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IMPROVING THE PATIENT’S LIFE THROUGH

MEDICAL EDUCATION

Reshaping the immune system in multiplesclerosis: a sustainable goal?

24 November 2016 - Baveno, Italy

New treatment strategies and evidence from clinical trials

Gavin Giovannoni

Version 2.0

Disclosures

Over the last 15 years I have received personal compensation for participating in advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals

Objectives

Learning objectives:

1. Therapeutic strategy in MS (immunology perspective)

2. Evolving therapeutic landscape

3. Define an immunosuppressant

(intermittent/induction therapy vs. persistent/maintenance therapy)

4. List the immunosuppressants used in the treatment of RRMS

5. Pros and cons of intermittent and persistent immunosuppression

6. Review the efficacy and safety of immunosuppressants licensed as DMTs in RR-MS

7. Review strategies to de-risk some of the major adverse events associated with the use

of immunosuppressants in MS

Therapeutic strategy: B- & T-cells and cytokines all play critical roles in the pathogenesis of MS

Th, T helper cell; Treg, regulatory T cell; Tr1, Type 1 regulatory T cell1. McFarland HF, Martin R. Nat Immunol 2007:8:913–9; 2. Cross AH, Waubant E. Biochim Biophys Acta 2011;

3. Weiner HL. Ann Neurol 2009;65:239–48; 4. Noseworthy JH et al. N Engl J Med 2000;343:938–52

Pathogenesis of MS

immune activationinnate and adaptive responses

focal inflammation

BBB breakdown

oligodendrocyte toxicity & demyelination

Acute axonal transection and loss

“autoimmune endophenotype”

axonal plasticity & remyelination

delayed neuroaxonal loss and gliosis

Gd-enhancement

T2 & T1 lesions

brain & spinal cord atrophy

release of soluble markers

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Overview of the changing MS landscape

1994 1996 20001998 2002 2004 2006 2008 2010 2012 2014

SC IFN beta-1b1995 (RMS)

IM IFN beta-1a1997 (RMS)

SC IFN beta-1a 1998 (RMS)

Natalizumab2006 (RRMS)

Glatiramer acetate20 mg/mL

2003 (RMS)Fingolimod

2011 (RRMS)

Alemtuzumab2013 (RRMS)Teriflunomide 2013 (RRMS)

2016

Dimethyl fumarate2014 (RRMS)Peginterferon beta-1a2014 (RRMS)

Daclizumab2016 (RMS)

Glatiramer acetate40 mg/mL2015 (RMS)

Ocrelizumab2017 (RMS/PPMS)

Oral Cladribine2017 (RMS/PPMS)

2018

Licensed Therapies

Unlicensed Therapies

* Immuno-suppressive therapies.

What is an immunosuppressant?

Definition: Immunosuppression is a reduction of the activation or efficacy of the immune system.

This definition refers to short-term/intermittent (induction) and long-term persistent immunosuppression

(maintenance).

For a drug to be considered an immunosuppressant it should:

Cause:

1) significant lymphopaenia2) be associated with opportunistic infections3) reduce the antibody response to vaccines4) be associated with secondary malignancies

1) Interferon-beta

2) Glatiramer acetate

3) Mitoxantrone

4) Natalizumab (selective compartment)

5) Fingolimod & other S1P modulators

6) Teriflunomide

7) Dimethyl fumarate

8) Alemtuzumab

9) Daclizumab

10) Ocrelizumab

11) Cladribine

BARTS-MS T2T-NEDA ALGORITHM T2T = treating-to-target; NEDA = no evident disease activity

Choose therapy

A B C

Define the individual’s MS

Treatment failure?

Individual measures:• Evidence of disease activity?• Tolerability/safety?• Adherence?• Drug or inhibitory markers,

e.g. NABs?

Monitoring

• MS prognosis based on clinical and MRI indices

• Life style and goals • Shared goals for therapy

Rebaseline

Rebaselining:• IFNβ, natalizumab, fingolimod,

teriflunomide, Dimethyl-Fumarate=3-6 months

• Glatiramer acetate=9 months• Alemtuzumab=24 months

Choose a therapeutic strategy

Maintenance-escalation Pulsed immune reconstitution therapy

Choose therapy

X Z

Rebaseline

Monitoring

Initiate or Switch or Escalate Rx Complete course / Re-treat

Breakthrough disease

Y

• Patient’s preferences?• Your choice?

