Kappos fingolimod moa-clin_results_vfinal_buenosaires1a

Fingolimod (Gilenya):Mode of Action

andClinical Trial Results

Prof. Ludwig KapposChair Neurology and Department of Biomedicine

University HospitalCH-4031 Basel

Disclosure

• L.K. is the Principal Investigator for the FTY 720 Phase II and FREEDOMS studies and has received research support from Actelion, Advancell, Allozyne, BaroFold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CLC Behring, Elan, Genmab, Genmark, GeNeuro SA, GlaxoSmithKline, Lilly, Merck Sereno, Medicinova, Novartis, Novo Nordisk, Peptimmune, Sanofi-Aventis, Santhera, Roche, Teva, UCB and Wyeth

Available therapies

Oral Immuno-modulators • Fumaric acid*• Laquinimod* • Teriflunomide*• oral VLA4-antagonists• Temsirolimus• Mycophenolic acid• Statins• Others…

Monoclonal Antibodies

• Alemtuzumab*• Rituximab• Ocrelizumab• Ofetimumab• (Atacicept) • Daclizumab

Cytotoxic agents • Cladribine*• Pixantrone• Treosulfane

Combination Therapy• IFNB-based• GA-based• Novel agents

Emerging Therapies and strategies

Disease Modifying Treatments (DMT) in MS (Immunomodulation/-suppression)Disease Modifying Treatments (DMT) in MS (Immunomodulation/-suppression)

IFNB

GA

Ag-specificTherapies• Altered peptide-

Ligands• MBP-, DNA-

vaccination• T-cell-, TCR-vaccination

Patientswith RR

MS ?

Natalizumab

?

Mitoxantrone

In yellow: agents in Phase III; *recently completed Phase III

FTY 720

4Fingolimod - a structural analogue of natural sphingosine1

1. Brinkmann V and Lynch KR. Curr Opin Immunol 2002; 2. Anliker B and Chun J. J Biol Chem 2004; 3. Lee MJ et al. Science 1998

Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that plays a key role in inflammation and repair

• Both sphingosine and fingolimod are phosphorylated by ubiquitous intracellular sphingosine kinases to their active forms and act via S1P receptors2 (G protein-coupled receptors, discovered in 19983)

OH

N H2

O H

Sphingosine

O H

OH

N H2Fingolimod

5Fingolimod-phosphate acts on four of five sphingosine 1-phosphate receptors1

EC, endothelial cells; SMC, smooth muscle cells; S1P, sphingosine 1-phosphate 1. Chun J and Hartung HP. Clin Neuropharmacol 2010; 2. Mandala S et al. Science 2002; 3. Baumruker T et al. Expert Opin Investig Drugs 2007; 4. Matloubian M et al. Nature 2004; 5. Brinkmann V. Pharmacol Ther 2007; 6. Mizugishi K et al. Mol Cell Biol 2005; 7. Massberg S andvon Andrian UH. N Engl J Med 2006; 8. Kimura A et al. Stem Cells 2007; 9. Jaillard C et al. J Neurosci 2005

S1P1 S1P3 S1P4 S1P5

Effects

Lymphocyte egress from

lymph nodes2–4

Lymphocytes (low expression)

CNS,oligodendrocytes,natural killer cells

Lymphocytes, neural cells, EC,

atrial myocytes, SMC

Neural cells, EC, atrial myocytes, SMC

Endothelial cell function, vasomotor tone and heart

rate5–7

CNS cell function and migration6,8,9

6

(Mehling M et al, Neurology 2011)

7

Tn, naive T cells; TCM, central memory T cell; TEM, effector memory T cell

Sallusto et al, Nature 1999; Mackay Nature 1999; Sallusto et al., Annu Rev Immunol 2004; Lanzavecchia et al Science 2000; Appay et al, Cytometry 2008; Westermann J and Pabst R. Clin Investig 1992; Pham et al, Immunity 2008

Fingolimod selectively modulates T cell recirculation through lymphoid organs

TCM TEM

CCR7Mediates retention in the lymph node

Lymph node(190 x 109 )

Tissue(290 x 109)

S1P1 favors egress and overrides CCR7

Loss of CCR7

Fingolimod induces internalization of S1P1 thereby favoring selective retention of CCR7+ Tnaive and TCM (incl. Th17) cells involved in MS pathology.

TEM, which are important for immune surveillance and maintenance of protective immunity, lack the homing and retention-promoting receptor CCR7, and are therefore largely spared by fingolimod.

T activatedCCR7-

CCR7+

X

T naive

Fingolimod

Blood (10x109)

<2% of total lymphocytes

8

Fingolimod has prophylactic and therapeutic effects in EAE rat model of MS1

EAE, experimental autoimmune encephalomyelitis 1. Foster CA et al. Brain Pathol 2009

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.00 5 10 15 20 25 30 35 40 45 50 55

Clin

ical

sco

re ±

SE

M

Days post-immunisation

Vehicle-treated

9


†Fingolimod dose 0.3 mg/kg; ***p≤0.001; EAE, experimental autoimmune encephalomyelitis 1. Foster CA et al. Brain Pathol 2009

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.00 5 10 15 20 25 30 35 40 45 50 55

Clin

ical

sco

re ±

SE

M

Prophylactic Day 0-11


***

Vehicle-treatedFingolimod† prophylactic

10



3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.00 5 10 15 20 25 30 35 40 45 50 55

Clin

ical

sco

re ±

SE

M


Therapeutic Day 12-28


*** ***

Vehicle-treatedFingolimod† prophylacticFingolimod† therapeutic

11



3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.00 5 10 15 20 25 30 35 40 45 50 55

