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Item 1. Business

2023-03-23 compared with 2022-03-30 · 294 added, 269 removed, 659 unchanged (46% of the section changed)

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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.

Our lead product candidate, CT1812, is an orally delivered, small molecule antagonist designed to penetrate the blood-brain barrier and bind selectively to the S2R complex.

We have initially focused on the development of CT1812 for the treatment of Alzheimer’s disease, or AD, by targeting the accumulation of β-amyloid, or Aβ, oligomers, which has been linked to the disease.

By displacing these Aβ oligomers from neuronal receptors in the S2R complex, we expect to demonstrate that CT1812 can slow the loss of synapses and cognitive decline observed in AD.

CT1812 is the first S2R antagonist to reach clinical trials and is currently in Phase 2 development for the treatment of AD.

The direct healthcare costs to care for patients with AD and other dementias in the United States is currently estimated to exceed $300 billion.

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.

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 has been linked to the disease.

We believe our evidence demonstrates that by binding to the S2R complex, CT1812 displaces Aβ oligomers from their neuronal receptors.

Based on this mechanism, we believe CT1812 has the potential to slow the loss of synapses and cognitive decline observed in AD.

CT1812 is the first S2R selective ligand modulator to reach clinical trials and is currently in Phase 2 development for the treatment of AD.

The direct healthcare costs to care for patients with AD and other dementias in the U.S.

is estimated as of April 18, 2022 to exceed $300 billion.

Approximately 6.5 million people in the U.S.

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Among people with AD, approximately 50% have mild disease, 30% have moderate disease and 20% have severe disease.

We are continuing to enroll patients in two ongoing Phase 2 clinical trials (SHINE and SEQUEL) with CT1812 in mild-to-moderate AD.

Preliminary results from an interim analysis of the first 24 patients in Part A of our ongoing SHINE Phase 2 clinical trial demonstrated a statistically significant decline in the presence of Aβ 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.

We anticipate top-line data in 2023.

Our ongoing SEQUEL Phase 2 clinical trial is also evaluating changes in brain function, as measured by quantitative electroencephalography, or qEEG, in mild-to-moderate AD with top-line data expected in the fourth quarter of 2022.

We have treated 164 subjects with CT1812 in our clinical trials to date including 76 patients with mild-to-moderate AD.

We are continuing to enroll patients in two ongoing Phase 2 clinical trials with CT1812:

COG0201 (SHINE) and COG1201 (SHIMMER) in dementia with Lewy bodies, or DLB.

Preliminary results from an interim analysis of the first 24 patients in Part A of our SHINE Phase 2 clinical trial 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.

We anticipate completing enrollment in 2023 with top-line data expected in 2024.

We have treated over 220 subjects with CT1812 in our clinical trials to date including over 90 patients with mild-to-moderate AD.

CT1812 has continued to be well tolerated and has been granted Fast Track designation by the U.S.

Food and Drug Administration, or FDA, in this indication.

Our clinical trials have been funded by approximately $168.9 million in cumulative grants awarded primarily by the National Institute of Aging, or NIA, a division of the National Institutes of Health, which includes a grant award of approximately $81.0 million from the NIA to fund our Phase 2 (COG0203) study of CT1812 in patients with early-stage AD.

We intend to enroll 540 patients in our COG0203 clinical trial with mild cognitive impairment, or MCI, due to AD or mild AD who have elevated levels of Aβ as determined by positron emission tomography, or PET, imaging or as measured in cerebral spinal fluid, or CSF.

Our clinical trials have been funded by approximately $171.0 million in cumulative grants awarded primarily by the National Institute of Aging, or NIA, a division of the National Institutes of Health.

Our awards include a grant award of approximately $81.0 million from the NIA to fund our Phase 2 START (COG0203) study of CT1812 in patients with early stage AD.

We intend to enroll 540 patients in our START trial with mild cognitive impairment, or MCI, due to AD or mild AD who have elevated levels of Aβ oligomers 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.

Patients will be randomized to receive CT1812 or a placebo for 18 months.

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.

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, and we expect to begin enrollment in the second half of 2022.

We intend to expand our CT1812 pipeline to include additional indications such as dry age-related macular degeneration, or dry AMD, a disease that results in the deterioration of the macula, causing distortion, loss of central vision and eventual blindness, for which there are currently no FDA approved treatments.

The S2R complex is expressed

in the retina in several cell types including the retinal pigment epithelial cells, or RPE, photoreceptors and retinal ganglion cells.

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 dry AMD.

After the completion of our ongoing preclinical studies and subject to discussion with the FDA, we intend to advance directly into a Phase 2 clinical trial in the second half of 2022, leveraging our knowledge of CT1812’s preclinical and clinical profile to date.

We have initiated discussions with the FDA regarding our plan.

We intend to expand our CT1812 pipeline to include additional indications such as geographic atrophy, or GA, secondary to dry age-related macular degeneration, or dry AMD.

GA is an advanced form of dry AMD.

