Efficacy and safety of immunosuppressants in RR-MS

Gavin Giovannoni

Barts-MS

Barts and The London School of Medicine and Dentistry

Disclosure

Gavin GiovannoniBlizard Institute Barts and The London School of Medicine and DentistryQueen Mary University London

Gavin Giovannoni has received compensation for serving as a consultant or speaker for, or has received research support from: AbbVie, Bayer Schering Healthcare, Biogen Idec, Canbex, Eisai, Elan, Five Prime Therapeutics, Genzyme, Genentech, GlaxoSmithKline, Ironwood Pharmaceuticals, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva Pharmaceutical Industries, UCB and Vertex Pharmaceuticals.

Objectives

Please state the learning objectives of your lecture

1. Define an immunosuppressant

2. List the immunosuppressants used in the treatment of RRMS

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

4. Review strategies to de-risk some of the major adverse events associated with the use of immunosuppressants in MS

5. Conclude with a list of emerging treatments

What is an immunosuppressant?

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

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

Which licensed DMTs are immunosuppresant?

1) Interferon-beta2) Glatiramer acetate3) Mitoxantrone4) Natalizumab5) Fingolimod & other S1P modulators6) Teriflunomide7) Dimethyl fumarate8) Alemtuzumab9) Daclizumab

10) Ocrelizumab11) Cladribine

Mitoxantrone

Hartung et al. Lancet 2002:360:2018-25.

MITOXANTRONE - PML (promyelocytic leukaemia)

Mistry et al. Engl J Med. 2005 Apr 14;352(15):1529-38.

Natalizumab

Natalizumab

Progressive multifocal leukoencephalopathy (PML)

Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.

Prior disease modifying treatments for MS

~50 % of PML cases have had prior chemotherapy

exposure both in Europe and US

28 cases – Clifford et al. Lancet Neurol. 2010 Apr;9(4):438-46.42 cases – Clifford et al; AAN 2010.

Slide courtesy of David Clifford

Natalizumab PML risk stratification tool

3-monthly MRIs

Lindå et al. N Engl J Med 2009;361:1081-7.

Lindå et al. N Engl J Med. 2009 Sep 10;361(11):1081-7.

Determinants of survival in PML

Marzocchetti et al., Neurology 2009;73:1551–1558

Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function

Khatri et al. Neurology 2009;72:402–409

Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function

Khatri et al. Neurology 2009;72:402–409

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

Immune reconstitution inflammatory syndrome (IRIS)

Rx: IV methylprednisolone 1g daily x 5 days, followed by tapered dose of oral steroids.

Prophylaxis: I recommend prophylactic corticosteroids if high burden of disease and/or posterior fossa involvement.

Clifford DB, et al. Lancet Neurol. 2010;9:438–446.

Factors associated with improved survival

1. Younger age at PML diagnosis

2. Lower pre-PML EDSS

3. Rapid diagnosis; shorter time from first symptoms of PML to diagnosis

4. Minimal diseasea. Asymptomatic presentationb. Localized PML extension on MRI at diagnosisc. No brainstem involvement

Vermersch P, et al. Neurology. 2011;76:1697-1704.Biogen Idec, data on file.

Fingolimod

-30%* (3-mo conf.)

-37%* (6-mo conf.)

-82%*** (Gd+)

-74%*** (T2)

-17%, NS (3-mo conf.)

-28%, NS (6-mo conf.)

-70%*** (Gd+)

-74%*** (T2)

-25%, NS (3-mo conf.)

