How close are we to a cure in multiple sclerosis?

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, Bayer-Schering Healthcare, Biogen-Idec, 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.

Professor Giovannoni would like to acknowledge and thank numerous colleagues for providing him with data and/or slides for this, and other, presentations.

3

Window of therapeutic efficacy

Coles et al. J Neurol. 2006 Jan;253(1):98-108..

David Baker’s Animal Model

Jackson et al. J Neuropathol Exp Neurol. 2009;68(6):616-25.

Day 7Day 0

ctrl Day 29 Day 58

Day 105 Early-tolerisation Late-tolerisation

Hampton et al. J Neuroimmunol. 2008;201-202:200-11.Pryce et al. J Neuroimmunol. 2005;165(1-2):41-52.

Prevention of relapsing CREAE after three paralytic episodesdoes not inhibit secondary progression and deterioration of mobility

Pryce et al. J Neuroimmunol 2005.

Durable Efficacy in RRMS Patients Receiving Two Annual Courses of Alemtuzumab and

No Additional Treatment for 4 Years: Pooled Analysis of CARE-MS I and II

Edward J Fox,1 Douglas L Arnold,2,3 Jeffrey A Cohen,4 Gavin Giovannoni,5 Hans-Peter Hartung,6 Eva Havrdova,7 Krzysztof W Selmaj,8 Volker Limmroth,9

David H Margolin,10 Karthinathan Thangavelu,10 Alasdair J Coles11; on behalf of the CARE-MS Investigators

1Central Texas Neurology Consultants, Round Rock, TX, USA; 2NeuroRx Research, Montréal, Québec, Canada; 3Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; 4Cleveland Clinic, Cleveland, OH, USA; 5Queen Mary University of London, Barts and The London School of Medicine, London, UK; 6Heinrich-Heine University, Düsseldorf, Germany; 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 8Medical University of Łódź, Łódź, Poland; 9Klinik für

Neurologie und Palliativmedizin, Köln, Germany; 10Sanofi Genzyme, Cambridge, MA, USA; 11University of Cambridge School of Clinical Medicine, Cambridge, UK

AAN 2016Presentation S51.005

Hypothesis: Alemtuzumab Mechanism of Action May Explain Durability of Effect

7

3. Repopulation

BT

T-cellprecursor

Pre/Pro B cell

Lymphocyteprecursor

Stem cell

BT

Lymphocytes repopulate over time3,4

1. Selection

Alemtuzumab binds to CD52, a cell surface antigen present on T and B lymphocytes1,2

Plasma cells

Neutrophils

Lymphocyte precursor

CD52

Macrophages

CD52Monocytes

CD

52

CD52

CD52

CD52

CD52

T

CD

52

CD52

CD52

CD52

CD52B

2. Depletion

CD52 BCD52T

LymphocyteprecursorDepletes circulating T and B lymphocytes1,2

T B

• Following depletion, a distinctive pattern of T- and B-cell repopulation and a shift in cytokines toward a less inflammatory pattern may both contribute to durable efficacy in the absence of continuous treatment

1. Hu Y et al. Immunology 2009;128:260-70; 2. Rao SP et al. PLoS One 2012;7:e39416; 3. Cox AL et al. Eur J Immunol 2005;35:3332-42;4. Hill-Cawthorne GA et al. J Neurol Neurosurg Psychiatry 2012;83:298-304.

AAN 2016

Durable Efficacy on Disability Outcomes Through 5 Years in Patients Receiving Only the Initial 2 Courses of Alemtuzumab

Through Year 5:• 84% had no evidence of 6-month confirmed disability worsening• 43% achieved 6-month confirmed disability improvement

– Of these, 96% were free from 6-month confirmed disability worsening

8

AAN 2016

aEDSS score improvement (≥1.0-point decrease), or stability (≤0.5-point change) compared with baseline EDSS.Confirmed disability worsening: ≥1-point EDSS increase over 6 months.Confirmed disability improvement: ≥1-point EDSS decrease over 6 months for patients with EDSS ≥2.0 at core study baseline.