Dry AMD is an eye disease that results in the deterioration of the macula, causing distortion, loss of central vision and eventual blindness, for which there are currently no FDA approved treatments.

The S2R complex is expressed in the retina in several cell types including the retinal pigment epithelial cells, or RPE, photoreceptors and retinal ganglion cells.

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.

We submitted an Investigational New Drug, or IND, application to the FDA at the end of 2022;

the IND was cleared at the end of January 2023.

Our first trial in dAMD is a Phase 2 trial called MAGNIFY and we plan initiate this in 2023.

In addition, we are developing other product candidates in the area of synucleinopathies.

Synucleinopathies are a group of degenerative diseases characterized by the abnormal accumulation of the alpha-synuclein protein in neural cell bodies, including Parkinson’s disease, or PD, and dementia with Lewy bodies, or DLB.

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.

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.

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We are currently engaged in two ongoing Phase 2 clinical trials, designed to evaluate safety, dosing and potential efficacy for CT1812 as a treatment for mild-to-moderate AD.

These trials include evaluations of CT1812’s ability to engage with the S2R complex enabling the displacement of Aβ oligomers, its impact in synaptic density and its restoration of synaptic function.

These trials include evaluations of CT1812’s ability to engage with the S2R complex enabling the restoration of synaptic function as measured by quantitative EEG, or qEEG.

In the largest of these trials, our COG0201 SHINE study, we are assessing CT1812’s ability to alter disease progression and cognition, with a target enrollment of 144 participants.

We are currently recruiting patients at sites in the United States and Europe, with additional sites expected to activate in 2023.

Early-stage AD

We plan to evaluate CT1812 in a 540-patient Phase 2 COG0203 clinical trial to investigate the potential for CT1812’s use at an earlier stage of AD.

In addition to cognitive and functional measures, such as CDR-SB, 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.

We will be enrolling patients in the second half of 2022.

We plan to evaluate CT1812 in a 540-patient Phase 2 COG0203 START clinical trial to investigate the potential for CT1812’s use at an earlier stage of AD.

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.

We expect to open sites in the first half of 2023.

This trial has been funded by a grant of approximately $81.0 million from the NIA.

We are evaluating CT1812 in a 120-patient Phase 2 COG1201 clinical trial to investigate the potential for CT1812’s use as a disease-modifying agent in DLB.

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 DLB.

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).

We are currently evaluating sites to commence our trial.

We are currently recruiting patients in the United States.

The trial has been funded by a grant of approximately $30.0 million from the NIA.

We are also evaluating the use of CT1812 to treat dry AMD.

We believe that human genetic and internal proteomic pathway analyses obtained through our AD trials provides evidence of a relationship between the S2R complex and dry AMD.

Geographic Atrophy Secondary to Dry AMD

We are also evaluating the use of CT1812 to treat GA secondary to dry AMD.

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.

We are currently engaged in preclinical development activities for this indication, including studies to elucidate the key mechanisms by which CT1812 and the S2R complex alter the biological processes that contribute to dry AMD.

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 dry AMD.

After the completion of our ongoing preclinical studies and discussion with the FDA, we intend to advance directly into a Phase 2 clinical trial in the second half of 2022, leveraging our knowledge of CT1812’s preclinical and clinical profile to date.

We have initiated discussions with the FDA regarding our plan.

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.

We submitted an Investigational New Drug, or IND, application to the FDA at the end of 2022;

the IND was cleared at the end of January 2023.

Our first trial in dAMD is a Phase 2 trial called MAGNIFY and we plan initiate this in 2023.

Discovery Initiatives

We are actively engaged in a number of early-stage discovery programs which are built upon our identification of five structurally distinct chemical series.

We are pursuing a number of early-stage discovery programs which are built upon our identification of five structurally distinct chemical series.

We believe we have identified several structurally distinct compounds that possess advantages for specific disease indications and patient populations.

Two of these next-generation S2R modulators have been identified for synucleinopathies and dry AMD and are being assessed as potential IND candidates.

One of our S2R modulators, CT2168, has shown potential disease modification in synucleinopathies such as DLB and PD.

Data indicate that this next-generation S2R modulator has activity in α-synuclein assays, indicating the potential to alleviate α-synuclein oligomer-induced neurotoxicity.

Another of our next-generation S2R modulators, CT2074, 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.

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-gen molecule to advance for this indication.

A few of these next- generation S2R modulators have been identified for synucleinopathies and dry AMD and are being assessed as potential IND candidates.

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.

Therefore, we believe S2R modulators may present a novel therapeutic approach for these indications and intend to pursue development as described below.

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Our lead product candidate, CT1812, has progressed through Phase 1 and into Phase 2 clinical trials.

Funding of the Phase 1 and into Phase 2 trials is primarily through the NIA.

We are evaluating CT1812 in other AD populations as well and developing CT1812 for patients with earlier symptomatic stages of AD and Mild Cognitive Impairment, which is a slight and noticeable measurable decline in cognitive abilities due to AD.

