Susan M. Catalano, Ph.D. - US grants

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) begins with the memory impairment and synapse loss that is seen in Mild Cognitive Impairment (MCI). Genetic and biochemical evidence from studies of human AD patients and animal models suggest that AD is caused by elevated levels or ratios of the amyloid beta 1-42 protein, leading to the formation of oligomeric structures that are much more neuroactive than the monomeric or fibrillar structures (Catalano et al., '06). Abeta oligomers bind to neurons and potently block hippocampal long term plasticity (Lambert et al., '98, Wang et al., '02, '04, Walsh et al., '02, '05, Klyubin et al., '05, '08, Puzzo et al., '05, '08, Yun et al., '06, Shankar et al., '08), likely by altering glutamate receptor trafficking to the plasma membrane (Kamentz et al., '03, Hseih et al., '06). These changes lead to a transient synaptic spine regression (Shrestha et al.,'06, Calabrese et al., '06, Shankar et al., '07, Lacor et al., '07) and inhibition of learning and memory (Cleary et al., '05, Poling et al., '08). These transient deficits lead us to hypothesize that if Abeta oligomer effects can be prevented and/or reversed by inhibiting oligomer formation or binding to neurons, or by inhibiting their effects on signaling, it will prevent oligomer-induced memory deficits, and slow or reverse Alzheimer's disease progression in humans. This provides a strong rationale to test this hypothesis by discovering small molecule therapeutics that inhibit the effects of Abeta oligomers on the brain. These therapeutics would significantly impact the lives of the 35 million patients worldwide suffering from AD and MCI, for whom no disease-modifying treatment exists. Cognition Therapeutics Inc.'s mission is to develop effective therapeutics for Abeta oligomer-related diseases, including AD, MCI and Down's syndrome. We have established initial discovery activities for identifying a potent and bioavailable Abeta oligomer inhibitor IND candidate. We intend to capitalize on these efforts by screening our unique small molecule library with an assay measuring oligomer formation, determine active compound mechanism of action in primary neuron assays, determine compound structure, screen structural analogues and obtain pharmacokinetic data on active compounds. These activities will leave Cognition well positioned for future studies of compound efficacy in behavioral models of Alzheimer's disease. The project will result in a first-in-class oligomer formation inhibitor suitable for commercialization as a preclinical candidate. PUBLIC HEALTH RELEVANCE: Cognition Therapeutics is focused on the discovery of drugs that stop or reverse the cognitive decline associated with Alzheimer's disease and other neurodegenerative diseases. During this project we propose to discover Abeta oligomer inhibitors by screening our unique small molecule library with an assay measuring oligomer formation, determine active compound mechanism of action in primary neuron assays, determine compound structure, screen structural analogues and obtain pharmacokinetic data on active compounds. The project will result in a first-in-class oligomer formation inhibitor suitable for commercialization as a preclinical candidate.

DESCRIPTION (provided by applicant): Recent key scientific discoveries have identified oligomers of the protein Abeta 42 as the synaptotoxic culprits in the Alzheimer's disease process. With increasing age, decline in brain levels of Abeta binding and clearance proteins and elevations in enzyme activity responsible for producing Abeta combine to produce an elevation of monomeric Abeta 42 levels. The hydrophobic C-terminus of this peptide then self-associates to form metastable oligomers that bind with high affinity to receptors located on a subset of neurons. Once bound, synaptotoxic Abeta oligomers alter glutamate receptor trafficking to the plasma membrane and inhibit long term potentiation, resulting in transient regression of spines, synapse loss and memory deficits (reviewed in Catalano et al., '06, Li et al., '10). Blocking Abeta oligomer effects is expected to prevent these memory deficits and slow or reverse neurodegeneration and Alzheimer's disease progression in humans. We have discovered first-in-class selective high affinity receptor antagonists that compete with human AD patient-derived oligomers for access to receptors that mediate synaptotoxicity, completely eliminate synapse loss and restore memory to normal in transgenic animals. These small molecules have excellent plasma stability and blood-brain- barrier permeability, but exhibit limited oral bioavailability due to oxidation by liver enzymes (first pass metabolism). While further preclinical development of these analogs is possible via alternate routes of systemic administration, improved oral bioavailability and oral formulation will significantly improve patiet compliance and increase the numbers of patients who could be helped by this therapeutic strategy. We propose to optimize the oral bioavailability of the CT0109 series by synthesis and testing of analogs designed to improve metabolic stability. Successful advancement of an orally bioavailable candidate could significantly impact the lives of the 35 million patients worldwide suffering from AD and MCI, for whom no disease-modifying treatment currently exists. PUBLIC HEALTH RELEVANCE: Abeta oligomers trigger synaptic dysfunction and lead to the cognitive decline in MCI and early AD. Prolonged oligomer exposure leads to more severe synaptotoxicity, memory deficits and accumulated pathology. Therapeutics targeting oligomers should block and potentially reverse disease symptoms and progress. Cognition Therapeutics has discovered first-in-class high affinity receptor antagonists that compete with oligomers for access to neuronal receptors that mediate synaptotoxicity, completely eliminate synapse loss and restore memory to normal in transgenic animals. The requested funding will enable optimization of these promising molecules for oral administration, facilitating their advancement to IND-enabling preclinical studies and eventual clinical trials. Such an optimized IND Abeta oligomer receptor antagonist candidate would be among the first small molecule drugs to reverse AD and MCI symptoms and block disease progression.

