The Future of MS Therapy

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MS-Selfie 16-Jan-2023

Prof G

www.ms-selfie.org

Disclosures

No relevant conflicts of interest in relation to this specific presentation.

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Over the last 5 years I have received personal compensation for participating in advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from: Abbvie, Atara Bio, Biogen, Canbex, Sanofi-Genzyme, Genentech, GSK, MSD, Merck KGaA, Novartis, Roche, Synthon BV and Teva.

Black swan

Black Swan

The potential role of EBV in MS

‘ - EBV

Priming of latent autoimmunity

persistent EBV infection

1° EBV infection

direct CNS infection

dual infection model

e.g. HERV transactivation

‘hit-and-run’ hypothesis

Infectious mononucleosis

molecular mimicry

B-cell survival advantage

Multiple Sclerosis

other environmental factors/triggers

‘driver or cog’ hypothesis

Giovannoni et al Mult Scler Relat Disord. 2022 Dec;68:104434.

Memory B Cells are Major Targets for Effective Immunotherapy in MS

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Baker et al. EBioMedicine. 2017 Feb;16:41-50.

REBOUND ACTIVITY AFTER NATALIZUMAB/FINGOLIMOD WITHDRAWAL

Rigau et al. Neurology 2012;79:2214-6.

Alroughani et al. BMJ Case Rep. 2014 Oct 15;2014. pii: bcr2014206314.

Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal.

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Serafini et al. J Neuroimmunol. 2017 Jun 15;307:14-17.

Highly-active RRMS, severe neurologic impairment (EDSS 7)

Treated with natalizumab - EDSS 4.5

Due to severe depression, stopped Nz after 37 infusions.

3½ months later rapid disease worsening

Brain MRI showed >50 T2-lesions, mostly Gd-enhancing

JCV-PCR -ve in CSF

Rapidly worsened, died d17

PM active MS rebound

JCV-PCR -ve in brain

Rituximab vs. Fingolimod after Natalizumab

Alping et al. Ann Neurol. 2016 Jun;79(6):950-8.

Disclaimer: please note rituximab is not licensed to treat MS in Germany

Charcot Project: viral aetiology

HIV and lower risk of MS: beginning to unravel a mystery using a record-linked database study

Nexø et al. Epidemiology 2013; 24:331-2

Treatment of HIV and Risk of MS

Gold et al. JNNP August 4, 2014 as 10.1136/jnnp-2014-307932.

Raltegravir → RRMS (INSPIRE STUDY)

ClinicalTrials.gov ID: NCT01767701

Kaiser / VA

Canada / Sweden

Black Swan

70-75%

Saha & Robertson. DOI: 10.1158/1078-0432.CCR-10-2578 Published May 2011

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EBV & B-cell biology

Therapeutic strategies�and prognostic factors

Early intervention and long-term prognosis

www.msbrainhealth.org�Image reproduced with permission from Giovannoni G, et al. Brain health: Time matters in multiple sclerosis. 2015 Available at www.msbrainhealth.org/report Accessed 26 May 2016.

Early intervention with high efficacy DMTs and long-term prognosis

www.msbrainhealth.org version 2.0�Image reproduced with permission from Giovannoni G, et al. Brain health: Time matters in multiple sclerosis. 2015 Available at www.msbrainhealth.org/report Accessed 26 May 2016.

Increasing disability

Time

Low efficacy DMTs

No treatment

Low efficacy DMTs

High efficacy DMTs

Flipping the pyramid

#AttackMS study overview

Natalizumab IV + oral MP x5 days

Placebo IV +

oral MP x5 days

CIS/McDonald MS

(optic neuritis, brainstem or spinal cord)

MRI suggestive of demyelination (at least 2 lesions in typical location)

Primary objectives:

• To establish whether it is feasible to enrol people at first manifestation of a clinically isolated syndrome of demyelination (CIS), or McDonald MS, within 14 days
• To test Natalizumab (Tysabri^®) 300mg, intravenously over 24 weeks for safety, efficacy, and to advance mechanistic understanding in pwMS.