We plan to initiate this clinical trial for COG0203 in patients with mild dementia associated with early-stage AD and will enroll patients in the second half of 2022.

The trial has been funded by a grant of approximately $81.0 million awarded from the NIA.

● Pursue the development of CT1812 for dry AMD .

We plan to evaluate CT1812 as a potential therapy for dry AMD, a common eye disease that results in the deterioration of the macula, causing visual distortion, loss of central vision and eventual blindness.

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 dry AMD.

We have initiated discussions with the FDA regarding our plan.

Funding of the Phase 1 and Phase 2 trials has come primarily from the NIA.

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.

Our START (COG0203) clinical trial in patients with mild dementia associated with early stage AD has been funded by a grant of approximately $81.0 million awarded from the NIA.

● Pursue the development of CT1812 for GA secondary to dry AMD .

We plan to evaluate CT1812 as a potential therapy for GA secondary to dry AMD.

GA is an advanced form of dry AMD.

Dry AMD is an eye disease that results in the deterioration of the macula, causing visual distortion, loss of central vision and eventual blindness.

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.

We submitted an IND application to the FDA at the end of 2022 to initiate a Phase 2 clinical trial of CT1812 in indication and it was cleared by the FDA at the end of January 2023.

We plan to initiate this Phase 2 clinical trial in 2023.

● Leverage our understanding of the S2R complex to develop product candidates for other CNS and degenerative diseases, including synucleinopathies.

We intend to develop and advance other product candidates to treat synucleinopathies, which include PD and DLB.

We are initiating a study of CT1812 in patients with DLB and are currently evaluating sites.

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.

We intend to develop and advance other product candidates to treat other conditions, potentially including the synucleinopathies, which include PD and DLB.

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.

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.

● Expand our pipeline through internal development, in-licensing and acquisitions .

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 our library generation and Novel Improved Conditioned Extraction, or NICE, screening platform.

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.

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.

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● Continue to pursue non-dilutive funding opportunities .

The majority of our clinical trials have been funded by approximately $168.9 million in cumulative grants awarded primarily by the NIA, which includes an approximately $81.0 million grant award from the NIA to fund our upcoming Phase 2 (COG0203) study of CT1812 in patients with early-stage AD.

The majority of our research and clinical efforts have been funded by approximately $171.0 million in cumulative grants awarded primarily by the NIA.

This includes awards totaling $10.9 million in support of preclinical studies and $160.1 million for clinical development, the largest of which was the 2020 award of $81.0 million supporting our upcoming Phase 2 START (COG0203) study of CT1812 in early-stage AD.

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.

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Collectively, our management team has a track record of managing drug development programs that have received regulatory approval and been successfully commercialized.

These include programs at Bristol-Myers Squibb Company and Pfizer Inc.

In addition, our management team has built companies that have initiated innovative technologies and investigational new drug programs.

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The two most common neurodegenerative diseases are AD and PD.

To our knowledge, no other biopharmaceutical company has focused solely on stopping the synaptic binding and signaling of soluble Aβ oligomers through the use of small molecule receptor antagonists, such as CT1812.

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.

Based on this expertise, we are able to discover and optimize small molecule receptor antagonists like CT1812 that we believe represent a functionally distinct and promising approach to synaptorestorative AD therapeutics where neurons remain viable and functional.

These molecules were designed to displace Aβ oligomers bound to neuronal receptors at synapses by selectively targeting and clearing Aβ oligomers from the brain into the CSF.

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.

These molecules were designed to displace Aβ oligomers bound to neuronal receptors at synapses and clearing Aβ oligomers from the brain into the CSF.

In addition to neurodegenerative diseases, other degenerative diseases include AMD.

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adults over 80 years of age.

We believe that human genetic and internal proteomic pathway analyses obtained through our AD trials provides evidence of a relationship between the S2R complex and dry AMD.

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 dry AMD.

We have initiated discussions with the FDA regarding our plan.

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.

We are currently engaged in preclinical development activities for dry AMD, including studies to elucidate the key mechanisms by which CT1812 and the S2R complex alter the biological processes that contribute to dry AMD.

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.

We submitted an IND application to the FDA at the end of 2022 to initiate a Phase 2 clinical trial of CT1812 in indication and it was cleared by the FDA at the end of January 2023.

We plan to initiate this Phase 2 clinical trial in 2023.

Other S2R modulators are being explored, currently in lead identification studies, prior to lead optimization and candidate selection for IND-enabling studies.

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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.

We believe the array of degenerative disorders which involve protein components of the S2R complex allows for the potential therapeutic use of proprietary S2R antagonists in numerous indications.

S2R affects diverse regulatory functions through specific interactions with the oligomer receptors and other membrane proteins.

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.

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.

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Chemical structures that we are currently evaluating as potential therapeutics for degenerative diseases originate from our NICE screening platform.

