Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification

Prior exploratory CSF analyses supported an impact of zervimesine on AD pathophysiology including amyloid biology, synaptic function, inflammation and lipoprotein-related biological processes.

“These exploratory analyses supported an impact of zervimesine on AD pathophysiology [1, 36, 39, 40] including amyloid biology, synaptic function [4–6], inflammation and lipoprotein-related biological processes [5, 6, 41]”

Deficits in cognitive performance seen in transgenic mice with Aβ accumulation are normalized following zervimesine treatment.

“deficits in cognitive performance seen in transgenic mice with Aβ accumulation are normalized following zervimesine treatment [1].”

Treatment of neurons with zervimesine restores the functional and synaptic deficits incurred by Aβ oligomers, including restoration of membrane trafficking and prevention of synapse loss.

“Treatment of neurons with zervimesine restores the functional and synaptic deficits incurred by Aβ oligomers, including the restoration of membrane trafficking, and the prevention of synapse loss [1].”

Zervimesine can displace toxic Aβ oligomers from binding to neuronal synapses.

“preclinical studies have shown that zervimesine can displace toxic Aβ oligomers from binding to neuronal synapses.”

Reduction in NfL levels in zervimesine-treated participants compared to placebo is consistent with preclinical studies demonstrating zervimesine rescue of synaptic loss and neuronal function in vitro and preservation of cognitive function in an in vivo AD model.

“Reduction in NfL levels in zervimesine-treated participants compared to placebo is consistent with preclinical studies demonstrating zervimesine rescue of synaptic loss and neuronal function in vitro and preservation of cognitive function in an in vivo AD model [1].”

After a single dose of zervimesine in mice, levels of Aβ oligomers were increased in minutes to hours.

“after a single dose of zervimesine, levels of Aβ oligomers were increased in minutes to hours [1].”

The reduction of Aβ40 and Aβ42 levels in zervimesine-treated participants compared to placebo may point to downstream effects of zervimesine on Aβ dynamics.

“Thus, the reduction of Aβ40 and Aβ42 levels in zervimesine-treated participants compared to placebo may point to downstream effects of zervimesine on Aβ dynamics”

Several S2R modulators (CT0093, CT0109, CT1344, CT1346, and CT1812) rescued memory and cognitive deficits in an Alzheimer's mouse model.

“Independently, several S2R modulators (CT0093, CT0109, CT1344, CT1346, and CT1812) rescued memory and cognitive deficits in an Alzheimer’s mouse model [2,64] (Figure 5).”

Synaptic loss is not necessarily permanent and synapses can be regained or formed again once amyloid-β oligomers are removed.

“Synaptic loss, however, is not necessarily permanent and synapses can be regained or formed again once amyloid-β oligomers are removed [64].”

S2R modulators restore cognitive deficits in Alzheimer transgenic mice.

“Lastly, to be discussed in greater detail below, S2R modulators restore cognitive deficits in Alzheimer transgenic mice [2,64].”

S2R modulators have been shown to rescue learning and memory in Alzheimer's mouse models.

“S2R modulators have been shown to rescue learning and memory in Alzheimer’s mouse models [2,64].”

In primary rat neurons, S2R modulators CT0093, CT0109, CT1344, CT1346, and CT1812 demonstrate synaptic protection and restoration of neuronal function.

“In primary rat neurons, S2R modulators by CT0093, CT0109, CT1344, CT1346, and CT1812 demonstrate synaptic protection (Figure 4) and restoration of neuronal function [2,64].”

The biophysical assessment in postmortem Alzheimer's disease brain corroborates in vitro and in vivo evidence of displacement of amyloid-β oligomers, representing a potential mechanism of action underlying protection against amyloid-β oligomer-induced synaptic degradation observed with S2R modulators.

“This interaction assessed biophysically, in the postmortem brain from individuals with Alzheimer’s disease, corroborates in vitro and in vivo evidence of displacement of amyloid-β oligomers [64], representing a potential mechanism of action underlying the protection against amyloid-β oligomer-induced synaptic degradation [153,154,155,156,157] observed with S2R modulators [64].”

In APPswe/PS1dE9 transgenic mice, significant cognitive deficits in fear recall and Morris water maze were prevented with CT1812 treatment.

“In both assays, the transgenic mice exhibited significant cognitive deficits that were prevented with CT1812 treatment (Figure 5).”

In preclinical studies, CT1812 slows amyloid-β oligomer-induced loss of synapses and restores synaptic activity.

“In preclinical studies, CT1812 also slows amyloid-β oligomer-induced loss of synapses and restores synaptic activity (Figure 4) [64]”

Given the ability of S2R modulators to rescue both amyloid-β oligomer and α-synuclein oligomer deficits, there is promise that S2R may be beneficial in patients with dementia with Lewy bodies.

“Given the ability of S2R modulators to rescue both amyloid-β oligomer and α-synuclein oligomer deficits [2,3,4,64], there is promise that S2R may be beneficial in patients with dementia with Lewy bodies.”

CT1812 selectively prevents and displaces amyloid-β oligomers from binding to neuronal synapses, thereby mitigating downstream toxicity.

“CT1812 selectively prevents and displaces amyloid-β oligomers from binding to neuronal synapses, thereby mitigating downstream toxicity.”

A previously published model proposes that CT1812 does not compete directly with oligomers at the same site.

“Therefore suggesting that CT1812 does not compete directly with oligomers at the same site [28]”