Disease Modifying Treatments:

Mediocrity and then some?

Dr Trevor Pickersgill

Consultant Neurologist

University Hospital of Wales

Royal Glamorgan Hospital

Hon Lecturer, Cardiff University

Declarations

Research post 1996-8 - Schering AG ESPMS trial Travel/Conference hospitality: Biogen-Idec, Merck-Serono,

Novartis Advisory Board Remuneration: Biogen-Idec, Teva Educational Grants: GSK, Teva, UCB Minor shareholder: GSK; ex-Genzyme Directorships: BMA, BMA Pension Trustees Ltd.

“Disease?”

Advice Explanation Expertise Support Signposting Now ‘rationers’ ‘prescribers’

“Modifying”

Theoretical model: treat early and aggressively

Treatmentat diagnosis Intervention

at diagnosis

Time

Disease Onset

Dis

abili

ty

Patients with a sustained (6 months) Expanded Disability Status Scale increase during the first 3 years of treatment.

La Mantia L et al. J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2012-303291

©2012 by BMJ Publishing Group Ltd

RM dob 1987….inflammation in 2005

….atrophy 2012….

“Treatment?”

K Harding et al ENS 2012

‘mild’ drugs?

The Pipeline

Teva/Serono

BIOGEN

Really…..?

The IFNB Multiple Sclerosis Study The IFNB Multiple Sclerosis Study Group. 1993 Neurology. 43: 655-Group. 1993 Neurology. 43: 655-661661Jacobs LD et al. 1996 Annals of Jacobs LD et al. 1996 Annals of Neurology. 39: 285-294Neurology. 39: 285-294The PRISMS Study Group. 1998 The PRISMS Study Group. 1998 Lancet. 352: 1498-1504Lancet. 352: 1498-1504Jacobs LD et al. 2000 New Jacobs LD et al. 2000 New England Journal of Med England Journal of Med Medicine. 343: 898-904Medicine. 343: 898-904European Study Group on European Study Group on Interferon-1b in Secondary Interferon-1b in Secondary Progressive MS. 1998 Lancet. Progressive MS. 1998 Lancet. 352: 1491-1497352: 1491-1497Comi G et al. 2001 Lancet. 357: Comi G et al. 2001 Lancet. 357: 1576-15821576-1582

The New Dawn:monoclonals

Alemtuzumab Natalizumab Daclizumab Ocrelizumab Rituximab

“I’ll name that DMT in......”

AKA.......

Natalizumab/Tysabri

Monthly IVI, £13K +MRI +monthly day case = c.£18k ‘twice’ as effective injectable DMT Reserved for ‘HARRMS’ (NICE) I.e. 2+attacks in 1 yr with active MRI

(significant increase in lesions or Gd+) 25+ UHW. PML......

MOA of Natalizumab

1. Leukocyte migration from blood to tissue

3. Modulation of leukocyte apoptosis

2. Leukocyte priming and activation

Cannella B et al. Ann Neurol. 1995;37:424-435. TYSABRI SmPC; Yednock TA et al. Nature. 1992;356:63-66

TYSABRI Efficacy Summary

68%

54%

reduction in relapse rate vs placebo over 2 years (p < 0.001)

reduction in the risk of EDSS progression, sustained for 24 weeks, as assessed over 2 years (p < 0.001)

28%of patients free from all of the following measures of disease activity: relapses, Gd+ lesions, T1 weighted hypointense and T2 weighted hyperintense lesions and disability progression at 2 years 2

TYSABRI SmPC; Polman CH, et al. NEJM 2006; 354(9): 899-910; 2. TY00-004, Data on file. Biogen Idec Ltd

ITT Population

Kaplan–Meier Plots of the Time to Sustained Progression of Disability among Patients Receiving Natalizumab, as Compared with Placebo.

Polman CH et al. N Engl J Med 2006;354:899-910.

29%

17%

-42%

The downside...PML

1 in 1000...? Think again........ Untreatable brain virus Competent immune system - asymptomatic Est 30-50% prevalence

Q’aeda

Another magic bullet?

Alemtuzumab Anti CD52 Cell lysis Lymphocyte depleter Annual infusions x2 Cheap..... .....but withdrawn autoimmunity

AKA......