The NICE screening platform allows us to generate proprietary small molecule libraries derived from natural chemical scaffolds through a proprietary process which we refer to as conditioned

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.

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.

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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.

As a result, the NICE screening platform is designed to accelerate drug development time while reducing development risk.

We believe these characteristics provide us with a screening platform that is differentiated from other discovery strategies.

As a result, the NICE screening platform was designed to accelerate drug development time while reducing development risk.

We believe this platform provides us with differentiated libraries which may lead to development candidates beyond CT1812.

Our Product Candidates

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We intend to develop therapeutics with the potential to overcome diseases associated with age-related toxic protein buildups that disrupt key cellular processes.

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, dry AMD, PD and DLB as depicted in the illustration below.

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.

Our Lead Product Candidate:

Our lead product candidate, CT1812, is an orally delivered, small molecule antagonist that penetrates the blood-brain and blood-retina barriers and binds selectively to the S2R complex;

and through its modulation 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.

Our lead product candidate, CT1812, is an orally delivered, small molecule modulator that penetrates the blood-brain and blood-retina barriers and binds selectively to the S2R complex;

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.

CT1812 originated from our initial efforts with our NICE screening platform which enables the generation of innovative leads.

Leads identified through NICE were then evaluated using proprietary in vitro assays designed to better

emulate in vivo synaptic activity.

Leads identified through NICE were then evaluated using proprietary in vitro assays designed to better emulate in vitro synaptic activity.

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.

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, dry AMD and synucleinopathies, such as DLB.

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.

CT1812 for the Treatment of Alzheimer’s Disease (AD)

CT1812 was designed to selectively target and displace Aβ oligomers bound to neuronal receptors at synapses by a new and differentiated mechanism of action.

CT1812 allosterically modulates, changing the conformation of a key multiprotein regulator of oligomer receptors, the sigma-2 receptor complex.

This destabilizes the Aβ oligomer binding site, increasing the off-rate and thereby displacing bound Aβ oligomers, which are then cleared from synapses.

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.

In our preclinical studies, CT1812 has demonstrated the potential to protect synapses, facilitate their restoration and improve cognitive performance.

These preclinical results are currently being validated in our ongoing Phase 2 clinical trials.

These preclinical results are currently being evaluated through our ongoing Phase 2 clinical trials.

Overview of the Disease

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The Centers for Disease Control listed AD as the primary cause of death for more than 119,000 Americans in 2021.

The disease is equally devastating worldwide, with the World Health Organization estimating that AD affects as many as 35 million people globally.

The disease is equally devastating worldwide, with the World Health Organization estimating that as of December 2022 AD affects as many as 35 million people globally.

Currently Approved AD Therapeutics

Only one disease-modifying therapeutic option has been approved by the FDA.

Specifically, Biogen’s Aduhelm received accelerated approval on June 7, 2021.

The FDA allows accelerated approval for drugs to treat serious conditions that fill an unmet medical need based on a surrogate endpoint.

A surrogate endpoint is a marker thought to predict clinical benefit but is not itself a measure of clinical benefit.

After receiving accelerated approval, drug companies are still required to conduct studies to confirm the clinical benefit.

If the required studies confirm the drug’s benefit, then the FDA grants traditional approval of the drug.

Aduhelm is a monoclonal antibody administered via infusion reported to reduce Aβ plaques, which is distinct from our small molecule approach to modulate the S2R, thereby blocking Aβ oligomers from binding to synapses.

Only two disease-modifying therapeutic option has been approved by the FDA.

Specifically, Biogen’s Aduhelm received accelerated approval on June 7, 2021 and the FDA granted accelerated approval to Eisai’s Leqembi in January 2023.

Aduhelm and Leqembi are monoclonal antibodies administered via infusion reported to reduce Aβ plaques and protofibrils, approaches that are distinct from our small molecule approach to modulate the S2R, thereby blocking Aβ oligomers from binding to synapses.

The only other therapies approved for AD are indicated to treat the symptoms of AD:

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Those focused on reducing the aberrant production, or removal, of intraneuronal neurofibrillary tangles of tau protein have yielded limited clinical benefit.

Development initiatives intended to inhibit hyperphosphorylation of the tau protein and related kinase activity,

enhance microtubule stability or block tau aggregation have largely been discontinued due to toxicity or a lack of efficacy.

Development initiatives intended to inhibit hyperphosphorylation of the tau protein and related kinase activity, enhance microtubule stability or block tau aggregation have largely been discontinued due to toxicity or a lack of efficacy.

Microglial activation and its role in AD-induced neuroinflammation has emerged as another potential target for therapeutic development as has the proper functioning of processes dictating synaptic plasticity, believed to be of central importance to neuronal activity and continued viability.

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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.

As with other treatment strategies, with the exception of Aduhelm, these approaches have likewise yielded few meaningful treatment advances.

We believe the overarching 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:

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:

fibrils, plaques and oligomers.