–

-55%*** (Gd+)

-35%** (T2)

Fingolimod in MS: efficacy from Phase III studies

FREEDOMS1

2 years, RRMS(n = 1272)vs placebo

FREEDOMS II2,3

2 years, RRMS(n = 1083)vs placebo

TRANSFORMS4

1 year, RRMS(n = 1292)vs IFNβ-1a IM

0 24Time (months)

0.0

–0.4–0.6

–1.4

-32%***

–0.2

–0.8

Mea

n ch

ange

in b

rain

vo

lum

e (%

)

–1.2–1.0

12

*** n = 368

n = 359

n = 357

n = 331

0 24Time (months)

0.0

–0.4

–0.6

–1.4 -35%***

–0.2

–0.8

–1.2

–1.0

126

*

**

***

Mea

n ch

ange

in b

rain

vol

ume

(%)

Time (months)0 24

0.0

–0.4–0.6

–1.4 -33%***

–0.2

–0.8

–1.2–1.0

126

****

***

n = 266

n = 249

Mea

n ch

ange

in b

rain

vol

ume

(%)

BRAIN VOLUME LOSSLESIONS†DISABILITY

PROGRESSIONRELAPSES

IFNβ-1a IM(n = 431)

Fingolimod (n = 429)

-52%***

AR

R

Placebo(n = 355)

Fingolimod (n = 358)

-48%***

AR

R

Placebo(n = 418)

Fingolimod (n = 425)

-54%***A

RR

Changes in disability progression shown here were measured using the EDSS scale. % change is vs comparator arm. *p<0.05; **p<0.01; ***p<0.001. †Number of Gd+ lesions or number of new/newly enlarged T2 lesions. ARR, annualised relapse rate;conf., confirmed; Gd+, gadolinium enhancing; NS, not significant; RRMS, relapsing–remitting MS. 1. From N Engl J Med, , Kappos L et al., , A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis, A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis, 362, 387-401. Copyright © (2010) Massachusetts Medical Society. Reproduced with permission from Massachusetts Medical Society; 2. Reproduced from Lancet Neurol 13(6). Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, Li B, Cappiello L, von Rosenstiel P, Lublin FD. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. pp545-56. ©2014 with permission from Elsevier; 3. Calabresi PA et al. Poster 015 presented at AAN 2012; 4. From N Engl J Med, Cohen JA et al., Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis, , Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis, 362, Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis, 362, 402-15. Copyright © (2010) Massachusetts Medical Society. Reproduced with permission from Massachusetts Medical Society

Dimethyl Fumarate

Annualized Relapse Rate over 2 Years

ARR calculated with negative binomial regression, adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age(<40 vs ≥40 years), study, region, and number of relapses in the 1-year prior to study entry***p<0.0001 vs placebo

49% 49%*** ***0.6

0.5

0.4

0.3

0.2

0.1

0Placebo (n=771)

BG-12 BID(n=769)

BG-12 TID(n=761)

0.371

0.191 0.191

Adj

uste

d A

RR

(95%

CI)

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

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

Daclizumab

CD4+ T

CD56bright NK

CD56bright NK

CD56bright NK

CD56bright NK

CD56bright NK

► Increased levels of IL-2 can induce expansion and activation of CD56bright NK cells through the

intermediate affinity receptor1-6

IL-2 intermediate-affinity (βγ) receptor

Anti-CD25 (daclizumab HYP)

IL-2 high-affinity (αβγ) receptor

IL-2

► CD25 blockade prevents IL-2 consumption by activated T cells and increases IL-2 production (via

inhibition of negative feedback)1-5

CD4+ TCD4+ T

► Activation of T cells induces expression of IL-2

high-affinity receptor and production of IL-21-5

Activation

CD4+ T

CD56bright NK

► Levels of bioavailable IL-2 are increased1-6

CD25 blockade induces a shift of IL-2 signalling from activated T-cells to CD56-bright NK cells

Adapted from 1. Amaravadi L et al. Presented at AAN; Washington, USA; 2015:P1.149; 2. Malek TR. Annu Rev Immunol. 2008;26:453-479; 3. Bielekova B. Neurotherapeutics. 2013;10:55-67; 4. Wiendl H et al. Nat Rev Neurol. 2013;9:394-404; 5. Pfender N et al. Exp Neurol. 2014;262:44-51; 6. Elkins J et al. Neurol Neuroimmunol Neuroinflamm. 2015;2:e65.

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.

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.

.

.

Alemtuzumab

Long-term efficacy over 5 years

CAMMS223

aCo-primary endpoints.

Coles AJ, et al. Neurology. 2012;76:1069-1078.

