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Right: Higher CSF concentration of CT1812 was associated with higher CSF concentration of A Os as measured by MIE (open circles) or Western blot (closed squares) in the same patients. CONCLUSION: The results demonstrate the first clinical evidence of target engagement of CT1812 and support that CT1812 can engage S2Rs in brain and selectively mobilize and clear toxic A Os from AD patient brains.
Subject Treatment Age Yrs Sex MMSE baseline APOE Patient 1 560 mg 67 F 18 E3/4 Patient 2 placebo 54 M 22 E3/3 Patient 3 560 mg 52 M 20 E2/3 A O in the CSF is related to CT1812 concentration High correlation between A O assays A O assays CT1812 concentration Left: A O concentration relative to pre-dose baseline measurements by MIE and by WB were highly correlated (Spearman r = 0.74).
CT1812 concentrations were measured by LC/MSMS. SAFETY: No subjects were withdrawn from the study due to treatment-emergent adverse events. The only serious adverse events were deemed unlikely to be related to study medication but instead due to the lumbar puncture procedure. -Patients were dosed at hour 0 (dotted vertical lines). -CSF concentrations of A Os (A, B, C) measured by MIE increased >5 fold (Patient 1) and >2.5 fold (Patient 3) with respect to baseline with no apparent change with placebo (Patient 2). -Similar changes in A Os (D, E, F) in treated patients were observed on WB -A 40 and A 42 (D,E,F) monomers increased <0.5 fold above baseline.
CSF was drawn from a lumbar catheter hourly over 28 hours, before and after a single p.o. dose of CT1812 (560 mg, two patients) or placebo (one patient). A O levels were measured via microimmunoelectrode (MIE) with oligomeric A selective antibody (A11) and by native western blots (WB), A 40 & A 42 monomer levels were measured via ELISA. All A measurements were normalized to the average of pre-dose levels.
BACKGROUND: CT1812 is a selective S2R modulator. In preclinical studies it has been shown to displace A Os from cultured neurons and from cortical tissue slices from postmortem AD patients. In transgenic hAPP/PS1 mice, CT1812 displaces A Os into the interstitial fluid in the brain and into CSF in the lateral ventricle. (Izzo, et al, Alz & Dementia 2021) CT1812 treatment increases CSF A Os, but not monomers METHODS: A randomized, double-blind, placebo-controlled trial in mild to moderate AD patients (MMSE 18-26, biomarker positive).
Catalano PhD1, JR Cirrito PhD2, ME Hamby PhD1 1.Cognition Therapeutics, Inc, Pittsburgh, PA, USA, 2.Washington University, St Louis, USA, 3.University of Pennsylvania, Philadelphia, USA, 4. University of Gothenburg, M lndal, Sweden, 5.Karolinska University Hospital, Stockholm, Sweden, 6.Aclairo, Vienna, USA, 7.Keck School of Medicine of USC, Los Angeles, USA, 8.University of Florida, Gainesville, USA, 9.Global R&D Partners, San Diego, USA Contact: mhamby@cogrx.com ClinicalTrials.gov: NCT03522129 Support by National Institute on Aging AG057780 AIMS: A Ph1b clinical trial was conducted to verify target engagement of the sigma-2 receptor (S2R) modulator CT1812 in Alzheimer's disease (AD) patients by measuring drug related increases in A oligomers (A Os) in CSF.