DESCRIPTION (provided by applicant): Cognition Therapeutics Inc.'s mission is to develop effective therapeutics for Alzheimer's, Mild Cognitive Impairment and Down's syndrome. Recent scientific discoveries in the Alzheimer's disease field have identified oligomers of the brain protein A¿ 42 as toxic culprits in the disease process. Drugs that antagonize the binding of this toxic protein to neuronal receptors and block the downstream pathological signaling that inhibits memory formation should prevent further damage, and unmask existing memory capacity as synapses recover. Drugs that stop oligomer-induced damage are therefore hypothesized to be disease-modifying treatments that would be effective throughout the course of the disease, and significantly impact the lives of the millions of Alzheimer's patients. Pharmaceutical industry efforts targeted specifically at oligomer blockade are currently limited. Cognition Therapeutics is one of the only companies uniquely focused on discovery of small molecule receptor antagonists of toxic soluble oligomers. We have discovered a CNS drug-like lead series of oligomer receptor antagonists, CT0093. Analogs in this series reduce binding of oligomers to synapses and completely block A¿ oligomer-induced membrane trafficking changes and synapse loss. CT0093 also completely blocks oligomer-induced memory deficits in Alzheimer's disease mouse models. This proposal will allow us to expand our preliminary medicinal chemistry analoging efforts and optimize the CT0093 molecular scaffold with the goal of obtaining a disease-modifying IND candidate drug.

? DESCRIPTION (provided by applicant): Cognition Therapeutics Inc. (CogRx) has discovered CT1812, a novel oligomer receptor antagonist that is the only drug candidate demonstrated to prevent and displace binding of Abeta oligomers to receptors on brain cells. By stopping the initiating event in the Abeta oligomer cascade, this first-in-class drug candidate completely blocks downstream synaptotoxicity and restores memory to normal in aged transgenic mouse models of Alzheimer's disease. CT1812 is an orally administered lipophilic isoindoline formulated as a fumarate salt that is rapidly absorbed and highly brain penetrant. It displaces receptor-bound Abeta oligomers by allosterically antagonizing the sigma-2/PGRMC1 receptor (Izzo et al., 2014a, b). CT1812 thus represents the first disease-modifying therapeutic that will test the oligomer hypothesis of Alzheimer's disease. Such a drug candidate would significantly impact the lives of the 35 million patients worldwide suffering from AD and MCI, for whom no disease-modifying treatment exists. This application proposes to assess the safety and pharmacokinetics of oral doses of CT1812 in a Phase I clinical trial in healthy volunteers. Successful completion of this Phase I safety trial will lay the groundwork for future studies of CT1812 in Alzheimer's patients.

