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Declared no potential conflicts of interests.
Óscar FernándezNeuroscience InstituteService of NeurologyUniversity Regional Hospital “Carlos Haya”Málaga, Spain
The emerging concept of long-term remission in MS: mechanisms of action, rationale and evidence
of new treatments with infrequent dosing
A journey from the past to the future of multiple sclerosis - Sao Paulo, Brazil - 22 August 2017
9.40 – 10.00
O. Fernández
Instituto de Investigación Biomédica (IBIMA)
Hospital Regional Universitario de Málaga
SPAIN
Agenda
• MS an inflammatory, demyelinating and neurodegenerative
disease
• Immunomodulation and Immunosuppression in MS
• Long-term remission: Continuous vs pulsed
immunosuppressants in MS
• Conclusions
The emerging concept of long-term remission in MS: mechanisms of action,
rationale and evidence of new treatments with infrequent dosing
Hemmer B, et al. Lancet Neurol 2015
MS is an autoimmune disease
MS an inflammatory, demyelinating and neurodegenerative disease
Franklin RJM et al. Nat Rev Neurol 2012;8:624-34; 2. Rodgers JM et al. Discov Med 2013;16:53-63.
Immunomodulation-immunosuppresion2
• Goal: Regulate the immune system
• Approach: Target pathophysiological immune processes that are altered in MS. Prevent ongoing neural degenerative processes and provide environment for future repair
Remyelination1
• Goal: Stimulate remyelination of denuded axons
• Approach: Target oligodendrocyte progenitor cells (OPCs) to promote their survival, migration, expansion and/or differentiation
Neuroprotection1
• Goal: Protect the CNS network (includes axons, oligodendrocytes, neurons, microglia and astrocytes) from damage
• Approach: Target innate immune cells and their toxic products while preserving their beneficial activities
Potential Mechanisms of Neuroprotection and Repair
MS an inflammatory, demyelinating and neurodegenerative disease
Compensatory Phase • Adaptative Immune S. • Altered BBB
• Restricted focal lesions • High remyelinative capability (80%)• OPC differentiation
Non- Compensatory Phase • Innate immune S (mycroglia)• Trapped inflammation behind BBB• B cell follicles • CNS global inflammation• Low remyelinative capability (20%)• Restricted OPC differentiation• Cortical demyelination
Fernández O. 2014
RIS CIS RRMS A-not A PROGRESSIVE MS – Act.-Progres.
MS EVOLUTION
MS an inflammatory, demyelinating and neurodegenerative disease
• Immunomodulation
Immunomodulation and Immunosuppression in MS
o An immunomodulator is any drug or substance that has an effect on the immune system.
o An immunomodulator can adjust the immune response to the correct level.
o Immunomodulators strengthen weak immune systems and control overactive immune systems.
Collins English Dictionary.
Copyright © HarperCollins Publishers/https://www.collinsdictionary.com/es/diccionario/ingles/immunomodulator
Acceded on the 30-July-2017
o An immunosuppressant isany drug or substance thatsuppresses the immune response.
o Different immunosuppressants suppress the immune system in different ways. If the immune system acts against the body's healthy tissues, immunosuppressants may be required to reduce immune system activity.
• Immunossupression
Collins English Dictionary.
Copyright © HarperCollins Publishers/https://www.collinsdictionary.com/es/diccionario/ingles/immunomodulator
Acceded on the 30-July-2017
Immunomodulation and Immunosuppression in MS
• Immunossupression
o Immunosuppression is a reduction of the activation or efficacy of the immune system.
o This definition refers to short-term/intermittent (induction/pulsed therapy) and long-term persistent immunosuppression (continuous or maintenance therapy).
o Immunosuppressant are associated with:
✓ Significant lymphopaenia✓Opportunistic infections ✓Reduced antibody response to vaccines ✓ Secondary malignancies
Immunomodulation and Immunosuppression in MS
Based in part on the presentation of G Giovannonni “how to manage higly active MS patients in practice?” presented at EXCEMED
2017 Annual conference in multiple Sclerosis. High quality care for improved patients outcomes. 3 March 2017 – Rome - Italy
•Interferon beta 1a s.c.