P<0.0001 P=0.0005P=0.0056

Mean EDSS Score6-Month SADa ARRa

Months 0-60Months 0-60 Months 0-60

66% reduction 69% reduction

IFNB-1a 44 μg Alemtuzumab12 mg

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

Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy

“Four alemtuzumab-treated patients (5%) fulfilled the definition of secondary progression of two consecutive SAD events.”

Safety Issues

0 12 24 36ObservationTreatment Cycles Duration (mo)

60Alemtuzumab12 mg/d IV

QD×3QD×5 ? QD×3

Short-termInfusion reactions

Infections: viral and opportunisticTravel

Baseline De-riskingVZV

Live vaccinesLatent TB

HPVPregnancy

Intermediate-term2° autoimmunity

PregnancyPulsed steroids

Travel

? Long-termImmune senescence

2° malignancy

Risks

Monitoring & prophylaxis

Baseline bloodsVZV serology

CXR & quantiferon TB assay Cervical smearPregnancy test

Monthly FBC & urinalysis3-monthly TFTs

Annual MRI

Pretreatment with steroids, anti-histamines and paracetamol

Herpes prophylaxis x 28 daysListeriosis prevention diet

Pre-planned rapid access to haematology, nephrology, dermatology, etc.

Patient education

Baseline counselling Signed consent Engaged with self-monitoring Lifelong monitoring

Active public engagement programme

Overall AE rates in clinical trials

• Rate of AEs with Alemtuzumab 12 mg, including those leading to treatment discontinuation, generally similar to those with IFNB-1a SC

aIncludes CAMMS223, CARE-MS I, and CARE-MS II. AE, adverse event.

Data on file. Genzyme Therapeutics, Ltd; Oxford, UK.

2-year active-controlled experiencea

• AE profiles similar for treatment-naïve patients and those who relapsed on prior therapy

AEsIFNB-1a SC 44 μg

n=496Alemtuzumab 12 mg

n=919AEs, n (%) 469 (94.6) 896 (97.5)

Grade 1 (mild) 400 (80.6) 815 (88.7)

Grade 2 (moderate) 402 (81.0) 831 (90.4)

Grade 3 (severe) 106 (21.4) 227 (24.7)

Grade 4 (very severe) 10 (2.0) 27 (2.9)

AEs leading to treatment discontinuation, n (%) 39 (7.9) 21 (2.3)

Serious AEs, n (%) 91 (18.3) 168 (18.3)

Serious AEs leading to treatment discontinuation, n (%) 10 (2.0) 7 (0.8)

Deaths 0 3

Rate of AEs over time

• Rate of AEs was similar in IFNB-1a- and Alemtuzumab-treated patients, except during month following Alemtuzumab administration, due to IARs1

— IAR rates lower with second vs first treatment course of Alemtuzumab1

•Similar pattern observed in CARE-MS II2 and CAMMS2233

Time, mo

Rat

e o

f A

Es(t

ota

l eve

nts

/to

tal p

erso

n-m

on

ths)

CARE-MS I1

0

1

2

3

4

5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Both treatment arms received 1 g methylprednisolone qd ×3 d at months 0 and 12.

1. Coles AJ, et al. Presented at: American Academy of Neurology; 2012; New Orleans, LA; 2. LaGanke CC, et al. Presented at: American Academy of Neurology; 2013; San Diego, CA. P01.174 3. Data on file, Genzyme Therapeutics, Ltd; Oxford, UK

Overview of IARs in clinical trials

CARE-MS I and II (Pooled)1

Ave

rage

Nu

mb

er o

f IA

R S

ymp

tom

s

Infusion Number

Course 1 Course 2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

1 2 3 4 5 1 2 3

• To manage IAR severity: — Pretreat with corticosteroids,

(ie, methylprednisolone) immediately before infusion with Alemtuzumab for first 3 days of any treatment course1

— Consider pretreatment with antihistamines and/or antipyretics

• Observe patient for IARs during and for 2 hours after Alemtuzumab infusion

• Physician and patient education

Premedication and Monitoring2

• Predominantly mild to moderate;decreased with each treatment course3

• 3% serious: pyrexia, urticaria, atrial fibrillation, nausea, chest discomfort, hypotension2

1. Data on file. Genzyme Therapeutics, Ltd; Oxford, UK; 2. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 3. Caon C. et al. Presented at: Consortium of Multiple Sclerosis Centers; 2012; San Diego, CA; DX41.

