Lactrims 2014 Genzyme Symposium

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Personalizing MS Management

November 28, 2014 VIII LACTRIMS Congress

A Genzyme-sponsored Symposium

Agenda

Time Title Presenter

12:30 Aubagio Clinical Data and Real-Life Utility Prof. Flavia Nelson Neurology Dept., The University of Texas

Medical School, Texas - USA

13:10 Alemtuzumab and The Changing MS Landscape Prof. Gavin Giovannoni Blizard Institute, Barts and The London

School of Medicine and Dentistry, Queen

Mary University of London, London -

United Kingdom

13:50 Discussion Dr. Miguel A. Macías Islas Hospital de Especialidades del Centro

Médico de Occidente, Instituto Mexicano

del Seguro Social, Guadalajara - Mexico

2

Aubagio Clinical Data and Real-Life Utility

Professor Flavia Nelson Associate Professor of the Neurology Dept., The University

of Texas Medical School at Houston

Disclosures

Professor Nelson has received:

Honoraria or consultation fees from: Biogen Idec; Teva; Sanofi-Aventis; Bayer, Novartis; and Genzyme, a Sanofi Company

Grants from: Novartis; and NIH

4

A Review of the Clinical Efficacy and Safety of Teriflunomide

Demonstrate the consistent efficacy profile of teriflunomide

– Efficacy of teriflunomide in first attack of MS (TOPIC)a

– Efficacy in relapsing forms of MS (TEMSO and TOWERb)

– Efficacy in highly active MS (pooled TEMSO and TOWER subgroup analysis)

– Effect on severity of relapses (TEMSO and TOWER)

– Long-term efficacy (TEMSO Extension)

Present an overview of teriflunomide’s safety and tolerability

5 aResults of TOPIC study have been recently published and FDA approved the extension of AUBAGIO`s label for the inclusion of these results. bFDA recently approved the extension of AUBAGIO`s label for the inclusion of TOWER results.

Introduction to Teriflunomide

Teriflunomide is a novel, once-daily, oral immunomodulator1

1. Aubagio (teriflunomide) USA Summary of Product Characteristics, September 2012; 2. Aubagio (teriflunomida) Peru Summary of Product Characteristics, 2014. 6

2013

• Argentina

• Chile

• México

First approved - USA in 20121

– Approved for treatment of patients with relapsing forms of MS

Registration approvals across Latin America*

2014

• Colombia

• Brasil

• Guatemala

• Uruguay

• Panamá

• Rep. Dominicana

• Peru

• Honduras

• Ecuador

• Costa Rica

Approved for adult patients with relapsing remitting MS2

*Lemtrada indication across Europe and Latin America countries is similar to that in Peru.

Teriflunomide Mechanism of Action

Teriflunomide acts selectively and reversibly to decrease proliferation of T and B autoreactive lymphocytes and largely preserves immune function

7 DHODH, dihydro-orotate dehydrogenase

Extensive Clinical Program

8 RMS, relapsing forms of MS; CIS, clinically isolated syndrome; IFN, interferon; GA, glatiramer acetate.

Clinical Program – General Information

Teriflunomide clinical program is among the largest scale programs, with > 2700

patients treated for 10 years

Teriflunomide has been evaluated in a broad spectrum of patients: early MS, relapsing

forms of MS and highly active disease

9

TOPIC3a

60% monofocal

40% multifocal

31,4% ≥ 1 Gd-enhanced

lesion

Phase 2 POC, TEMSO, TOWER, TENERE4-7

≥ 88% RRMS ≤ 12% SPMS

Phase 2 POC,

TEMSO, TOWER,

TENERE4-7

≤ 4% PRMS

Dis

ab

ilit

y

Time

Clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery2

Initial relapsing-remitting disease course followed by progression with or

without occasional relapses, minor remissions, and

plateaus2

Progressive disease from onset, with clear acute relapses, with or without full recovery2

Clinical Isolated Syndrome (CIS)

Progressive

Relapsing (PRMS)

Secondary

Progressive (SPMS)

Relapsing-Remitting

(RRMS)

A single, symptomatic, neurological episode and/or radiological

finding that is consistent with MS1

1. Lipsy RJ et al. J Manag Care Pharm 2009;15:S2-15; 2. Lublin FD, Reingold SC. Neurology 1996;46:907-11; 3. Miller AE et al. Lancet Neurol. 2014; 13(10):977-86; 4.

O’Connor P et al. Neurology. 2006;66:894-900; 5. O’Connor P et al. N Engl J Med. 2011;365:1293-303; 6. Confavreux C et al. Lancet Neurol. 2014;13(3):247-56; 7.

Vermersch P et al. Mult Scler J. 2014;20(6):705-16; Images adapted from Lublin FD, Reingold SC. Neurology 1996;46:907-11.

Gd, gadolinium; POC, proof of concept

TOPIC: Teriflunomide vs. Placebo in Patients with First Clinical Symptom of Multiple Sclerosis

Endpoints

– Primary: Conversion to clinically definite MS (CDMS)

– Key secondary: Occurrence of a new clinical relapse or MRI lesion (Gd enhancement or new T2 lesion)

10

CIS, clinically isolated syndrome; MRI, magnetic resonance image; Gd, gadolinium. aMedian exposures: placebo, 504 days; teriflunomide 7 mg, 524 days; 14 mg, 633 days

Miller AE et al. Lancet Neurol 2014; 13(10):977-86.

Patients with CIS

Randomized 1:1:1

N=618

Screening

Placebo

Teriflunomide 7 mg

Teriflunomide 14 mg

R

Teriflunomide 7 mg

Teriflunomide 14 mg R

Core Study Planned duration 108 weeksa

Extension Patients completing core study

or relapsing after ≥24 weeks on study

Placebo group re-randomized 1:1

Teriflunomide 7 mg

Teriflunomide 14 mg

TOPIC: Baseline Disease Characteristics Were Similar Across Treatment Groups

Placebo

(n=197)

Teriflunomide

7 mg (n=205)

Teriflunomide

14 mg (n=216)

Mean age, years (SD) 32.0 (8.4) 31.6 (9.0) 32.8 (8.1)

Female, % 68.5 63.4 71.3

Caucasian/white, % 95.4 96.6 96.3

Mean time since neurological event, months

(SD) 1.88 (0.52) 1.89 (0.56) 1.80 (0.56)

Prior use of systemic corticosteroids, % 17.8 10.2 17.1

Onset presentation, %

Monofocal

Multifocal

57.9

42.1

59.5

40.5

59.7

40.3

Baseline Gd-enhancing lesions, % 29.4 32.2 32.4

Mean baseline total lesion volumea, mL (SD) 9.15 (10.69) 8.07 (9.98) 8.78 (9.36)

SD, standard deviation; Gd, gadolinium. aVolume of T2 hyperintense and T1 hypointense lesions, mL

Miller AE et al. Lancet Neurol 2014; 13(10):977-86. 11

TOPIC: Teriflunomide Significantly Increased Time to Conversion to CDMS vs. Placebo

37% reduction HR: 0.628

(95% CI: 0.416, 0.949)

p=0.0271

Co

nve

rsio

n r

ate

(%

)

Weeks

40

0

5

10

15

20

25

30

35

0 12 24 36 48 60 72 84 96 108


(95% CI: 0.379, 0.869)

p=0.0087

Placebo Teriflunomide 7 mg Teriflunomide 14 mg

CDMS, clinically definite MS.


