MENACTRIMS 2017, Dubai, 24-Nov-2017

Gavin GiovannoniBarts and The London

WHO ARE THE PATIENTS WHO CAN BENEFIT FROM IMMUNE RECONSTITUTION THERAPIES?

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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, Almirall, Atara Bio, Bayer-Schering Healthcare, Biogen, Canbex, Eisai, Élan, FivePrime, Genentech, Genzyme, GSK, GW Pharma, Ironwood, Merck, Merck Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

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Contents

Introduction to IRTs and Cladribine Tablets01

Efficacy in patients with high disease activity02

Efficacy in patients with SPMS03

Case studies04

01 INTRODUCTION TO IRTs CLADRIBINE TABLETSa

aCladribine Tablets are indicated for the treatment of adult patients with highly active relapsing multiple sclerosis as defined by clinical or imaging features

What is Immune Reconstitution Therapy?

An immune reconstitution therapy (IRT) is given intermittently and has the ability to induce long-term remission because of the favorable qualitative change in the immune system

aInflammatory activity in MS typically refers to clinical relapses and/or focal MRI activity (new T2 lesions and/or gadolinium-enhancing lesions)

An IRT is not given continuously, and additional courses of the therapy are only given if there is a recurrence of inflammatory activitya and if this is allowed by the label

Immune reconstitution

therapy

Short-course administration with transient reduction of immune function followed by reconstitution with long-term favorable qualitative change in immune system

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Proposed Classification of DMT for RMS

Immune reconstitution therapy (IRT)

Short-course therapy that “reconstitutes” the immune system, resulting in long-term qualitative changes in immune function

eg, alemtuzumab

IRT that affects both theinnate and adaptive

immune systems

Nonselective IRT(NIRT)Immunomodulation Chronic

immunosuppression

Maintenance/escalation therapy (MET)

eg, interferon β

Chronic therapy that is maintained and/or escalated over time that results in changes in immune function only during active treatment

eg, fingolimod

MET that results incontinuous immunomodulation

MET that results incontinuous immunosuppression

eg, ocrelizumab, cladribine Tablets

IRT that selectively affectsthe adaptive immune system

Selective IRT(SIRT)

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Immunomodulation/immunostimulation

Chronic drug administration resulting in modulation of immune function without

immunosuppressionClinical efficacy only

during active treatment

Selective, continuousimmunosuppression

Chronic drug administration resulting in ongoing suppression of

immune functionClinical efficacy only

during active treatment

Broad spectrum immunosuppression

Prior to 1990s MS treatment options

limited to broad spectrum immunosuppressants

aAzathioprine and cyclophosphamide are not approved for the treatment of MS and have been used off-label. IFN, interferon; im, intramuscular; sc, subcutaneous; SmPC, summary of product characteristics. 1. Betaferon® SmPC April 2017; 2. Avonex® SmPC July 2017; 3. Rebif® SmPC July 2017; 4. Copaxone® SmPC January 2017; 5. Tysabri® SmPC May 2017; 6. Gilenya® SmPC June 2017; 7. Lemtrada® SmPC July 2016; 8. Aubagio® SmPC June 2017; 9. Tecfidera® SmPC June 2017; 10. Zinbryta® SmPC July 2017; 11. Ocrevus® US Prescribing Information March 2017; 12. https://www.merckgroup.com/en/news/mavenclad-25-08-2017.html [Accessed September 2017]

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The current MS treatment landscape

Therapies with potential for remission?

Non-continuous administration Clinical efficacy extends well beyond

period of active treatment

Maintenance/escalation therapy (MET)

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Alemtuzumab7 Ocrelizumab11

sc IFN β-1b1

im IFN β-1a2

sc IFN β-1a3

Natalizumab5

Glatiramer acetate4 Fingolimod6 Daclizumab10

Dimethyl fumarate9

Cyclophosphamidea

Azathioprinea

Teriflunomide8

Goals: Increase efficacy | Improve safety | Increase selectivity

Cladribine Tablets12

8ADA, adenosine deaminaseLeist TP, Weissert R. Clin Neuropharmacol 2011;34:28–35

Development of cladribine

A synthetic purine

nucleoside analogue,

first synthesized at

the Scripps Research

Institute in

California in the late

1970s

The parenteral formulation of cladribine has been licensed for the treatment of hairy cell

leukaemia and chronic lymphocytic leukaemia for over 20 years

• Cladribine was designed by adding a single chlorine atom to deoxyadenosine, making it largely resistant to degradation by ADA

