the evolving landscape of ms john woolmore consultant neurologist uhb fin14-c173. date of...
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The evolving landscape of MS
John WoolmoreConsultant 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. 2008;29:558–565.129
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
• Ocrelizumab
• Firategast alpha4beta1 integrin
• Ofatumumab
• BAF 312 - S1P1 and S1 P5
• Anti Lingo BIIB033
• Copaxone/glatriamer TIW
• Plegridy 2 weekly IFN beta1a sub cut
• (Laquinimod)
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
Tecfidera
Sustained-Release Dimethyl Fumarate
Through Activation of Nrf2, DMF/MMF Activate Both Anti-Oxidant and Anti-Inflammatory Responses
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.
Under normal conditions,Nrf2 is sequestered in thecytoplasm via Keap1
DMF/MMF cause Nrf2 to translocate to the nucleus (imitates physiological stress response)
Nrf2 activates intrinsicdefense mechanisms
1
2
3Keap1
Cytoplasm
Nucleus Inflammatory response
Antioxidant response
Nrf2
DMF/MMF
DEFINE: Proportion of Patients Relapsed (INEC-Confirmed)
Placebo408 356 321 282 243 224 205 190 115
DMF BID410 353 324 303 286 267 255 243 154
DMF TID416 346 322 301 286 270 251 244 166
Number of Patients at Risk
HR (95% CI):BID vs placebo=0.51 (0.40, 0.66); 49% risk reduction; P<0.0001TID vs placebo=0.50 (0.39, 0.65); 50% risk reduction; P<0.0001
Placebo (n=408)DMF 240 mg BID (n=410)DMF 240 mg TID (n=416)
Time on Study (weeks)
0.6
0.5
0.4
0.3
0.2
0.1
0
Pro
babi
lity
of R
elap
se
BL 12 24 36 48 60 72 84 96
0.461
0.2700.260
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)
Placebo (n=408) BG-12 BID (n=410) BG-12 TID (n=416)0
0.6
Ad
just
ed
An
nu
aliz
ed
Re
-la
pse
Ra
te (
95
% C
I)*
0.364
0.1720.189
53%reductionvs placeboP<0.0001
48%reductionvs placeboP<0.0001
*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)
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.
Indicates ≥3% higher incidence in either dimethyl fumarate group vs placebo.
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) 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)
Integrated Safety Analysis: Events Leading to Study Drug Discontinuation (≥1% in Any 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.
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) 13 (2)
GI events
Diarrhea
Nausea
Vomiting
Abdominal pain, upper
Abdominal pain
2 (<1)
0
0
2 (<1)
0
7 (<1)
6 (<1)
8 (1)
6 (<1)
5 (<1)
15 (2)
14 (2)
12 (1)
10 (1)
9 (1)
4% discontinuation for GI events in DMF BID group
Natalizumab
AFFIRM: Annualized Relapse RateOverall Population
0.73
0.23
Years 0–2
0.78
0.67
0.270.20
Year 0–1 Years 1–2
Placebo n=315Natalizumab n=627
68%reduction vs placebo
P<0.001
66%reduction vs placebo
P<0.001
70%reduction vs placebo
P<0.001
68% reduction in annualized relapse rate vs placebo
CI=confidence interval.Polman CH et al. N Engl J Med. 2006;354:899-910.
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Annu
alize
d Re
laps
e Ra
te (9
5% C
I)
5
AFFIRM: Risk of Disability ProgressionOverall Population
6-Month Sustained†
0
0.1
0.2
0.3
0.4
Week0 12 24 36 48 60 72 84 96 108 120
Prop
ortio
n w
ith S
usta
ined
Pro
gres
sion
Natalizumab 11%
Placebo 23%
Number of Patients at Risk
PlaceboNatalizumab
315 298 287 269 253 246 237 225 216 211627 611 594 581 559 540 532 521 509 503
211502
54% risk reductionHR=0.46 P<0.001
*Primary endpoint; †prespecified sensitivity analysis. HR=hazard ratio.Polman CH et al. N Engl J Med. 2006;354:899-910.
6
3-Month Sustained*
Placebo 29%
Natalizumab 17%
0
0.1
0.2
0.3
0.4
0 12 24 36 48 60 72 84 96 108 120
Number of Patients at Risk
PlaceboNatalizumab
315 296 283 264 248 240 229 216 208 200627 601 582 567 546 525 517 503 490 478
199473
Prop
ortio
n w
ith S
usta
ined
Pro
gres
sion 42% risk reduction
HR=0.58 P<0.001
Week
•Updated Sept 2012
Natalizumab: long-term efficacy data from STRATA1
Annualized Relapse Rate
1. Rudick, et al. ECTRIMS 2013; P593.
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.
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.