Accordingly, these efforts may demonstrate success clearing fibrils and the largely inert plaques, but fail to address the specific neurotoxic effects of Aβ oligomers.

We believe that unlike previously pursued approaches, our strategy of targeting the S2R has the potential to prevent Aβ oligomer toxicity by acting directly at the synapse, thereby preventing synaptotoxicity, a mechanism we are testing in the clinic currently.

Such efforts may demonstrate success clearing fibrils and the largely inert plaques but fail to address the specific neurotoxic effects of Aβ oligomers.

Conversely, as exemplified by Leqembi’s clinical results, we believe that preferentially targeting Aβ protofibrils/oligomers has the potential to prevent synaptotoxicity.

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.

The Role of Aβ Oligomers on Synapses and the Downstream Impact to Brain Function and AD

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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.

The preferential binding of CT1812 to the S2R complex produces conformational changes that alters the binding affinity of Aβ oligomers.

CT1812 binding to the S2R complex likely modulates the conformation of the S2R complex, which in turn allosterically alters the conformation of the oligomer binding pocket on the oligomer receptors.

The preferential binding of CT1812 to the S2R complex produces changes that alters the binding affinity of Aβ oligomers to their targets.

CT1812 binding to the S2R complex likely modulates the conformation of the S2R complex, which in turn allosterically alters the conformation of the oligomer binding pocket on the oligomer

Binding pocket destabilization leads to displacement of Aβ oligomers from the neurons and neuronal synapse.

Once displaced, Aβ oligomers are unable to rebind as long as threshold concentrations of CT1812 are present and are rapidly removed from the synapse.

loss of synapses and restores synaptic activity, which may reverse downstream alterations related to membrane trafficking.

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.

The Use of an S2R Targeted Approach is Supported by the A673T Mutation

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.

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, and is notable in that carriers of the mutation are four-fold less likely to develop AD.

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.

Importantly, carriers of the mutation are four-fold less likely to develop AD.

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.

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The smaller the Kd value, the greater the binding affinity.

Bmax refers to the maximum amount of a ligand that can bind specifically to a receptors.

Bmax refers to the maximum amount of a ligand that can bind specifically to a receptor.

Intensity is measured in arbitrary fluorescent units.

We believe that CT1812 is the only drug currently in clinical trials that mimics the effects of the A673T mutation.

As the images presented below suggest, both CT1812 and the A673T mutation similarly reduce the binding of toxic Aβ oligomers to synapses.

We believe that drugs 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.

We believe that CT1812 is the only drug candidate currently in clinical trials that mimics the effects of the A673T mutation.

As the images presented below suggest, both CT1812 and the A673T mutation similarly reduced the binding of toxic Aβ oligomers to synapses.

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.

CT1812 Clinical Results in AD

We have completed four clinical trial evaluations of CT1812, in both healthy volunteers and patients with mild-to-moderate AD, with two clinical trials ongoing and one additional trial with topline results currently available and final results expected in the second half of 2022.

We have completed seven clinical trial evaluations of CT1812, in both healthy volunteers and patients with mild-to-moderate AD, with three clinical trials ongoing.

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 conduct initial assessments of its therapeutic potential.

The following is the status of our completed and ongoing clinical trials.

Overview of our completed, ongoing and planned clinical studies

Overview of our completed, ongoing and planned clinical studies of CT1812 for AD and dementia

COG0201 — Phase 2 (SHINE) Clinical Trial

Our COG0201 SHINE study is a randomized, double-blind, placebo-controlled Phase 2 clinical trial designed to enroll up to a total of 120 patients with mild-to-moderate AD to evaluate the safety and potential efficacy of CT1812.

Our ongoing COG0201 SHINE study is a randomized, double-blind, placebo-controlled Phase 2 clinical trial designed to enroll up to a total of 144 patients with mild-to-moderate AD to evaluate the safety and potential efficacy of CT1812.

Participants are divided in two CT1812 dose groups (100 mg or 300 mg) and one placebo group, dosed daily for six months.

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ADAS-Cog 11 is a globally recognized cognitive scale that is used to assess cognition in patients with AD.

Preliminary results from an interim analysis of the first 24 patients from the COG0201 study demonstrated that CT1812 continued to be generally well tolerated.

Preliminary data from an interim analysis of the first 24 patients from the COG0201 study demonstrated that CT1812 continued to be generally well tolerated.

There were four serious adverse events, or SAEs, which were not drug-related and occurred in a single placebo patient.

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We observed mild and transient elevations of liver enzymes in three patients without any other indications of liver injury.

These results were consistent with findings from earlier clinical studies.

The preliminary results also demonstrated a significant decline in the presence of Aβ 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.

These data were consistent with findings from earlier clinical studies.

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.

These results were observed in patients receiving CT1812 or placebo in addition to background therapies they may have already been receiving for AD.

We believe these preliminary results provide promising evidence of CT1812’s cognitive and biological impact on the 24 patients included in the interim analysis of the SHINE study.

