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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)