• High intracellular cladribine levels – due to resistance to degradation by ADA – reduce B and T lymphocyte counts

Deoxyadenosine Cladribine

DEGRADED BY ADA RESISTANT TO ADAhttps://www.merckgroup.com/en/news/mavenclad-25-08-2017.html [Accessed September 2017]

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Cladribine Tablets are administered as two courses separated by 1 year, followed by observation up to the end of Year 4

Each course consists of two treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year

Year 1 Year 2 Year 3 Year 4

No additional active treatment with Cladribine Tablets

Week 1

Week 5

Week 1

Week 5

10 days of treatment 10 days of treatmentNo additional active treatment in Year 1

No additional active treatment in Year 2

For a dose of 3.5 mg/kg body weight over 2 years in an average patient weighing 50 to <60 kgWeight-based dosing. Recommended treatment over 2 years; 1 treatment course per year, followed by observation for another 2 yearsMAVENCLAD® SmPC, September 2017; Giovannoni G et al. ECTRIMS 2016 [Abstract 553; Poster P636]; Giovannoni G et al. ECTRIMS 2016 [Abstract 554; Oral 164]; Soelberg Sørensen P et al. ECF 2016 [Abstract and Poster]

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Durable efficacy to Year 4 despite no further active treatment after Year 2 and recovery of median total lymphocyte count to normal levels

aPooled data from CLARITY, CLARITY EXT and PREMIERE; figure includes treatment gap; bGraded according to the Common Terminology Criteria for Adverse Events (CTCAE): 1, <lower limit of normal–800/mm3; 2, <800–500/mm3; 3, <500–200/mm3; 4, <200/mm3. Visits with sample size ≥30 are displayed 1. Giovannoni G et al. ECTRIMS 2016 [Abstract 553; Poster P636]; 2. Giovannoni G et al. ECTRIMS 2016 [Abstract 554; Oral 164]

Number of 434 415 263 378 358 86 94 69 patients 683 645 437 624 574 298 265 167 147 131 116 106 66 32

Median (Q1–Q3)

lymphocytecount

(109/L)a

CLARITY CLARITY EXT

Grade 1b

Grade 2

Grade 3

Grade 4

Proportion of patients qualifying relapse free (%)1

Figure adapted from Soelberg Sørensen P et al. ECF 2016 [Abstract and Poster]

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Cladribine Tablets is a selective immune reconstitution therapy (SIRT) for treating patients with active RMS

Short-course therapy resulting inlong-term qualitative changes in immune

function

aPooled data from CLARITY, CLARITY EXT and PREMIERE; figure includes treatment gap; bGraded according to the Common Terminology Criteria for Adverse Events (CTCAE): 1, <lower limit of normal–800/mm3; 2, <800–500/mm3; 3, <500–200/mm3; 4, <200/mm3. Visits with sample size ≥30 are displayed. EXCEMED CME on PIRT accessed at https://www.excemed.org/resources/how-transfer-concept-clinical-practice June 2017

Selective reduction of lymphocytes with treatment followed by gradual recovery

Number of 434 415 263 378 358 86 94 69 patients 683 645 437 624 574 298 265 167 147 131 116 106 66 32

Median (Q1–Q3)

lymphocytecount

(109/L)a

CLARITY CLARITY EXT

Grade 1b

Grade 2

Grade 3

Grade 4

Figure adapted from Soelberg Sørensen P et al. ECF 2016 [Abstract and Poster]

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Cladribine Tablets has been tested across the spectrum of MS populations

Early Active Active despite ongoing therapy

Real-world setting

aEDSS score of 0–5.0; b≥1 relapse within past 12 months, EDSS score ≤5.5, ≤2 prior DMD failures; c≥1 relapse within 48 weeks prior to screening, EDSS score of 1.0–5.5. FCDE, first clinical demyelinating event; IFN, interferon; RCT, randomized controlled trial; RMS, relapsing MS; RRMS, relapsing–remitting MS1. Leist TP et al. Lancet Neurol 2014;13:257-67; 2. Freedman M et al. AAN 2016 [P3.035]; 3. Giovannoni G et al. N Engl J Med 2010;362:416-26; 4. Giovannoni G et al. Lancet Neurol 2011;10:329–37; 5. Comi G et al. J Neurol 2013;260:1136-46; 6. Giovannoni G et al. AAN 2016 [P3.028]; 7. Comi G et al. AAN 2016 [P2.114]; 8. Montalban X, et al. AAN 2016 [P3.029]; 9. https://clinicaltrials.gov/ct2/show/NCT01013350; 10. Kalincik, T et al. ECTRIMS 2016 [P621]