These results indicate that patients treated with CT1812 showed relative stability on a measure of cognitive performance compared to the placebo group.

We believe these preliminary data provide promising evidence of CT1812’s potential cognitive and biological impact.

These data also indicate that patients treated with CT1812 showed relative stability on a measure of cognitive performance compared to the placebo group.

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.

After review of these results, which are presented in the graph below, we decided to continue trial enrollment, and are identifying sites and screening patients for this study.

Results indicate a three-point improvement in cognitive decline in CT1812-treated patients.

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.

Preliminary data showed a three-point improvement in cognitive decline in CT1812-treated patients.

From this, we identified product candidate pharmacodynamic biomarkers that could reflect processes of target engagement, pathway engagement and/or early disease modification.

The SHINE trial was not powered to detect statistically significant treatment differences.

The interim analysis of the SHINE trial (SHINE A) was not powered to detect statistically significant treatment differences.

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.

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COG0202 — Phase 2 (SEQUEL) Trial

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 quantitative EEG measurement, as reflected by relative theta power.

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.

The trial is configured as a two-arm crossover trial, in which half of the participants will receive 300 mg of CT1812 daily for 29 days.

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After a 14-day wash out period, these participants will receive CT1812 treatment for an additional 29 days.

CSF and EEG evaluations are taken periodically throughout the duration of the trial.

We anticipate reporting topline data from this trial in fourth quarter of 2022.

CSF and qEEG evaluations are taken periodically throughout the duration of the trial.

We completed enrollment in the first quarter of 2023 and expect to report topline data later in 2023.

COG0105 — Phase 1 (SPARC) Trial

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A statistically 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.

Additional analyses are underway, including examination of CSF biomarkers including Aβ, tTau, pTau181 and a host of synaptic biomarkers.

This trial was completed in 2021.

COG0104 — Phase 1 (SNAP) Trial

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Five CSF samples were collected before and 24 samples collected after administration of a single 560 mg oral dose of CT1812 or placebo.

CSF samples from trial participants were analyzed to measure the concentration of Aβ oligomers over the trial period.

CSF samples from each trial participant were analyzed to measure the concentration of Aβ oligomers over the trial period.

Results of this 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.

These findings were observed using two independent methods, microimmunoelectrode and western blots.

These findings were measured using two independent methods, microimmunoelectrodes and western blots.

This effect of CT1812 was specific to Aβ oligomers, as no CT1812-related increase in Aβ 1-40 or 1-42 monomer was observed.

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First evidence of target engagement in humans, which mirrors that found preclinically;

we believe this reinforces that our mechanism of action extends to patients with AD

and we believe this reinforces that our mechanism of action extends to patients with AD

COG0102 — Phase 1 Trial

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Participants were administered one of three oral doses of CT1812, either 90 mg, 280 mg or 560 mg, once daily for 28 days.

The primary endpoint of the trial was safety with a secondary objective of establishing the

pharmacokinetic, or PK, profile of CT1812.

The primary endpoint of the trial was safety with a secondary objective of establishing the pharmacokinetic, or PK, profile of CT1812.

Also included as exploratory endpoints were measurement of CT1812 in CSF, and protein expression changes in CSF and plasma.

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Neurogranin is a synaptic damage marker that increases in the CSF of AD patients reflecting its decrease in the brain.

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 drug to slow Aβ oligomer-induced synapse loss.

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.

Another synaptic damage biomarker that is elevated in the CSF of AD patients is synaptotagmin-1.

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.

This analysis of CT1812’s impact on synaptotagmin-1 levels is presented in the right graph below.

This analysis of CT1812’s impact on

synaptotagmin-1 levels is presented in the right graph below.

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.

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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.

Each participant in this segment of the trial received a single dose of CT1812 each day for 14 days.

participant in this segment of the trial received a single dose of CT1812 each day for 14 days.

The doses evaluated in this second segment were 280 mg, 560 mg and 840 mg.

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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.

A dose of 560 mg

of CT1812 was administered to each of the trial participants for the following six consecutive days.

A dose of 560 mg of CT1812 was administered to each of the trial participants for the following six consecutive days.

The day 6 dose of CT1812 was administered concomitantly with the four-substrate cocktail and PK assessments were repeated.

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Our Upcoming COG0203 Phase 2 Clinical Trial Fully Funded by NIA Grant of approximately $81.0 million

Our COG0203 study 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.

We intend to enroll 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.

The trial is being conducted in collaboration with the ACTC and will utilize up to 35 academic sites associated with the consortium.

Patients will be randomized to receive CT1812 or a placebo for 18 months.

Our COG0203, referred to as START, study 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.

We intend to enroll 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.

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.

Patients will be randomized to receive CT1812 or placebo for 18 months.

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.

We have received a grant of approximately $81.0 million from the NIA to fully fund this trial.

We have received a grant of approximately $81.0 million from the NIA to fund this trial.

Preclinical Results

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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.

