1

Optimizing Early Therapy:

Future Options and Considerations

Gavin Giovannoni

Bernd Kieseier

Disclosures

▪ Professor Giovannoni has provided consultation to

Bayer-Schering Healthcare, Biogen-Idec, Genzyme,

GlaxoSmithKline, Merck-Serono, Novartis, Protein

Discovery Laboratories, Teva-Aventis, UCB Pharma.

Ironwood, Eisai, Vertex, Roche, Synthon, Canbex. He

has received grant support from Bayer-Schering

Healthcare, Biogen-Idec, Merck-Serono, Merz, Novartis,

Teva-Aventis, GW Pharma

▪ Professor Kieseier has provided consultation to Bayer

Schering, Biogen Idec, Medac, Merck Serono, Novartis,

Sanofi-Aventis, Talecris, Teva. He has received grant

support from Bayer Schering, Biogen Idec, Biotest,

Merck Serono, Teva

2

C-1900

Phase 2

6-months MRI

257 patients

Phase 1 Healthy Volunteer Studies

• C-1903 Food Effect

• 109HV101 Cardiac QTc

• 109HV102 Absorption, Metabolism,

Excretion

• 109HV103 Drug-Drug Interaction

with Avonex

• 109HV104 Drug-Drug Interaction

with Glatiramer Acetate (GA)

• 109HV105 Relative Bioavailability

• 109HV106 PK, Safety, Tolerability

• 109HV107 PK Bioequivalence

• 109HV321 Tolerability study

Study 303 (109MS303)

Dose-blind, open-label

extension study

1738 patients

Study 201 (109MS201)

Phase 2 IFN/GA

6-months add-on

Safety/MRI

108 patients Completed Studies

Ongoing Studies

Study 301 (109MS301)

Phase 3, 2-year

monotherapy

1237 patients

109MS101

Phase 1

PK

48 patients

By the filing date, 2560 MS patients had received dimethyl fumarate;

approximately 3600 person-years of exposure

• 109HV108 PK in Asia Pacific

MS Clinical Development Plan

Study 302 (109MS302)

Phase 3, 2-year monotherapy

GA comparator group

1430 patients

3 PK=pharmacokinetics; MRI=magnetic resonance imaging; IFN=interferon.

CHMP Opinion: Dimethyl Fumarate

Category Opinion

Indication Treatment of adult patients with relapsing remitting multiple sclerosis

Active

substance

Dimethyl fumarate, a nervous system drug (N07XX09), that primarily

acts by triggering the activation of the nuclear factor (erythroid-derived

2)-like 2 (Nrf2) transcriptional pathway.

Benefits Ability to reduce the number of relapses in patients with relapsing-

remitting multiple sclerosis

Most common

side effects

Flushing and gastrointestinal events (eg, diarrhea, nausea, and

abdominal pain)

4

Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be

published in the European public assessment report (EPAR) and made available in all official European Union (EU) languages after the

marketing authorization has been granted by the European Commission (EC).

CHMP=Committee on Human Medicinal Products.

▪ A pharmacovigilance plan will be implemented

▪ Treatment should be initiated under the supervision of a physician experienced in the

treatment of the disease

Dimethyl Fumarate: Research into Mechanism of

Action Concurrent with Clinical Development

5

Inflammation,

tissue damage

Nrf2

Cell tissue and

cytoprotection

Protective

response against

neurotoxic insult

Dimethyl Fumarate

Anti-inflammatory

response

Scannevin RH et al. J Pharmacol Exp Ther. 2012;341:274-284; Kappos L et al. Lancet. 2008;372:1463−1472;

Gold R et al. N Engl J Med. 2012;367:1098−1107; Fox RJ et al. N Engl J Med 2012;367:1087−1097.

