“The race is on—don’t miss the bus!”, were the words of David Liebeskind (University of California Los Angeles Health, Los Angeles, USA) as he discussed the apparent promise of cytoprotection in acute ischaemic stroke care during a session at the 2024 Society of Vascular and Interventional Neurology (SVIN) annual meeting (20–22 November, San Diego, USA).
“I predict that there is a coming revolution in cytoprotection,” Liebeskind stated. “And, my opinion is that we’re not going to have one drug; we’re going to have many drugs in the future. There are a lot of groups—at least 12–18 companies—that are doing or planning to do trials in the very near future.”
The rollercoaster ride that neuroprotection for stroke has been on over the past few decades was exemplified on the second day of SVIN 2024. Opening a session devoted to this topic, Patrick Lyden (University of Southern California, Los Angeles, USA) highlighted the more than 1,000 different neuroprotective candidates that have garnered excitement and shown early promise before ultimately proving to be futile in improving stroke outcomes once evaluated in larger clinical trials.
Lyden also drew attention to the “landmark moment” represented by SAINT II—a randomised trial published in 2007 that, having deemed the neuroprotectant NXY-059 ineffective in the treatment of acute ischaemic stroke patients, appeared to extinguish any remaining hope for the field.
But, as Lyden put it, the stroke research community “took a breath”, regrouped, and—with a collective mindset now focused on the concept of ‘cerebral cytoprotection’ and preserving the whole brain rather than ‘neuroprotection’ paradigms revolving around only the central nervous system (CNS)—pressed forward. And even additional, more recent neutral findings in trials like ESCAPE-NA1 and ESCAPE-NEXT with Nerinetide (NoNO Inc), and MASTERS-2 with MultiStem (Athersys), have done little to dampen overall enthusiasm across much of the community.
Prevailing criticisms levelled at these and many other failed neuroprotection studies relate to trial design. Michael Hill (University of Calgary, Calgary, Canada) addressed this in a later talk speculating on the ‘ideal’ clinical study of a given neuroprotective candidate. Hill initially drew attention to the wide array of reasons why stroke patients may experience negative outcomes despite receiving neuroprotection therapy—with age, socioeconomic status, stroke severity, comorbid illness, delayed treatment, choice of anaesthesia technique, poor adherence, lack of follow-up, haemorrhagic events and other complications being among the many potential contributing factors.
Homing in on problems surrounding poor outcomes further down the line, Hill also argued that—as neuroprotection is an acute treatment—these late outcomes can be ameliorated by achieving better early outcomes. And, with regard to trial design in particular, he highlighted the need for appropriate patient selection, noting that the emerging concept of premorbid frailty could serve to mediate outcomes in future studies.
Hill echoed points made by both Lyden and Liebeskind on the importance of switching gears from neuroprotection to cytoprotection moving forward, as the latter is more comprehensive and represents a more appropriate definition for many of the therapeutic candidates being investigated today.
Two of these candidates were discussed in detail during the same session at SVIN 2024. Initially, Marc Ribo (Vall d’Hebron University Hospital, Barcelona, Spain) provided an update on the APRIL trial, which has indicated the safety and tolerability of the drug ApTOLL (AptaTargets) when administered as an adjunct to mechanical thrombectomy for acute ischaemic stroke. Later in the session, Tareq Kass-Hout (University of Chicago, Chicago, USA) outlined the potential benefits of rapid intravascular hypothermia in combination with thrombectomy, as per randomised data from the RECCLAIM II study. According to Hill, while alternative agents including edaravone-dexborneol—a ‘free radical scavenger’—and butylphthalide—a celery-seed extract—have been approved for use in some Asian countries for many years, the evidence for these compounds in the more modern era of reperfusion therapy is much less certain. Other approaches currently being explored include normobaric hyperoxia and remote ischaemic conditioning.
The encouraging yet still unclear future of this space was perhaps most apparent at the beginning and end of Hill’s presentation on the ideal neuroprotection trial, as he opened by stating, “I don’t know the answer”, before closing with a similar sentiment and adding that “I don’t think there is a perfect pathway yet”.
In Hill’s view, while reperfusion has traditionally been the “mainstay” of treatment, it is entirely feasible that multiple different compounds and approaches may work, with many ideas currently being tested and retested, and the pathway to a positive clinical trial could vary depending on the drug in question.
“No, it’s not a reality yet,” Liebeskind added, drawing the session to a close. “Cytoprotection is not fully fledged in terms of approvals, and not ready for routine clinical practice in the USA. But, I think there is a revolution coming that started very recently—a parallel revolution to what’s happened in thrombolytics and endovascular therapy.”
Outlining a key lesson to be learned from the prior failures of neuroprotection trials, he stated: “My very strong opinion is that the starting point should be as an adjunct to thrombectomy. I would not mess around with studies that are non-adjunctive. It’s not that there won’t be a yield there, but it’s not the first order of business.”
Liebeskind went on to note that, over the past 18–24 months, there has been a “marked acceleration” regarding cytoprotection, leading to a “very rapidly growing” list of drugs progressing through early-stage evaluations.
“We have to be very careful in terms of the trial design but, that being said, in terms of the focus on adjunctive therapy [with thrombectomy] and the use of imaging, most companies and groups are aligned,” he continued. “The methodology is being very quickly harmonised. I think there’s a lot of work that can be done and there are a lot of data that are available, but things are aligning.”
Providing an additional, parting message on this topic, Liebeskind asserted that “we need to use imaging” when evaluating cytoprotection therapies—specifically advocating cerebral blood volume (CBV) measurement, which has been somewhat “neglected” as a perfusion component despite its advantages versus Alberta stroke programme early computed tomography score (ASPECTS) in terms of predicting ischaemic lesion growth and cytoprotective dose calculations.