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Blinded phase

Open label

Baseline

W8

W4

CSF

n = 20/arm

Placebo

Nz

W12

W16

W24

W20

Primary outcome: lesion MTR

End of study

OCT & VEP

OCT & VEP

DMT

Nz as per routine care, or switch to different DMT

Randomisation within 14 days of symptom onset

Placebo

Nz

Nz

Nz

Nz

Nz

Nz

Nz

sNfL

MRI

Slide courtesy of Prof. Klaus Schmierer

No treatments between courses

Immune reconstitution

Immunodepletion

Immune reconstitution

Consolidation and/or maintenance therapy

Induction therapy (mitoxantrone followed by IFNbeta/GA)

MS

NEDA

High efficacy

induction therapy

MS in remission (long-term / ? cure)

MS in remission (long-term / ? cure)

Immune-reconstitution therapy (IRT) (mitoxantrone alemtuzumab, cladribine, HSCT)

MS

Course 1

Course 2

Immunodepletion

NEDA

Giovannoni G. Curr Opin Neurol. 2018 Jun;31(3):233-243.

✅

✅

?

?

Progression independent of relapse activity (PIRA) is evident in RRMS

NB: Patients were rebaselined according to a roving EDSS reference system vs a fixed study baseline;�*Defined as a relapse that was recorded from ≤30 days prior to the reference EDSS assessment to ≤30 days post progression assessment. �EDSS, Expanded Disability Status Scale; RRMS, relapsing-remitting MS;

Adapted from Kappos L, et al. Mult Scler 2018;24:963–973.

Cumulative probability (%)

100

90

80

70

60

50

40

30

20

10

0

0

24

48

72

96

120

144

168

192

216

240

264

288

Weeks from the first natalizumab infusion

Confirmed EDSS progression unrelated to concurrent relapse*

Overall confirmed EDSS worsening

37.1%

24.5%

~2/3

Analysis of 5,562 patients with RRMS in the Tysabri Observational Programme (TOP)

PIRA represented 66% �of overall confirmed disability worsening

Predictors of long-term outcome in subjects

with MS treated with interferon beta-1a

Bermel et al. Ann Neurol 2012.

Prentice Criteria for a surrogate endpoint

1. Baseline measurement are predictive of outcome
2. Changes in the measurement over time is predictive of outcome
3. Changes in the measurement to external forces (therapy) is predictive of outcome�

Prentice. Stat Med. 1989 Apr;8(4):431-40.

Predictors of long‐term disability accrual in relapse‐onset multiple sclerosis

Jokubaitis et al. MS-BASE .Annals of Neurology, 2016; 80(1):89-100.

Prentice Criteria for a surrogate endpoint

1. Baseline measurement are predictive of outcome
2. Changes in the measurement over time is predictive of outcome
3. Changes in the measurement to external forces (therapy) is predictive of outcome�

Prentice. Stat Med. 1989 Apr;8(4):431-40.

Ofatumumab (anti-CD20) vs. Teriflunomide (ASCLEPIOS I and II)

�focal inflammation vs. neurodegeneration (end-organ damage)

Hauser et al. ECTRIMS 2019

≠

Slides courtesy of Stephen Hauser.

Higher dose study designs in patients with RMS (MUSETTE) or PPMS (GAVOTTE)

• Immunoglobulin and oligoclonal bands in CSF will be assessed in a sub-study of up to 288 patients

^aComposite measure of disability progression based on worsening EDSS scores and 9-hole peg test and/or timed 25-foot walk test.

12w-cCDP, 12-week confirmed composite disability progression; CSF, cerebrospinal fluid; EDSS, Expanded Disability Status Scale; PPMS, primary progressive multiple sclerosis; RMS, relapsing multiple sclerosis.

• Patients with RMS or PPMS will be randomized (2:1) to either the approved 600 mg dose or the higher dose�(1200 mg [patients <75 kg] or 1800 mg [patients ≥ 75 kg]) administered every 24 weeks for ≥120 weeks
• Primary endpoint: 12w-cCDP (analysis performed after at least 205 events have occurred)^a

Study in patients with RMS (MUSETTE)

• Patient sample size, N=780
• Age: 18-55 years; EDSS score, 0 – 5.5
• Stratification for region, age, EDSS, weight

Study in patients with PPMS (GAVOTTE)

• Patient sample size, N=687
• Age: 18-55 years; EDSS score 3 – 6.5
• Stratification for region, age, sex, weight

Slides courtesy of Stephen Hauser.

