1 unchanged sentence
Currently available therapies for these diseases are limited, with many diseases having no approved therapies or treatments.
−Removed: Our goal is to develop disease modifying treatments for patients with these degenerative disorders by initially leveraging our expertise in the σ-2 (sigma-2) receptor, or S2R, which is expressed by multiple cell types, including neuronal synapses, and acts as a key regulator of cellular damage commonly associated with certain age-related degenerative diseases of the CNS and retina.
−Removed: We believe that targeting the S2R complex represents a mechanism that is functionally distinct from other current approaches in clinical development for the treatment of degenerative diseases.
−Removed: Our lead product candidate, CT1812, is an orally delivered, small molecule modulator designed to penetrate the blood-brain barrier and bind selectively to the S2R complex.
−Removed: We have initially focused on the development of CT1812 for the treatment of Alzheimer’s disease, or AD, by targeting β-amyloid, or Aβ oligomers, which have been linked to the disease.
−Removed: We believe our evidence demonstrates that by binding to the S2R complex, CT1812 displaces Aβ oligomers from their neuronal receptors.
−Removed: Based on this mechanism, we believe CT1812 has the potential to slow the loss of synapses and cognitive decline observed in AD.
−Removed: CT1812 is the first S2R selective ligand modulator to reach clinical trials and is currently in Phase 2 development for the treatment of AD.
+Added: Our goal is to develop disease-modifying treatments for patients with these degenerative disorders.
+Added: Our lead product candidate, zervimesine, also known as CT1812, is an orally delivered, small molecule designed to protect neuronal synapses by preventing the binding of oligomers of pathogenic proteins including β-amyloid, or Aβ and ɑ-synuclein.
+Added: These and similar protein oligomers have been linked to the progression of degenerative diseases such as Alzheimer’s disease, or AD, and dementia with Lewy bodies, or DLB.
+Added: The United States Adopted Name (USAN) Council adopted zervimesine as the USAN for CT1812 in December 2024.
+Added: The company’s initial focus has been on the development of zervimesine for the treatment of Alzheimer’s disease.
+Added: We believe our evidence demonstrates that zervimesine displaces Aβ oligomers from their neuronal receptors.
+Added: Based on this mechanism, we believe zervimesine has the potential to slow the loss of synapses and cognitive decline observed in AD.
The direct healthcare costs to care for patients with AD and other dementias in the United States is estimated to exceed $350 billion.
Approximately 7 million people in the United States have been diagnosed with AD, and the World Health Organization estimates that AD affects as many as 35 million people globally.
−Removed: Among people with AD, approximately 50% have mild disease, 30% have moderate disease and 20% have severe disease.
−Removed: We are continuing to enroll patients in the Phase 2 COG1201 (SHIMMER) study of CT1812 in mild-to-moderate dementia with Lewy bodies, or DLB.
−Removed: Enrollment concluded in the Phase 2 COG0201 (SHINE) study of CT1812 in mild-to-moderate AD.
−Removed: Preliminary results from an interim analysis of the first 24 patients demonstrated a statistically significant decline in the presence of Aβ monomers and a positive trend on cognitive function as measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, or ADAS-Cog, in patients receiving CT1812 compared to placebo.
−Removed: We anticipate top-line results in mid-2024 after the last participants have completed six months of treatment.
−Removed: As of November 21, 2023, approximately 278 subjects with dementia have received CT1812 in our clinical trials, including subjects with AD and DLB.
−Removed: CT1812 has continued to be well tolerated and has been granted Fast Track designation by the U.S.
+Added: Enrollment has concluded in the company’s Phase 2 COG0201 (SHINE) study of zervimesine in mild-to-moderate AD.
+Added: Top-line results were reported in 2024.
+Added: Enrollment is ongoing in the COG0203 (START) Phase 2 study of zervimesine in patients with Mild Cognitive Impairment (MCI) and early-stage AD.
+Added: We are conducting the START clinical trial in collaboration with the Alzheimer’s Clinical Trial Consortium, or ACTC, an NIA-funded clinical trials network designed to accelerate studies for therapeutics for AD and related dementias.
+Added: Both studies are supported by grant awards totaling $110 million from the National Institute of Aging, or NIA, a division of the National Institutes of Health, or NIH.
+Added: In addition, company research produced evidence that zervimesine prevents the binding of ɑ-synuclein to neurons, rescuing cellular function that is compromised in DLB.
+Added: Based on this information, we conducted the Phase 2 COG1201 (SHIMMER) clinical trial in 130 adults with mild-to-moderate DLB, which concluded in 2024.
+Added: Top-line results were presented in December 2024 and later at the International Lewy Body Dementia Conference (ILBDC) in January 2025.
+Added: The trial was funded by a grant of approximately $30 million from the NIA.
+Added: Our clinical trials have been funded by approximately $171 million in cumulative grants awarded primarily by the NIA.
+Added: As of October 15, 2024, approximately 477 subjects have received zervimesine in our clinical trials, including people with AD, DLB and dry AMD.
+Added: Zervimesine has continued to be generally well tolerated and has been granted Fast Track designation by the U.S.
Food and Drug Administration, or FDA, for AD.
−Removed: Our clinical trials have been funded by approximately $171 million in cumulative grants awarded primarily by the National Institute of Aging, or NIA, a division of the National Institutes of Health, or NIH.
−Removed: Our awards include a grant award of approximately $81 million from the NIA to fund our Phase 2 START (COG0203) study of CT1812 in patients with early-stage AD.
−Removed: We received clearance from the FDA to proceed with the START clinical trial and recruitment has commenced.
−Removed: We intend to enroll 540 adults with mild cognitive impairment, or MCI, due to AD or mild AD who have elevated levels of Aβ as determined by a clinical diagnosis of AD confirmed with amyloid biomarkers positron emission tomography, or PET, imaging and/or cerebrospinal fluid, or CSF, biomarkers.
−Removed: Participants are being randomized to receive CT1812 or a placebo for 18 months.
−Removed: In addition to cognitive and functional measures, such as the Clinical Dementia Rating Scale, or CDR, Sum of Boxes, or SB, and ADAS-Cog, we intend to use a variety of biomarkers to measure target and/or pathway engagement and assess changes in neurodegeneration and disease progression.
−Removed: We are conducting this clinical trial in collaboration with the Alzheimer’s Clinical Trial Consortium, or ACTC, an NIA-funded clinical trials network designed to accelerate studies for therapeutics for AD and related dementias.
−Removed: We expanded our CT1812 pipeline to include geographic atrophy, or GA, secondary to dry age-related macular degeneration, or dry AMD as an additional indication.
−Removed: GA is an advanced form of dry AMD, an eye disease that results in the deterioration of the macula, causing distortion, loss of central vision and eventual blindness.
−Removed: The S2R complex is expressed in the retina in several cell types including the retinal pigment epithelial cells, or RPE, photoreceptors and
−Removed: retinal ganglion cells.
−Removed: We believe that an S2R modulator, such as CT1812, may help to regulate the damage-response processes related to these cells that are impaired in GA secondary to dry AMD.
−Removed: We submitted an Investigational New Drug, or IND, application to the FDA at the end of 2022 and we announced dosing of the first patient in our Phase 2 COG2201 (MAGNIFY) study in July 2023.
−Removed: We intend to enroll up to 246 adults in this study.
−Removed: In addition, we are developing other product candidates in the area of synucleinopathies.
−Removed: Synucleinopathies are a group of degenerative diseases characterized by the abnormal accumulation of the α-synuclein protein in neural cell bodies, including Parkinson’s disease, or PD, and DLB.
−Removed: We are developing a pipeline of innovative, small molecule product candidates that are designed to target the S2R complex, a key regulator of the cellular damage response for diseases such as AD, dry AMD, geographic atrophy (an advanced form of dry AMD), or GA, and other conditions for which there is significant unmet medical need.
−Removed: Our current pipeline is summarized below:
−Removed: Mild-to-Moderate AD
−Removed: Phase 2 COG0201 (SHINE) clinical trial, is designed to evaluate safety, dosing and potential efficacy for CT1812 as a treatment for mild-to moderate AD and enrolled 158 adults with mild-to-moderate (MMSE 18-26) AD.
−Removed: In SHINE, the largest of our trials, we are assessing CT1812’s ability to alter disease progression and cognition.
−Removed: Top-line results are expected in mid-2024 after the last participants have completed six months of treatment.
−Removed: In addition, we completed the Phase 2 COG0202 (SEQUEL) study and presented complete results in October 2023 at the Clinical Trials on Alzheimer’s Disease (CTAD) conference.
−Removed: The SEQUEL trial included evaluations of CT1812’s ability to engage with the S2R complex enabling the restoration of synaptic function as measured by quantitative EEG, or qEEG.
−Removed: Early-stage AD
−Removed: We received clearance from the FDA to proceed with our Phase 2 START (COG0203) clinical trial to evaluate CT1812 in up to 540 adult patients, which is designed to investigate the potential for CT1812’s use at an earlier stage of AD.
−Removed: In addition to cognitive and functional measures, such as CDR-SB (Clinical Dementia Rating Sum of Boxes), ADAS-Cog and volumetric magnetic resonance imaging, or vMRI, we intend to use a variety of biomarkers to measure target and/or pathway engagement and assess changes in neurodegeneration and disease progression.
−Removed: This trial has been funded by a grant of approximately $81 million from the NIA.
−Removed: We are evaluating CT1812 in a 120-patient Phase 2 COG1201 SHIMMER clinical trial to investigate the potential for CT1812’s use as a disease-modifying agent in adults with mild-to-moderate DLB.
−Removed: We are assessing cognitive and functional measures such as Montreal Cognitive Assessment (MoCA), Cognitive Drug Research Battery (CDR), Clinician Assessment of Fluctuation (CAF), Epworth Sleepiness Scale (ESS), Unified Parkinson’s Disease Rating Scale — Part III (MDS-UPDRS3), Clinical Global Impression of Change (ADCS-CGIC), ADCS-Activities of Daily Living (ADCS-ADL) and Neuropsychiatric Inventory (NPI).
−Removed: We are currently recruiting patients in the United States.
−Removed: The trial has been funded by a grant of approximately $30 million from the NIA.
−Removed: Geographic Atrophy Secondary to Dry AMD
−Removed: We are also evaluating the use of CT1812 to treat GA secondary to dry AMD in Phase 2 COG2201 (MAGNIFY) study.
−Removed: We are assessing the change in GA lesion size over the treatment duration, as measured by fundus autofluorescence (FAF) imaging, as well as CT1812’s safety and tolerability.
−Removed: We believe that human genetic and proteomic pathway analyses obtained through our AD trials provides evidence of a relationship between the S2R complex and dry AMD.
−Removed: Preclinical data suggest that modulating the S2R complex can alter the biological processes that contribute to dry AMD.
−Removed: We believe that an S2R modulator, such as CT1812, may help to regulate the damage-response processes related to these cells that are impaired in GA secondary to dry AMD.
−Removed: We submitted an Investigational New Drug, or IND, application to the FDA at the end of 2022;
−Removed: the IND was cleared at the end of January 2023;
−Removed: and we announced the initiation of dosing in July 2023.
−Removed: Discovery Initiatives
−Removed: We are pursuing a number of early-stage discovery programs which are built upon our identification of five structurally distinct chemical series.
−Removed: We believe we have identified several structurally distinct compounds that possess advantages for specific disease indications and patient populations.
−Removed: A few of these next-generation S2R modulators have been identified for synucleinopathies and dry AMD and are being assessed as potential IND candidates.
−Removed: For example, one of our next-generation S2R modulators has shown activity in cell-based dry AMD assays, suggesting the potential to maintain homeostatic functions of RPEs, ameliorate lysosomal dysfunction, and prevent RPE cell death.
−Removed: It has further demonstrated retinal exposures above 80% receptor occupancy with oral administration and favorable PK properties, including high degree of bioavailability and high retina-to-plasma ratio, which we believe may provide us with a suitable next-generation molecule to advance for this indication.
−Removed: Therefore, we believe S2R modulators may present a novel therapeutic approach for these indications and intend to pursue development as described below.
−Removed: Our objectives are to develop and advance our portfolio, beginning with our lead product candidate, CT1812, through clinical development for the treatment of age-related degenerative diseases and disorders of the CNS and retina and to leverage our understanding of the S2R complex and its regulation of pathways to pursue indications in other degenerative disorders.
+Added: Recent Developments
+Added: In 2024, we reported top-line results from both the Phase 2 COG0201 (SHINE) clinical trial, which evaluated zervimesine in 153 adults with mild-to-moderate (MMSE 18-26) AD, and the Phase 2 COG1201 (SHIMMER) clinical trial in 130 adults with mild-to-moderate DLB.
+Added: Top-line SHINE results were presented in July 2024 at the Alzheimer’s Association International Conference (AAIC) and additional data from a biomarker-defined population of AD patients from the SHINE study were presented in October 2024 at the Clinical Trials on Alzheimer’s Disease (CTAD) conference.
+Added: Top-line results were presented during an investor webinar in December 2024.
+Added: Top-line SHIMMER results were presented at the International Lewy Body Dementia Conference (ILBDC) in January 2025.
+Added: We initiated the Phase 2 COG2201 (MAGNIFY) clinical study of zervimesine in 2023 based on evidence that zervimesine may be effective in the treatment of GA secondary to dry AMD.
+Added: Based on the favorable results from our dementia programs and the need to preserve capital, we made the strategic decision in January 2025 to focus our resources on the development of zervimesine in AD and DLB.
+Added: As a result, in February 2025 we voluntarily concluded the MAGNIFY clinical study and began investigator site wind-down procedures.
+Added: The conclusion of the study was not the result of any safety concerns.
+Added: At the time of the study conclusion, 100 participants had been enrolled in the trial.
+Added: Results are being compiled by the contract research organization (CRO) following participant completion of final clinic visits.
+Added: We intend to conduct an analysis of the changes in GA lesion size as well as safety and tolerability, which will be reported in the second quarter of 2025.
+Added: We continue to believe that zervimesine has the potential to alter the biological processes that contribute to dry AMD.
+Added: Our objectives are to develop and advance our portfolio, beginning with our lead product candidate, zervimesine.
+Added: We want to leverage our understanding of zeryimesine’s mechanism and its ability to regulate pathways and biological processes.
The key elements of our strategy include:
−Removed: ● Advance clinical development of our lead product candidate, CT1812, in mild-to-moderate AD and earlier stages of the disease .
−Removed: Our lead product candidate, CT1812, has progressed through Phase 1 and into Phase 2 clinical trials.
−Removed: Funding of the Phase 1 and Phase 2 trials has come primarily from the NIA.
