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Meccanismi d’azione dei trattamenti: implicazioni sull’efficacia e la sicurezza

Marinella ClericoUniversità degli studi di Torino, A.O.U. San Luigi Gonzaga, Orbassano (TO)

aAzathioprine and cyclophosphamide are not approved for the treatment of MS and have been used off-label

IFN, interferon; im, intramuscular; sc, subcutaneous; SmPC, Summary of Product Characteristics

1. Betaferon® EU SmPC, Sep 2017; 2. Avonex® EU SmPC, Jul 2017; 3. Rebif® EU SmPC, Feb 2018; 4. Copaxone® UK SmPC, Jun 2017; 5. Tysabri® EU SmPC, May 2017;

6. Gilenya® EU SmPC, Feb 2018; 7. Lemtrada® EU SmPC, Feb 2018; 8. Aubagio® EU SmPC, Dec 2017; 9. Tecfidera® EU SmPC, Jan 2018; 10. MAVENCLAD® EU SmPC,

Feb 2018; 11. Ocrevus® EU SmPC, Jan 2018

1994

The goal of treatment is to increase efficacy, improve safety and increase selectivity

Immunomodulation/

immunostimulation

Chronic drug administration

resulting in modulation of immune

function without immunosuppression

Clinical efficacy only

during active treatment

Long periods between

administrations

Non-continuous

administration

Clinical efficacy extends

well

beyond period of active

treatment

Broad-spectrum

immunosuppres

sion

Prior to 1990s,

MS treatment

options limited to

broad-spectrum

immunosuppressa

nts

Selective, continuous

immunosuppression

Chronic drug administration

resulting in ongoing

suppression of

immune function

Clinical efficacy only

during active treatment

Cyclophosphami

dea

Azathioprin

ea

sc IFN β-1b1

im IFN β-1a2

sc IFN β-1a3

Glatiramer acetate4

Alemtuzumab7

Ocrelizumab11

Cladribine Tablets10

Natalizumab5

Dimethyl

fumarate9

Teriflunomide8

Fingolimod6

199

6

199

8

200

0200

2200

4

200

6

200

8201

0

201

2201

4

201

6201

8

The current MS treatment landscape

0

10

20

30

40

50

60

OPERA I1

Ocrelizumaba

vs sc IFN β-1a

Sponsored by Genentech

OPERA II1

Ocrelizumaba

vs sc IFN β-1a

Sponsored by Genentech

CLARITY2

Cladribine Tablets

vs placebo

CARE-MS I3

Alemtuzumabvs sc IFN β-1a

Sponsored by Sanofi

AFFIRM4

Natalizumab vs placebo

Sponsored by Biogen

****** ***

* ***

FREEDOMS5

Fingolimodvs placebo

Sponsored by Novartis

**

CARE-MS II6

Alemtuzumab vs sc IFN β-1a

Sponsored by Sanofi

***

DEFINE7

Dimethyl fumarate

vs placebo

Sponsored by Biogen

*

**

TEMSO8

Teriflunomidevs placebo

Sponsored by Sanofi

Pat

ien

ts a

chie

vin

g N

EDA

(%

)

Data cannot be directly compared between trials because of distinct study

designs and/or patient populations

*p<0.05, **p<0.001, ***p<0.0001 study drug vs comparator. aOcrelizumab is approved for the treatment of MS in the US and EU. NEDA defined as no relapses, no 3-month confirmed CDP, and no new T1 Gd+ lesions and no new enlarging or enlarged T2 lesions on cranial MRI (except CLARITY, CARE-MS I and CARE-MS II: based on no 6-month CDP). CDP, confirmed disability progression; Gd+, gadolinium-enhancing; IFN, interferon; MRI,magnetic resonance imaging; NEDA, no evidence of disease activity; sc, subcutaneous.

1. Traboulsee A, et al. Neurology 2016;86 [PL02.004]; 2. Giovannoni G, et al. Lancet Neurol 2011;10:329‒37; 3. Cohen AJ, et al. Lancet 2012;380:1819–28; 4. Havrdova E, et al. Lancet Neurol 2009;8:254‒60; 5. Bevan CJ, Cree BA. JAMA Neurol 2014;71:269‒70; 6. Coles AJ, et al. Lancet 2012;380:1829–39; 7. Giovannoni G, et al. Neurology 2012;78 [PD5.005]; 8. Freedman M, et al. Neurology 2012;78 [PD5.007].

NEDA is achievable with existing MS therapies

The complex therapeutic landscape of DMDs in MS can be

organized through consideration of efficacy, safety and

treatment burden1

1. Coles AJ. Ann Indian Acad Neurol 2015;18(Suppl. 1):S30–34; 2. MAVENCLAD® SmPC, July 2018.

aSuggested placement based on approved indication and monitoring in EU SmPC2.

DMD, disease-modifying drug; DMF, dimethyl fumarate; GA, glatiramer acetate; IFN, interferon; JC, John Cunningham virus.

IFN β

GA

Teriflunomide

DMF

Fingolimod

Alemtuzumab

Natalizumab

in JC–Natalizumab

in JC+

Mitoxantrone

Autologous stem cell

transplantation

Cladribine

Tabletsa

Increasing burden of treatment

(worse safety, more difficult administration)

Figure adapted from Coles AJ.

Ann Indian Acad Neurol

2015;18(Suppl 1):S30–34.

Different therapies provide options across multiple levels of disease activity depending on their benefit:risk profile

IL, interleukin; LTβR, lymphotoxin-β receptor; LTβ, lymphotoxin-β; TNF, tumor necrosis factor.

FORMATION OF ECTOPIC

GERMINAL CENTRESPlasma cellB cell

‘Normal’antibodies

Pathologicalautoantibodies

Antibody-dependent

cell-mediatedcytotoxicity

MacrophageFc

FcC3

Target tissue

CytotoxicT cells

Target tissue

TNFIL-6

IL-1

Cytokines

Macrophage

TNF

Antibody T cell

Dendriticcell

IL-10IL-6

Cytokines

B cell B cell

SECRETION OF ANTIBODY

CytokinesTNF, IL-6, IL-10

B cell

LTR

Meningeal ectopicgerminal centers

Follicular

Dendritic cell

LT

Complement

Toxins

Target tissue

ANTIGEN PRESENTATION

TO T CELLS

CD4 T cell

B cell

CytokinesTNF, IL-6, IL-10

Target tissue

B cell growth Factors

SECRETION

OF CYTOKINE3,4

CD4 T cellhelp

CytokinesIL-4,IL-10, IL-13

CD4 T cell

1. Dalakas MS. Clin Pract Neurol 2008;4:557–67.

Figure reprinted by permission from Macmillan Publishers Ltd: Nat Clin Pract Neurol, Dalakas MC. B cells as therapeutic targets in autoimmune neurological disorders. Volume 4:pp. 557–567, copyright 2008

B & T cells exert different functions in neuroinflammation1,2

B, B cell; BBB, blood–brain barrier; CNS, central nervous system; IFN, interferon; HCA2, hydroxycarboxylic acid receptor 2; MoA, mechanism of action; nrf 2, nuclear factor (erythroid-derived 2)-like 2; S1P1, sphingosine-1-phosphate receptor 1; T, T cell; Th, T-helper cell.

