So I was fortunate to be one of the two MPIs on an NIH grant to fund a Phase IIa study of zervimesine or CT1812, which is a sigma receptor antagonist and blocks the ability of the oligomeric receptor on the cell surface to bind to beta-pleated sheets. So it displaces alpha-synuclein, which is important for Lewy body dementia. It also displaces amyloid, which is important for Alzheimer’s disease...
So I was fortunate to be one of the two MPIs on an NIH grant to fund a Phase IIa study of zervimesine or CT1812, which is a sigma receptor antagonist and blocks the ability of the oligomeric receptor on the cell surface to bind to beta-pleated sheets. So it displaces alpha-synuclein, which is important for Lewy body dementia. It also displaces amyloid, which is important for Alzheimer’s disease. And so there was a study done in Alzheimer’s disease, but I was fortunate to be the overall PI for the study in mild to moderate dementia with Lewy bodies. So the SHIMMER trial was a Phase IIa study. We recruited over 130 individuals. It was roughly a six-month study. And it was three arms, so two doses of zervimesine, 100 or 300 milligrams, and a placebo. And so we were able to look at this. And so it’s a Phase IIa study, so it’s essential to remember that the study is not powered for efficacy. Phase IIa’s are largely looking at safety and tolerability, and it was well-tolerated. The 100 milligram dose was almost not different than the placebo group. The 300 milligram dose, which probably will not be carried forward, had a slightly higher adverse event rate, although still not in an unacceptable range.
When we looked at the efficacy measures, though, we really saw some interesting patterns. One of the challenges in dementia with Lewy bodies is that because there’s a collection of different symptoms, generally treating one of the symptoms using an off-label medicine will often make other symptoms worse. So if you treat the movement of dementia with Lewy bodies, you may make cognition and behavior worse. If you treat the behavior of dementia with Lewy bodies, you tend to make the cognition and the movement disorder worse. So it’s really been very, very difficult to sort of maximize therapy. What we found here was in the SHIMMER trial is that we had a favorable profile across all of the outcomes. So only one sort of reached statistical significance, that’s with behavior, but the others had very nice trends showing that while we were able to reduce behavioral symptoms and the caregiver burden associated with behavioral symptoms, we also reduced the amount of cognitive decline, we reduced the amount of motor decline, we saw improvements in activities of daily living compared to the placebo group. So across the board, we were able to demonstrate a very favorable profile for treating with zervimesine in mild to moderate dementia with Lewy bodies. We didn’t see any biomarker changes. Again, we’re underpowered to do so. And there are not a lot of great biomarkers for alpha-synuclein that are easy to use. We use skin biopsies, and we did see no real change in the amount of alpha-synuclein in the skin biopsies. So we think this is really kind of more neuroprotective. So the alpha-synuclein may not be necessarily reduced, but the impact of alpha-synuclein binding to cells and causing neurotoxicity may be reduced. So that’s why we don’t think that necessarily looking at the alpha-synuclein would be the best way to do this. So we’re very excited about that. And so there are plans to then hopefully move forward with future trials. Right now, there’s an expanded access program. So there are 32 individuals from the Phase IIa study that are on long-term treatment. It’ll be very interesting to follow these people over time to see a long-term effect.
At the meeting that we’re at for the ADPD meeting, we’re going to show some posters that focus on some other aspects of the disease. One of them is on behavior symptoms. And so we were able to demonstrate a potential slowing of some of the behaviors, particularly in the neuropsychiatric symptoms. And that’s very exciting because these are some of the most disturbing symptoms, particularly hallucinations, delusions, anxiety, and agitation. So these are features that are very challenging for families of people living with dementia with Lewy bodies to deal with. And what we saw was those four features showed a particularly robust response to zervimesine. So in the poster that we’re showing, we’re really going to dive down deeper into this to try to understand what the effects are on each of these individual behaviors. And that’s important because that’ll help us understand what to look for and how to design the next study. A complementary poster would be because we saw features across several different parts of the disease showing favorable profile, could we create a composite score that would allow us to capture all aspects of the disease? So rather than relying simply on a cognitive marker or on a behavioral marker, could we combine cognition, behavior, movement, and function in some way that would help us understand the global changes that could occur with the disease? And this would be similar to some of the more recent Alzheimer’s studies that, particularly with the monoclonal antibodies, that use composites to try to capture the full aspect of the treatment effect on the disease. So we’re very excited about these posters. I think it gives us a great way of understanding the true outcomes we got from the Phase IIa study, and we’ll inform the design of the Phase IIb/III studies that hopefully will come in the future.
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