−Removed: We are evaluating CT1812 in earlier symptomatic stages of AD and MCI, which is a slight and noticeable measurable decline in cognitive abilities due to AD.
−Removed: Our START (COG0203) clinical trial in patients with mild dementia associated with early-stage AD has been funded by a grant of approximately $81 million awarded from the NIA.
−Removed: ● Advance clinical development of CT1812 for GA secondary to dry AMD .
−Removed: We are evaluating CT1812 as a potential therapy for GA secondary to dry AMD.
−Removed: GA is an advanced form of dry AMD.
−Removed: Dry AMD is an eye disease that results in the deterioration of the macula, causing visual distortion, loss of central vision and eventual blindness.
−Removed: We are currently evaluating CT1812 in a 246-patient Phase 2 study of CT1812 in patients with GA.
−Removed: ● Leverage our understanding of the S2R complex to develop product candidates for other CNS and degenerative diseases, including synucleinopathies.
−Removed: We intend to develop and advance other product candidates to treat other conditions, potentially including the synucleinopathies, which include PD and DLB.
−Removed: We are evaluating CT1812 in a 120-patient Phase 2 COG1201 study of CT1812 in patients with DLB, which is funded primarily through the NIA and are currently recruiting patients.
−Removed: Preclinical data published in February 2021 showed that the S2R complex may play an integral role in the pathology of PD and we believe these results merit further study.
+Added: ● Advance clinical development of our lead product candidate, zervimesine, in mild-to-moderate AD and earlier stages of the disease .
+Added: Our lead product candidate, zervimesine, has progressed through Phase 2 clinical trials.
+Added: Funding of trials to this point has come primarily from the NIA.
+Added: We are evaluating zervimesine in earlier symptomatic stages of AD and MCI, which is a slight and noticeable measurable decline in cognitive abilities due to AD.
+Added: Our COG0203 (START) clinical trial in patients with mild dementia associated with early-stage AD has been funded by a grant of approximately $81 million awarded by the NIA.
+Added: ● Develop product candidates for other CNS and degenerative diseases, including synucleinopathies .
+Added: We intend to develop and advance other product candidates to treat other conditions, potentially including the synucleinopathies, which include Parkinson’s disease (PD) and DLB.
+Added: Preclinical data published in February 2021 showed that our candidate’s mechanism may play an integral role in the pathology of DLB and PD, which we believed merited further study.
+Added: To that end, we conducted a 130-patient Phase 2 COG1201 (SHIMMER) study of zervimesine in patients with DLB, which was funded primarily through the NIA.
● Expand our pipeline through internal development, in-licensing and acquisitions .
−Removed: We intend to leverage our expertise in drug development and business development to evaluate additional product candidates as well as bring forward novel chemical matter using libraries generated with our Novel Improved Conditioned Extraction, or NICE, screening platform as well as other molecule generation and screening strategies.
+Added: We intend to leverage our expertise in drug development and business development to evaluate additional product candidates as well as bring forward novel chemical matter using libraries generated with our molecule generation and screening strategies.
To achieve this objective, we may supplement our internal development initiatives through selective in-licensing arrangements, as well as investments in strategic collaborations, and partnerships which complement our initiatives.
−Removed: ● Optimize the value of CT1812 and other product candidates in major markets.
−Removed: We currently retain all worldwide rights to CT1812 for all indications.
−Removed: We plan to develop and pursue approval of CT1812 and other future product candidates in major markets.
+Added: ● Optimize the value of zervimesine and other product candidates in major markets.
+Added: We currently retain all worldwide rights to zervimesine for all indications.
+Added: We plan to develop and pursue approval of zervimesine and other future product candidates in major markets.
Where appropriate, we may use strategic collaborations or partnerships to accelerate development and maximize the commercial potential of our programs.
−Removed: We and our key opinion leaders believe CT1812 also can be used in combination with other therapeutics and thus may have many partnering opportunities.
+Added: We and our key opinion leaders believe zervimesine also can be used in combination with other therapeutics and thus may have many partnering opportunities.
● Continue to pursue non-dilutive funding opportunities .
The majority of our research and clinical efforts have been funded by approximately $171 million in cumulative grants awarded primarily by the NIA.
−Removed: This includes awards totaling $11 million in support of preclinical studies and $160 million for clinical development, the largest of which was the 2020 award of $81 million supporting our upcoming Phase 2 START (COG0203) study of CT1812 in early-stage AD.
−Removed: These grants are non-dilutive and allow us to collaborate with research institutions in pursuing the development of our product candidates for age-related degenerative diseases.
−Removed: We intend to continue our work with these research institutions and plan to seek additional non-dilutive funding for our clinical development when possible.
−Removed: Our Team and Collaborators
−Removed: We have assembled a management team with extensive experience with CNS and degenerative diseases, significant expertise in the S2R biology domain, as well as drug discovery, clinical development, general management and business development.
−Removed: Collectively, our management team has a track record of managing drug development programs that have received regulatory approval and been successfully commercialized.
−Removed: In addition, our management team has built companies that have initiated innovative technologies and investigational new drug programs.
−Removed: We augment the strengths of our management team with an experienced board of directors and scientific and medical advisory boards.
−Removed: We believe our team, with its deep scientific and drug development background, positions us to become a leader in the development of therapies for age-related degenerative diseases and disorders.
−Removed: Since our inception, we have collaborated and worked closely with key healthcare organizations and thought leading institutions in the field of degenerative diseases to develop and advance our therapeutic candidates.
−Removed: To date, we have received approximately $171 million in cumulative grants awarded primarily from the NIA to support our clinical trials.
−Removed: Our Approach to Treating Age-Related Degenerative Diseases of the CNS and Retina
−Removed: Age-related degenerative diseases are defined by an age-related decline of cellular function often resulting in cell death.
−Removed: Neurodegenerative diseases, perhaps the most prominent of these degenerative disorders, are a variety of conditions defined by progressive degeneration of nerve cells, or neurons, which often leads to neuronal death, causing decline in cognition or other functions, resulting in decreased quality of life and shorter life span.
−Removed: The two most common neurodegenerative diseases are AD and PD.
−Removed: To our knowledge, no other biopharmaceutical company has focused solely on stopping the synaptic binding of soluble Aβ oligomers through the use of small molecule receptor modulators, such as CT1812.
−Removed: We believe our deep expertise in oligomer and synaptic biology provides us with a competitive advantage and led to the creation of (1) proprietary assays that target the critical molecular step causing memory loss and (2) proprietary chemical libraries yielding highly brain penetrant small molecule drugs.
−Removed: Based on this expertise, we are able to discover and optimize small molecule receptor modulators like CT1812 that we believe represent a functionally distinct and promising approach to synaptorestorative AD therapeutics where neurons remain viable and functional.
−Removed: These molecules were designed to displace Aβ oligomers bound to neuronal receptors at synapses and clearing Aβ oligomers from the brain into the CSF.
−Removed: In addition to neurodegenerative diseases, other degenerative diseases include AMD.
−Removed: AMD is a common eye disease that results in the deterioration of the macula, causing visual distortion, loss of central vision and eventual blindness.
−Removed: An estimated 18 million adults in the United States have some form of AMD, which is the leading cause of vision loss in people over 60 years of age.
−Removed: We believe that human genetic and proteomic pathway analyses obtained through our AD trials provides evidence of a relationship between the S2R complex and dry AMD.
−Removed: Preclinical data suggest that modulation of the S2R complex can alter the biological processes that contribute to dry AMD.
−Removed: We believe that an S2R modulator, such as CT1812, may help to regulate the damage-response processes related to these cells that are impaired in dry AMD.
−Removed: We submitted an IND application to the FDA at the end of 2022;
−Removed: it was cleared by the FDA at the end of January 2023;
−Removed: and we reported that the first participant was dosed in the Phase 2 COG2201 (MAGNIFY) study in July 2023.
−Removed: We intend to enroll approximately 246 adult patients who will be randomized to receive once-daily oral CT1812 or placebo for 24 months.
−Removed: The Sigma-2 Receptor Complex
−Removed: The S2R complex is comprised of transmembrane protein 97, or TMEM97, a four-domain transmembrane protein that forms a complex with progesterone receptor membrane component 1, or PGRMC1.
−Removed: The S2R complex is expressed in the CNS, the retina, as well as peripheral organs, including the pancreas, liver and kidney.
−Removed: Within the brain, the S2R complex is found in several areas, including the cerebellum, cortex, hippocampus and substantia nigra, and is enriched in neurons as compared to glial cells in the adult brain.
−Removed: In the retina, the S2R complex is expressed in several cell types including the RPE cells, photoreceptors and retinal ganglion cells.
−Removed: The sigma-2 receptor (S2R) complex
−Removed: Internal and third-party studies suggest that the role of PGRMC1 and TMEM97, the protein components of the S2R complex, regulate cell damage response processes, including cholesterol biosynthesis, vesicle trafficking, progesterone signaling, lipid membrane-bound protein trafficking and receptor stabilization at the cell surface.
−Removed: In addition, the S2R complex regulates autophagy, the cellular process by which altered cellular proteins are degraded and removed.
−Removed: The aberrant activity of these processes, believed to be triggered by cellular stresses, is a hallmark of the dysfunction related to degenerative diseases.
−Removed: The S2R complex is a key regulator of processes that have been implicated in several age-related degenerative diseases and disorders including AD, retinal diseases, such as dry AMD, and synucleinopathies, such as PD and DLB.
−Removed: S2R affects diverse regulatory functions through specific interactions with the oligomer receptors and other membrane proteins.
−Removed: We believe the array of degenerative disorders which involve protein components of the S2R complex allows for the potential therapeutic use of proprietary S2R modulators in numerous indications.
−Removed: While a fuller understanding of the molecular mechanisms involving the S2R complex remains to be elucidated, evidence suggests that targeting the S2R complex may provide therapeutic benefit to a wide range of age- related degenerative diseases and disorders.
−Removed: We believe modulating the S2R complex to normalize cellular function may provide a restoration of normal cellular processes.
−Removed: Biomarker and Imaging-Driven Evidence
−Removed: Biomarkers have become increasingly important in the development of treatments for neurodegenerative diseases for a number of reasons, including monitoring drug activity in patients, assessing changes in disease pathology during treatment and identifying responder populations for clinical trials.
−Removed: Given that biomarker-enabled therapeutics have a higher rate of success at gaining product approval, we elected to employ biomarkers in our programs to mitigate clinical development risk.
−Removed: To that end, in addition to a number of cognitive tests, our clinical trials use a variety of biomarkers to measure target and/or pathway engagement and assess changes in disease progression.
−Removed: For example, in AD, changes in cerebrospinal fluid, or CSF, concentrations of neurogranin and synaptotagmin-1 can be indicative of damage to synapses.
−Removed: In PD and other synucleinopathies, changes in markers such as α-synuclein species, lysosomal enzymes, markers of amyloid and tau pathology, and neurofilament light chain can indicate dysfunction in membrane trafficking and autophagy processes.
−Removed: Quantitative EEG and PET imaging agents as well as vMRI may have utility in several neurodegenerative disorders to measure synaptic function, synaptic density and brain atrophy, respectively.
−Removed: Our Novel, Improved Conditioned Extracts (NICE) Screening Platform
−Removed: Chemical structures that we are currently evaluating as potential therapeutics for degenerative diseases originate from our NICE screening platform.
−Removed: The NICE screening platform allowed us to generate proprietary small molecule libraries derived from natural chemical scaffolds through a proprietary process which we refer to as conditioned extraction.
−Removed: Conditioned extraction, a process pioneered by a cofounder, allows us to eliminate undesirable properties of well characterized, biologically active compounds sourced from natural products, while retaining their biological activity.
−Removed: The resulting molecular configurations are then subjected to proprietary functional in vitro screening assays designed to replicate the mature brain and its intricate connections and patterns of electrical signaling.
−Removed: Unlike most other screening assays, such as cells lines derived from immortalized neuronal tumor cells, our use of mature primary neuronal cultures provides us with information-rich measurements more indicative of normal brain function and predicative of functional benefit.
−Removed: We have utilized our NICE screening platform in conjunction with these mature primary neuronal cultures to develop product candidates for our proprietary Early Alzheimer’s Screening System, or EASSY.
−Removed: The candidate library produced by the NICE screening platform is predisposed to compounds with attractive drug-like properties such as low molecular weight, low number of reactive hydrogen bonds, lipophilicity and relatively neutral chemistry properties.
−Removed: These characteristics reduce the reactivity of the molecules and related toxicities, while also enhancing their ability to cross the blood-brain and blood-retina barriers.
−Removed: As a result, the NICE screening platform was designed to accelerate drug development time while reducing development risk.
−Removed: We believe this platform provides us with differentiated libraries which may lead to development candidates beyond CT1812.
−Removed: Our Product Candidates
−Removed: We are leveraging our expertise in the biology of the S2R complex, synaptic function and plasticity, and our understanding of the role of toxic age-related soluble proteins, to construct a pipeline of innovative, differentiated small molecule product candidates that are intended to restore normal cellular damage responses.
−Removed: We intend to develop therapeutics with the potential to overcome diseases associated with age-related toxic protein buildups that disrupt key cellular processes.
−Removed: Our initial product candidates target diseases characterized by dysfunction or dysregulation of the S2R complex that leads to cellular degeneration, as observed in age-related degenerative diseases and disorders, such as AD, GA secondary to dry AMD, PD and DLB as depicted in the illustration below.
−Removed: Our Lead Product Candidate:
−Removed: Our lead product candidate, CT1812, is an investigational orally delivered, small molecule modulator that penetrates the blood-brain and blood-retina barriers and binds selectively to the S2R complex;
−Removed: and through its modulation of S2R restores normal function of synapses, as well as critical cellular processes such as autophagy, cholesterol biosynthesis, vesicle trafficking, progesterone signaling, lipid membrane-bound protein trafficking and receptor stabilization at the cell surface.
−Removed: CT1812 originated from our initial efforts with our NICE screening platform which enables the generation of innovative leads.
−Removed: Leads identified through NICE were then evaluated using proprietary in vitro assays designed to better emulate in vitro synaptic activity.
−Removed: We believe the use of these assays allows us to identify functionally active structures which may impact neuronal behavior significantly faster than alternate screening approaches.
−Removed: We currently retain worldwide rights to CT1812 for all indications and are developing CT1812 as a potential treatment for a range of diseases including AD, GA secondary to dry AMD and synucleinopathies, such as DLB.
−Removed: CT1812 for the Treatment of Alzheimer’s Disease (AD)
−Removed: CT1812 was designed to selectively target and displace Aβ oligomers bound to neuronal receptors at synapses by a new and differentiated mechanism of action.