Transcriptional profiling suggests

dimethyl fumarate activates the

Nrf2 Oxidative Stress Response

Pathway

WT Nrf2 Knockout0

200

400

600

800

7

Gen

es In

du

ced

by D

MF

4 h

r T

reatm

en

t (p

< 1

0-5

)

Confirmation in Nrf2 Knockout Mice

C-1900

Phase 2

6-months MRI

257 patients

Phase 1 Healthy Volunteer Studies

• C-1903 Food Effect

• 109HV101 Cardiac QTc

• 109HV102 Absorption, Metabolism,

Excretion

• 109HV103 Drug-Drug Interaction

with Avonex

• 109HV104 Drug-Drug Interaction

with Glatiramer Acetate (GA)

• 109HV105 Relative Bioavailability

• 109HV106 PK, Safety, Tolerability

• 109HV107 PK Bioequivalence

• 109HV321 Tolerability study

Study 303 (109MS303)

Dose-blind, open-label

extension study

1738 patients

Study 201 (109MS201)

Phase 2 IFN/GA

6-months add-on

Safety/MRI

108 patients Completed Studies

Ongoing Studies

Study 301 (109MS301)

Phase 3, 2-year

monotherapy

1237 patients

109MS101

Phase 1

PK

48 patients

By the filing date, 2560 MS patients had received dimethyl fumarate;

approximately 3600 person-years of exposure

• 109HV108 PK in Asia Pacific

MS Clinical Development Plan

Study 302 (109MS302)

Phase 3, 2-year monotherapy

GA comparator group

1430 patients

6 PK=pharmacokinetics; MRI=magnetic resonance imaging; IFN=interferon.

*Any patient with significant protocol-defined disability progression may switch to open-label MS treatment at any time; CONFIRM: any patient with 2

INEC-confirmed relapses at any time may switch to open-label MS treatment after 48 weeks on study; †double-blind only for dimethyl fumarate and

placebo; rater-blinded for all arms; INEC fully blinded to all arms.

DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS; CONFIRM=Comparator and an Oral Fumarate in

Relapsing-Remitting MS; PO=by mouth; TID=3 times daily; BID=twice daily; GA=glatiramer acetate; SC=subcutaneous; INEC=independent neurology

evaluation committee.

Gold R et al. N Engl J Med. 2012;367:1098-1107; Fox R et al. N Engl J Med. 2012;367:1087-1197.

*Any patient with significant protocol-defined disability progression may switch to open-label MS treatment at any time; DEFINE: any patient with 1 INEC-

confirmed relapse on or after week 24 may switch to open-label MS treatment after 48 weeks on study; †double-blind only for dimethyl fumarate and

placebo; rater-blinded for all arms; INEC fully blinded to all arms.

Dimethyl Fumarate Phase 3 Study Schematic:

DEFINE and CONFIRM

7

Screening

240 mg PO BID (480 mg/day)

240 mg PO TID (720 mg/day)

Optional open-label MS treatment*

Placebo Randomization

1:1:1

Year 1 Year 2

GA SC (20 mg/day)

Multicenter, double-blind, dose-comparison study

(N=1237; MRI N=540)

Multicenter, double-blind, reference comparator,

dose-comparison study (N=1430; MRI N=681)†

Randomization

1:1:1:1

0.40

0.220.20

0.29

0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo

(n=363)

240 mg BID

(n=359)

240 mg TID

(n=345)

GA

(n=350)

0.36

0.170.19

0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo(n=408)

240 mg BID(n=410)

240 mg TID(n=416)

44%

reduction

vs placebo

P<0.001

51%

reduction

vs placebo

P<0.001

*Annualized relapse rate calculated with negative binomial regression, with prespecified adjustment for baseline EDSS score (≤2.0 vs >2.0),

baseline age (<40 vs ≥40 years), region, and number of relapses in the 1 year prior to study entry; data after switch to alternative MS therapy

were excluded; Gold R et al. N Engl J Med. 2012;367:1098-1107; Fox R et al. N Engl J Med. 2012;367:1087-1197.

29%

reduction

vs placebo

P<0.05

Annualized Relapse Rate at 2 Years

8

53%

reduction

vs placebo

P<0.001

48%

reduction

vs placebo

P<0.001

An

nu

ali

ze

d R

ela

ps

e R

ate

* (9

5%

CI)

An

nu

ali

ze

d R

ela

pse

Rate

* (9

5%

CI)

CONFIRM DEFINE

New or Newly Enlarging

T2-Hyperintense Lesions at 2 Years*

9

*Negative binomial regression analysis, adjusted for region and baseline T2 lesion volume.

Gold R et al. N Engl J Med. 2012;367:1098-1107; Fox R et al. N Engl J Med. 2012;367:1087-1197.