Adapted from: Loleit V, et al. Curr Pharm Biotechnol. 2014;15:276–96; Scannevin R, et al. J Pharmacol Exp Ther. 2012;341:274–84; Chen H, et al. J Clin Invest. 2014;124:2188–92.

Mechanisms of action of distinct MS immunotherapies

Alemtuzumab/Ocrelizumab/Cladribine

CD52Lysis of mature B and T cells

D: Proposed MoA: anti-migratory

FingolimodNatalizumab

Lymph node

BBB

CNS

S1P1

B

T

α4-integrin

A: Proposed MoA: Immunomodulation/pleiotropic effects

Limits pyrimidine availability for rapid cell division

Azathioprine, cyclophosphamide,mitoxanthrone, Teriflunomide

IFNs

Activation of 100+ IFN-response genes

Activation of 700+ nrf 2 responsive genes and HCA2

Glatiramer acetate

Modulation of APC and Th1:Th2 balance

Dimethyl fumarate

C: Proposed MoA: targeted cell lysis

Periphery

B: Proposed MoA: reduced proliferation

T

B

CD20

ALMOST ALL OF THESE TREATMENTS INDUCE TRANSIENT EFFECTS ON THE IMMUNE SYSTEM AND NOT PERMANENT CHANGES

PML

Herpes encephalitis

Rebound on withdrawal

1. Selective adhesion molecule blocker

2. Infusion reactionsa. Anaphylactoidb. Associated with anti-drug

antibodies3. Blocks CNS immune surveillance

a. PMLb. CNS infectionsc. Possible link with CNS

lymphomas4. Rebound activity post-washout

Khatri et al. Neurology 2009;72:402–09.

EXCEMED. Schmierer K. ECF 2017. Available at: https://www.excemed.org/resources/high-efficacy-treatments-management-[Accessed Nov 2018]

Natalizumab

https://www.excemed.org/resources/high-efficacy-treatments-management-

O Major, et al. Lancet Neurol 2018,17:467-80

Proposed stages of PML pathogenesis in patients treated with natalizumab

Singer et al. Ther Adv Neurol Disord 2017

Ho et al. Lancet Neurol 2017

Natalizumab: evaluation of risk

Warnke et al. J Neurol Neurosurg Psychiatry 2013

Natalizumab: seroconversion to JCV+

Dong-Si T et al. Ann Clin Transl Neurol 2014;1:755–64.

Figures reprinted from Dong-Si T et al, Outcme and survival of asymptomatic PML in natalizumab-treated MS patients, Ann Clin Transl Neurol, 2014

EXCEMED. Schmierer K. ECF 2017. Available at: https://www.excemed.org/resources/high-efficacy-treatments-management-[Accessed Nov 2018]

Natalizumab: asymptomatic PML

https://www.excemed.org/resources/high-efficacy-treatments-management-

Clerico et al.EODS 2017

Natalizumab: AE other than PML

APC

Lymp

h

node

S1P-RT

Gliosis

S1P-

R

Fingolimod

Fingolimo

d

CNS /

Immune and

Neural

system

Periphery /

Immune

system

Oligo’s

VZV - Chickenpox &

ZosterTB

Cryptococcosis HistoplasmosisKaposi’s PMLBasal Cell

Ca

etc…..

.

Rebound on withdrawal

PRES and other vascular complications

Macular oedema

Conduction Block

Lymphopenia

1. SIP modulatora. Lymphopenia (prolonged)b. Bradycardia/Conduction blockc. Vascular complications

(macular oedema, hypertension, PRES)

d. Bronchoconstriction2. Immunosuppression

a. Opportunistic infectionsb. Secondary malignanciesc. Blunted vaccine response

EXCEMED. Schmierer K. ECF 2017. Available at: https://www.excemed.org/resources/high-efficacy-treatments-management-patients[Accessed Nov 2018]

Fingolimod

https://www.excemed.org/resources/high-efficacy-treatments-management-patients

Figure adapted from Giovannoni et al, Switching patients at high risk of PML from natalizumab to another disease-modifying therapy, Pract Neurol. 2016

Figures reprinted from Francis G et al, Temporal profile of lymphocyte counts and

relationship with infections with fingolimod therapy, Mult Scler, 2014

1. Francis G et al. Mult Scler 2014;20:471–80; 2. Giovannoni et al. Pract Neurol. 2016 Oct;16:389-93

Fingolimod

Fingolimod

1. Crawford A et al. J Immunol 2006;176:3498–506. 2. Bar-Or A, et al. Ann Neurol 2010;67:452–61. 3. Lisak RP et al. J Neuroimmunol 2012;246:85–95. 4. Weber MS et al. Biochim Biophys Acta 2011;1812:239–45. 5. Serafini B et al. Brain Pathol 2004;14:164–74. 6. Magliozzi R et al. Ann Neurol 2010;68:477–93.cc. 7. EXCEMED. Schmierer K. ECF 2017. Available at: https://www.excemed.org/resources/high-efficacy-treatments-management-patients [Accessed Mar 2018]

Antigen

presenta

tion1,2

Autoantibody

production4

Ectopic lymphoid

follicle-like

aggregates5,6

Cytokine

production2,3

PML Breast CaVZV & herpes

Ocrelizumab


17

T-cell population changes and serious infection rates in the controlled periods of the pivotal phase III trials of ocrelizumab in multiple sclerosis. ECTRIMS Online Library. Vermersch P. Oct 26, 2017; 200323.

18T-cell population changes and serious infection rates in the controlled periods of the pivotal phase III trials of ocrelizumab in multiple sclerosis. ECTRIMS Online Library. Vermersch P. Oct 26, 2017; 200323.

19

T-cell population changes and serious infection rates in the controlled periods of the pivotal phase III trials of ocrelizumab in multiple sclerosis. ECTRIMS Online Library. Vermersch P. Oct 26, 2017; 200323.

