The evolving landscape of MS

John WoolmoreConsultant Neurologist UHB

FIN14-C173. Date of preparation: September 2014

Plan

• Introduction

• Established therapies

• Newer therapies, “on the horizon”

• MOA, pivotal trials, other efficacy data, safety

• NHS England

• Conclusion and questions

Putative targets for MS therapies

Barten et al Drug Des Devel Ther. 2010;4:343-366; Linker et al, Trends Pharmacol Sci. 2008;29:558–565.129

Established therapies

• ABCR/BRACE

• Tysabri

• Gilenya

• (mitoxantrone)

Newer therapies

• Lemtrada, Alemtuzumab, Campath

• Tecfidera, Dimethyl fumarate, BG 12

• Aubagio, Teriflunomide, (leflunomide)

On the horizon

• Daclizumab - anti IL-2

• Ocrelizumab

• Firategast alpha4beta1 integrin

• Ofatumumab

• BAF 312 - S1P1 and S1 P5

• Anti Lingo BIIB033

• Copaxone/glatriamer TIW

• Plegridy 2 weekly IFN beta1a sub cut

• (Laquinimod)

Daclizumab

• DECIDE - Presented 11/9/14 ECTRIMS 2014, Kappos et al

• DAC HYP once monthly s/c vs IFNB1a

• 45% reduction in ARR

• Relapse risk reduction rate 41%

• T2 MRI rate 54% reduction, GAD 65%

• 6 month disability progression reduced by 27%

• Treatment discontinuation 9% - cutaneous events main AEs

Tecfidera

Sustained-Release Dimethyl Fumarate

Through Activation of Nrf2, DMF/MMF Activate Both Anti-Oxidant and Anti-Inflammatory Responses

Nrf2=nuclear factor (erythroid-derived 2)-like 2; Keap1=kelch-like ECH-associated protein.van Horssen J et al. Biochem Biophys Acta. 2011;1812:141-150; Linker RA et al. Brain. 2011;134:679-692; Scannevin R et al. J Pharmacol Exp Ther. 2012;341:274-284.

Under normal conditions,Nrf2 is sequestered in thecytoplasm via Keap1

DMF/MMF cause Nrf2 to translocate to the nucleus (imitates physiological stress response)

Nrf2 activates intrinsicdefense mechanisms

1

2

3Keap1

Cytoplasm

Nucleus Inflammatory response

Antioxidant response

Nrf2

DMF/MMF

DEFINE: Proportion of Patients Relapsed (INEC-Confirmed)

Placebo408 356 321 282 243 224 205 190 115

DMF BID410 353 324 303 286 267 255 243 154

DMF TID416 346 322 301 286 270 251 244 166

Number of Patients at Risk

HR (95% CI):BID vs placebo=0.51 (0.40, 0.66); 49% risk reduction; P<0.0001TID vs placebo=0.50 (0.39, 0.65); 50% risk reduction; P<0.0001

Placebo (n=408)DMF 240 mg BID (n=410)DMF 240 mg TID (n=416)

Time on Study (weeks)

0.6

0.5

0.4

0.3

0.2

0.1

0

Pro

babi

lity

of R

elap

se

BL 12 24 36 48 60 72 84 96

0.461

0.2700.260

DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS; INEC=independent neurology evaluation committee; HR=hazard ration; CI=confidence interval; BID=twice daily; TID=3 times daily; BL=baseline; MS=multiple sclerosis.Gold R et al. Presented at ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands. S34.

DEFINE: Annualized Relapse Rate at 2 Years (Secondary Endpoint)

Placebo (n=408) BG-12 BID (n=410) BG-12 TID (n=416)0

0.6

Ad

just

ed

An

nu

aliz

ed

Re

-la

pse

Ra

te (

95

% C

I)*

0.364

0.1720.189

53%reductionvs placeboP<0.0001

48%reductionvs placeboP<0.0001

*Annualized relapse rate calculated with negative binomial regression, adjusted 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. DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS; CI=confidence interval;BID=twice daily; TID=3 times daily; EDSS=Expanded Disability Status Scale; MS=multiple sclerosis.Gold R et al. Presented at ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands. S34.

Integrated Safety Analysis: Common Adverse Events (≥10% in Any Group)

DMF 240mg BID is the licensed dose , 240mg BID and 240mg TID DMF doses were assessed for safety and efficacy in DEFINE and CONFIRM.The overall incidence of any GI event was 31%, 40%, and 43% in the placebo, dimethyl fumarate bid, and dimethyl fumarate 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.