TOPIC: Teriflunomide Significantly Reduced the Risk of a New Clinical Relapse or MRI Lesion

MRI, magnetic resonance imagne

P values compared with placebo. Reduction refers to relative reduction in risk

100 O

cc

urr

en

ce

of

rela

ps

es

or

ne

w le

sio

ns

(%)

10

20

30

40

50

60

70

80

90



(95% CI: 0.540, 0.871)

p=0.0020


(95% CI: 0.515, 0.822)

p=0.0003

0 12 24 36 48 60 72 84 96 108

Weeks

0


TOPIC: Change From Baseline in Total Lesion Volumea at Week 108 was Lower for Teriflunomide 14 mg vs. Placebo

Percentage changes at Week 108: placebo 28%; teriflunomide 7 mg 18%; teriflunomide 14 mg 5%

SE, standard error. aVolume of T2 hyperintense and T1 hypointense lesions, mL

Me

an

± S

E c

ha

ng

e f

rom

bas

eli

ne

0 12 24 48 72 108

2.0

-1.2

-0.8

-0.4

0.0

0.4

0.8

1.2

1.6

p=0.7789

p=0.0374


Weeks


TOPIC: Analysis Using 2010 McDonald Diagnostic Criteria

• McDonald 2010 criteria was applied retrospectively in the TOPIC Phase 3 study of patients with CIS

• Patients were grouped according to baseline disease characteristics (meeting new criteria, not meeting new criteria, or unclassifiable)

• The effect of teriflunomide on occurrence of a new clinical relapse or MRI lesion was analyzed for the group of patients not meeting 2010 McDonald criteria for MS at baseline

Randomized

N=618

Meeting Criteria

n=78

Not Meeting Criteria

n=245

Ambiguous

n=291

Not exposed to study medication

n=4

CIS, clinically isolated syndrome; MRI, magnetic resonance image.

Adapted from Wolinsky J et al. Presented on ACTRIMS/ECTRIMS, 2014, P095. 15

TOPIC: Efficacy Analysis Using 2010 McDonald Diagnostic Criteria

Risk of a New Clinical Relapse or MRI Lesion (Patients Not Meeting 2010 McDonald Criteria)

Oc

cu

rre

nce (

%) 38% reduction

HR: 0.617

(95% CI: 0.402, 0.945)

P=0.0265


(95% CI: 0.399, 0.932)

P=0.0222

No. of patients

Teriflunomide 14 mg

Teriflunomide 7 mg

Placebo

89

82

74

73

70

55

53

49

35

31

24

16

29

15

12

0 12 48 72 96

Weeks

0

20

40

70

90

100

24 36 60 84 108

10

80

60

50

30

Teriflunomide 14 mg

Teriflunomide 7 mg

Placebo

47

43

25

45

38

22

31

26

17

31

17

13

21

12

8

MRI, magnetic resonance image

Adapted from Wolinsky J et al. Presented on ACTRIMS/ECTRIMS, 2014, P095. 16

This analysis confirms the results of the main TOPIC study, showing the efficacy of teriflunomide in the treatment of patients with early-stage MS and the consistency of treatment effect using various endpoints and diagnostic criteria.

TOPIC: MRI Outcomes (Subgroup Analyses)

Treatment with teriflunomide 14 mg resulted in consistent beneficial effect on number of Gd-enhancing lesions per scan and TLV in subgroups of patients defined by gender, age, number of Gd-enhancing lesions at baseline, baseline TLV, and baseline monofocal/multifocal status.

17

Effect Of Teriflunomide 14 mg on Gd Enhancing T1

Lesions Per MRI Scan By Subgroup

Effect Of Teriflunomide 14 mg on TLV Change From

Baseline At Week 108 by Subgroup

MRI, magnetic resonance image; TLV, total lesion volume.

Adapted from Wolinsky J et al. Presented on ACTRIMS/ECTRIMS, 2014, P040.

The most common TEAEs occurring at a greater frequency in the teriflunomide groups than with placebo were ALT increased, headache, hair thinningb, diarrhoea, paraesthesia and upper respiratory tract infection

Discontinuations were protocol-mandated in the event of confirmed ALT >3-fold ULN, and any occurrence of neutrophil count of <1,000 cells/μL – Discontinuations due to ALT increase were reported for 4.7%, 5.3%, and 4.2% of patients receiving placebo,

teriflunomide 7 mg and teriflunomide 14 mg, respectively

– There were three discontinuations for neutropenia (teriflunomide 7 mg, n=2; teriflunomide 14 mg, n=1)

TOPIC: Safety and Tolerability Profile in Early MS Similar to Established Safety Profile

18

Patients, n (%) Placebo

(n=191)

Teriflunomide

7 mg (n=207)

Teriflunomide

14 mg (n=216)

Any treatment-emergent AE (TEAE) 155 (81.2) 161 (77.8) 183 (84.7)

Treatment-emergent serious AE (SAE) 18 (9.4) 18 (8.7) 24 (11.1)

Deatha 1 (0.5)a 0 0

TEAE leading to permanent treatment discontinuation

19 (9.9) 25 (12.1) 18 (8.3)

AE, adverse event; ALT, alanine aminotransferase; ULN, upper limit of normal. aPatient suicide in placebo group; bMedDRA preferred term, Alopecia

Miller AE et al. Lancet Neurol 2014; 13(10):977-86.

TEMSO (n=1088)1 TOWER (n=1169)2

Mean age, years (SD) 37.9 (8.8) 37.9 (9.3)

Female, % 72.2 71.1

Race, %

Caucasian/White

Asian

Other

97.5

1.4

1.1

82.1

14.5

3.4

Time since first symptom of MS, years

Mean (SD)

Median (range)

8.7 (6.9)

6.8 (0.3–35.7)

8.0 (6.7)

6.3 (0.1–36.9)

No. of relapses within past 2 years

Mean (SD)

Median (range)

2.2 (1.1)

2.0 (1–12)

2.1 (1.2)

2.0 (1–9)

MS subtype, %

Relapsing-remitting

Secondary progressive

Progressive relapsing

91.5

4.7

3.9

97.5

0.8

1.7

Baseline EDSS score

Mean (SD)

2.7 (1.3)

2.7 (1.4)

Previous DMT in past 2 years, % 27.0 32.8

TEMSO & TOWER – Patients with Relapsing MS: Baseline Disease Characteristics Were Similar Across Both Trials

19

SD, standard deviation; EDSS, Expanded Disability Status Scale; DMT, Disease-modifying Therapy.

1. O’Connor P et al. N Engl J Med. 2011;365:1293-303; 2. Confavreux C et al. Lancet Neurol. 2014;13(3):247-56.

0.54

0.37 0.37

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.50

0.39

0.32

0.0

0.1

0.2

0.3

0.4

0.5

0.6

TEMSO & TOWER: Teriflunomide Consistently Reduced Relapse Rates vs. Placebo in Patients with Relapsing MS

20 RRR, relative risk reduction


An

nu

ali

ze

d R

ela

ps

e R

ate

An

nu

ali

ze

d R

ela

ps

e R

ate

n=388 n=407 n=370

Placebo 7 mg 14 mg Placebo 7 mg 14 mg

RRR: 31%

p<0.001

n=365 n=358 n=363

RRR: 31%

p<0.001

RRR: 36%

p=0.0001

RRR: 22%

p=0.0183

TEMSO1 TOWER2

TEMSO & TOWER: Teriflunomide 14 mg Consistently and Significantly Reduced Risk of 12-week Disability Progression vs. Placebo

21

27%

22%

20%

TEMSO1 TOWER2

HR, hazard ratio


0

0 36 72 84 96 108 48 60

Su

sta

ine

d D

isa

bilit

y P

rog

res

sio

n (

%)

30

24

Weeks

10

20

12

40

7 mg vs. placebo: HR: 0.763, p=0.0835

14 mg vs. placebo: HR 0.702, p=0.0279

Teriflunomide 14 mg

Teriflunomide 7 mg

Placebo

21%

22%

16%

40

0 12 24 36 48 60 72 84 96 108 120 132

Weeks

30

20

0

10

7 mg vs. placebo: HR 0.955, p=0.7620

14 mg vs. placebo: HR 0.685, p=0.0442

Su

sta

ine

d D

isa

bilit

y

Pro

gre

ss

ion

(%

)

Teriflunomide 14 mg

Teriflunomide 7 mg

Placebo

TEMSO & TOWER Enrolled Patients With Active Disease

22

TEMSO (n=1088)1 TOWER (n=1169)2

Mean age, years (SD) 37.9 (8.8) 37.9 (9.3)

Female, % 72.2 71.1

Race, %

Caucasian/White

Asian

Other

97.5

1.4

1.1

82.1

14.5

3.4

Time since first symptom of MS, years

Mean (SD)

Median (range)

8.7 (6.9)

6.8 (0.3–35.7)

8.0 (6.7)

6.3 (0.1–36.9)

No. of relapses within past 2 years

Mean (SD)

Median (range)

2.2 (1.1)

2.0 (1–12)

2.1 (1.2)

2.0 (1–9)

MS subtype, %

Relapsing-remitting

Secondary progressive

Progressive relapsing

91.5

4.7

3.9

97.5

0.8

1.7

Baseline EDSS score

Mean (SD)

2.7 (1.3)

2.7 (1.4)

Previous DMT in past 2 years, % 27.0 32.8

SD, standard deviation; EDSS, expanded disability status scale; DMT, disease-modifying therapy.