CT1812 prevents Aβ oligomer-mediated synaptic damage

CT1812 prevented Aβ oligomer-mediated synaptic damage

Results showed that CT1812 also slowed the loss of synapses that is triggered by Aβ oligomers.

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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.

CT1812 slows loss of synapse numbers in the presence of Aβ oligomers

CT1812 slowed loss of synapse numbers in the presence of Aβ oligomers

The protective benefits of CT1812 observed in these in vitro assays are supported by functional in vivo assessments of CT1812.

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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.

CT1812 restores functional capabilities in a mouse model of AD

CT1812 for the Treatment of Dry Age-Related Macular Degeneration (Dry AMD)

We believe that several lines of evidence suggest that modulation of the S2R complex may provide significant therapeutic utility for the treatment of dry AMD.

Human genetics points to TMEM97 as a promising therapeutic target for dry AMD, as indicated via several large-scale, independent genome-wide association, or GWA, studies.

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 dry AMD.

CT1812 restored functional capabilities in a mouse model of AD

CT1812 for the Treatment of Geographic Atrophy (GA) Secondary to Dry Age-Related Macular Degeneration (Dry AMD)

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.

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.

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.

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

PK assessment indicates that we can achieve therapeutic levels (>80% receptor occupancy) of CT1812 in retinal tissue through oral administration.

We intend to initiate this trial in the fourth quarter of 2022.

We submitted an IND application to the FDA at the end of 2022 to initiate a Phase 2 clinical trial of CT1812 in indication and it was cleared by the FDA at the end of January 2023.

We plan to initiate this Phase 2 clinical trial in 2023.

We believe that well-characterized clinical endpoints and a defined regulatory path increase the attractiveness of this indication.

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Dry AMD is a progressive condition and accounts for up to 90% of all AMD cases.

Advanced dry AMD, or GA, affects approximately 2 million people in the U.S.

There are no approved therapeutics available for dry AMD.

Advanced dry AMD, or GA, affects approximately two million people in the U.S.

There is currently one approved therapeutic for dry AMD.

Other treatments in development are primarily invasive, including intravitreal injections, stem cell replacement and gene therapy approaches.

We believe the limited treatment options available for patients with dry AMD, coupled with newly implicated biochemical pathways, make dry AMD an attractive target for the development of therapeutics.

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.

There are two types of AMD, the first of which is neovascular, or wet AMD, and non-neovascular, or dry AMD.

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.

This thickening disrupts the cytoarchitecture of the retinal pigment epithelium, or 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.

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.

The anatomy of the eye and the regions impacted by AMD

Limitations of Current Treatments

Treatments for dry AMD are currently limited to vitamins and over-the-counter zinc.

While there are no therapeutics approved by the FDA to treat dry AMD, there is considerable development activity ongoing involving numerous targets.

Treatments for dry AMD and GA secondary to dry AMD are currently limited to vitamins and over-the-counter zinc.

While there are no therapeutics approved by the FDA to treat dry AMD or GA secondary to dry AMD, there is considerable development activity ongoing involving numerous targets.

Among the areas of ongoing interest are efforts targeting the complement pathway and its role in inflammation, as mutations in this pathway have been associated with higher risk of dry AMD.

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Rationale for S2R Mechanism of Action

Indications of S2R Involvement in Dry AMD

We believe that several lines of evidence suggest that modulation of the S2R complex may provide significant therapeutic utility for the treatment of dry AMD.

First, human genetics point to TMEM97 as a promising therapeutic target, as indicated via several large-scale, independent genome-wide association, or GWA, studies.

Indications of S2R Involvement in Geographic Atrophy Secondary to Dry AMD

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.

First, human genetics point to TMEM97 as a promising therapeutic target, as indicated via several large-scale, independent GWA studies.

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.

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However, knockdown of TMEM97 in in vitro models of the disease partially rescues RPE cells from oxidative stress-induced cell death.

Investigation of the effects of pharmacological perturbation of the S2R complex signaling is currently ongoing to determine if the rescue of cell death mediated by decreasing TMEM97 expression can be replicated by S2R antagonists, such as CT1812.

Unbiased Analysis of Clinical Trial Sample Proteomics Data:

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Preclinical Support for Clinical Trials

Early proof-of-concept studies indicate a clear role of S2R modulators in rescuing key aspects of dry AMD.

Mechanistic studies and pathway analysis suggest a key role of S2R modulators in dry AMD.

We believe that proof-of-concept studies indicate a clear role of S2R modulators in rescuing key aspects of dry AMD.

Pathway analysis of transcriptomic data suggest a key role of S2R modulators in regulating pathways involved in cell survival and inflammation.

Mechanistic Studies Indicate CT1812 Plays a Role in Cell Survival

and Inflammatory Pathways in RPE Cells

Functional studies support a role of S2R modulators in preventing cell death in a concentration dependent manner, as indicated by the chart below, which suggests that S2R modulators may prevent RPE cell death in dry AMD.

