michael hutchinson - natalizumab therapy for ms - 2009

Farmleigh, November, 2009

NATALIZUMAB THERAPY FOR MULTIPLE SCLEROSIS

Michael Hutchinson St Vincent’s University Hospital

Dublin, Ireland


Multiple sclerosis

Commonest disabling neurological disease of young adults relapsing phase 15 -20 yrs acute inflammatory demyelination & axonal injury - plaque formation - relapses. secondary progressive phase axonal degeneration & atrophy - progressive disability.


Multiple Sclerosis in Ireland

  8000 people with MS in Ireland

  Twice as common in Donegal than Wexford

  Onset: 30 yrs. F:M ratio 2:1 relapsing onset in 85%

  About 1/3 of patients fail to respond to first line therapies (DMTs)

  300 + people on natalizumab (Tysabri)

  Total cost of DMTs 30 m/ annum

253/105

126/105

mainly a genetic effect


relapsing- remitting phase:first 15-20 yrs

MRI course

Cerebral atrophy

T2 lesion load

Secondary progressive 20 - 40 yrs


Trapp et al., N Eng J Med 1998


Trapp et al., N Eng J Med 1998;338:278-85

T cell migration

demyelination /axonal injury

axonal transection

Inflammatory demyelination


therapies for MS - time lines

  1993-7: IFNβ-1b sc, IFNβ-1a im, IFNβ-1a sc.   1998: glatiramer acetate   2000: mitoxantrone   2006: natalizumab

  2010: oral therapies: cladribine, fingolimod   2012: alemtuzumab   2012: daclizumab, oral fumerate, teriflunomide   2013: rituximab


Why new drugs are needed in MS

 Modest effects of first line DMTs  30% reduction in relapse rates in RRMS  Minimal effects on sustained disability progression.  Little effect in highly active RRMS (30% population)  NAbs in 30% of some IFNB preparations

 Toxicity of mitoxantrone  1/300 treatment related leukaemia, cardiomyopathy.

  Increasing evidence that to prevent secondary axonal degeneration inflammation must be adequately (completely) suppressed.


Natalizumab: anti- α4 integrin Ab why it is important

 First of a range of monoclonal antibodies for CNS inflammatory disease.

 First disease modifying therapy for MS which was designed to block an essential mechanism in the disease.

 The most effective available therapy for RRMS

 Unexpected side-effect profile.


Cell adhesion molecules

 Selectins, cadherins, integrins, ICAM-1, VCAM-1

  Integrins: heterodimers of α and β subunits

 α4β1 important in adhesion & migration at BBB  Expressed on most leucocytes except polymorphs   Interacts with VCAM-1 on activated endothelium  Fibronectin in ECM interacts with α4β1 in CD3 mediated

T-cell proliferation  Osteopontin with α4β1 integrin induces Th-1 activity

Natalizumab: Sites of Action

1. Leukocyte migration from blood to tissue

3. Modulation of leukocyte apoptosis

2. Leukocyte priming and activation

Natalizumab

Natalizumab


The history of α4β1 integrin

treated

Antibodies to α4β1 integrin ameliorate EAE Yednock et al. Nature 1992;356:63-66


AFFIRM study

 Pivotal phase 3 RCT of natalizumab in RRMS   2:1 randomisation natalizumab v placebo  natalizumab 300 mg (n=627) or placebo (n=315)

by iv infusion every 4 weeks for 2 years.  Endpoints

 Reduction in sustained disability progression  Reduction in relapse rate  Reduction in MRI activity   Improvement in HRQol

•  Polman et al. New Eng J Med. 2006

15

Prop

ortio

n W

ith S

usta

ined

Pro

gres

sion

Natalizumab 315 298 287 269 253 246 237 225 216 211 627 611 594 581 559 540 532 521 509 503

Number of Patients at Risk Placebo

0.0

0.1

0.2

0.3

0.4

Natalizumab 11%

Placebo 23%

HR=0.46 (0.33, 0.64)

P<0.0001

Weeks 0 12 24 36 48 60 72 84 96 108 120

211 502

16

TYSABRI 29%

Number of Patients at Risk Placebo TYSABRI

Prob

abili

ty o

f Rel

apse

0.0

0.1

0.2

0.4

0.6

0.7

Weeks 0 24

Placebo 58%

315 257 229 204 182 164 154 141 133 129 627 577 542 515 487 464 447 436 424 418

84 112 120

0.3

0.5

48 12 36 60 104 96 72

124 46 413 143


(EMEA) guidelines for natalizumab

1)   Patients who have failed to respond to an adequate course of beta-interferon: one relapse in the previous year while on therapy and MRI evidence of active disease,

2)   Severe relapsing-remitting MS, defined by two + disabling relapses in one year, and with MRI evidence of active disease

Most RRMS patients start natalizumab because of a suboptimal response to first-line therapy.

Highly active multiple sclerosis before natalizumab

Multiple gadolinium enhancing lesions

Highly active MS June ‘08

after one year of natalizumab

2008

2009

SVUH cohort on natalizumab

3 patients allergic(2 mtx, 1 alem)

ARR in 1st year = 0.386% reduction (16 rs in 12 pts)

30 pts 2 yrs+ therapyno relapses in 2nd yr

41/53 (77%) relapse freein first year of therapy

4 pts two relapses(3 alem,1 ritux)

63 continued therapy53 for at least one year

2 EDSS progression stopped therapy

68 patients onnatalizumab (Jun 09)ARR in yr prior: 2.18

53 suboptimal IFNB response15 highly active RRMS


Problems with natalizumab


Natalizumab: adverse effects

 Progressive multifocal leucoencephalopathy  27 cases to date worldwide since July 2006  Risk appears to increase with number of infusions  Range 12-35 infusions, average 25  Risk for patients >24 infusions 0.4 - 1.3 cases/1000.  Monitored by TOUCH (USA) and by TYGRIS (EU)


Managing the risk for PML

 Clinical vigilance, baseline MRI brain  Screening for JCViraemia useless  All patients assessed for new symptoms before

every infusion  New symptoms or signs

  - MRI brain  Any concerns

 no infusion  CSF - JCV DNA?   If doubt repeat CSF.


What is the future for natalizumab?  Until 2012 (?) only contender for highly active

RRMS: 20- 30% of the RRMS population.   alemtuzumab may supplant its use if

 a) the rate of PML after 24 months increases  b) other long term adverse effects appear  c) the efficacy / safety of alemtuzumab is better &

includes prevention of atrophy / neuroprotection.

N Eng J Med 2008;359:1786


Managing PML in natalizumab Rx

Discontinue natalizumab infusions Plasma exchange x 4 Anticipate: Immune reconstitution inflammatory

syndrome (IRIS). Associated with increased inflammation and clinical worsening IV methylprednisolone

PML IRIS

gadolinium

michael hutchinson - natalizumab therapy for ms - 2009

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