Event, n (%)Placebo(n=836)

DMF bid(n=769)

DMF tid(n=823)

Any adverse event 769 (92) 733 (95) 767 (93)

Flushing 39 (5) 265 (34) 240 (29)

MS relapse 360 (43) 221 (29) 211 (26)

Nasopharyngitis 169 (20) 170 (22) 179 (22)

Headache 137 (16) 133 (17) 138 (17)

Diarrhea 86 (10) 107 (14) 136 (17)

Urinary tract infection 96 (11) 107 (14) 95 (12)

Upper respiratory tract infection 88 (11) 99 (13) 101 (12)

Nausea 72 (9) 93 (12) 115 (14)

Fatigue 91 (11) 94 (12) 103 (13)

Back pain 92 (11) 94 (12) 84 (10)

Abdominal pain upper 47 (6) 76 (10) 94 (11)

Proteinuria* 59 (7) 67 (9) 85 (10)

Integrated Safety Analysis: Events Leading to Study Drug Discontinuation (≥1% in Any Group)

GI=gastrointestinal.DMF 240mg BID is the licensed dose , 240mg BID and 240mg TID DMF doses were assessed for safety and efficacy in DEFINE and CONFIRM.Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.

Event, n (%)Placebo(n=836)

DMF bid(n=769)

DMF tid(n=823)

Discontinued study drug due to adverse event 94 (11) 109 (14) 117 (14)

MS relapse 48 (6) 11 (1) 13 (2)

Flushing 1 (<1) 24 (3) 13 (2)

GI events

Diarrhea

Nausea

Vomiting

Abdominal pain, upper

Abdominal pain

2 (<1)

0

0

2 (<1)

0

7 (<1)

6 (<1)

8 (1)

6 (<1)

5 (<1)

15 (2)

14 (2)

12 (1)

10 (1)

9 (1)

4% discontinuation for GI events in DMF BID group

Natalizumab

AFFIRM: Annualized Relapse RateOverall Population

0.73

0.23

Years 0–2

0.78

0.67

0.270.20

Year 0–1 Years 1–2

Placebo n=315Natalizumab n=627

68%reduction vs placebo

P<0.001

66%reduction vs placebo

P<0.001

70%reduction vs placebo

P<0.001

68% reduction in annualized relapse rate vs placebo

CI=confidence interval.Polman CH et al. N Engl J Med. 2006;354:899-910.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Annu

alize

d Re

laps

e Ra

te (9

5% C

I)

5

AFFIRM: Risk of Disability ProgressionOverall Population

6-Month Sustained†

0

0.1

0.2

0.3

0.4

Week0 12 24 36 48 60 72 84 96 108 120

Prop

ortio

n w

ith S

usta

ined

Pro

gres

sion

Natalizumab 11%

Placebo 23%

Number of Patients at Risk

PlaceboNatalizumab

315 298 287 269 253 246 237 225 216 211627 611 594 581 559 540 532 521 509 503

211502

54% risk reductionHR=0.46 P<0.001

*Primary endpoint; †prespecified sensitivity analysis. HR=hazard ratio.Polman CH et al. N Engl J Med. 2006;354:899-910.

6

3-Month Sustained*

Placebo 29%

Natalizumab 17%

0

0.1

0.2

0.3

0.4

0 12 24 36 48 60 72 84 96 108 120

Number of Patients at Risk

PlaceboNatalizumab

315 296 283 264 248 240 229 216 208 200627 601 582 567 546 525 517 503 490 478

199473

Prop

ortio

n w

ith S

usta

ined

Pro

gres

sion 42% risk reduction

HR=0.58 P<0.001

Week

•Updated Sept 2012

Natalizumab: long-term efficacy data from STRATA1

Annualized Relapse Rate

1. Rudick, et al. ECTRIMS 2013; P593.

STRATA is an ongoing, open-label, multinational study to evaluate the long-term safety and efficacy of natalizumab in RRMS patients who completed the feeder studies AFFIRM, SENTINEL and GLANCE.

Natalizumab PML Incidence Estimates by Treatment Epoch

Calculations based on exposure through 31st May 2014 and 472 confirmed cases as of 4th June 2014

Biogen Idec, data on file.

