WOW! Incompetent for well over a decade and still no protocol on this! (We will never get any urgency to solve this as long as we still call it neuroprotection rather than the neuronal cascade of death. Which term suggests urgency to lay people?)
Neuroprotective Agent Improved Outcomes After Acute Ischemic Stroke
In patients with relatively moderate strokes who went without recanalization therapies for the most part, 10-day treatment with loberamisal led to excellent functional outcomes, defined as modified Rankin Scale (mRS) scores of 0-1 at 90 days (69.7% vs 56.3% with placebo; risk ratio 1.24, 95% CI 1.12-1.36), reported Shuya Li, MD, PhD, of Beijing Tiantan Hospital in China, at the International Stroke Conference.
What's more, the postsynaptic density (PSD)-95-targeting, dual antidepressant-anxiolytic also had a favorable safety profile based on the 1,000-person LAIS trial, Li reported.
"The results of the study are intriguing," commented Michael Tymianski, MD, PhD, of the University of Toronto. "This treatment is aimed at stroke patients who do not fit the acute ischemic stroke treatment protocol in that they do not receive recanalization therapies."
"The drug as used in this study seems to be administered over a 10-day period after the stroke onset in the absence of reperfusion. Thus the mechanism of action is less likely to be neuroprotection, but perhaps through some form of recovery enhancement," Tymianski told MedPage Today.
Loberamisal marks a notable development in the long search for a good neuroprotectant with clinical efficacy for reducing secondary neuronal damage and promoting neurological recovery. The LAIS trial arrives after years of mixed or outright failed neuroprotection trials in acute ischemic stroke.
In the ESCAPE-NA1 trial, for instance, the PSD-95 inhibitor nerinetide failed to improve stroke patients' outcomes when given in conjunction with endovascular therapy (EVT), though those not given alteplase did appear to benefit.
More recently, the novel sublingual combination of edaravone (Radicava) with dexborneol was shown to improve functional outcomes in the phase III TASTE-SL trial from China -- though its relatively low power and nonsignificant secondary results promptly invited skepticism.
Loberamisal is a novel dual-target, small-molecule inhibitor of the PSD-95-neuronal nitric oxide synthase interaction that selectively potentiates alpha-2 GABA A receptors. The 40-mg dose was selected for phase III study following a dose-finding study, Li reported.
LAIS was conducted from 2024 to 2025 in 32 Chinese centers and included patients with acute ischemic stroke within 48 hours of symptom onset who had NIH Stroke Scale scores of 7-20. Patients were excluded if they were planned for EVT, were on antidepressant or anxiolytic medications, or had used other neuroprotective agents (e.g., edaravone or edaravone dexborneol) before enrollment.
Patients were randomized to loberamisal (n=502; 40 mg daily for 10 days) or placebo (n=495).
The randomized cohort had an average age of 63 years, and roughly 65% were men. About one in three had a history of stroke, and median baseline NIH Stroke Scale score was 8.0. The mean time from stroke onset to treatment was just over 25 hours. About 17% received IV thrombolysis in the trial.
As for secondary efficacy outcomes, the loberamisal group was no more likely to have significant improvements in NIH Stroke Scale scores; the two study groups also had similarly few limitations in activities of daily living per the Barthel Index.
The incidence of serious adverse events was also similar between groups (8.6% with loberamisal vs 10.7% with placebo, P=0.283), as were all-cause mortality rates (1.2% vs 2.0%, P=0.300) and discontinuation of treatment due to adverse events (1.2% for both).
Tymianski highlighted the oddities in these findings: the efficacy outcomes outside of the mRS scores would be expected to have been positive -- "since they are other measures of clinical benefit that should co-correlate with improved functional outcome" -- and the serious adverse event rate was so low in this population, as opposed to rates approaching 50% in his own experience.
"Future trials would need to clarify whether these results, both safety and efficacy, are applicable to populations outside of China, whether they are useful for stroke patients who also receive reperfusion therapies, whether there is potential for these agents to improve outcomes for patients with more severe strokes, and whether there is potential for this therapy to improve on functional independence (mRS 0-2), which may be of relevance to patients with moderate and severe strokes," he said.
In any case, he added, the LAIS group is to be congratulated "for having accessed a small molecule that purportedly targets PSD-95."
"To our knowledge, this has been elusive, and no small molecule that we have tested to date has actually bound to this target," he noted.
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