Download The evolving landscape of MS

The evolving landscape of MS
John Woolmore
Consultant Neurologist UHB
FIN14-C173. Date of preparation: September 2014
Plan
•
Introduction
•
Established therapies
•
Newer therapies, “on the horizon”
•
MOA, pivotal trials, other efficacy data, safety
•
NHS England
•
Conclusion and questions
Putative targets for MS therapies
Barten et al Drug Des Devel Ther. 2010;4:343-366; Linker et al, Trends Pharmacol Sci.
Established therapies
•
ABCR/BRACE
•
Tysabri
•
Gilenya
•
(mitoxantrone)
Newer therapies
•
Lemtrada, Alemtuzumab, Campath
•
Tecfidera, Dimethyl fumarate, BG 12
•
Aubagio, Teriflunomide, (leflunomide)
On the horizon
•
Daclizumab - anti IL-2
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Ocrelizumab
•
Firategast alpha4beta1 integrin
•
Ofatumumab
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BAF 312 - S1P1 and S1 P5
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Anti Lingo BIIB033
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Copaxone/glatriamer TIW
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Plegridy 2 weekly IFN beta1a sub cut
•
(Laquinimod)
Daclizumab
•
DECIDE - Presented 11/9/14 ECTRIMS 2014, Kappos et al
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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
Tecfidera
Sustained-Release Dimethyl
Fumarate
Through Activation of Nrf2, DMF/MMF Activate Both Anti-Oxidant and Anti-Inflammatory Responses
DMF/MMF
Under normal conditions,
1 Nrf2 is sequestered in the
cytoplasm via Keap1
2
DMF/MMF cause Nrf2 to translocate to the
nucleus (imitates physiological stress response)
Nrf2
Keap1
Nrf2 activates intrinsic
3 defense mechanisms
Cytoplasm
Antioxidant 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;1812:141-150; Linker RA et al. Brain. 2011;134:679-692;
Scannevin R et al. J Pharmacol Exp Ther. 2012;341:274-284.
Inflammatory response
DEFINE: Proportion of Patients Relapsed
(INEC-Confirmed)
0.6
Probability of Relapse
0.5
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
0.4
0.3
0.2
0.270
0.260
0.1
0
Placebo (n=408)
DMF 240 mg BID (n=410)
DMF 240 mg TID (n=416)
BL
12
24
36
48
60
Time on Study (weeks)
Number
of 243
Patients at
Risk
282
224
Placebo408
356
321
DMF BID410
353
324
303
286
DMF TID416
346
322
301
286
72
84
96
205
190
115
267
255
243
154
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.
DEFINE: Annualized Relapse Rate at 2 Years (Secondary Endpoint)
53%
reduction
vs placebo
P<0.0001
Adjusted Annualized
Relapse Rate (95% CI)*
0.6
48%
reduction
vs placebo
P<0.0001
0.364
0.172
0.189
0.
Placebo (n=408)
BG-12 BID (n=410) BG-12 TID (n=416)
*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.
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)
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)
107 (14)
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)
94 (12)
84 (10)
Abdominal pain upper
47 (6)
76 (10)
94 (11)
Proteinuria*
59 (7)
67 (9)
85 (10)
Flushing
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.
Integrated Safety Analysis: Events Leading to Study Drug Discontinuation (≥1% in Any Group)
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)
13 (2)
Event, n (%)
GI events
4% discontinuation for GI events in DMF BID group
Diarrhea
2 (<1)
7 (<1)
15 (2)
Nausea
0
6 (<1)
14 (2)
Vomiting
0
8 (1)
12 (1)
2 (<1)
6 (<1)
10 (1)
0
5 (<1)
9 (1)
Abdominal pain, upper
Abdominal pain
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.
Natalizumab
AFFIRM: Annualized Relapse Rate
Overall Population

68% reduction in annualized relapse rate vs placebo
1.0
Annualized Relapse Rate (95% CI)
0.9
0.8
0.7
Placebo n=315
Natalizumab n=627
0.78
0.73
68%
reduction
vs placebo
P<0.001
66%
reduction
vs placebo
P<0.001
0.67
70%
reduction
vs placebo
P<0.001
0.6
0.5
0.4
0.3
0.27
0.23
0.20
0.2
0.1
0
Years 0–2
CI=confidence interval.
Polman CH et al. N Engl J Med. 2006;354:899-910.
5
Year 0–1
Years 1–2
AFFIRM: Risk of Disability Progression
Overall Population
6-Month Sustained†
0.4
42% risk reduction
HR=0.58 P<0.001
Placebo 29%
0.3
0.2
0.1
Natalizumab 17%
0
0
12
24
36
48
60 72
Week
84
96 108 120
Proportion with Sustained Progression
Proportion with Sustained Progression
3-Month Sustained*
0.4
54% risk reduction
HR=0.46 P<0.001
0.3
Placebo 23%
0.2
0.1
Natalizumab 11%
0
0
12
24 36
315
627
296
601
283
582
264
567
248
546
240
525
229
517
*Primary endpoint; †prespecified sensitivity analysis.
HR=hazard ratio.
Polman CH et al. N Engl J Med. 2006;354:899-910.
6
Updated Sept 2012
60 72
Week
84
96 108 120
225
521
216
509
Number of Patients at Risk
Number of Patients at Risk
Placebo
Natalizumab
48
216
503
208
490
200
478
199
473
Placebo 315
Natalizumab 627
298
611
287
594
269
581
253
559
246
540
237
532
211
503
211
502
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.
