Gavin Giovannoni

Version 2.0

Disclosures

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-Serono, Novartis, Roche, Synthon BV and Teva.

Spoilt for choice

Evolving 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)

Glatiramer acetate40 mg/mL2015 (RMS)

Ocrelizumab**2017 (RMS/PPMS)

Oral Cladribine2017 (RMS)

2018

BMT/HSCT#

1997 (RMS)

Mitoxantrone*2000 (RMS/R-SPMS)

Immune reconstitution therapies (IRTs)Maintenance treatments

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

2019

Siponimod2019 (RRMS/SPMS)

Alem, alemtuzumab; Clad, cladribine tablets; DMF, dimethyl fumarate; Fingo, fingolimod; HDA, high disease activity; GA, glatiramer acetate; *HSCT, hematopoietic stem cell transplantation; IFN beta, interferon-beta; Mitox, Mitoxantrone; Nz, natalizumab; Ocre, ocrelizumab; RES, rapidly-evolving severe; Teri, teriflunomide

NHS treatment ladder

RES Nz CladHDA Fingo Clad

Level 1

Level 2

Level 3Active Ocre

HDA Clad

HDA Fingo Clad

ActiveHSCT*

Alem OcreRES Nz Mitox

RES Nz Mitox HSCTmaintenanceIRT

Active

IFN beta

Teri

GA

DMF

Ocre

Alem

Alem

Alem

Alem

Therapeutic targets

Prognostic profiling

Different therapeutic strategies

𝛃

Therapeutic approaches

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

Prognostic score1. Age of onset (<40 vs. >40 years) (1)2. Sex (F vs. M) (1)3. Sites: unifocal vs. multifocal onset (1)4. System:

a. Motor: no vs. yes (1)b. Cerebellar: no vs. yes (1)c. Bladder: no vs. yes (1)d. Cognition

i. Impairment: no vs. yes (1)ii. Learner: yes vs. no (1)

5. Recovery: complete vs. partial or no recovery from initial relapses (1) 6. Relapse rate: low/ ≤ 2 vs. high / >2 in the first 2 year (1)7. Early disability: EDSS < 3.0 vs. EDSS ≥ 3.0 within 5 years (1)8. MRI

a. Baseline lesion load: low / <9 T2 vs. ≥ 9 T2 lesions (1)b. Active: no Gd-enhancing vs. Gd-enhancing lesions (1)c. Posterior fossa lesions: no vs. yes (1)d. Spinal cord lesions: no vs. yes (1)e. Brain atrophy: no vs. yes (1)

9. Retinal thinning OCT: no vs. yes (1)10. CSF

a. OCBs (oligoclonal IgG bands): no vs. yes (1)b. Raised neurofilament levels: no vs. yes (1)

11. Vitamin D levels: low vs. normal (1)12. Smoker: no vs. yes (1)13. Comorbidities (diabetes/prediabetes, hypertension, hypercholesterolaemia, obesity): no vs. yes (4)

(25)

<30% good prognosis

30-50% intermediate prognosis

>70% poor prognosis

Adapted from Miller et al., Lancet Neurology 2005: 4; 281-288

ImmunosuppressionA reduction of the activation or efficacy of the immune system

This definition refers to short-term (IRTs) and long-term persistent immunosuppression (maintenance).

For a drug to be considered an immunosuppressant it should cause:

1) significant lymphopaenia2) be associated with opportunistic infections3) reduce the antibody response to vaccines4) be associated with secondary malignancies

1) Interferon-beta2) Glatiramer acetate3) Mitoxantrone4) Natalizumab (selective compartment)5) Fingolimod, Siponimod & other S1P

modulators6) Teriflunomide7) Dimethyl fumarate8) Alemtuzumab9) Ocrelizumab (Anti-CD20)

10) Cladribine (purine analogue)

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

ImmunosuppressionContinuous (e.g. natalizumab, fingolimod) Short-term (e.g. alemtuzumab, cladribine, HSCT)

