New mechanisms-based therapies in acute ischaemic stroke

Rapid reconstitution of blood flow by recanalization has been the primary therapeutic strategy in acute ischaemic stroke (AIS) after large vessel occlusion (LVO). In recent years, thrombolysis and endovascular mechanical thrombectomy (EVT), alone or combined, have seen ongoing refinement, including the extension of treatment time windows. Despite nearly achieving a 100% technical success rate in EVT for full recanalization (referred to as eTICI ≥ 2b), the individual prognosis of LVO stroke remains poor, with only about 35%–55% favourable outcome and 14%–28% mortality at 3 months.1 Mortality reaches 36%–40% when infarcts have progressed to consume large brain volumes before EVT recanalization is performed.2 These data show that recanalization is a pre-requisite for a better functional outcome, but individual prognosis remains poor for a large group of treated patients. This calls for add-on treatments. Experimental stroke models and observational clinical studies strongly indicate that progressive brain infarction throughout the delay from onset to treatment (during occlusion) and beyond successful recanalization [ischaemia/reperfusion (I/R) injury] mostly account for poor outcome. Novel mechanisms-based pharmacological approaches to delay or limit progressive brain infarction, such as classical neuroprotection3 and targeting stroke-induced inflammation,4 are currently in clinical development. The basic idea of neuroprotection in AIS has been to enhance the tolerance of neurons and other brain cells to ischaemia/hypoxia to ‘freeze’ the penumbral tissue-at-risk. The penumbra, which is provisionally nourished by cerebral collateral blood flow, represents ischaemic but salvable brain tissue exhibiting neurological dysfunction but sustained structural metabolism (Figure 1A). Clinical stroke trials employing neuroprotectants have failed for decades, probably because cerebral blood flow was not restored timely and efficiently. Highly effective recanalization by EVT changed the scene for neuroprotection. The synaptic scaffolding protein PSD-95 represents a major hub for excitotoxicity by connecting N-methyl-D-aspartate glutamate receptor to downstream neurotoxic signalling (Figure 1B). Nerinetide is a PSD-95 inhibitor, which penetrates the blood–brain barrier after intravenous application and reduced ischaemic brain damage in experimental cerebral I/R injury in rodents and primates.3 Clinical testing of nerinetide is advanced. Recently, two randomized controlled trials (FRONTIER and ESCAPE-NEXT) built on a favourable safety profile previously demonstrated in Phase II/III clinical trials (ENACT, ESCAPE-NA1). One crucial difference in the design of FRONTIER was pre-hospital randomization and administration of i.v. nerinetide vs. placebo in the field by trained paramedics in a population of suspected stroke. This enabled earlier administration before hospital arrival within 3 h after symptom onset or last-seen normal (median of 60 min for nerinetide vs. 68 min for placebo) than in-hospital administration defined by ESCAPE-NEXT (inclusion within 12 h). The FRONTIER and ESCAPE-NEXT results were presented in October 2023 at the 15th World Stroke Congress (Toronto, Canada), and their publications are pending. Already, their results seem to be of fundamental importance: FRONTIER clearly appears to pave the way for the concept of pre-hospital ultra-early neuroprotection to enhance the beneficial effects of recanalization by ‘buying time’, likely through ‘freezing the penumbra’ to delay definite brain infarction. ESCAPE-NEXT as pivotal Phase III trial with a purely in-hospital treatment protocol failed to demonstrate efficacy as important evidence whose interpretation remains open: Later application of this promising concept of neuroprotection either does not work or it may be much more difficult to validate. An overview on key events following the occlusion of the middle cerebral artery in acute ischaemic stroke. (A) Immediate hypoxic/anoxic neuronal necrosis occurs within the ischaemic core, while neurons temporarily survive in the surrounding area, designated ischaemic penumbra. (B) Ischaemic cell death is partly driven by excitotoxicity leading to calcium overload and N-methyl-D-aspartate receptor–mediated downstream neurotoxicity, which involves PSD-95 as a hub, the target molecule for nerinetide treatment. (C) In parallel, a detrimental inflammatory response forms within the ischaemic brain vasculature supplied by collateral blood flow, which involves T-cell and platelet activation as promising intravascular therapeutic targets, while the pathophysiological role of rapidly accumulating neutrophils is less clear, prompting further investigation. Created with BioRender.com Acute ischaemic stroke evokes a strong inflammatory response, which seems to unfold within the