1. Rudick, et al. ECTRIMS 2013; P593.
Incidence per 1000 patients
Natalizumab PML Incidence Estimates by
Treatment Epoch
4.0
3.99
3.64
3.5
3.32
2.97
3.0
2.68
2.65
2.5
2.05
2.0
1.72
1.42
1.5
2.21
1.82
2.41
1.93
0.85
0.67
0.51
1.0
0.5
0.13
0.07
0.03
0.0
Calculations based on exposure through 31st May 2014 and 472 confirmed cases as of 4th June 2014
Biogen Idec, data on file.
2.02
1.49
Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration*
Anti-JCV
Antibody Status
Negative
Positive
Prior IS Use
No
Natalizumab
Exposure
1–24 months
0.1/1000
25–48 months
95% CI 0.01-0.35
49–72 months
No Prior IS Use
Yes
Prior IS Use
0.7/1000
1.8/1000
95% CI 0.5-1.0
95% CI 1.1-2.7
5.3/1000
11.2/1000
95% CI 4.4-6.2
95% CI 8.6-14.3
6.1/1000
95% CI 4.8-7.8
Insufficient data
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 2013. 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 2013. 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.
Teriflunomide
Alemtuzumab
Relapse Reduction:
in RRMS and SPMS Patients
Relapse frequency significantly reduced in
RRMS cohort (p<0.0001)
2.21/patient/yr before treatment vs.
0.19/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
2
Relapses per 3-month
Period, n
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 Rates in RRMS Cohort
1
0
-42
-36
-30
-24
-18-12-6 0
6 12 18 24
30
Months
Before
Alemtuzumab
Treatment
Course=3 or 5 daily 20-mg intravenous administrations.
Coles AJ et al. J Neurol 2006;253:98-108.
a
36 42 48
After
Alemtuzumab
Treatment
Change in EDSS:
in RRMS and SPMS Patients
 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;253:98-108.
‹#›
Fingolimod in MS: efficacy from Phase III studies
0.20
0.10
TRANSFORMS4
1 year, RRMS
(n = 1292)
vs IFNβ-1a IM
-82%*** (Gd+)
-74%*** (T2)
-30%* (3-mo conf.)
-37%* (6-mo conf.)
Placebo
Fingolimod
1
2
(n = 418)
0.5mg
(n = 425)
ARR
ARR
0.30
0.20
0.
40
0.10
-48%***
0.
21
0.00
-70%***
(Gd+)
-74%*** (T2)
-17%, NS (3-mo conf.)
-28%, NS (6-mo conf.)
Placebo
1 Fingolimod
2 0.5mg
(n = 355)
(n = 358)
0.40
East
0.30
0.
33
ARR
ARR
2 years, RRMS
(n = 1083)
vs placebo
0.
18
0.00
0.40
FREEDOMS II2,3
0.
40
-54%***
0.20
0.10
0.00
-52%***
0.
16
IFNβ-1a
1 IM Fingolimod
2
(n = 431)
0.5mg
(n = 429)
-55%*** (Gd+)
-35%** (T2)
-25%, NS (3-mo conf.)
–
BRAIN VOLUME
LOSS
Mean change in brain volume
(%)
ARR
2 years, RRMS
(n =1272)
vs placebo
0.30
ARR
FREEDOMS1
DISABILITY
PROGRESSION
Mean change in brain volume
(%)
0.40
LESIONS†
Mean change in brain
volume (%)
RELAPSES
‹#›
0
Time (months)
6
12
24
0.0
**
–0.2
–0.4
*
–0.6
n = 357
–0.8
***
–1.0
n = 331
–1.2
-35%***
–1.4
0
Time (months)
6
12
24
0.0
–0.2
–0.4
*
***
n = 266
–0.6
***
–0.8
–1.0
–1.2
–1.4
0
0.0
–0.2
-33%***
n = 249
Time (months)
12
24
*** n = 368
–0.4
–0.6
n = 359
–0.8
–1.0
–1.2
-32%***
–1.4
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. pp545-56. ©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
© Novartis
Pharma AG 5/2014 192144
Intramuscular Interferon for Relapsing Multiple Sclerosis, 362: 402–415. Copyright © (2010) Massachusetts Medical Society. Reproduced with permission from Massachusetts Medical
Society
Safety Profile
Safety signals of note (as per
Gilenya Risk Management Plan)
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
‹#›
Incidence of adverse events in FREEDOMS
Fingolimod 0.5mg
(n=425)
Placebo
(n=418)
401 (94%)
387 (93%)
32 (8%)
32 (8%)
43 (10%)
56 (13%)
0 (0%)
2 (<1%)
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
50 (12%)
29 (7%)
Fatigue
48 (11%)
45 (11%)
Cough
43 (10%)
34 (8%)
All adverse events
Patients with ≥1 event
Study drug discontinuation
because of adverse event
Serious adverse events
Patients with ≥1 event
Deaths
Most common adverse events
(increased incidence in
fingolimod group vs placebo)
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.
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
Natalizumab
JCVFingolimod
Alemt
uzum
ab
The landscape
Natalizumab
JCV+
Mitoxantrone
BG12
Efficacy
Teriflunomide
Burden of Therapy for Patient
Questions