Mean EDSS Score Over 5 Years

No. ofPatients

445 440 444 440 444 418 417 409 403 395 381

0

Patients With Improved/Stable EDSS Scorea

No. ofPatients 444 417 403 381

89.9 89.4 87.187.3

Years 0–2

Years 0–3

Years 0–4

Years 0–5

≥1-Point improvementStable (≤0.5-point change)

Prop

ortio

n of

Pat

ient

s, %

Most Patients Receiving Only the Initial 2 Courses of Alemtuzumab Achieved NEDA Through 5 Years

9

AAN 2016

No. of Patients

254/370278/384297/407316/427

• 51% of patients achieved sustained NEDA over Years 3–5

NEDA (no evidence of disease activity): no evidence of clinical disease activity (relapse and 6-month disability worsening) and MRI disease activity (new Gd-enhancing T1 on current MRI and new/enlarging T2 hyperintense lesions since last MRI).

Prop

ortio

n of

Pat

ient

s, %

(95%

CI)

Proportion of Patients With NEDA Over 5 Years

Core Studies Extension Study

Alemtuzumab 12 mg (no retreatment or other DMT)

Slowing of Brain Volume Loss Through 5 Years in Patients Receiving Only the Initial 2 Courses of Alemtuzumab

• Median yearly BVL progressively decreased over 3 years and remained low in Years 4 and 5

10

Percentage BVL From Baseline

AAN 2016

Year

Med

ian

Cha

nge

From

B

asel

ine,

% (9

5% C

I)

No. of Patients 43

8432

430

407

384

373

Extension StudyCore Studies

Alemtuzumab 12 mg (no retreatment or other DMT)

Median Annual Brain Volume Change

Extension StudyCore StudiesNo. of Patients 432 429 407 378 358

Alemtuzumab 12 mg (no retreatment or other DMT)

Year

BPF=brain parenchymal fraction; BVL=brain volume loss

Tuohy t al. J Neurol Neurosurg Psychiatry 2014;0:1–8.

Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy

“Four alemtuzumab-treated patients (5%) fulfilled the definition of secondary progression of two consecutive SAD events.”

Autoreactive T Cell

Non-autoreactive T Cell

Autologous hemopoeitic stem cell (HSCT) or bone marrow transplantation (BMT)

Association of non-myeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis

Burt et al. JAMA. 2015 Jan 20;313(3):275-84

Please note that this was an open-label study and there were no treatment related deaths.

High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report

Nash et al. JAMA Neurol. 2015 Feb;72(2):159-69.

Atkins et al. Lancet. 2016 Jun 8. Pii: S0140-6736(16)30169-6. doi: 10.1016/S0140-6736(16)30169-6.

100

90

80

70

60

50

40

30

20

10

0

M3 M6 M9 M12 M15 M18 M21 M24

Time to McDonald MS conversion from randomization date (Months)

203 (0) 165 (37) 119 (82) 113 (87) 108 (88) 87 (95) 71 (96) 39 (98) 1 (99)Cladribine 5.25 mg/kg

204 (0) 167 (36) 114 (88) 108 (92) 92 (102) 82 (104) 71 (107) 39 (110) 3 (110)Cladribine 3.5 mg/kg

201 (0) 143 (58) 71 (128) 58 (141) 43 (154) 32 (162) 23 (165) 13 (169) 2 (169)Placebo

Patients at risk (conversions):

87.1%

51.4%

56.1%

Hazard ratio vs placebob

5.25 mg/kg: 0.425, p<0.00013.5 mg/kg: 0.496, p<0.0001

Cu

mu

lati

ve in

cid

ence

(%

)

Risk reduction5.25 mg/kg: 57.5%3.5 mg/kg: 50.4%

Cladribine reduces the risk of conversion to MS in treatment-naïve patients with a first clinical demyelinating event (FCDE)

– Cladribine 5.25 mg/kg

– Cladribine 3.5 mg/kg

– Placebo

ORACLE-MS

M0

aPatients enrolled in ORACLE-MS were treatment-naïve with an FCDE at high risk of converting to MS. bCox proportional hazards model controlling for the randomization stratification factor (region). FCDE, first clinical demyelinating event; M, Month. Leist TP et al. Lancet Neurol 2014;13:257-67

Survival Curves

85%

50%

30%

0%

15yrs 25yrs 40yrs 50yrs

100%Benign MS

Proportioned of treated MSers are cured

Naturalhistory

Unrealisticexpectation

Delayed onset of SPMS

CUREREMISSION

survival analysis

“moderately effective maintenance treatments”

“ pulsed immune reconstitution therapy or PIRT”

Secondary Progression

MS is a neurodegenerative

disease hypothesis

No Secondary ProgressionMS is an autoimmune

disease hypothesis

15-20 yearexperiment

Multiple Sclerosis

Environ-ment

Genes

Defining an MS cure?