TEMSO & TOWER: Teriflunomide Improved ARR and 12-Week Disability Progression in a High Disease Activity Subgroups

High disease activity was defined as ≥2 relapses in the year before study entry

23 Kappos L et al. ECTRIMS 2012, S0153

An

nu

alize

d R

ela

ps

e R

ate

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 Placebo Teriflunomide

7 mg

Teriflunomide

14 mg

0.728

0.499 0.484

31% Risk

reduction

(p<0.001)

34% Risk

reduction

(p=0.001)

Dis

ab

ilit

y P

rog

ressio

n

Co

nfi

rme

d f

or

12

We

ek

s (

%)

40

35

30

25

20

15

10

5

31%

23%

0 0 12 24 36 48 60 72 84 96 108 120 132

Weeks

18%

Teriflunomide 7 mg

Teriflunomide 14 mg 29%

46% 0.088

0.004

Placebo

Teriflunomide 7 mg

Teriflunomide 14 mg

Risk reduction p value

ARR

12-week SAD

ARR, annualized relapse rate;

SAD, sustained accumulation disability

TEMSO & TOWER: Evaluation of the Effect of Teriflunomide in Subgroups Defined by Prior Treatment (Pooled Analyses)

These pooled subgroup analyses support the beneficial effects of teriflunomide across a broad range of patients with RRMS, including robust activity in those patients who have previously used and discontinued other DMTs

24

Adjusted ARR by Prior Treatment Disability Progression by Prior Treatment

ARR, annualized relapse rate; DMT, disease-modifying therapy; RRMS, relapsing-remitting MS.

Adapted from Freedman M et al. Presented on ACTRIMS/ECTRIMS, 2014, P046.

An

nu

ali

ze

d r

ela

ps

e r

ate

Pro

ba

bilit

y o

f

dis

ab

ilit

y p

rog

res

sio

n

0.423 0.464 0.303 0.463 0.536 0.329 0.794 0.641 0.472 0.0

0.2

0.4

0.6

0.8

1.0

>1 Prior DMT 1 Prior DMT No Prior DMT

0.072 0.201 0.178 0.218 0.345 0.176 0.298 0.299 0.238 0.0

0.1

0.2

0.3

0.4

>1 Prior DMT 1 Prior DMT No Prior DMT

Teriflunomide 14 mg

Teriflunomide 7 mg

Placebo

46.7%

41.6% 27.7%

16.4% 35.9%

30.2%

78.6%

33.4%

46.6%

5.0%

17.4%

20.8%

Patients (n) 41 32 36 189 193 192 498 547 523 Patients (n) 41 32 36 189 193 192 498 547 523

Post hoc analysis of pooled data of ARR and 12-week confirmed disability progression conducted on patient subgroups defined by prior MS therapy

Teriflunomide 7 mg vs. placebo Teriflunomide 14 mg vs. placebo

TOWER1,a

-31

-16 -17 -22

-37

-54

-34 -36

-60

-50

-40

-30

-20

-10

0

Relapses WithSequelae

EDSS/FS at 30days


InvestigatorAssessment

RelapsesLeading to

Hospitalization

RelapsesRequiring IV

Corticosteroids

p=0.0104

p=0.0021

p=0.297

p=0.0004

p=0.0155

p=0.0337

p=0.0002

p=0.0263

RR

R v

s.

Pla

ce

bo

(%

)

-32-25

-36-29

-36

-53-59

-34

-60

-50

-40

-30

-20

-10

0


EDSS/FS at 30days


InvestigatorAssessment

RelapsesLeading to

Hospitalization

RelapsesRequiring IV

Corticosteroids

p=0.0019

p=0.0011

p=0.0705

p<0.0001

p=0.0014

p=0.0003 p=0.0151

p<0.0001

TEMSO1,2

TEMSO & TOWER: Teriflunomide Significantly Reduced Relapse Severity Related Outcomes vs. Placebo

More robust effect with 14-mg dose compared with 7-mg dose across all relapse outcomes (those with neurological sequelae, and those requiring healthcare resources)

.

a Modified intent-to-treat population.

EDSS, Expanded Disability Status Scale; FS, Functional Score; IV, intravenous; RRR, relative risk reduction.

1. O’Connor P et al. N Engl J Med. 2011;365:1293-303; 2. Confavreux C et al. Lancet Neurol. 2014;13(3):247-56 25

TEMSO Extension: ARR Remained Low over 9 Years

In addition, mean EDSS remained relatively stable for all groups throughout the extension study

26 ARR, annualized relapse rate; EDSS, Expanded Disability Status Scale.

Freedman MS et al. ECTRIMS 2013, P544.

Extension Study Core Study

Annualized relapse rate

TEMSO1

TOWER2

Placebo

(n=360)

Teriflunomide

7 mg

(n=368)

Teriflunomide

14 mg

(n=358)

Placebo

(n=385)

Teriflunomide

7 mg

(n=409)

Teriflunomide

14 mg

(n=371)

TEAEs, n (%) 315 (87.5) 328 (89.1) 325 (90.8)

320 (83.1) 344 (84.1) 320 (86.3)

Treatment-

emergent SAEs,

n (%)

46 (12.8) 52 (14.1) 57 (15.9)

47 (12.2) 52 (12.7) 44 (11.9)

TEAEs leading

to permanent

treatment

discontinuation,

n (%)

29 (8.1) 36 (9.8) 39 (10.9)

24 (6.2) 53 (13.0) 58 (15.6)

TEAEs leading

to death,

n (%)

0 0 0

1 (0.3)a 1 (0.2)b 2 (0.5)c

TEMSO & TOWER Safety: Overview of Treatment-emergent AEs and SAEs

1. O'Connor et al. N Engl J Med 2011;365:1293–303; 2. Kappos et al. Mult Scler J 2012; 18:9–53

AEs, adverse events; SAEs, serious Aes; TEAEs, treatment-emergent AEs. aRespiratory infection following paraplegia; bMotor-vehicle accident; cOne suicide, one death due to Gram-negative septicaemia.

There was no evidence that teriflunomide was a causative factor in any of the deaths in TOWER 27

AEs, adverse events. aMedical Dictionary for Regulatory Activities (MedDRA) preferred term, alopecia

Treatment-emergent adverse events (TEAEs) by MedDRA preferred term

1. O'Connor et al. N Engl J Med 2011;365:1293–303; 2. Kappos et al. Mult Scler J 2012; 18:9–53; 3. Freedman MS et al. ECTRIMS 2013, P544.

Incidence ≥10% in either teriflunomide group and >2% in comparison with placebo

TEMSO & TOWER Safety: TEAEs Occurring More Frequently with Teriflunomide Treatment than with Placebo

Most AEs observed with teriflunomide were mild to moderate in severity, rarely led to treatment discontinuation, and resolved spontaneously without complication while remaining on therapy

Lower incidence of AEs seen in extension phase, and no unexpected safety findings3

TEMSO1 TOWER2

Placebo

(n=360)

Teriflunomide

7 mg

(n=368)

Teriflunomide

14 mg

(n=358)

Placebo

(n=385)

Teriflunomide

7 mg

(n=409)

Teriflunomide

14 mg

(n=371)

Alanine

aminotransferase

increase (%)

7 12 14

8 11 14

Hair thinninga (%) 3 10 13

4 10 13

Diarrhoea (%) 9 15 18

7 12 11

Headache (%) 18 22 19

11 15 12

Influenza (%) 10 9 12

Nausea (%) 7 9 14

28

Pooled Safety Data From the Teriflunomide Clinical Development Program

Overview of Treatment-Emergent Adverse Events (TEAEs)

All data are presented as n (%); maximum intensity calculation = number of patients with mild, moderate, or severe TEAEs/all TEAEs.