20T-cell population changes and serious infection rates in the controlled periods of the pivotal phase III trials of ocrelizumab in multiple sclerosis. ECTRIMS Online Library. Vermersch P. Oct 26, 2017; 200323.

21ECTRIMS 2017. P668. T-cell population changes and serious infection rates in the controlled periods of the pivotal phase III trials of ocrelizumabin multiple sclerosis

22

Reductions in immunoglobulin levels following natalizumab-to-rituximab crossover in a multiple sclerosis cohort: implications for next generation B cell-targeted therapies

ECTRIMS Online Library. Foley M. Oct 27, 2017; 200872

PML risk is increased in primary hypogammaglobulinemia patients and with anti-CD20 therapy, occurring primarily with concomitant immunosuppressant use.

Further evaluation of chronic hypogammaglobulinemia secondary to anti-CD20 therapy as a risk factor for PML is warranted, especially in high risk populations.

AUC, area under the curve; EDSS, Expanded Disability Status Scale; SPMS, secondary progressive MS; SRD, sustained reduction in disability1. Tuohy O et al. J Neurol Neurosurg Psychiatry 2015;86:208–15; 2. Coles AJ et al. Lancet 1999;354:1691–5; 3. Lemtrada® EU SmPC, Feb 2018; 4. Coles AJ et al. Lancet 2012;380:1829–39

• CD4 and CD8 counts were 30–40% of pre-treatment values 18

months after treatment2

• B cells repopulated more rapidly, with counts reaching 179% of

pre-treatment values by 18 months2

• Adverse reactions included infusion-associated reactions, immune

thrombocytopenia, nephropathies, infection risk and risk of

secondary autoimmune disorders1–4

Durable efficacy with alemtuzumab is demonstrated by a 12-month sustained reduction in disability and

stable/improved EDSS1

Haematological changes after alemtuzumab2

1.61.41.21.00.80.60.40.20.0

0.5

0.4

0.3

0.2

0.1

0.0

T c

ells (

x10

9/L

)

B c

ells (

x10

9/L

)

Pre Post

(Day 2)

3 6 9 12 15 18

Months after alemtuzumab (20 mg x 5)

B cells CD8+ T cells CD4+ T cells

Figure reproduced from Coles AJ et al. Lancet

1999;354:1691–5

Months since first treatment

12-month sustained

reduction in disability2

% S

RD

of

at-

risk p

op

ula

tio

n

60

0 12 24 36 48 60 72 84 96 108 120

50

40

30

20

10

0

ED

SS

-ye

ars

30

20

10

0

-10

-30

-50

-20

-40

Net better

n=43 (50%)

Net unchanged

n=9 (10%)

Net worse

n=35 (40%)

AUC values: EDSS change from

baseline vs follow-up2

Figures adapted from Tuohy O et al. J Neurol Neurosurg Psychiatry

2015;86:208–15

Alemtuzumab reduce MS disease activity through targeting T and B cells

V

Z

V

T

B Listeria Nocardia

Molluscum HPVCMVEBV

PCP

Etc...

Thomas et al. Neurol NeuroimmunolNeuroinflamm 2016;3:e228;

AVN

1. Non-selective leukocyte depletiona. Leukopaenia (neutrophils &

monocytes)b. Lymphopaenia (prolonged)c. Infusion reactions (moderate to

severe)d. Complications of corticosteroids

2. Immunosuppressiona. Opportunistic infections

i. Acute bacterial, e.g. Listeriosis

ii. Typical opportunistic, e.g. CMV

3. Aberrant immune reconstitutiona. Secondary autoimmunityb. Anti-drug antibodies

InnateImmunity

AdaptiveImmunity

AVN = avsacular necrosis, HPV = human papiloma virus, PCP = Pneumocystis carinii

pneumonia, VZV = varicella zoster virus

EXCEMED. Schmierer K. ECF 2017. Available at: https://www.excemed.org/resources/high-efficacy-treatments-management-patients[Accessed Nov 2018]


1. Baker D et al. JAMA Neurol 2017; doi:10.1001/jamaneurol.2017.0676; 2. Coles AJ et al. Lancet 1999;354:1691–5

CD4 T cells

Naïve CD4

T cells

Memory CD4

T cells

CD8 T cells

CD4 regulatory

T cells

CD8 regulatory

T cells

CD19 B cells

Mature naïve

B cells

Memory

B cells

Immature B cells

Figure from Coles AJ et al. Lancet

1999;354:1691–5

Figures adapted from Baker D et al. JAMA Neurol 2017;

doi:10.1001/jamaneurol.2017.0676

Figures adapted from

Baker D et al. JAMA

Neurol 2017;

doi:10.1001/jamaneurol.

2017.0676

Alemtuzumab depletes subsets of B and T cells1,2

Baker D et al. Mult Scler Relat Disorder 2017;18:181–83.

Figures reprinted from Baker D et al, Marked neutropenia: Significant but rare in people with multiple sclerosis after alemtuzumab treatment, Mult Scler Relat Disord, 2017

Treg

Th17Th1

Treg

Th17

Th1

Treg

Th17

Th1

CD4 T cells

MBP specificcells

Durelli et al.AAN 2016

Clerico et al.AAN 2018

Identified Risk

Rate in Alemtuzumab-

Treated Patients Notes

ITP

Auto-immune Events

~1% (1 fatality

prior

to implementation

of monitoring

program)2

• Onset generally occurred 14-36 mo after first exposure2

• Most cases responded to first-line medical therapy2

0.3%

(anti-GBM n=2)2

• Generally occurred within 39 mo after last administration2

• Responded to timely medical treatment and did not develop

permanent kidney failure3

Nephropath

ies

Thyroid

disorders

(Hypo/hyper)

~36%a

(serious, 1%)2

• Onset occurred 6-61 mo after first Alemtuzumab exposure;

peaked in year 3 and declined thereafter4

• Most mild to moderate, most managed with conventional

medical therapy, however, some patients required surgical

intervention2

• Higher incidence in patients with history of thyroid disorders2

IARs>90%

(serious, 3%)2

• Occurred within 24 h of Alemtuzumab administration2

• Most mild to moderate; rarely led to treatment

discontinuation2

• May be caused by cytokine release following mAb-mediated

cell lysis2

Infections71%

(serious, 2.7%)2

• Incidence highest during first mo after infusion; rate

decreased over time4

• More common with Alemtuzumab; mostly mild to moderate2

• Generally of typical duration; resolved following conventional

medical treatment1

aThrough 48 mo after first exposure. IAR, infusion-associated reaction; ITP, immune thrombocytopenia; GBM, glomerular basement membrane; mAb, monoclonal antibody.1. EXCEMED. Schmierer K. ECF 2017. Available at: https://www.excemed.org/resources/high-efficacy-treatments-management-patients [Accessed Mar 2018];

2. Alemtuzumab SmPC, June 2016; 3. Havrdova, E et al. Ther Clin Risk Manag. 2017;13:1423-1437; 4. Coles A et al. Neurology. 2012;78:1069–78; 5. Willis et al. MSJ 2016;22:1215–23.