•Interferon beta 1b s.c.
•Interferon beta 1a i.m
•Pegylated IFNB 1a s.c.
•Glatiramer Acetate
•Mitoxantrone
•Natalizumab
•Fingolimod
•Teriflunomide
•Dimethylfumarate
•Alemtuzumab
•aHSCT
• Daclizumab• Cladribine• Ocrelizumab• Siponimod• Ofatumumab• Laquinimod
*
* Not commercialized in Spain
Available drugs in the treatment of MS
O. Fernández ECTRIMS 2015
Immunomodulation and Immunosuppression in MS
Immunomodulation and Immunosuppression in MS
http://multiple-sclerosis-research.blogspot.com/2015/01/acute-remyelination-of-ms-lesions.html. Accedd on the 1st of August 2017
• Immunomodulators
o Interferon-beta o Glatiramer acetate
• Immunossupressants
o Mitoxantroneo Natalizumab (selective compartment) o Fingolimod & other S1P modulators o Teriflunomideo Dimethyl fumarateo Alemtuzumabo Daclizumabo Cladribineo Ocrelizumab
Immunomodulation and Immunosuppression in MS
• Is by definition given continuously, without an interruption in dosing
o Cannot induce prolonged immunomodulation/suppression
o Most commonly it cannot induce long-term remission and it does not result in a cure
o A relapse or the evidence of MRI activity (new Gad+ or new or enlarging T2 lesions) while on therapy is an indication of suboptimal response
Continuous / Maintenance Therapy
Long-term remission: Continuous vs pulsed immunosuppressants in MS
Based in part on the presentation of G Giovannonni “how to manage higly active MS patients in practice?” presented at EXCEMED
2017 Annual conference in multiple Sclerosis. High quality care for improved patients outcomes. 3 March 2017 – Rome - Italy
• Induction/Pulsed therapy is by definition given as a short course, i.e. intermittently
and not continuously
o Can induce profound immunomodulation/suppression of short/medium-term
duration, with reconstitution
o Has the ability to induce long-term clinical remission and in some cases the
possibility of a cure
o Additional courses of the therapy are only given if there is a recurrence of activity
(clinical relapses and/or MRI activity - new T2 lesions and/or Gd-enhancing
lesions)
o In some cases the therapy has to be applied at regular intervals (really
pulsed therapy) to maintain the effect
Induction / Pulsed Therapy
Based in part on the presentation of G Giovannonni “how to manage higly active MS patients in practice?” presented at EXCEMED
2017 Annual conference in multiple Sclerosis. High quality care for improved patients outcomes. 3 March 2017 – Rome - Italy
Long-term remission: Continuous vs pulsed immunosuppressants in MS
Escalation when needed (Tx failure)
Tx with IMMDs or IMSs
Continuous / Maintenance Therapy
Continuous
Continuous and them Pulsed (potencial de-escalation)
Fernández O. 2017
Long-term remission: Continuous vs pulsed immunosuppressants in MS
Induction / Pulsed Therapy
Induction with complete remission
Induction therapy with regular re-induction (pulsed therapy) Induction and de-escalation (continuous)
Induction therapy and re-induction if failure
Fernández O. 2017
Long-term remission: Continuous vs pulsed immunosuppressants in MS
Continuous / Maintenance
• Persistent immunomodulation/suppression
• Risk increases with time (cumulative)
o Increase risk of PML (complex pathogenesis)
o Increased risk of other opportunistic infections
o Increased risk of secondary malignancy
• Live vaccines contraindicated
• High-risk of exotic infections
• Pregnancy not recommended
• Long-term burden of pharmacovigilance
• Therapies:
GA, IFNβ, teriflunomide, BG12, fingolimod,
natalizumab (?), daclizumab (?)
Induction / Pulsed
• Intense and short-term (?) immunosuppression
• Risk short-term (front-loaded)
o Low risk of PML
o Low risk of other opportunistic infections
o Low risk of secondary malignancy
• Live vaccines not necessarily contraindicated
• Low-risk of exotic infections if travel occurs after
immune reconstitution
• Pregnancy safe post immune reconstitution
• Less of a pharmacovigilance burden (?)