Clin

ical

sco

re ±

SE

M


Therapeutic Day 12-28

RescueDay 40-53


***

*** ***

Vehicle-treatedFingolimod† prophylacticFingolimod† therapeuticFingolimod† rescue

12

Fingolimod treatment restores nerve conduction in EAE

MOG-induced relapsing-remitting EAE in DA rats

Neuronal function determined by recording SEP

DA, dark agouti; EAE, experimental autoimmune encephalomyelitis; MOG, myelin-oligodendrocyte glycoprotein; SEP, somatosensory-evoked action potentials Balatoni B et al. Brain Res Bulletin 2007

Clinical score: 1, flaccid tail; 2, hind limb weakness or ataxia; 3, full paralysis of hind limbs

Clin

ica

l sco

re


0.0

4.0

0 55

Fingolimod

3.0

2.0

1.0

Control

5 10 15 20 25 30 35 40 45 50

Treatment

EPrecording

SEP (electrical stimulation)

SE

P r

eco

rdin

gs

Da

y 5

3

FingolimodPositive controlNaïve

N2

P1

Fingolimod preserved and maintained electrophysiological nerve conduction in EAE

Proof of Concept in MS

2006;355:1124-40

FTY- Phase II, POC study

(NEJM 2006;355:1124-40)

15

Fingolimod Phase II study: patients free from Gd+ lesions after 5 years

*Calculated at each time point using the number of patients with an available MRI scan as the denominatorExtension phase ITT populationKappos L et al. ECTRIMS 2009, Montalban et al. MSJ 2011

80

0

60

100

Pa

tie

nts

fre

e f

rom

Gd

+ l

es

ion

s (

%)*

0

Time (months)

PlaceboPlacebo / fingolimodFingolimod 1.25 mgFingolimod 5.0 mg / 1.25 mg

40

1 2 3 4 5 6 12 24 36 48 60(n = 220) (n = 188) (n = 170) (n = 149) (n = 140)

(n =

278

)(n

= 2

66)

(n =

266

)(n

= 2

60)

(n =

261

)(n

= 2

54)

(n =

260

)

Placebo re-randomised to fingolimod

78.2%76.7%47.0%

88.7%83.1%79.2%

86.9%81.0%85.9%

89.3%87.5%89.7%

95.6%98.1%96.1%

93.0%91.7%91.1%

16

Annualize Relapse Rates in Different Epochs of the POC Study by Completion Status and Randomization

17

Phase II Study – Key findings:

Pronounced antiinflammatory effect on MRI outcomes

Already after 6 mths significant ARR reduction by 50%

Identical effect with lower dose (1.25mg) that was thought not to be effective in preventing transplant rejection

No indication of decreasing efficacy over > 6 years, good tolerability

Valuable data about selective effects on immune cells

18

80

70

60

50

40

30

20

10

0

Fingolimod selectively inhibits naïve and central memory T cell egress but spares effector memory T cells

Adapted from Mehling M et al. Neurology 2008

Per

cent

age

of C

D4+

cel

ls

Untreated MS

Fingolimod-treated MS

Naïve(CCR7+CD45RA+)

Central memory T cells

(CCR7+CD45RA-)

Effector memory T cells

(CCR7-CD45RA- [TEM] and CCR7-CD45RA+

[TEMRA])

p<0.001

p<0.001

p<0.001

Selective retention:

immunological effector functions

are preserved

19

Fingolimod reduces the proportion of Th17 cells in the circulation of people with MS*

Pro-inflammatory Th17 cells reside mainly in the TCM pool and are enriched in the CSF and lesions of MS patients1–3

* Mehling M et al. Neurology 2010; Purified blood T cells from patients with MS treated with fingolimod during the Phase II study and controls. Flow cytometry analysis of IL-17 producing CD4+ T cells. 1. Tzartos JS et al. Am J Pathol 2008; 2. Kébir et al. Ann Neurol 2009; 3.Brucklacher-Waldert et al. Brain 2009. TCM, central memory T cell

Fingolimod-treated MS

1.5

1.0

0.5

0.0

IL1

7+

T c

ells

(%

) in

CD

4+

T c

ells

*

Healthy donors Untreated MS IFNβ-treated MS

p<0.01

p<0.01

p<0.01

Fingolimodtreatment

Fingolimod reduces the proportion of circulating

Th17 cells in people with MS

from POC to Clinical Practice

JapanRRMSn = 168

FREEDOMS II(vs placebo)

in RRMSn = 1083

INFORMSPPMS

n ~ 900

Ongoing Ongoing

> 5000 people with MS treated with fingolimod + 1079 (pharmacology)

2845 patients with relapsing MS in completed clinical studies +

1079 in short term pharmacology trials

Fingolimod Clinical Development

POC: proof of concept

Phase II

Phase III

POC Study (2201) in

RRMS(+SPMS)

n = 281

FREEDOMS (vs placebo)in RRMSn = 1272

TRANSFORMS (vs IFNB1a qw)

in RRMSn = 1292

Pharmacology trials

n = 1079

22

23Kappos L et al. N Engl J Med 2010

Once-daily fingolimod 1.25 mg capsule

Once-daily fingolimod 0.5 mg capsule

Once-daily placebo capsule

Randomisation Month 24Month 12

MRI

Visit

Month 6

Extension study(fingolimod 0.5 mg)

FREEDOMS: Phase III study of fingolimod vs placebo in RRMS (N = 1272)

24-month, randomised, double-blind, placebo-controlled, parallel-group, multicentre study

24

FREEDOMS: baseline characteristics

1272 patients in 22 countries across Europe, Canada, Australia, Israel, Russia and South Africa