−Removed: CT1812 binds to S2R which interacts directly with components of the oligomer receptor, resulting in displacement of bound oligomers, which are then cleared from synapses.
−Removed: In our preclinical studies, CT1812 has demonstrated the potential to protect synapses, facilitate their restoration and improve cognitive performance.
−Removed: These preclinical results are currently being evaluated through our ongoing Phase 2 clinical trials.
+Added: We intend to continue our work with these research institutions and potentially expand to include pharmaceutical partners, advocacy organizations and others to seek additional non-dilutive funding for our clinical development when possible.
+Added: Zervimesine for the Treatment of Dementias:
+Added: Neurodegenerative diseases including AD and DLB are defined by progressive degeneration of nerve cells, or neurons, which often leads to neuronal death, causing dementia, a progressive decline in memory, language, problem-solving and other cognitive functions, results in decreased quality of life and shorter life span.
+Added: Two of the most common causes of dementia are AD and DLB.
+Added: Zervimesine is designed to stop the binding of Aβ and ɑ-synuclein oligomers to neuronal synapses, thereby protecting neurons from the toxic effects of these pathogenic protein species.
+Added: We believe that zervimesine represents a functionally distinct and promising approach to synaptoprotective therapeutics where neurons remain viable and functional.
+Added: Study Identifier
+Added: Clinical Phase
+Added: Alzheimer’s Disease (AD)
+Added: COG0203 (START)
+Added: The study is enrolling up to 540 participants with MCI or early AD
+Added: mild-moderate
+Added: COG0201 (SHINE)
+Added: Phase 2 (n=153)
+Added: Participants treated with zervimesine experienced a cognitive benefit compared to placebo
+Added: mild-moderate
+Added: COG0202 (SEQUEL)
+Added: Phase 2 (n=16)
+Added: Participants treated with zervimesine exhibited improvement across prespecified EEG parameters
+Added: mild-moderate
+Added: COG0105 (SPARC)
+Added: Phase 1 (n=23)
+Added: Treatment with zervimesine was assessed using various imaging modalities, including PET imaging and volumetric MRI (vMRI)
+Added: mild-moderate
+Added: COG0104 (SNAP)
+Added: Phase 1 (n=3)
+Added: Confirmed preclinical findings showing an increase in Aβ oligomers in CSF, suggesting increased off-rate from receptors
+Added: Dementia with Lewy Bodies (DLB)
+Added: mild-moderate
+Added: COG1201 (SHIMMER)
+Added: Phase 2 (n=130)
+Added: Participants treated with zervimesine experienced benefits across behavioral, functional, cognitive and motor scales
+Added: Alzheimer’s Disease (AD)
+Added: Zervimesine was designed to selectively target and displace Aβ oligomers bound to neuronal receptors at synapses, a new and differentiated mechanism of action.
+Added: In our preclinical studies, zervimesine has demonstrated the potential to protect synapses, facilitate their restoration and improve cognitive performance.
Overview of the Disease
3 unchanged sentences
Due to the size of the affected population, we believe that AD is one of the most significant unmet medical needs of our time.
−Removed: Nearly six million Americans have been diagnosed with AD and disease prevalence is expected to more than double by 2050.
+Added: Nearly seven million Americans are living with AD and disease prevalence is expected to more than double by 2050.
The direct healthcare costs to care for patients with AD and other dementias in the United States is currently estimated to exceed $350 billion and projected to increase to $1 trillion by 2050.
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Currently Approved AD Therapeutics
−Removed: Only two disease-modifying therapeutic options have been approved by the FDA:
−Removed: Biogen’s Aduhelm, which received accelerated approval on June 7, 2021 and Eisai’s Leqembi, which received complete approval in July 2023.
−Removed: Aduhelm and Leqembi are monoclonal antibodies administered via infusion reported to reduce Aβ plaques and protofibrils, and representing approaches that are distinct from our small molecule approach to modulate the S2R, thereby blocking Aβ oligomers from binding to synapses.
+Added: Only two FDA-approved disease-modifying therapeutic options for AD are currently available in the United States:
+Added: Eisai’s Leqembi (lecanemab), which received complete approval in July 2023;
+Added: and Eli Lilly’s Kisunla (donanemab), which was approved in July 2024.
+Added: Both are approved for the treatment of people with MCI or mild Alzheimer’s disease (MMSE between 22 and 30).
+Added: Biogen’s Aduhelm (aducanumab) was approved in July 2021 but was discontinued in January 2024.
+Added: Leqembi and Kisunla are monoclonal antibodies administered via infusion designed to slow the progression of cognitive decline by reducing Aβ plaques and protofibrils.
+Added: They represent approaches that are distinct from our small molecule approach of blocking the binding of Aβ oligomers to synapses.
Other therapies approved for AD are indicated to treat the symptoms of AD:
4 unchanged sentences
These therapeutic products do not modify or alter the progression of the underlying disease and provide only modest efficacy in treating the symptoms.
−Removed: Therapeutic Approaches in Development to Treat the Underlying Disease Have Shown Little Success
+Added: Current Status of AD Therapeutic Approaches
Numerous therapeutic approaches have been evaluated to remedy the causes of AD.
6 unchanged sentences
As a result, the reduction in the levels of Aβ aggregates at the synapse has been a prominent objective of a significant number of therapeutic candidates, including active and passive immunotherapies, designed specifically to target Aβ aggregates.
−Removed: Several therapeutics in this class have recently been approved by the FDA, including Aduhelm and Leqembi, which are monoclonal antibodies designed to reduce Aβ plaques and protofibrils, approaches that are distinct from but potentially complementary to our small molecule approach of targeting the S2R to prevent Aβ oligomer toxicity at the synapse.
−Removed: We believe a common issue with therapeutic interventions intended to limit Aβ aggregate concentrations in the brain is that they fail to discriminate between different forms of Aβ aggregates:
−Removed: fibrils, plaques and oligomers.
−Removed: Such efforts may demonstrate success clearing fibrils and the largely inert plaques but fail to address the specific neurotoxic effects of Aβ oligomers.
−Removed: Conversely, as exemplified by Leqembi’s clinical results, we believe that preferentially targeting Aβ protofibrils/oligomers has the potential to prevent synaptotoxicity.
−Removed: Our strategy of targeting the S2R to prevent Aβ oligomer toxicity at the synapse is distinct from these immunotherapeutic approaches, but we believe may be complementary.
+Added: As exemplified by Leqembi’s clinical results, we believe that preferentially targeting Aβ protofibrils/oligomers has the potential to prevent synaptotoxicity.
+Added: Several therapeutics in this class have recently been approved by the FDA, including Aduhelm, Leqembi and Kisunla, which are monoclonal antibodies designed to reduce Aβ plaques and protofibrils, approaches that are distinct from but potentially complementary to our small molecule approach of blocking Aβ oligomer binding.
+Added: Emerging Role of Biomarkers in AD
+Added: Biomarkers have become increasingly important in the development of treatments for neurodegenerative diseases for a number of reasons, including monitoring drug activity in patients, assessing changes in disease pathology during treatment and identifying responder populations for clinical trials.
+Added: Given that biomarker-enabled therapeutics have a higher rate of success at gaining product approval, we elected to employ biomarkers in our programs to mitigate clinical development risk.
+Added: To that end, in addition to a number of cognitive tests, our clinical trials use a variety of biomarkers to measure target and/or pathway engagement and assess changes in disease progression.
+Added: For example, in AD, tangles of Aβ and phosphorylated tau (p-tau) build up in the brain and can be visualized through a positron emission tomography, or PET scan.
+Added: Recently, tests have been developed that can detect levels of p‐tau in blood plasma.
+Added: Increasing levels of p-tau, whether visualized with PET or measured in blood plasma, indicates increasing disease burden.
+Added: Data generated by pharmaceutical companies indicates that individuals with lower AD pathology at baseline, as reflected by lower levels of p‑tau, have greater response to amyloid-based therapies.
+Added: Other potentially useful biomarkers include neurofilament light chain, which can indicate dysfunction in membrane trafficking and autophagy processes.
+Added: Quantitative EEG and PET imaging agents as well as vMRI may also have utility in several neurodegenerative disorders to measure synaptic function, synaptic density and brain atrophy, respectively.
The Role of Aβ Oligomers on Synapses and the Downstream Impact to Brain Function and AD
3 unchanged sentences
Neurons do not divide or reproduce as part of normal physiological function.
−Removed: Emerging scientific evidence suggests that Aβ oligomers, formed over time through the buildup of Aβ and its aggregates, bind to specific parts of the synaptic structure and interfere with the normal process of memory formation.
+Added: Scientific evidence has demonstrated that Aβ oligomers, formed over time through the buildup of Aβ and its aggregates, bind to specific parts of the synaptic structure and interfere with the normal process of memory formation.
This ligand-like activity confers to Aβ oligomers potent synaptotoxic activity.
5 unchanged sentences
We are further encouraged by the numerous precedents which exist that demonstrate the therapeutic utility of blocking ligand-receptor interactions in the brain with small molecule drugs capable of crossing the blood-brain barrier.
−Removed: CT1812 Uses a Differentiated Mechanism of Action to Selectively Target Aβ Oligomers
−Removed: Our proprietary CT1812 product candidate employs a novel and fundamentally different mechanism which through alteration of S2R activity selectively facilitates removal of neurotoxic Aβ oligomers.
+Added: Zervimesine’s Mechanism of Action Prevents Binding of Aβ Oligomers
+Added: Our proprietary zervimesine product candidate employs a novel and fundamentally different mechanism compared to other approved or experimental treatments, which facilitates removal of neurotoxic Aβ oligomers through alteration of S2R activity.
Experimental evidence suggests that Aβ oligomers likely occupy binding sites contiguous to the S2R complex.
−Removed: Binding at these locations is believed to produce structural distortions which inhibit the proper functioning of the S2R complex including its role in regulating critical signaling pathways.
−Removed: The preferential binding of CT1812 to the S2R complex produces changes that alters the binding affinity of Aβ oligomers to their targets.
−Removed: CT1812 binding to the S2R complex likely modulates the conformation of the
−Removed: S2R complex, which in turn allosterically alters the conformation of the oligomer binding pocket on the oligomer receptors.
−Removed: Binding pocket destabilization leads to displacement of Aβ oligomers from the neurons and neuronal synapse.
−Removed: Once displaced, Aβ oligomers are unable to rebind as long as threshold concentrations of CT1812 are present, and are then rapidly removed from the synapse.
−Removed: Based on our preclinical studies, we believe that CT1812 not only prevents binding of Aβ oligomers, displacing them from the S2R complex sites at neuronal synapses, but also slows Aβ oligomer-induced loss of synapses and restores synaptic activity, which may reverse downstream alterations related to membrane trafficking.
−Removed: The Use of an S2R Targeted Approach is Supported by the A673T Mutation
−Removed: We believe the benefit of the mechanism by which CT1812 stops the toxic impact of Aβ oligomers on cellular function is further supported by an analysis of the Aβ sequence variant, A673T, which is commonly referred to as the “Icelandic” mutation.
−Removed: The A673T mutation is the first variant associated with a mutation in the protein structure of Aβ, first identified through a genomic analysis of the Icelandic population.
−Removed: Importantly, carriers of the mutation are four-fold less likely to develop AD.
−Removed: The A673T mutation, which involves the substitution of the amino acid alanine for threonine at position 673 of the precursor molecule, not only produces fewer Aβ monomers, but our research indicated that the toxic Aβ oligomers generated have four-fold lower affinity for brain cell synapses.
−Removed: This reduced binding is evidenced in the results of in vitro experiments, which are presented below.
−Removed: Whereas wildtype Aβ oligomer binding is pronounced, the binding of the A673T variant is much lower.
−Removed: Binding affinities of wildtype versus mutant Aβ oligomers to synapses
−Removed: (intensity in arbitrary fluorescent units)
−Removed: wt Aβ (1 – 42) oligomers
−Removed: Site 1:442 ± 70
−Removed: 7.98 × 10 5 ± 0.29 × 10 5
−Removed: A673T mutant Aβ (1 – 42) oligomers
−Removed: Site 1:1,955 ± 502
−Removed: 5.98 × 10 5 ± 0.50 × 10 5
−Removed: Kd is a constant used to evaluate and rank the strengths of interactions for ligands and their receptors.
−Removed: The smaller the Kd value, the greater the binding affinity.
−Removed: Bmax refers to the maximum amount of a ligand that can bind specifically to a receptor.
−Removed: Intensity is measured in arbitrary fluorescent units.
−Removed: We believe that CT1812 is the only drug candidate currently in clinical trials that mimics the effects of the A673T mutation.
−Removed: As the images presented below suggest, both CT1812 and the A673T mutation similarly reduced the binding of toxic Aβ oligomers to synapses.
−Removed: We believe that drug candidates like CT1812 that mimic the protective effects of the A673T mutation are more likely to succeed in the clinical setting in patients with mild-to-moderate AD.
−Removed: CT1812 Clinical Results in AD
−Removed: We have completed multiple clinical trial evaluations of CT1812, in both healthy volunteers and patients with mild-to-moderate AD, with two clinical trials ongoing (SHINE, which has concluded enrollment, and START, which is currently recruiting).
−Removed: The clinical trials we have conducted to date have enabled us to evaluate the safety profile of CT1812, as well as validate its mechanism through proof-of-concept trials and to conduct initial assessments of its therapeutic potential.
+Added: The preferential binding of zervimesine to the S2R complex produces changes that alter the binding affinity of Aβ oligomers to their targets.
+Added: Zervimesine binding to the S2R complex is hypothesized to modulate the conformation of the S2R complex, which in turn allosterically alters the oligomer receptors causing displacement of Aβ oligomers from the neurons and neuronal synapse.
+Added: Displaced Aβ oligomers are less able to rebind as long as threshold concentrations of zervimesine are present and are rapidly removed from the synapse.
+Added: Based on our preclinical studies, we believe that zervimesine not only prevents binding of Aβ oligomers, displacing them from neuronal synapses, but also slows Aβ oligomer-induced loss of synapses and restores synaptic activity, which may reverse downstream synaptotoxic effects.
+Added: Zervimesine Clinical Results in AD
+Added: We have completed multiple clinical trial evaluations of zervimesine, in both healthy volunteers and patients with mild-to-moderate AD, and have one clinical trial ongoing (START) in patients with MCI or early AD.
+Added: The clinical trials we have conducted to date have enabled us to evaluate the safety profile of zervimesine;
+Added: validate its mechanism through proof-of-concept trials;
+Added: assess clinical efficacy signals;
+Added: and identify predictive biomarkers of treatment response.
The following is the status of our completed and ongoing clinical trials.