Teriflunomide 14 mg

(n=1002) Teriflunomide 7 mg

(n=1045)

Placebo

(n=997)

All TEAEs 885 (88.3) 895 (85.6) 853 (85.6)

Serious TEAEs 133 (13.3) 125 (12.0) 119 (11.9)

TEAEs leading to permanent

discontinuation 125 (12.5) 117 (11.2) 75 (7.5)

Intensity

Mild 281 (31.8) 294 (32.8) 285 (33.4)

Moderate 477 (53.9) 480 (53.6) 448 (52.5)

Severe 127 (14.4) 121 (13.5) 120 (14.1)

Adapted from Leist T et al. Presented on ACTRIMS/ECTRIMS, 2014, P097.

• No new or unexpected safety signals beyond those seen in individual trials were

identified in these pooled analyses

• TEAEs reported more frequently with teriflunomide (≥10% in either teriflunomide group,

and ≥2% greater than placebo) were hair thinning, diarrhea, ALT increase, nausea, and

headache

Pooled safety data from >6800 patient-years of teriflunomide exposure were

consistent with those of individual studies and did not identify any unexpected safety signals with either dose

29

70 pregnancies occurred in female patients exposed to teriflunomide in Phase II and III clinical trials

– Fetal teriflunomide exposure ranged from no exposure to up to 11 weeks2

– No malformations were reported; median birth weight (3.3 kg for 18 documented cases) and mean gestational age (39 weeks for 23 documented cases) were within typical ranges for the general population1,3

The rate of known spontaneous abortion among patients treated with teriflunomide (18.6%) was within the range reported for women without MS (17%-22%)1,4

aFollowing the data cut-off, the ongoing pregnancy resulted in the delivery of a baby boy at 39 weeks of pregnancy

1. Adapted from Kieseier B et al. Presented on ACTRIMS/ECTRIMS, 2014, P846; 2. Data on file, Sanofi/Genzyme. 3. Martin JA et al. Births Final

Data for 2011. National Vital Statistics Report; Vol. 62 No. 1. 2013. 4. Garcia-Enguidanos et al. Eur J Obstet Gynecol Reprod Biol. 2002;102:111-119.

Treatment

Pregnancy Outcomes in Female Patients (n)

Data Cutoff: October 18, 2013

Live Birth Induced

Abortion

Spontaneous

Abortion

Ongoing

Pregnancy

Unknown

Teriflunomide 26 29 13 1a 1

Placebo 2 8 1 0 0

IFNβ 2 0 0 0 0

• No structural or functional abnormalities have been reported in newborns of female

patients exposed to teriflunomide in clinical trials

Pregnancy Outcomes for Female Patients and Partners of Male Patients in the Teriflunomide Clinical Development Program

30

Across teriflunomide clinical trials, 19 pregnancies were reported in the female partners of male patients treated with teriflunomide

All newborns were healthy and free from structural and functional abnormalities

Treatment

Pregnancy Outcomes in Partners of Male Patients (n)

Data Cut-Off: October 18, 2013

Live Birth Induced Abortion Spontaneous

Abortion

Teriflunomide 16 2 1

Placebo 2 1 0

Adapted from Kieseier B et al. Presented on ACTRIMS/ECTRIMS, 2014, P846.

Pregnancy Outcomes for Female Patients and Partners of Male Patients in the Teriflunomide Clinical Development Program

31

Pregnancy data from the teriflunomide clinical trial program have not shown a teratogenic signal. When reliable contraception is used, teriflunomide is a therapeutic option for women of childbearing potential and for male patients with female partners of childbearing potential.

Summary

Benefit:risk profile supports broad indication in RRMS (EU) and relapsing forms of MS (US, Australia and other countries) – Consistent efficacy results across different populations and disease

activity, with more robust efficacy for 14 mg than 7 mg • Early MS (TOPIC) and MS with relapses (TEMSO/TOWER)

– Efficacy in mild/moderate and high disease activity subgroups (TEMSO/TOWER)

– Efficacy in reducing relapse severity-related outcomes

– Efficacy maintained over the long term

Teriflunomide 14 mg is the only oral MS therapy to significantly delay progression of disability in two Phase III trials

Well characterized safety and tolerability profile – Similar profile for 7 mg and 14 mg

– Consistent findings across studies (TOPIC, TEMSO, TOWER)

– No late emerging adverse events

Data support use as a platform therapy

32 RRMS, relapsing-remitting MS.

Aubagio (teriflunomide) EU Summary of Product Characteristics. August 2013

Alemtuzumab and The Changing MS Landscape

Professor Gavin Giovannoni Blizard Institute, Barts and The London School of Medicine

and Dentistry, London, UK

Disclosures

Over the last 15 years Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Professor Giovannoni would like to acknowledge and thank Genzyme for making available data slides for this presentation. He would also like to thank numerous colleagues for providing him with slides for this, and other, presentations.

Professor Giovannoni’s trip to LACTRIMS was kindly sponsored by Genzyme, therefore please interpret anything he says about Genzyme’s products in this context.

This presentation was prepared by Professor Giovannoni with the aim of presenting the phase 2 & 3 alemtuzumab data to the attendees at LACTRIMS (Lima, Peru; November 2014).

How early is early? (1st-line vs. delayed access)

35

Why Treat Early in MS?

36

Reduce axonal loss

Pathology

Slow brain volume loss

Imaging

Delay or prevent disability

Clinical

Trapp et al, 1998

Confavreaux, Compston, 2005

Losseff et al,1996

The Burden of MS Increases with Disability Progression

As disability increases in MS patients, health status deteriorates1

– At least two-thirds of patients with RRMS are unemployed due to the disease2

– Approximately 21% of patients with MS for less than 5 years are unemployed3

– Social relationships are impacted by multiple interrelated factors related to physical disability and psychological status4

– Reduced ability to work, pursue leisure activities, and carry on usual life roles due to MS results in diminished quality of life5

37

1.0

0.8

0.6

0.4

0.2

0

–0.2

–0.4

0 1 2 3 4 5 6 6.5 7 8 9

Uti

lity

Sc

ore

Expanded Disability Status Scale

Essentially restricted to bed,

chair, or wheelchair

Austria

Belgium

Germany

Italy

The Netherlands

Spain

Sweden

Switzerland

UK

UKa

UKa

(Perfect health)

a Utility score <0 indicates that patients felt their health state was worse than death.

1. Orme M et al. Value Health 2007;10:54-60; 2. Morales-Gonzales. Mult Scler 2004;10:47-54; 3. Zwibel HL, Smrtka J. Am J Managed Care

2011;17:S139-S45; 4. Gilchrist AC, Creed FH. J Psychosomatic Res 1994;38:193-201. Image adapted from Naci et al. J Med Econ 2010;13:78-89.

The Shifting Treatment Paradigm for MS

38 Miller JR. J Manag Care Pharm 2004;10(suppl b):S4-11.

Time

Disease onset

Dis

ab

ilit

y

Natural course of disease

Later

treatment Later intervention

Treatment

at diagnosis

Intervention at diagnosis

What about the patient wanting to have children? (PD & PK of alemtuzumab and MOA)

39

Alemtuzumab: A Humanized Monoclonal Antibody Approved for Treatment of Patients with Active RRMS

A humanized monoclonal antibody that selectively targets

CD52, a protein abundant on the surface of B and T

lymphocytes1

Novel dosing regimen: administered 12 mg/day via intravenous

(IV) infusions on 5 consecutive days at baseline and on 3

consecutive days 12 months later2,3

1. Hu Y et al. Immunology 2009;128:260-70; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380:1829-39; 4. Lemtrada (alemtuzumab) Peru Summary of

Product Characteristics, 2014; 5. Lemtrada (alemtuzumab) EU Summary of Product Characteristics, September 2013. 40

2014

• México

• Brasil

• Argentina

• Guatemala

• Chile

• Peru

• USA

Registration approvals across the Americas*

First approved - EU in 20135*

Approved for adult patients with relapsing-remitting MS (RRMS) with active

disease defined by clinical or imaging features4

*Lemtrada indication across Europe and America countries is similar to that in Peru.