Fingolimod

Placebo 0.5 mg 1.25 mg

Randomised, N 418 425 429

Age (years), mean 37.2 36.6 37.4

Female, % 71 70 69

Duration of MS (years), mean 8.1 8.0 8.4

No. of relapses in last 2 years, mean 2.2 2.1 2.1

EDSS score, mean 2.5 2.3 2.4

Patients free from Gd+ lesions, % 63 62 61

Treatment-naïve patients, % 60 57 60

ITT populationKappos L et al. N Engl J Med 2010

25

FREEDOMS: Effect on annualised relapse rate vs placebo

0.0

0.1

0.2

0.3

0.4

Ann

ualis

ed r

elap

se r

ate

(95%

CI)

0.16(0.13–0.19)

0.18(0.15–0.22)

0.40(0.34–0.47)

Placebo (n = 418)

Fingolimod 0.5 mg(n = 425)


−54% vs placebop<0.001

−60% vs placebop<0.001

ITT populationKappos L et al. N Engl J Med 2010

26

FREEDOMS: Effect on risk of disability progression confirmed after 3 or 6 months, at 2 years

*Log-rank test comparing the survival distributions between treatment groups; †Cox’s proportional hazard model adjusted for treatment, country, baseline EDSS and age

1. Kappos L et al. N Engl J Med 2010; 362: 387-401.

FREEDOMS 2-year results1

0

30

Pat

ient

s w

ith E

DS

S

prog

ress

ion

con

firm

ed

afte

r 3

mo

nth

s (%

)

0

20

10

90 180 270 360 450 540 630 720

PlaceboFingolimod 0.5 mg

p=0.02 for fingolimod vs placebo*

0

30

0

20

10

90 180 270 360 450 540 630 720

p=0.01 for fingolimod vs placebo*

Pat

ient

s w

ith E

DS

S

prog

ress

ion

con

firm

ed

afte

r 6

mo

nth

s (%

)

Time (days)

30% reductionin risk of

progression(HR: 0.70 vs placebo)†

37% reductionin risk of

progression(HR: 0.63 vs placebo)†

19.0%

12.5%

24.1%

17.7%

27

12-month, randomised, double-blind, double-dummy, active-control, multicentre study

Ongoing

Once-daily fingolimod 0.5 mg capsuleand matching weekly placebo IM

Once-daily fingolimod 1.25 mg capsuleand matching weekly placebo IM

Once-weekly IFNβ-1a 30 µg IMand matching daily placebo capsule

Randomisation Month 12Month 6

MRI

Clinical visitEDSS

Extension study(fingolimod 0.5 mg)

TRANSFORMS: Phase III study of fingolimod vs IFNβ-1a IM qw in RRMS (N = 1292)

Cohen JA et al. N Engl J Med 2010

28

TRANSFORMS: baseline characteristics

1292 patients in 18 countries across Europe, Canada, Australia, Israel, Russia and South Africa

Fingolimod

IFNβ-1a IM 0.5 mg 1.25 mg

Randomised, n 435 431 426

Age (years), mean 36.0 36.7 35.8

Female, % 68 65 69

Duration of MS (years), mean 7.4 7.5 7.3

No. of relapses in last 2 years, mean 2.3 2.3 2.2

EDSS score, mean 2.2 2.2 2.2

Participants free from Gd+ lesions, % 63 67 66

Treatment-naïve patients, % 44 45 42

Randomised populationCohen JA et al. N Engl J Med 2010

29

0.33

0.16

0.20

0.0

0.1

0.2

0.3

0.4

0.5

TRANSFORMS: Annualised relapse rate vs IFNβ-1a IM

IFNβ-1a IM(n = 431)



Ann

ualis

ed r

elap

se r

ate

(95%

CI)

−52% vs IFNβ-1ap<0.001

−38% vs IFNβ-1ap<0.001

(0.26–0.42)

(0.12–0.21)(0.16–0.26)

ITT populationCohen JA et al. N Engl J Med 2010

30

Phase III clinical outcome measures: Efficacy summary

*p≤0.05; **p≤0.01; ***p≤0.001MSFC, MS functional composite

FREEDOMSat Month 24 vs placebo

TRANSFORMSat Month 12 vs IFNβ-1a

Outcome 0.5 mg 1.25 mg 0.5 mg 1.25 mg

ARR 54%*** 60%*** 52%*** 38%***

Time to relapse (HR) 52%*** 62%*** 48%*** 37%***

Proportion relapse-free 49%*** 58%*** 18%*** 15%***

Time to disability progression – 3 months (HR)

30%* 32%* 29% 15%

Time to disability progression – 6 months (HR)

37%** 40%** - -

MSFC mean difference (z-score)

0.09* 0.07* 0.07* 0.11***

0.2 0.4 0.6 0.8 1.0 1.2 1.4

Favors fingolimod

Sex

Female (n = 594)

Male (n = 249)

Age (years)

≤ 40 (n = 544)

> 40 (n = 299)

Previous treatment

Untreated (n = 493)

Treated (n = 350)

FREEDOMS 2-year results2FREEDOMS 2-year results2TRANSFORMS 1-year results1TRANSFORMS 1-year results1

0.2 0.4 0.6 0.8 1.0 1.2 1.4

Favors fingolimod Favors IFNb-1a IM

Sex

Female (n = 573)

Male (n = 287)

Age (years)

≤ 40 (n = 562)

> 40 (n = 298)

Previous treatment

Untreated (n = 366)

Treated (n = 494)

Favors placebo

0.44 (0.32–0.62)

0.61 (0.37–1.01)

0.41 (0.28–0.58)

0.68 (0.42–1.10)