Hill-Cawthorne et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):298-304.

Treating-2-Target

Relapses

Unreported relapses

Clinical disease progression

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions not detected by MRI

Brain atrophy

Spinal fluid neurofilament levels

OCB-ve

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

NED

A

END

-ORG

AN

DA

MA

GE

Where to from here?

1. Safer & more cost-effective PIRTs (pulsed immune reconstitution therapies)a. Cladribine

i. EMA (oral cladribine, Merck)ii. Investigator-led studies (sc cladribine, PI - Dr Klaus Schmierer)

b. Anti-CD20i. Ocrelizumab (Roche)ii. Ofatumumab (Novartis)iii. Ublituximab (TG Therapeutics)iv. Rituximab (Investigator-led study, COR-NIH/Kaiser, PI Anette Langer-Gould)

c. HSCT

i. Non-myeloablative HSCT vs. current best care (alemtuzumab (CD52), natalizumab (VLA-4), ocrelizumab (CD20) (PI: Paulo Muraro, Imperial)

ii. Non-myeloablative vs. myeloablative (PI: Basil Sharrack, Sheffield)

2. Follow the biologya. Long-lived plasma cells

i. Proteasome inhibitors (Takeda, Dr Sharmilee Gnanpavan)ii. Teriflunomide (Genzyme-Sanofi, Giovannoni)iii. Cladribine (Merck / Klaus Schmierer)iv. BTK inhibitors (Merck)

delayed worsening1 stabilised2

improved function3 recovered function4

Managing expectations: what does a cure mean?

✓

Does the biology of MS change with time?

Intrathecal Antibody Response

local OCBs

local & systemic OCBs

systemic OCBs

normal / polyclonal

CSFSerum

Intrathecal or central compartment

Systemic or peripheral compartment

C

S

C

S

C

S

C

S

Meningeal Perivascular

Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology

Magliozzi et al. Brain 2007; 130:1089-1104.

Cortical and white matter demyelinationFemale

Age 47 years

MS for 30 years

MS 463 007

Proportion of cortex demyelinated= 59%

Schmierer-Lab, Blizard Institute

BARTS-MS T2T-NEDA ALGORITHM T2T = treating-to-target; NEDA = no evident disease activity

Choose therapy

A B C

Define the individual’s MS

Treatment failure?

• Patient’s preferences?• Your choice?

Individual measures:• Evidence of disease activity?• Tolerability/safety?• Adherence?• Drug or inhibitory markers,

e.g. NABs?

Monitoring

• MS prognosis based on clinical and MRI indices

• Life style and goals • Shared goals for therapy

Rebaseline

Rebaselining:• IFNβ, natalizumab, fingolimod,

teriflunomide, Dimethyl-Fumarate=3-6 months

• Glatiramer acetate=9 months• Alemtuzumab=24 months

Choose a therapeutic strategy

Maintenance-escalation Pulsed immune reconstitution therapy

Choose therapy

X Z

Rebaseline

Monitoring

Initiate or Switch or Escalate Rx Complete course / Re-treat

Breakthrough disease

Y

• Patient’s preferences?• Your choice?

NoYes Yes

• Only one licensed induction therapy at present

IFNβ = interferon-beta; NABs = neutralizing antibodies; Rx = treatment

Sept-20021st attack

July-20032nd attack

June 2004Alemtuzumab 2005 - 2014

NEDA

June 2005Alemtuzumab

EDSS 3.5 EDSS 0.0

VZVEDSS 6.0

20041st attack

20052nd attack

Nov 2006Alemtuzumab

2008 - 2014NEDA

Nov 2007Alemtuzumab

EDSS 1.5 EDSS 3.5

Feb 2006IFNbeta

EDSS 7.0 EDSS 3.5 Grave’s

Jun 2006 Oct 2006

20 month vs. 32 month delay or 2 relapses

EDSS = 3.5: unable to run, play tennis or walk down stairs quickly without the use of a handrail

EDSS = 0.0: fully functional

The cost of delayed access to highly active treatment