Haemolytic anaemia

Goodpasture’s Syn.

ITP Bullous Pemphigoid

Immune neutropenia

Grave’s orbitopathy

Neonatal hyperthyroidism

Acquired Haemophilia

Pernicious Anaemia

Etc...

Cervical dysplasia5 MGUS5

+

10% pre/malignant 6.1 yrsFUp

Alemtuzumab risks identified in clinical trials1


No correlation between lymphocytepharmacodynamics and autoimmune adverse events following alemtuzumabtreatment in patients with relapsing-remitting multiple sclerosisH. Wiendl et al. ECTRIMS Online Library. Oct 11, 2018; 228723

aOne of the kinases is deoxycitidine kinase (dCK). The phosphatase is 5’-nucleotidase. ADA, adenosine deaminase; CNS, central nervous system.

1. Leist TP, et al. Clin Neuropharmacol 2011;34:28–35; 2. Goodlett CR, et al. Alcohol Res Health 2001;25:175–84; 3. Bredesen DE. Neuroscientist 1996;2:181–190; 4. Charras GT. J Microscopy 2008;231:466–78; 5. Jacobs BM, et al. J Neurol Neurosurg Psychiatry 2018;0:1–6.

❷ Accumulates intracellularly due to protection from

ADA degradation

Slow

degradation

by ADA

Activated cladribine is

inactivated by a

specific phosphatasea

Phosphatase

inactivation

❸ Cladribine is activated by specific kinases

Kinase

activationa

Activated

cladribine

❹ Activated cladribine induces lymphocyte apoptosis

Lymphocyte

reduction

❶ Cladribine enters cell via nucleoside transporterCladribine

Cladribine

Cladribine works by a 4-step

mechanism1:

Apoptosis does not lead to localized

inflammation, unlike cell lysis2–4

In addition to its pro-apoptotic effects,

cladribine promotes immune tolerance

and reduces immune cell infiltration

into the CNS5

Cladribine has to be transported into cells and activated in order to exert its effect

ADA, adenosine deaminase.1. Leist TP and Weissert R. Clin Neuropharmacol 2011;34:28–35; 2. Giovannoni G. Neurotherapeutics 2017;14:874–87; 3. Warrington R et al. Allergy Asthma Clin Immunol 2011;7:Suppl 1:S1.

31

Abnormal B and T

lymphocyte functions are

thought to play a central

role in the pathogenesis

of MS2

B and T lymphocytes have

essential roles in normal

immune functioning

(infection defense and

tumor surveillance)3

B and T lymphocytes have essential

roles in normal immune functioning

(infection resistance and tumour

surveillance)

Cladribine is an analog

of deoxyadenosine that is

resistant to degradation by

ADA1

2’deoxyadenosi

ne

Cladribine

Cladribine has been rationally designed to exploit the kinase-to-phosphatase enzyme

profile of lymphocytes vs other cells to preferentially reduce lymphocytes1

Cladribine was purposefully designed to selectively target B and T cells1,2

B and T lymphocytes have a

higher kinase-to-phosphatase

ratio than other cells4

aThe kinase is deoxycytidine kinase; the phosphatase is 5’-nucleotidase; bData for NT5C, NT5C2L1 and NT5C3 were not available to include as there was no probe set for these genes at the time of analysis. NK, natural killer.

1. Carson D et al. Proc Natl Acad Sci USA 1980;77:6865–9; 2. Carson DA et al. Blood 1983;62:737–43; 3. Salvat C et al. ECTRIMS 2009 [P280]; 4. Leist TP, Weissert R. Clin Neuropharmacol 2011;34:28–35.

Figure adapted from Salvat C et al. ECTRIMS 2009 [P280]

Figure adapted from Leist TP, Weissert R. Clin Neuropharmacol

2011;34:28–35

CD4+ T lymphocytes

CD8+ T lymphocytes

Skin

Heart

Brain

Ovary

Liver

Kidney

Lung

Testis germ cell

Testis

mRNA expression of

activating kinasea

mRNA expression of

inactivating phosphatasea,b

mRNA expression of

inactivating phosphatasea

mRNA expression of

activating kinasea

CD4+ T cells

CD8+ T cells

CD19+ B cells

NK cells

Cladribine selectivity is due to lymphocytes having a higher kinase-to-phosphatase ratio than other cells1–4

Cladribine Tablets

Placebo

BL, baseline; LA, last assessment; Q, quartile.Figures adapted from Soelberg-Sørensen P et al. ECTRIMS 2017 [P655].1. Soelberg-Sørensen P et al. ECTRIMS 2017 [P655]; 2. Soelberg-Sørensen P et al. ENS 2010 [P442]; 3. Bisset LR et al. Eur J Haematol 2004;72:203–12.

Rapid reduction of B

lymphocytes,

followed by reconstitution

Moderate reduction of T

lymphocytes,

followed by reconstitution

CD19+ B lymphocytes1

0

100

50

150

200

300

250

350

400

0 24 48 72 96 120 144 168 192 216 240

Normal range in adults (72–460 cells/µL)3

Weeks

Cladribine Tablets

Placebo

0 24 48 72 96 120 144 168 192 216 240

200

400

600

800

1000

300

500

700

900


Weeks

Me

dia

n (

Q1

–Q

3)

CD

4+

T lym

ph

ocyte

s (

cells

/µL

)

CD4+ T lymphocytes1

79

220

81

203

61

137

74

191

78

195 38 56 68 64 49 33

79

220

81

203

61

137

74

191

78

195 38 56 68 64 49 33

Me

dia

n (

Q1

–Q

3)

CD

19

+ B

lym

ph

ocyte

s (

cells

/µL

)

Cladribine has a selective and transient effect on lymphocyte depletion, followed by a distinct pattern of reconstitution1,2

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

BL 3 6 9 12 15 18 21 24LA

CD16+/CD56+ NK CELLS

BL, baseline; LA, last assessment; NK, natural killer.1. Baker D et al. Neurol Neuroimmunol Neuroinfamm 2017;4:e360; 2. Giovannoni G et al. N Engl J Med 2010;362:416–26; 3. Soelberg-Sørensen P et al. ENS 2009 [P359]; 4. Soelberg-Sørensen P et al. ENS 2010 [P442]; 5. Rieckmann P et al. ECTRIMS 2009 [P816]; 6. Soelberg-Sørensen P et al. ECTRIMS 2009 [P472]. 7. Bisset LR et al. Eur J Haematol 2004;72:203–12; 8. Soelberg-Sørensen P et al. ECTRIMS 2017 [P1141].