Abstract ? Project Summary Cognition Therapeutics Inc. (CogRx) has discovered CT1812, a novel oligomer receptor antagonist that is the only drug candidate demonstrated to prevent and displace binding of Abeta oligomers to receptors on brain cells. By stopping the initiating event in the Abeta oligomer cascade, this first-in?class drug candidate completely blocks downstream synaptotoxicity and restores memory to normal in aged transgenic mouse models of Alzheimer?s disease. CT1812 is an orally administered lipophilic isoindoline formulated as a fumarate salt that is rapidly absorbed and highly brain penetrant. It displaces receptor-bound Abeta oligomers by allosterically antagonizing the sigma-2/PGRMC1 receptor (Izzo et al., 2014a, b). CT1812 thus represents the first disease-modifying therapeutic that will test the oligomer hypothesis of Alzheimer?s disease. Such a drug candidate would significantly impact the lives of the 35 million patients worldwide suffering from AD and MCI, for whom no disease-modifying treatment exists. This application proposes to assess the safety and pharmacokinetics of oral doses of CT1812 in a Phase Ib clinical trial in early Alzheimer?s patients. Successful completion of this Phase Ib safety trial will lay the groundwork for future studies of CT1812?s therapeutic effectiveness in larger Phase 2 trials in Alzheimer?s patients.

Cognition Therapeutics Inc. (CogRx) has discovered CT1812, a novel oligomer receptor antagonist that is the only drug candidate demonstrated to prevent and displace binding of Abeta oligomers to receptors on brain cells. By stopping the initiating event in the Abeta oligomer cascade, this first-in?class drug candidate completely blocks downstream synaptotoxicity and restores memory to normal in aged transgenic mouse models of Alzheimer?s disease. CT1812 displaces receptor-bound Abeta oligomers by allosterically antagonizing the sigma-2/PGRMC1 receptor (Izzo et al., 2014a, b). CT1812 thus represents the first diseasemodifying therapeutic that will test the oligomer hypothesis of Alzheimer?s disease. Such a drug candidate would significantly impact the lives of the 35 million patients worldwide suffering from AD and MCI, for whom no disease-modifying treatment exists. This proposal seeks to identify biomarkers of CT1812 functional target engagement. The project proposes 1) measuring changes in expression levels of proteins regulated by sigma- 2/PGRMC1 in the presence of Abeta oligomers that are blocked by CogRx?s sigma-2/PGRMC1 antagonists in neurons and 2) determining if such changes are observed in the brains, CSF or serum of transgenic mice treated with CT1812. The proposed studies will also conduct unbiased proteomic investigations on biofluids from wild type and transgenic AD mice treated with CT1812 or vehicle to identify patterns of altered protein expression associated with drug engagement with target in settings of disease. With this data, we propose to construct a pathway from CT1812 target engagement to peripherally available biomarker using targeted reaction monitoring (MRM) proteomics data. The successful outcome of this project is the development of an assay to measure candidate biomarkers in humans for exploratory investigation in the clinic.

ABSTRACT. Soluble oligomers of beta amyloid (A?) protein are the most potent neuroactive structural form of this protein and evidence suggests they cause the synaptotoxic changes resulting in cognitive decline in Alzheimer?s disease (AD) (Selkoe and Hardy 2016, Viola and Klein 2015). A safe and effective drug against A? oligomers should prevent and reverse this synaptotoxicity. CT1812 is the first drug that selectively displaces oligomers from synaptic receptor sites and clears oligomers from the brain into the cerebrospinal fluid (CSF). This first-in-class drug works by displacing A? oligomers bound to neuronal receptors at synapses. It accomplish this by allosterically modulating a key protein regulator of oligomer receptors (the sigma- 2/PGRMC1 protein complex), thus destabilizing the oligomer binding site and increasing the off-rate of oligomers, which are then rapidly cleared into the CSF (within hours). As a result, CT1812 restores synapse number and cognitive performance to normal in preclinical AD mouse models (Izzo et al., 2014a, b). This project proposes to evaluate whether CT1812 can rapidly clear A? oligomers into the CSF in Alzheimer?s patients by conducting a Phase 1b randomized, double-blind, placebo-controlled clinical trial in 16 A?-positive mild to moderate Alzheimer?s patients (MMSE 18-26). Following indwelling catheter placement in the lumbar spinal cord by an experienced anesthesiologist and collection of hourly baseline CSF samples for 4 hours, a single oral dose of CT1812 or placebo is given, followed by hourly sampling of the CSF for 24 hours. Samples are subsequently analyzed for A? oligomer concentrations by oligomer-selective immunoassay. Our primary aim is to evaluate oligomer concentrations in the CSF in CT1812-treated vs. placebo-treated AD patients over 24 hours and correlate these levels with concentrations of CT1812 in the plasma and CSF. Our secondary aim is to evaluate changes in CSF protein markers associated with Alzheimer?s disease and synaptic damage (including neurogranin and SNAP25). By measuring oligomers displaced by CT1812 and cleared into CSF, this trial can directly test the mechanism of action of CT1812 and identify CSF oligomers as a biomarker of CT1812 target engagement in AD patients. We hypothesize that increases in CSF oligomer concentration following CT1812 treatment, but not placebo treatment, will be demonstrated in this trial, and that these changes will correlate with the overall plasma and CSF concentrations of CT1812. Completion of this pilot study in AD patients will inform the design and methods of the subsequent Phase 2a proof of concept trials with CT1812. Advancement of CT1812 clinical development would substantially improve the lives of the 36 million people worldwide suffering from AD and MCI due to AD, for whom no disease-modifying pharmacological treatments exist.