−Removed: Overview of our completed, ongoing and planned clinical studies of CT1812 for AD and dementia
+Added: Overview of our Completed and Ongoing Clinical Studies of Zervimesine for AD
COG0201 — Phase 2 (SHINE) Clinical Trial
−Removed: Our ongoing COG0201 SHINE study is a randomized, double-blind, placebo-controlled Phase 2 clinical trial to evaluate the safety and potential efficacy of CT1812.
−Removed: A total of 153 adult participants were enrolled and divided in two CT1812 dose groups (100 mg or 300 mg) and one placebo group, dosed daily for six months.
−Removed: Endpoints include safety and biomarker evidence of disease modification as well as cognitive function, as measured by the ADAS-Cog 11-item version, or ADAS-Cog 11.
+Added: Our COG0201 SHINE study was a randomized, double-blind, placebo-controlled Phase 2 clinical trial designed to evaluate the safety and efficacy of zervimesine.
+Added: A total of 153 adults with mild-to-moderate AD were enrolled and divided into two zervimesine dose groups (100 mg or 300 mg) and one placebo group, dosed daily for six months.
+Added: Endpoints included safety and biomarker evidence of disease modification as well as cognitive function, as measured by ADAS-Cog 11.
ADAS-Cog 11 is a globally recognized cognitive scale that is used to assess cognition in patients with AD.
−Removed: Top-line results are expected in mid-2024 after the last participants have completed six months of treatment.
−Removed: Preliminary data from an interim analysis of the first 24 patients from the COG0201 study demonstrated that CT1812 continued to be generally well tolerated.
−Removed: There were four serious adverse events, or SAEs, which were not drug-related and occurred in a single placebo patient.
−Removed: The patient was discontinued due to one of the SAEs.
−Removed: Treatment emergent adverse events, or TEAEs, were well balanced across all treatment groups.
−Removed: We observed mild and transient elevations of liver enzymes in three patients without any other indications of liver injury.
−Removed: These data were consistent with findings from earlier clinical trials.
−Removed: The preliminary data also demonstrated a significant decline in the presence of Aβ monomers and a three-point mean improvement in the rate of cognitive decline as measured by ADAS-Cog 11, in patients receiving CT1812 when compared to placebo.
−Removed: These results were observed in patients receiving CT1812 or placebo in addition to background therapies they may have already been receiving for AD.
−Removed: We believe these preliminary data provide promising evidence of CT1812’s potential cognitive and biological impact.
−Removed: These data also indicate that patients treated with CT1812 showed relative stability on a measure of cognitive performance compared to the placebo group.
−Removed: A mean difference in the rate of decline of approximately three points was observed between the CT1812 dose groups receiving either 100 mg or 300 mg versus the placebo group based on the ADAS-Cog 11 measurements.
−Removed: Preliminary data showed a three-point improvement in cognitive decline in CT1812-treated patients.
−Removed: Proteomic measurements were also performed of CSF and plasma from these patients, from which we have comprehensive datasets of whole proteome changes observed in AD patients given CT1812 versus placebo for six months.
+Added: Top-line results were reported in July 2024 with additional data reported in October 2024.
+Added: A prespecified analysis conducted on SHINE results identified plasma p-tau217 as a biomarker that may predict an optimal therapeutic response in patients with mild-to-moderate AD.
+Added: Participants treated with zervimesine (pooled 100 mg and 300 mg) who had baseline levels of plasma p-tau217 below the median of 1.0 pg/mL experienced a 95% reduction of cognitive decline at week 26 as measured by ADAS-Cog 11 relative to placebo-treated participants.
+Added: We believe P-tau217 is an important biomarker that has shown the ability to distinguish Alzheimer’s disease from other neurodegenerative disorders with a high degree of accuracy compared to other available biomarkers.
+Added: In the overall modified intent-to-treat, or mITT, population in SHINE, participants treated with once-daily oral zervimesine experienced less cognitive decline than those treated with placebo.
+Added: As measured with ADAS-Cog 11, zervimesine-treated participants (pooled 100 mg and 300 mg) experienced a mean 38% slowing of decline at six months versus baseline compared to placebo-treated, but did not achieve statistical significance.
+Added: There were consistent trends favoring zervimesine in other cognitive measures:
+Added: ADAS-Cog 13, cognitive composite, MMSE;
+Added: as well as in functional measures of activities of daily living (ADCS-ADL) and of clinical global impression of change (ADCS-CGIC).
+Added: No discontinuations due to AEs occurred in the 100 mg zervimesine group.
+Added: At the 300 mg dose, ten participants (nine at scheduled visits and one at an unscheduled visit) experienced treatment-emergent liver enzyme test (“LFT”) increases (greater than 3xULN) that subsided after cessation of drug without evidence of serious liver injury.
+Added: There were no LFT elevations observed in the 100 mg dose.
+Added: Proteomic measurements were also performed on cerebrospinal fluid (CSF) and plasma from these patients, from which we have comprehensive datasets of whole proteome changes observed in AD patients given zervimesine versus placebo for six months.
From this, we identified product candidate pharmacodynamic biomarkers that could reflect processes of target engagement, pathway engagement and/or early disease modification.
−Removed: The interim analysis of the SHINE trial (SHINE A) was not powered to detect statistically significant treatment differences.
−Removed: Nevertheless, p-values were calculated at the time of the interim analysis with respect to the clinical and biomarker outcomes to help inform on the potential importance of observed numerical treatment differences.
−Removed: For these interim analyses, p-values<0.05 were considered “significant” while p values>0.05 were considered “non-significant.” The approximately three-point treatment difference relative to placebo observed for the pooled dose groups that was observed on the ADAS-Cog 11 was non-significant (p>0.05;
−Removed: p=0.1295), while the treatment difference relative to placebo that observed for the reduction in CSF Aβ 42 protein at the 300 mg dose was significant (p<0.05;
COG0203 — Phase 2 START Clinical Trial
−Removed: Our COG0203 study, referred to as START, is a randomized, double-blind, placebo-controlled Phase 2 clinical trial designed to enroll 540 patients with early-stage AD and powered to show a change in the rate of cognitive and functional decline.
−Removed: We are currently recruiting patients with MCI due to AD or mild AD who have elevated levels of Aβ as determined by PET imaging or as measured in CSF.
−Removed: The trial is being conducted in collaboration with the ACTC and will utilize approximately 50-60 sites including research sites associated with the consortium, as well as other qualified sites that are not part of the consortium.
−Removed: Patients will be randomized to receive CT1812 or placebo for 18 months.
−Removed: In addition to a battery of cognitive measures, we intend to use a variety of biomarkers to measure target engagement and assess changes in neurodegeneration and disease progression.
−Removed: We have received a grant of approximately $81 million from the NIA to fund this trial.
−Removed: Completed Proof-of-Concept Clinical Trials for the Mechanism of CT1812
−Removed: We have conducted a series of clinical proof-of-concept trials intended to assess target engagement and the impact of CT1812 on synaptic activity.
−Removed: These proof-of-concept trials are presented in more detail below.
+Added: Our COG0203 study, referred to as START, is a randomized, double-blind, placebo-controlled Phase 2 clinical trial that is currently enrolling 540 patients with early-stage AD and using the Clinical Dementia Rating Scale Sum of Boxes;
+Added: or CDR-SB to show a change in the rate of cognitive and functional decline.
+Added: We are recruiting patients with MCI due to AD or mild AD who have elevated levels of Aβ as determined by PET imaging or as measured in CSF.
+Added: The trial is being conducted in collaboration with ACTC and will utilize approximately 50-60 sites including research sites associated with the consortium, as well as other qualified sites that are not part of the consortium.
+Added: Patients will be randomized to receive zervimesine or placebo for 18 months.
+Added: In addition to a battery of cognitive and functional measures, we intend to use a variety of biomarkers to measure target engagement and assess changes in neurodegeneration and disease progression.
+Added: We have been awarded a grant of approximately $81 million from the NIA to fund this trial.
+Added: Completed Proof-of-Concept Clinical Trials for the Mechanism of Zervimesine
COG0202 — Phase 2 SEQUEL Clinical Trial
−Removed: Our COG0202 SEQUEL study is a randomized, double-blind, placebo-controlled Phase 2 clinical trial of 16 patients with mild-to-moderate AD to evaluate the potential efficacy of CT1812 in restoring synaptic function in patients through qEEG measurement, as reflected by relative theta power.
−Removed: The trial is a two-arm crossover trial, in which half of the participants received 300 mg of CT1812 daily for 29 days.
+Added: Our COG0202 SEQUEL study is a randomized, double-blind, placebo-controlled Phase 2 clinical trial of 16 patients with mild-to-moderate AD to evaluate the potential efficacy of zervimesine in restoring synaptic function in patients through quantitative EEG (qEEG) measurement, as reflected by relative theta power.
+Added: The trial is a two-arm crossover trial, in which half of the participants received 300 mg of zervimesine daily for 29 days.
After a 14-day wash out period, these participants received placebo for an additional 29 days.
The other half of the participants received placebo daily for 29 days.
−Removed: After a 14-day wash out period, these participants received CT1812 treatment for an additional 29 days.
+Added: After a 14-day wash out period, these participants received zervimesine treatment for an additional 29 days.
CSF and qEEG evaluations were taken periodically throughout the duration of the trial.
We completed enrollment in the first quarter of 2023 and presented results in October 2023.
−Removed: Results showed that CT1812-treated participants exhibited a statistically significant change in relative theta in the central region of the brain and consistent trends of improvement across all prespecified EEG parameters, reflecting improved synaptic function after just a matter of weeks.
+Added: Results showed that zervimesine-treated participants exhibited a significant change in relative theta in the central region of the brain and consistent trends of improvement across all prespecified EEG parameters, reflecting improved synaptic function after just a matter of weeks.
COG0105 — Phase 1 SPARC Clinical Trial
The COG0105 SPARC study is a randomized, double-blind, placebo-controlled Phase 1 clinical trial of 23 patients with mild-to-moderate AD.
−Removed: The primary objectives of the study were to evaluate CT1812 for safety and tolerability.
−Removed: The secondary objectives were to evaluate potential effects of CT1812 on biologically relevant endpoints using various imaging modalities, including PET imaging and vMRI as well as CSF biomarkers, and cognitive and clinical endpoints.
−Removed: Participants were randomized to receive treatment with 100 mg or 300 mg of CT1812 or placebo once daily for 24 weeks.
−Removed: A preliminary analysis has been made of safety, clinical laboratory measurements, PET imaging, functional MRI and vMRI, CSF biomarkers and clinical outcomes in patients treated with CT1812 compared to those in patients receiving placebo.
−Removed: Seventeen patients completed the study protocol, eleven in the CT1812 arm (six in the 100 mg cohort;
+Added: The primary objectives of the study were to evaluate zervimesine for safety and tolerability.
+Added: The secondary objectives were to evaluate potential effects of zervimesine on biologically relevant endpoints using various imaging modalities, including PET imaging and volumetric MRI (vMRI) as well as CSF biomarkers, and cognitive and clinical endpoints.
+Added: Participants were randomized to receive treatment with 100 mg or 300 mg of zervimesine or placebo once daily for 24 weeks.
+Added: A preliminary analysis has been made of safety, clinical laboratory measurements, PET imaging, functional MRI and vMRI, CSF biomarkers and clinical outcomes in patients treated with zervimesine compared to those in patients receiving placebo.
+Added: Seventeen patients completed the study protocol, eleven in the zervimesine arm (six in the 100 mg cohort;
five in the 300 mg cohort) and six in the placebo arm.
−Removed: CT1812 was well tolerated with similar adverse event rates across treatment arms.
−Removed: Most adverse events were mild-to-moderate in severity with no deaths and no treatment-related SAEs reported.
+Added: Zervimesine was well tolerated with similar adverse event rates across treatment arms.
+Added: Most adverse events were mild or moderate in severity with no deaths and no treatment-related SAEs reported.
We observed mild and transient elevations of liver enzymes without any other indications of liver injury in two patients in the 300 mg group.
2 unchanged sentences
In addition, there were no significant treatment differences on SV2A signal change compared to baseline.
−Removed: However, vMRI showed a trend (p=0.0641) towards a significant reduction in the loss of composite brain volume in CT1812- treated patients (pooled) compared to placebo.
−Removed: A statistically significant (p<0.05) reduction in loss of brain volume was also observed in three brain regions
−Removed: (hippocampus, prefrontal cortex and pericentral cortex) in treated patients (pooled) compared to placebo, as shown in the table below.
+Added: However, vMRI showed a trend (p=0.0641) towards a significant reduction in the loss of composite brain volume in zervimesine-treated patients (pooled) compared to placebo.
+Added: A significant (p<0.05) reduction in loss of brain volume was also observed in three brain regions (hippocampus, prefrontal cortex and pericentral cortex) in treated patients (pooled) compared to placebo, as shown in the table below.
LS Mean Change from Baseline in vMRI (composite) over Time by Treatment
COG0104 — Phase 1 SNAP Clinical Trial
−Removed: Our COG0104 SNAP study was a randomized, double-blind, placebo-controlled Phase 1 clinical trial that enrolled three patients with mild-to-moderate AD to measure the effects of CT1812 on displacement of Aβ oligomers.
−Removed: Patients were randomized 2:1 to receive a single dose of CT1812 or placebo.
+Added: Our COG0104 SNAP study was a randomized, double-blind, placebo-controlled Phase 1 clinical trial that enrolled three patients with mild-to-moderate AD to measure the effects of zervimesine on displacement of Aβ oligomers.
+Added: Patients were randomized 2:1 to receive a single dose of zervimesine (n=2) or placebo (n=1).
Patients enrolled in the trial had an indwelling catheter placed in the lumbar CSF space.
CSF samples were collected hourly over a 28-hour period.
−Removed: Five CSF samples were collected before and 24 samples collected after administration of a single 560 mg oral dose of CT1812 or placebo.
+Added: Five CSF samples were collected before and 24 samples collected after administration of a single 560 mg oral dose of zervimesine or placebo.
CSF samples from each trial participant were analyzed to measure the concentration of Aβ oligomers over the trial period.
−Removed: Results of this clinical trial revealed an increase in Aβ oligomer levels in the CSF over the 24-hour period following treatment with CT1812, but not in the patient administered placebo.
+Added: Results of this clinical trial revealed an increase in Aβ oligomer levels in the CSF over the 24-hour period following treatment with zervimesine, but not in the patient administered placebo.
These findings were measured using two independent methods, microimmunoelectrodes and western blots.
−Removed: This effect of CT1812 was specific to Aβ oligomers, as no CT1812-related increase in Aβ 1-40 or 1-42 monomer was observed.
−Removed: We believe these results provide the early proof of principle of CT1812 target engagement in AD patients.