0.45 (0.27–0.75)

0.50 (0.36–0.70)

0.50 (0.39–0.64)

0.33 (0.22–0.50)

0.33 (0.25–0.43)

0.76 (0.54–1.09)

0.36 (0.27–0.49)

0.54 (0.39–0.73)

Subgroup Analysis I: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Demographics

1., 2. :Cohen J et al NEJM 2010; Kappos L et al NEJM 2010; von Rosenstiel P et al. ECTRIMS 2010 (poster)

FREEDOMS 2-year results2FREEDOMS 2-year results2

High disease activity at baseline*Yes (n = 140)

No (n = 701)

Number of Gd-enhancing T1 lesions at baseline

0 (n = 525)

≥ 1 (n = 315)

Number of relapses in year before study

0 or 1 (n = 528)

> 1 (n = 315)

Number of relapses in 2 years before study

1 (n = 256)

2 (n = 360)

> 2 (n = 226)

Subgroup Analysis II: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Disease Activity

*High disease activity was defined as ≥1 Gd-enhancing lesion at baseline and ≥2 relapses in the year prior to the study1., 2. :Cohen J et al NEJM 2010; Kappos L et al NEJM 2010; von Rosenstiel P et al. ECTRIMS 2010 (poster)

TRANSFORMS 1-year results1TRANSFORMS 1-year results1

0.2 0.4 0.6 0.8 1.0 1.2 1.4

Favors fingolimod Favors placebo

0.2 0.4 0.6 0.8 1.0 1.2 1.4

Favors fingolimod Favors IFNb-1a IM

High disease activity at baseline*Yes (n = 121)

No (n = 734)

Number of Gd-enhancing T1 lesions at baseline

0 (n = 556)

≥ 1 (n = 296)

Number of relapses in year before study

0 or 1 (n = 535)

> 1 (n = 325)

Number of relapses in 2 years before study

1 (n = 239)

2 (n = 362)

> 2 (n = 258)

0.48 (0.24–0.94)

0.51 (0.37–0.70)

0.56 (0.39–0.81)

0.44 (0.28–0.69)

0.53 (0.36–0.78)

0.43 (0.29–0.65)

0.50 (0.27–0.91)

0.49 (0.31–0.76)

0.50 (0.32–0.78)

0.37 (0.24–0.57)

0.46 (0.36–0.59)

0.48 (0.36–0.65)

0.40 (0.29–0.55)

0.52 (0.39–0.69)

0.37 (0.27–0.51)

0.37 (0.24–0.58)

0.45 (0.32–0.63)

0.50 (0.34–0.72)

Subgroup Analysis III: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Disease Severity

Baseline EDSS score

0.0–3.5 (n = 709)

≥ 4.0 (n = 134)

Baseline T2 lesion volume (mm3)

≤ 3300 (n = 418)

> 3300 (n = 422)

FREEDOMS 2-year results2FREEDOMS 2-year results2

1., 2. :Cohen J et al NEJM 2010; Kappos L et al NEJM 2010; von Rosenstiel P et al. ECTRIMS 2010 (poster)

TRANSFORMS 1-year results1TRANSFORMS 1-year results1

Baseline EDSS score

0.0–3.5 (n = 733)

≥ 4.0 (n = 127)

Baseline T2 lesion volume (mm3)

≤ 3300 (n = 477)

> 3300 (n = 376)

0.2 0.4 0.6 0.8 1.0 1.2 1.4

Favors fingolimod

0.2 0.4 0.6 0.8 1.0 1.2 1.4

Favors fingolimod Favors IFNb-1a IM Favors placebo

0.46 (0.33–0.63)

0.57 (0.31–1.08)

0.50 (0.33–0.74)

0.50 (0.34–0.75)

0.48 (0.38–0.60)

0.34 (0.20–0.58)

0.40 (0.29–0.57)

0.47 (0.36–0.63)

FREEDOMS: 3-Month Confirmed Disability ProgressionKM (SE) estimates by sub-group

<=40 >40 Male female treated Treatment naiveAge Gender Prior treatment history

0

5

10

15

20

25

30

35

21.1

28.7

25

23.723.7

24.3

15.8

21.4

13.3

19.4

19.9

1616.8 16.4

17.516.3

17.316.2

Placebo Fingolimod 0.5mg Fingolimod 1.25mg

Pat

ien

t p

rop

ort

ion

s (%

)

KM, Kaplan Meier; SE, Standard Error


0 or

1 >1 1 2

>2

0.0-

3.5

>3.

5

No of relapses in the year prior to en-rollment

No of relapses in the 2 years prior to enrollment EDSS

0

5

10

15

20

25

30

35

40

23.824.5

18.8

24.5

29.3

21.6

36.3

18.1 17 18.619

14.4

1815.717.1

15.7

13

20.2

15.7 17.1 14.3


Pat

ien

t p

rop

ort

ion

s (%

)

Havrdova E et al ENS 2011


0 >=1 <=3300mm3 >3300mm3Gd-enhancing lesions Volume of T2 lesions

0

5

10

15

20

25

30

23

26.2

19.9

28.3

18.117 16.9

18.4

14.5

19.7

17.316.4


Pat

ien

t p

rop

ort

ion

s (%

)