CLARITY3–5

(Double-blind RCT)Patients with RRMSb

ONWARD8

(Double-blind RCT, as add-on to sc IFN β-1a)

Patients with active RMS despite ongoing IFN

therapyc

ORACLE-MS1,2

(Double-blind RCT)Treatment-naive patients

with an FCDE at high risk of converting to MSa

CLARITY EXTENSION6,7

(Double-blind RCT)Patients with RRMS who

completed CLARITY

PREMIERE Registry9

(Multicentre cohort study)Patients who participated in clinical trials investigating

Cladribine Tablets

RECORD-MS10

(Prospective, post-authorization safety study)

Patients who participated in clinical trials investigating

Cladribine Tablets in Australia

02EFFICACY IN PATIENTS WITH HIGH DISEASE ACTIVITY

CLADRIBINE TABLETS

Year 2: 2nd 48 weeks

Placebo3.5

mg/kgPCb

Cladribine Tablets 3.5 mg/kg

7.0 mg/kgCCb

Cladribine Tablets 3.5 mg/kg

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The efficacy and safety of Cladribine Tablets was investigated in a 96-week, Phase III, double-blind, multicentre trial in patients with RRMS

Patients with RRMS (n=1326)

randomized 1:1:1

Year 2: 2nd 48 weeks

Year 1: 1st 48 weeks

2-year double-blind perioda

6-month SUPF

Year 1: 1st 48 weeks

2-year extensiona

aBoth CLARITY and CLARITY EXT studies were conducted over 2 years (24 months, with each month defined as 4 weeks; 96 weeks in total for each study); CLARITY EXT also included a 6-month SUPF (please note that this was a protocol amendment so some patients experienced an additional delay between the end of CLARITY EXT and the beginning of the SUPF); bTotal cumulative dose over 4 years. CP, Cladribine Tablets (3.5 mg/kg) in CLARITY, placebo in CLARITY EXT; PC, placebo in CLARITY, Cladribine Tablets (3.5 mg/kg) in CLARITY EXT; CC, Cladribine Tablets (3.5 mg/kg) in CLARITY, Cladribine Tablets (3.5 mg/kg) in CLARITY EXTEDSS, expanded disability status score; MRI, magnetic resonance imaging; RRMS, relapsing–remitting MS; SCRN, screening; SUPF, supplementary follow-up periodGiovannoni G et al. N Engl J Med 2010;362:416–26; Giovannoni G et al. AAN 2016 [P3.028]

Cladribine Tablets 3.5 mg/kg

Placebo3.5

mg/kgCPb

CLARITY CLARITY EXT Total dose

3.5 mg/kg Cladribine Tablets dose shown

Inclusion criteria: • Diagnosis of RRMS according to McDonald 2001 criteria • Experienced ≥1 relapse in the previous year

• MRI lesions consistent with MS• EDSS score ≤5.5

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Cladribine Tablets significantly increased the proportion of patients free of disease activity1 and reduced brain atrophy2 over 2 years

Relapses 80%

relapse freep<0.0001

6-monthconfirmed EDSS

91% progression free

p=0.0064

NEDA47%

p<0.0001

Active T262%

lesion freep<0.0001

T1 Gd+87%

lesion freep<0.0001

20% reduction in brain atrophy vs

placebo

CLARITY

NEDA was defined as no relapses, no 6-month confirmed EDSS progression and no new T1 Gd+ lesions and no active T2 lesions on cranial MRI. Post hoc analysisEDSS, Expanded Disability Status Scale; Gd+, gadolinium-enhancing; MRI, magnetic resonance imaging; NEDA, no evidence of disease activity1. Giovannoni G et al. Lancet Neurol 2011;10:329–37; 2. De Stefano N et al. Mult Scler J 2017

CLARITY

CLARITY: delayed time to 6-month confirmed EDSS progression across subgroups

82% RR

82% RR

47% RR

Subgroup at baseline

HR (95% CI)

Definition Overall (N=870) 0.53 (0.36, 0.79)

