CARE-MS I

Update der Multiplen Sklerose:
Fakten und Ausblick
Sven G. Meuth
Münster, 05.12.2015
2
Real World
Downloaded from http://www.pointpark.edu/news/real-and-world-marketing-campaign-receives-two-cuppieawards
3
Biomarker
4
Talk 80 – Schwab et al.: PML risk stratification during natalizumab
therapy using anti-JCV antibody index and L-selectin
4. Low CD62L – high probability for
JCV seropositivity
3. Prospective validation
Efalizumab PML
Rituximab PML
Natalizumab acute-PML
HIV-PML
SLE-PML
Lymphopenia-PML
HD
100
90
80
70
60
50
40
30
20
10
0
Natalizumab pre-PML
2. Low CD62L in all forms of PML
% CD62L+ cells of
live CD4+ T cells
1. CD62L proposed as biomarker
5. CD62L and JCV index correlate and
can be used synergistically
as little as 2% at high risk
6. Soluble CD62L as evidence for in
vivo relevance
Therapie
6
Daclizumab HYP: Wirkmechanismus
TCR-Signaling induziert
Expansion von T-Zellen
Expression von CD25 und IL-2
IL-2 Rezeptor
Daclizumab HYP
CD4
CD4+
Aktivierung
Vermehrte Verfügbarkeit
von IL-2
CD56bright
NK
CD56bright
NK
CD56bright
NK
CD4+
CD56bright
NK
CD4+
CD56bright
NK
CD25-Blockade mit Daclizumab HYP
hemmt den Verbrauch von IL-2 durch T-Zellen,
blockiert die Feedbackhemmung der IL-2 Produktion
Vermehrt verfügbares IL2
fördert die über den intermediäraffinen
βγ-Rezeptor vermittelte Expansion von
regulatorischen NK-Zellen
Elkins J et al. Neurol Neuroimmunol Neuroinflamm 2015; 2:e65.
Malek TR. Annu Rev Immunol 2008; 26:453-79.
Wiendl H et al. Nat Rev Neurol 2013; 9:394-404.
TY-GER-0505b
DECIDE: Jährliche Schubrate (ARR)
0,45
0,4
ARR
0,35
0,393
45% ARR-Reduktion
(95% CI: 35.5%, 53.1%)
p<0.0001
0,3
0,25
0,2
0,216
0,15
0,1
0,05
0
IFN beta-1a 30 mcg
DAC HYP 150 mg
(n=922)
(n=919)
Geschätzt nach einem negativen binomialen Regressionsmodell adjustiert nach: Baseline-Schubrate, vorhergehende
Anwendung von IFN beta, Baseline EDSS (≤2,5 vs. > 2,5) und Baseline Alter (≤ 35 vs. >35). Die Patienten wurden anhand
folgender Kriterien zensiert: 1) Beginn einer alternativen MS-Medikation, 2) Absetzten der Medikation nach 180 Tagen im
Anschluss an die Behandlungsphase oder 3) Ende der Behandlungsphase.
Kappos L et al. Presented at ECTRIMS-ACTRIMS; September 10–13, 2014, Boston, MA. Oral presentation FC1.1.
BIIB-GER-0615
DECIDE:
Überblick zur Verträglichkeit
IFN beta-1a
30 µg
(n=922)
DAC HYP
150 mg
(n=919)
842 (91)
838 (91)
Mild
241 (26)
229 (25)
Moderat
493 (53)
482 (52)
Schwerwiegend
108 (12)
127 (14)
SUE (ausschließlich MS-Schübe), n (%)
88 (10)
141 (15)
Abbruch der Behandlung aufgrund von UEs
(ausschließlich MS-Schübe), n
81 (9)
130 (14)
4
1
UE, n (%)
Alle UEs
UE nach Schweregrad
Todesfälle*, n
*Alle Todesfälle wurden als nicht behandlungsbezogen eingestuft. Der Todesfall in der DAC-HYP-Gruppe wurde durch eine
Aspirationspneumonie verursacht. Der entsprechende Patient hatte nach dem Ausscheiden aus der Studie einen MS-Schub,
wobei der Hirnstamm involviert war. Die Todesfälle in der IFN-beta-1a-Gruppe waren auf folgende Ursachen zurückzuführen:
Myokardinfarkt, Suizid, metastatischer Pankreas-Tumor und Peritonitis. UE, unerwünschtes Ereignis; SUE, schwerwiegendes
unerwünschtes Ereignis
Kappos L et al. Presented at ECTRIMS-ACTRIMS; September 10–13, 2014, Boston, MA. Oral presentation FC1.1.