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 Action

1. 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

B T

CD52 B

CD52 T T cell precursor

Pre/Pro B cell

B CD52

T CD52

Monocytes

Macrophages

Neutrophils

Lymphocyte precursor

Targets T and B cells thought

to mediate MS inflammation1

41



Stem cell

Cambridge Cohort: T- and B-cell Pharmacodynamics in a Subset of SPMS Patients

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

42

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Pre Post

(Day 2)

3 6 9 12 15 18 Months after Alemtuzumab (20 mg × 5)

T c

ells (×

10

9/L

)

0.0

0.1

0.2

0.3

0.4

0.5

B c

ell

s (×

10

9/L

)

B cells

CD4+ T cells CD8+ T cells

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

CARE-MS I: Alemtuzumab Pharmacokinetics

Unique PK/PD profile of alemtuzumab allows for 2 short treatment courses

– Alemtuzumab is administered on 5 consecutive days at Month 0 and on another 3 days 12 months later

– Serum concentrations are low or undetectable within 1 month after dosing

43 Lycke J et al. EFNS 2012.

Alemtuzumab administration

1500

4000

4500

2500

3500

500

0

2000

3000

1000

Day 0

Co

ncen

trati

on

(n

g/m

L)

Day 5 Day 10 Day 15 Day 20 Day 25 Month 1

First treatment course

Time

1500

4000

4500

2500

3500

500

0

2000

3000

1000

0 1 3 6 9 12 24 15 18 21

Co

nc

en

tra

tio

n (

ng

/mL

)

13

Months

Anti-murine CD52 Therapy Provides Anti-inflammatory and Neuroprotective Effects in EAE

Anti-muCD52 therapy reduces lymphocytic infiltration, demyelination, and axonal damage in vivo

The therapeutic benefits of anti-muCD52 treatment was associated with reduction in the number of T lymphocytes in the spleen and CNS, reduced frequency of autoreactive MOG-specific T cells, decreased cytokine production by MOG-stimulated splenocytes ex vivo, decreased inflammatory CNS lesions and reduced level of demyelination and axonal damage, and preservation of axonal conduction in the spinal cord.

44

Vehicle

Anti-muCD52

Adapted from Turner MJ et al. Presented on ACTRIMS/ECTRIMS, 2014, P388.

Alemtuzumab and Pregnancy

Placental transfer and potential pharmacologic activity of LEMTRADA were observed in mice during

gestation and following delivery. A reproductive toxicity study in pregnant mice exposed to intravenous

doses of alemtuzumab resulted in significant increases in the number of dams with all conceptuses dead

or resorbed, along with a concomitant reduction in the number of dams with viable foetuses

Serum concentrations were low or undetectable within approximately 30 days following each treatment

course. Therefore, women of child bearing potential should use effective contraceptive measures when

receiving a course of treatment with LEMTRADA and for 4 months following that course of treatment.

Autoimmune thyroid disorders have been observed in an estimated 36% of patients treated with

LEMTRADA. Untreated hypothyroidism in pregnant women there is an increased risk for miscarriage and

foetal effects such as mental retardation and dwarfism.

Serious thyroid events occurred in <1% of patients, including Graves‟ disease. In mothers with Graves‟

disease, maternal thyroid stimulating hormone receptor antibodies can be transferred to a developing

foetus and can cause transient neonatal Graves‟ disease.

45 Lemtrada (alemtuzumab) Peru Summary of Product Characteristics, 2014

Is it realistic to expect improvement in disability? (Efficacy data)

46

Freedom from daily, weekly, or monthly dosing

2 treatment courses separated by 12 months

Administered as IV infusion rather than IV push or bolus

– Each infusion 12 mg/d, lasts ~4 hours

Patients should be monitored until 48 months after last infusion

Durable response despite low/undetectable serum concentrations within ~30 days after each course

LEMTRADA Treatment Innovative dosing model

In open-label follow-up of LEMTRADA clinical trials, some patients received additional “as needed” treatment with LEMTRADA upon documented evidence of

resumed MS disease activity. The additional course(s) of LEMTRADA were administered at 12 mg/day for

3 consecutive days (36 mg total dose) at least 12 months after the prior treatment course. The benefits and risks of ˃2 treatment courses have not been fully

established, but results suggest that the safety profile does not appear to change with additional courses.

If additional treatment courses are to be given, they must be administered at least 12 months after the prior course.

LEMTRADA Summary of Product Characteristics. Genzyme Therapeutics Ltd, UK; September 2013.

Months 0 14 12 2 6 4 10 8 16

1 year later … 5 days of

treatment

3 days of

treatment

CAMMS2231

(completed)

CARE-MS I2

(completed)

CARE-MS II3

(completed)

Extension4,5

(ongoing)

Phase 2 3 3 3

Patient

population

Active RRMS,

treatment-naïve

Active RRMS,

treatment-naïve

Active RRMS,

relapsed on prior therapy

RRMS patients enrolled

into phase 2 and 3

studies

Patients, n 334 581 840 1322

Study

duration, yrs 3 2 2 4

Inclusion

criteria

EDSS ≤3

Onset ≤3 yrs

Enhancing lesion

EDSS ≤3

Onset ≤5 yrs

EDSS ≤5

Onset ≤10 yrs

CAMMS223,

CARE-MS I & II

patients

Treatment

arms

Alemtuzumab 12 mg

Alemtuzumab 24 mg

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

—

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

Alemtuzumab 24 mg

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

(Re-treatment as needed

after 2 fixed courses)

Co-primary

outcomes

Relapse rate

Sustained accumulation of disability (SAD)

Relapse rate

SAD

Long-term safety and

efficacy outcomes

Alemtuzumab Clinical Development Program vs. High-dose SC IFNB-1a

RRMS, relapsing-remitting MS; EDSS, expanded disability status scale; SC, subcutaneous.

1. Coles AJ et al. N Engl J Med 2008;359:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380:1829-39; 4. Brinar V

et al. ENS 2011. P912; 5. Fox E et al. AAN 2013. S41.001.

Rebif® is a registered trademark of EMD Serono, Inc. 48

0.39

0.18

0

0.1

0.2

0.3

0.4

0.5

0.6

ARR, annualized relapse rate.

1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Lemtrada (alemtuzumab) EU Summary

of Product Characteristics, September 2013.