HRA + TNRAs for HRA plus patients with ≥1 relapse in the year prior to study entry while on DMD

and ≥1 T1 Gd+ or ≥9 T2 lesions

HRA + TNR (n=289) 0.18 (0.07, 0.43)

Non-HRA + TNR (n=581) 0.82 (0.51, 1.30)

HRAPatients with ≥2 relapses during the year

prior to study entry, regardless of prior use of DMD

HRA (n=261) 0.18 (0.08, 0.44)

Non-HRA (n=609) 0.81 (0.51, 1.28)

HR (95% CI)6-month confirmed EDSS progression

CLARITY: Effect in Patients with More Rapid EDSS Progression on Study

Favors Cladribine Tablets 3.5 mg/kg Favors placebo

CI, confidence interval; DMD, disease-modifying drug; EDSS, Expanded Disability Status Scale; Gd+, gadolinium-enhancing; HR, hazard ratio; HRA, high relapse activity; TNR, treatment nonresponse. Giovannoni G et al. ECF 2016 [Abstract/Poster]

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03 ONWARD:EFFICACY IN PATIENTS WITH SPMS

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The ONWARD study evaluated use of Cladribine Tablets as add-on therapy to IFN-β therapy in a 96-week, Phase IIb, placebo-controlled trial of patients with RMS

aProtocol amendment: high levels of Grade 3/4 lymphopenia in the 5.25 mg/kg + IFN β group led to a protocol amendment and discontinuation of this group; bAll efficacy analyses were exploratory and were not powered to detect statistical differences between groupsIFN, interferon; MRI, magnetic resonance imaging; RMS, relapsing MS; RRMS, relapsing–remitting MS; SPMS, secondary progressive MSMontalban X et al. AAN 2016 [P3.029]

Study objectives Primary: To evaluate the safety and tolerability of Cladribine Tablets as an add-on to IFN β in patients with RMS

Secondary:b To explore the efficacy of Cladribine Tablets as an add-on to IFN β over 2 years as measured by MRI and

clinical efficacy outcomes

Under an amended protocol,a

172 patients with RMS were

randomized 2:1

Placebo + IFN β (n=48)

Cladribine Tablets 3.5 mg/kgb + IFN β (n=124)

Year 1 (1st 48 weeks) Year 2 (2nd 48 weeks)

Double-blind period

ONWARD included patients with both RRMSand relapsing SPMS

RRMS SPMS Total

Cladribine Tablets (n) 107 17 124

Placebo (n) 40 8 48

ARR during the ONWARD study for patients classified as SPMS and RRMS

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Cladribine Tablets, as an add-on therapy to IFN β, significantlyreduced ARR in patients with relapsing SPMS

A statistically significant reduction in ARR was observed with Cladribine Tablets compared to placebo in patients with SPMS and patients with RRMS

ARR, annualized relapse rate; CI, confidence interval; IFN, interferon; RRMS, relapsing–remitting MS; SPMS, secondary progressive MSEuropean Public Assessment Report for MAVENCLAD®, September 2017

Patients with SPMS (n=26) Patients with RRMS (n=171)

Placebo + IFN β(n=9)

Cladribine Tablets 3.5 mg/kg + IFN β

(n=17)

Placebo + IFN β(n=48)

Cladribine Tablets 3.5 mg/kg + IFN β

(n=107)

Adjusted ARR (95% CI) 0.30 (0.13, 0.73) 0.03 (0.00, 0.24) 0.31 (0.21, 0.45) 0.15 (0.11, 0.22)

Risk ratio (95% CI) – 0.11 (0.01, 0.94) – 0.50 (0.30, 0.84)

p-value – p=0.0439 – p=0.0090

ONWARD

Subgroup at baseline

Favours Cladribine Tablets(3.5 and 5.25 mg/kg)

Favours placebo

RR (95% CI)

Overall (N=1067) 0.43 (0.35, 0.52)

EDSS score≤3 (n=653) 0.40 (0.31, 0.53)

≥3.5 (n=414) 0.47 (0.34, 0.64)

1540 patients in total (placebo, n=494; Cladribine Tablets 3.5 mg/kg, n=573; Cladribine Tablets 5.25 mg/kg, n=473)CI, confidence interval; EDSS, Expanded Disability Status Scale; RR, risk ratio; SPMS, secondary progressive MS1. MAVENCLAD® SmPC, September 2017; 2. Giovannoni G et al. ECTRIMS 2016 [P643]20

