Farmleigh, November, 2009
NATALIZUMAB THERAPY FOR MULTIPLE SCLEROSIS
Michael Hutchinson St Vincent’s University Hospital
Dublin, Ireland
Farmleigh, November, 2009
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.
Farmleigh, November, 2009
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
Farmleigh, November, 2009
relapsing- remitting phase:first 15-20 yrs
MRI course
Cerebral atrophy
T2 lesion load
Secondary progressive 20 - 40 yrs
Farmleigh, November, 2009
Trapp et al., N Eng J Med 1998
Farmleigh, November, 2009
Trapp et al., N Eng J Med 1998;338:278-85
T cell migration
demyelination /axonal injury
axonal transection
Inflammatory demyelination
Farmleigh, November, 2009
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
Farmleigh, November, 2009
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.
Farmleigh, November, 2009
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.
Farmleigh, November, 2009
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
Farmleigh, November, 2009
Natalizumab: Sites of Action
1. Leukocyte migration from blood to tissue
3. Modulation of leukocyte apoptosis
2. Leukocyte priming and activation
Natalizumab
Natalizumab
Farmleigh, November, 2009
The history of α4β1 integrin
treated
Antibodies to α4β1 integrin ameliorate EAE Yednock et al. Nature 1992;356:63-66
Farmleigh, November, 2009
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
Farmleigh, November, 2009
(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
Farmleigh, November, 2009
Problems with natalizumab
Farmleigh, November, 2009
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)
Farmleigh, November, 2009
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.
Farmleigh, November, 2009
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
Farmleigh, November, 2009
Farmleigh, November, 2009
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