NoYes Yes

IFNβ = interferon-beta; NABs = neutralizing antibodies; Rx = treatment

Maintenance Therapies vs. Pulsed Immune Reconstitution Therapies (PIRTs)

Maintenance Therapies• Continuous treatment• Low to very high efficacy• Reversible• Perceived to be lower risk

• Cumulative, or increased, risk with time• Examples

• Laquinimod, GA, IFNβ, teriflunomide, BG12, fingolimod, natalizumab, daclizumab

• Breakthrough disease• Suboptimal or failure to respond• NEDA reliable metric for efficacy

• Rebound activity• Highly likely• Can be life-threatening

• Pregnancy• No potential for a cure

• Rebound• SPMS and progressive brain atrophy

PIRTs• Short-courses or pulsed therapy• High to very high efficacy• Irreversible• Perceived to be higher risk

• Frontloading of risk or reduced risk with time• Examples

• Mitoxantrone, cladribine, alemtuzumab, anti-CD20 (?), HSCT- BMT

• Breakthrough disease• Marker for retreatment• NEDA unreliable to assess efficacy

• Rebound activity• Less likely• Unlikely to be life-threatening

• Pregnancy• Potentially ‘curative’?

• 15–20-year experiment

The following are not licensed for MS in the UK: laquinimod, daclizumab mitoxantrone, cladribine, anti-CD20 therapies, and BMTPIRTs = pulsed immune reconstitution therapies

Immunosuppression

Continuous 1. Persistent immunosuppression2. Risk increases with time (cumulative)

a. Increase risk of PML (complex pathogenesis)

b. Increased risk of other opportunistic infections

c. Increased risk of secondary malignancy3. Live vaccines contraindicated4. High-risk of exotic infections

a. Dengueb. Zikac. Etc.

5. Pregnancy not recommended6. Long-term burden of pharmacovigilance

Short-term 1. Short-term immunosuppression2. Risk short-term (front-loaded)

a. Low risk of PML b. Low risk of other opportunistic infectionsc. Low risk of secondary malignancy

3. Live vaccines not necessarily contraindicated4. Low-risk of exotic infections if travel occurs

after immune reconstitution

5. Pregnancy safe post immune reconstitution6. Less of a pharmacovigilance burden

Natalizumab

Natalizumab Efficacy

Global Natalizumab PML Incidence Estimates by Treatment Epoch: March 2016

Biogen Data on File, July 2016 www.ms-res.org

Wenning et al. N Engl J Med. 2009;361:1075-80.

Determinants of survival in PML

Marzocchetti et al., Neurology 2009;73:1551–1558 Khatri et al. Neurology 2009;72:402–409.

Fingolimod

APC

Lymph node

S1P-RT

GliosisS1P-R

Fingolimod

Fingolimod

CNS / Immune and Neural

system

Periphery / Immune system

OGD

• Oral, once per day (0.5 mg)

• First in a novel class of therapeutic compounds

• Binds to S1P-Rs expressed on lymphocytes and neural cells in the CNS

• Reversible and selective retention of circulating lymphocytes in lymph nodesnaïve and central memory T cells retained

– immunosurveillance effector memory T cells largely spared

• Acts from within the CNS

– crosses the BBB into the CNS

– reduces astrogliosis and lesional astrocyte activation (S1P receptors are present on astrocytes)

Fingolimod therapeutic MOA in MS

VZV - Chickenpox & Zoster TB

Cryptococcosis HistoplasmosisKaposi’s PML Basal Cell Ca

etc…...

Francis et al. MSJ 2013 Giovannoni et al. Pract Neurol. 2016 Oct;16(5):389-93.