In pooled analyses of CLARITY and ONWARD, patients with EDSS score ≥3.5 treated with Cladribine Tablets had reduced risk of relapse vs placebo

CLARITY/ONWARD

• In a subgroup analysis, EDSS score ≥3.5 was used as a proxy for SPMS1

• Reduction in relapse risk observed in the proxy SPMS group was consistent with the risk reduction observed in the EDSS score ≤3 subgroup1,2

Figure adapted from Giovannoni G et al. ECTRIMS 2016 [P643]

21RRMS, relapsing-remitting MS; SPMS, secondary progressive MSMAVENCLAD® SmPC, September 2017

Cladribine Tablets is indicated for the treatment of adult patients with highly active relapsing multiple

sclerosis as defined by clinical or imaging features

This includes both RRMS and SPMS with relapses

AE, adverse event; ARR, annualized relapse rate; CDMS, clinically definite MS; EDSS, expanded disability status scale; RMS, relapsing MS; RRMS, relapsing-remitting MS; SPMS, secondary progressive MS1. Leist TP et al. Lancet Neurol 2014;13:257-67; 2. Freedman M et al. AAN 2016 [P3.035]; 3. Giovannoni G et al. N Engl J Med 2010;362:416-26; 4. Giovannoni G et al. Lancet Neurol 2011;10:329–37; 5. Comi G et al. J Neurol 2013;260:1136-46; 6. Giovannoni G et al. AAN 2016 [P3.028]; 7. Comi G et al. AAN 2016 [P2.114]; 8. Montalban X, et al. AAN 2016 [P3.029]; 9. Clinicaltrials.gov/NCT01013350; 10. Kalincik, T et al. ECTRIMS 2016 [P621]; 11. Rammohan K et al. Mult Scler Relat Disord 2012;1:49–54; 12. MAVENCLAD® SmPC, September 2017; 13. Giovannoni G et al. EAN 2017 [EP1157]; 14. European Public Assessment Report for MAVENCLAD®, September 2017; 15. Giovannoni G et al. ECTRIMS 2016 [P643]22

Summary

• Cladribine Tablets has been tested across the spectrum of MS populations1–11

• Cladribine Tablets is indicated for the treatment of highly active RMS, which includes RRMS and relapsing SPMS12

Patient subgroups

In patients with high disease activity, relative risk of relapse and disease progression were significantly reduced with Cladribine Tablets vs placebo13

High disease activity

In a post hoc analysis of ONWARD, a statistically significant reduction in ARR was observed with Cladribine Tablets versus placebo in patients with relapsing SPMS and patients with RRMS14

Pooled analyses of CLARITY and ONWARD data demonstrate a consistent reduction of ARR in patients with EDSS score ≥3.5 (proxy for SPMS)15

SPMS

04 CASE STUDIES

Case study 1

42-yr old journalist, married with 2 children, War correspondent - frequent travel to Afghanistan, Ukraine, Iraq and Syria

Diagnosed RRMS late 2014: Initial symptoms of sensory symptoms in feet and Lhermitte’s phenomenon Treated with dimethyl fumarate (Tecfidera) Two disabling attacks in 2015 - ataxia and spinal cord lesion with weak legs

Diagnosis: Rapidly-evolving severe MS (RES)

Treatment: Eligible for Fingolimod, Natalizumab and Alemtuzumab

Natalizumab contra-indicated as found to be JCV-seropositive (index 1.86) Offered fingolimod - was not keen about long-term immunosuppression Interested in HSCT (not eligible under local guidelines) or alemtuzumab

Major concerns about monitoring and accessing urgent treatment when abroad as war correspondentJoint decision to treat him with cladribine (two cycles given - Jan/Feb 2016 and 2017)

Case study 2

48-year woman (born 1969), married, two children, employed as a counsellor

1996 - probable 1st symptoms with mild transient sensory symptoms in legs

2001 - Diagnosed with MS after an episode of weakness in right hand

2003 - R-optic neuritis

2004 - Weakness in legs with bladder involvement

2005 - 2007 - CLARITY study (active treatment)

2008-2010 - CLARITY EXTENSION (placebo)

2005 - 2015 - NEDA, EDSS 3.0 (stable), walking unrestricted.

April 2015 - numbness and pain R side of face, MRI new T2 lesion in brainstem

Refused platform DMTs (interferon-beta, GA, DMF, Teriflunomide, Alemtuzumab)

Treated with parenteral cladribine June 2015

QUESTIONS