Ne

w o

r N

ew

ly E

nla

rgin

g T

2 L

es

ion

s*

(me

an

)

17.0

2.6

4.4

0

5

10

15

20

25

Placebo(n=165)

240 mg BID (n=152)

240 mg TID(n=152)

Ne

w o

r N

ew

ly E

nla

rgin

g T

2 L

es

ion

s*

(me

an

)

74%

reduction

vs placebo

P<0.001

85%

reduction

vs placebo

P<0.001

17.4

5.1 4.7

8.0

0

5

10

15

20

25

Placebo(n=139)

240 mg BID(n=140)

240 mg TID(n=140)

GA(n=153)

71%

reduction

vs placebo

P<0.001

73%

reduction

vs placebo

P<0.001

54%

reduction

vs placebo

P<0.001

CONFIRM DEFINE

Gd+ Lesions at 2 Years*

10

*Ordinal logistic regression analysis, adjusted for region and baseline number of Gd+ lesions.

Gd+=gadolinium-enhancing.

Gold R et al. N Engl J Med. 2012;367:1098-1107; Fox R et al. N Engl J Med. 2012;367:1087-1197.

Gd

+ L

es

ion

s (

me

an

)

1.8

0.1

0.5

0.0

0.5

1.0

1.5

2.0

2.5

Placebo (n=165) 240 mg BID (n=152)

240 mg TID(n=152)

Gd

+ L

es

ion

s (

me

an

)

2.0

0.5 0.4

0.7

0.0

0.5

1.0

1.5

2.0

2.5

Placebo(n=144)

240 mg BID(n=147)

240 mg TID(n=144)

GA(n=161)

73%

reduction

vs placebo

P=0.001

90%

reduction

vs placebo

P<0.001

74%

reduction

vs placebo

P<0.001

65%

reduction

vs placebo

P=0.001

61%

reduction

vs placebo

P=0.001

CONFIRM DEFINE

New T1-Hypointense Lesions at 2 Years*

11

Ne

w T

1-H

yp

oin

ten

se

Le

sio

ns

* (m

ea

n)

5.6

1.5

2.1

0

5

10

Placebo (n=165) 240 mg BID(n=152)

240 mg TID(n=152)

New

T1-H

yp

oin

ten

se L

esio

ns*

(mean

)

7.0

3.0

2.4

4.1

0

5

10

Placebo(n=139)

240 mg BID(n=140)

240 mg TID(n=140)

GA(n=154)

*Negative binomial regression analysis, adjusted for region and baseline T1 lesion volume.

Arnold DL et al. Presented at ECTRIMS, October 19–22, 2011. Amsterdam, The Netherlands. P831; Fox R et al.

N Engl J Med. 2012;367:1087-1197.

63%

reduction

vs placebo

P<0.001

72%

reduction

vs placebo

P<0.001

57%

reduction

vs placebo

P<0.001

65%

reduction

vs placebo

P<0.001

41%

reduction

vs placebo

P<0.001

CONFIRM DEFINE

12-Week Confirmed Disability Progression

12

*Estimated proportion of patients with progression and time to progression up to 96 weeks based on the Kaplan-Meier product limit method; †based on Cox proportion hazards model, adjusted for baseline EDSS score (≤2.0 vs >2.0), region, and baseline age (<40 vs ≥40 years).

Gold R et al. N Engl J Med. 2012;367:1098-1107; Fox R et al. N Engl J Med. 2012;367:1087-1197.

Pa

tie

nts

wit

h D

isa

bil

ity P

rog

res

sio

n*

(%)

12 24 36 48 60 72 84 96

Time on Study (weeks)

0

10

20

30 240 mg BID=38% risk reduction, P=0.005†

240 mg TID=34% risk reduction, P=0.013†

18

16

27

BL

Placebo

240 mg BID

240 mg TID

12 24 36 48 60 72 84 96

Time on Study (weeks)

0

240 mg BID=21% risk reduction, P=0.25†

240 mg TID=24% risk reduction, P=0.20†

GA=7% risk reduction, P=0.70†

16

17

BL

Placebo

240 mg BID

240 mg TID

13

GA

10

20

30

Pati

en

ts w

ith

Dis

ab

ilit

y P

rog

ressio

n*

(%)

13

CONFIRM DEFINE

Dimethyl Fumarate Activation of the Nrf2

Pathway in MS Patients

13

Changes of Blood NQO1 Over Time

in DEFINE Phase 3 Trial

0 10 20 30 40 50-5%

0%

5%

10%

15%

20%

25%

30%

35%Placebo

BID

TID

Week

No

rmalized

%C

han

ge N

QO

1

*

*

* *

*P<0.05 compared with placebo.