compartment of the local cerebral vasculature. During EVT, the vessel occluding embolus has to be passed routinely by a microcatheter for removal. This has allowed microcatheter aspiration of local pial blood directly from the centre of the ischaemic territory during its supply by retrograde blood flow through pial collaterals. In these unique samples, a robust local intravascular ‘thrombo-inflammatory’ response can be observed as indicated by a significant increase in neutrophil counts, a shift in the composition of T-cell subpopulations and high concentrations of CXCL-4 and CXCL-7 released by activated platelets attracting and activating immune cells5 (Figure 1C). In experimental stroke, it could be demonstrated that T cells in collaboration with platelets facilitate initial infarct expansion into the penumbra and I/R injury employing homophilic CD84 interactions6 (Figure 1C). Blocking of neutrophils, however, has revealed equivocal results. The preference for targeting T cells in AIS trials has been fuelled by clinically approved treatments for multiple sclerosis (MS). Natalizumab is a humanized monoclonal antibody against leucocyte very late antigen 4, which blocks binding to vascular cell adhesion molecule 1 and thereby T-cell migration across the blood–brain barrier. This highly effective treatment in MS failed in a clinical Phase IIb trial in AIS. Patients received a single dose of 300 or 600 mg IV natalizumab or placebo <9 or >9 to <24 h from last well seen, but the defined composite outcome of an excellent outcome was not reached.7 A reason for failure, among others, might have been that T cells in AIS probably exert their detrimental effect at the luminal site of the cerebral vasculature not requiring entry into the brain parenchyma. FTY720 (fingolimod) is another immunomodulatory agent approved for MS, which induces rapid lymphopenia by arresting lymphocytes in lymph nodes. In experimental stroke, lymphopenic mice developed smaller infarcts. Several smaller uncontrolled trials of FTY720 in Chinese AIS patients reported smaller lesion volumes and less severe neurological deficits without significant side effects when given alone or in combination with EVT/thrombolysis.8 However, larger, adequately powered and controlled studies in different patient populations are essential to prove efficacy. Upon vascular injury, platelets tether to the vessel wall via the receptor complex glycoprotein (GP)Ib-IX-V and binding to von Willebrand Factor followed by firm adherence via glycoprotein VI (GPVI), the principal platelet collagen receptor (Figure 1C). For firm thrombus formation, activated platelets must aggregate via GPIIb/IIIa receptors. In 2008, the Abciximab in Emergency for Treatment of Stroke Trial targeting platelet GPIIb/IIIa was stopped prematurely because of a dramatic increase in intracranial haemorrhages (ICHs) and futility in the subgroup without ICH. The recently completed Phase II ACTIMS trial took another approach by targeting GPVI (largely dispensable for normal hemostasis) by applying glenzocimab, a Fab fragment against human GPVI, within 3 h after AIS onset. Interestingly, the incidence of symptomatic ICH was only 1% and lower in comparison with 8% in the placebo group, and no safety issues were reported. However, the highest dose of 1000 mg glenzocimab given did not affect functional autonomy and mortality at Day 90 (reviewed by9). While publication of the original data is still pending, a clinical Phase III trial (ACTISAVE) recruiting larger patient numbers is currently under way to prove clinical efficacy. Studies in a mouse stroke model previously demonstrated a major role of GPVI in AIS: depletion of GPVI by JAQ1 antibodies ameliorated infarct development without bleeding complications10 and concomitantly reduced T-cell and neutrophil infiltration. Thus, the targeting of GPVI may act by attenuating stroke-induced inflammation rather than exerting anti-thrombotic effects. The search for adjunctive treatments in AIS has entered a new era, considering the substantial improvement in the efficiency of recanalization of embolic cerebrovascular occlusion through endovascular mechanical means. The complexity of intertwined mechanisms underlying progressive stroke, including excitotoxicity, inflammation, platelet and glial activation, requires particular attention to define ‘windows of opportunity’ for mechanisms-based additional interventions. G.S. and M.K.S filed a patent on CD84 in acute ischaemic stroke which is pending (PCT/EP 19183678.2), M.P. participated in the ESCAPE-NEXT trial as local investigator, and A.M.K. declares no disclosure of interest for this contribution. The work in the authors’ laboratories presented in this article was partly funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) project number 374031971-TRR 240.

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