Cladribine has a transient and mild effect on platelets and monocytes1


200

150

100

50

0

BL 3 6 9 12 15 18 21 24LA

Me

dia

n c

ell

co

un

t (c

ells

/µL

)

Study monthsM

edia

n c

ell

count (c

ells

×1

09/ µ

L)

Study months

Threshold

2.03 x 109/L8

Figures adapted from Soelberg Sørensen P et al. ECTRIMS 2009 [P472]Figure adapted from Rieckmann P et al. ECTRIMS 2009 [P816]

Rapid reduction of NK cells,

followed by reconstitution5 Modest effect on neutrophils6

MAVENCLAD®

(n=81)

Placebo (n=79)

MAVENCLAD®

(n=81)

Placebo (n=79)

Cladribine has a minimal impact on innate immune cell counts1–4

1. Baker D, et al. Neurol Neuroimmunol Neuroinflamm 2017;4:e360; 2. Giovannoni G, et al. N Engl J Med 2010;362:416 – 26; 3. Cohen JA, et al. Lancet 2012;380:1819 – 28.

CD4+ cellsd CD8+ cellsd

Cladribine 3.5 mg/kgbPlaceboa Alemtuzumab 12mg/dc

an=68–80; bn=77–86 cn=171–184. dData are from two separate studies: MAVENCLAD® data from CLARITY2 and alemtuzumab from CARE-MS I.3 Figures adapted from Baker D et al. Neurol Neuroimmunol Neuroinflamm 2017;4:e360.

Cladribine Tablets: Moderate T-cell effect1

36ECTRIMS 2017.P667. Effects of Cladribine Tablets on CD4+ T cell subsets in the ORACLE-MS study: results from an analysis of lymphocyte surface markers

Cladribine Tablets: Moderate T-cell effect


Cladribine Tablets: Moderate T-cell effect

1. Soelberg-Sørensen PS, et al. ACTRIMS 2018 [P084]; 2.Baker D, et al. JAMA neurol 2107;74:961–69; 3. Ceronie B, et al. J. Neurol 2018;265:1199–1209; 4. Baker D, et al. Brain 2108;141:2834–47; 5. Stuve O, et al. ACTRIMS 2018 [P059]; 6.Baker D, et al. Neurol, Neuroimmuno Neuroinflamm 2017;74:961–969.

Figure adapted from Soelberg-Sørensen PS et al. ACTRIMS 2018 [P084]

1200

100

50

150

300

300

250

350

400

0 24 48 72 144 168 192 216 240

LLN

No secondary

autoimmunity

96

CD19+ B lymphocytes

Weeks

CD19+ repopulation is a composite of a number of B cell subsets2-4

Immature B cells repopulate from bone marrow4

• In presence of CD4 T regs5,

• In presence of CD8 T cells5,6

Med

ian

(Q

1 –

Q3 C

D19

+ B

lym

ph

oc

yte

s (

cell

s/µ

l)

79

22

0

81

20

3

61

13

7

74

19

1

78

19

5

38 56 68 64 49 33

Placebo

Cladribine tablets 3.5 mg/kg

Number of

patients

CD19+ B cells were markedly reduced, but on recovery they did not overshoot baseline levels1,2

aIn the clinical study database (1,976 patients, 8,650 patient-years) no case of PML has been reported, accurate at date of creation – Oct 2018. However, a baseline MRI should be considered before initiating MAVENCLAD® (usually within 3 months). This is particularly recommended if patients are switched from other MS agents that have a risk of PML; bCases of PML have been reported for parenteral cladribine in patients treated for hairy cell leukemia with a different treatment regimen. cPatients treated with a cumulative dose of MAVENCLAD® over 2 years as monotherapy; dCladribine can reduce the body’s immune defense and may increase the likelihood of infections2; eMalignancies were observed more frequently in cladribine-treated patients than in patients who received placebo in clinical trials. AE, adverse event. DMD, disease-modifying drug; MoA, mechanism of action; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy.

1. PREMIERE, 2009 https://clinicaltrials.gov/ct2/show/NCT01013350 [Accessed Oct 2018]; 2. MAVENCLAD® EU SmPC, July 2018;3. Cook S, et al. Mult Scler 2011;17:578–93; 4. Pakpoor J, et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158.

LYMPHOPENIA

Transient, mostly mild-to-moderate lymphopenia

was observed2

<1% of patientsc treated developed grade 4 (<200 cells/mm3)

lymphopenia2

MALIGNANCY

No conclusive evidence for an increased risk compared with

the general populatione,3

Cladribine has a malignancy rate comparable to other

DMDs4

INFECTIONS

Overall, risk is

comparable to placebo,

except for

herpes zosterd,2

Herpes zoster-associated

serious or severe events

rare and manageable3

Cladribine has up to 10 years of safety follow-up1

Cladribine had no reported cases of PML in

MSa,b,2

No reported cases of secondary

autoimmunity in MS1

Cladribine has a well-characterized safety profile

aCladribine can reduce the body’s immune defence and may increase the likelihood of infections2 Data shown is from CLARITY trial only. AE, adverse event; URTI, upper respiratory tract infection.

1. Giovannoni G, et al. N Engl J Med 2010;362:416–26; 2. Cook S, et al. ECTRIMS 2017; [P1142].

Most frequently

reported adverse

events

MAVENCLAD®

3.5mg/kg

N=430 (%)

Placebo

N=435 (%)

Any adverse event 80.7 73.3

Most common adverse

eventsa

Headache 24.2 17.2

Lymphocytopenia 21.6 1.8

Nasopharingytis 14.4 12.9

URTI 12.6 9.7

Nausea 10.0 9.0

Any serious adverse

events

8.4 6.4

Infections and

infestations

2.3 1.6

Neoplasmsb 1.4 0.0

Death 0.5 0.5

There was no

incidence of

opportunistic

infectionsa,2

0.7%

Grade 42

<200 cells/μL

24.9%

Grade 32

500–200 cells/μL

74.4%

Grade 0–22

>500 cells/μL

Transient, mostly mild-to-moderate lymphopenia was observed following Cladribine dosing1

CI, confidence interval; SIR, standardized incidence ratio. aSIR calculated against the GLOBOCAN (2012) reference population; non-melanoma skin cancer excluded due to inconsistent reporting in GLOBOCAN 2012. bThe aim of the GLOBOCAN (2012) project is to provide contemporary estimates of the incidence of, mortality and prevalence from major types of cancer, at national level, for 184 countries of the world. cThis cohort also contains data from combinations/indications that are not approved by the competent authority. However, the safety data have been included in the overall assessment. dIntegrated safety analysis of CLARITY, CLARITY EXT, ORACLE-MS, PREMIERE (oral monotherapy cohort) compared to global malignancy database GLOBOCAN 2012.