−Removed: Further, we believe that they corroborate our mechanism of action previously demonstrated in preclinical studies, providing the first evidence that our preclinical studies translate to patients with AD.
+Added: This effect of zervimesine was specific to Aβ oligomers, as no zervimesine-related increase in Aβ 1-40 or 1-42 monomer was observed.
+Added: We believe that these results corroborate our mechanism of action previously demonstrated in preclinical studies, providing the first evidence that our preclinical studies translate to patients with AD.
First evidence of target engagement in humans, which mirrors that found preclinically;
2 unchanged sentences
Our COG0102 study was a randomized, double-blind, placebo-controlled, Phase 1 clinical trial of 19 patients with mild-to-moderate AD.
−Removed: Participants were administered one of three oral doses of CT1812, either 90 mg, 280 mg or 560 mg, once daily for 28 days.
−Removed: The primary endpoint of the trial was safety with a secondary objective of establishing the pharmacokinetic, or PK, profile of CT1812.
−Removed: Also included as exploratory endpoints were measurement of CT1812 in CSF, and protein expression changes in CSF and plasma.
−Removed: In order to gauge the impact of CT1812 on synaptic damage due to AD, we measured concentrations of synaptic proteins, neurogranin and synaptotagmin-1, in CSF samples from these patients using clinically validated standardized assays.
−Removed: Our evaluation of AD protein biomarkers in the CSF revealed that neurogranin levels, shown in the left graph below, in patients treated with CT1812 for 28 days was significantly decreased compared to levels measured in patients administered placebo (p =0.05, analysis of covariance).
−Removed: Neurogranin is a synaptic damage marker that increases in the CSF of AD patients reflecting its decrease in the brain.
−Removed: The lowering of synaptic damage markers in the CSF is consistent with CT1812’s mechanism of action as observed in our preclinical studies and demonstrates the potential of the CT1812 to slow Aβ oligomer- induced synapse loss.
−Removed: Another synaptic damage biomarker that is elevated in the CSF of AD patients is synaptotagmin-1.
−Removed: CSF levels of synaptotagmin-1 were similar at baseline and end of study in patients treated with CT1812, whereas its levels in the placebo group displayed a marked increase over the same time period.
−Removed: This analysis of CT1812’s impact on synaptotagmin-1 levels
−Removed: is presented in the right graph below.
−Removed: Consistent with our belief that targeting the S2R has the potential to prevent Aβ oligomer toxicity, we observed a reduction in neurogranin and synaptotagmin in CSF, which are measures of synaptic damage, suggesting that CT1812 may have the ability to protect synapses in AD patients.
−Removed: Treatment with CT1812 was associated with lower levels of neurogranin and
−Removed: synaptotagmin-1 compared to placebo
−Removed: CT1812 was well tolerated in the COG0102 study.
−Removed: All AEs were mild to moderate.
+Added: Participants were administered one of three oral doses of zervimesine, either 90 mg, 280 mg or 560 mg, once daily for 28 days.
+Added: The primary endpoint of the trial was safety with a secondary objective of establishing the pharmacokinetic, or PK, profile of zervimesine.
+Added: Also included as exploratory endpoints were measurement of zervimesine in CSF, and protein expression changes in CSF and plasma.
+Added: Zervimesine was well tolerated in the COG0102 study.
+Added: All AEs were mild or moderate.
Some of the participants in the highest dose group experienced lymphocytopenia or elevated liver enzymes.
−Removed: These laboratory abnormalities resolved in most patients with continued dosing of CT1812.
−Removed: One trial participant was discontinued from CT1812 prior to study completion because of elevated liver enzymes with subsequent resolution of this abnormality.
+Added: These laboratory abnormalities resolved in most patients with continued dosing of zervimesine.
+Added: One trial participant was discontinued from zervimesine prior to study completion because of elevated liver enzymes with subsequent resolution of this abnormality.
Lymphocytopenia or elevated liver enzymes were not observed in either the 90 mg or 280 mg dosing cohorts.
There were no SAEs.
−Removed: Our Phase 1 Safety Trials
−Removed: In addition to Phase 1 clinical trials conducted in our targeted patient population, we also conducted a series of Phase 1 clinical trials in healthy volunteers designed to evaluate the safety profile of CT1812, as well as determine potential drug-food or drug-drug interactions.
−Removed: These trials and their results, which are summarized below, indicated that CT1812 was generally well tolerated.
+Added: Our Phase 1 Safety Trials with Zervimesine
+Added: In addition to Phase 1 clinical trials conducted in our targeted patient population, we also conducted a series of Phase 1 clinical trials in healthy volunteers to evaluate the safety profile of zervimesine;
+Added: as well as numerous preclinical in vitro and in vivo studies to assess its neuroprotective function as well as determine potential drug-food or drug-drug interactions.
+Added: These trials and their results, which are summarized below, indicated that zervimesine was generally well tolerated.
COG0101 — First in Human Phase 1 Clinical Trial
−Removed: Our COG0101 study was a randomized, double-blind, placebo-controlled ascending dose Phase 1 multi-cohort clinical trial of 93 healthy volunteers to assess the safety and potential drug-food interactions of CT1812.
+Added: Our COG0101 study was a randomized, double-blind, placebo-controlled ascending dose Phase 1 multi-cohort clinical trial of 93 healthy volunteers to assess the safety and potential drug-food interactions of zervimesine.
The trial was conducted in two segments.
−Removed: The first segment was structured as an ascending single dose trial, in which participants received one dose of CT1812 with increasing doses given to each of six cohorts.
−Removed: In this segment of the trial, eight participants were enrolled per dosing cohort with six participants receiving CT1812 and two receiving placebo.
+Added: The first segment was structured as an ascending single dose trial, in which participants received one dose of zervimesine with increasing doses given to each of six cohorts.
+Added: In this segment of the trial, eight participants were enrolled per dosing cohort with six participants receiving zervimesine and two receiving placebo.
The doses evaluated were 10 mg, 30 mg, 90 mg, 180 mg, 450 mg and 1,120 mg.
2 unchanged sentences
The second segment was configured as a multiple ascending dose trial, that enrolled 39 healthy volunteers, divided in three cohorts of ten participants, with one additional cohort consisting of nine healthy elderly volunteers.
−Removed: participant in this segment of the trial received a single dose of CT1812 each day for 14 days.
+Added: Each participant in this segment of the trial received a single dose of zervimesine each day for 14 days.
The doses evaluated in this second segment were 280 mg, 560 mg and 840 mg.
−Removed: CT1812 CSF concentrations correlated to a >80% S2R predicted receptor occupancy in brain
−Removed: Following completion of each trial cohort, bioanalytical evaluation of plasma CT1812 PK was conducted.
−Removed: This trial demonstrated that administration of CT1812 in single doses of up to 1,120 mg, administered once, as well as up to 840 mg of CT1812 dosed for 14 consecutive days was well tolerated.
−Removed: Significantly, CT1812 concentrations detected in the CSF correlated to an estimated receptor occupancy in the brain of greater than 80%.
+Added: Zervimesine CSF concentrations correlated to a >80% S2R predicted receptor occupancy in brain
+Added: Following completion of each trial cohort, bioanalytical evaluation of plasma zervimesine PK was conducted.
+Added: This trial demonstrated that administration of zervimesine in single doses of up to 1,120 mg, administered once, as well as up to 840 mg of zervimesine dosed for 14 consecutive days was well tolerated.
+Added: Significantly, zervimesine concentrations detected in the CSF correlated to an estimated receptor occupancy in the brain of greater than 80%.
There was one SAE in the multiple-dose portion of the study that was deemed unrelated to study drug.
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COG0103 — Phase 1 Clinical Trial
−Removed: Our COG0103 study was a Phase 1 clinical trial of 15 healthy volunteers designed to evaluate the potential effects of CT1812 on select CYP isoenzymes:
+Added: Our COG0103 study was a Phase 1 clinical trial of 15 healthy volunteers designed to evaluate the potential effects of zervimesine on select CYP isoenzymes:
CYP2C19, CYP2C9, CYP2D6 and CYP3A4/5.
1 unchanged sentence
20 mg omeprazole, 500 mg tolbutamide, 50 mg dextromethorphan and 4 mg midazolam.
−Removed: The 15 healthy volunteers who participated in the trial received the substrates of these isoenzymes two days prior to the initial dose of CT1812 and PK assessments were performed.
−Removed: A dose of 560 mg of CT1812 was administered to each of the trial participants for the following six consecutive days.
−Removed: The day 6 dose of CT1812 was administered concomitantly with the four-substrate cocktail and PK assessments were repeated.
−Removed: A weak drug interaction was observed between CT1812 and midazolam and dextromethorphan.
+Added: The 15 healthy volunteers who participated in the trial received the substrates of these isoenzymes two days prior to the initial dose of zervimesine and PK assessments were performed.
+Added: A dose of 560 mg of zervimesine was administered to each of the trial participants for the following six consecutive days.
+Added: The Day 6 dose of zervimesine was administered concomitantly with the four-substrate cocktail and PK assessments were repeated.
+Added: A weak drug interaction was observed between zervimesine and midazolam and dextromethorphan.
A lack of any clinically meaningful interaction was observed with coadministration of omeprazole or tolbutamide.
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Preclinical Results
−Removed: Prior to entering clinical trials, the therapeutic potential of CT1812 was observed in numerous preclinical studies.
+Added: Prior to entering clinical trials, the therapeutic potential of zervimesine was observed in numerous preclinical studies.
As is demonstrated in the images below, the addition of Aβ oligomers to neuronal cell cultures resulted in synaptotoxicity as illustrated by the reduced expression of synaptic markers neurogranin, synaptotagmin and SV2A.
The lack of immunoreactivity of these three synaptic proteins can be seen in the middle column of the image below.
−Removed: However, the presence of CT1812 blocked the Aβ oligomer-induced loss of synapses, as reflected by the presence of synaptic protein expression displayed in the right-hand column below.
−Removed: CT1812 prevented Aβ oligomer-mediated synaptic damage
−Removed: Results showed that CT1812 also slowed the loss of synapses that is triggered by Aβ oligomers.
−Removed: A higher resolution image of the cell culture exposed to Aβ oligomer is shown below, before the addition of CT1812, which is presented on the left, and after the addition of CT1812, which is presented on the right.
−Removed: Aβ oligomers shown in red bind to synaptic receptors and reduce numbers of synapses shown in green.
−Removed: The addition of CT1812 displaces Aβ oligomer binding and appears to block the effects induced by the Aβ oligomers, with the synapse numbers remaining at levels similar to normal.
−Removed: CT1812 slowed loss of synapse numbers in the presence of Aβ oligomers
−Removed: The protective benefits of CT1812 observed in these in vitro assays are supported by functional in vivo assessments of CT1812.
+Added: However, the presence of zervimesine blocked the Aβ oligomer-induced loss of synapses, as reflected by the presence of synaptic protein expression displayed in the right-hand column below.
+Added: Zervimesine prevented Aβ oligomer-mediated synaptic damage
+Added: Results showed that zervimesine also slowed the loss of synapses that is triggered by Aβ oligomers.
+Added: A higher resolution image of the cell culture exposed to Aβ oligomer is shown below, before the addition of zervimesine, which is presented on the left, and after the addition of zervimesine, which is presented on the right.
+Added: Aβ oligomers shown in red bind to synaptic receptors and reduces the number of synapses shown in green.
+Added: The addition of zervimesine displaces Aβ oligomer binding and appears to block the effects induced by the Aβ oligomers, with the synapse numbers remaining at levels similar to normal.
+Added: Zervimesine slowed loss of synapse numbers in the presence of Aβ oligomers
+Added: The protective benefits of zervimesine observed in these in vitro assays are supported by functional in vivo assessments of zervimesine.
In one such preclinical study, the memory of mice was tested based on the subject’s ability to recall fear-inducing triggers and its performance in a maze.
The mice exhibiting symptoms of AD, depicted by the red bars in the image below, performed significantly worse in both the fear and maze tests when compared to normal, non-transgenic mice, represented by the blue bars.
−Removed: However, after administration of CT1812, the AD mice, represented by the solid green bars, were seen to perform at a level similar to that achieved by normal mice.
−Removed: We believe these results are illustrative of CT1812’s ability to restore synaptic proteins and numbers to normal levels and with it, the animal’s functional capabilities.
−Removed: CT1812 restored functional capabilities in a mouse model of AD
−Removed: CT1812 for the Treatment of Geographic Atrophy (GA) Secondary to Dry Age-Related Macular Degeneration (Dry AMD)
−Removed: We believe that several lines of evidence suggest that modulation of the S2R complex may provide significant therapeutic utility for the treatment of GA secondary to dry AMD.
−Removed: Human genetics points to TMEM97 as a promising therapeutic target for GA secondary to dry AMD, as indicated via several large- scale, independent genome-wide association, or GWA, studies.
−Removed: In addition, unbiased pathway analysis of AD patient proteomic data obtained during our clinical trials provides independent evidence of a relationship between the S2R complex and GA secondary to dry AMD.
−Removed: Early proof-of-concept studies with CT1812 indicate a role of S2R modulators in rescuing key aspects of dry AMD including maintaining homeostatic functions of RPEs, ameliorating lysosomal dysfunction and preventing RPE cell death.
−Removed: PK assessment indicates that we can achieve therapeutic levels (>80% receptor occupancy) of CT1812 in retinal tissue through oral administration.
−Removed: We submitted an IND application to the FDA at the end of 2022 to initiate a Phase 2 clinical trial of CT1812 in this indication;
−Removed: it was cleared by the FDA at the end of January 2023;
−Removed: and we announced in July 2023 that participant dosing had commenced in the Phase 2 COG2201 (MAGNIFY) study.
−Removed: CT1812 will be given orally, once daily for 24 months to
−Removed: determine if it can slow disease progression.
−Removed: Approximately 246 patients will be randomized to receive once-daily oral CT1812 or placebo for 24 months.
−Removed: We are assessing the change in GA lesion size over the treatment duration, as measured by fundus autofluorescence (FAF) imaging, as well as CT1812’s safety and tolerability.
−Removed: We believe that well-characterized clinical endpoints and a defined regulatory path make dry AMD an attractive indication.
−Removed: Overview of the Disease
−Removed: AMD is the leading cause of blindness in people over 50 years of age in the United States, afflicting approximately 11 million people in the United States, including an estimated 12% of all U.S.
−Removed: adults over 80 years of age.
−Removed: Dry AMD is a progressive condition and accounts for up to 90% of all AMD cases.
−Removed: Advanced dry AMD, or GA, affects approximately two million people in the United States.
−Removed: There are currently two approved therapeutics for dry AMD, both of which are intravitreal injections designed to regulate the complement system.
