ecf actelion satellite symposium treating ms beyond monotherapy

Treating MS beyond monotherapy

MS treatment history, current unmet needs

Prof. Gavin GiovannoniBarts and The London School of Medicine and Dentistry

Disclosures

Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Actelion, Atara Bio, Almirall, Bayer-Schering Healthcare, Biogen, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

The therapeutic landscape

1994 1996 20001998 2002 2004 2006 2008 2010 2012 2014

SC IFN beta-1b1995 (RMS)

IM IFN beta-1a1997 (RMS)

SC IFN beta-1a 1998 (RMS)

Natalizumab2006 (RRMS)

Glatiramer acetate20 mg/mL

2003 (RMS)Fingolimod

2011 (RRMS)

Alemtuzumab2013 (RRMS)Teriflunomide 2013 (RRMS)

2016

Dimethyl fumarate2014 (RRMS)Peginterferon beta-1a2014 (RRMS)

Daclizumab2016 (RMS)

Glatiramer acetate40 mg/mL2015 (RMS)

Ocrelizumab2017 (RMS/PPMS)

Oral Cladribine2017 (RMS)

2018

Neuroaxonal loss & failure of recovery

Dis

abili

ty

Time

Acute relapse-associated

axonal damageDelayed

relapse-associated neurodegeneration

Post-inflammatoryneurodegeneration

Ageing

days-weeks months-years years-decades decades

reserve threshold

1

2

4

3

*

Therapeutic hierarchy

1. Smoking2. Exercise3. Diet4. Sleep5. Co-morbidities6. Infections7. Concomitant medications8. Menopause - HRT

Residual deficits:• Walking distance >500m• Unable to run • Exercise induces intermittent sensory

symptoms in L arm• Mild urinary frequency

17-yr girl, myelitisJun-2000

1st-yr University L-optic neuritis

Feb-2001

clumsy left hand

Jan -2002

pins & needles in legs

Oct-2003

R optic neuritisMar-2004

Brainstem syndrome; diplopia and ataxia

Dec 2007

Cervical cord relapseweak L arm with pain

Jan 2008

Bladder dysfunction

depression, anxiety and

fatigue

Reduced mobility

Mild urinary frequency

No depression ,anxiety or fatigue

Fully mobile

NEDA (no evident disease activity)Feb-2008 to May-2014

IFN-betaFeb-2001

Natalizumab

Jan-2008

ED

SS

IFN-beta NatalizumabJun-2000 Nov 2017

6.0

3.5 3.5

JCV positive - index 2.9

2014-Bridging fingolimod


2015 - Alemtuzumab

2017 - Baby

Is this patient in long-term remission?





Feb-2001

clumsy left hand

Jan -2002

Oct-2003



Dec 2007


Jan 2008

Bladder dysfunction


fatigue

Reduced mobility



Fully mobile

NEDA (no evident disease activity)

Feb-2008 to May-2014

IFN-beta

Feb-2001

Natalizumab

Jan-2008

ED

SS


6.0

3.5 3.5




2015 - Alemtuzumab

2017 - Baby

✳ higher-efficacy

✳ neuroprotection

✳ safer

✳ anti-JCV

✳ remyelination

✳ neurorestoration

✳ unmet need

✳ comorbidities

Higher efficacy

Comparison of Switch to Fingolimod or Interferon Beta/Glatiramer Acetate in Active Multiple Sclerosis

He et al. JAMA Neurol. 2015;72(4):405-413.

Proportions of Patients Without Relapses in the Matched CohortsHR indicates hazard ratio.

Figure Legend:

Would interferon-beta, GA and fingolimod be more effective in combination than when used as a monotherapy?

✳ higher-efficacy

Reasoning by analogy

Crohn's Disease Rheumatoid Arthritis

Phenytoin neuroprotection acute optic neuritis

Phenytoin

Participants with AON N=86

Phenytoin (4 mg/kg OD)

Placebo

Randomised within 2 wks of symptom

onset

Treatment period

3 months

Monitoring period

3 months

Primary outcome measures

Primary outcome measure: RNFL thickness

RNFL thickness Macular volume

1. Kapoor R et al. Presented at AAN; Washington, USA; 2015; 2. https://clinicaltrials.gov/ct2/show/NCT01451593;

Neuroprotection

1. Kapoor R et al. Presented at AAN; Washington, USA; 2015; 2. https://clinicaltrials.gov/ct2/show/NCT01451593;

Neuroprotection

Should add-on protection become a standard of care in the management of MS?

✳ neuroprotection

*Adjusted for baseline characteristics.

13

Neuroprotection

Anti-JCV

I predict a future in which all patients who are JCV+ve are treated with an antiviral to clear them of the virus.

✳ anti-JCV

Alemtuzumab innate immunodeficiency

VZV TB Listeria Nocardia

Molluscum HPVCMV EBV

PCP Etc...

Thomas et al. Neurol Neuroimmunol Neuroinflamm 2016;3:e228;

AVN

AAN 2017, Boston

InnateImmunity

AdaptiveImmunity

AVN = avsacular necrosis, HPV = human papiloma virus, PCP = Pneumocystis carinii pneumonia, VZV = varicalle zoster virus

Safer

Combination of antiviral and antibacterial prophylaxis

✳ safer

Nogo, MAG, OMgP

Lingo-1-NgR-p75NTR

GAP-43

NCAM

Neuregulin

Agents in development or completed PoC trials:

1. Benztropine: anticholinergic

2. Opicinumab: anti-LINGO-1

3. Clemastine: anti-histamine/anti-cholinergi (M3)

4. GSK239512: histamine H3 receptor antagonist

5. IRX4204 & bexarotene: RXR agonist

6. rHIgM22: oligodendrocyte target

7. VX15: anti-SEMA4D

8. MD1003 (High-dose biotin): myelin biosynthesis

9. Elezanumab (ABT-555): anti-RGMa

Figure courtesy of Sharmilee Gnanapavan

Remyelination

▪ Fully human, anti-LINGO IgG1 antagonist monoclonal antibody.