0

0.5

1

1.5

2

2.5

0 4 8 12 16 20 24

Haematological Effects of CAMPATH-1H

Time post Campath Infusion (Hours) 95% reduction within 1hr. Unaffected by steroids

Lym

ph

ocy

tes

(x10

9 /l)

0

1

2

3

4

1 10 100 1000

Days post CAMPATH-1HL

ymp

ho

cyte

s (x

109 /

l)

Normal Range

Moreau, T., A. Coles, et al. (1996). Moreau, T., A. Coles, et al. (1996). BrainBrain 119 (Pt 1)119 (Pt 1): 225-37: 225-37

Lymphocyte recovery after Alemtuzumab

Cossburn et al Neurology 2012(in press)

Campath rash

Cumulative number of relapses over time

P <0.0001

72%87%

RiskReduction

Annualized Relapse Rate (95% C.I.)

Interferon-beta 1a0.35 (0.27, 0.44)

Alemtuzumab Low-Dose

0.11 (0.07, 0.16)

Alemtuzumab High-Dose

0.05 (0.03, 0.09)Coles et al. AAN 2007.

Mean EDSS Score Over Time

-0.57 (-0.30, -0.83)

-0.72 (-0.46, -0.98) P<0.0001

Alemtuzumabv. IFNB1a

Error bars = S.E.

CARE-MS I/II

The downside......

30% thyroid

3% ITP

Goodpasture’s

Lymphoma

The newest downside....

Ocrelizumab ‘ritux-max’ CD20 Phase 2 n=220 6 monthly infusion MRI

Others

Rituximab 1 small trial

Daclizumab IL2recA chain CD25

The Oral Explosion....

Fingolimod

BG12/DMF

Teriflunomide “Aubagio”

Laquinimod

Cladribine

Ponesimod ??

CLADRIBINE

The ‘winner’ of the race to market CLARITY NEJM 2010 N=1326 Placebo v high v low dose 0.33 v 0.15 relapse rate 10 tumours (5 fibroids!) Withdrawn from market worldwide

Efficacy Outcome Measures Relating to Relapse and Progression of Disability during the 96-Week Study Period (Intention-to-Treat Population).

Giovannoni G et al. N Engl J Med 2010;362:416-426.

Name that (oral) DMT....

FINGOLIMOD

S1P receptor modulator TRANSFORMS v Avonex FREEDOMS v placebo EDSS 0-5.5 ARR=1 N=1200 82% completion -54% RR MRI and disability Oral once daily

Isaria sinclarii

FINGOLIMOD

First dose in hospital Cardiac SEs First dose brady 1/2 deg HB Opthalmological - mac oedema Skin - 11 cancers (4 pl) £20,000

Gilenya prevents lymphocyte exit from lymph nodes

Gilenya causes: Internalisation of

the S1P1 receptor Inhibition of

lymphocyte exit along the S1P gradient

CNS, central nervous system; S1P, sphingosine 1-phosphateModel based on Brinkmann V et al. J Biol Chem 2002; Matloubian M et al. Nature 2004; Brinkmann V. Br J Pharmacol 2009

Gilenya induces reversible retention of circulating lymphocytes in lymph nodes, reducing peripheral lymphocyte counts and their recirculation to the CNS

Annualized Relapse Rate at 12 Months and the Time to the First Relapse.

Cohen JA et al. N Engl J Med 2010;362:402-415.

0

0.1

0.2

0.3

0.4

Fingolimod significantly reduced annualized relapse rates versus IFNβ-1a IM and placebo

0

0.1

0.2

0.3

0.4

TRANSFORMS 1-year results1TRANSFORMS 1-year results1 FREEDOMS 2-year results2FREEDOMS 2-year results2

EDSS, Expanded Disability Status Scale; IM, intramuscular 1. Table 2 page 8 FDA Advisory Committee presentation (10 June 2010). 2. Cohen JA et al. N Engl J Med 2010;362:402–15.

p < 0.001 for fingolimod versus IFNβ-1a IM p < 0.001 for fingolimod versus placebo

IFNβ-1a IM(n = 431)

Fingolimod 0.5 mg(n = 429)

Placebo(n = 418)

Fingolimod 0.5 mg(n = 425)

0.33

0.16

0.40

0.18

Ann

ualiz

ed r

elap

se r

ate

Ann

ualiz

ed r

elap

se r

ate

Annualized Relapse Rate estimate and p value are calculated using negative binomial regression model adjusted for treatment group, country, number of relapses in previous 2 years and baseline EDSS score.