−Removed: Other treatments in development are primarily invasive, including intravitreal injections, stem cell replacement and gene therapy approaches.
−Removed: We believe the limited treatment options available for patients with dry AMD, coupled with newly implicated biochemical pathways, make GA secondary to dry AMD an attractive target for the development of therapeutics.
−Removed: There are two types of AMD, the first of which is neovascular, or wet AMD, and non-neovascular, or dry AMD.
−Removed: Dry AMD, which accounts for approximately 90% of all AMD cases, is a progressive condition that involves a dysregulation of cellular processes, among which is the accumulation of lipid deposits, known as drusen, that causes a thickening of the Bruch’s membrane.
−Removed: This thickening disrupts the cytoarchitecture of the RPE, and this disruption, coupled with oxidative stress and inflammation, leads to the diminished health and function of RPE and photoreceptor cells, with accumulated damage resulting in cell death and visual impairment.
−Removed: The anatomy of the eye and the regions impacted by AMD
−Removed: Limitations of Current Treatments
−Removed: There are currently two FDA-approved therapeutics for dry AMD:
−Removed: Apellis Pharmaceuticals’ SYFOVRE and Astellas Pharma’s Izervay, both of which are designed to inhibit complement factors.
−Removed: In addition, there is considerable development activity ongoing involving numerous targets.
−Removed: Beyond complement inhibitors, other areas of ongoing interest include cell and gene therapy approaches to regenerate RPE cells and rescue the loss of photoreceptors.
−Removed: Small molecule visual cycle
−Removed: modulators are also under evaluation to maintain retinal integrity.
−Removed: Most of these approaches require invasive administration.
−Removed: Rationale for S2R Mechanism of Action
−Removed: Indications of S2R Involvement in Geographic Atrophy Secondary to Dry AMD
−Removed: We believe that several lines of evidence suggest that modulation of the S2R complex may provide significant therapeutic utility for the treatment of GA secondary to dry AMD.
−Removed: First, human genetics point to TMEM97 as a promising therapeutic target, as indicated via several large-scale, independent GWA studies.
−Removed: These studies indicate a genetic mutation known as a single nucleotide polymorphism, or SNP, in the TMEM-VTN locus confers decreased risk for dry AMD.
−Removed: It remains unknown if this mutation confers a change in TMEM97 expression levels.
−Removed: However, knockdown of TMEM97 in in vitro models of the disease partially rescues RPE cells from oxidative stress-induced cell death.
−Removed: Further investigation of the role of the S2R complex in dry AMD is ongoing.
−Removed: Unbiased Analysis of Clinical Trial Sample Proteomics Data:
−Removed: Top Disease Ontologies
−Removed: Unbiased pathway analysis of AD patient proteomic data obtained during the COG0102 and SHINE Part-A clinical trials provides independent evidence of the relationship between the S2R complex and dry AMD.
−Removed: Analyses of CSF were performed to ascertain which predesignated functional disease ontologies may be affected by the administration of CT1812.
−Removed: These analyses identified GA and macular degeneration as two of the top indications affected, with GA presenting the most significant relationship.
−Removed: Subsequent analyses identified several subsets of proteins altered by CT1812 that are involved in dry AMD.
−Removed: In subsequent analyses examining the overlap of proteins altered in CSF and plasma biofluids of AD patients treated with CT1812 versus placebo, we identified a set of proteins, altered by CT1812 that have been previously shown by other groups to be disrupted in dry AMD or GA, compared to age-matched controls.
−Removed: Subsequent analysis identified several pathways in which these proteins are involved, many of which have known genetic or biological links to processes disrupted in dry AMD.
−Removed: We believe the collective insights provided by these analyses provide early proof of concept that an S2R modulator may be capable of altering AMD relevant proteins and pathways in an aged patient population.
−Removed: Preclinical Support for Clinical Trials
−Removed: We believe that proof-of-concept studies indicate a clear role of S2R modulators in rescuing key aspects of dry AMD.
−Removed: Pathway analysis of transcriptomic data suggests a key role of S2R modulators in regulating pathways involved in cell survival and inflammation.
−Removed: Mechanistic Studies Indicate CT1812 Plays a Role in Cell Survival
−Removed: and Inflammatory Pathways in RPE Cells
−Removed: Additional functional studies indicate S2R modulators may ameliorate disruptions in homeostatic functions of RPEs, including ameliorating lysosomal dysfunction and salvaging the ability of RPE cells to recycle photoreceptor outer segments.
−Removed: Working Hypothesis of Mechanism of Action in Dry AMD
−Removed: We believe preclinical studies provide further evidence supporting a clinical trial for CT1812 as a potential treatment for GA secondary to dry AMD.
−Removed: PK assessment indicates that we can achieve therapeutic levels (>80% receptor occupancy) of CT1812 in retinal tissue through oral administration.
−Removed: Moreover, as is illustrated in the graph below, CT1812 levels recorded in the retina were similar to those in the brain, suggesting that the doses used to achieve potential therapeutic levels in the retina needed to achieve efficacy will be similar to the doses for AD.
−Removed: Similarities in CT1812 concentrations following oral administration in the brain and retina
−Removed: Additional studies have been conducted to elucidate the key mechanisms by which CT1812 and the S2R complex alter the biological processes that contribute to dry AMD.
−Removed: In vivo preclinical studies are evaluating the utility of CT1812 to impede the death of retinal ganglion cells.
−Removed: Not only is it anticipated that these proof-of-concept studies will allow us to further elucidate the mechanism by which the S2R complex modulators act upon the various disease pathologies, but the learnings from this may also inform appropriate patient selection, time of intervention and clinical outcome measurements to enable a successful clinical trial design.
−Removed: COG2201 — Phase 2 MAGNIFY Clinical Trial
−Removed: We believe that an S2R antagonist, such as CT1812, may help to regulate the damage-response processes related to these cells that are impaired in GA secondary to dry AMD.
−Removed: We submitted an IND application to the FDA at the end of 2022 to initiate a Phase 2 clinical trial of CT1812 in this indication;
−Removed: it was cleared by the FDA, and we announced that the first participant was dosed in July 2023 in the Phase 2 COG2201 (MAGNIFY) study.
−Removed: CT1812 will be given orally, once daily for 24 months to determine if it can slow disease progression.
−Removed: Approximately 246 patients will be randomized to receive once-daily oral CT1812 or placebo for 24 months.
−Removed: We are assessing the change in GA lesion size over the treatment duration, as measured by fundus autofluorescence (FAF) imaging, as well as CT1812’s safety and tolerability.
−Removed: S2R Modulators for the Treatment of Synucleinopathies
−Removed: Substantial cellular and clinical biomarker evidence demonstrate that our S2R modulators, including our clinical drug candidate CT1812, have a beneficial impact on the pathways impaired in synucleinopathies, namely the localization of α-synuclein aggregates in Lewy bodies, which is a chief hallmark of PD and other synucleinopathies.
+Added: However, after administration of zervimesine, the AD mice, represented by the solid green bars, were seen to perform at a level similar to that achieved by normal mice.
+Added: We believe these results are illustrative of zervimesine’s ability to restore synaptic proteins and numbers to normal levels and with it, the animal’s functional capabilities.
+Added: Zervimesine restored functional capabilities in a mouse model of AD
+Added: Dementia with Lewy Bodies (DLB)
+Added: Substantial cellular and clinical biomarker evidence demonstrate that zervimesine may have a beneficial impact on the pathways impaired in synucleinopathies, namely the localization of α-synuclein aggregates in Lewy bodies, which is a chief hallmark of DLB, Parkinson’s disease (PD) and other synucleinopathies.
More recently, human genetic evidence has linked SNCA, the gene encoding α-synuclein, to the pathology of synucleinopathies.
−Removed: We have conducted preclinical studies of S2R ligands in our library, including CT1812, to explore the potential of S2R antagonists to rescue the biological processes that are impaired in synucleinopathies.
−Removed: Subject to discussion with the FDA, we intend to conduct clinical studies in DLB, PD and potentially other synucleinopathies as outlined below.
−Removed: An Overview of Synucleinopathies
−Removed: Synucleinopathies are a group of neurodegenerative disorders in which the protein α-synuclein accumulates abnormally to form inclusions in the cell bodies or axons of neurons or oligodendrocytes.
−Removed: Two of the primary synucleinopathies are PD and DLB, which each involve motor and cognitive dysfunction.
−Removed: While the cell types and brain structures that are affected in PD and DLB vary markedly between the disorders, synucleinopathies share a characteristic accumulation of α-synuclein aggregates into fibrils, the major constituent of the Lewy bodies that occur inside brain neurons in these diseases.
−Removed: Increasing evidence suggests that α-synuclein also aggregates into oligomers, and that oligomers are more toxic than fibrils.
−Removed: α -synuclein oligomers contribute to neurodegeneration through a variety of mechanisms including disrupting normal autophagy and inducing synaptic dysfunction and loss.
−Removed: Synaptic dysfunction and loss contribute to the cognitive and motor symptoms of these diseases.
−Removed: Synucleinopathies are second only to AD in terms of neurodegenerative disease prevalence.
−Removed: In the United States, as many as 1 million people suffer from PD and an estimated 1.4 million from DLB.
−Removed: According to the Parkinson’s Foundation and the Lewy Body Dementia Association, the direct healthcare costs for patients with PD and DLB are estimated to be approximately $25 billion and $31 billion per year, respectively.
−Removed: For PD, these direct medical costs include an estimated $2 billion for medications annually in the United States.
+Added: We have conducted preclinical studies of compounds in our library, including zervimesine, to explore their potential to rescue the biological processes that are impaired in synucleinopathies.
+Added: We are currently developing zervimesine for the treatment of DLB.
+Added: An Overview of DLB
+Added: DLB is the second most common cause of dementia.
+Added: The abnormal accumulation of the protein α-synuclein into fibrils, the primary component of the Lewy bodies within brain neurons, is characteristic of DLB.
+Added: Increasing evidence suggests that α-synuclein oligomers disrupt key cellular processes including autophagy and elicit neuronal dysfunction and loss of synapses.
+Added: DLB is challenging to diagnose and identify as it shares many Alzheimer’s disease symptoms.
+Added: DLB is referred to as a “whole-body” disease, as it disrupts biological processes affecting autonomic, digestive, cognitive, and motor systems.
+Added: Varied initial symptoms may include day-to-day fluctuations in alertness level, hallucinations, delusions, movement disorders and REM sleep disorder (acting out dreams while sleeping).
+Added: In the United States, an estimated 1.4 million are diagnosed with DLB.
+Added: According to the Lewy Body Dementia Association, the direct healthcare costs for patients with DLB are estimated to be approximately $31 billion per year.
Limitations of Current Treatments
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While some existing products provide meaningful symptomatic relief, they have significant side effect risks, fail to address the progression of the disease, and over time gradually lose their effectiveness in treating the symptoms of the disease.
−Removed: There are no currently approved disease-modifying therapeutics for PD or other synucleinopathies.
−Removed: Rationale for S2R Mechanism of Action for Synucleinopathies
−Removed: α-synuclein is a protein primarily found in neural tissue that plays a role in neurotransmission.
−Removed: In synucleinopathies such as DLB and PD, α-synuclein builds up in brain cells and forms oligomers that saturably bind to neurons where they impair critical cellular processes, causing synaptic dysfunction and eventual loss.
−Removed: Our decision to pursue the treatment of synucleinopathies with S2R compounds is based on internal and third-party data, indicating that the S2R components PGRMC1 and TMEM97 regulate cell pathways known to be impaired in synucleinopathies, such as autophagy, vesicle trafficking and lipid synthesis;
+Added: There are no currently approved disease-modifying therapeutics for DLB.
+Added: Rationale for Zervimesine in the Treatment of DLB
+Added: The protein α-synuclein is primarily found in neural tissue that plays a role in neurotransmission.
+Added: In DLB, α-synuclein builds up in brain cells and forms oligomers that saturably bind to neurons where they impair critical cellular processes, causing synaptic dysfunction.
+Added: Our decision to pursue the treatment of synucleinopathies with zervimesine is based on internal and third-party data, indicating that zervimesine can prevent binding synuclein oligomers and that the S2R components PGRMC1 and TMEM97 regulate cell pathways known to be impaired in synucleinopathies, such as autophagy, vesicle trafficking and lipid synthesis;
α-synuclein oligomers bind directly to PGRMC1;
and synucleinopathies share certain mechanistic similarities with AD, including pathologies related to aberrant oligomeric protein formations.
−Removed: As summarized below, we believe our preclinical studies provide compelling evidence supporting the use of CT1812 and our next-generation S2R modulators as potential therapeutics to treat synucleinopathies.
+Added: As summarized below, we believe our preclinical studies provide compelling evidence supporting the use of zervimesine as a potential therapeutic to treat DLB.
As with oligomers of the Aβ protein in AD, oligomers of α-synuclein are highly toxic when bound to brains cells and internalized.
2 unchanged sentences
The S2R complex components, PGRMC1 and TMEM97, directly regulate these processes and activities which are compromised by the binding and internalization of α-synuclein oligomers.
−Removed: Compounds that bind to S2R and block α-synuclein binding and/or internalization are therefore expected to be disease-modifying.
+Added: Compounds that block α-synuclein binding and/or internalization are therefore expected to be disease-modifying.
Preclinical Study Support for Clinical Trials
−Removed: The results of in vitro studies suggest that S2R modulator, such as CT1812, may have disease modifying effect on the synucleinopathies by reversing pathway disruption and dysregulation caused by α-synuclein oligomers.
+Added: The results of in vitro studies suggest that S2R modulator, such as zervimesine, may have disease-modifying effect on the synucleinopathies by reversing pathway disruption and dysregulation caused by α-synuclein oligomers.
In work funded by grants from the Michael J.
−Removed: Fox Foundation, α-synuclein oligomers were found to bind to brain cells in culture and are
−Removed: internalized as indicated by the red dots in the image to the left below.
−Removed: With the addition of S2R modulator CT1812, the binding and thus internalization of the α-synuclein oligomers is inhibited as indicated in the image to the right below.
−Removed: CT1812 blocked the binding and internalization of α-synuclein oligomers in the neuronal synapses
−Removed: The potential for S2R modulators to reverse the deleterious cellular effects of α-synuclein oligomers is also reflected in the in vitro analysis of LAMP2A expression presented below.
+Added: Fox Foundation, α-synuclein oligomers were found to bind to brain cells in culture and are internalized as indicated by the red dots in the image to the left below.
+Added: With the addition of zervimesine, the binding and thus internalization of the α-synuclein oligomers is inhibited as indicated in the image to the right below.