ABSTRACT. Soluble oligomers of beta amyloid (A?) protein are the most potent neuroactive structural form of this protein and evidence suggests they cause the synaptotoxic changes resulting in cognitive decline in Alzheimer?s disease (AD) (Selkoe and Hardy 2016, Viola and Klein 2015). A safe and effective drug against A? oligomers should prevent and reverse this synaptotoxicity. CT1812 is the first drug that selectively displaces oligomers from synaptic receptor sites and clears oligomers from the brain into the cerebrospinal fluid (CSF). These first-in-class drugs work by displacing A? oligomers bound to neuronal receptors at synapses. They accomplish this by allosterically modulating a key protein regulator of oligomer receptors (the sigma- 2/PGRMC1 protein complex), thus destabilizing the oligomer binding site and increasing the off-rate of oligomers, which are then cleared into the CSF. As a result, CT1812 restores synapse number and cognitive performance to normal in preclinical AD mouse models (Izzo et al., 2014a, b). This project proposes to evaluate the effect of CT1812 on synapse number and cognitive function in a Phase 1b randomized, double-blind, placebo-controlled clinical trial in AD patients. By combining measurements of cognitive function with novel Positron Emission Tomography (PET) imaging of synaptic density in the same patients, this trial can directly test the mechanism of action of CT1812 and the A? oligomer hypothesis of AD. The PET tracer 11C-UCB-J, which quantitatively images the synaptic protein SV2A, has been used as a measure of synaptic density in humans (Finnema et al., 2016) and can be used as a biomarker of synaptic density loss and regrowth in Alzheimer?s patients. We propose to conduct a clinical trial in 20 A?-positive mild to moderate Alzheimer?s patients (MMSE 18-26) receiving CT1812 or placebo once daily for 3 months, with synaptic density measured via 11C-UCB-J scans and cognitive testing (ADAS-Cog14, ADCS-ADL, CDR-SB) at baseline and 3 months. Our primary aim is to evaluate the correlation between changes in synaptic density and changes in cognitive function. Our secondary aim is to evaluate the correlation between changes in synaptic density and changes in glucose metabolism. We hypothesize that increases in synaptic density as measured with PET will be demonstrated in this cohort, and that these changes will correlate with cognitive improvement. Completion of this pilot study in AD patients will inform the design and methods of the subsequent Phase 2a proof of concept trials with CT1812. Advancement of CT1812 clinical development would substantially improve the lives of the 36 million people worldwide suffering from AD and MCI due to AD, for whom no disease-modifying pharmacological treatments exist.