Dimethyl Fumarate

Dimethyl Fumarate: ARR 2-years

DEFINE1,2

2 years, RRMS(n = 1237)

vs placebo

CONFIRM3

2 years, RRMS(n = 1430)

vs placebo

Placebo(n = 363)

DMF(n = 359)

-44%***

GA(n = 350)

AR

R

Placebo(n = 408)

DMF (n = 410)

-53%***A

RR

DMF

Nf-қB transcription

pathway alteration

MФ

Macrophage function

DMF

Nrf2

OSR

Periphery / Immune system

CNS / Immune and

Neural system

• Oral, 240 mg BID

• Dimethyl fumarate

– constituent of Fumaderm®, a treatment for psoriasis

– rapidly hydrolysed in vivo to MMF (active metabolite)1,2

• Exact mechanism of action not fully elucidated, several potential targets1-3

• Primary effect on the immune system is thought to be alteration of the Nf-қB and Nrf2 pathways4,5

– affects inflammatory cytokines, chemokines, adhesion molecules, and T cell apoptosis

• Other putative mechanisms of action include

– preclinical evidence suggests that DMF may exert neuroprotective effects via upregulation of Nrf2 to defend against the oxidative stress response (OSR)4,5

– suppression of macrophage function via Nrf2-dependent and Nrf2-independent pathways6

Characterizing absolute lymphocyte count profiles in dimethyl fumarate–treated patients with MS

Fox et al. Neurol Clin Pract. 2016 Jun;6(3):220-229.

Alemtuzumab

1. Weber MS et al. Results Probl Cell Differ 2010;51:115-26; 2. Hu Y et al. Immunology 2009;128;260-70; 3.Turner MJ et al. J Neuroimmunol 2013;261:29-36; 4. Cox AL et al. Eur J Immunol 2005;35:3332-42; 5. Fox EJ. Exp Rev Neurother 2010;10:1789-97.

Alemtuzumab: mechanism of action1. Selection

• Animal studies indicate that innate immune cells that express lower levels of CD52 are minimally or transiently impacted by alemtuzumab treatment2

2. Depletion

Decreases MS inflammation

• Alemtuzumab selectively depletes circulating T and B cells2,3

• Many lymphocytes remain present in lymphoid organs after treatment2,3

3. Repopulation

Reduces MS disease activity• Lymphocyte progenitor cells are presumably

unaffected by alemtuzumab2,4,5

• A distinctive pattern of T- and B-cell repopulation begins within weeks, potentially changing the balance of the immune system2,4,5

BT

CD52 B

CD52T T cellprecursor

Pre/Pro B cell

BCD52

T CD52

Monocytes

Macrophages

Neutrophils

Lymphocyte precursor

Targets T and B cells thought to mediate MS inflammation1

Lymphocyteprecursor

Lymphocyteprecursor

Stem cell

T- and B-cell Pharmacodynamics• Alemtuzumab depleted circulating lymphocytes in SPMS

patients treated between 1994–1997 (N=29)

– CD4 and CD8 counts were 30-40% of pretreatment values 18 months later1

– B cells repopulated more rapidly, with counts reaching 179% of pretreatment values at 18 months

Coles AJ et al. Lancet 1999;354:1691-5.

Tuohy et al. J Neurol Neurosurg Psychiatry 2014;0:1–8.

“Four alemtuzumab-treated patients (5%) fulfilled the definition of secondary progression of two

consecutive SAD events.”

VZV TB Listeria Nocardia

Molluscum HPV

Risks identified in clinical trials

aThrough 48 mo after first exposure.ITP, immune thrombocytopenia; GBM, glomerular basement membrane; mAb, monoclonal antibody.

1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Wynn D, et al. Presented at: European Committee for Treatment and Research in Multiple Sclerosis; 2013; Copenhagen;

P597; 3. Coles AJ, et al. Neurology. 2012;78:1069-1078.

Identified RiskRate in

Alemtuzumab-Treated Patients Notes

ITP

Auto-immune Events

~1% (1 fatality prior

to implementation of monitoring

program)1

• Onset generally occurred 14-36 mo after first exposure1

• Most cases responded to first-line medical therapy1

0.3% (anti-GBM n=2)1

• Generally occurred within 39 mo after last administration1

• Responded to timely medical treatment and did not develop permanent kidney failure2

Nephropathies

Thyroid disorders(Hypo-/hyper-)

~36%a (serious, 1%)1

• Onset occurred 6-61 mo after first Alemtuzumab exposure; peaked in year 3 and declined thereafter3

• Most mild to moderate, most managed with conventional medical therapy, however, some patients required surgical intervention1

• Higher incidence in patients with history of thyroid disorders1

IARs >90% (serious, 3%)1

• Occurred within 24 h of Alemtuzumab administration1

• Most mild to moderate; rarely led to treatment discontinuation1

• May be caused by cytokine release following mAb-mediated cell lysis1

Infections 71% (serious, 2.7%)1

• Incidence highest during first mo after infusion; rate decreased over time2

• More common with Alemtuzumab; mostly mild to moderate1

• Generally of typical duration; resolved following conventional medical treatment1

Switching

Giovannoni et al. Pract Neurol. 2016 Oct;16(5):389-93.