Basal Cell Ca

Zoster

Cumulative Risk Frontloading Risk

Listeria

TB

Nocardia PCP

Lymphoma

Cryptococcosis

2° autoimmunity post- Az

Acute immunosuppression: innate and T-cellChronic immunosuppression

Derisking immunosuppressionBaseline

1. FBC - Leukocytes / platelets2. LFTs, U&E, TFTs, Urine3. Pregnancy tests4. Immunoglobulin levels5. Serum protein electrophoresis6. Serology

a. JCVb. HIV-1&2c. Hepatitis B&Cd. VZVe. Syphilisf. TB Elispot

g. Measles, mumps & rubella7. Cervical smear / HPV-PCR8. Vaccinations

a. VZVb. Pneumococcus, Meningococcus,

H. influenzae Bc. HPVd. MMR

9. MRI10. LP - CSF analysis sequencing11. Listeria, PCP, Nocardia prophylaxis

a. Dietb. Prophylactic antibiotics

Infusion-DMTs & IRTs

1. Infusion reactionsa. Corticosteroidsb. Antihistaminesc. Antipyretics

2. Antibioticsa. Anti-herpes

i. Valaciclovirii. Famciclovir

b. Listeria/PCP prophylaxisi. Co-trimoxazole

Monitoring

1. Bloodsa. FBC - leukopaeniab. TFTs, LFTs, U&E, …..

2. Urinea. Autoimmuneb. Renal dysfunction

3. MRIa. Disease activityb. PML

4. Infectiona. Serologyb. CSF

5. Disease activity6. Pregnancy7. Malignancy

a. Skin, Cervical, Breastb. Etc.

1

2

3

Natalizumab

PML

Giovannoni et al. ECTRIMS 2018. P604

External Interval dosing (EID), Zhovtis et al. ACTRIMS 2018

Alemtuzumab

VZV TB Listeria Nocardia

Molluscum HPVCMV EBV

PCP Etc...

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

AVN

InnateImmunity

AdaptiveImmunity

aThrough 48 mo after first exposure. ITP, immune thrombocytopenia; GBM, glomerular basement membrane; mAb, monoclonal antibody.1. Alemtuzumab SmPC. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Wynn D, et al. Presented at: ECTRIMS; 2013; Copenhagen; P597;

3. Coles AJ, et al. Neurology. 2012;78:1069-1078. 4. Willis et al. 2016 Aug;22(9):1215-23.AVN = avascular necrosis, HPV = human papillomavirus, PCP = Pneumocystis carinii pneumonia, VZV = varicella zoster virus

.

Haemolytic anaemia

Goodpasture’s Syndrome

ITP Bullous Pemphigoid

Immune neutropenia

Grave’s orbitopathy

Neonatal hyperthyroidism

Acquired Haemophilia

Pernicious Anaemia

Pure red cell aplasia

Etc…

Cervical dysplasia4 MGUS4

+10% pre/malignant 6.1 yrs FUp

Live vaccines Hypersensitivity pneumonitis

DMT Sequencing - Giovannoni et al. Pract Neurol. 2016 Oct;16(5):389-93. Carry-over PML

2° autoimmunity

Grave’s disease

Stroke

Ocrelizumab

Carry-over PML Breast Ca VZV & herpesInfusion reactions

Lymphocyte kinetics

Rituximab-induced changes in hematolymphoid tissues

Control Anti-CD20 (rituximab)

H&E H&E CD79a

CD3 CD3Pax5 Pax5

CD79a

Cioc et al. Am J Clin Pathol 2008;130:604-612.

Pre-vaccination

Geo

met

ric m

ean

titre

(IgG

IU/m

L)

4 weekspost-vaccination

8 weekspost-vaccination

Anti-tetanus titre

Protective titre level

Triangles denote KLH administration. DMT, disease modifying treatment;Ig, immunoglobulin; IFN, interferon; KLH, keyhole limpet; OCR, ocrelizumab;PPV, Pneumococcal polysaccharide vaccine. 1. Stokmaier D, et al. Presented at AAN 2018 (Platform presentation S36.002); 2. Ocrelizumab Summary of Product Characteristics; Sept 2018.