Abstract ? Project Summary Cognition Therapeutics Inc.?s mission is to develop effective therapeutics for Alzheimer?s disease (AD). Recent scientific discoveries have identified oligomers of the brain protein Amyloid beta 42 (A?Os) as toxic culprits in disease progression. Cognition has identified a subset of sigma-2 receptor binding modulators that displace A?Os from neurons and block the downstream pathological signaling that inhibits memory formation. This approach is in contrast to traditional A?O intervention strategies, which either block the expression of Abeta or clear A?Os or block their formation. These compounds should prevent further A?O-induced damage, and unmask existing memory capacity as synapses recover. These receptor binding modulators are hypothesized to be disease-modifying treatments that would be effective throughout the course of the disease, and significantly impact the lives of the millions of Alzheimer?s patients. Pharmaceutical industry efforts targeted specifically at A?O displacement are currently limited. Cognition Therapeutics is one of the only companies uniquely focused on discovery of small molecule A?O-displacing therapeutics. Cognition Therapeutics has discovered two CNS drug-like series of A?O-displacing compounds, Analogs of both series displace oligomers from neurons and completely block A?O-induced membrane trafficking changes and synapse loss. Members of these series are highly brain-penetrant and completely block oligomer-induced memory deficits in Alzheimer?s disease mouse models. Drug candidate CT1812 from Series 1 is progressing through clinical trials. Cognition now seeks to leverage the accumulated knowledge of SAR from both series plus the known sigma-2 receptor binding modulators to define and develop new lead candidates for the clinical pipeline. Additional candidates with different physicochemical and structural properties would de-risk the clinical development-to-NDA process for these first-in-class treatments. This proposal will allow us to expand our portfolio of A?O-displacing molecules with the goal of identifying orally efficacious candidates for further development as therapeutics for AD.

ABSTRACT. Soluble oligomers of beta amyloid (A?) protein are the most potent neuroactive structural form of this protein and evidence suggests they cause the synaptotoxic changes resulting in cognitive decline in Alzheimer?s disease (AD) (Selkoe and Hardy 2016, Viola and Klein 2015). A safe and effective drug against A? oligomers should prevent and reverse this synaptotoxicity. CT1812 is the first drug that selectively displaces oligomers from synaptic receptor sites and clears oligomers from the brain into the cerebrospinal fluid (CSF). These first-in-class drugs work by displacing A? oligomers bound to neuronal receptors at synapses. They accomplish this by allosterically modulating a key protein regulator of oligomer receptors (the sigma- 2/PGRMC1 protein complex), thus destabilizing the oligomer binding site and increasing the off-rate of oligomers, which are then cleared into the CSF. As a result, CT1812 restores synapse number and cognitive performance to normal in preclinical AD mouse models (Izzo et al., 2014a, b). This clinical trial project proposes to evaluate the safety and efficacy of three doses of CT1812 on cognitive function in a Phase II randomized, double-blind, placebo-controlled parallel group clinical trial in mild to moderate AD patients. This trial proposes to test CT1812 administered once daily to patients for 6 months, and is designed to measure the short-term cognitive improvement arising from rapid disinhibition of synapses. Since therapeutics directed against A? oligomers should prevent and reverse synaptotoxicity associated with disease and be effective throughout the clinical course of the illness, this drug is being tested in patients with mild to moderate Alzheimer?s disease. This trial will directly test the A? oligomer hypothesis of AD and the effectiveness of CT1812 to improve symptoms of cognitive decline in Alzheimer?s patients. We propose to conduct a trial in 160 A?-positive mild to moderate Alzheimer?s patients (MMSE 18-26) receiving one of three doses of CT1812 or placebo once daily for 6 months, with cognitive testing (ADAS- Cog14, ADCS-ADL, CDR-SB) at baseline, 3 and 6 months. Our primary aim will be to evaluate the safety and efficacy of CT1812 to improve cognitive function. Our secondary aim is to evaluate the effect of CT1812 on changes in serum and CSF protein biomarkers associated with Alzheimer?s disease and synaptic damage (including neurogranin and SNAP25). We hypothesize that rapid increases in synaptic function will correlate with symptom improvement detectable in individual patients within the duration of this proof of concept trial. Completion of this study in AD patients will inform the design and methods of the subsequent long term disease modification Phase III trials with CT1812. Advancement of CT1812 clinical development would substantially improve the lives of the 36 million people worldwide suffering from AD and MCI due to AD, for whom no disease-modifying pharmacological treatments exist.