NQO1=NADPH (nicotinamide adenine dinucleotide phosphate) quinone oxidoreductase; BID=twice daily; TID=3 times daily.

Biogen Idec, data on file.

Integrated Analysis: Overview of Safety*

14

Event, % Patients

Placebo

(n=836)

240 mg BID

(n=769)

240 mg TID

(n=823)

Any adverse event 92 95 93

Serious adverse event† 21 18 15

Discontinuation due to adverse event 11 14 14

Study withdrawal due to adverse event 4 8 8

Infection 56 60 60

Serious infection 1.4 2.2 1.8

Malignancy <1 <1 <1

Death <1‡ <1§ <1¶

*The safety population for the integrated analysis includes patients treated with placebo or dimethyl fumarate 240 mg TID from the phase 2 dose-

ranging study, as well as all patients from the phase 3 studies, DEFINE and CONFIRM; †includes MS relapses fitting the classification of a serious

adverse event; ‡due to ischemic stroke after switch to alternative MS medication; §due to road traffic accident/traumatic brain injury after study

withdrawal; ¶due to road traffic accident and MS relapse complicated by intraventricular hemorrhage after last dose (within 30 days of study

withdrawal).

Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.

Integrated Analysis: Common Adverse Events

(≥10% in Any Group)

15

Event, % Patients

Placebo

(n=836)

240 mg BID

(n=769)

240 mg TID

(n=823)

Flushing 5 34 29

MS relapse 43 29 26

Nasopharyngitis 20 22 22

Headache 16 17 17

Diarrhea 10 14 17

Urinary tract infection 11 14 12

Upper respiratory tract infection 11 13 12

Nausea 9 12 14

Fatigue 11 12 13

Back pain 11 12 10

Abdominal pain upper 6 10 11

Proteinuria* 7 9 10

The overall incidence of any GI event was 31%, 40%, and 43% in the placebo, 240 mg BID, and 240 mg TID groups, respectively; *no notable differences

in levels of BUN and creatinine, urine β2-microglobulin, and urine microalbumin were observed across treatment groups with monitoring every 4 weeks.

GI=gastrointestinal; BUN=blood urea nitrogen.

Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.

Indicates ≥3% higher incidence in either dimethyl fumarate group vs placebo.

Integrated Analysis: Events Leading to Study

Drug Discontinuation (≥1% in Any Group)

16

Event, % Patients

Placebo

(n=836)

BG-12

240 mg BID

(n=769)

BG-12

240 mg TID

(n=823)

Discontinued study drug 11 14 14

MS relapse 6 1 2

Flushing <1 3 2

GI event

Diarrhea

Nausea

Vomiting

Abdominal pain, upper

Abdominal pain

<1

<1

0

0

<1

0

4

<1

<1

1

<1

<1

6

2

2

1

1

1

Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.

Integrated Analysis: Incidence of Flushing Events*

and Gastrointestinal Events† by Study Month

17

*Flushing events included the preferred terms “flushing,” “hot flush,” “erythema,” “generalized erythema,” “burning sensation,” “skin burning

sensation,” “feeling hot,” and “hyperemia”; †gastrointestinal events included the preferred terms in the level 2 subordinate standardized

MedDRA queries “gastrointestinal nonspecific inflammations” or “gastrointestinal nonspecific symptoms and therapeutic procedures.”

Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.

Placebo (n=408)

240 mg BID (n=410)

240 mg TID (n=416)

10

5

25

30

35

20

15

0 1 2 3 4 5 6 7 8 9 10 11 12 24

Month

Pa

tie

nts

(%

)

30

25

20

15

10

5

0 1 2 3 4 5 6 7 8 9 10 11 12 24

Month

Pa

tie

nts

(%

)

35

Flushing Events

Gastrointestinal Events

GI Events in First 3 Months of Treatment

for BID Dose (n=769)

Events, n (%)

Abdominal Pain

Adverse Events

Nausea/

Vomiting

Adverse Events

Diarrhea

Adverse Events

Any type of this event 121a 120a 78a

Severity

Mild

Moderate

Severe

68 (56)

42 (35)

11 (9)

65 (54)

49 (41)

6 (5)

49 (63)

26 (33)

3 (4)

Symptomatic Therapy 46 (38) 39 (33) 20 (26)

Resolvedb 113 (93) 114 (95) 75 (96)

18

aUsed as the denominator for percentages.; patients may have experienced more than one event. bEvents may have resolved at any time during the

study. GI events=preferred terms in the level 2 subordinate standardized MedDRA queries: “Gastrointestinal nonspecific inflammations” or

“gastrointestinal nonspecific symptoms and therapeutic procedures.”

