A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer's disease

Abstract

Background: Effective, disease-modifying therapeutics for the treatment of Alzheimer's disease (AD) remain a large unmet need. Extensive evidence suggests that amyloid beta (Aβ) is central to AD pathophysiology, and Aβ oligomers are among the most toxic forms of Aβ. CT1812 is a novel brain penetrant sigma-2 receptor ligand that interferes with the binding of Aβ oligomers to neurons. Preclinical studies of CT1812 have demonstrated its ability to displace Aβ oligomers from neurons, restore synapses in cell cultures, and improve cognitive measures in mouse models of AD. CT1812 was found to be generally safe and well tolerated in a placebo-controlled phase 1 clinical trial in healthy volunteers and phase 1a/2 clinical trials in patients with mild to moderate dementia due to AD. The unique objective of this study was to incorporate synaptic positron emission tomography (PET) imaging as an outcome measure for CT1812 in AD patients.

Methods: The present phase 1/2 study was a randomized, double-blind, placebo-controlled, parallel-group trial conducted in 23 participants with mild to moderate dementia due to AD to primarily evaluate the safety of CT1812 and secondarily its pharmacodynamic effects. Participants received either placebo or 100 mg or 300 mg per day of oral CT1812 for 24 weeks. Pharmacodynamic effects were assessed using the exploratory efficacy endpoints synaptic vesicle glycoprotein 2A (SV2A) PET, fluorodeoxyglucose (FDG) PET, volumetric MRI, cognitive clinical measures, as well as cerebrospinal fluid (CSF) biomarkers of AD pathology and synaptic degeneration.

Results: No treatment differences relative to placebo were observed in the change from baseline at 24 weeks in either SV2A or FDG PET signal, the cognitive clinical rating scales, or in CSF biomarkers. Composite region volumetric MRI revealed a trend towards tissue preservation in participants treated with either dose of CT1812, and nominally significant differences with both doses of CT1812 compared to placebo were found in the pericentral, prefrontal, and hippocampal cortices. CT1812 was safe and well tolerated.

Conclusions: The safety findings of this 24-week study and the observed changes on volumetric MRI with CT1812 support its further clinical development.

Trial registration: The clinical trial described in this manuscript is registered at clinicaltrials.gov (NCT03493282).

Keywords: Alzheimer’s disease; Amyloid beta oligomers; Biomarkers; FDG PET; SV2A PET; Sigma-2 receptor.

Fig. 1

Study design CONSORT diagram. Forty-three participants were assessed for eligibility and 23 participants were randomized to receive placebo or 100 or 300 mg CT1812 once daily for 24 weeks. Two participants in the 100 mg and two in the 300 mg CT1812 group discontinued intervention due to AEs, and one in the 300 mg group became unavailable when pandemic-related travel restrictions precluded their return to the USA. One participant in the placebo group discontinued after experiencing an AE. PET was performed at baseline, 12 and 24 weeks to detect SV2A and at baseline and 24 weeks to detect FDG. MRI was performed and clinical outcomes were assessed at baseline, 12 and 24 weeks. CSF was sampled for biomarker assessments at baseline and 24 weeks. The participant numbers indicated for each assessment category are for the 24-week analysis

Fig. 2

Neuroimaging measure changes from baseline through 24 weeks in composite region of interest. A-B PET was performed to detect SV2A at baseline, 12 and 24 weeks (A) and to detect FDG at baseline and 24 weeks (B). No statistical differences were observed between treatment groups in change from baseline for either SV2A or FDG. Actual change relative to the cerebellum reference region is shown; error bars represent SE values. C Subjects were assessed using MRI at baseline, 12, and 24 weeks. The mean change from baseline in volumetric MRI (mL) (error bars: SE) for the composite of brain regions showed a trend towards less volume loss for the combined dose groups vs. placebo

Fig. 3

Change in clinical outcome measures through 24 weeks. Subjects were assessed using the ADAS-Cog11 (A), ADCS-ADL (B), MMSE (C), and CDR-SB (D) at baseline, 6, 12, 18 and 24 weeks. Data shown are LS Mean difference change (at 24 weeks) from baseline and SE from the linear mixed-effects model for repeated measures (MMRM). There were no differences throughout the 5 study visits. No significant differences were seen between any of the treatment groups in change from baseline through 24 weeks

Fig. 4

Change in CSF biomarkers from baseline at 24 weeks. CSF was collected at baseline and 24 weeks and analyzed for biomarkers associated with AD including Aβ40 (A), Aβ42 (B), Tau (C), pTau (D), neurogranin (E), synaptotagmin (F), SNAP-25 (G), and NfL (H). The mean changes from baseline (error bars: SE) are shown. No significant differences were demonstrated between any treatment groups in the change from baseline at 24 weeks