Neuroprotection in neurology: why is it so difficult?
Swiss MS Society State of the Art Symposium, Lucerne 2014 Lorenz Hirt
Neuroprotection • Strategy to protect neurons • To prevent them from dying • To preserve their function
Neuronal death in Neurology • Single damaging event
• Recurring damaging events
• Continuous injury Degeneration
• Stroke, TBI
• Recurrent stroke Recurrent TBI
• Relapsing-remitt. MS • Neurodegenerative
disorders Primary progressive MS
Ischemic core and penumbra Ischemic stroke, right middle cerebral artery territory
Perfusion-‐CT, 2h a2er symptom onset
CT, 2h a2er symptom onset
ACA
MCA
PCA
ECA
MCA
PCA
ICA
BA
Mike O'Neill, Lilly
Middle cerebral artery occlusion (MCAO) model in the mouse
Zoom of ÒVM H3-5 Ó
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Mechanisms of cell death in Ischemic penumbra • Excitotoxicity • Peri-infarct depolarisation • Apoptosis • Inflammation
– Numerous cellular mechanisms and molecular pathways involved
Dirnagl & al 1999
Neuroprotection in cerebral ischemia ? • Can cell death mechanisms be targeted
directly ? • Stroke: Restoring blood flow protects
• NINDS study / ECASS-3: rtPA i.v. within 4.5h from symptom onset improves the functional outcome at 3 months
• Indirect neuroprotection (effect on blood flow) • Hypothermia protects the ischemic brain in
cardiac arrest (Holzer & al NEJM 2002; Bernard & al, NEJM 2002) and neonatal hypoxic ischemic encephalopathy (Jacobs & al 2007)
Strategies targeting cell death mechanisms ?
• Not all patients qualify for thrombolysis / recanalisation therapies (10%)
• Not all patients benefit sufficiently • Time-window
Experimental approaches
• More than 1000 potential neuroprotective strategies tested
Dirnagl & al 1999
NEUROPROTECTION
STAIR recommendations Stroke, 1999 • Stroke therapy academic industry roundtable • Recommendations for preclinical trials • Randomised & blinded • Physiological parameters (CBF,
temperature, BP, blood gases, adverse reactions)
• 2 models or more • Both permanent and transient
ischemia • 2 independent labs ore more • 2 species or more including larger
animals • Late time-points
• Morphology & functional outcome as outcome measures
• Dose response curves • Concentration in tissue • Therapeutic window (delayed
administration) • Treatment duration • Both young and older animals • Both male and female • Drug combination, with TPA
Review of approaches 1957-2003
• O’Collins et al, Ann Neurol 2006 • 1026 experimental treatments • Evaluation: Average score of 4.2 out of 10
according to STAIR recommendations • Low score indicates that several problems
were identified in the studies • 114 advanced into clinical trials
Decision to go into a clinical trial • How was the decision taken ? • No difference in score between treatments that
entered clinical trial and those that did not • Other and yet unspecified criteria? • Proprietary issues ? • In half of the 114 compounds that were tested in
trials, negative trial results were published before the preclinical data
O’Collins et al, 2006, Moskowitz 2010
1,026 Experimental treatments in acute stroke
Annals of Neurology Volume 59, Issue 3, pages 467-‐477, 1 FEB 2006 DOI: 10.1002/ana.20741 hQp://onlinelibrary.wiley.com/doi/10.1002/ana.20741/full#fig4
STAIR score
NXY-059 • Traps free radicals • Highly rated quality of preclinical data (maximum
STAIR score) and level of efficacy • SAINT I & SAINT II trials • 5028 patients enrolled • Acute ischemic stroke • treatment within 6h • Primary endpoint: distribution of disability scores
at 3 months (mRS) No difference in disability score distribution,
mortality, rates of haemorrhage. Diener & al Stroke 2008
NXY-059 in experimental stroke: individual animal meta-analysis
• Data obtained from sponsor (AZ) or lead author • Fifteen studies (26 conditions, 12 laboratories) • 4 unpublished studies • 544 rats, 9 mice, 32 marmosets • Randomization (40%), blinding of surgeon (53%), outcome assessor
(63%)
Bath et al, BJP 2009
Forrest plot
Bath et al, BJP 2009
Funnel plot
Bath et al, BJP 2009
NXY-059 in experimental stroke: individual animal meta-analysis • Data obtained from sponsor (AZ) or lead author • Fifteen studies (26 conditions, 12 laboratories) • 4 unpublished studies • 544 rats, 9 mice, 32 marmosets • Randomization (40%), blinding of surgeon (53%), outcome assessor
(63%) • Efficacy in transient, permanent, thrombotic ischemia, up to 180min
post occlusion • Conclusion: NXY-059 effective in experimental stroke although
efficacy was probably overestimated due to publication bias. • Efficacy in young male animals is a poor predictor of clinical
outcome
Bath et al, BJP 2009
Drug activity ? • In most cases, there is a proposed
mechanism of action, tested in the experimental setting (e.g. free radical scavenging)
• In clinical trials however, the outcome measure is mostly the neurological outcome at 3 months
• No indication whether the proposed mechanism of action does occur
• This is a major limitation to understand the failure in clinical trials
Moskowitz 2010
Drug activity ? • Drug activity is not tested in humans, we
don’t know if the failure of the neuroprotection trials occurs because of – Bad concept – Poor target – Bad drug – Ineffective administration (e.g. timing, dosing)
Moskowitz 2010
Lack of back-testing • Compounds that failed in clinical testing
were abandoned by the sponsors • If a compound fails in a clinical trial, it
would be necessary to take it back to the lab rather than to abandon it
Moskowitz, Stroke 2010
Other concerns • Clinical outcome measures are unrefined
and not appropriate for all lesion locations • Differences in lesion volume perhaps not
sensitive enough: The measurement of the volume of salvaged penumbra might be a more suitable endpoint
Moskowitz, Stroke 2010
JNK (c-Jun-N-terminal kinase)
Dirnagl & al 1999
-‐ Selec[ve inhibitor: D-‐JNKI1 Bonny et al, 2001
Borsello & al, Nature Med 2003
D-JNKI1: intra-cerebro-ventricular injection 30 min middle cerebral artery occlusion in the mouse
Lesio
n volume
* Good therapeu[c window
Permanent MCAO
• D-JNKI1/XG102 attenuates lesion volume
• Improves the behavioral outcome
• JNK is activated after 1h
Hirt & al, Stroke 2004
30 min MCAO, i.v. injection at 6h
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Wiegler & al, CVD 2010
XG-102 iv, exploration
D-‐JNKI1 i.v. administra[on Blinded
D-‐JNKI1 0.1mg/kg 6h a2er 30 min ischemia
Wiegler & al, 2008
D-‐JNKI1 (n=9)
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tPA &D-‐JNKI1, i.v.