ABSTRACT. Cognition Therapeutics, Inc. (CogRx) is developing ElaytaTM (CT1812), a disease-modifying drug for Alzheimer?s disease (AD). CT1812 is the first highly brain penetrant selective sigma-2 receptor antagonist small molecule. This first-in-class drug candidate selectively displaces amyloid-? oligomers bound to neuronal receptors at synapses and protects synapses from toxic oligomer effects, clearing them from the brain into the cerebrospinal fluid (CSF). When administered once daily for 28 days to mild to moderate AD patients, CT1812 significantly reduces concentrations of synaptic degeneration markers in AD patient CSF. Based on our review of publicly-disclosed clinical trial data, no other therapeutic currently in development selectively targets the most toxic form of the A? protein ? oligomers. No other AD drug candidate reduces synaptic damage markers as much, and as rapidly, as CT1812 in Alzheimer's patients. Our Aim in the proposed trial is to identify non-invasive measures to quantify the CNS impact of CT1812 demonstrated ability to reduce synaptic damage in AD patients. This pilot trial project proposes to evaluate the effect of one month of CT1812 treatment on quantitative EEG in a Phase 1b randomized double-blind, placebo-controlled, crossover clinical trial in AD patients. We hypothesize that the rapid reduction in synaptic damage CSF biomarkers seen in previous clinical trials will be accompanied by a reduction in global theta power and provide information on the suitability of this sensitive non-invasive qEEG method of measuring synaptic function for measuring patient response to drug treatment in future efficacy studies. Completion of this pilot study in AD patients will inform the design and methods of the subsequent Phase 2a proof of concept trials with CT1812.

Cognition Therapeutics, Inc. (CogRx) is developing CT1812, a disease-modifying drug for Alzheimer?s disease. CT1812 is the first highly brain penetrant selective sigma-2 receptor antagonist small molecule. This drug candidate selectively displaces amyloid-? oligomers bound to neuronal receptors at synapses and protects synapses from toxic oligomer effects, clearing oligomers from the brain into the cerebrospinal fluid. When administered once daily for 28 days to mild to moderate AD patients, CT1812 significantly increases CSF concentration of A?Os, increases plasma concentrations of lipids and metabolites, and reduces concentrations of synaptic degeneration markers in AD patient CSF, consistent with the disease-modifying and synaptoprotective mechanism of action established in preclinical studies. No other therapeutic currently in development selectively targets the most toxic form of the A? protein ? oligomers (A?Os) and has demonstrated selective clearance of A?O into CSF in AD patients. No other AD drug candidate has demonstrated normalization of dysregulated protein and lipid/metabolite analytes in AD patient biofluids or reported reduction of synaptic damage markers in AD patients as much, and as rapidly, as CT1812. We hypothesize that the effects of oligomer displacement and clearance on cognitive function wil l be detectable in symptomatic patients, and the effect on disease modification will be detectable in presymptomatic patients. CogRx discovered CT1812, its mechanism of action and the role of the sigma-2 receptor complex in AD. No other group is pursuing this mechanism of action for Alzheimer?s disease treatment. CT1812 has been demonstrated to be safe and well tolerated in healthy volunteers and mild-to moderate AD patients in placebo-controlled Phase 1b/2a trials. Adverse events were predominantly mild and included headache and GI disturbances. Two doses of CT1812 are currently being evaluated in follow-on safety trials in mild to moderate AD patients (Q.D. for 6 months, MMSE 18-26). These same two doses will be tested in early AD patients (MMSE 20-30) in the current trial, with treatment duration extended to 18 months. This project proposes to conduct a randomized, double-blind, placebo-controlled, Phase 2 trial to evaluate the safety and tolerability of two doses of CT1812 in patients with early AD (MMSE 20-30, corresponding to FDA late stage 2 to early stage 4) given q.d. over 18 months. This trial will determine whether CT1812 beneficially affects cognition as measured by CDR-SB and other secondary cognitive measures, as well as measuring the impact of CT1812 on biomarkers of target engagement (CSF concentrations of A? oligomers and synaptic degeneration proteins) and disease modification (CSF concentrations of total tau and NfL, serum NfL as well as hippocampal and whole brain volume change by MRI). Completion of this study in early AD patients will inform the design and methods of the subsequent long term disease modification Phase 3 trials with CT1812.