No increase in infection rate over 2 years

Time, mo

Inci

den

ce o

f In

fect

ion

s

0.0

0.1

0.2

0.3

0.4

0.5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

IFNB-1aAlem12 mg

389811

388811

387811

386811

384811

379811

377811

375811

373811

372810

371810

368810

363810

362807

358807

357806

355805

354804

353803

352803

352797

351796

349785

342761

CARE-MS I and II (pooled data)

IFNB-1a 44μg

Alemtuzumab12 mg

Alem: alemtuzumab

Havrdova E, et al. Presented at: European Committee for Research and Treatment in Multiple Sclerosis; 2013, Copenhagen; P603.

• Risk highest in first month after first treatment; rates decreased over time

• No increase in infection risk that would indicate cumulative immunosuppressive effects

Overview of infections in clinical trials

• More frequent with Alemtuzumab vs INFB-1a (71% vs 53%)1

• Predominately mild to moderate1

• Generally of typical duration, resolved following conventional treatment1

• Did not correlate with lymphocyte counts3

• Total or subgroups CD4, CD8, CD19

2-year active-controlled experience2a,b

IFNB-1a SC 44 μg

n=496

Alemtuzumab 12 mgn=919

Grade 1, 2 258 (52.0) 618 (67.2)

Grade 3 6 (1.2) 33 (3.6)

Grade 4 0 (0.0) 1 (0.1)

Serious AEs, n (%) 5 (1.0) 25 (2.7)

Nasopharyngitis 82 (16.5) 216 (23.5)

Urinary tract infection 40 (8.1) 162 (17.7)

Upper respiratory tract infection 57 (11.5) 141 (15.3)

Sinusitis 34 (6.9) 100 (10.9)

Oral herpes 6 (1.2) 79 (8.6)

Influenza 25 (5.0) 77 (8.4)

Bronchitis 16 (3.2) 64 (7.0)

Herpes zoster 4 (0.8) 38 (4.1)

Gastroenteritis 5 (1.0) 36 (3.9)

Pharyngitis 7 (1.4) 36 (3.9)

• Prophylaxis with oral anti-herpes agent (acyclovir 200 mg twice a day used in clinical trials) starting first day of treatment, continuing for 1 mo after treatment course

Risk Mitigation (Monitoring)1

aInfections with incidence of ≥5.0% in any treatment group shown.bIncludes CAMMS223, CARE-MS I, and CARE-MS II.cEvents occurring in ≥5% of Alemtuzumab-treated patients, based on all available follow-up.

1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Data on file. Oxford, UK: Genzyme Therapeutics, Ltd; 3. Havrdova E, et al. Presented at: European Committee for Research and Treatment in Multiple Sclerosis; 2013; Copenhagen; P603.

Nephropathy cases in detail

aCreatinine normal range, 0.6-1.1 mg/dL.CKD, chronic kidney disease; URTI, upper respiratory tract infection.

Wynn D, et al. Presented at: European Committee for Research and Treatment in Multiple Sclerosis; 2013; Copenhagen; P597.