BIIB-GER-0615
UEs von besonderem Interesse
IFN beta-1a
30 µg
(n = 922)
DAC HYP
150 mg
(n = 919)
523 (57)
595 (65)
15 (2)
40 (4)
177 (19)
342 (37)
1 (<1)
14 (2)
ALT oder AST >5x ULN
31 (3)
59 (6)
ALT >3x ULN und Bilirubin (gesamt) >2x ULN
1 (<1)
7 (<1)
1
1
Charakteristika
Infektionen
Alle UEs
SUEs
Kutane Ereignisse
Alle UEs
SUEs
Auffällige Leberwerte
Hy’s-Law-Fälle*
*Clinical assessment of causality based on structured approach (Rockey et al. 2010. Hepatology 51:2117). One case in each
group with causality score of “probable” or higher. ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; ULN,
upper limit of normal.
Kappos L et al. Presented at ECTRIMS-ACTRIMS; September 10–13, 2014, Boston, MA. Oral presentation FC1.1.
BIIB-GER-0615
Therapie
11
CARE-MS Verlängerungsstudien
Extension Study3
(Safety and Efficacy Follow-Up)
CARE-MS I or II
Core Studies
Received
Alemtuzumab1,2
n=742/811
Monitor for MS
activity in
extension trial
to month 48
Received
SC IFNB-1a1,2
n=290/389
Administer
two annual
treatment
courses
No
Relapse
or 2 active
MRI
lesions?
Yes
May receive one
optional re-treatment
course (12 mg IV x 3
days)
not sooner than
12 months after the
previous course
Other DMTs used at
investigators
discretion
1. Coles AJ et al. ACTRIMS-ECTRIMS 2014; P090; 2. Hartung H-P et al. ACTRIMS-ECTRIMS 2014; P043; 3..
Fox E et al. AAN 2013, S41.001; 4. Data on File. Genzyme, a Sanofi Company.
Alemtuzumab-Behandlungsphasen über 5 Jahre
Patienten, die Alemtuzumab in den Zulassungsstudien
bekamen
CARE-MS I – Year 5 Re-treatments1
CARE-MS II – Year 5 Re-treatments2
Alemtuzumab 12 mg
0
1
2
3
Frequency of Retreatment Over
Years 2–5
~2% of patients received other DMTs
through year 5
Alemtuzumab 12 mg
0
1
2
3
Frequency of Retreatment Over
Years 2–5
~8% of patients received other
DMTs through year 5
1. Havrdova E et al. ECTRIMS 2015. Platform; 2. Fox E et al. ECTRIMS 2015. P1102.
ARR über 5 Jahre
Patienten, die Alemtuzumab in den Zulassungsstudien
bekamen
CARE-MS II2
CARE-MS I1
SC IFNB-1a 44 μg
Alemtuzumab 12 mg
SC IFNB-1a 44 μg
Alemtuzumab 12 mg
P<0.0001
(↓55%)
Year 0–2
(Core study)
68% of patients had not
received alemtuzumab
treatment since Month 12
Year 3
Year 5
Year 4
(Extension) (Extension) (Extension)
P<0.0001
(↓49%)
Year 0–2
(Core study)
60% of patients had not
received alemtuzumab
treatment since Month 12
Year 3
Year 5
Year 4
(Extension) (Extension) (Extension)
– ARR in alemtuzumab patients was stable in Years 3, 4, and 5 compared with the core
study
1. Havrdova E et al. ECTRIMS 2015. Platform; 2. Fox E et al. ECTRIMS 2015. P1102.
CARE-MS I and II
Core and Extension
EDSS Ergebnisse über 5 Jahrea
Patienten, die Alemtuzumab in den Zulassungsstudien bekamen
Improved or remained stable
CARE-MS II2
Proportion of Patients, %
Proportion of Patients, %
CARE-MS I1
Worsened
All Alemtuzumab Patients
Alemtuzumab
(No retreatment
or other DMT)
All Alemtuzumab Patients
Alemtuzumab
(No retreatment
or other DMT)
Most patients had improved or stable EDSS over 5 years despite the majority of patients not receiving alemtuzumab since
Month 12 (68% - CARE-MS I; 60% - CARE-MS II)1,2
a≥0.5-Point increase (worsening) or decrease (improvement) in EDSS score from core study baseline
