The following is excerpted from the question-and-answer section of the transcript.
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Question: Thomas Shrader - BTIG - Analyst
: Tom Shrader from BTID. For Dr. Noebels, we think a lot about the -- Dr. Noble, we're starting to think a lot about these seizure effects in Alzheimer's.
And your comments about the anti-inflammatory effects of KCC2. How strong are they relative direct modulation of immune cells. Is this truly a
good way to go after inflammation? Or is it a (inaudible) thank you.
Jeffrey Noebels
Thank you for that beautiful question. Actually, I think we don't know what we need to know about that and we're going to find out in the future.
But I think there's no -- there's little question that the hyperexcitability itself can drive that cascade. So I think there's -- it's not exactly my area, but
I think there's a lot of work of seizures triaging microcell expansion in epilepsy surround glioblastoma. There's this enormous interesting reaction.
And I think in a number of experimental settings, we see this correlation between increased excitability, decreased KCC2 and increased inflammation.
So it's a circle. And where does the circle start probably in different conditions, we could begin with the hyperexcitability and trigger that alternatively,
some viral-induced inflammation can work the other way around. So we don't know yet and probably multiple answers. But getting at that little
key piece of like what is the specific pad or molecular trigger and signal, I don't think we know yet.
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Question: Thomas Shrader - BTIG - Analyst
: You also mentioned the subacute signature which are seen everywhere. What do you see though -- what do you think of those as endpoints in
clinical trials to get an early read. And so the company is over considering using this approach to get an early read on efficacy?
Unidentified Company Representative
Well, so two parts to that answer of that interesting question. Of course, we would love to identify seizure and hyperexcitability early on in Alzheimer's
disease. We know in the animal models, the spiking that is not quite a seizure, but a clear evidence of abnormal excited building in the circuitry
starts very early in the animals, even before you see the amyloid plaques and other cell death. So -- there's something about in these models, a
beta that triggers some important cascade. So in a patient, we would love to get there early and actually prove our main hypothesis that that the
abnormal electrical signal in circuitry is probably the most important reason for the dementia and the lack of ability to remember things, in a traffic
jam, you can't you can't get to where you want to go, and that's what's going on during a seizure.
Now what about these interictal spikes that's been shown in a lot of epilepsy studies that actually just single spikes can depress synaptic activity
for several seconds after that. So this continuous spiking is not good for your memory circuitry either. So two reasons to stop it and to detect it
early and stop it. Now how we detect it. That's been -- that was a problem for 10 years until Alex Lam at Mass General said well, why don't we use
the noninvasive, not too many people like to have a whole drill and their skull to have depth electrodes put in, just to find out whether you have
seizures or not. But through a small little for Raymond in your T-bone, you can thread semi noninvasively in electrode so it's very close. And as she
showed, could detect the seizure activity. Interestingly, they only happened during sleep. So that means you have to get ready for a long period
of time.
My feeling is that that electrical signature is not going to be simple to detect in a clinical trial just for practical reasons. There must be other
biomarkers, and she's working on machine learning from the cortical EEG, which -- where you don't necessarily see seizure activity, but it may be
changed in a complicated way during deep subcortical seizure so that you can actually perhaps design a tool that would detect deep seizures. And
they're working on that. It's not ready yet.
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