Daclizumab

Annualized Relapse Rate (ARR)

45% Reduction (95% CI: 35.5%, 53.1%)

p<0.0001

(n=922) (n=919)

AR

R

Estimated from a negative binomial regression model adjusted for baseline relapse rate, history of prior IFN beta use, baseline EDSS (≤2.5 vs > 2.5) and baseline age (≤35 vs >35). Patients were censored at the earliest of the following events: 1) start of alternative MS medication, 2) 180 days post treatment discontinuation or 3) end of treatment period. CI, confidence interval.

Adapted from: Amaravadi L, et al. Poster presentation at AAN 2015;P1.149;

IL-2

Daclizumab blocks high-affinity IL-2 receptor signalling, resulting in higher levels of IL-2

available for signalling through intermediate-affinity IL-2 receptor

IL-2 intermediate-affinity (βγ) receptor

IL-2 high-affinity (βαγ) receptor

Daclizumab

Activation

CD4+

TactCD4+ cell

CD4+Tact cell

CD56brig

ht

Bielekova B, et al. Arch Neurol. 2009;66:483–89.

AEs of Special Interest

IFN beta-1a 30 mcg

(n=922)

DAC HYP 150 mg

(n=919)

Infections, n (%)

Any AE

SAEs

523 (57)

15 (2)

595 (65)

40 (4)

Cutaneous events, n (%)

Any AE

SAEs

177 (19)

1 (<1)

342 (37)

14 (2)

Hepatic laboratory abnormalities, n (%)

ALT or AST >5x ULN

ALT >3x ULN and Total Bilirubin >2x ULN

Hy’s Law Cases*

31 (3)

1 (<1)

1

59 (6)

7 (<1)

1

*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.

Ocrelizumab

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.

Antigen

presentatio

n1,2

Autoantibody

production4

Ectopic lymphoid

follicle-like

aggregates5,6

Cytokine

production2,3

B cells play key functional roles in MS

Antigen

presentatio

n1,2

Autoantibody

production4

Ectopic lymphoid

follicle-like

aggregates5,6

Cytokine

production2,3

B cells play key functional roles in MS

Antigen

presentatio

n1,2

Autoantibody

production4

Ectopic lymphoid

follicle-like

aggregates5,6

Cytokine

production2,3

B cells play key functional roles in MS

Antigen

presentatio

n1,2

Autoantibody

production4

Ectopic lymphoid

follicle-like

aggregates5,6

Cytokine

production2,3

B cells play key functional roles in MS

Antigen

presentati

on1,2

Autoantibody

production4

Ectopic lymphoid

follicle-like

aggregates5,6

Cytokine

production2,

3

B cells play key functional roles in MS

Antigen

presentati

on1,2

Autoantibody

production4

Ectopic lymphoid

follicle-like

aggregates5,6

Cytokine

production2,

3

B cells play key functional roles in MS

Antigen

presentati

on1,2

Autoantibody

production4

Ectopic lymphoid

follicle-like

aggregates5,6

Cytokine

production2,

3

B cells play key functional roles in MS

n (%)

Placebon=239

Ocrelizumab 600 mgn=486

Deaths

1 (0.4)

Road traffic accidentSudden cardiac death

Aspiration

4 (0.8)

Pulmonary embolismPneumonia

Pancreas carcinomaPneumonia aspiration

Malignancies

2 (0.8)

Cervix adenocarcinoma in situ (N=1)

Basal cell carcinoma (N=1)

11 (2.3)

Breast cancers (N=4)Endometrial adenocarcinoma (N=1)

T-cell lymphoma (N=1)Histiocytoma (sarcoma) (N=1)