1. Havrdova E et al. ECTRIMS 2015. Platform; 2. Fox E et al. ECTRIMS 2015. P1102.
CARE-MS I and II
Core and Extension
Schilddrüsenautoimmunität über 5 Jahre
Patienten, die Alemtuzumab in den Zulassungsstudien
bekamen
Incidence of Thyroid Adverse Events by Year in
CARE-MS I Core and Extension1
No. of Patients
376
376
360
344
340
Incidence of Thyroid Adverse Events by Year in
CARE-MS II Core and Extension2
No. of Patients
435
434
412
1. Havrdova E et al. ECTRIMS 2015. Platform; 2. Fox E et al. ECTRIMS 2015. P1102; 3. Twyman CL et
al. AAN 2014, P2.199; 4. LEMTRADA (alemtuzumab). Summary of Product Characteristics. 2013.
Genzyme Therapeutics Ltd, Oxford, United Kingdom.
387
367
CARE-MS Core and
Extension
ALAIN01: Alemtuzumab in Autoimmune
Inflammatory Neurodegeneration
Phase IV Study
Design: single center, proof-of-principle study
15 patients with highly active RRMS, Age: 18-55 Jahre
AIM: Understanding MOA and adverse effects
Therapie
18
Efficacy and Safety of Ocrelizumab in Relapsing Multiple
Sclerosis – Results of the Phase III Double-blind, Interferon
beta-1a-controlled OPERA
SL Hauser, GC Comi, H-P Hartung, K Selmaj, A Traboulsee, A Bar-Or, DL Arnold, G
Klingelschmitt, F Lublin, H Garren, L Kappos,
on behalf of the OPERA I and II clinical investigators
OPERA I, NCT01247324; OPERA II, NCT01412333
31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis
2015
Platform presentation number 228
B cells can contribute to the pathophysiology of MS
Cytokine production2,3
Antigen
presentation1,2
Autoantibody production4
Ectopic lymphoid
follicle-like aggregates5,6
1. Crawford A, et al. J Immunol 2006;176(6):3498–506. 2. Bar-Or A, et al. Ann Neurol 2010;67(4):452–61.
3. Lisak RP, et al. J Neuroimmunol 2012;246(1-2):85–95. 4. Weber MS, et al. Biochim Biophys Acta 2011;1812(2):239–45.
5. Serafini B, et al. Brain Pathol 2004;14(2):164–74. 6. Magliozzi R, et al. Ann Neurol 2010;68(4):477–93.
OLE
∙ 18–55 yrs
∙ ≥2 clinical
relapses within
last 2 yrs or 1
relapse in last yr
∙ EDSS of 0.0–5.5
OLE screening period
∙ RMS diagnosis
1:1 Randomisation
OPERA I and II: Two identical studies evaluating the efficacy
and safety of ocrelizumab in RMS
Safety follow-up
≈48 weeks from date of last infusion
B-cell monitoring‡
‡Continued
monitoring occurs if B cells are not repleted.
EDSS, Expanded Disability Status Scale; IFN, interferon; i.v., intravenous; OLE, open-label extension; RMS, relapsing multiple sclerosis; s.c., subcutaneous.
21
Primary endpoint:
Significant reduction in ARR compared with IFN β-1a
OPERA I
0,4
0,3
46%
0,292
0,2
OPERA II
0,5
ARR reduction
vs IFN β-1a
p<0.0001
0,156
0,1
0,0
Adjusted ARR at 96 Weeks*
Adjusted ARR at 96 Weeks*
0,5
0,4
0,3
47%
0,290
0,2
ARR reduction
vs IFN β-1a
p<0.0001
0,155
0,1
0,0
IFN β-1a
44 μg
(n=411)
Ocrelizumab
600 mg
(n=410)
IFN β-1a
44 μg
(n=418)
Ocrelizumab
600 mg
(n=417)
ITT
*Adjusted ARR calculated by negative binomial regression and adjusted for baseline EDSS score (<4.0 vs ≥4.0), and geographic region
(US vs ROW).
