, NS (3-mo conf.)
-28%, NS (6-mo conf.)
-55%*** (Gd+)
-35%** (T2)
-25%, NS (3-mo conf.) –
Placebo (n = 418)
Fingolimod 0.5mg (n = 425)
-54%***
ARR
n = 357
n = 331 24
Time (months)
0.0
–0.4
–0.6
–1.4
-35%***
–0.2
–0.8
–1.2
–1.0 12 6 * **
***
Mean change in brain volume (%)
FREEDOMS1
2 years, RRMS (n =1272)
vs placebo
Placebo (n = 355)
Fingolimod 0.5mg (n = 358)
-48%***
ARR
Time (months) 24
0.0
–0.4
–0.6
–1.4
-33%***
–0.2
–0.8
–1.2
–1.0 12 6 *
***
n = 266
n = 249
Mean change in brain volume (%)
Key points
The therapeutic benefit of fingolimod has been seen in three large Phase III clinical trials
Fingolimod reduces the 4 key measures of disease activity:
relapses
MRI lesions
disability progression
brain volume loss
Notes
The primary endpoint for all three studies was ARR
Fingolimod was dosed at 0.5 mg / day
IFNβ-1a IM was dosed at 30 μg / week
This slide is intended to provide a brief overview of the efficacy of fingolimod. Further information on fingolimod and the specific trials can be found in Section 4 of this slide module
FREEDOMS II2,3
2 years, RRMS (n = 1083)
vs placebo
IFNβ-1a IM (n = 431)
Fingolimod 0.5mg (n = 429)
-52%***
ARR 24
Time (months)
0.0
–0.4
–0.6
–1.4
-32%***
–0.2
–0.8
Mean change in brain volume (%)
–1.2
–1.0 12
***
n = 368
n = 359
TRANSFORMS4
1 year, RRMS (n = 1292)
vs IFNβ-1a IM
Data are presented from separate clinical trials Caution is required when indirectly comparing studies due to differences in trial designs and populations
Changes in disability progression shown here were measured using the EDSS scale. % change is vs comparator arm. *p<0.05; **p<0.01; ***p<0.001 vs placebo. †Number of Gd+ lesions or number of new / newly enlarged T2 lesions. ARR, annualised relapse rate; conf., confirmed; IM, intramuscularly; NS, not significant; RRMS, relapsing–remitting MS. 1. From N Engl J Med; Kappos L et al. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis, 362: 387–401. Copyright © (2010) Massachusetts Medical Society. Reproduced with permission from Massachusetts Medical Society; 2. Reproduced from Lancet Neurol 13(6) Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, Li B, Cappiello L, von Rosenstiel P, Lublin FD. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. pp ©2014 with permission from Elsevier; 3. Calabresi PA et al. Poster 015 presented at AAN 2012; 4. From N Engl J Med; Cohen JA et al. Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis, 362: 402–415. Copyright © (2010) Massachusetts Medical Society. Reproduced with permission from Massachusetts Medical Society

34. Safety Profile Incidence of adverse events in FREEDOMS
Safety signals of note (as per Gilenya Risk Management Plan)
Fingolimod 0.5mg
(n=425)
Placebo
(n=418)
All adverse events
Patients with ≥1 event
401 (94%)
387 (93%)
Study drug discontinuation because of adverse event
32 (8%)
Serious adverse events
43 (10%)
56 (13%)
Deaths
0 (0%)
2 (<1%)
Most common adverse events (increased incidence in fingolimod group vs placebo)
Headache
107 (25%)
96 (23%)
Elevated liver enzyme levels
67 (16%)
21 (5%)
Influenza virus infection
55 (13%)
41 (10%)
Diarrhoea
50 (12%)
31 (7%)
Back pain
29 (7%)
Fatigue
48 (11%)
45 (11%)
Cough
34 (8%)
Treatment initiation results in transient decreases in heart rate and may be associated with atrioventricular conduction delays
In clinical trials, macular oedema occurred in 0.4% of fingolimod patients
Lower respiratory tract infections were more common compared to placebo
Liver enzyme elevations observed, primarily during first 12 months of treatment
Vaccination may be less effective during, and for up to 2 months after, treatment
Hypertension was reported for 6.1% of fingolimod patients vs 3.8% placebo patients
There are very limited data on the use of fingolimod in pregnant women; pregnancy should be avoided while on treatment
This is not a complete list; please refer to prescribing information for full information. Gilenya® 0.5mg/day is the only dose approved for the treatment of MS. Kappos L et al. N Engl J Med 2010; Novartis. Gilenya® Summary of Product Characteristics.

35. NICE/ NHSEng - Positioning
First line ABCR/BRACE/Tecfidera/Aubagio/Lemtrada
Second line - highly active - Gilenya/ Lemtrada
n.b. Gilenya post ABCR/BRACE
RES MS - Tysabri/ Lemtrada

36. Burden of Therapy for Patient
The landscape
Natalizumab
JCV-
Natalizumab
JCV+
Burden of Therapy for Patient
Alemtuzumab
Fingolimod
Mitoxantrone
BG12
Efficacy
Teriflunomide

37. Questions