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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

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

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

• 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.

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.

Acceded on the 30-July-2017

• 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

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

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

• 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

• 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

Escalation when needed (Tx failure)

Tx with IMMDs or IMSs

Continuous / Maintenance Therapy

Continuous

Continuous and them Pulsed (potencial de-escalation)

Fernández O. 2017

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

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

Algoritm used in the treatment of MS

Sorensen PS. Acta Neurol Scand 2016; 1–19

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

Terminology and definitions used to describe a more high-risk disease course

Alemtuzumab

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)

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

End of Core

Extension Study

CARE-MS I

Alemtuzumab 12 mg

0,27 0,22 0,240,19 0,16

CARE-MS II

Y3 Y4 Y5 Y6 Y0-6End of Core

Extension 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 StudiesEDSS Score Over Time

0 6 12 18 24 30 36 42 48 54 60 66 72

CARE-MS Ia

0 6 12 18 24 30 36 42 48 54 60 66 72

CARE-MS IIa

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

Patients Treated With Alemtuzumab in Core StudiesNEDA

6963 61 63 57

Y3 Y4 Y5 Y6

CARE-MS I

Alemtuzumab 12 mg

End of Core Study

6153 55 58 59

Y3 Y4 Y5 Y6

CARE-MS II

End of Core Study

Extension StudyExtension Study

-0,87-0,98

-1,14-1,37-1,44

Baselin

Y1 Y2 Y3 Y4 Y5Baseline Y6Extension StudyCore Study

BPF Change From Baseline Median Yearly BPF Change

-0,25 -0,19 -0,18 -0,19 -0,17

-1,2-1,0-0,8-0,6-0,4-0,20,00,2

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

Baselin

Y1 Y2 Y3 Y4 Y5Baseline Y6Extension StudyCore Study

BPF Change From Baseline

Y1 Y2 Y3 Y4 Y5 Y6

Median Yearly BPF Change

-0,22-0,11 -0,19 -0,09 -0,10

-1,2-1,0-0,8-0,6-0,4-0,20,00,2

ge, % 0

Y1 Y2 Y3 Y4 Y5 Y6

Extension StudyCore Study

Patients Treated With Alemtuzumab in Core StudiesAlemtuzumab Retreatment in Extension

41 0,1

No. of Retreatments Following Core Study

20 3 5

Pooled CARE-MS I/II

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

Cladribine

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

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

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

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

• 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

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

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)

*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.

IFN β-1a 44 μg

(n=411)

Ocrelizumab 600 mg(n=410)

IFN β-1a 44 μg

(n=418)

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.

IFN β-1a 828 784 741 696 665 632 608 583 449

OCR 827 795 765 737 716 702 688 672 526

9.812.0

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)

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.

IFN β-1a 44 μg

(n=384)

64%improvement

NEDA is defined as: no protocol-defined relapses, no CDP events, no new or enlarging T2 lesions, and no Gd+

T1 lesions

OPERA I

IFN β-1a 44 μg

(n=375)

89%improvement

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

0 24 48 96

IFN β-1a 44 μg

Ocrelizumab 600 mg

OPERA IPercentage Change in Brain Volume

from Baseline to Week 96

0 24 48 96

IFN β-1a 44 μg

Ocrelizumab 600 mg

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.

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

Thanks for the attention

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