Age/Sex/Trial

Months From

Last Dose

Dose (Courses; Cumulative

Dose)

Serum Creatinine at Diagnosis

mg/dL (μmol/L) Prodrome

Treatment→

OutcomeAnti-GBM cases

35 yr/female/CAMMS223 39

12 mg(2 courses;

96 mg) 1.8 (163) URTI, rash,

hematuriaStandard Rx →

CKD3a

23 yr/female/Extension 4

12 mg (3 courses;

132 mg)

0.7 (63)(Normal)a

Proteinuria; hematuria

Standard Rx → CKD 1

Membranous nephropathy

26 yr/female/CARE-MS II 5

12 mg(2 courses;

96 mg)

0.6 (54)(Normal)a

Proteinuria, hematuria,

hypoalbuminemia, peripheral edema

Furosemide + ACEI →Symptoms improved

58 yr/female/CAMMS3409 EXT

1312 mg

(2 courses;96 mg)

1.5 (135) Proteinuria, hematuria, edema

Initial: diuretics + albumin

Ongoing: diuretics

All cases (0.3% in clinical trials) detected by safety monitoring program; none resulted in renal failureMonitoring, education essential for early detection, effective management

Autoimmune-related thyroid AE incidencePhase II through complete follow-up (6.7 years)

• Occurred in 34% of patients taking Alemtuzumab vs 6.5% of those taking INFB (P<0.0001)1

• Majority were hyperthyroidism1

• 4 events identified as serious (0.4 events per 100 person-years)2

• Delayed onset: peaked in third year after initial Alemtuzumab treatment, declined thereafter1,2

Phase III Studies3

CARE-MS I CARE-MS IIINFbeta 1a s.c

44 µg

N=187

Alemtuzumab12 mg

N=376

INFbeta 1a s.c 44 µg

N=202

Alemtuzumab12 mg

N=435

Any thyroid AEa (n, %) 12 (6.4) 68 (18.1) 10 (5.0) 69 (15.9)

Hyperthyroidism 3 (1.6) 31 (8.2) 1 (0.5) 19 (4.4)

Hypothyroidism 6 (3.2) 29 (7.7) 3 (1.5) 29 (6.7)

Goiter 0 6 (1.6) 1 (0.5) 6 (1.4)

Thyroid mass 0 1 (0.3) 0 0

Lab investigations 5 (2.7) 21 (5.6) 6 (3.0) 22 (5.1)

Thyroid SAE (n, %) 0 4 (1.1) 0 2 (0.5)

Thyroid carcinoma (n, %)

0 2 (1) 0 1 (<1)

aSome patients had >1 episode of thyroid dysfunction; for example, treatment of one hyperthyroidism case in CARE-MS II resulted in development of hypothyroidism.SAE, serious adverse event.

1. Daniels GH, et al. J Clin Endocrinol Metab. 2014;99:80-89; 2. Coles AJ, et al. Neurology. 2012;78:1069-1078; 3. Habek M, et al. Presented at: European Neurological Society; 2012; Prague; P340.

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

Autoimmune

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 from Natalizumab to Alemtuzumab

Natalizumab

Natalizumab

Alemtuzumab

Asymptomatic PML?LP-JCV DNA & MRI

Alemtuzumab

Natalizumab AlemtuzumabOral bridging agent (Teriflunomide, DMF or Fingolimod)

RebaselineMRI **

Asymptomatic PML?LP-JCV DNA & MRI

3-6 MONTH WASHOUT

Asymptomatic PML?*LP-JCV DNA & MRI

RebaselineMRI

Option 1: Immediate switch (high risk if carry-over PML develops)

Option 2: Washout (intermediate risk; mainly related to rebound of MS disease activity)

Option 3: Bridging (low risk; mainly related to using a low efficacy bridging agent and using alemtuzumab after the bridging agent)

6-12 MONTHS

* For this option the shorter the washout the more important the screen for asymptomatic PML becomes. ** PML screening and baseline MRI studies are don’t use the same types of scans hence the need for both.

Temporal profile of lymphocyte counts with fingolimod therapy

Francis et al. MSJ 2013

Switching from Fingolimod to Alemtuzumab

Fingolimod

Fingolimod

Alemtuzumab

Alemtuzumab

Fingolimod AlemtuzumabBridging agent (IFN-beta, GA, Teriflunomide or DMF)

Only treat with alemtuzumab once lymphocyte counts normalize*

2 to 6 12 MONTH WASHOUT

Only treat with alemtuzumab once lymphocyte counts normalize*

Option 1: Immediate switch (high-risk if persistent lymphopaenia occurs)

Option 2: Washout (intermediate risk; mainly related to rebound of MS disease activity)

Option 3: Bridging (low risk; mainly related to MS rebound as a result of using a low efficacy bridging agent after fingolimod)

3-12 MONTHS

* What constitutes a normal level post-fingolimod needs to be defined; I would be reluctant to give alemtuzumab to anyone with a total lymphocyte count below 1.0x109 .