Teriflunomide as a maintenance treatment after ocrelizumab induction (iTeri Study)

Teriflunomide 14mg daily PO

Ocrelizumab

(600mg ivi 6-monthly

RMS treated with ocrelizumab for at least 18 months (4 courses)

MRI suggestive of demyelination & CSF with OCBs

Randomised

Primary outcome: 24 months - CSF immunoglobulin light chain levels

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Secondary outcomes:

BVL 24 months relative to baseline

12 & 24 months - Plasma neurofilament levels (area under the curve)

Cortical gray matter atrophy

T1 lesion volume

MRI new T2 lesions (inflammation)

Proportion of subjects OCB-ve

Disease improvement (EDSS, T25W, 9HPT, SDMT, ….)

NEDA

Safety

Antibody response to FLU virus in year 2

` Plasma immunoglobulin levels at year 2

Barts-MS, version 1.0, 03-Oct-2019

Power exploratory n = ?? / arm

M0

M6

M12

M3

M9

M15

M18

M21

M24

Lumbar puncture & CSF

Lumbar puncture & CSF

Study

End

Relapses

Unreported relapses

Clinical disease progression

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions �not detected by MRI

Brain atrophy (whole brain/regional) / SELs

Spinal fluid and blood neurofilament levels

NEDA

End-organ damage

Biomarkers

Spinal fluid oligoclonal bands / CNS B-cell follicles

Treat-2-Target - beyond NEIDA (no evident inflammatory activity)

Neurorestoration

Remyelination

Neuroprotection

Optimising anti-inflammatories

Brain Health

Smouldering MS

Pathological drivers of smouldering MS

TSPO PET, translocator protein-18 kDa positron emission tomography

1. Mahad DH, et al. Lancet Neurol 2015;14:183–193; 2. Colasanti A, et al. J Nucl Med 2014;55:1112–1118;�3. Absinta M, et al. Neurology 2015;85:18–28; 4. Dal-Bianco A, et al. Acta Neuropath 2017;133:25–42�5. Laule & Moore. Brain Pathol, 28 (5), 750-764 Sep 2018. �6. Huhn et al. Front. Neurol., 11 February 2019 | https://doi.org/10.3389/fneur.2019.00084

Potential imaging markers

Pathological drivers

Meningeal enhancement³

TSPO PET �binding²

Slowly expanding�lesions⁴

Myelin water �imaging⁵

Sodium

imaging⁶

Demyelination

Hot microglia

B & plasma cells

Iron

Energy deficits

Viruses

Cladribine induces long lasting OCB disappearance in RMS patients: 10-year observational study

Rejdak et al. Mult Scler Relat Disord. 2019 Jan;27:117-120.

CNS plasma cell and B cell-targeted treatments for MS

Baker et al. Mult Scler Relat Disord. 2019 Jun 26;35:19-25.

1. Cladribine
2. BTKi
1. Evobrutinib
2. Tolebrutinib
3. Fenebrutinb
4. Remibrutinib
5. Orelabrutinib
6. Etc.
3. Proteasome inhibitors
• Ixazomib
4. CD19 targeted CART

Evobrutinib reduced SEL volume in a dose-dependent manner

^*P value <0.05�BID, twice daily; CI, confidence interval; QD, once daily; SEL, slowly expanding lesions.

SEL volume decreased with increasing evobrutinib dose relative to the placebo

Favors evobrutinib

Favors placebo

Decreasing SEL volume (mm³)

Increasing SEL volume (mm³)

Doug Arnold, AAN 2022; slide courtesy of Merck KGaA

Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus

Mackensen et al. Nat Med. 2022 Nov 3. doi: 10.1038/s41591-022-02091-9.

Phenytoin for neuroprotection in patients with acute optic neuritis:�a randomised, placebo-controlled, phase 2 trial

Phase 3 add-on neuroprotection

study

Raftopoulos et al. Lancet Neurol. 2016 Mar;15(3):259-69.