Alemtuzumab Significantly Reduced Annualized Relapse Rate vs. SC IFNB-1a in Treatment-naïve Patients

At 5 years, significant reduction in ARR for alemtuzumab vs. SC IFNB-1a was maintained in CAMMS2233

– 66% reduction vs. SC IFNB-1a

49

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

An

nu

ali

ze

d R

ela

ps

e R

ate

N=187 N=376

CARE-MS I2

0.36

0.11

0

0.1

0.2

0.3

0.4

0.5

0.6

CAMMS2231

An

nu

ali

ze

d R

ela

ps

e R

ate

N=111 N=112

Risk reduction: 69%

p<0.001

Risk reduction: 55%

p<0.0001

SAD, sustained accumulation disability. aPost hoc analysis

1. Cohen JA et al. Lancet 2012;380:1819-28; 2. Data on file, Genzyme Corporation.

Six-month Sustained Accumulation of Disability in Treatment-naïve Patients

Pa

tien

ts w

ith

SA

D (

%)

50% Risk reduction

vs. SC IFNB-1a

p=0.0029 14%

7%

SC IFNB-1a 44 μg

Alemtuzumab 12 mg

CARE-MS I1 Pooled Treatment-naïve

(CAMMS223 and CARE-MS I)2,a

30% Risk reduction

vs. SC IFNB-1a

p=0.22

Pa

tie

nts

wit

h S

AD

(%

)

25

15

10

5

0

20

0 3 6 9 12 15 18 21 24

8%

11%

SC IFNB-1a 44 μg

Alemtuzumab 12 mg

Follow-up Month Follow-up Month

25

15

10

5

0

20

0 3 6 9 12 15 18 21 24

50

Although numerically in favor of

alemtuzumab, the reduction in

risk of SAD vs. SC IFNB-1a did

not achieve statistical significance

in CARE-MS I1

In the pooled analysis of

treatment-naïve patients,

alemtuzumab significantly

reduced risk of 6-month SAD

vs. SC IFNB-1a2

CARE-MS I: Reduction in Brain Atrophy

Brain atrophy was reduced by 42% in alemtuzumab patients vs. SC IFNB-1a patients over 2 years1

BPF is considered to be a marker of neurodegeneration in MS2

51

-0.94

-0.50

-1.49

-0.59

-0.25

-0.87

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

SC IFNB-1a

Alemtuzumab 12 mg p<0.0001

p<0.0001

p=0.0052

Med

ian

Perc

en

t C

han

ge

fro

m B

aselin

e

Year 1 Year 2 Cumulative

Brain Parenchymal Fraction

1. Arnold DL et al. AAN 2012, Presentation S11.006; 2. Shiee N et al. PLoS One 2012;7(5):e37049.

Treatment-naïve Patients Were More Likely to be Disease Activity-Free with Alemtuzumab vs. SC IFNB-1a

Clinical Disease

Activity-free

MRI Activity-free MS Disease Activity-

free

p<0.0001

p=0.0388

OR=1.75 p=0.0064

1. Giovannoni G et al. ENS 2012; 2. Cohen JA et al. Lancet 2012;380:1819-28.

Alemtuzumab-treated patients were ~2 times more likely to be free of overall MS disease activity compared with SC IFNB-1a–treated patients over 2 years1,2

Treatment-naïve: CARE-MS I1,2

52

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

CAMMS2231

(completed)

CARE-MS I2

(completed)

CARE-MS II3

(completed)

Extension4,5

(ongoing)

Phase 2 3 3 3

Patient

population

Active RRMS,

treatment-naïve

Active RRMS,

treatment-naïve

Active RRMS,

relapsed on prior therapy

RRMS patients enrolled

into phase 2 and 3

studies

Patients, n 334 581 840 1322

Study

duration, yrs 3 2 2 4

Inclusion

criteria

EDSS ≤3

Onset ≤3 yrs

Enhancing lesion

EDSS ≤3

Onset ≤5 yrs

EDSS ≤5

Onset ≤10 yrs

CAMMS223,

CARE-MS I & II

patients

Treatment

arms

Alemtuzumab 12 mg

Alemtuzumab 24 mg

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

—

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

Alemtuzumab 24 mg

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

(Re-treatment as needed

after 2 fixed courses)

Co-primary

outcomes

Relapse rate

Sustained accumulation of disability (SAD)

Relapse rate

SAD

Long-term safety and

efficacy outcomes

Alemtuzumab Clinical Development Program vs. High-dose SC IFNB-1a

RRMS, relapsing-remitting MS; EDSS, expanded disability status scale; SC, subcutaneous.

1. Coles AJ et al. N Engl J Med 2008;359:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380:1829-39; 4. Brinar V

et al. ENS 2011. P912; 5. Fox E et al. AAN 2013. S41.001.

Rebif® is a registered trademark of EMD Serono, Inc. 53

0.52 0.26 0.0

0.2

0.4

0.6

0.8

An

nu

alized

Rela

pse

Rate

(95%

CI)

Alemtuzumab Significantly Reduced Clinical Disease Activity in Patients Who Relapsed on Prior Therapy

Benefits on clinical disease activity were similar regardless of type,

duration, or number of prior treatments2

ARR, annualized relapse rate; CI, confidence interval.

1. Coles AJ et al. Lancet 2012;380:1829-39; 2. Freedman MS et al. AAN 2013, P07.111.

ARR: CARE-MS II1

Alemtuzumab

12 mg

(n=426)

SC IFNB-1a

44 µg

(n=202)

21%

13%

42% Risk reduction

p=0.0084

6-Month Sustained Accumulation of

Disability: CARE-MS II1

54

SC IFNB-1a 44 μg

Alemtuzumab 12 mg

Risk reduction: 49%

p<0.0001

CARE-MS II: Reduction in Brain Atrophy

55

Over 2 years, brain atrophy was reduced by 23% in patients who received alemtuzumab compared with SC IFNB-1a1

BPF is considered to be a marker of neurodegeneration in MS2

1. Arnold DL, et al. ECTRIMS 2012; P877; 2. Shiee N et al. PLoS One 2012;7(5):e37049.

Brain Parenchymal Fraction

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

Me

dia

n P

erc

en

t C

ha

ng

e f

rom

Ba

se

lin

e -0.2

-0.4

-0.6

-0.8

-1.0

-1.2

0.0

0.2

p=0.0012

-0.81

-0.61

-0.22 -0.35

-0.47 -0.54 p=0.15

p=0.08

Year 1–2 Year 0–1 Years 0–2

41.1

31.5

13.6

59.6 52.9

32.2

0

20

40

60

80

100

Clinical Disease Activity-free MRI Activity-free MS Disease Activity-free

Pe

rce

nta

ge

of

Pa

tie

nts

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

Patients Who Relapsed on Prior Therapy Were More Likely to Be Disease Activity-free with Alemtuzumab vs. SC IFNB-1a

Alemtuzumab-treated patients were 3 times more likely to be free of overall MS disease activity compared with SC IFNB-1a–treated patients over 2 years

1. Hartung HP et al AAN 2013; P07.093; 2. Coles AJ et al. Lancet 2012;380:1829-39.

OR=3.03

p<0.0001

p<0.0001 p<0.0001

Relapsed on Prior Therapy: CARE-MS II1,2

56

CARE-MS II: Alemtuzumab improved pre-existing disability

57

SRD, sustained reduction of disabilitu

aSecondary endpoint; defined as decrease of ≥1 EDSS point lasting at least 6 months, assessed in patients

with baseline EDSS ≥2.0. bTertiary endpoint. cMeasured by SRD score in relapsing patients.

Coles AJ, et al. Lancet. 2012;380:1829-1839.

IFNB-1a 44 μg Alemtuzumab12 mg

‒0.17

P<0.0001

+0.24

ED

SS

Sco

re, m

ea

n

3.25

3.00

2.75

2.50

2.25

Follow-Up Month

0 3 6 9 12 15 18 21 24

40

30

20

10

0 Patients

With 6

-Month

SR

D (

%)

29%

13%

P=0.0002

Mean EDSS Change From Baselinea SRDb

Follow-Up Month

0 3 6 9 12 15 18 21 24

How durable is the treatment response to alemtuzumab?

(Duration of response and need to retreat)

58

CARE-MS Extension Study Designed to Evaluate Long-term Outcomes with Alemtuzumab

Received SC IFNB-1a

Extension Study (Safety & Efficacy Follow-up)1

May receive optional re-treatment course(s) of either alemtuzumab 12 mg (3 day course; not

sooner than 12 months after the previous course) or

another DMT

No

Yes

Administer 2 annual

alemtuzumab treatment courses

Relapse or 2 active

MRI lesions?