Humoral responses to antigens present but attenuated following anti-CD20 (ocrelizumab) treatment

Positive response to number of S. pneumoniaeserotypes 4 weeks after 23-PPV administration

Number of S. pneumoniae serotypes

100

100

100

100

Prop

ortio

n of

pa

tient

s (%

)

≥2 ≥3 ≥4 ≥5 ≥12 A/California/7/2009(H1N1)

B/Phuket/3073/2013

A/Switzerland/9715293/2013

(H3N2)

B/Brisbane/60/2008

A/Hong Kong/4801/2014

2535

2233

2030

1018

45

3233

2531

2527

1216

56

Seroprotection to individual influenza strains

Post-administration week

Prior Week 4 Week 12Week 8

Geo

met

ric m

ean

titre

uni

ts (I

gM) IgM responses to KLH neoantigen

OCR (all)Control (IFN β or no DMT)

Reasoning by analogy

Relapses (NEDA-1)

Unreported relapses

Clinical disease progression (NEDA-2)

Subclinical relapses: focal MRI activity (NEDA-3)

Focal gray and white matter lesions not detected by MRI

Brain atrophy (NEDA-4)

Spinal fluid neurofilament levels (NEDA-5)

MS Iceberg - Treat-2-Target

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Treat early and long-term prognosis

www.msbrainhealth.orgImage 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.

Incr

easi

ng d

isab

ility

Time

Intervention at diagnosis

Intervention later

Potentialrange ofoutcomes

No treatment

Later intervention

Intervention at diagnosis

Cox estimates of the cumulative probability of reaching EDSS=6 according to age and the period of diagnosis after adjusting for age of diagnosis and the frequency of EDSS visits.EDSS, Expanded Disability Status Scale; HR, hazard ratio.

Capra R, et al. Mult Scler 2017;23:1757–1761.

The course of MS been improved by earlier diagnosis and the increased availability of disease-modifying therapies

100

80

60

40

20

0

15

25

35

45

55

65Age

Similar to reference rate

Reduced by 37% (HR 0.63, p=0.05)

Reduced by 46% (HR 0.54, p=0.02)

Follow-up too short to analyse

Patients with EDSS 6.0 at age 50:27% if diagnosed before 200015% if diagnosed after 2000

(p<0.001)

1991–1995 (n=118)

1980–1990 (n=96)

1996–2000 (n=240)

2001–2005 (n=278)

2006–2010 (n=327)

2011+ (n=265)

Reference rate

Prob

abili

ty o

f rea

chin

g ED

SS 6

.0

Rate at which patients reached EDSS 6.0:

Cox proportional hazards regression adjusted for propensity score.CI, confidence interval; EDSS, Expanded Disability Status Scale. Kavaliunas A, et al. Mult Scler 2017;23:1233–1240.

Prompt treatment initiation after diagnosis delays disability progression

0.6

0.7

0.8

0.9

1.0

Prop

ortio

n of

pat

ient

s su

rviv

ing

0 50 100 150 200Follow-up time (months)

<1 year

1–3 years

>3 years

Time from diagnosis to treatment initiation:

• Single-centre study in newly diagnosed patients with MS (n=639); median follow-up: 99 months• The risk of reaching irreversible EDSS 4.0 increased by 7.4% (95% CI: 4.8–10.1) for each year of treatment delay

Association of initial DMT with later

conversion to SPMS

Brown et al. JAMA. 2019;321(2):175-187.

PoorPrognosis

IntermediatePrognosis

GoodPrognosis

NormalAgeing

Natural History

PoorPrognosis

IntermediatePrognosis

GoodPrognosis

NormalAgeing

Low Efficacy DMTs

PoorPrognosis

IntermediatePrognosis

GoodPrognosis

NormalAgeing

High Efficacy DMTs

PoorPrognosis

IntermediatePrognosis

GoodPrognosis

NormalAgeing

The future(Combination therapies)

International policy initiative

www.msbrainhealth.orgDMT, disease-modifying therapy.

Images used with permission from Giovannoni G, et al. Brain health: Time matters in multiple sclerosis. 2015 www.msbrainhealth.org/report. Accessed 26 May 2016.