1. MAVENCLAD® European Public Assessment Report, June 2017.

8,3 8,0

0

5

10

15

20

25

30

Observed

Monotherapy oral cohortc,d (3.5 mg/kg)

Expected

(GLOBOCAN 2012b)

standardized incidence ratio:

0.97(95% CI 0.44, 1.85)

Expected vs observed malignancies with

Cladribine1

(N=923; 3433 patient years)

Un

iqu

e e

ven

ts o

f m

alig

nan

cy

a

Cladribine had no increased risk of malignancy compared with the general population

aIn the all-exposed cohort, the malignancy rate for cladribine during Years 1–4 (0.38) was identical to the rate during Years 5–8+, demonstrating that the malignancy rate

remained constant over time. PY, patient-years

1. Galazka A et al. ECTRIMS 2017 [P1878].

0,29 0,28

0,00

0,05

0,10

0,15

0,20

0,25

0,30

0,35

0,40

0,45

0,50

Years 1–4 Years 5–8+

No

. o

f m

alig

nan

cie

s p

er

100 P

YIncidence of malignancy per 100 PY

(monotherapy oral cohort)a,1

Patients with events 8 2

Time at risk, years 2715.45 711.84

n = 923

In up to 10 years of follow-up, there was no increase in malignancy incidence1

44

1. EXCEMED. Giovannoni G. EAN 2017 https://www.excemed.org/resources/how-transfer-concept-clinical-practice June 2017 [Accessed Feb 2018]; 2. Baker D et al. Neurol NeuroimmunolNeuroinflamm 2017;4:e360; 3. Massacesi L et al. PLoS One 2014;9:e113371; 4. Cassetta I et al. Cochrane Database Syst Rev 2007;17:CD003982; 5. Kieseier BC. CNS Drugs 2011;25:491–502; 6. Weber MS et al. Neurotherapeutics 2007;4:647–53.

Maintenance/escalation therapythat results in continuous immunosuppression1

Short-course therapythat reconstitutes the immune system

resulting in long-term qualitative changes

in immune function1

Maintenance/escalation therapythat results in continuous immunomodulation1

Maintenance/escalation therapy: Chronic therapy that is maintained and/or

escalated over time resulting in changes in immune function only during active treatment1

Immune reconstitution

therapy1,2

Chronic

immunosuppression3,4 Immunomodulation5,6

New classification pouposed: Immune reconstitution therapy (IRT) is a novel approach that differs from both chronic immunosuppression and immunomodulation1

aApproved in the US and EU.IRT, immune reconstitution therapy.

Giovannoni G. Sequencing workshop treatment algorithm 2018.https://www.slideshare.net/gavingiovannoni/sequencing-workshop-treatment-algorithm [Accessed Nov 2018].

A reduction of the activation or efficacy of the immune system

• This definition refers to short-term (IRTs) and long-term persistent immunosuppression(maintenance)

For a drug to be considered an immunosuppressant, it could cause:

• 1) significant lymphopenia

• 2) be associated with opportunistic infections

• 3) reduce the antibody response to vaccines

• 4) be associated with secondary malignancies

Immunosuppression

https://www.slideshare.net/gavingiovannoni/sequencing-workshop-treatment-algorithm

BL, baseline; CSF, cerebrospinal fluid; DMD, disease-modifying drug; IFN, interferon;LLN, lower limit of normal; m, Month; ON, on-treatment; OND, other neurological disease;PRE, pre-treatment; W, Week.

1. Ghadiri M, et al. Mult Scler 2017;23:1225–32; 2. Giovannoni G. EXCEMED CME on PIRT, June 2017;

3. Stϋve O, et al. Ann Neurol 2006;59:743–7;4. Spencer CM, et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e76.

Treatment with fingolimod leads to

persistent reduction in peripheral lymphocyte counts with recovery

upon cessation1,a

Ocrelizumabdecreases CD19+ cells to negligible levels by Week 2 of treatment,

with return to LLN more than 1 year after

cessation2

Natalizumab causes reductions in T cells

and B cells in the CSF that persist for up to 6

months after treatment cessation3

Current DMDs are associated with continuous immunosuppression during treatment, with variable rate of lymphocyte recovery upon cessation

DMF causes chronic reductions in lymphocytes4

0.0

0.5

1.0

1.5

2.0

2.5

PRE ON W2 W3–4 M8–9

Tota

l lym

ph

ocy

te c

ou

nt

(x1

09

cells

/L)

LLN

0.0041<0.0001

Time

Lower Limit of Normal

<0.0001

<0.0001

CD

4+

T ce

lls/m

L (C

SF)

0.45<0.0001

0

5000

10,000

15,000

20,000

25,000

Time

Placebo (N=54)Ocrelizumab 1000 mg (N=55)Ocrelizumab 600 mg (N=55)im IFN -1a (N=54)

LLN

Lymphocytes

Month

Tota

l lym

ph

ocy

te c

ou

nt

(x1

09

cells

/L)

N=16

N=16

N=35

N=23

N=14

N=34

N=21

N=15

N=17

Many maintenance/escalation therapies chronically lower lymphocyte levels

https://www.excemed.org/live-events/immune-system-resetting-and-long-term-remission-multiple-sclerosis-rationale-and-possibilities-excemed-satellite-symposium-3rd-ean-congress

1. Winkelmann A et al. Clin Exp Immunol 2014;175:425–38; 2. Dendrou CA et al. Nat Rev Immunol 2015;15:545–58;

3. Nath A, Berger JR. Curr Treat Options Neurol 2012;14:241–55; 4. Stokmaier D et al. EAN 2018 [POD399];

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

The immune

system defends

against infections

and tumours

Neutrophil

deficits

T-cell or

monocyte

abnormalities

Humoral

immunity

disorders

Bacteria, fungi

Bacteria,

parasites, viruses,

fungi

Bacteria

Immunosuppression increases infection risk

Some lymphocyte-targeting therapies are associated with an increased risk of

malignancy,

which varies between therapies and individual studies2,5

Immunosuppression may decrease efficacy of vaccines4

Continual B-cell

suppression

Decreased humoral

response to

vaccination

Potential risks of continuous immunosuppression1–4

Basal Cell

Carcinoma

Zoster

Cumulative Risk

Frontloading Risk

Listeria

TB

Nocardia PCP

Lymphoma

Cryptococcosis

2°autoimmunity

post- Az

Short-termAcute immunosuppression: innate and T-cell

Continuous Chronic immunosuppression

Giovannoni G. Sequencing workshop treatment algorithm 2018.https://www.slideshare.net/gavingiovannoni/sequencing-workshop-treatment-algorithm [Accessed Nov 2018].