• Therapies:
Mitoxantrone, alemtuzumab, cladribine,HSCT-BMT
anti-CD20 (?)
Continuous / Maintenance vs Induction / Pulsed Therapy
Based in part on the presentation of G Giovannonni “how to manage higly active MS patients in practice?” presented at EXCEMED
2017 Annual conference in multiple Sclerosis. High quality care for improved patients outcomes. 3 March 2017 – Rome - Italy
Long-term remission: Continuous vs pulsed immunosuppressants in MS
Algoritm used in the treatment of MS
Sorensen PS. Acta Neurol Scand 2016; 1–19
Long-term remission: Continuous vs pulsed immunosuppressants in MS
Terminology and definitions used to describe a more high-risk disease course
Fernández O. Is there a change of paradigm towards more effective treatment early in the course of apparent high-risk MS?.
Multiple Sclerosis and Related Disorders 17 (2017) 75–83
Long-term remission: Continuous vs pulsed immunosuppressants in MS
Fernández O. Is there a change of paradigm towards more effective treatment early in the course of apparent high-risk MS?.
Multiple Sclerosis and Related Disorders 17 (2017) 75–83
Terminology and definitions used to describe a more high-risk disease course
Long-term remission: Continuous vs pulsed immunosuppressants in MS
Alemtuzumab
Long-term remission: Continuous vs pulsed immunosuppressants in MS
Gallo et al. Multiple Sclerosis and Demyelinating Disorders (2017) 2:7
CD52 is a short peptide of 12 amino acids highly expressed on T and B lymphocytes, and at very low levels on natural killer cells (NK), monocytes and macrophages (Mo), while neutrophils (N), dendritic cells (DC) and bone marrow stem
cells (SC) do not express this molecule
Alemtuzumab (MoA)
ADCC
CDC
Apoptosis
Gallo et al. Multiple Sclerosis and Demyelinating Disorders (2017) 2:7
Time-course repopulation of lymphocyte subpopulations in alemtuzumab-treated multiple sclerosis patients
Long-term Efficacy Outcomes After Alemtuzumab for Relapsing Multiple Sclerosis
ARR = annualized relapse rate
Patients Treated With Alemtuzumab in Core StudiesARR
Alemtuzumab 12 mg
Y3 Y4 Y5 Y6 Y0-6
0,130,19
0,16 0,15 0,12 0,170,0
0,2
0,4
0,6
0,8
1,0
AR
R
End of Core
Study
Extension Study
CARE-MS I
Y2
Alemtuzumab 12 mg
0,27 0,22 0,240,19 0,16
0,23
0,0
0,2
0,4
0,6
0,8
1,0
AR
R
CARE-MS II
Y3 Y4 Y5 Y6 Y0-6End of Core
Study
Extension Study
Y2
Long-term Efficacy Outcomes After Alemtuzumab for Relapsing Multiple Sclerosis: Results From the CAMMS03409 Trial
Coles AJ, Arnold DL, Bass AD, et al. Long-term Efficacy and Safety Outcomes After Alemtuzumab for Relapsing Multiple Sclerosis: Results From the
CAMMS03409 Trial. Data presented at the American Academy of Neurology 2017 Annual Meeting (AAN)
Patients Treated With Alemtuzumab in Core StudiesEDSS Score Over Time
Mea
n (
SE)
EDSS
Sco
re
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
4,0
0 6 12 18 24 30 36 42 48 54 60 66 72
Month
CARE-MS Ia
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
4,0
0 6 12 18 24 30 36 42 48 54 60 66 72
CARE-MS IIa
Month
Mea
n (
SE)
EDSS
Sco
re
aObserved valuesbMixed model for repeated measures analysis.
