AAN 2025 | The RESCUE and RESTORE trials: RNS60 after EVT in LVO strokes

So the RESCUE was a proof of concept Phase II trial. It only enrolled 82 subjects divided into three groups, two high doses of RN-60, two doses of RN-60, one ml per kilogram per hour and half a ml per kilogram per hour and a dose-matched placebo for the higher group the one ml per kilogram per hour. The primary objective was safety. So we looked at number of SAEs among treatment groups and number of deaths among these treatment groups, and there were no concerns around safety in the trial. And we looked at the study, obviously, having only 82 participants was not powered for any efficacy endpoint. We wanted to have trends and see if the neuroprotective or cerebroproprotective is actually working in protecting the infarct growth or the infarct expansion after EVT. So all participants underwent EVT standard of care. The LVO patients were selected and the drugs started infusing the drug right at the end of EVT before arterial access closure and the drug infusion continued for 48 hours. The unique feature about this trial was that we captured the size or the state of the infarct by an MRI right after EVT, and we treated that as our baseline for the drug because the EVT will have its independent beneficial effect. We wanted to keep the drug effect separate from that. So we captured an MRI at the end of EVT when the drug infusion starts, And then we repeated an MRI 48 hours later when the drug infusion stopped and wanted to see how the infarct behaved or expanded over that period as a result of drug treatment. And we were very happy to see that there was actually a significant reduction in the infarct growth during that period of drug infusion, which is an early indicator of a cerebral protective drug working as it should by preventing the infarct growth and neuronal cell death during that acute phase of the disease or acute phase of treatment. And after that 48-hour infusion, the drug was stopped and the participants were followed for 90 days. And at the end of 90-day, we used very standard stroke endpoints, such as 90-day MRS, dichotomized 0 to 2, 3 to 6, as well as BI, Barton Index, and participants who were, or proportional participants who were higher than 95, EQ5D, NIHSS, and all of the indicators, all of the endpoints, while none was statistically significant in this small study, each one of the endpoints consistently favored the high dose of RNS60. In other words, the high participants in the high dose of RNS60 were benefited compared to placebo when we looked at each and every of this pre-specified endpoint. So that was basically the design of the study, just like any other standard EVT or adjunct therapy study, you infuse the drug after EVT was completed and infused for 48 hours and looked at 90 days for all the recovery endpoints. So as I already stated, the main finding was safety, that was the primary endpoint and the study made its primary endpoint. There was no difference between SAEs or the number of deaths between the different groups, if anything numerically number of deaths was lower in the active group but it’s a small study so we’re just going to keep an eye on it in the next trial. As far as efficacy is concerned our primary focus was on that infarct growth as I mentioned because infarcts do grow even after EVT for the next 48 to 72 hours and a neuroprotective drug or a cerebral protective drug should be able to lower or slow down or prevent the growth at that time by protecting the penumbra. That was our hypothesis for RNS60 and we were very happy to see that during that first 48 hours, RNS60 actually protected the penumbra like we saw in the preclinical models and actually slowed or reduced growth of the infarct by 50%, which was actually the growth of the infarct at 40 days correlated with the MRS at 90 days. So it was a good indicator of cerebral protective function or therapeutic function of a drug at that time point. And at 90 days, we actually saw that higher number of participants in the RNS60 high group attained MRS 0 to 2 and BI over 95. So more participants, 63% for the MRS 0 to 2 and approximately 70% for the BIA more than 95% of RNS60 high group participants were independent at 90 days. So overall, the studies showed the drug to be safe, to be efficacious in reducing infarct growth at 48 hours, and also to indicate at least numerically, not statistically significant, but numerically show a consistently favorable response at 90 days when treated with a high dose. So we are convinced from this proof-of-concept study that RNS60 acted as a cerebral protective drug and actually that justifies testing it in a larger trial that is appropriately powered for efficacy, which RESCUE was not. So we have started preparation for a larger trial which we are calling RESTORE. We did a sub population analysis. What I forgot to mention was RESCUE enrolled patients from 24 hour of last known well and we did a subgroup analysis to find that the subpopulation of 12 hour since last known well group which was about 80% of the participants, they actually did better, had a stronger response to the drug. So we are planning to power the next study based on that less than 12-hour subpopulation and enroll that subpopulation, so any participant who has had stroke in less than 12-hour time point, and pretty much do the same study like we did in RESCUE. So study design remains very similar that we start treating the participants at the end of EVT for 48 hours. And in a sub-study in about 100 subjects, we will look at that infarct growth that we talked about. We will only use one dose of the drug this time. So it will be one-to-one randomization of RNS60 and placebo. So about 50 participants in each will have the imaging sub-study. The entire study will have about 600 participants, and we will follow them until day 90 for our MRS, NBI, and NIH-assist measurements and EQ5D measurements. So this will be a Phase IIB/III study, more like a Phase III study, appropriately controlled and powered to show us an efficacy that we saw. We only saw a signal in RESCUE, but to confirm that in a larger trial. And we are actually engaging with the sites at this point. We expect this to be a global study involving about 90 sites. So we are highly interested to hear from sites. If they’re interested, we are actively engaging them right now. The most interesting finding for us was the ability to translate our preclinical model, which are notorious sometimes in stroke. However, when we conducted the non-human primate model testing the drug, we saw a very similar range of, very similar extent of neuroprotective or cellular protective effect. We are happy to see that in the proof of concept study. So we think that our data, the preclinical data translated well in the human population or in the disease population that we tested. However, I would definitely like to highlight that RESCUE was a proof of concept study. It was not powered. So we need to do a larger appropriately powered study to confirm what we saw. While RESCUE was promising, it is still an early Phase II. So we have to be careful and we need to do the larger study to confirm any efficacy signal that we saw.

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