Bar-Or A et al. Presented at LACTRIMS. November 28-30, 2012; Rio de Janeiro, Brazil.

Dimethyl Fumarate Efficacy and Safety:

Conclusions

▪ Compared with placebo, dimethyl fumarate significantly reduced

- Annualized relapse rate and MRI activity

- 12-week confirmed disability progression (DEFINE only)

- No serious safety signals in ~3600 patient-years exposure

▪ Most common adverse events were flushing and GI events

- Majority were mild to moderate

- Few discontinued treatment (3% due to flushing and 4% due to

GI intolerability)

- Strategies for management are under further investigation (aspirin,

administration with food, dose reduction, symptomatic treatment)

19

CHMP Opinion: Teriflunomide

Category Opinion

Indication Treatment of adult patients with relapsing-remitting multiple sclerosis

Active

substance

Teriflunomide, a selective immunosuppressant (L04AA31) with anti-

inflammatory properties. The exact mechanism by which teriflunomide

exerts its therapeutic effect in MS is not fully understood, but it is

known to reduce the proliferation of lymphocytes by blocking the

mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH).

Benefits Ability to reduce the relapse rate in patients with relapsing-remitting

multiple sclerosis

Most common

side effects

Upper respiratory tract infections, urinary tract infections, diarrhea,

nausea, paraesthesia (pins and needles), alopecia (loss of hair) and

increase in the liver enzyme alanine aminotransferase

20

Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC),

which will be published in the European public assessment report (EPAR) and made available in all official European Union

(EU) languages after the marketing authorization has been granted by the European Commission (EC).

▪ A pharmacovigilance plan will be implemented

▪ Treatment should be initiated under the supervision of a physician experienced in the

treatment of the disease

Extension

Extension

Extension

Extension

Teriflunomide Clinical Development Program

Monotherapy

21

Extension

TERACLES: Phase

3 adjunctive therapy

program

TEMSO RMS/placebo

TOWER: RMS/placebo

TENERE: RMS/IFNβ

TOPIC: CIS/placebo

Phase 2 IFN*

Phase 2 GA

Extension

June 2012

TERIKIDS:

pediatric study

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Adjunctive therapy

*Phase 2 study with IFN add-on included any currently available IFNs.

Accelerated elimination of teriflunomide by cholestyramine was utilized in all studies, as required.

RMS=relapsing multiple sclerosis; IFNβ=interferon beta; CIS=clinically isolated syndrome; GA=glatiramer

acetate. Data available at http://clinicaltrials.gov. Accessed June 15, 2012.

Phase 2 RMS/placebo

TEMSO and TOWER Study Design

22

Randomization

N=1088

Reallocation of

placebo group

O’Connor PW et al. N Engl J Med. 2011;365:1293-1303; O’Connor PW et al. Presented at: ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands. P924;

Kappos L et al. MS Presented at ECTRIMS. October 10-13, 2012; Lyon, France. P153.

14 mg/day

14 mg/day

Placebo (n=363) 7 mg/day

Teriflunomide 7 mg/day (n=365)

Teriflunomide 14 mg/day (n=358)

Screening

Week –4 0 12 24 36 48 60 72 84 96 108

7 mg/day

RMS patients

screened

N=1388

Entry into extension* or

post-study washout

Randomization

N=1169 Placebo (n=388)

Teriflunomide

Teriflunomide

Screening

Week –4 0 12 24 36 48 60 72 84 96 108 120 132 144 152

14 mg/day

14 mg/day

Extension

Study ended when last patient randomized completed 48 weeks of treatment

Variable study treatment duration of 48–152 weeks

Minimum treatment time

TEMSO

TOWER

7 mg/day (n=407)

14 mg/day (n=370)

0.54

0.37 0.37

0

0.1

0.2

0.3

0.4

0.5

0.6

Teriflunomide: Annualized Relapse Rate

23

Placebo Teriflunomide

7 mg

Teriflunomide

14 mg

Ad

juste

d*

An

nu

ali

ze

d R

ela

pse

Rate

n=363 n=365 n=358

31.2% P<0.001

31.5% P<0.001

0.50

0.39

0.33

0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo Teriflunomide

7 mg

Teriflunomide

14 mg

Ad

juste

d*

An

nu

ali

ze

d R

ela

pse

Rate

n=388 n=407 n=370

22.3% P<0.02

36.3% P<0.001

*Adjusted for EDSS score strata at baseline and takes into account duration of treatment. 1O’Connor PW et al. N Engl J Med. 2011;365:1293-1303; 2Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P153.