Wiegler & al, Cerebrovasc Dis 2008
D-‐JNKI1 (n=6) D-‐JNKI1
Mister R, 66 y.o.
• Untreated arterial hypertension
• Sudden headache, falls of his chair in café
• Admission at 60min: Le2-‐sided weakness and hemianopia
• Thrombolysis, before the CT-‐scan ?
CT (75min)
Bacterial collagenase (0.1U)
Intracerebral haemorrhage model in mice: the JNK pathway
200 µm
JNK pathway acIvaIon
Michel-‐Monigadon & al, Cerebrovasc Dis 2010
• AQenuated lesion size (œdema at 2d) • AQenuated neurologic deficit (at 1d)
Michel-‐Monigadon & al, CVD 2010
D-‐JNKI1 is well tolerated in intracerebral haemorrhage
NaCl D-‐JNKI1
D-‐JNKI1 and stroke o Promising compound o Tested in at least 5 labs, at least 6 models, at least 2 species o i.v. administra[on o Compa[ble with thrombolysis (rTPA) o Favourable effect in intracerebral haemorrhage o Toxicity studies in animals: safe o Phase Ib trial, 10 pa[ents, CHUV: safe
TRANSLATION ?
o Administra[on to healthy volunteers i.v., NCT01570205 o Clinical trial underway, in neurosensorial deafness
(Auris Medical, AM-‐111, phase II, 3 European countries)
STAIR update (VII) Albers & al, Stroke 2011 • Stroke therapy academic industry roundtable • Failure of neuroprotection may relate
to – Imperfect clinical trial design (delayed time
to treatment) – Choice of agents with insufficient preclinical
data to support the clinical trial design
• The same time-window may exist as for thrombolysis
• Multiple mechanisms – Drug with multiple targets – Combination of single target agents
• Hope in studying natural and induced forms of tolerance
• Expansion of iv TPA requires that neuroprotective agents be tested on back-ground TPA
• Expansion of iv TPA requires further efforts to study reperfusion injury in patients
• Selective cerebral delivery (intra-arterial catheters)
• Prehospital trials – Early administration – Require preclinical safety data in
hemorrhagic stroke • Remote preconditioning • Stroke is a systemic disease
– Activation of lymphoid organs with mobilisation of monocytes and lymphocytes to the brain
Endovascular therapeu[c hypothermia for acute ischemic stroke: ICTuS 2/3 protocol Lyden & al, Int J Stroke 2014
Together ! • Collaboration between experimental stroke researchers • Consensus on quality standards & endpoints, sharing and comparing
results (including neutral & negative results) • Reciprocal audits, data monitoring, round robin tests • Network could organize multicenter trials to replicate key-results, or phase
III trials • Well-defined study protocols, robust sample size calculation • Sufficiently large scale to detect small but relevant effects • Stratified of factorial design (different strains, species, severities, with/out
comorbidities) leading to robust findings
Neuroprotection in stroke ? • Proof of principle in numerous
experimental models • No success so far in patients • No strong argument that it can’t work • Translation is very challenging
Acknowledgements Stroke lab, DNC, CHUV Ximena CasBllo Tovar Lara Buscemi Melanie Price Former lab members Corinne Benakis Carole Berthet Wilfredo Puentes Yvo Piazza Maïté Willaredt Delphine Michel Jonathan Thevenet Osvaldo Mirante Karine Wiegler Marlise de Castro Ribeiro CrisBna Granziera
Funding FNS 3200-‐68306.2; FN 3100AO-‐112484; FN 310030_135617
CTI 7057.2 and CTI 8909.1 Fonds interdisciplinaire FBM / Swissheart / NovarBs
FoundaBon /FondaBon Biaggi
Christophe Bonny, Didier Coquoz, ChrisBan Pasquali, Anne Vaslin XIGEN Anne Angelillo-‐Scherrer, Haematology, CHUV Jérôme Badaut, Loma Linda University, USA Peter Clarke, Tiziana Borsello, Paola Bezzi, Vanessa Ginet, Julien Puyal DNF, UNIL Denis Monard, F.M.I, Basel Hongxia Lei, Rolf Grueger, EPFL, Lausanne Pierre Magistreh, Igor Allaman, EPFL
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