Monitor for MS activity through extension trial

Month 48

Received alemtuzumab

(Month 0 and 12)

CARE-MS I or II

Pivotal Studies

IV, intravenous; QD, once-daily; DMT, disease-modifying therapy. 1. Fox E et al. AAN 2013, S41.001; 2. Adapted from Coles AJ et al. Presented on ACTRIMS/ECTRIMS, 2014, P090; 3. Adapted from Hartung HP et al. Presented on

ACTRIMS/ECTRIMS, 2014, P043. 59

Extension study treatments use LEMTRADA 12 mg IV1

– Former LEMTRADA patients: retreatment as needed (QD×3)

– Former SC IFNB-1a patients: 2 courses (QD×5 at entry, QD×3 12 months later, then retreatment as needed)

Use of other DMTs allowed based on investigator’s clinical decision1

Efficacy of Alemtuzumab in Patients With RRMS: 4-Year Follow-up of the CARE-MS I and II Studies

RRMS, relapsing-remitting MS; ARR, annualized relapse rate; CI, confidence interval.

1. Adapted from Coles AJ et al. Presented on ACTRIMS/ECTRIMS, 2014, P090; 2. Adapted from Hartung HP et al. Presented on ACTRIMS/ECTRIMS, 2014, P043.

ARRs in Patients Who Received Alemtuzumab 12 mg in the CARE-MS Core Studies

• Over 4 years, the ARR was 0.16 (95% CI, 0.13-0.19) and 0.24 (95% CI, 0.21-

0.27) in CARE-MS I and CARE-MS II, respectively

0.39

0.52

0.18 0.19

0.14

0.26

0.22 0.23

0

0.1

0.2

0.3

0.4

0.5

0.6

An

nu

ali

zed

rela

pse r

ate

Years 0-2 Year 3 Year 4 Years 0-2 Year 3 Year 4

CARE-MS I1 CARE-MS II2

↓55%

↓49%

SC IFNB-1a 44 μg

Alemtuzumab 12 mg

60


Pro

po

rtio

n o

f p

ati

en

ts (

%)

Improved

Remained stable

Worsened

25.8

73.5 79.3

26.5 20.7

74.3 69.0

31.0

66.2

33.8

67.0

33.0

0

10

20

30

40

50

60

70

80

AlemtuzumabYears 0-3


AlemtuzumabYear 3-4

74.2

Pro

po

rtio

n o

f p

ati

en

ts (

%)

0

10

20

30

40

50

60

70

80



AlemtuzumabYear 3-4

Improvement in preexisting disability, as measured by sustained reduction in disability (SRD), was newly achieved by some patients in Years 3 and 4


Proportion With Improved, Stable, or Worsened* EDSS Scores From Baseline

to Year 4 Among Patients Who Received Alemtuzumab 12 mg in the Core Study

RRMS, relapsing-remitting MS; EDSS, expanded disability status scale; DMT, disease-modifying therapy

*≥0.5-point increase (worsening) or decrease (improvement) in EDSS score from core study baseline.

1. Adapted from Coles AJ et al. Presented on ACTRIMS/ECTRIMS, 2014, P090; 2. Adapted from Hartung HP et al. Presented on ACTRIMS/ECTRIMS, 2014, P043. 61

The efficacy of alemtuzumab in patients with active RRMS was maintained over 4 years, even though most patients were not treated with alemtuzumab or another DMT for 3 years since receiving 2 courses of alemtuzumab


EDSS scores, assessed 2 years after the first of 2 courses of alemtuzumab, either remained stable or improved in 73.1% and 69.2% of patients in CARE-MS I and CARE-MS II, respectively

Patients who received SC IFNB-1a in the core study demonstrated improvement in relapse and disability endpoints after switching to alemtuzumab.

62

RRMS, relapsing-remitting MS; ARR, annualized relapse rate; EDSS, expanded disability status scale.


ARRs Before and After Switching to Alemtuzumab


0.39

0.12

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Core studyYears 0-2 during

SC IFNB-1a treatment

Extension studyYears 0-2 after

switching to alemtuzumab

↓69% after switching

to alemtuzumab

AR

R (

95%

CI)

SC IFNB-1a 44g

Alemtuzumab 12 mg

0.52

0.15

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Core studyYears 0-2 during

SC IFNB-1a treatment

Extension studyYears 0-2 after

switching to alemtuzumab

↓71% after switching

to alemtuzumab

AR

R (

95%

CI)

Disease-Free Outcomes With Alemtuzumab: 3-Year Follow-up of the CARE-MS Studies

The majority of patients were free of detectable clinical, MRI, and MS disease activity in Year 3 regardless of prior treatment history.

The effects of alemtuzumab on disease activity were largely maintained between Year 2 and Year 3, despite most patients not receiving treatment in Year 3.

63 MRI, magnetic resonance image; CI, confidence interval.

Adapted from Havrdova E et al. Presented on ACTRIMS/ECTRIMS, 2014, FC1.4.

38 46 50

67 64

0

20

40

60

80

100

Year 1 Year 2 Year 3

Pro

po

rtio

n o

f

pati

en

ts, %

(9

5%

CI)

↑32.2% P=0.0062

↑45.8% P<0.0001

CARE-MS I:

MS Disease Activity Free By Year

SC IFNB-1a

ALEM 12 mg

174

369

170

356

—

349

SC IFNB-1a

ALEM 12 mg

187

405

173

434

—

393

27 31

44

56 55

0

20

40

60

80

100

Year 1 Year 2 Year 3

Pro

po

rtio

n o

f

pati

en

ts, %

(9

5%

CI)

↑61.2% P<0.0001

CARE-MS II:

MS Disease Activity Free By Year

↑84.3%

P<0.0001

Percent Change in Brain Parenchymal Fraction: 3-Year Follow-up From CARE-MS I and CARE-MS II

Alemtuzumab slowed the reduction in BPF over 3 years

The median yearly rate of brain volume loss with alemtuzumab decreased progressively over time

64

*Alemtuzumab vs SC IFNB-1a, P<0.0001. †Alemtuzumab vs SC IFNB-1a, P=0.0121.

1. Adapted from Arnold DL et al. Presented on ACTRIMS/ECTRIMS, 2014, FC2.2. 2. Adapted from Fisher E et al. Presented on ACTRIMS/ECTRIMS, 2014, P103.

BPF=brain parenchymal fraction

No. of Patients

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

185 176 171

371 367 351 323

–

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Me

dia

n c

ha

ng

e f

rom

ba

se

lin

e,

% (

95

% C

I) *

*

42% slowing of brain

volume loss vs

SC IFNB-1a at Year 2

0 1 2 3 Year

CARE-MS I1

No. of Patients

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

199 187 167

419 405 396 359

0 1 2 3

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Year

24% slowing of

brain volume loss

vs SC IFNB-1a at

Year 2

†

Me

dia

n c

ha

ng

e f

rom

ba

se

lin

e,

% (

95

% C

I)

–

CARE-MS II2 Alemtuzumab 12 mg

SC IFNB-1a 44 µg

Median yearly

BPF Change

— -0.94% -0.50%

— -0.59% -0.25% -0.19%

– Median yearly

BPF Change

— -0.54% -0.35%

— -0.48% -0.22% -0.10%

–

CARE-MS I and II Extension: Need to retreat

65

Year 31 Year 42,3

Alemtuzumab

patients entered

the extension (n)

Not receive

retreatment

Alemtuzumab

patients entered

the extension (n)

Not receive

retreatment

CARE-MS I

349 82% 349

73% (21% and 5% received

1 or 2 additional

courses, respectively)

CARE-MS II

393 80% 393

68% (24% and 7% received

1 or 2 additional

courses, respectively)

1. Adapted from Havrdova E et al. Presented on ACTRIMS/ECTRIMS, 2014, FC1.4; 2. Adapted from Coles AJ et al. Presented on ACTRIMS/ECTRIMS, 2014, P090; 3. Adapted from Hartung HP et al. Presented on ACTRIMS/ECTRIMS, 2014, P043.