TOWER2 TEMSO1

Teriflunomide: 12-week Sustained

Disability Progression

24

HRR=hazard ratio reduction 1O’Connor PW et al. N Engl J Med. 2011;365:1293-1303; 2Kappos L et al. MS Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P153.

0

10

20

30

40

12

-week S

usta

ine

d D

isa

bilit

y P

rog

res

sio

n (

%)

0 12 24 36 48 60 72 84 96 108

Weeks

27.3

21.7 20.2

Placebo

Teriflunomide 7 mg

Teriflunomide 14 mg

Placebo

Teri 7 mg

Terif14 mg

363

365

358

336

343

329

306

309

302

279

290

285

258

266

262

242

252

251

224

238

234

211

234

227

200

224

217

160

178

175

Number of Patients at Risk

HRR=23.7%; P=0.08

HRR=29.8%; P=0.03

TOWER2 TEMSO1

12-W

ee

k C

on

firm

ed

Dis

ab

ilit

y P

rog

ress

ion

(%

)

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

0

10

20

30

40

Weeks

21.0 22.2

15.8

HRR=4.5%; P=0.76

HRR=31.5%; P=0.04

Placebo

Teriflunomide 7 mg

Teriflunomide 14 mg

Placebo

Teri 7 mg

Terif14 mg

388

406

370

354

375

340

325

337

310

295

314

286

271

286

267

241

248

245

195

202

211

156

163

162

128

114

124

83

77

87

Number of Patients at Risk 57

61

63

33

38

40

42.3

48.6

37.8

0

10

20

30

40

50

60

TENERE Outcomes

25

Annualized Relapse Rate Treatment Failure

SC IFNβ-1a Teriflunomide

7 mg

Teriflunomide

14 mg

Pa

tie

nts

(%

)

n=104 n=109 n=111

0.22

0.41

0.26

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

SC IFNβ-1a Teriflunomide

7 mg

Teriflunomide

14 mg

Ad

juste

d*

An

nu

ali

ze

d R

ela

pse

Rate

n=104 n=109 n=111

*Adjusted annualized relapse rate, confirmed relapse.

TENERE=Teriflunomide and Rebif® in Patients with RMS; SC=subcutaneous; IFNβ=interferon beta.

Vermersch P et al. Presented at ENS; June 9–12, 2012; Prague, Czech Republic.

P=0.03

1.67

0.81

0.39

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

Placebo(n=363)

Teriflunomide7 mg (n=365)

Teriflunomide14 mg (n=358)

TEMSO: MRI Outcomes

TEMSO=Teriflunomide Multiple Sclerosis Oral trial.

O’Connor PW et al. N Engl J Med. 2011;365:1293-1303.

1.33

0.57

0.26

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Placebo(n=363)

Teriflunomide7 mg (n=365)

Teriflunomide14 mg (n=358)

Gd

+ L

esio

ns p

er

T1

-Weig

hte

d S

can

57%

reduction

P<0.001 80%

reduction

P<0.001

Gd+ Lesions

T1-Hypointense

Lesions T2 Lesions

Vo

lum

e C

han

ge (

mL

)

44.0%

reduction

P=0.04 76.7%

reduction

P<0.001

Vo

lum

e C

han

ge (

mL

)

16.7%

reduction

P=0.19 31.3%

reduction

P=0.02

0.53 0.5

0.33

0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo(n=363)

Teriflunomide7 mg (n=365)

Teriflunomide14 mg (n=358)

26

Teriflunomide: Overview of Adverse Events and

Serious Adverse Events

27

Proportion

of Patients (%)

TEMSO TOWER

Placebo

(n=363)

Teri

7 mg

(n=368)

Teri

14 mg

(n=358)

Placebo

(n=385)

Teri

7 mg

(n=409)

Teri

14 mg

(n=371)

Any adverse event 87.5 89.1 90.8 83.1 84.1 86.3

Serious adverse events 12.8 14.1 15.9 12.2 12.7 11.9

Deaths 0 0 0 0.3 0.2 0.5

Adverse events leading to

treatment discontinuation 8.1 9.8 10.9 6.2 13.0 15.6

O’Connor PW et al. N Engl J Med. 2011;365:1293-1303;

Kappos L et al. MS Presented at ECTRIMS; October 10−13, 2012; Lyon, France. P153.