▪ Phase 1 in healthy volunteers & MS subjects completed ▪ Phase 2 in Acute Optic Neuritis completed ▪ Phase 2 in Relapsing MS completed

▪ Multiple sclerosis▪ Other demyelinating diseases

▪ LINGO-1 selectively expressed in neurons and oligodendrocytes▪ negative regulator of oligodendrocyte differentiation, myelination, remyelination and

axonal regeneration▪ Blocking LINGO-1 by Opicinumab may enhance oligodendrocyte differentiation,

remyelination, and axonal regeneration

→

Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial.

Cadavid et al. Lancet Neurol. 2017 Mar;16(3):189-199.

RENEW1,2

Anti-LINGO-1(multi-centre)

Anti-LINGO-1 (100 mg/kg IV Q4W x 6)

Placebo (IV Q4W x 6)Participants with first episode of

unilateral AON (n=82)

Randomised within 4 weeks of symptom onset

Dosing period20 weeks

Assessments at24 and 32 weeks

3–5 days’ IV steroids

EoS follow-up 32 weeksPrimary outcome: VEP

Opicinumab - Estimated Overall Response Scores (± SE)

Larger and more durable treatment effect over 72 weeks demonstrated in a post hoc subpopulation defined by disease duration and baseline brain MTR & DTI-RD

SYNERGY efficacy population Post hoc subpopulationPlacebo (n = 91)10 mg/kg opicinumab (n = 94)

Placebo (n = 25) 10 mg/kg opicinumab (n = 21)

Ove

rall

resp

onse

sco

re (±

SE

)

Weeks Weeks

Sheikh S, et al., Poster Session 1, P718, MSParis2017

All MD1003Placebo-controlled

p=0.014*

n=42

n=91

n=82

n=41

*Mann-Whitney U test months

24-month-treatment with-MD1003 (high doses of biotin) in progressive multiple sclerosis: results of the MS-SPI trial extension phase

Tourbah, et al. AAN 2016

24-mth treatment with MD1003 (high-dose biotin) in progressive MS: MS-SPI trial ext. phase

Mean change in EDSS from baseline

Which patients will benefit from add-on remyelination therapies?

✳ remyelination

*

Axonal sproutingAxonal modelling Synaptogenesis Cortical Plasticity

Kerschensteiner et al. J Exp Med. 2004;200(8):1027-38.

Waxman. Nat Rev Neurosci. 2006;7(12):932-41.

Stampanoni et al. Mult Scler. 2017 Jul doi: 10.1177/1352458517721358.

Neurorestoration

Co-morbidities

Combination therapy with a cocktail of drugs targeting MS-related comorbidities.

✳ comorbidities

Vascular Comorbidity Accelerates Disability Progression!

Marrie et al. Neurology 2010;74:1041–1047.

Normal brain volume loss with age

Loss of brain reserve Schippling et al. J Neurol. 2017 Mar;264(3):520-528.

Anti-ageing

Combination therapy with antiageing treatments.

✳ antiageing

Optimising MS managementD

isab

ility

Time

Acute relapse-associated

axonal damageDelayed

relapse-associated neurodegeneration

Post-inflammatoryneurodegeneration

Ageing

days-weeks months-years years-decades decades

reserve threshold

1

2

Acute neuroprotection Remyelination

Chronic neuroprotectionAnti-ageingAnti-inflammatory

4

3

✳ combination therapy





Feb-2001

clumsy left hand

Jan -2002

Oct-2003



Dec 2007


Jan 2008

Bladder dysfunction


fatigue

Reduced mobility



Fully mobile

NEDA (no evident disease activity)

Feb-2008 to May-2014

IFN-beta

Feb-2001

Natalizumab

Jan-2008

ED

SS


6.0

3.5 3.5




2015 - Alemtuzumab

2017 - Baby

✳ higher-efficacy

✳ neuroprotection

✳ safer

✳ anti-JCV

✳ remyelination


✳ unmet need

✳ comorbidities

*

1. Smoking2. Exercise3. Diet4. Sleep5. Co-morbidities6. Infections7. Concomitant medications8. Menopause - HRT

Therapeutic hierarchy

n...,2 ,1

Conclusions

∙ MS is a complex disease

– Multiple immunological and cellular targets

– Combination therapies makes sense (complementary modes of action)

– Adopt strategies from other disease areas, e.g. rheumatology, gastroenterology, transplantation and oncology

∙ Biology underlying the recovery of function is complex and involve many biological processes

– Synaptic

– Axonal

– Cortical

– Interacts with systems biology (ageing, comorbidities, concomitant medications, exercise and lifestyle factors)

∙ Can we afford not develop combination therapies?

✳ higher-efficacy ✳ neuroprotection

✳ safer

✳ anti-JCV

✳ remyelination


✳ unmet need

Addressed by combination therapies

✳ comorbidities

✳ ageing

ecf actelion satellite symposium treating ms beyond monotherapy

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