Havrdova E et al ENS 2011

Effects on MRI Outcomes

38Phase 3 MRI Outcome Measures – Mean Reductions Relative to Control

*p<0.05; **p<0.01; ***p<0.001

FREEDOMS TRANSFORMS


T2 count 74%*** 74%*** 35%** 42%***

Gd+ count 82%*** 82%*** 55%*** 73%***

Atrophy 35%*** 32%*** 31%*** 33%***

38

39Phase III MRI Outcome Measures – Mean Reductions Relative to Control

*p<0.05; **p<0.01; ***p<0.001

FREEDOMS TRANSFORMS


T2 count 74%*** 74%*** 35%** 42%***

Gd+ count 82%*** 82%*** 55%*** 73%***

Atrophy 35%*** 32%*** 31%*** 33%***

39

FREEDOMSOverall rate of

brain atrophy

reduced by

32-36% with

fingolimod

over 2 years

vs placebo

TRANSFORMSOverall rate of

brain atrophy

reduced by

31-33% with

fingolimod

over 1 year

vs IFNb-1a

Placebo

Fingolimod 1.25 mg Fingolimod 0.5 mg

FREEDOMS1

*

****

***

***

***

***

Fingolimod Phase III Studies:Brain volume changes compared to Placebo, IFNB1a and healthy individuals

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

00 6 12 24

Time (months)

Mea

n ch

ange

from

bas

elin

e (%

)

Evaluable ITT population. *p<0.05 for fingolimod vs placebo; **p<0.01 for fingolimod vs placebo; ***p≤0.001 for fingolimod vs placebo / IFNβ-1a 1. Kappos L et al. N Engl J Med 2010; 2. Cohen JA et al. N Engl J Med 2010

***

IFNβ-1a


TRANSFORMS2

Green shaded area represents the estimated rate of brain volume loss in healthy individuals (0.2–0.4% per year)3,4

***

Fingolimod Phase III Studies:Brain volume changes compared to Placebo, IFNB1a and healthy individuals

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

00 6 12 24

Time (months)

Mea

n ch

ange

from

bas

elin

e (%

)

*

****

***

***

***

Evaluable ITT population. *p<0.05 for fingolimod vs placebo; **p<0.01 for fingolimod vs placebo; ***p≤0.001 for fingolimod vs placebo / IFNβ-1a 1. Kappos L et al. N Engl J Med 2010; 2. Cohen JA et al. N Engl J Med 2010; 3. Fotenos AF et al. Arch Neurol 2008; 4. Simon JH. Mult Scler 2006

***

Placebo


FREEDOMS1

IFNβ-1a


TRANSFORMS2

Effects of Fingolimod on Brain Volume in FREEDOMS / TRANSFORMS

Evaluable ITT population. FREEDOMS: *p=0.03 vs Placebo at M 12; **p=0.001 vs Placebo at M 12; †Evaluable patients at M 24

Fingolimod 0.5 mg

(n = 357)†

Fingolimod 1.25 mg

(n = 334)†

Placebo(n = 331)†

0.0

-0.2

-0.4

-0.6

-0.8

-1.4

p<0.001vs Placebo at

M 24

-1.0

-1.2 p<0.001vs Placebo at

M 24

Months 0-12

-0.65

-0.50*-0.44**

FREEDOMS1 – 24 M data

-0.66

-0.34-0.45

TRANSFORMS2 – 12 M data

Fingolimod 0.5 mg

(n = 368)


IFNβ-1a IM(n = 359)

-0.45

-0.31 -0.30

p<0.001vs IFNβ-1a

at M 12

p<0.001vs IFNβ-1a

At M 12

Me

an

Ch

an

ge

in

Bra

in V

olu

me

at

12

Ma

s c

om

pa

red

to

Ba

se

lin

e (

%)

Me

an

Ch

an

ge

in

Bra

in V

olu

me

at

12

an

d 2

4 M

a

s c

om

pa

red

to

Ba

se

lin

e (

%)

Months 12-24

0.0

-0.2

-0.4

-0.6

-0.8

-1.4

-1.0

-1.2

1. Kappos L et al. N Engl J Med 2010; 2. Cohen JA et al. N Engl J Med 2010

FREEDOMS: Effect on PBVC by baseline Gd-lesion status#O280, Kappos et al

Brain volume decreased more rapidly in patients with Gd-enhancing lesions at baseline (A) than in

patients without these lesions (B) , irrespective of treatment group

Both fingolimod doses significantly reduced the rate of brain volume loss versus placebo, irrespective of

baseline inflammatory lesion status

A Time (months)

Me

an

ch

an

ge

fro

m

ba

se

lin

e(%

)

B Time (months)

Mea

n ch

ange

from

ba

selin

e(%

)

Kappos L et al, ENS 2011

Conclusions from brain volume measurements Over 2 years, fingolimod therapy significantly reduced the overall rate of brain volume

loss, irrespective of inflammatory Gd-enhancing lesions at baseline.

Brain volume loss occurred more quickly in patients with, than in those without, Gd-

enhancing lesions at baseline, irrespective of treatment group.

In patients without Gd-lesions at baseline the reduction in brain volume loss was apparent

within the first 6 months and was sustained over the 2-year study

In patients with Gd-lesions at baseline the reduction in brain volume loss was more

apparent in the 2nd year than the 1st year

Despite the anti-inflammatory effect of fingolimod on MRI lesions, which could result in

initial pseudoatrophy in Gd+ patients, fingolimod did not lead to a greater rate of brain

volume loss compared to placebo (suggestive of a superimposed neuroprotective effect?)