TEMSO: Safety and Tolerability*

(Adverse Events with Incidence ≥10% in Any Group)

Adverse Events, %

Placebo

(n=360)

Teriflunomide 7 mg

(n=368)

Teriflunomide 14 mg

(n=358)

Any class 87.5 89.1 90.8

Nasopharyngitis 27.2 25.5 26.0

Headache† 17.8 22.0 18.7

Diarrhea† 8.9 14.7 17.9

Fatigue 14.2 12.8 14.5

Elevated ALT† 6.7 12.0 14.2

Nausea† 7.2 9.0 13.7

Hair thinning, decreased

hair density†

3.3 10.3 13.1

Influenza 10.0 9.2 12.0

Back pain 13.1 10.6 11.5

Urinary tract infection 9.7 7.3 10.3

Pain in arms or legs‡ 13.1 7.1 9.2

28

*Events are displayed in order of decreasing incidence in the teriflunomide 14 mg group; †adverse events occurring at a higher rate in the

teriflunomide group; ‡adverse events occurring at a higher rate in the placebo group.

ALT=alanine aminotransferase.

O’Connor PW et al. N Engl J Med. 2011;365:1293-1303.

Difference in incidence of ≥3% between teriflunomide and placebo.

Teriflunomide: Common Adverse Events

29

Adverse Event, %

TEMSO TOWER

Placebo

(n=360)

Teri

7 mg

(n=368)

Teri

14 mg

(n=358)

Placebo

(n=385)

Teri

7 mg

(n=409)

Teri

14 mg

(n=371)

Diarrhea 8.9 14.7 17.9 7.3 12.0 11.1

Nausea 7.2 9.0 13.7 8.8 8.3 10.2

Elevated ALT 6.7 12.0 14.2 8.3 11.2 14.0

Hair thinning/

decreased hair density 3.3 10.3 13.1 4.4 10.3 13.5

Hypersensitivity or skin

disorders 7.2 10.3 11.2 Not Reported

O’Connor PW et al. N Engl J Med. 2011;365:1293-1303;

Kappos L et al. MS Presented at ECTRIMS; October 10−13, 2012; Lyon, France. P153.

TEMSO: Pregnancy Concerns

▪ Pregnancy was reported as an adverse event, and 11 pregnancies occurred

during the study1

- 4 spontaneous abortions (1 in placebo and 3 in teriflunomide 14 mg group)

- 6 induced abortions (5 in teriflunomide 7 mg and 1 in teriflunomide 14 mg)

- 1 patient in the teriflunomide 14 mg group delivered a healthy baby1

▪ Patients who withdrew from the study for any reason or who did not

participate in the extension study underwent an 11-day elimination period,

during which they received cholestyramine or activated charcoal1

▪ If a pregnancy is planned, plasma levels of teriflunomide have to be <0.02

mg/L in 2 separate tests 14 days apart2

▪ Without cholestyramine, half-lives (t½) of up to 96 days have been found

(population kinetics analysis). For full safety in the worst case scenario, an

estimated 11×t½, or approximately 2 years, would be needed to reach a

plasma level of <0.02 mg/L3

30

1. O’Connor MD et al. N Engl J Med. 2011;365:1293-1303; 2. Claussen MC et al. Clin Immunol. 2012;142:49-56;

3. Aubagio (teriflunomide) [prescribing information]. Cambridge, MA: Genzyme Corporation; 2012.

Key Takeaways

▪ Two new oral therapies are coming soon

▪ Indicated for treatment of adults with RRMS

▪ The CHMP considers there to be a favourable benefit-risk balance for both

therapies on the basis of the data submitted:

- Quality

- Safety

- Efficacy

▪ Recommendations for approval were published on March 21, 2013

31

EMA/167896/2013 and EMA/167897/2013. Committee for Medicinal Products for Human Use. © European Medicines Agency, 2013.