EDSS Score Mean Change From Baseline to Month 72b
• CARE-MS I: +0.09• CARE-MS II: +0.18
Long-term Efficacy Outcomes After Alemtuzumab for Relapsing Multiple Sclerosis: Results From the CAMMS03409 Trial
Coles AJ, Arnold DL, Bass AD, et al. Long-term Efficacy and Safety Outcomes After Alemtuzumab for Relapsing Multiple Sclerosis: Results From the
CAMMS03409 Trial. Data presented at the American Academy of Neurology 2017 Annual Meeting (AAN)
Patients Treated With Alemtuzumab in Core StudiesNEDA
6963 61 63 57
0
20
40
60
80
100
Pa
tie
nts
, %
Y3 Y4 Y5 Y6
CARE-MS I
Y2
Alemtuzumab 12 mg
End of Core Study
6153 55 58 59
0
20
40
60
80
100
Pa
tie
nts
, %
Y3 Y4 Y5 Y6
CARE-MS II
Y2
End of Core Study
Extension StudyExtension Study
Long-term Efficacy Outcomes After Alemtuzumab for Relapsing Multiple Sclerosis: Results From the CAMMS03409 Trial
Coles AJ, Arnold DL, Bass AD, et al. Long-term Efficacy and Safety Outcomes After Alemtuzumab for Relapsing Multiple Sclerosis: Results From the
CAMMS03409 Trial. Data presented at the American Academy of Neurology 2017 Annual Meeting (AAN)
-0,59
-0,87-0,98
-1,14-1,37-1,44
-2,0
-1,5
-1,0
-0,5
0,0
Med
ian
BP
F C
han
ge F
rom
Baselin
e, %
0
Y1 Y2 Y3 Y4 Y5Baseline Y6Extension StudyCore Study
BPF Change From Baseline Median Yearly BPF Change
-0,59
-0,25 -0,19 -0,18 -0,19 -0,17
-1,2-1,0-0,8-0,6-0,4-0,20,00,2
Med
ian
Yearl
y B
PF
Ch
an
ge, % 0
Patients Treated With Alemtuzumab in Core Studies
Brain Volume Loss
CARE-MS I
CARE-MS II
-0,47-0,61 -0,69
-0,88 -0,85-0,96
-2,0
-1,5
-1,0
-0,5
0,0
Med
ian
BP
F C
han
ge F
rom
Baselin
e, %
0
Y1 Y2 Y3 Y4 Y5Baseline Y6Extension StudyCore Study
BPF Change From Baseline
Y1 Y2 Y3 Y4 Y5 Y6
Median Yearly BPF Change
-0,47
-0,22-0,11 -0,19 -0,09 -0,10
-1,2-1,0-0,8-0,6-0,4-0,20,00,2
Med
ian
Yearl
y B
PF
Ch
an
ge, % 0
Y1 Y2 Y3 Y4 Y5 Y6
Extension StudyCore Study
Extension StudyCore Study
Long-term Efficacy Outcomes After Alemtuzumab for Relapsing Multiple Sclerosis: Results From the CAMMS03409 Trial
Coles AJ, Arnold DL, Bass AD, et al. Long-term Efficacy and Safety Outcomes After Alemtuzumab for Relapsing Multiple Sclerosis: Results From the
CAMMS03409 Trial. Data presented at the American Academy of Neurology 2017 Annual Meeting (AAN)
Patients Treated With Alemtuzumab in Core StudiesAlemtuzumab Retreatment in Extension
56
27
12
41 0,1
0
20
40
60
80
100
Pa
tie
nts
, %
41
No. of Retreatments Following Core Study
20 3 5
Pooled CARE-MS I/II
Long-term Efficacy Outcomes After Alemtuzumab for Relapsing Multiple Sclerosis: Results From the CAMMS03409 Trial
Coles AJ, Arnold DL, Bass AD, et al. Long-term Efficacy and Safety Outcomes After Alemtuzumab for Relapsing Multiple Sclerosis: Results From the
CAMMS03409 Trial. Data presented at the American Academy of Neurology 2017 Annual Meeting (AAN)
Long-term Efficacy of Alemtuzumab Over 10 Years: Long-term Follow-up of Patients With RRMS From the CAMMS223 Study
P3.053. Coles AJ, Habek M, Bass AD, et al. Durable Efficacy of Alemtuzumab Over 10 Years: Long-term Follow-up of Patients With RRMS From the
CAMMS223 Study Presented at the 68th American Academy of Neurology (AAN) Annual Meeting April 15–21, 2016 Vancouver, BC, Canada
P3.053. Coles AJ, Habek M, Bass AD, et al. Durable Efficacy of Alemtuzumab Over 10 Years: Long-term Follow-up of Patients With RRMS From the
