Latest trial results and BartsMS updates

Ben Turner

TREATMENT PYRAMID

STOP

SAVE

REPAIR

RESTORE

ANTI-INFLAMMATORY

INDUCTION

Lemtrada

ESCALATION

First Line

Avonex

Betaseron

Extavia

Rebif

Glatiramer Acetate

Aubagio

Tecfidera

Tysabri

Second Line

Gilenya

Tysabri

Increasing

Efficacy/

Side-Effect Risk

RRMS = Considered Cost-Effective Most PPMS/SPMS = Considered Non Cost-Effective

CHOICE

No Evidence of

Disease Activity

4

Daclizumab High-Yield Process (DAC HYP): First in Class IL-2 Immunomodulator

4

IL2Rβ (CD122) γcommon

(CD132)

α IL-2

β γ

IL-2

β γ

High Affinity

IL-2 Receptor IL2R (CD25)

CD, cluster of differentiation; IL, interleukin; NK, natural killer. 1. Depper JM et al. J Immunol. 1983;131:690-696; 2. McDyer JF et al. J Immunol. 2002;169:2736-2746; 3. Wuest SC et al. Nat Med. 2011;17:604-610; 4. Bielekova B. Proc Natl Acad Sci. 2006;103:5941-5946; 5. Martin JF et al. J Immunol. 2010;185:1311-1320; 6. Perry JSA et al. Sci Transl Med. 2012;4:145ra106.

Intermediate Affinity

IL-2 Receptor

•DAC HYP selectively blocks the high-affinity IL2R by binding the subunit (CD25) • Promotes a shift of IL-2 signaling towards the

intermediate-affinity IL-2R

Biological impact of DAC HYP • Inhibition of activated T cell responses1−3

• Expansion of CD56bright NK cells4,5

•Normalization of lymphoid tissue inducer cell numbers6

5

Annualized Relapse Rate (ARR)

0.393

0.216

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

IFN beta-1a 30 mcg DAC HYP 150 mg

45% Reduction (95% CI: 35.5%, 53.1%) p<0.0001

5

(n=922) (n=919)

AR

R

Estimated from a negative binomial regression model adjusted for baseline relapse rate, history of prior IFN beta use, baseline EDSS (≤2.5 vs > 2.5) and baseline age (≤35 vs >35). Patients were censored at the earliest of the following events: 1) start of alternative MS medication, 2) 180 days post treatment discontinuation or 3) end of treatment period. CI, confidence interval.

Source doc: 205ms301-efficacy-2014-08-04 Adobe p. 6/doc p. 1

6

0

0.1

0.2

IFN beta-1a 30 mcg (n=922)

DAC HYP 150 mg (n=919)

0

0.1

0.2

IFN beta-1a 30 mcg (n=922)

DAC HYP 150 mg (n=919)

3-Month and 6-Month Confirmed Disability Progression

Risk reduction: 16%; p=0.16

Proportion with progression Week 48: 6% vs. 8% Week 96: 12% vs. 14% Week 144: 16% vs. 20%

BL 12 24 36 48 60 72 84 96 108 120 132 144 Time on study (weeks)

BL 12 24 36 48 60 72 84 96 108 120 132 144 Time on study (weeks)

Risk reduction: 27%; p=0.0332

Proportion with progression Week 48: 4% vs. 7% Week 96: 9% vs. 12% Week 144: 13% vs. 18%

3-month* 6-month†

Pro

po

rtio

n o

f p

atie

nts

wit

h

con

firm

ed

pro

gres

sio

n o

f d

isab

ility

3-month disability Source doc: 205ms301-efficacy-2014-08-04 Adobe p. 132/doc p. 127 1-0.84=16%

6-month disability Source doc: t-ef-dxprog-6mo-edss p.1 and 2 1-0.73=27%

*3-month confirmed: Patients censored after tentative progression (n=67) analyzed per primary method in the statistical analysis plan: all imputed as non-progressors; †6-month confirmed: Patients censored after tentative progression (n=108) imputed per observed rate in trial; tertiary endpoint. Estimated proportions are the average over imputed datasets. For both endpoints risk reductions based on Cox proportional hazards model adjusted for baseline EDSS, history of prior IFN use, and age.

The Reduction in Gd-Enhancing T1 Lesions by OCR Is Maintained Through 144 Weeks

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

0 4 8 12 16 20 24 48 72 96 120 144

Me

an

nu

mb

er

T1

Gd

-en

ha

nc

ing

le

sio

ns

Primary endpoint: OCR vs placebo1

Weeks

* *

1. Kappos L, et al. Lancet. 2011;378(9805):1779–87; 2. Kappos L, et al. Abstract presented (P362) ECTRIMS 2012 , October 12

OCR 600 mg arm (n=55)

OCR 1000 mg arm (n=55)

Placebo (n=54)

IFN-β1a (n=54)

- ‘Core Study' (0–96 weeks) - ‘Follow-Up' (97–144 weeks)a

*p<0.0001 for both OCR doses vs placebo, N (for primary analysis): Placebo=54, OCR 600 mg=51, OCR 1000 mg=52, IFN-β1a=522

aPatients who withdrew during earlier treatment cycles were also included in the follow-up periods

Patients with baseline MRI

Ocrelizumab Significantly Reduced ARR by Week 24 (ITT)

0.0

0.2

0.4

0.6

0.8

1.0

Placebo

(n=54)

IFN-β1a

(n=54)

p=0.0019

p=0.0136

OCR 600 mg

arm (n=55)

OCR 1000 mg

arm (n=55)

0.213 0.127

0.557 62% 77%

Ad

jus

ted

AR

R*

(95

% C

I)

*Adjusted for geographical region. CI, confidence interval.