Post Mark

eting

1-12 Infusio

ns

13-24 Infusio

ns

25-36 Infusio

ns

37-48 Infusio

ns

49-60 Infusio

ns

61-72 Infusio

ns0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.03.99

0.13

0.85

2.05

2.65

2.972.68

3.32

0.03

0.51

1.42

1.82 1.93

1.49

3.64

0.07

0.67

1.72

2.212.41

2.02

Inci

denc

e pe

r 100

0 pa

tient

s

0.1/100095% CI 0.01-0.35

No Yes

Anti-JCVAntibody Status

Negative Positive

Prior IS Use

NatalizumabExposure

No Prior IS Use Prior IS Use

1–24 months 0.7/100095% CI 0.5-1.0

1.8/100095% CI 1.1-2.7

25–48 months 5.3/100095% CI 4.4-6.2

11.2/100095% CI 8.6-14.3

49–72 months 6.1/100095% CI 4.8-7.8 Insufficient data

Data beyond 4 years of treatment are limited. There are insufficient data to adequately determine PML risk in anti-JCV antibody positive patients with prior IS use and >48 months of natalizumab exposure.

*Based on natalizumab exposure and 343 confirmed PML cases as of 5 th March 2013. Prior IS data in overall natalizumab-treated patients based on proportion of patients with IS use prior to natalizumab therapy in TYGRIS as of May 2011; and prior IS data in PML patients as of 5 th March 2013. The analysis assumes that 55% of natalizumab-treated MS patients were anti-JCV antibody positive and that all PML patients test positive for anti-JCV antibodies prior to the onset and diagnosis of PML. The estimate of PML incidence in anti-JCV antibody negative patients is based on the assumption that all patients received at least 1 dose of natalizumab . Assuming that all patients received at least 18 doses of natalizumab, the estimate of PML incidence in anti-JCV antibody negative patients was generally consistent (0.16/1000; 95% CI 0.02–0.56).

Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration*

Biogen Idec, data on file.

Teriflunomide

Alemtuzumab

Relapse Reduction: in RRMS and SPMS Patients

Graph shows episodes reported in RRMS cohort (n=22) before and after treatment with 2 coursesa of alemtuzumab at Months 0 and 12 (red lines)Relapse frequency significantly reduced in

RRMS cohort (p<0.0001)2.21/patient/yr before treatment vs.

0.19/patient/yr after treatment 91% reduction

Similar results were seen in the SPMS cohortThe relapse rate fell from 0.7/patient/yr to

0.01/patient/yr (p<0.001; data not shown), which translates to a 98.5% reduction

a Course=3 or 5 daily 20-mg intravenous administrations.Coles AJ et al. J Neurol 2006;253:98-108.

-42-36-30-24-18-12-6 0 6 12182430364248

0

1

2

Relapse Rates in RRMS Cohort

Before Alemtuzumab Treatment

After Alemtuzumab

Treatment

Rela

pse

s per

3-m

onth

Peri

od,

n

Months

Change in EDSS: in RRMS and SPMS Patients

Note: Gradients above the equator represent increasing disability and below the equator represent reducing disability.Coles AJ et al. J Neurol 2006;253:98-108.

• 1 year after alemtuzumab treatment, 33/36 SPMS patients had maintained their pre-treatment EDSS values

• However, this proportion decreased with time and this cohort showed an overall worsening of disability

‹#›

‹#›

© Novartis Pharma AG 5/2014 192144

Changes in disability progression shown here were measured using the EDSS scale. % change is vs comparator arm. *p<0.05; **p<0.01; ***p<0.001 vs placebo. †Number of Gd+ lesions or number of new / newly enlarged T2 lesions. ARR, annualised relapse rate; conf., confirmed; IM, intramuscularly; NS, not significant; RRMS, relapsing–remitting MS. 1. From N Engl J Med; Kappos L et al. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing

Multiple Sclerosis, 362: 387–401. Copyright © (2010) Massachusetts Medical Society. Reproduced with permission from Massachusetts Medical Society; 2. Reproduced from Lancet Neurol 13(6) Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, Li B, Cappiello L, von Rosenstiel P, Lublin FD. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. pp545-56. ©2014 with permission from Elsevier; 3. Calabresi PA et al. Poster 015 presented at AAN 2012; 4. From N Engl J Med; Cohen JA et al. Oral Fingolimod

or Intramuscular Interferon for Relapsing Multiple Sclerosis, 362: 402–415. Copyright © (2010) Massachusetts Medical Society. Reproduced with permission from Massachusetts Medical Society

-82%*** (Gd+)

-74%*** (T2)

-30%* (3-mo conf.)