ABSTRACT. Soluble oligomers of beta amyloid (A?) protein are the most potent neuroactive structural form of this protein and evidence suggests they cause the synaptotoxic changes resulting in cognitive decline in Alzheimer's disease (AD) (Selkoe and Hardy 2016, Viola and Klein 2015). Cognition Therapeutics, Inc. (CogRx) is developing CT1812, the first brain penetrant small molecule that selectively clears toxic oligomers from the brain into the cerebrospinal fluid (CSF). This drug candidate displaces A?Os bound to neuronal receptors at synapses and protects synapses from toxic oligomer effects. When administered once daily for 28 days to mild to moderate AD patients, CT1812 significantly reduces concentrations of synaptic degeneration markers in AD patient CSF, and phospho-tau. CT1812's mechanism of action can potentially halt or slow cognitive decline, significantly alleviating the suffering of AD patients. An ongoing study COG0201 (SHINE) funded by the NIA under the award AG058660 is evaluating the safety and efficacy of two doses of CT1812 on cognitive function in a Phase 2 randomized, double-blind, placebo-controlled parallel group clinical trial in mild to moderate AD patients. This important proof of concept trial will be critical for CT1812's continued development. Excellent progress has been made on this study and award. Study COG0201 is proceeding well at nine clinical research sites across the US and Australia. Regulatory interactions have resulted in changes to the study design which have increased per patient costs; this competing revision application requests additional funds to enroll sufficient patients and reach the appropriate number of patients per group and adequately measure changes in cognitive function (N=48/group) and complete a fully powered trial (revised AIM 1). Adequately powered assessment of clinical outcomes is vital to CT1812's further development. Completion of this study in AD patients will inform the design and methods of the subsequent disease modification Phase III trials with CT1812. Advancement of CT1812 clinical development would substantially improve the lives of the 50 million people worldwide suffering from AD, for whom no disease-modifying pharmacological treatments exist.

Cognition Therapeutics, Inc. (CogRx) is developing CT1812, a disease-modifying drug for Alzheimer?s disease. CT1812 is the first highly brain penetrant selective sigma-2 receptor antagonist small molecule. This drug candidate selectively displaces amyloid-? oligomers bound to neuronal receptors at synapses and protects synapses from toxic oligomer effects, clearing oligomers from the brain into the cerebrospinal fluid. When administered once daily for 28 days to mild to moderate AD patients, CT1812 significantly increases CSF concentration of A?Os, increases plasma concentrations of lipids and metabolites, and reduces concentrations of synaptic degeneration markers in AD patient CSF, consistent with the disease-modifying and synaptoprotective mechanism of action established in preclinical studies. No other therapeutic currently in development selectively targets the most toxic form of the A? protein ? oligomers (A?Os) and has demonstrated selective clearance of A?O into CSF in AD patients. No other AD drug candidate has demonstrated normalization of dysregulated protein and lipid/metabolite analytes in AD patient biofluids or reported reduction of synaptic damage markers in AD patients as much, and as rapidly, as CT1812. We hypothesize that the effects of oligomer displacement and clearance on cognitive function wil l be detectable in symptomatic patients, and the effect on disease modification will be detectable in presymptomatic patients. CogRx discovered CT1812, its mechanism of action and the role of the sigma-2 receptor complex in AD. No other group is pursuing this mechanism of action for Alzheimer?s disease treatment. CT1812 has been demonstrated to be safe and well tolerated in healthy volunteers and mild-to moderate AD patients in placebo-controlled Phase 1b/2a trials. Adverse events were predominantly mild and included headache and GI disturbances. Two doses of CT1812 are currently being evaluated in follow-on safety trials in mild to moderate AD patients (Q.D. for 6 months, MMSE 18-26). These same two doses will be tested in early AD patients (MMSE 20-30) in the current trial, with treatment duration extended to 18 months. This project proposes to conduct a randomized, double-blind, placebo-controlled, Phase 2 trial to evaluate the safety and tolerability of two doses of CT1812 in patients with early AD (MMSE 20-30, corresponding to FDA late stage 2 to early stage 4) given q.d. over 18 months. This trial will determine whether CT1812 beneficially affects cognition as measured by CDR-SB and other secondary cognitive measures, as well as measuring the impact of CT1812 on biomarkers of target engagement (CSF concentrations of A? oligomers and synaptic degeneration proteins) and disease modification (CSF concentrations of total tau and NfL, serum NfL as well as hippocampal and whole brain volume change by MRI). Completion of this study in early AD patients will inform the design and methods of the subsequent long term disease modification Phase 3 trials with CT1812.