Agents in development or completed PoC trials:�

1. High-dose biotin: MD1003 (SPI2 phase 3)
2. Benztropine: anticholinergic
3. Opicinumab: anti-LINGO-1 (AFFINITY-2b -ve)
4. Clemastine: anticholinergic (M4) (➝ phase 2 + metformin)
5. GSK239512: H3 receptor antagonist (phase 2)
6. IRX4204 & bexarotene: RXR agonist (phase 2)
7. rHIgM22: oligodendrocyte target
8. VX15: anti-SEMA4D
9. Elezanumab: anti-RGMa (RMS/PMS +ve phase ➝ phase 3)

Figure courtesy of Sharmilee Gnanapavan.

Remyelination

Mistake / Warning: active add-on rehabilitation & exercise

Exercise / Rehabilitation Essential

Axonal�sprouting

Axonal�remodelling

Synaptogenesis

Cortical�Plasticity

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

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

Courtesy Paul Matthews�Imperial College.

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

*

Rehabilitation

Non-MS targets�‘Brain Health’

• Smoking
• Alcohol
• Exercise
• Aerobic
• HIIT
• Diet / metabolic hacking or enhancement
• Caloric restriction
• Intermittent fasting
• Ketogenic diet
• Nutriceuticals
• Sleep hygiene
• Comorbidities
• Metabolic syndrome
• Head injuries
• Infections
• UTIs
• Periodontitis
• Sinusitis
• Respiratory
• Concomitant medications
• Anticholinergics
• Anti-ageing medications
• HRT
• Metformin
• Social determinants of health
• Low levels of education
• Poverty & deprivation
• Social isolation
• Social capital
• Etc.
• Wellness

The holistic management of MS

Therapeutic pyramid

Anti-inflammatory

Neuroprotection

Remyelination

Neurorestoration

MS-specific targets

Essential

Add-on

Anti-ageing

Brain Health�Physical Health

Prehabilitation

Exercise diminishes plasma neurofilament light chain and reroutes the kynurenine pathway in MS

Joisten et al. Neurol Neuroimmunol Neuroinflamm. 2021 Mar 29;8(3):e982.

Moderate continuous training (MCT)

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vs.

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High intensity interval training (HIIT)

*

Metformin and fasting restores CNS remyelination

capacity by rejuvenating aged stem cells

Neumann et al. Cell Stem Cell 2019; 25(4):473-485.

Vasconcelos et al. Front Pharmacol. 2019 Feb 4;10:33.

*

Diet - prolonged fasting

Image from; Department of Biochemistry and Nutrition, University of New England.

*

• Evaluate the efficacy and safety of opicinumab as an add-on therapy to anti-inflammatory disease-modifying therapies (DMTs) in participants with relapsing MS.

Efficacy and Safety of Opicinumab in Participants with Relapsing Multiple Sclerosis: A Randomized, Placebo-Controlled, Phase 2 Trial (AFFINITY Part 1)

Calabresi P,¹ Giovannoni G,² Hartung H-P,^3-6 Naismith RT,⁷ Fox R,⁸ Sormani M-P,⁹ Arnold DL,^10,11 Valis M,¹² Newsome SD,¹ Bartholomé E,¹³ Belkin MI,¹⁴ Cheng W,¹⁵ �Ke J,¹⁵ Riester K,¹⁵ Javor A,¹⁵ Lyons J,¹⁵ Bradley DP,¹⁵ Fisher E,¹⁵ Naylor ML,^15* Belachew S,¹⁵ Deykin A,¹⁵ Franchimont N,¹⁵ Zhu B,¹⁵ on behalf of the AFFINITY study investigators

¹Johns Hopkins Hospital, Baltimore, USA; ²Barts and The London School of Medicine and Dentistry, London, UK; ³Heinrich-Heine University, Dusseldorf, Germany; ⁴Brain and Mind Center, University of Sydney, Sydney, Australia; ⁵Medical University of Vienna, Vienna, Austria; ⁶Palacky University Olomouc, Olomouc, Czech Republic; ⁷Washington University, St. Louis, USA; ⁸Cleveland Clinic, Cleveland, USA; ⁹University of Genoa, Genova, Italy; ¹⁰NeuroRx Research; ¹¹Montreal Neurological Institute, McGill University, Montreal, Canada; ¹²Charles University in Prague, Hradec Králové, Czech Republic; ¹³CHU-Tivoli, La Louvière, Belgium; ¹⁴Michigan Institute for Neurological Disorders, Farmington Hills, USA; ¹⁵Biogen, Cambridge, MA, USA.