#O280, Kappos et al

Adverse Event Profile and overall Safety

50

Fingolimod adverse event experience

Phase III placebo-controlled(FREEDOMS)

Allstudies+

Placebo

n = 418

Fingolimod Fingolimod

0.5 mgn = 425

1.25 mgn = 429

0.5 mgn = 1176

1.25 mgn = 1302

Event, N (%)

At least one AE 387 (92.6) 401 (94.4) 404 (94.2) 1054 (89.6) 1203 (92.4)

AE leading to study drug discontinuation* 32 (7.7) 32 (7.5) 61 (14.2) 92 (7.8) 186 (14.3)

Any serious AE 56 (13.4) 43 (10.1) 51 (11.9) 111 (9.4) 170 (13.1)

Deaths 2 (0.5) 0 1 (0.2) 0 5** (0.3)

+Includes all available data from Phase II and Phase III core and extension studies with treatment durations varying between 1 to 6 years – data cut-off from 120 day safety update; *Includes events occurring in patients whose primary or secondary reason for discontinuing the study drug was an AE (including abnormal laboratory findings) **Includes 1 fatal disseminated varicella infection and 1 fatal Herpes simplex Encephalitis (TRANSFORMS)

51

Adverse events of special interest

FREEDOMS All studies+

Fingolimod Fingolimod

Event, n (%) Placebo(n = 418)

0.5 mg(n = 425)

1.25 mg(n = 429)

0.5 mg (n = 1176)

1.25 mg (n = 1302)

AV block, 1st degree,6 hours post-dose

6 (1.5) n = 413

20 (4.8)n = 417

35 (8.3)n = 423

55 (4.8)n = 1156

113 (8.8)n = 1282

AV block, 2nd degree Mobitz I, 6 hours post-dose

0n = 413

1 (0.2)n = 417

2 (0.5)n = 423

2 (0.2)n = 1156

10 (0.8)n = 1282

Hypertension 16 (3.8) 26 (6.1) 27 (6.3) 74 (6.3) 100 (7.7)

Macular oedema0

n = 4130

n = 4237 (1.7)n = 420

4 (0.3)n = 1167

14 (1.1)n = 1266

At least one infection 301 (72.0) 304 (71.5) 294 (68.5) 751 (63.9) 847 (65.1)

Any serious infection 8 (1.9) 7 (1.6) 11 (2.6) 18 (1.5) 33 (2.5)

Malignancies 10 (2.4) 4 (0.9) 4 (0.9) 17 (1.4) 14 (1.1)

+Includes all available data from Phase II and Phase III core and extension studies with treatment durations varying between 1 to 6 years – data cut-off from 120 day safety update AV, atrioventricular

52

Effects of Fingolimod on Lymphocytes

53

Lymphocyte count during treatment with fingolimod: FREEDOMS

Values represent the mean; error bars are the standard deviation.Francis G et al. AAN April 2011; Lymphocytes and Fingolimod Temporal pattern and relationship with Infections (S30.001)

Basel

ine

2 w

ks

1 m

o

2 m

os

3 m

os

6 m

os

9 m

os12

mos

15 m

os18

mos

21 m

os24

mos

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

2.2

2.4

Placebo (N=418) 0.5 mg Fingolimod (N=425) 1.25 mg Fingolimod (N=429)

Me

an

± S

D ly

mp

ho

cyte

co

un

t (×

10

9/L

)

Lymphocyte counts dropped rapidly, approaching steady state levels in 2- 4 weeks and remained stable on continued therapy.

LLN, lower limit of normal range; Population: all fingolimod-treated patients in MS trials who discontinued treatment. Francis et al ECTRIMS 2010

Rapid redistribution

– fingolimod reduces blood lymphocyte count within 4-6 hours (max after 1-2 weeks)

– lymphocytes are retained in the lymph nodes and are not destroyed

Reversible effect

– lymphocyte function is maintained

Recovery to normal levels within 1-2 months

Absolute lymphocyte count (109/L)

LLN

Fingolimod leads to Selective and Reversible redistribution of lymphocytes, with no lymphocytotoxicity

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

2.2

2.4

Baseline(n=537)

End oftreatment(n=519)

0-45 daysafter disc(n=295)

45 days-3months afterdisc (n=358)

3-6 monthsafter disc(n=130)

6-9 monthsafter disc

(n=72)

9-12 monthsafter disc

(n=55)

Q1 Mean Q3

55

Phase III placebo-controlled(D2301)

All studies

Placebo Fingolimod Fingolimod

N=418

0.5 mg 1.25 mg 0.5 mg 1.25 mg

N=425 N=429 N=1176 N=1302

At least one infection, n(%) 301 (72.0) 304 (71.5) 294 (68.5) 751 (63.9) 847 (65.1)

Infections (events per 100 patient-years)

128.1 126.9 123.0 120.7 121.9

Any severe infection, n (%) 13 (3.1) 12 (2.8) 15 (3.5) 29 (2.5) 44 (3.4)

Any serious infection, n (%) 8 (1.9) 7 (1.6) 11 (2.6) 18 (1.5) 33 (2.5)

Infections of interest:

LRTI and lung infections* 25 (6.0) 41 (9.6) 49 (11.4) 100 (8.5) 130 (10.0)

Any Herpes infection 33 (7.9) 37 (8.7) 25 (5.8) 95 (8.1) 122 (9.4)

Varicella-zoster 4 (1.0) 7 (1.6) 3 (0.7) 19 (1.9) 30 (2.6)

Herpes Infection SAEs - 1 (0.2) 1 (0.2) 3 (0.3) 8 (0.6)

Infections

*LTRI = Lower respiratory tract infections. Only type of infection with higher incidence (>1% difference vs placebo) in the 1.25 mg group in Phase III. Bronchitis was the most frequently reported LRTI. Francis G et al. AAN April 2011; Lymphocytes and Fingolimod Temporal pattern and relationship with Infections (S30.001)

56

InfectionsSimilar incidence in all treatment groupsIncreased incidence in lower respiratory tract infections

Phase III placebo-controlled(FREEDOMS)