+Added: Zervimesine blocked the binding and internalization of α-synuclein oligomers in the neuronal synapses
+Added: The potential for S2R modulators like zervimesine to reverse the deleterious cellular effects of α-synuclein oligomers is also reflected in the in vitro analysis of LAMP2A expression presented below.
LAMP2A is a critical component of chaperone-mediated autophagy, one of several processes that eliminate damaged cellular proteins.
4 unchanged sentences
Importantly, oligomer-related inhibition was noted to be four-fold higher than that observed with high concentrations of monomeric α-synuclein, illustrative of the significantly greater toxicity of α-synuclein oligomers.
−Removed: The addition of CT1812 was observed to reverse the membrane trafficking deficit related to the presence of α-synuclein oligomer, while having no effect on membrane activity when dosed in its absence.
+Added: The addition of zervimesine was observed to reverse the membrane trafficking deficit related to the presence of α-synuclein oligomer, while having no effect on membrane activity when dosed in its absence.
S2R antagonists reversed the effects of α-synuclein oligomers on LAMP2A expression and trafficking
COG1201 — Phase 2 SHIMMER Clinical Trial
−Removed: We are actively enrolling participants in our Phase 2, SHIMMER (COG1201) clinical trial, which is studying the use of CT1812 to treat adults with mild-to-moderate DLB.
−Removed: The design of this trial is a double-blind, randomized, six-month trial involving three dose groups, two active treatment cohorts and a placebo group.
−Removed: We intend to enroll approximately 120 patients with equal participant numbers in each of the three dose groups, with daily (QD) dosing.
−Removed: Eligibility requirements include individuals between 50 and 80 years of age that have received a diagnosis of DLB and have a mini-mental state exam, or MMSE, score of between 18 and 27.
−Removed: Clinical endpoints of the trial include safety and physical activity measurements, cognitive assessments, and PK and pharmacodynamic biomarker analyses compared to baseline measurements recorded at the beginning of the trial.
−Removed: In addition, CSF will be collected and analyzed for α-synuclein content and established patterns of differential protein expression.
+Added: We completed the double-blind, randomized Phase 2 COG1201 (SHIMMER) clinical trial of zervimesine in adults with mild-to-moderate DLB.
+Added: We enrolled 130 participants who were randomized evenly to one of three dose groups:
+Added: two treated with once-daily oral zervimesine (100 mg or 300 mg) and one treated with placebo.
+Added: To be eligible, participants were between 50 and 80 years of age, received a diagnosis of probable DLB, and had a mini-mental state exam, or MMSE, score of between 18 and 27.
+Added: Clinical endpoints of the trial included safety and tolerability, neuropsychiatric, functional, cognitive and physical activity measurements.
+Added: PK and pharmacodynamic biomarker analyses were also conducted.
+Added: The study met its primary endpoint of safety and tolerability.
+Added: Zervimesine-treated DLB patients scored an average of 86% better than placebo-treated patients on the neuropsychiatric inventory (NPI) A-L at the end of the study.
+Added: This tool describes the frequency and severity of 12 behavioral symptoms including hallucinations, delusions and anxiety.
+Added: Compared to placebo-treated participants, those treated with zervimesine performed an average of 52% better on the ADCS-ADL scale, a measure of activities of daily living;
+Added: an average of 91% better on the CAF, a measure of cognitive fluctuations;
+Added: an average of 62% better on the Unified Parkinson's Disease Rating Scale (UPDRS) Part III, a measure of motor function such as gait, balance, and tremor.
+Added: Other Initiatives
+Added: Zervimesine and other chemical structures in our pipeline originate from a screening technique developed by Cognition’s founding scientists.
+Added: This screening technique relies on the use of mature primary neuronal cultures designed to replicate the mature brain and its intricate connections and patterns of electrical signaling.
+Added: provides us with information-rich measurements more indicative of normal brain function and predicative of functional benefit.
+Added: Cognition has generated proprietary small molecule libraries derived from natural chemical scaffolds through a proprietary process which we refer to as conditioned extraction.
+Added: Conditioned extraction was pioneered by a cofounder and allows us to eliminate undesirable properties of well characterized, biologically active compounds sourced from natural products, while retaining their biological activity.
+Added: The resulting molecular configurations are then subjected to proprietary functional in vitro screening using the mature primary neuronal cultures.
+Added: The candidate library produced through this process is predisposed to compounds with attractive drug-like properties such as low molecular weight, low number of reactive hydrogen bonds, lipophilicity and relatively neutral chemistry properties.
+Added: These characteristics reduce the reactivity of the molecules and related toxicities, while also enhancing their ability to cross the blood-brain and blood-retina barriers, which we believe will reduce development risk.
+Added: We also believe this platform provides us with differentiated libraries which may lead to development candidates beyond zervimesine.
+Added: Geographic Atrophy (GA) Secondary to Dry Age-Related Macular Degeneration (Dry AMD)
+Added: We believe that several lines of evidence suggest that zervimesine may be effective in the treatment of GA secondary to dry AMD.
+Added: Human genetics points to TMEM97 as a promising therapeutic target for GA secondary to dry AMD, as indicated via several large-scale, independent genome-wide association, or GWA, studies.
+Added: In addition, unbiased pathway analysis of AD patient proteomic data obtained during our clinical trials provides independent evidence of a relationship between the S2R complex and GA secondary to dry AMD.
+Added: Early proof-of-concept studies with zervimesine indicate a role of S2R modulators in rescuing key aspects of dry AMD including maintaining homeostatic functions of retinal pigment epithelial cells (RPEs), ameliorating lysosomal dysfunction and preventing RPE cell death.
+Added: PK assessment indicates that we can achieve therapeutic levels (>80% receptor occupancy) of zervimesine in retinal tissue through oral administration.
+Added: In 2023 we initiated the Phase 2 COG2201 MAGNIFY study of zervimesine in adults with geographic atrophy secondary to dry AMD.
+Added: In December 2024 MAGNIFY passed a masked futility analysis conducted by the contract research organization, or CRO, which provided evidence that zervimesine treated patients were experiencing a slower lesion growth rate than those on placebo.
+Added: However, in January 2025, we made the strategic decision to focus our resources on our promising dementia programs in AD and DLB.
+Added: Therefore, we voluntarily discontinued the MAGNIFY clinical study.
+Added: The discontinuation was not the result of any safety concerns.
+Added: At the time of the discontinuation, 100 participants had been enrolled.
+Added: Results are being compiled by the contract research organization (CRO) following participant completion of final clinic visits.
+Added: We will conduct an analysis of the changes in GA lesion size as well as safety and tolerability, which will be reported at a later date.
+Added: We continue to believe that zervimesine has the potential to alter the biological processes that contribute to dry AMD.
+Added: Proposed Synucleinopathies Clinical Program
+Added: Subject to additional funding, we may plan to study several next-generation S2R modulators derived from chemically distinct series to measure their ability to rescue cell death in synucleinopathies such as PD and DLB.
+Added: We may also study α-synuclein pathology and motor deficits in two mechanistically distinct in vivo models of synucleinopathies.
+Added: In parallel, these studies will elucidate the mechanism of action by which S2R modulators are efficacious in PD and DLB and provide essential data to support potential biomarker nomination for PD and DLB.
Additional Product Candidates
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The complex likely contains a number of relevant binding sites that may allow for multiple disease intervention approaches, making it an attractive therapeutic target.
−Removed: Accordingly, we are actively engaged in a number of earlier-stage discovery programs which are built upon our identification of five structurally distinct chemical series.
+Added: Accordingly, we have engaged in a number of earlier-stage discovery programs which are built upon our identification of five structurally distinct chemical series.
From these series we have multiple leads which will be optimized from each of our lead series.
Each of these leads has demonstrated favorable potency with variable selectivity in early preclinical testing and each of the molecular series possesses distinct bioavailability and PK properties, including differences in half-life and blood-brain and blood-retina permeability.
−Removed: Proposed Synucleinopathies Clinical Program
−Removed: Subject to additional funding, we plan to study several next-generation S2R modulators derived from chemically distinct series to measure their ability to rescue cell death in synucleinopathies such as PD and DLB.
−Removed: We would also study α-synuclein pathology and motor deficits in two mechanistically distinct in vivo models of synucleinopathies.
−Removed: these studies will elucidate the mechanism of action by which S2R modulators are efficacious in PD and DLB and provide essential data to support potential biomarker nomination for PD and DLB.
+Added: Our Team and Collaborators
+Added: We have assembled a management team with extensive experience with CNS and degenerative diseases, significant expertise in the drug discovery, clinical development, general management and business development.
+Added: Collectively, our management team has a track record of managing drug development programs that have received regulatory approval and been successfully commercialized.
+Added: In addition, our management team has built companies that have initiated innovative technologies and investigational new drug programs.
+Added: We augment the strengths of our management team with an experienced board of directors and scientific and medical advisory boards.
+Added: We believe our team, with its deep scientific and drug development background, positions us to become a leader in the development of therapies for age-related degenerative diseases and disorders.
+Added: Since our inception, we have collaborated and worked closely with key healthcare organizations and thought leading institutions in the field of degenerative diseases to develop and advance our therapeutic candidates.
+Added: To date, we have been awarded approximately $171 million in cumulative grants awarded primarily from the NIA to support our clinical trials.
Grant Funding
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Fox Foundation and other groups to pursue our commonly aligned interests of developing therapeutics for neurodegenerative disorders.
−Removed: Taken together, the company has been awarded approximately $171 million in cumulative grants for the advancement of our pipeline programs.
−Removed: Of this, approximately $81 million in cumulative non-dilutive grants have been awarded by the NIA to fund development of CT1812 for the treatment of AD.
+Added: The company has been awarded $171 million in cumulative grants for the advancement of our pipeline programs.
As of December 31, 2024, we had approximately $50 million available from NIA funds for applicable expenses to be incurred in the future.
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National Institute on Aging (NIH)
−Removed: COG0203 Ph2 Study with ACTC
+Added: COG0203 Ph2 START Study with ACTC
National Institute on Aging (NIH)
3 unchanged sentences
National Institute on Aging (NIH)
+Added: COG1201 Ph2 SHIMMER Study:
NIH and others
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provisional applications, three pending U.S.
−Removed: patent applications, one pending Patent
−Removed: Cooperation Treaty applications and forty five foreign pending patent applications directed to the composition of matter of, pharmaceutical compositions of, methods of use of, and methods for selecting subsets of patients for treatment with our chemical structures, including our lead CT1812.
−Removed: Our current issued patents relating to CT1812 are projected to begin to expire no earlier than 2035, with the composition of matter patent covering CT1812 set to naturally expire in 2035, subject to adjustment or extension of patent term available in a particular jurisdiction.
−Removed: We will likely be awarded Patent Term Extension, or PTE, when CT1812 is approved as a New Chemical Entity, or NCE, that will extend the term of the CT1812 composition of matter patent by up to five years, and we anticipate pursuing additional patents to further protect CT1812 and to further extend the patent term associated with CT1812.
+Added: patent applications, one pending Patent Cooperation Treaty applications and forty five foreign pending patent applications directed to the composition of matter of, pharmaceutical compositions of, methods of use of, and methods for selecting subsets of patients for treatment with our chemical structures, including our lead zervimesine .
+Added: Our current issued patents relating to zervimesine are projected to begin to expire no earlier than 2035, with the composition of matter patent covering zervimesine set to naturally expire in 2035, subject to adjustment or extension of patent term available in a particular jurisdiction.
+Added: We will likely be awarded Patent Term Extension, or PTE, when zervimesine is approved as a New Chemical Entity, or NCE, that will extend the term of the zervimesine composition of matter patent by up to five years, and we anticipate pursuing additional patents to further protect zervimesine and to further extend the patent term associated with zervimesine .
We expect to file additional patent applications in support of current and new product candidates as well as new platform and core technologies.
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patents and pending U.S.
−Removed: patent applications, as well as granted patents and pending patent applications in numerous foreign jurisdictions, relating to compositions of matter and pharmaceutical compositions of CT1812, analogs of CT1812, and the use of CT1812 for the treatment in certain diseases, disorders and conditions including AD, GA secondary to dry AMD, PD, and synucleinopathies.
−Removed: The first of these patent families is directed to compositions of matter of CT1812, pharmaceutical compositions of CT1812, methods of using CT1812 for inhibiting amyloid beta effects on a neuronal cell, and methods of using CT1812 to treat AD, and we are the exclusive owner of this patent family in the United States and certain foreign jurisdictions, including Australia, Brazil, Canada, China, the European Union, Hong Kong, India, Israel, Japan, South Korea, Mexico, New Zealand, Russia, and South Africa.
−Removed: As of March 1, 2024, this patent family includes granted patents claiming composition of matter of CT1812, pharmaceutical compositions of CT1812, methods of using CT1812 for inhibiting amyloid beta effects on a neuronal cell, and methods of using CT1812 to treat AD in the United States (three patents), Australia, Brazil, China, the European Union, Hong Kong, India, Israel, Japan, New Zealand, Mexico, South Korea, Russia and South Africa.
+Added: patent applications, as well as granted patents and pending patent applications in numerous foreign jurisdictions, relating to compositions of matter and pharmaceutical compositions of zervimesine , analogs of zervimesine , and the use of zervimesine for the treatment in certain diseases, disorders and conditions including AD, GA secondary to dry AMD, DLB, PD, and other synucleinopathies.
+Added: The first of these patent families is directed to compositions of matter of zervimesine, pharmaceutical compositions of zervimesine, methods of using zervimesine for inhibiting amyloid beta effects on a neuronal cell, and methods of using zervimesine to treat AD, and we are the exclusive owner of this patent family in the United States and certain foreign jurisdictions, including Australia, Brazil, Canada, China, the European Union, Hong Kong, India, Israel, Japan, South Korea, Mexico, New Zealand, Russia, and South Africa.
+Added: As of March 1, 2025, this patent family includes granted patents claiming composition of matter of zervimesine , pharmaceutical compositions of zervimesine , methods of using zervimesine for inhibiting amyloid beta effects on a neuronal cell, and methods of using zervimesine to treat AD in the United States (three patents), Australia, Brazil, China, the European Union, Hong Kong, India, Israel, Japan, New Zealand, Mexico, South Korea, Russia and South Africa.
This patent family also includes a pending U.S.
−Removed: patent application and pending application in certain foreign jurisdictions including India and the European Union.
+Added: patent application and pending application in the European Union.
This patent family has a natural expiration date in 2035 subject to any adjustment or extension of patent term that may be available in in a particular jurisdiction such as PTE following approval of the New Drug Application, or NDA, in the United States or extension of patent term via a Supplementary Protection Certificate, or SPC, following EMEA marketing authorization.