CAMMS223 Study Presented at the 68th American Academy of Neurology (AAN) Annual Meeting April 15–21, 2016 Vancouver, BC, Canada
Long-term Efficacy of Alemtuzumab Over 10 Years: Long-term Follow-up of Patients With RRMS From the CAMMS223 Study
P3.053. Coles AJ, Habek M, Bass AD, et al. Durable Efficacy of Alemtuzumab Over 10 Years: Long-term Follow-up of Patients With RRMS From the
CAMMS223 Study Presented at the 68th American Academy of Neurology (AAN) Annual Meeting April 15–21, 2016 Vancouver, BC, Canada
Long-term Efficacy of Alemtuzumab Over 10 Years: Long-term Follow-up of Patients With RRMS From the CAMMS223 Study
Cladribine
Long-term remission: Continuous vs pulsed immunosuppressants in MS
Cladribine produces a selective lymphocyte
reduction for CD4+ T and B cells
• Minor effects on CD8+ T and NK cells
• Acts as a prodrug activated by deoxycytidine kinase
(DCK), producing apoptosis
• Cladribine also crosses the BBB reaching 25% of
plasmatic levels
OH
HOO
N NCI
N
NH2
N
C10H12CIN5O3
MW = 285,69
Synthetic analogue of purine nucleoside
2-cloro-2’-deoxyadenosine (2-CdA)
Cladribine (MoA)
P+ P–
Nucleus
DCK 5'-NTaseADA
Protein transporter of nucleosides
The enzyme ADA
(adenosindeaminase)
eliminates excess of
nucleosides
…Cladribine is directly phosphorylated by DCK
Cladribine inhibits the degradation by ADA
Cladribine is a chlorated analogue of purines, nucleosides that are the substrate for the formation of DNA
At the end, phosphorylated cladribine in excess is dephosphorylated by 5´-Nucleotidase
Cladribine (MoA)
Nucleus
Lymphocytes
Cladribine-
phosphate
Cladribine
…Producing an excesive accumulation of
cladribine nucleotides , that induce pro-apototic
processes
Lymphocytes have a superior ratio of DCK towards 5´nucleotidase in comparison with other cellular subtypes
DCK 5'-NTase
Cladribine (MoA)
Soelberg-Sorensen P, et al. Durable Efficacy of Cladribine Tablets in Patients with Multiple Sclerosis: Analysis of Relapse Rates and Relapse-free Patients in
the CLARITY and CLARITY Extension Studies. Presented at American Academy of Neurology (AAN) 2017; April 22-28, 2017; Boston, MA, USA
Giovannoni G, et al. N Engl J Med 2010;362:416–426.
Tablets of 10 mg• First course: 5 consecutive days in the first mo.
and for five consecutive days in the second mo. • Second course is taken 12 months later
similarly (5 days x 2 mo.)
Cladribine: the CLARITY and CLARITY Extension Studies
Soelberg-Sorensen P, et al. Durable Efficacy of Cladribine Tablets in Patients with Multiple Sclerosis: Analysis of Relapse Rates and Relapse-free Patients in
the CLARITY and CLARITY Extension Studies. Presented at American Academy of Neurology (AAN) 2017; April 22-28, 2017; Boston, MA, USA
Giovannoni G, et al. N Engl J Med 2010;362:416–426.
Cladribine: the CLARITY and CLARITY Extension Studies
G. Giovannoni, et al. Efficacy of Cladribine Tablets 3.5 mg/kg in High Disease Activity (HDA) Subgroups of Patients with Relapsing Multiple Sclerosis (RMS) in
the CLARITY Study. Presented at American Academy of Neurology (AAN) 2017; April 22-28, 2017; Boston, MA, USA
Giovannoni G, et al. N Engl J Med 2010;362:416–426.
Cladribine: the CLARITY Study
Cladribine: the CLARITY Study
Effect of treatment on mean PBVC for months 0–6, 6–24, and rate of disability-progression-free survival in PBVC/year tertiles in the CLARITY study.