aNot licensed; blicensed in the US, Germany, Austria and France; clicensed in Europe, Canada, Argentina, Australia and UAE.BMT, bone marrow transplant; HSCT, hematopoietic stem cell transplant; IFN, interferon; IM, intramuscular; PI, prescribing information; PPMS, primary progressive MS; RMS, relapsing MS;R-SPMS, relapsing secondary progressive MS; SC, subcutaneous; SmPC, summary of product characteristics.

Immunosuppression


Baseline

1. FBC—leukocytes/platelets2. LFTs, U&E, TFTs, urine3. Pregnancy tests4. Immunoglobulin levels5. Serum protein

electrophoresis6. Serology

a. JCVb. HIV-1&2c. Hepatitis B&Cd. VZVe. Syphilisf. TB Elispot

7. Cervical smear8. Vaccinations9. MRI10. LP—CSF analysis

sequencing11. Listeria, PCP prophylaxis

a. Dietb. Prophylactic

antibiotics

Infusion—DMTs & IRTs

1. Infusion reactions

a. Corticosteroid

s

b. Antihistamine

s

c. Antipyretics

2. Antibiotics

a. Anti-herpes

b. Listeria/PCP

prophylaxis

Monitoring

1. Bloods

a. FBC—

leukopenia

b. TFTs, LFTs,

U&E, …..

2. Urine

a. Autoimmune

b. Renal

dysfunction

3. MRI

a. Disease activity

b. PML

4. Infection

a. Serology

b. CSF

5. Disease activity

6. Pregnancy

7. Malignancy

a. Skin, Cervical,

Breast

b. Etc.

12

3

CSF, cerebrospinal fluid; DMT, disease-modifying therapy; FPC, full blood count; HIV, human immunodeficiency virus; IRT, immune reconstitution therapy; JCV, John Cunningham virus; LFT, liver function test; LP, lumbar puncture; MRI, magnetic resonance imaging; PCP, pneumocystis carinii pneumonia; PML, progressive multifocal leukoencephalopathy TB, tuberculosis; TFT, thyroid function test; U&E, urea and electrolytes; VZV, varicella zoster virus

Giovannoni G. Sequencing workshop treatment algorithm 2018.https://www.slideshare.net/gavingiovannoni/sequencing-workshop-treatment-algorithm [Accessed May 2018].

De-risking immunosuppression


1. Gilenya® SmPC, 2017; 2. Lemtrada® SmPC, 2016. 3. Tysabri® SmPC, 2017; 4. HSCT NHS guidelines.http://nssg.oxford-haematology.org.uk/bmt/long-term/B-2-13-allograft-and-autograft-immunisation-schedule.pdf; 5. MAVENCLAD® SmPC, July 2018;

IRTsMaintenance

5

1

3

4

natalizu

mab

Vaccines2

It is recommended that patients have completed local immunisation requirements

at least 6 weeks prior to treatment with alemtuzumab. The ability to generate an

immune response to any vaccine following alemtuzumab treatment has not been

studied.

The safety of immunistation with live viral vaccines following a course of

alemtuzumab treatment has not been formally studied in controlled clinical trials in

MS and should not be administered to MS patients who have recently received a

course of alemtuzumab.

Varicella zoster virus antibody testing/vaccination

As for any immune modulation medicinal product, before initiation a course of

alemtuzumab treatment, patients without a history of chickenpox or without

vaccination against varicella zoster virus (VZV) should be tested for antibodies to

VZV. VZV vaccination of antibody-negative patients should be considered prior

to treatment initiation with alemtuzumab. To allow for the full effect of the VZV

vaccination to occur, treatment with alemtuzumab should be postponed for 6

weeks following vaccination

Vaccinations

http://nssg.oxford-haematology.org.uk/bmt/long-term/B-2-13-allograft-and-autograft-immunisation-schedule.pdf

APPROVED MULTIPLE SCLEROSIS TREATMENTSAFETY

All the following slides are adapted from A Consensus Paper bythe Multiple Sclerosis Coalition updated on March 2017

Drug Side effects Warnings/precautions

Glatiramer acetate (Copaxone®) 20mg SC daily or 40mg SC threetimes weekly

Indication: relapsing forms of MS (Glatopa® - therapeutic equivalent) 20mg SC daily

Indication: relapsing forms of MS

Pregnancy Cat: B

• injection-site reactions• Lipoatrophy• vasodilation, rash, dyspnea -

chest pain• lymphadenopathy

immediate transient post-injectionreaction (flushing, chest pain, palpitations, anxiety, dyspnea, throatconstriction, and/or urticaria) -lipoatrophy and skin necrosis -potential effects on immune response


interferon beta-1a (Avonex®) 30mcg IM weeklyIndication: relapsing forms of MS Pregnancy Cat: C

• flu-like symptoms• depression • ↑hepatic transaminases

• depression, suicide, psychosis

• hepatic injury• anaphylaxis and other

allergic reactions• CHF • ↓peripheral blood counts• Seizures• other autoimmune

disorders• thrombotic

microangiopathy


interferon beta-1a(Rebif®) 22mcg or 44mcg SC three times weekly Indication: relapsing forms of MS Pregnancy Cat: C

• injection-site reactions• flu-like symptoms• abdominal pain• Depression• ↑hepatic transaminases• hematologic

abnormalities

• depression, suicide, psychosis


allergic reactions• injection-site reactions

including• ↓peripheral blood counts• Seizures• other autoimmune


microangiopathy


interferon beta-1b(Betaseron®) (Extavia®) 0.25mg SC every other day Indication: relapsing forms of MS Pregnancy Cat: C

• flu-like symptoms • injection-site reactions• ↑hepatic transaminases • ↓ WBC


allergic reactions• depression and suicide• CHF• injection-site necrosis• ↓ WBC -flu-like

symptoms• seizures• thrombotic

microangiopathy


peginterferon beta-1a (Plegridy®) 125mcg SC every two weeks Indication: relapsing forms of MS Pregnancy Cat: C