*with Biogen at the time of analysis.

• AFFINITY Part 1 did not meet the primary or key secondary efficacy endpoints.
• Pre-specified subgroup analyses showed potential efficacy signals on ODRS in participants with older age (≥40 y), higher EDSS (≥3.0), longer disease duration (≥6 y), and receiving dimethyl fumarate as anti-inflammatory DMT.
• No clear efficacy signals were observed on pre-specified brain MRI endpoints.
• Safety data from AFFINITY Part 1 were consistent with known safety profile of opicinumab. No new safety signals were observed.
• Further analyses of the opicinumab AFFINITY and SYNERGY datasets regarding patient population and MRI biomarkers may inform the design of future trials aiming at enhancing remyelination in MS.

Acknowledgments: This study was sponsored by Biogen (Cambridge, MA, USA). Writing and editorial support for the preparation of this poster was provided by Excel Scientific Solutions (Fairfield, CT, USA): funding was provided by Biogen.

DMF = dimethyl fumarate; EDSS = Expanded Disability Status Scale; MRI: magnetic resonance imaging; MS: multiple sclerosis; ODRS = Overall Disability Response Score.

Click on a button below to navigate through the poster

Introduction

Methods

Results

Objective

Conclusions

147 | 37th Congress of the European Committee for Treatment & Research in Multiple Sclerosis | October 13-15, 2021

Conclusions

DMF = dimethyl fumarate; DMT = disease-modifying therapy; IFN-β = interferon beta; NAT = natalizumab; ODRS = Overall Disability Response Score.

• Among the 3 DMT subgroups, the DMF subgroup showed the numerically largest ODRS difference between opicinumab and placebo groups.

(4 of 6)

*Adjusted mean of ODRS at 72 weeks in opicinumab group and in placebo group.

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Results

Introduction

Methods

Results

Conclusions

Vascular Comorbidity Accelerates Disability Progression!

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

6yrs

Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial

Chataway et al. Lancet 2014; 383: 2213–21.

BSI (Boundary Shift Integral)

41

Holistic management of MS

Rehabilitation

Non-MS targets�‘Brain Health’

• Smoking
• Alcohol
• Exercise
• Aerobic
• HIIT
• Diet / metabolic hacking or enhancement
• Caloric restriction
• Intermittent fasting
• Ketogenic diet
• Nutriceuticals
• Sleep hygiene
• Comorbidities
• Metabolic syndrome
• Head injuries
• Infections
• UTIs
• Periodontitis
• Sinusitis
• Respiratory
• Concomitant medications
• Anticholinergics
• Anti-ageing medications
• HRT
• Metformin
• Social determinants of health
• Low levels of education
• Poverty & deprivation
• Social isolation
• Social capital
• Etc.
• Wellness

The holistic management of MS

Therapeutic pyramid

Anti-inflammatory

Neuroprotection

Remyelination

Neurorestoration

MS-specific targets

Essential

Add-on

Anti-ageing

Brain Health�Physical Health

Prehabilitation

Conclusions

Conclusions

1. New data and insights are challenging the MS dogma
1. EBV is likely the cause of MS and driver of MS disease activity
2. Implications for prevention (vaccines) and treatment (antivirals and immunotherapy)
2. The ‘real MS’ is not relapses or focal MRI activity, but rather smouldering MS
• We need to treat beyond NEIDA to tackle end-organ damage
• Several pathological drivers or therapeutic targets
1. Chronic demyelination
2. Hot microglia or innate inflammation
3. Intrathecal B-cell and plasma cell activity
4. Energy deficits
5. Early ageing
3. Major implications for treatment
• We will be moving into an era of induction-maintenance and combination therapies
4. Holistic management of MS
• There is more to treating MS than tacking MS-specific mechanisms only
5. Faster adoption of therapeutic strategies

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Questions