0.17 or 52% reduction

0.22 or 54% reduction

Data refers to study group broader than the CHMP licensed indication. Fingolimod is indicated in patients with highly active and rapidly evolving severe RRMS. A consistent treatment effect was demonstrated in the licensed highly active subgroups.”

Fingolimod reduced ARR in patients with highly active RRMS despite prior DMT, at 1 year (TRANSFORMS)

*IFN and ≥1 relapse in the year prior to study, plus either ≥1 Gd-enhancing lesions or ≥9 T2 lesions at baseline;**IFN in the year prior to study, plus equal or more relapses in Year -1 than in Year -2; based on relapse rate ratio; ***Aggregate ARR is presented. Cohen J et al. ENS 2011; poster P901

Patients with highly active disease despite prior IFNβ

(relapse criteria only)**

0.51

0.20

0

0.2

0.4

0.6

0.8

0.51

0.20

0

0.2

0.4

0.6

0.8

0.43

0.21

0

0.2

0.4

0.6

0.8

n = 149 n = 138 n = 431n = 160 n = 166 n = 429

Overall TRANSFORMS population***

AR

R

AR

R

AR

R

-0.22 or -52% vs. IFNβ-1a IM

p<0.001

-0.31 or -61% vs. IFNβ-1a IM

p<0.001

-0.31 or -61% vs. IFNβ-1a IM

p<0.001

Patients with highly active disease despite prior IFNβ (relapse and MRI criteria)*

IFNβ-1a IM Fingolimod 0.5 mg

Subgroups relevant to the approved EU label

FIN12-C117Date of preparation September 2012

TERIFLUNOMIDE Selective and reversible inhibitior DHODH dihydro-orotate

dehydrogensae Mitoch enzyme Inhibits proliferation B/T cells Approved FDA 2012 2 phase 3 trials TEMSO/TOWER/TOPIC/TENERE N=1088 ARR 31% SAD 30% (27-31%)

Annualized Relapse Rate and Sustained Disability

Progression.

TEMSOO'Connor P et al. N Engl J Med 2011;365:1293-1303.

TOWER

2nd phase 3 trial terif 1+relapse 1yr 2+ 2yrs 48wks n=1169 70% completed study ARR -22.3% -36.3% Free relapses 55.4% v

37.7% SAD 22/21% v 15.8%

Alopecia 13% TENERE: no superiority

Rebif TOPIC - CIS

Effective, well tolerated, more long term safety data needed

2M pt-yrs in RA

BG12/DMF

Anti inflamm antioxidative stress ?cytoprotective

DEFINE v pl /CONFIRM v pl v GLA Fox NEJM 2012

50% RR SAD 33%

BG-12/DMF Risk relapse 2yrs 43% New/enlarging T2 75% N=2307 120 v 240 v pl v GLA (n=360) At least 1 relapse 12m -83% Gd+ Flushing/GI SEs

Clinical Outcomes at 2 Years in the Intention-to-

Treat Population.

Fox RJ et al. N Engl J Med 2012;367:1087-1097.

LAQUNIMOD

ALLEGRO 23% RR 36% SAD BRAVO More pronounced effect on disability than

RR??

Clinical Outcomes and MRI Measures of Efficacy According to Study

Group.

ALLEGRO

Comi G et al. N Engl J Med 2012;366:1000-1009.

Treatment Map

CIS RRMS HARRMS

ABCR

NATFING

ALEM

NEW ORALS

Monoclonals

Adapted from X Montalban ECTRIMS 2012

Acknowledgements

Slideshare - Prof G Giovannoni Helen Durham Centre: Dr Katharine Harding Dr Mark Cossburn Prof Neil Robertson Dr Sebastian Luppe Dr Claire Hurst