• flu-like symptoms • injection-site reactions• ↑hepatic transaminases • ↓ WBC

• depression, suicide• hepatic injury• anaphylaxis and other

allergic reactions• CHF• ↓peripheral blood counts• Seizures• other autoimmune


microangiopathy


dimethyl fumarate(Tecfidera®) 240mg PO twice dailyIndication: relapsing forms of MS Pregnancy Cat: C

• anaphylaxis and angioedema

• progressive multifocal leukoencephalopathy (PML)

• lymphopenia• elevated AST• liver injury• flushing• GI symptoms -pruritis -

rash

• anaphylaxis and angioedema

• PML• lymphopenia (discontinue

treatment in patientswith persistentlymphopenia (<500) over 6 months) -flushing

• liver injury


fingolimod (Gilenya®) 0.5mg PO dailyIndication: relapsing forms of MS Pregnancy Cat: C

• Headache• Influenza• Diarrhea• back pain• ↑hepatic enzymes• Cough• bradycardia during first dose• macular edema• Lymphopenia• bronchitis/pneumonia

• bradyarrhythmia and/or atrioventricular block following first dose

• risk of infections including serious infections – monitor for infection during treatment and for 2 months after d/c

• avoid live attenuated vaccines during treatment and for 2 months after d/c

• PML • cryptococcal infections• macular edema• posterior reversible encephalopathy

syndrome (PRES)• ↓pulmonary function tests (FEV1)• hepatic injury• ↑BP • basal cell carcinoma• fetal risk: women should avoid

conception for two months aftertreatment d/c

• ↓lymphocyte counts for 2 months afterdrug d/c


Teriflunomide (Aubagio®) 7mg or 14mg PO daily Indication: relapsing forms of MS Pregnancy Cat: X

• ALT elevation• Alopecia• Diarrhea• Influenza• Nausea• Paresthesia

• hepatotoxicity• risk of teratogenicity• elimination of teriflunomide can be accelerated by administration

of cholestyramine or activated charcoal for 11 days (confirmundetectable drug level before conception)

• ↓neutrophils, lymphocytes and platelets• risk of infection, including tuberculosis (TB screen prior to

treatment)• no live virus vaccines• potential increased risk of malignancy• peripheral neuropathy (consider discontinuation of treatment)• acute renal failure• treatment-emergent hyperkalemia• ↑ renal uric acid clearance • interstitial lung disease• Stevens-Johnson syndrome and toxic epidermal necrolysis (stop

treatment) • ↑ BP• may decrease WBC: recent CBC prior to initiation; monitor for

infections; consider suspension for serious infections; do not start in presence of infection

• concomitant use with immunosuppressants has not been evaluated Note: some of these were carried over from leflunomideuse in RA

Boxed Warning hepatotoxicity and risk of teratogenicity


Alemtuzumab (Lemtrada®) 12mg/day IV on five consecutive days followed 12 months later by 12mg/day on three consecutive days Indication: relapsing forms of MS – generally for patients who have had an inadequate response to two or more MS therapies Pregnancy Cat: C

->90% of patients in clinical trials experienced infusion reactions: skin rash, fever, headache, muscle aches, temporary reoccurrence of previousneurologic symptoms. More serious butuncommon infusion reactions: anaphylaxis and heart rhythmabnormalities. -serious adversereactions: autoimmunity, infusionreactions, malignancies, immune thrombocytopenia (ITP), glomerularnephropathies, thyroid disorder, otherautoimmune cytopenias, infections, pneumonitis -immediate and significantdepletion of lymphocytes; herpes simplex and zoster infections more common in patients who receivedalemtuzumab in the clinical trials, especially soon after the infusions. Prophylaxis with anti-viral agent isrecommended for at least two months or until CD4 count is >200.

• infusion reactions• autoimmunity (thyroid disorders, immune

thrombocytopenia (ITP), glomerularnephropathies, other cytopenias)

• infections• no live virus vaccinations following infusion• malignancies (thyroid, melanoma,

lymphoproliferative) • pneumonitis

Boxed WarningBecause of the risk of autoimmunity, life threatening infusion reactions, and malignancies, alemtuzumab is available only through restricted distribution under a Risk Evaluation Mitigation Strategy (REMS) program.


Mitoxantrone(Novantrone®) 12mg/m2 IV every three months; maximum cumulative dose: 140mg/m2 Indication: worsening relapsing-remitting, progressive-relapsing, secondary progressive MS Pregnancy Cat: D

• temporary blue discolorationof sclera and urine

• Nausea• Alopecia• menstrual disorders

including amenorrhea and infertility -infections (URI, UTI, stomatitis)

• cardiac toxicity (arrhythmia, abnormal EKG, congestive heart failure).

• severe local tissue damage if there is extravasation

• Cardiotoxicity• acute myelogenous leukemia• myelosuppression

Boxed Warning cardiotoxicity and secondary leukemia (monitoring required long-term following discontinuation)


Natalizumab(Tysabri®) 300mg IV every 28 days Indication: relapsing forms of MS Pregnancy Cat: C

• Headache• Fatigue• urinary tract infection• lower respiratory tract infection• Arthralgia• Urticaria• Gastroenteritis• Vaginitis• Depression• Diarrhea

• PML• Hepatotoxicity• herpes encephalitis and meningitis caused by

herpes simplex and varicella zoster viruses• Hypersensitivities• Immunosuppression/infections

Boxed Warning Because of the risk of PML, natalizumab is available only through a restricted distribution program called the TOUCH® Prescribing Program.


ocrelizumab(Ocrevus™) 600mg IV every 6 months Indication: relapsing or primary progressive forms of MS

Pregnancy Cat: No category assigned due to changes to FDA labeling procedures for pregnancy and lactation. No human data: in monkeys, administration during organogenesis and continuing through the neonatal period resulted in perinatal deaths, renal toxicity, lymphoid follicle formation in the bone marrow and severe decreases in circulating B-lymphocytes in neonates.

• infusion reactions (potentially life-threatening)

• infections• possible increased risk of

malignancies (including breast cancer, which occurred in 6 of 781 treated patients and no placebo patients)

• infusion reactions, which can include: pruritis, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia; premedication and observation period recommended

• infections, including respiratory tract infections, herpes and potentially PML -hepatitis B reactivation -possible increased immunosuppressive effect if immunosuppressant used prior to or after ocrelizumab

• administer all vaccinations at least 6 weeks prior to administration of ocrelizumab; no live-attenuated or live vaccines during treatment and until B-cell repletion -malignancies

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