All completed studies


N=418

0.5 mg 1.25 mg 0.5 mg 1.25 mg

N=425 N=429 N=1176 N=1302

At least one infection, n(%) 301 (72.0) 304 (71.5) 294 (68.5) 751 (63.9) 847 (65.1)

Infections (events per 100 patient-years) 128.1 126.9 123.0 120.7 121.9

Any severe infection, n (%) 13 (3.1) 12 (2.8) 15 (3.5) 29 (2.5) 44 (3.4)

Any serious infection, n (%) 8 (1.9) 7 (1.6) 11 (2.6) 18 (1.5) 33 (2.5)

Infections of interest:

LRTI and lung infections* 25 (6.0) 41 (9.6) 49 (11.4) 100 (8.5) 130 (10.0)

Any Herpes infection 33 (7.9) 37 (8.7) 25 (5.8) 95 (8.1) 122 (9.4)

Varicella-zoster 4 (1.0) 7 (1.6) 3 (0.7) 19 (1.9) 30 (2.6)

Herpes Infection SAEs - 1 (0.2) 1 (0.2) 3 (0.3) 8 (0.6)

*LTRI = Lower respiratory tract infections. Only type of infection with higher incidence (>1% difference vs. placebo) in the 1.25 mg group in Phase III. Bronchitis was the most frequently reported LRTI.

57

Incidence of overall infections/per year categorized by mean lymphocyte counts: FREEDOMS core study group

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

<0.2(n=23)

0.2-0.3

(n=169)

0.3-0.4

(n=194)

0.4-0.5

(n=169)

0.5-0.7

(n=150)

>0.7

(n=102)

Placebo

(n=414)

Fingolimod

0.5 mg

(n=422)

Fingolimod

1.25 mg

(n=423)

Mean lymphocyte count (x10^9 / L)

Inci

denc

e ra

te p

er p

atie

nt-y

ear

of a

ny in

fect

ions

Infections by Lymphocyte Count Infections Overall

Francis G et al. AAN April 2011; Lymphocytes and Fingolimod Temporal pattern and relationship with Infections (S30.001)

59

Fingolimod preserved immune response to novel antigens in healthy volunteers

KLH, keyhole limpet haemocyanin; PPV, pneumococcal polysaccharides vaccineSchmouder R et al. Poster P412 presented at ECTRIMS 2010

95.590.9

100.0

90.990.5

57.1

0

20

40

60

80

100

>2-fold >4-fold

86.4

54.5

77.3

40.9

57.1

9.50

20

40

60

80

100

>2-fold >4-fold

Res

po

nd

er r

ate

(%)

Res

po

nd

er r

ate

(%)

Increase in anti-KLH IgG levels from pre-immunisation

Increase in anti-PPV-23 IgG levels from pre-immunisation

Fingolimod 0.5 mg (n = 22)

Fingolimod 1.25 mg* (n = 22)

Placebo (n = 22)

Ability to increase T cell-dependent and T cell-independent antibody response in response to novel antigens was retained

60

0

20

40

60

80

100

0 7 14 28

Fingolimod preserved immune response to influenza vaccination in patients with MS

¨ After vaccination, in patients with MS treated with fingolimod

– vaccine-triggered T cells in blood were similar to healthy controls

– increases in anti-influenza A / B IgM and IgG similar to those in healthy controls

0

20

40

60

80

100

0 7 14 28

Ser

op

rote

cted

pat

ien

ts (

%)

Days

Anti-influenza A IgG

Ser

op

rote

cted

pat

ien

ts (

%)

Days

Anti-influenza B IgG

Healthy controls (n = 18) MS fingolimod (n = 14*)

*Six patients received fingolimod 0.5 mg and eight patients received fingolimod 1.25 mg;

Mehling M et al. Ann Neurol 2011

62

First dose effects of fingolimod on heart rate

63

Fingolimod : cardiac electrophysiological activity

Fingolimod, via S1PRs, activates a G-protein-activated inwardly rectifying K (GIRK) channel

The resulting current, IKACh, causes sinus slowing and increased AV nodal conduction and refractoriness1

Electrophysiological effects are transient due to receptor internalization/desensitization despite continued exposure with higher plasma drug concentrations

1Koyrakh L et al. Am J Transplant 2005;5:529–36ACh, acetylcholine; AV, atrioventricular; K, potassium; M2, muscarinic acetylcholine receptor 2

64

Transient effect of fingolimod on heart rate

Mild symptomatic bradycardia observed in 0.5% of patients receiving fingolimod 0.5 mg

The HR changes attenuated with continued therapy and returned to baseline levels by month 1

Pooled FREEDOMS and TRANSFORMS safety population. Data are mean ± SD. AV, atrioventricularDiMarco JP et al. Poster P830 at ECTRIMS 2010

65

Transient dose-dependent slowing of AV conduction after first fingolimod dose

Placebo Interferon beta-1a IM

Fingolimod 0.5 mg

Fingolimod 1.25 mg

Patients, n 418 431 854 849

ECG recordings, n 413 422 837 840

First-degree AV block 6 (1.5) 12 (2.8) 39 (4.7) 82 (9.8)

Wenckebach (Mobitz Type I) second-degree AV block

0 0 2 (0.2) 6 (0.7)

2:1 second-degree AV block

0 0 0 2 (0.2)

1 month ECG, n 407 414 835 824

First degree AV block 3 (0.7) 16 (3.9) 16 (1.9) 16 (1.9)

Second degree AV block Mobitz I 0 0 0 0

2:1 AV block 0 0 0 0

Third degree AV block 0 0 0 0

FREEDOMS 2-year/TRANSFORMS 1-year safety population

AV conduction changes attenuated with continued therapy and no effect on conduction system observed by month 1 .