Post Mark
eting
1-12 Infusio
ns
13-24 Infusio
ns
25-36 Infusio
ns
37-48 Infusio
ns
49-60 Infusio
ns
61-72 Infusio
ns0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.03.99
0.13
0.85
2.05
2.65
2.972.68
3.32
0.03
0.51
1.42
1.82 1.93
1.49
3.64
0.07
0.67
1.72
2.212.41
2.02
Inci
denc
e pe
r 100
0 pa
tient
s
0.1/100095% CI 0.01-0.35
No Yes
Anti-JCVAntibody Status
Negative Positive
Prior IS Use
NatalizumabExposure
No Prior IS Use Prior IS Use
1–24 months 0.7/100095% CI 0.5-1.0
1.8/100095% CI 1.1-2.7
25–48 months 5.3/100095% CI 4.4-6.2
11.2/100095% CI 8.6-14.3
49–72 months 6.1/100095% 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 5 th 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 5 th 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).
Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration*
Biogen Idec, data on file.
Teriflunomide
Alemtuzumab
Relapse Reduction: in RRMS and SPMS Patients
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.
0.19/patient/yr after treatment 91% reduction
Similar results were seen in the SPMS cohortThe 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
a Course=3 or 5 daily 20-mg intravenous administrations.Coles AJ et al. J Neurol 2006;253:98-108.
-42-36-30-24-18-12-6 0 6 12182430364248
0
1
2
Relapse Rates in RRMS Cohort
Before Alemtuzumab Treatment
After Alemtuzumab
Treatment
Rela
pse
s per
3-m
onth
Peri
od,
n
Months
Change in EDSS: in RRMS and SPMS Patients
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.
• 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
‹#›
‹#›
© Novartis Pharma AG 5/2014 192144
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 Intramuscular Interferon for Relapsing Multiple Sclerosis, 362: 402–415. Copyright © (2010) Massachusetts Medical Society. Reproduced with permission from Massachusetts Medical Society
-82%*** (Gd+)
-74%*** (T2)
-30%* (3-mo conf.)
-37%* (6-mo conf.)
-70%*** (Gd+)
-74%*** (T2)
-17%, NS (3-mo conf.)
-28%, NS (6-mo conf.)
-55%*** (Gd+)
-35%** (T2)
-25%, NS (3-mo conf.)
–
Fingolimod in MS: efficacy from Phase III studies
FREEDOMS1
2 years, RRMS(n =1272)vs placebo
FREEDOMS II2,3
2 years, RRMS(n = 1083)vs placebo
TRANSFORMS4
1 year, RRMS(n = 1292)vs IFNβ-1a IM
0 24Time (months)
0.0
–0.4
–0.6
–1.4
-32%***
–0.2
–0.8
Me
an
cha
ng
e in
bra
in
volu
me
(%
)
–1.2
–1.0
12
***n = 368
n = 359
n = 357
n = 331
0 24Time (months)
0.0
–0.4
–0.6
–1.4 -35%***
–0.2
–0.8
–1.2
–1.0
126
*
**
***
Me
an
cha
ng
e in
bra
in v
olu
me
(%
)
Time (months)0 24
0.0
–0.4
–0.6
–1.4 -33%***
–0.2
–0.8
–1.2
–1.0
126
****
***
n = 266
n = 249
Me
an
cha
ng
e in
bra
in v
olu
me
(%
)
BRAIN VOLUME LOSS
DISABILITY PROGRESSIONLESIONS†RELAPSES
1 20.00
0.10
0.20
0.30
0.40
0.33 0.1
6
East
AR
R
IFNβ-1a IM(n = 431)
Fingolimod 0.5mg
(n = 429)
-52%***
AR
R
1 20.00
0.10
0.20
0.30
0.40
0.40
0.21
AR
R
Placebo(n = 355)
Fingolimod 0.5mg
(n = 358)
-48%***
AR
R
1 20.00
0.10
0.20
0.30
0.40
0.40
0.18
AR
R
Placebo(n = 418)
Fingolimod 0.5mg
(n = 425)
-54%***A
RR
Data are presented from separate clinical trialsCaution is required when indirectly comparing studies due to differences in trial designs and populations
‹#›
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%) 32 (8%)
Serious adverse events
Patients with ≥1 event 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 50 (12%) 29 (7%)
Fatigue 48 (11%) 45 (11%)
Cough 43 (10%) 34 (8%)
Incidence of adverse events in FREEDOMS
Safety Profile
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.
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
Safety signals of note (as per Gilenya Risk Management Plan)
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
Efficacy
The landscape
Burden of Therapy for Patient
Ale
mt
uzu
mab
Fingolimod
BG12
Teriflunomide
NatalizumabJCV+
NatalizumabJCV-
Mitoxantrone
Questions