ARR, annualised relapse rate; EDSS, Expanded Disability Status Scale; IFN, interferon; ROW, rest of the world.
Secondary endpoints: Significant reduction in CDP in
the pre-specified pooled analysis of OPERA I and
OPERA II
Time to 12-week CDP
Time to 24-week CDP
15.2
12.0
9.8
7.6
Risk reduction: 40%
HR (95% CI): 0.60 (0.45, 0.81); p=0.0006
n
n
IFN β-1a 828
OCR
Risk reduction: 40%
HR (95% CI): 0.60 (0.43, 0.84); p=0.0025
827
784
795
741
765
696
737
665
716
632
702
608
688
583
672
449
IFN β-1a 828
785
747
705
677
644
622
600
466
526
OCR 827
797
772
748
731
717
704
688
540
ITT
CDP, confirmed disability progression; CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR,
ocrelizumab.
Serious adverse events were low over 96 weeks
n (%)
IFN β-1a
44 μg
(n=826)
Ocrelizumab
600 mg
(n=825)
Overall patients with ≥1 SAE
72 (8.7)
57 (6.9)
Infections and infestations
24 (2.9)
11 (1.3)
Nervous system disorders
11 (1.3)
8 (1.0)
Injury, poisoning, and procedural complications
10 (1.2)
6 (0.7)
During OPERA I and OPERA II, three deaths occurred
•
IFN β-1a 44 μg arm: suicide, mechanical ileus
•
Ocrelizumab 600 mg arm: suicide
Six malignancies were reported:
•
IFN β-1a 44 μg arm: mantle cell lymphoma and squamous cell carcinoma
•
Ocrelizumab 600 mg arm: renal cancer, melanoma and two breast cancers
IFN, interferon; SAE, serious adverse event.
Most common AE associated with ocrelizumab was infusionrelated reactions (IRR)
Mostly mild-to-moderate in severity*,†
Mild
30
Moderate
Severe
Life threatening
30
IFN β-1a
44 μg
25
25
Ocrelizumab
600 mg
0.1
1.7
Patients With IRR (%)
Patients With IRR (%)
7.4
20
15
10
5
0.1
1.3
5.1
0
20
15
2.6
10
5
0.9
1.7
Infusion 1 Infusion 2
Dose 1
0.5
1.5
0.1
1.0
0.5
1.4
Dose 2 Dose 3 Dose 4
0.4
0.4
18.3
1.8
1.1
10.8
7.4
3.6
0
1.8
6.0
Infusion 1 Infusion 2
Dose 1
Dose 2 Dose 3 Dose 4
11 patients (1.3%) withdrew from ocrelizumab treatment due to an IRR during the first infusion
*Numbers in columns represent the proportion of patients experiencing a grade of IRR. †Grading per Common Terminology
Criteria. Note: All received 100 mg i.v. methylprednisolone. AE, adverse event; IFN, interferon.
Therapie
26
Anti-LINGO-1 Monoclonal Antibody BIIB033 Improves
Optic Nerve Latency in Acute Optic Neuritis:
Primary Efficacy Analysis of the RENEW Study
Aktas O, Vanopdenbosch L, Comi G, Ziemssen T, Ziemssen F,
Izquierdo G, Frederiksen J, Andersson M, Mareš J,
Lizrova Preiningerova J, Chai Y, Xu L, Cadavid D,
on behalf of the RENEW Study Investigators
Funding source: This study was supported by Biogen (Cambridge, MA, USA)
Financial Disclosures
OA: advisor fees/honoraria/research support from Bayer HealthCare, Biogen, Chugai, Genzyme, MedImmune, Merck Serono,
Novartis, Roche, the Serono Symposia International Foundation and Teva; LV: honoraria/consulting/advisor fees from Biogen,
Genzyme, Merck Serono and Novartis; GC: consulting/speaker fees from Almirall, Bayer HealthCare, Biogen, Chugai, Genzyme,
Merck Serono, Novartis, Receptos, Roche, Sanofi-Aventis, the Serono Symposia International Foundation and Teva; TZ: consulting
fees/research support from Almirall, Bayer HealthCare, Biogen, Genzyme, GlaxoSmithKline, Merck Serono, MSD, Novartis, SanofiAventis, Synthon and Teva; FZ: consulting fees/research support from Alimera, Allergan, Bayer HealthCare and Novartis; GI: speaker
fees from and advisory boards for Almirall, Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi-Aventis and Teva; JF: advisory
boards for and honoraria/travel funding from Almirall, Biogen, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva; speaker
fees from Biogen, Merck Serono and Teva; advisor for Takeda; MA: nothing to disclose; JM: research support from Biogen; JLP:
consulting fees/research support from Biogen, Genzyme, Novartis and Teva; YC, LX and DC: employees of and stockholders in
Biogen.