0.364

ANTI-INFLAMMATORY

HEMATOPOEITIC STEM CELL THERAPY (HSCT)

INDUCE & STORE = CD34+ STEM CELLS REMOVE IMMUNE SYSTEM (DRUGS/ANTIBODIES) RE-BOOT WITH NEW IMMUNE-SYSTEM

Third Line-ULTIMATE INDUCTION THERAPY

RELAPSING-REMITTING DISEASE: IMPROVED EDSS: IMPROVED MRI LESIONS REDUCED PROGRESSIVE DISEASE (>10 YEARS): NO IMPROVEMENT IN EDSS INECTION RISK: HIGH FATALITIES: NO EVIDENT (MORTALITY RATE USED TO BE ~5%) IS THIS ANY BETTER THAN ALEMTUZUMAB?:NEED A TRIAL

ANTI-INFLAMMATORY

CURRENT TRIALS AT UCLP

CHARCOT PROJECT INSPIRE TRIAL ANTI-VIRAL THERAPY: RESULTS EXPECTED Q2 2015 CD19 B CELL DEPLETING

NEUROPROTECTION

PHARMA-LED PHASE III TRIALS COMPLETING SOON Target Treatment of Progressive MS

• GILENYA/FINGOLIMOD: SPHINGOSINE-1-PHOSPHATE RECEPTOR MODULATOR S1P1R modulation inhibits white blood cell targeting the cns S1P5R modulation inhibits glial cells in the brain (results April 2015)

• OCRELIZUMAB: CD20 B CELLS DEPELETING MONOCLONCAL ANTIBODY Deplete B cells in the brain to stop grey matter lesions

• TYSABRI/NATALIZUMAB: (ASCEND TRIAL) CD49d ALPHA 4 INTEGRIN BLOCKING ANTIBODY Inhibits white blood cells from entering the brain/anti-inflammatory

• MD1003: SUPER ACTIVE BIOTIN/VITAMIN H (Results April 2015) Redox modulation: increases nerural energy in mitochondria

GOOD NEWS: TRIAL EXTENSION UNDERWAY

BAD NEWS: TRIAL IN PPMS APPEARS TO HAVE FAILED-Based on financial reports GOOD NEWS: OUR PROGRESSIVE EAE MODELS PREDICTED THIS

NEUROPROTECTION

INVESTIGATOR-LED PHASE II TRIALS Target Treatment of Progressive MS

• RILUZOLE: ION CHANNEL/GLUTAMATE RECEPTOR BLOCKER blocks glial cell activity/protects demyelinated nerves

• AMILORIDE: ION (ACID SENSISING ION CHANNEL) BLOCKERS IN OPTIC NEURITIS

• OXCARBAZEPINE: ION (SODIUM CHANNEL BLOCKER) (USED IN ADDITION TO CURRENT DMT) Blocks glial cell activity/protects demyelinated axons

• AMILORIDE: ION (ACID SENSING ION CHANNEL) BLOCKER blocks glial cell activity/protects demyelinated nerves

• FLUOXETINE: (PROZAC). SEROTONIN RE-UPTAKE INHIBITOR Inhibits astrocyte activity

• PHENYTONIN: SODIUM CHANNEL BLOCKER IN OPTIC NEURITIS Like oxcarbazepine but can be loaded (administered) quickly

NEUROPROTECTION

OPTIC NEURITIS (PHENYTOIN) STUDY Target Treatment of Progressive MS

Retina (Back of Eye)

As axons in optic nerve as damaged the neurons in the retina are lost and the retina thins (red layer=retinal nerve fibre layer. Orange = ganglion cell layer + inner plexiform layer

Too Late?

Amiloride Anti-LINGO

Trial

Phenytoin Trial

Trial Result Published in April (Dr Raj Kapoor)

Sad Kapoor

(Neuro)

Trial Fails

Happy Kapoor

(neuro)

Trial Success

Gabilondo et al.2015 Ann Neurol

REPAIR

REMYELINATION CLINICAL TRIALS IN MULTIPLE SCLEROSIS

• BEXAROTENE: RXR ANTAGONIST

• CLEMASTINE: ANTI-CHOLINERGIC, ANTI-HISTAMINE H1 RECEPTOR

• GSK239512: HISTAMINE H3 RECEPTORANTAGONISTS

• B11B033: ANTI-LINGO1 MONOCLONAL ANTIBODY

B11B033: ANTI-LINGO1 TREATMENT IN OPTIC NEURITIS

Full Results published in April but Headline Results Reported

Trend for Optic Nerve Signal to increase suggestive of Remyelination (P=0.0504)

Retinal Nerve Fibre Layer Not affected (Treatment not started for about a month)

• OLFACTORY ENSHEATHING CELLS

• Neurorestoration may be Feasible

NEURORESTORATION

Tabakow P et al. Cell transplant 2014

• STEM CELLS TRIALS ONGOING IN MS