Do you tell your patients about brain atrophy? (focus on NEDA and preventing end-organ damage)

66

Axonal and Brain Volume Loss Starts Early in MS

Subclinical inflammation, demyelination, and neurodegeneration may be present for months, or even years, before a patient experiences clinical symptoms1

67 MRI, magnetic resonance imaging; RRMS, relapsing-remitting MS; SPMS, secondary progressive MS

1. Stüve O et al. Drugs 2008;68:73-83; Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.

MRI Events

SPMS First

clinical

event

Time (Years)

RRMS Subclinical

disease

Inflammation

Brain volume

Axonal loss

Dis

ea

se

Se

ve

rity

Treatment objectives in relapsing MS

68

Functional

Improvement

Maintain reserve

capacity

NEDA

Reduced ongoing

damage

CNS Repair

Healthy

ageing

Improved Quality of Life / Brain Health

Treat Early

No evident disease activity: NEDA

69 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-target

No evidence of disease activity defined as:1,2

× No relapses

× No sustained disability progression

× No MRI activity

× No new or enlarging T2 lesions

× No Gd-enhancing lesions

Normalisation of brain volume loss (NEDA-4)

Treating-2-target

70

Choose therapy

A B C

Define the individual’s MS

Treatment failure?

• Patient’s preferences?

• Your choice?

Individual measures:

• Evidence of disease activity?

• Tolerability/safety?

• Adherence?

• Drug or inhibitory markers?

Monitoring

• MS prognosis

• Life style and goals

• Shared goals for therapy

Rebaseline

Rebaseline: • IFNβ, natalizumab,

fingolimod, teriflunomide,

DMF=3-6 months

• Glatiramer acetate=9

months

• Alemtuzumab=24 months

DMF, dimethyl fumarate.

Choose a therapeutic strategy

Maintenance-escalation Induction

Choose therapy

X Z

Rebaseline

Monitoring

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

Breakthrough disease

Y

• Patient’s preferences?

• Your choice?

No Yes Yes

• Only one licensed induction

therapy at present

Can you de-risking alemtuzumab treatment; how to deal with infusion reactions, infections and secondary autoimmunity? (Safety and reducing problems with using the drug)

71

Alemtuzumab: Overview of Adverse Events

72

Adverse events Description

Infusion-associated

reactions (IARs)1-4

• IARs were common, predominantly mild to moderate, and reduced with

steroid pre-treatment.

Autoimmune

thyroid events1-4

• The majority of first occurring thyroid AEs occurred after Year 1 (12

months after first course), with the highest incidence occurring in Year

3 and declined thereafter1. Serious thyroid events occurred in <1% of

alemtuzumad treated patients.

• Majority of thyroid events responded to conventional treatment.

ITP1-4 • ITP has been reported in 1.5% of patients

• With the exception of a fatal index case, all subsequent ITP cases

were detected early through the safety monitoring program and

responded to treatment.

Nephropathy1-5 • Nephropathies are rare (incidence ~0.3%) and occurred within 48

months of the last alemtuzumab treatment course (the recommended

monitoring period).

• All cases in the MS clinical program were detected by the safety

monitoring program and none resulted in renal failure5.

Infections1-4 • Infections with alemtuzumab were predominantly mild to moderate and

responded to conventional treatment.

• Lymphocyte counts did not correlate with occurrence of infection.

ITP, Immune thrombocytopenic purpura, AEs, adverse events.

1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380(9856):1829-39;

4. Fox E et al. AAN 2013, S41.001; 5. Wynn D et al. ECTRIMS 2013. P597.

Safety of Alemtuzumab in Patients With RRMS: 4-Year Follow-Up of the CARE-MS I and II Studies

The incidence of most AEs, including infection, during the extension period was comparable or reduced compared with the core study.

The safety profile of alemtuzumab after switching from SC IFNB-1a was similar to that observed in patients receiving alemtuzumab in the core studies.

73


Incidence of AEs and Serious AEs by Year in Patients Receiving Alemtuzumab 12 mg* in

the Core Study

Year on alemtuzumab 1 2 3 4

No. of patients at risk 376 376 360 344

Serious AE, % 12.0 7.7 10.0 8.4

1 2 3 4

376 376 360 344

1.6 0.3 1.7 0.6

1 2 3 4

376 376 360 344

0.5 0.8 3.9 1.5

Pati

en

ts (

%)

Year on alemtuzumab 1 2 3 4

No. of patients at risk 435 434 412 387

Serious AE, % 12.6 9.9 9.5 13.7

1 2 3 4

435 434 412 387

0.0 0.5 2.4 1.0

1 2 3 4

435 304 412 387

2.1 1.8 1.2 2.3

0

20

40

60

80

100

Any AE Infection Thyroid AE

Pati

en

ts (

%)

0

20

40

60

80

100

Any AE Infection Thyroid AE

RRMS, relapsing-remitting MS; AEs, adverse events.

*Nine patients in CARE-MS II were randomized to alemtuzumab 24 mg but received the 12-mg dose; these patients are included in core

study safety analyses for the 12-mg arm.


Comprehensive Risk Management Strategy

74

Risks Labelling Education Laboratory tests PASS

Identified

IARs

Posology

•Prophylaxis (steroids) & symptomatic treatment

(anti-histamines/anti-pyretics)

•Cardiac history

•Resources to manage serious reactions

Serious Infection

Posology

•Prophylaxis (anti-herpes agent)

Contraindication

•HIV

Warning & Precautions

•Active infections, concomitant immunosuppression, vaccination

Pap smear

TB screening

HBV/HCV screening

Varicella screening

Auto-immune


•Pre-existing autoimmune conditions

Thyroid Disorders


•Signs & symptoms, need for monitoring

•Guidance on re-treatment in presence of thyroid disease Quarterly (TSH )

ITP Warning & Precautions

•Signs & symptoms, need for monitoring Monthly CBC

Glomerulonephritis Warning & Precautions

•Signs & symptoms, need for monitoring Monthly urine

and creatinine

Potential

Cytopenia Warning & Precautions Monthly CBC

Malignancies Warning & Precautions - Pre-existing & ongoing conditions

Pros and cons of maintenance vs. induction therapies

75

Maintenance therapies

• Continuous treatment

• Low to very high efficacy

• Reversible

• Perceived to be lower risk

• Examples • Laquinimod, GA, IFN-beta, 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 • Contra-indicated

• No potential for a cure • Rebound

• SPMS & progressive brain atrophy

Induction therapies

• Short-courses or pulsed therapy

• Very high efficacy

• Irreversible

• Perceived to be higher risk

• Examples • Mitoxantrone, cladribine, alemtuzumab, anti-

CD20 (?), BMT

• Breakthrough disease • Marker for retreatment

• NEDA unreliable to assess efficacy

• Rebound activity • Less likely

• Unlikely to be life-threatening

• Pregnancy • Strategy of choice

• Potentially curative • 15-20 year experiment

• BMT, alemtuzumab, cladribine

Alemtuzumab in Active RRMS: Summary

The positive benefit:risk profile of alemtuzumab supports its use in RRMS patients with active disease regardless of duration of illness or prior treatment history

– Demonstrated superior efficacy in clinical and MRI measures vs. SC-IFNB-1a in patients with active RRMS who were treatment-naïve or who relapsed on prior therapy1,2

• Patients treated with alemtuzumab were more likely to be free of MS disease activity and to have improvement of pre-existing disability1-3

– Durable efficacy was demonstrated through 4 years, despite low rate of re-treatment4

– Well-characterized safety profile

• Infections were predominantly mild-to-moderate, with a low rate of serious infections1,2,4

• Autoimmune adverse events were detectable and manageable with proactive risk-minimization procedures in the clinical trials, including physician and patient education and regular monitoring1,2,4

Questions

– How early is early?

– What about the patient wanting to have children?

– Is it realistic to expect improvement in disability?

– How durable is the treatment response to alemtuzumab?

– Do you tell your patients about brain atrophy (end-organ damage)?

– Can you de-risking alemtuzumab treatment; how to deal with infusion reactions, infections and secondary autoimmunity?

1. Cohen JA et al. Lancet 2012;380:1819-28; 2. Coles AJ et al. Lancet 2012;380(9856):1829-39; 3. Hartung HP et al. ECTRIMS 2013, P592;

4. Fox E et al. AAN 2013, S41.001. 76

Discussion

Lactrims 2014 Genzyme Symposium

Health & Medicine

Transcript of Lactrims 2014 Genzyme Symposium