De Stefano N, et al. Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis
treated with cladribine tablets. MSJ 2017
aHSCT
Long-term remission: Continuous vs pulsed immunosuppressants in MS
• Proportion of patients maintaining the no evidence of disease activity (NEDA) status over time under different treatment strategies.
• Points connected by a line represent longitudinal observations in the same study.
Sormani MA, et al. Multiple Sclerosis Journal 2016
Proportion With No Evidence of Disease Activity (NEDA ) with different treatments (accumulated)
Autologous Hematopoietic SC Transplantation - NEDA
Ocrelizumab
Long-term remission: Continuous vs pulsed immunosuppressants in MS
Targeting CD20+ B cells may preserve B cell reconstitution and long-term immune memory
Image adapted from Krumbholz M, et al. Nat Rev Neurol 2012;8(11):613–23. 1. Hauser SL. Mult Scler 2015;21(1):8–21. 2. Pescovitz MD. Am J Transplant 2006;6(5 pt 1):859–66.3. Leandro MJ, et al. Arthritis Rheum 2006;54(2):613–20. 4. DiLillo DJ, et al. J Immunol 2008;180(1):361–71.
B-cell Reconstitution1-3
v
Long-term Immune Memory1,2,4
Ocrelizumab is a humanised monoclonal antibody that selectively depletes CD20+ B cells
Ocrelizumab (MoA)
T-Cell ActivationB cells are highly efficient at
presenting antigen to and activating T cells3,4
Formation of Ectopic Follicle-Like Structures
Ectopic B-cell follicles are found in the meninges of patients with MS7
Cytokine ProductionB cells from patients with MS
have abnormal proinflammatory profiles5,6
1. Colombo M, et al. J Immunol. 2000;164(5):2782–9; 2. Qin Y, et al. J Clin Invest. 1998;102(5):1045–50; 3. Constant SL. J Immunol. 1999;162(10):5695–703; 4. Crawford A, et al. J Immunol.2006;176(6):3498–506; 5. Bar-Or A, et al. Ann Neurol. 2010;67(4):452–61; 6. Lisak RP et al. J Neuroimmunol. 2012;246(1-2):85–95; 7. Uccelli A, et al. Trends Immunol. 2005;26(5):254–9.
Autoantibody ProductionB-cell clones produce antibodies in
the CSF and CNS1,2
Growing Evidence Supports Multiple Roles for B Cells in MS Pathophysiology
Ocrelizumab (MoA)
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.
0,292
0,156
0,0
0,1
0,2
0,3
0,4
0,5
IFN β-1a 44 μg
(n=411)
Ocrelizumab 600 mg(n=410)
Ad
just
ed
AR
R a
t 9
6 W
ee
ks*
0,290
0,155
0,0
0,1
0,2
0,3
0,4
0,5
IFN β-1a 44 μg
(n=418)
Ocrelizumab 600 mg(n=417)
Ad
just
ed
AR
R a
t 9
6 W
ee
ks*
46% ARR reduction vs
IFN β-1ap<0.0001
OPERA I OPERA II
47%ARR reduction
vs IFN β-1ap<0.0001
Hauser, SL, et al. Ocrelizumab versus Interferon Beta-1ª in Relapsing Multiple Sclerosis. NEJM 2016; DOI: 10.1056
Primary endpoint:Significant reduction in ARR compared with IFN β-1a
Ocrelizumab
Risk reduction: 40%HR (95% CI): 0.60 (0.45, 0.81); p=0.0006
Risk reduction: 40%HR (95% CI): 0.60 (0.43, 0.84); p=0.0025
Time to 12-week CDP Time to 24-week CDP
ITTCDP, confirmed disability progression; CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR, ocrelizumab.
n
IFN β-1a 828 784 741 696 665 632 608 583 449
OCR 827 795 765 737 716 702 688 672 526
15.2
9.812.0
7.6
n
IFN β-1a 828 785 747 705 677 644 622 600 466
OCR 827 797 772 748 731 717 704 688 540
Secondary endpoints: Significant reduction in CDP in the pre-specified pooled analysis of OPERA I and OPERA II
Ocrelizumab
Hauser, SL, et al. Ocrelizumab versus Interferon Beta-1ª in Relapsing Multiple Sclerosis. NEJM 2016; DOI: 10.1056
No evidence of disease activity (NEDA)
ITT
Exploratory endpoints
*Compared using the Cochran–Mantel–Haenszel test stratified by geographic region (US vs ROW) and baseline EDSS score (<4.0 vs ≥4.0).
EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; IFN, interferon; ROW, rest of the world.
29,2
47,9
0
10
20
30
40
50
60
70
80
IFN β-1a 44 μg
(n=384)
Ocrelizumab 600 mg(n=382)
Pro
po
rtio
n o
f P
atie
nts
With
NED
A(%
)*
NEDA
64%improvement
vs IFN β-1ap<0.0001
NEDA is defined as: no protocol-defined relapses, no CDP events, no new or enlarging T2 lesions, and no Gd+
T1 lesions
OPERA I
25,1
47,5
0
10
20
30
40
50
60
70
80
IFN β-1a 44 μg
(n=375)
Ocrelizumab 600 mg(n=379)
Pro
po
rtio
n o
f P
atie
nts
Wit
h N
EDA
(%)*
89%improvement
vs IFN β-1ap<0.0001
NEDA is defined as: no protocol-defined relapses, no CDP events, no new or enlarging T2 lesions, and no Gd+
T1 lesions
NEDAOPERA II
Percentage Change in Brain Volume from Baseline to Week 96
-1,6
-1,2
-0,8
-0,4
0
0 24 48 96
%C
ha
ng
e F
rom
Ba
selin
e t
o
We
ek
96
(M
ea
n, 9
5%
CI)
IFN β-1a 44 μg
Ocrelizumab 600 mg
Week
OPERA IPercentage Change in Brain Volume
from Baseline to Week 96
-1,6
-1,2
-0,8
-0,4
0
0 24 48 96
%C
ha
ng
e F
rom
Ba
selin
e t
o
We
ek
96
(M
ea
n, 9
5%
CI)
IFN β-1a 44 μg
Ocrelizumab 600 mg
Week
OPERA II
Change in brain volume
Exploratory endpoints compared with IFN β-1a:
23.5%reduction in rate of brain volume loss vs IFN β-1a
p<0.0001
23.8%reduction in rate of brain volume loss vs IFN β-1a
p=0.0001
Hauser, SL, et al. Ocrelizumab versus Interferon Beta-1ª in Relapsing Multiple Sclerosis. NEJM 2016; DOI:10.1056
http://www.nejm.org/doi/suppl/10.1056/NEJMoa1601277/suppl_file/nejmoa1601277_appendix.pdf
Ocrelizumab
Primary endpoint: Significant reduction in 12-week CDP
24% reduction in risk of CDP
HR (95% CI): 0.76 (0.59, 0.98); p=0.0321
Time to 12-week Confirmed Disability Progression
Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and age.Patients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression.CDP, confirmed disability progression; EDSS, Expanded Disability Status Scale; HR, hazard ratio; ITT, intent to treat.
n
Placebo 244 232 212 199 189 180 172 162 153 145 136 120 85 66 46 30 20 7 2
Ocrelizumab 487 462 450 431 414 391 376 355 338 319 304 281 207 166 136 80 47 20 7
Ocrelizumab
Montalban X, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis- NEJM 2016. DOI: 10.1056
Conclusions
• MS is an autoimmune disease in which T (CD4+ and CD8+) and B cells participate in
the immune attack, early in the disease. In later phases the innate immune becomes
predominant
• Increasing evidence suggests that early, optimal intervention is needed to prevent
inflammatory events that ultimately lead to a progressive disease course.
• Because patients with high-risk MS accumulate irreversible neurologic damage more
rapidly than other patients, they have a limited opportunity in which to change the
disease trajectory
• Most probably, these patients are the best candidates for early treatment with
strong, high and long-term efficacy DMTs (Induction/pulsed), either as initial
treatment or in response to the earliest sign of suboptimal DMT response.
• Although the available data on high-efficacy DMTs in high-risk patients are imperfect,
results of subgroup analyses and smaller studies are promising
Fernández O. Is there a change of paradigm towards more effective treatment early in the course of apparent high-risk MS?.
Multiple Sclerosis and Related Disorders 17 (2017) 75–83
Thanks for the attention