Yes, for the past decade or more, we’ve been interested in understanding why E4 carriers are not responding to omega-3s. So we’ve screened the pathway for brain omega-3 metabolism and found that an enzyme known as calcium-dependent phospholipase A2 was activated or increasingly activated in the ApoE4 brain. We found it in cells, in animal models, and in post-mortem human brain tissues...
Yes, for the past decade or more, we’ve been interested in understanding why E4 carriers are not responding to omega-3s. So we’ve screened the pathway for brain omega-3 metabolism and found that an enzyme known as calcium-dependent phospholipase A2 was activated or increasingly activated in the ApoE4 brain. We found it in cells, in animal models, and in post-mortem human brain tissues. Then we asked, would it be possible for this enzyme to be a target of therapeutics. Over the past five years, we’ve used AI to screen billions of small molecules from a database and select those which can penetrate the brain, those which have safety profiles in silico. And after repeated iterations from 2022 all the way till now, we’ve had the first, second, and now a third generation compound. Our lead compound we call BRI-50460. And we’re sharing very exciting data suggesting that BRI-50460 can inhibit cPLA2 with an IC50 of less than one nanomole. This small molecule also has an excellent blood-brain barrier penetrance, getting inside the brain with a ratio of more than 30%, which is excellent for brain-penetrating drugs, and does engage with this pathway inside the brain. Historically, we haven’t really had successful cPLA2 inhibitors because they were not specific, and they did not specifically get inside the brain. And this is, to our excitement, this is real progress. Now we have a small molecule that doesn’t inhibit the other PLA2s, which would minimize off-target effects, gets inside the brain, and in preliminary data that we are just finishing, we show that this can actually reverse the actual omega-3 depletion or loss in the brain in ApoE4 models. So if we assume that lower omega-3s are a risk factor for dementia, we have done trials trying supplementation, and we didn’t find that supplementation is very effective. In contrast, if we can stop or reduce or mitigate the pathway that breaks down omega-3s, we can keep them in the brain functional and working. And this is the focus of developing this class of therapeutics.
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