−Removed: Upon approval of the NDA for CT1812 in the United States, the patents in this family claiming compositions of matter of CT1812, pharmaceutical compositions of CT1812, and methods of using CT1812 for inhibiting amyloid beta effects on a neuronal cell, and methods of using CT1812 to treat AD will be eligible to be listed in the FDA’s publication “Approved Drug Products with Therapeutic Equivalence Evaluations,” or the Orange Book.
+Added: Upon approval of the NDA for zervimesine in the United States, the patents in this family claiming compositions of matter of zervimesine , pharmaceutical compositions of zervimesine , and methods of using zervimesine for inhibiting amyloid beta effects on a neuronal cell, and methods of using zervimesine to treat AD will be eligible to be listed in the FDA’s publication “Approved Drug Products with Therapeutic Equivalence Evaluations,” or the Orange Book.
These patents complement the regulatory exclusivity by providing the basis for an additional waiting period prior to the FDA’s approval of an abbreviated new drug application, or ANDA, or 505(b)(2) applicant.
−Removed: If an ANDA or 505(b)(2) applicant were to file its application referencing the NDA for CT1812 before expiration of our composition of matter, pharmaceutical composition, and method of use patents and the applicant asserted that our patents identified on the Orange Book to be invalid or not be infringed, it may be subject to additional waiting periods prior to the FDA’s approval (including a statutory 30-month stay if we sue for infringement, or a shorter period if the patent expires or there are certain settlements or judicial decisions in the patent litigation, starting at the end of the five-year NCE regulatory exclusivity period).
−Removed: In addition to patent exclusivity, under the provisions of the Hatch-Waxman Act, upon any approval in the United States, we believe that CT1812 will be eligible for five-year NCE regulatory exclusivity, during which time no 505(b)(2) NDA or ANDA can be approved that contains the same active moiety as the chemical entity in the CT1812 NDA.
−Removed: When approved in Europe, CT1812 will also be eligible for 10 years of data and market exclusivity which is extendible for an additional year upon market authorization for one or more new indications during the first eight years of the data and market exclusivity period.
−Removed: We also own seven families of pending patent applications directed to methods for selecting subsets of patients with AD for treatment with CT1812, methods of modulating amyloid beta monomer and oligomer levels using CT812, methods of treating GA secondary to dry AMD with CT1812 and methods of treating various neurologic diseases including PD and synucleinopathies with CT1812, as well as a pending provisional application directed to treating certain subsets of AD patients with CT1812 and treating Niemann-Pick disease.
−Removed: Any of these applications, if issued, will have a natural
−Removed: expiration between 2038 and 2044, subject to any adjustment or extension of patent term that may be available such as PTE following NDA approval in the United States as well as any term limitations based upon earlier expiring patents.
+Added: If an ANDA or 505(b)(2) applicant were to file its application referencing the NDA for zervimesine before expiration of our composition of matter, pharmaceutical composition, and method of use patents and the applicant asserted that our patents identified on the Orange Book to be invalid or not be infringed, it may be subject to additional waiting periods prior to the FDA’s approval (including a statutory 30-month stay if we sue for infringement, or a shorter period if the patent expires or there are certain settlements or judicial decisions in the patent litigation, starting at the end of the five-year NCE regulatory exclusivity period).
+Added: In addition to patent exclusivity, under the provisions of the Hatch-Waxman Act, upon any approval in the United States, we believe that zervimesine will be eligible for five-year NCE regulatory exclusivity, during which time no 505(b)(2) NDA or ANDA can be approved that contains the same active moiety as the chemical entity in the zervimesine NDA.
+Added: When approved in Europe, zervimesine will also be eligible for 10 years of data and market exclusivity which is extendible for an additional year upon market authorization for one or more new indications during the first eight years of the data and market exclusivity period.
+Added: We also own seven families of pending patent applications directed to methods for selecting subsets of patients with AD for treatment with zervimesine , methods of modulating amyloid beta monomer and oligomer levels using zervimesine , methods of treating GA secondary to dry AMD with zervimesine and methods of treating various neurologic diseases including PD, DLB and other synucleinopathies with zervimesine , as well as a pending provisional application directed to treating certain subsets of AD patients with zervimesine and treating Niemann-Pick disease.
+Added: Any of these applications, if issued, will have a natural expiration between 2038 and 2044, subject to any adjustment or extension of patent term that may be available such as PTE following NDA approval in the United States as well as any term limitations based upon earlier expiring patents.
Additional Product Candidates
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We expect this strategy will enable us to maintain a more efficient infrastructure, avoiding dependence on our own manufacturing facility and equipment, while simultaneously enabling us to focus our expertise on the clinical development and future commercialization of our products.
−Removed: Currently, we rely on and have agreements with a single third-party contract manufacturer to supply the drug substance for CT1812 and with a single third-party contract manufacturer to manufacture clinical trial supplies of CT1812, and we expect to enter into commercial supply agreements with such manufacturers prior to any potential approval of CT1812.
−Removed: We continue to develop a commercial route for CT1812 API and to meet all requirements for our planned clinical trials.
−Removed: The current API manufacturer is able to supply all of our needs for the planned clinical studies.
−Removed: CT1812 drug product is manufactured via conventional pharmaceutical processing procedures, employing commercially available excipients and packaging materials.
+Added: Currently, we rely on and have agreements with a single third-party contract manufacturer to supply the zervimesine drug substance and with a single third-party contract manufacturer to manufacture clinical trial supplies of zervimesine.
+Added: We expect to enter into commercial supply agreements with such manufacturers prior to any potential approval of zervimesine.
+Added: We continue to develop the commercial route for zervimesine drug substance and to meet all requirements for our planned clinical trials.
+Added: The current drug substance manufacturer is able to support all of our needs for the planned clinical studies and commercial supplies.
+Added: Zervimesine drug product is manufactured via conventional pharmaceutical processing procedures, employing commercially-available excipients and packaging materials.
The procedure and equipment employed for manufacture and analysis are consistent with standard pharmaceutical production, and are transferable to a range of manufacturing facilities, if needed.
−Removed: We have selected a larger third-party drug product manufacturer and will be executing technology transfer of drug product manufacture to a larger manufacturer.
−Removed: We will also maintain the current drug substance and product manufacturer as part of our supply chain strategy.
+Added: We will transition from our current drug product manufacturer to a larger third-party manufacturer for our late-stage clinical and commercial supply.
Commercialization Strategy
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Our competitors compete with us on the level of the technologies employed, or on the level of development of product candidates.
−Removed: In addition, many small biotechnology companies have formed collaborations with large,
−Removed: established companies to (i) obtain support for their research, development and commercialization of products or (ii) combine several treatment approaches to develop longer lasting or more efficacious treatments that may potentially directly compete with our current or future product candidates.
+Added: In addition, many small biotechnology companies have formed collaborations with large, established companies to (i) obtain support for their research, development and commercialization of products or (ii) combine several treatment approaches to develop longer lasting or more efficacious treatments that may potentially directly compete with our current or future product candidates.
We anticipate that we will continue to face increasing competition as new therapies and combinations thereof, technologies, and data emerge.
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Our commercial opportunity could be reduced or eliminated if one or more of our competitors develop and commercialize products that are safer, more effective, better tolerated, or of greater convenience or economic benefit than our proposed product offering.
−Removed: Currently available therapies for these diseases are limited, with two approved disease-modifying treatments each for Alzheimer’s disease and geographic atrophy (GA) secondary to dry AMD but no approved treatments for dementia with Lewy bodies.
+Added: Currently available therapies for these diseases are limited, with two approved disease-modifying treatments each for Alzheimer’s disease but no approved treatments for dementia with Lewy bodies.
However, our competitors also may be in a position to obtain FDA or other regulatory approval for their products more rapidly, resulting in a stronger or dominant market position before we are able to enter the market.
6 unchanged sentences
We are dedicated to conducting business with the highest standards of corporate responsibility.
−Removed: Our goal is to build a culture of diverse and passionate people striving to positively impact patients, our communities, and broader society.
+Added: Our goal is to build a culture of talented and passionate people striving to positively impact patients, our communities, and broader society.
Our human capital resource priorities include attracting, recruiting, retaining, incentivizing and integrating our existing and new employees.
−Removed: We believe that a diverse, equitable, and inclusive workplace allows our company to best fulfill our mission.
−Removed: We are committed to continuing our efforts to increase diversity throughout our company and foster an inclusive work environment that supports our employees and the communities we serve.
+Added: We promote values such as purpose, drive, transparency, and fairness in our workplace.
The principal purposes of our equity and cash incentive plans are to attract, retain and reward personnel through the granting of stock-based and cash-based compensation awards, in order to increase stockholder value and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.
−Removed: During 2023, the Company has taken proactive steps to enhance and improve our policies related to employee welfare and engagement.
+Added: During 2024, the Company took proactive steps to enhance and improve our policies related to employee welfare and engagement.
Government Regulation
1 unchanged sentence
Generally, before a new drug can be marketed, considerable data must be generated, which demonstrate the drug’s quality, safety, and efficacy.
−Removed: data must then be organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.
+Added: Such data must then be organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.
Drug Development Process
20 unchanged sentences
The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical studies.
−Removed: The IND also includes results of animal and in vitro studies assessing the toxicology, PK, pharmacology, and
−Removed: pharmacodynamic characteristics of the product;
+Added: The IND also includes results of animal and in vitro studies assessing the toxicology, PK, pharmacology, and pharmacodynamic characteristics of the product;
chemistry, manufacturing, and controls information;
24 unchanged sentences
Sponsor may voluntarily pause or stop a clinical trial, or the FDA may place a trial on full or partial clinical hold at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk or concerns related to chemistry, manufacturing and controls.
−Removed: A clinical hold is an order issued by the FDA to delay or suspend an investigation Following the issuance of a clinical hold or a partial clinical hold, a clinical trial may only proceed after FDA has notified the sponsor that any deficiencies have been corrected and FDA is authorizing the trial to proceed.
−Removed: In addition, an IRB representing each institution participating in the clinical trial must review and approve the
−Removed: plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review and reapprove the study at least annually.
+Added: A clinical hold is an order issued by the FDA to delay or suspend an investigation.
+Added: Following the issuance of a clinical hold or a partial clinical hold, a clinical trial may only proceed after FDA has notified the sponsor that any deficiencies have been corrected and FDA is authorizing the trial to proceed.
+Added: In addition, an IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review and reapprove the study at least annually.
The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects.
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Under the Prescription Drug User Fee Act, or PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission.
−Removed: This review typically takes 12 months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after the application is submitted.
−Removed: The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review The FDA may request additional information rather than accept an NDA for filing.
+Added: This review typically takes 12 months from the date the NDA is submitted to FDA because the FDA has approximately
+Added: two months to make a “filing” decision after the application is submitted.
+Added: The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review.
+Added: The FDA may request additional information rather than accept an NDA for filing.
In this event, the NDA must be resubmitted with the additional information.
4 unchanged sentences
Before approving an NDA, the FDA will typically inspect the facility or facilities where the product is manufactured.
−Removed: The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP and adequate to assure consistent production of the product within required specifications.
+Added: The FDA will not approve an application unless it determines that the manufacturing processes and facilities comply with cGMP and is adequate to assure consistent production of the product within required specifications.
Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCPs.
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The sponsor of a fast track designated product has opportunities for more frequent interactions with the applicable FDA review team during product development.
−Removed: With regard to a fast track
−Removed: designated product, the FDA may also consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.
+Added: With regard to a fast track designated product, the FDA may also consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.
Any drug candidate submitted to the FDA for approval, including a drug candidate with a Fast Track designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.
20 unchanged sentences
There are continuing, annual program fees for any marketed products.
−Removed: Drug manufacturers
−Removed: and their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP, which impose certain procedural and documentation requirements upon us and our third-party manufacturers.
+Added: Drug manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP, which impose certain procedural and documentation requirements upon us and our third-party manufacturers.
Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented.
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Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances.
−Removed: The FDA does not regulate the behavior of physicians in their choice of treatments.
+Added: The FDA does not regulate the behavior of physicians in their choice
+Added: of treatments.
The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.
The federal government has levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label promotion.
−Removed: The FDA and other
−Removed: regulatory agencies have also required that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.
+Added: The FDA and other regulatory agencies have also required that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.
However, companies may share truthful and not misleading information that is otherwise consistent with a product’s FDA-approved labelling.
+Added: From time to time, legislation is drafted, introduced, passed in Congress and signed into law that could significantly change the statutory provisions governing the approval, manufacturing, and marketing of products regulated by the FDA.
+Added: In addition to new legislation, FDA regulations, guidance, and policies are often revised or reinterpreted by the agency in ways that may significantly affect the manner in which pharmaceutical products are regulated and marketed.
Patent Term Restoration and Marketing Exclusivity
Market exclusivity provisions authorized under the FDCA can delay the submission and approval of certain marketing applications for products containing the same active ingredient.
−Removed: The FDCA provides a five- year period of non-patent marketing exclusivity within the United States to the first applicant to obtain approval of an NDA for a NCE.
+Added: The FDCA provides a five- year period of non-patent marketing exclusivity within the United States to the first applicant to obtain approval of an NDA for an NCE.
A drug is an NCE if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.
21 unchanged sentences
Five-year and three-year exclusivity will not delay the submission or approval of a full NDA.
−Removed: However, an applicant submitting a full NDA would be required to
−Removed: conduct or obtain a right of reference to any nonclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.
+Added: However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to any nonclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.
Pediatric exclusivity is another type of marketing exclusivity available in the United States.
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Among other things, the Affordable Care Act expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum Medicaid rebate for both branded and generic products, expanded the 340B program, and revised the definition of average manufacturer price, or AMP, which could increase the amount of Medicaid rebates manufacturers are required to pay to states.
−Removed: The legislation also extended Medicaid rebates, previously due only on fee-for-service Medicaid utilization, to include the utilization of Medicaid managed care organizations as well and
−Removed: created an alternative rebate formula for certain new formulations of certain existing products that is intended to increase the amount of rebates due on those products.
+Added: The legislation also extended Medicaid rebates, previously due only on fee-for-service Medicaid utilization, to include the utilization of Medicaid managed care organizations as well and created an alternative rebate formula for certain new formulations of certain existing products that is intended to increase the amount of rebates due on those products.
There have been significant ongoing efforts to modify or eliminate the Affordable Care Act.
3 unchanged sentences
The American Taxpayer Relief Act of 2012 further reduced Medicare payments to several types of providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
−Removed: The American Rescue Plan Act of 2021 eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.
+Added: The American Rescue Plan Act of 2021 eliminated the statutory Medicaid drug rebate cap, previously set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, effective January 1, 2024.
These laws and regulations may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.
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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.