66

Systolic & Diastolic Blood Pressure over Time: Safety population (FREEDOMS :D2301)

An average increase of blood pressure of 2 mmHg systolic and 1 mmHg diastolic was seen with fingolimod after 2 months which stabilized by 6 months

Presentation FDA-Advisory Committee Meeting June 10, 2010

67

Ophthalmic Effects of Fingolimod

68

Clinical Characteristics of 16 Macular oedema (ME) Patients in MS Clinical Studies

0.5 mg 1.25 mg Bilateral Unilateral Smoker Non smoker Uveitis Optic neuritisFingolimod dose Eventual eye involvement Smoking habit Medical history

0

2

4

6

8

10

12

14

16

88%

12%

25%

75%

50% 50%

25%

38%

Num

ber

of p

atien

ts

Low incidence (0.2%) of ME in the 0.5mg fingolimod group

Zarbin M et al. AAN Aprill 2011; Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in Multiple Sclerosis (MS) (Poster 208)

Total no of patients studied n= 2615

69

Hepatic effects of Fingolimod

70

ALT / Bilirubin

Phase III placebo-controlled(D2301)

All studies


N=414

0.5 mg 1.25 mg 0.5 mg 1.25 mg

ALT N=424 N=425 N=1172 N=1287

≥3 x ULN 7 (1.7) 36 (8.5) 53 (12.5) 94 (8.0) 150 (11.7)

≥5 x ULN 4 (1.0) 8 (1.9) 13 (3.1) 18 (1.5) 34 (2.6)

≥10 x ULN - 1 (0.2) - 2 (0.2) 4 (0.3)

Bilirubin > 1 x ULN 39 (9.4) 47 (11.1) 42 (9.9) 119 (10.2) 126 (9.8)

FREEDOMS 2 year safety populationALT: Alanine transaminase; ULN: Upper limit of normal

71

Adverse events: fingolimod compared with placebo

Fingolimod 0.5 mg (N = 425)Placebo (N = 418)

Lymphopenia

Hepatic enzyme increased

Gamma-glutamyltransferase increased

Tinea versicolour

Vision blurred

Migraine

Alanine aminotransferase increased

Back pain

Bronchitis

Relative risk with 95% CI

Hypertension

Overall AEs

Diarrhoea

Dyspnoea

Urinary tract infection

Micturition urgency

Musculoskeletal stiffness

Somnolence

Leukopenia

0.016 0.125 1 8 64 5120.002

Higher with fingolimod 0.5 mgHigher with placebo

Safety populationPresentation FDA-Advisory Committee Meeting June 10, 2010; Collins AW et al. Poster P843 at ECTRIMS 2010

72

Adverse events: fingolimod compared with IFNβ-1a IM

Fingolimod 0.5 mg (N = 429)IFNβ-1a IM (N = 431)

Alanine aminotransferase increased

Gamma-glutamyltransferase increased

Hypertension

Relative risk with 95% CI

Overall AEs

Chills

Hepatic enzyme increased

Higher with fingolimod 0.5 mgHigher with IFNβ-1a IM

0.004 0.016 0.063 1 40.250 16 64 256

Bronchitis

Depression

Arthralgia

Myalgia

Pyrexia

Infusion-related reaction

Influenza-like illness

Safety populationPresentation FDA-Advisory Committee Meeting June 10, 2010

73

Safety conclusions

Based on > 4,500 patient-years in > 2,600 MS patients with comprehensive multi-organ safety assessments in all studies

Overall incidence of SAEs and AEs leading to drug discontinuation similar between 0.5 mg dose and comparator (placebo & IFNβ-1a IM)

Similar incidence for overall (with the exception of LRTIs) and serious/severe infections in fingolimod and comparator arms (IFNβ-1a IM, or placebo)

No clear relationship between lymphocyte count, mean or nadir, and infection

No signal for malignancy, but long-term risk including lymphomas must be closely followed as part of a Risk Management Plan

Data in pregnancy is limited – strict contraception recommended in females of childbearing potential

Fingolimod database has >90% power to detect serious events occurring more frequently than 1/3000 patient-years (1/1500 patients)

74

Safety conclusions

Related to specific mode of action

– Transient Bradyarrhythmias on treatment initiation

– symptomatic in <0.5% for fingolimod 0.5mg

– ECG changes: mainly transient 1st and 2nd degree type 1 AV block (Wenckebach) on Day 1 of treatment;

– Macular oedema

– Fingolimod 0.5mg is associated with low incidence (0.2%)

– Most ME cases diagnosed within 3-4 months of treatment initiation and resolved after study drug discontinuation

– Elevation of liver enzymes

– Asymptomatic dose-dependent elevations of liver enzymes (8% had 3-fold increase in 0.5 mg group)

– No patient developed liver failure

Where Might Fingolimod Fit in the Treatment Algorithm?

Factors affecting burden of therapy include convenience, tolerability, shortterm and longterm safety. GA=glatiramer acetate.

Burden of Therapy

Efficacy

NatalizumabImmuno-

suppressiveTherapies

IFNβGA

75

Fingolimod ?

Where Might Fingolimod Fit in the Treatment Algorithm?

Factors affecting burden of therapy include convenience, tolerability, shortterm and longterm safety. GA=glatiramer acetate.

Burden of Therapy

Efficacy

NatalizumabImmuno-

suppressiveTherapies

IFNβGA

76

Fingolimod

Interdisciplinary Team of the MS-Center in Basel

Thank you for your attention !

Health & Medicine

Kappos fingolimod moa-clin_results_vfinal_buenosaires1a