Treat with alemtuzumab before lymphocyte counts normalize

* What constitutes a normal level in this situation needs to be defined; I would be reluctant to give alemtuzumab to anyone with a total lymphocyte count below 1.0x109 .

Pregnancy

Considerations for Women of Childbearing Potential

Interferon β• In monkeys, increased rate of abortion. No malformations in surviving

animals• Initiation of treatment is contraindicated during pregnancy

Glatiramer acetate• Animal studies are insufficient with respect to effects on pregnancy;

embryonal/foetal development, parturition, and postnatal development

• Contraindicated during pregnancy

Natalizumab• Studies in guinea pigs and monkeys showed no evidence of

teratogenic effects or effects on growth of offspring• Should not be used during pregnancy unless the clinical condition of

the woman requires treatment with natalizumab

Fingolimod• Animal studies have shown reproductive toxicity, including foetal loss

and teratogenicity• While on treatment, women should not become pregnant; if

pregnancy occurs, discontinuation of fingolimod is recommended

Animal studies, Clinical recommendations

Data from summary of product of characteristics (SmPC) for each therapy.

Considerations for Women of Child-bearing Potential

Teriflunomide

• Embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic range

• Contraindicated in pregnancy• Patient advised to contact physician if pregnancy is suspected;

institution of accelerated elimination may decrease risk to foetus

Alemtuzumab

• Dosing mice for 5 days during gestation resulted in significant increases in dead or resorbed conceptuses and reduction in viable foetuses

• Placental transfer and potential pharmacologic activity observed• Contraception advised during treatment and for 4 months following• Should be administered during pregnancy only if the potential benefit

justifies the potential risk to the foetus• Thyroid disease poses special risks in women who are pregnant

(potential miscarriage, foetal effects such as mental retardation and dwarfism, transient neonatal Graves’ disease)

Dimethyl fumarate• No malformations have been observed at any dose in rats or rabbits• Should be used during pregnancy only if clearly needed and if the

potential benefit justifies the potential risk to the foetus

Animal studies, Clinical recommendations

Data from summary of product of characteristics (SmPC) for each therapy.

Alemtuzumab pharmacokinetics in MS

Clinical effects persist after Alemtuzumab is cleared from circulation

• Alemtuzumab serum concentrations low or undetectable within ~30 days after treatment

Alemtuzumab 12 mg administered at time 0 and 12 months.

Kovarova I, et al. Presented at: European Neurological Society; 2012; Prague; P341.

CARE-MS I: Mean Serum Concentration Over Time

Time on Study, mo

4,000

0

2,000

3,000

1,000

0 1 3 6 9 12 2415 18 21

Con

cent

ratio

n (n

g/m

L)

13

Alemtuzumab 12 mg

Alemtuzumab 12 mg

What’s relevant for your clinical practice?

• Multiple sclerosis is an autoimmune disease• DMTs are either immunomodulatory and/or

immunosuppressive• Risks of MS vs. Benefits of treatment vs. Risks of treatment• De-risking treatments

– Baseline screening– Monitoring– Timely switching

• DMT specific knowledge• Databasing• Pharmacovigilance monitoring• Pregnancy

– Registries• CME

Take-home messages

1. Immunosuppressive therapies are one of the mainstays of the treatment of multiple sclerosis and the benefits need to weighed-up against the risks of long-term immunosuppression and the risks of untreated or undertreated MS.

2. Most DMTs can be derisked with appropriate screening and pharmacovigilance

3. Decision to treat should be a shared decision and patients should take an active part in the monitoring of their disease and treatments

Take-home message

“Most DMTs can be derisked with appropriate screening and pharmacovigilance.”