Aim is to encourage the widespread adoption of a therapeutic strategy that aims to maximize the lifelong brain health of every person with MS

Prevent end-organ damage

Goal: maximize lifelong brain health

Early referralAnd diagnosis Early treatment Comprehensive

economic approach

Monitoring

Swift action onevidence of

disease activity

Real-world evidence

Access to DMTs

Shareddecision-making

Lifestyle and other factorsGenerate Consult

Blueteq - Top 20 trusts % of each DMT

Slide courtesy of Joela Mathews, NHSE Blueteq database

NHS factors to consider in the management of MS1. Epidemiology of MS

a. Increasing incidence and prevalence of MS2. Quality Standards

a. NICEb. International Quality Standards

3. NHS & NHSE reconfigurationsa. Blueteqb. Reduction in prescribing centresc. Algorithm / MDTs Annual EDSSd. GIRFT / Right Care / STPs / Technology / etc.e. Innovationf. Long-term conditions & service models

g. Cost Improvement Programmes (Austerity)h. Manpower pressures (Brexit / Pensions / Burnout / etc.)

4. DMTsa. Increasing complexity of treatment and changing treatment strategyb. Increasing pharmacovigilance requirementsc. Treatment of primary and secondary progressive MS

5. Variance

Holistic management of MS

2000 Olympics Cycling Medals

2004 Olympics Cycling Medals

1996 Olympics Cycling Medals

Dave Brailsford - marginal gains

"If we break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together.”

"The whole principle came from the idea that if you broke down everything you could think of that goes into riding a bike, and then improved it by 1%, you will get a significant increase when you put them all together.” Dave Brailsford

Dave Brailsford - marginal gains

*

Marginal gains - addressing the unmet need

Therapeutic pyramid• Smoking• Exercise• Diet

○ Caloric restriction○ Intermittent fasting○ Ketogenic diet

• Sleep• Comorbidities• Infections

○ UTIs○ Periodontitis○ Sinusitis○ Respiratory

• Concomitant medications○ Anticholinergics

• Drugs○ Metformin

• Social determinants of health○ Social isolation○ Social capital

• HRT• Wellness

Anti-inflammatory

Neuroprotection

Remyelination

Neurorestoration

Anti-ageing

MS-specific targets Non-MS targets‘Brain Health’

Holistic management of MS

Conclusions• MS is still a bad disease

• Mortality, disability, unemployment, divorce, cognitive impairment, etc.• Early effective therapy is the only realistic option of preventing end-organ damage

• NEDA and T2T are current treatment target (zero tolerance)• Beyond NEDA we need to target end-organ damage (brain atrophy, CSF NF levels, etc.)

• Brain Health initiative• Are you prepared to join the challenge?• Pledge your support?• Be an early adopter?

• Marginal gains - MS and non-MS specific mechanisms• MSology has become a sub-specialty

• Chronic immunosuppression and its complications• NHS is providing some interesting challenges in managing MS in 2020

www.ms-res.org

www.clinicspeak.com

Back-up slides

ImmunosuppressionContinuous (e.g. fingo, siponimod, natalizumab)

1. Persistent immunosuppression2. Risk increases with time (cumulative)

a. Increase risk of PML (complex pathogenesis)b. Increased risk of other opportunistic infectionsc. Increased risk of secondary malignancy

3. Live vaccines contraindicated4. High-risk of exotic infections

a. Dengueb. Zikac. Etc.

5. Pregnancy not recommended6. Long-term burden of pharmacovigilance

Short-term (e.g. alemtuzumab, cladribine)

1. Short-term immunosuppression2. Risk short-term (front-loaded)

a. Low risk of PML

b. Low risk of other opportunistic infections

c. Low risk of secondary malignancy

3. Live vaccines not necessarily contraindicated4. Low-risk of exotic infections if travel occurs

after immune reconstitution

5. Pregnancy safe post immune reconstitution6. Less of a pharmacovigilance burden

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

Defining a cure: a working definition

Immunoablation and autologous HSCT for aggressive MS: a multicentre single-group phase 2 trial

Atkins et al. Lancet 2016; 388: 576–85