Writing support was provided by Excel Scientific Solutions (Horsham, UK) and funded by Biogen.
Anti-LINGO1: Das „Schicksal“ demyelinisierter Axone
Neuron
Oligodendrozyt
Myelin
Axon
Demyelinisierung
Remyelinisierung
„Functional Recovery“
Modifiziert nach Franklin RJ., Ffrench-Constant C. Nat Rev Neurosci. 2008 Nov;9(11):839-55.
Keine
Remyelinisierung
Progressive Degeneration
Der anti-LINGO-1 Antikörper fördert die Remyelinisierung
in Mausmodellen
Anti-LINGO-1
*
remyelinisierte Axone
*
*
*
*
EAE
Lysolecithin
Cuprizone
Kontrolle
Mi S. et al. Nat Neurosci. 2004;7:221-228.; Mi S. et al. Nat Neurosci. 2005;8:745-751.; Mi S. et al. Ann Neurol. 2009;65:304-315
BIIB-GER-0263
Methods and Results
METHODS for RENEW (NCT01721161)
–
Population: subjects (18–50 years of age) with a first unilateral acute optic neuritis (AON) episode.
–
Treatment: High-dose steroids, randomised to 100 mg/kg anti-LINGO-1 IV or placebo once every 4 weeks
(6 doses) and followed to Week 32
–
Primary endpoint: improvement in optic nerve conduction latency by full-field (FF)-VEP
–
Additional efficacy analyses (per-protocol / PP population):
–
Change in FF-VEP latency in the affected eye vs baseline of the fellow eye in subgroups stratified by baseline
characteristics (post hoc)
–
Number of subjects with FF-VEP latency recovery in the affected eye at Week 24 by treatment group (pre-specified)
RESULTS
Anti-LINGO-1 improved FFVEP latency of the affected
eye relative to placebo
following acute optic neuritis
•
Consistent
improved
22.24 with14.69
n=33
optic n=36
nerve remyelination
•
Treatment effect more
robust in the PP population
20.83
n=41
17.34
n=41
22.35
n=36
13.22
n=33
21.15
n=41
15.08
n=41
ANCOVA = analysis of covariance; CI = confidence interval; MMRM = mixed-effect model repeated measure; ms = millisecond.
Results (continued)
Subgroup analysis showed greater latency improvement with anti-LINGO-1 in:
FF-VEP treatment difference, msa
Pb
Age < 33 y
≥ 33 y
−0.89
−14.17
.87
.01
Treated < 25 days from AON onset
≥ 25 days from AON onset
−9.01
−6.68
.12
.19
LCLA score = 0, 2.5% Sloan chart
> 0, 2.5% Sloan chart
−6.46
−3.79
.27
.48
HCVA score < 49
≥ 49
−10.92
−4.14
.08
.41
Characteristic
aFF-VEP
= full-field visual evoked potential; HCVA = high-contrast visual acuity; IV = intravenous;
LCLA = low-contrast letter acuity. bFF-VEP treatment difference at Week 24 vs. placebo, based on ANCOVA.
• Older subjects
(≥ 33 years)
• Subjects given the
first dose earlier
• Subjects with more
severe baseline
visual acuity
impairment
Number of patients with FF-VEP latency recovery was increased with anti-LINGO-1:a
– Recovery definition: affected eye FF-VEP latency ≤ 10% worse than the fellow eye
 Week 12: 13 subjects had normal/nearly
normal affected eye FF-VEP latency
- 9 (30%) from the anti-LINGO-1 group
- 4 (13%) from the placebo group (P=.10b)

Week 24: 24 subjects had normal/nearly
normal affected eye FF-VEP latency
- 15 (54%) from the anti-LINGO-1 group
- 9 (27%) from the placebo group (P=.04b)
aPer-protocol population, subjects whose affected eye latency was already normal (≤ 3% worse than fellow eye) at Baseline were
not included. bChi-square.
[email protected]