-37%* (6-mo conf.)

-70%*** (Gd+)

-74%*** (T2)

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

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

-55%*** (Gd+)

-35%** (T2)

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

–

Fingolimod in MS: efficacy from Phase III studies

FREEDOMS1

2 years, RRMS(n =1272)vs placebo

FREEDOMS II2,3

2 years, RRMS(n = 1083)vs placebo

TRANSFORMS4

1 year, RRMS(n = 1292)vs IFNβ-1a IM

0 24Time (months)

0.0

–0.4

–0.6

–1.4

-32%***

–0.2

–0.8

Me

an

cha

ng

e in

bra

in

volu

me

(%

)

–1.2

–1.0

12

***n = 368

n = 359

n = 357

n = 331

0 24Time (months)

0.0

–0.4

–0.6

–1.4 -35%***

–0.2

–0.8

–1.2

–1.0

126

*

**

***

Me

an

cha

ng

e in

bra

in v

olu

me

(%

)

Time (months)0 24

0.0

–0.4

–0.6

–1.4 -33%***

–0.2

–0.8

–1.2

–1.0

126

****

***

n = 266

n = 249

Me

an

cha

ng

e in

bra

in v

olu

me

(%

)

BRAIN VOLUME LOSS

DISABILITY PROGRESSIONLESIONS†RELAPSES

1 20.00

0.10

0.20

0.30

0.40

0.33 0.1

6

East

AR

R

IFNβ-1a IM(n = 431)

Fingolimod 0.5mg

(n = 429)

-52%***

AR

R

1 20.00

0.10

0.20

0.30

0.40

0.40

0.21

AR

R

Placebo(n = 355)

Fingolimod 0.5mg

(n = 358)

-48%***

AR

R

1 20.00

0.10

0.20

0.30

0.40

0.40

0.18

AR

R

Placebo(n = 418)

Fingolimod 0.5mg

(n = 425)

-54%***A

RR

Data are presented from separate clinical trialsCaution is required when indirectly comparing studies due to differences in trial designs and populations

‹#›

Fingolimod 0.5mg

(n=425)

Placebo

(n=418)

All adverse events

Patients with ≥1 event 401 (94%) 387 (93%)

Study drug discontinuation because of adverse event

32 (8%) 32 (8%)

Serious adverse events

Patients with ≥1 event 43 (10%) 56 (13%)

Deaths 0 (0%) 2 (<1%)

Most common adverse events (increased incidence in fingolimod group vs placebo)

Headache 107 (25%) 96 (23%)

Elevated liver enzyme levels 67 (16%) 21 (5%)

Influenza virus infection 55 (13%) 41 (10%)

Diarrhoea 50 (12%) 31 (7%)

Back pain 50 (12%) 29 (7%)

Fatigue 48 (11%) 45 (11%)

Cough 43 (10%) 34 (8%)

Incidence of adverse events in FREEDOMS

Safety Profile

This is not a complete list; please refer to prescribing information for full information. Gilenya® 0.5mg/day is the only dose approved for the treatment of MS. Kappos L et al. N Engl J Med 2010; Novartis. Gilenya® Summary of Product Characteristics.

Treatment initiation results in transient decreases in heart rate and may be associated

with atrioventricular conduction delays

In clinical trials, macular oedema occurred in 0.4% of fingolimod patients

Lower respiratory tract infections were more common compared to placebo

Liver enzyme elevations observed, primarily during first 12 months of treatment

Vaccination may be less effective during, and for up to 2 months after, treatment

Hypertension was reported for 6.1% of fingolimod patients vs 3.8% placebo patients

There are very limited data on the use of fingolimod in pregnant women; pregnancy

should be avoided while on treatment

Safety signals of note (as per Gilenya Risk Management Plan)

NICE/ NHSEng - Positioning

• First line ABCR/BRACE/Tecfidera/Aubagio/Lemtrada

• Second line - highly active - Gilenya/ Lemtrada

• n.b. Gilenya post ABCR/BRACE

• RES MS - Tysabri/ Lemtrada

Efficacy

The landscape

Burden of Therapy for Patient

Ale

mt

uzu

mab

Fingolimod

BG12

Teriflunomide

NatalizumabJCV+

NatalizumabJCV-

Mitoxantrone

Questions