Basal cell carcinoma (N=3)

Oral cladribine

Cladribine must enter cells and be activated in order to exert its effect

Cladribine works by a 4-step mechanism:1. Cladribine enters cell via nucleoside

transporter2. Accumulates intracellularly due to ADA

resistance3. Cladribine is activated by specific kinases4. Activated Cladribine induces selective

lymphocyte reduction

* One of the kinases is deoxycitidine kinase (DCK). The phosphatase is 5’-nucleotidase. Leist TP, Weissert R. Clin Neuropharmacol 2011;34:28–35.

deoxyadenosine cladribine

Efficacy & Safety

Giovannoni G et al. N Engl J Med 2010;362:416–26.

Pakpoor J et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158

Burden of Treatment

Treatment frequency

aTotal number of administrations over the first 12 months of treatment. b3.5 mg/kg. 5 days of treatment separated by 1 month; total number of tablets dependent on weight. c These agents are under clinical investigation and have not been proven to be safe and effective. There is no guarantee they will be approved in the sought-after indication. IFN, interferon; sc, subcutaneous; SmPC, Summary of Product Characteristics. 1. Rebif® EU SmPC; 2. Copaxone® SPC; 3. Aubagio® EU

SmPC; 4. Tecfidera® EU SmPC; 5. Tysabri® EU SmPC; 6. Gilenya® EU SmPC; 7. Lemtrada® EU SmPC; 8. Zinbryta® EU SmPC; 9. Giovannoni G, et al. N Engl J Med 2010;362:416–26; 10. Kappos L et al. Lancet 2011;378:1779–87; 11. Katsarava Z et al. BMC Neurol 2015;15:170; 12. Kruk ME, Schwalbe N. Clin Ther 2006;28:1989–95; 13. Devonshire V et al. Eur J Neurol 2011;18:69–77

Natalizumab5

Teriflunomide3

Dimethyl fumarate4

Fingolimod6

Alemtuzumab7

Daclizumab8

Cladribine tabletsc,9

Ocrelizumabc,10

1 2 3 4 5 6 7 8 9 10 11 12

Month

Glatiramer acetate2

sc IFN β-1a1

Totala

156

10b

12

4

730

5

12

365

365

365

Pre-dose

NEDA-6, 7, ….9

Gd, gadolinium.1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.

Treat-2-targetWhat is NEDA?

× No relapses× No sustained disability progression (EDSS)× No MRI activity

× No new or enlarging T2 lesions × No Gd-enhancing lesions

✓ Normalisation of brain atrophy rates✓ Normalisation of CSF neurofilament levels

✓ Normalisation of retinal nerve fibre layer thickness loss✓ PROM✓ Cognition

✓ OCBs

DAF1,2

Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology

Magliozzi et al. Brain 2007; 130:1089-1104.

NEDA-6, 7, ….10

Gd, gadolinium.1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.

Treat-2-targetWhat is NEDA?

× No relapses× No sustained disability progression (EDSS)× No MRI activity

× No new or enlarging T2 lesions × No Gd-enhancing lesions

✓ Normalisation of brain atrophy rates✓ Normalisation of CSF neurofilament levels✓ Normalisation of retinal nerve fibre layer thickness loss✓ PROM✓ Cognition✓ OCBs

✓ Recovery of function

DAF1,2

Remyelination targets1. BIIB033: anti-LINGO-1 2. GSK239512: histamine H(3) receptor antagonist 3. Clemastine: anti-histamine4. IRX4204 & Bexarotene: RXR-agonists 5. rHIgM22: penatmeric IgM that binds oligodendrocytes6. Benztropine: anticholinergic7. VX15: anti-SEMA4D monoclonal antibody8. ABT555: anti-repulsive guidance molecule (RGMa)

• Treatment of MS is increasingly complex− Monitoring requirement, e.g. lymphopaenia, LFTs, etc. − De-risking strategies, e.g. JCV-testing − maintenance/escalation vs. PIRT− Long-term vs. short-term immunosuppression (cumulative vs.

front-loading of risk)− Burden of treatment

• Emerging therapies; daclizumab, ocrelizumab and oral cladribine− All address an unmet need

• Combination therapy strategies

Conclusion