Functional Data Indicates That σ-2 Modulators Rescue Cell Death in RPE Cells

Additional functional studies extend our method of action, or MoA, beyond rescuing cell death, and suggest 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.

Working Hypothesis of MoA in Dry AMD

We believe preclinical studies provide further evidence supporting a clinical trial for CT1812 as a potential treatment for dry AMD.

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.

Working Hypothesis of Mechanism of Action in Dry AMD

We believe preclinical studies provide further evidence supporting a clinical trial for CT1812 as a potential treatment for GA secondary to dry AMD.

PK assessment indicates that we can achieve therapeutic levels (>80% receptor occupancy) of CT1812 in retinal tissue through oral administration.

Moreover, as is illustrated in the graph below, CT1812 levels recorded in the retina were similar to those in the brain, suggesting that the dose(s) used to achieve potential therapeutic levels in the retina needed to achieve efficacy will be similar to the dose(s) for AD.

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.

Similarities in CT1812 concentrations following oral administration in the brain and retina

Our next-generation S2R modulator, CT2074, shows good retinal exposures above 80% receptor occupancy with oral administration.

This modulator has favorable PK properties, including high degree of bioavailability and high retina-to-plasma ratio, and shows activity in rescuing deficits in AMD assays.

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.

In vitro and in vivo preclinical studies are evaluating the utility of CT1812 to impede the death of retinal ganglion cells.

In vivo preclinical studies are evaluating the utility of CT1812 to impede the death of retinal ganglion cells.

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.

Proposed Phase 2 Clinical Trial Design

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 dry AMD.

After the completion of our ongoing preclinical studies and subject to discussion with the FDA, we intend to initiate Phase 2 clinical trial in the second half of 2022, leveraging our knowledge of CT1812’s preclinical and clinical profile to date.

We have initiated discussions with the FDA regarding our plan to leverage results of our previous clinical trials to accelerate clinical development of CT1812 as a treatment for dry AMD.

We anticipate eligibility requirements are anticipated to include individuals 50 years of age or older that have received a diagnosis of dry AMD, with a best corrected visual acuity, or BCVA, score of 24 letters or more, with GA of between 2.5 mm 2 and 17.5 mm 2 .

The proposed primary endpoint of the trial is change in GA lesion area using fundus autofluorescence imaging.

Proposed secondary endpoints are expected to include change in the square root of the GA lesion area, low luminance visual acuity, or LLVA, and BCVA, low luminance visual acuity deficit and drusen volume as measured by optical coherence tomography.

We plan on measuring these outcomes at three-month intervals.

Planned Phase 2 Clinical Trial Design

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.

We submitted an IND application to the FDA at the end of 2022 to initiate a Phase 2 clinical trial of CT1812 in indication and it was cleared by the FDA at the end of January 2023.

We plan to initiate this Phase 2 clinical trial in 2023.

We plan to enroll individuals 50 years of age or older that have received a diagnosis of GA secondary to dry AMD, with a best corrected visual acuity, or BCVA, score of 24 letters or more, with GA of between 2.5 mm2 and 17.5 mm2.

The primary endpoint of the trial will be change in GA lesion area using fundus autofluorescence imaging.

The secondary endpoints will include change in the square root of the GA lesion area, low luminance visual acuity, or LLVA, and BCVA, low luminance visual acuity deficit and drusen volume as measured by optical coherence tomography.

We will measure these outcomes at three-to-six month intervals.

S2R Modulators for the Treatment of Synucleinopathies

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.

of α-synuclein aggregates in Lewy bodies, which is a chief hallmark of PD and other synucleinopathies.

More recently, human genetic evidence has linked SNCA, the gene encoding α-synuclein, to the pathology of synucleinopathies.

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An Overview of Synucleinopathies

Synucleinopathies are a group of neurodegenerative disorders in which the protein alpha-synuclein accumulates abnormally to form inclusions in the cell bodies or axons of neurons or oligodendrocytes.

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.

Two of the primary synucleinopathies are PD and DLB, which each involve motor and cognitive dysfunction.

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upregulation of the autophagy receptor LAMP2A, dysregulation of lipid metabolism and a reduction in membrane trafficking.

complex components, PGRMC1 and TMEM97, directly regulate these processes, activities which are compromised by the binding and internalization of α-synuclein oligomers.

The S2R complex components, PGRMC1 and TMEM97, directly regulate these processes, activities which are compromised by the binding and internalization of α-synuclein oligomers.

Compounds that bind to S2R and block α-synuclein binding and/or internalization are therefore expected to be disease-modifying.

Preclinical Study Support for Clinical Trials

The results of in vitro studies suggest that S2R antagonists, such as CT1812, may have disease modifying effect on the synucleinopathies by reversing pathway disruption and dysregulation caused by α-synuclein oligomers.

In work funded by a grant from the Michael J.

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.

In work funded by grants from the Michael J.

Fox Foundation, α-synuclein oligomers were found to bind to brain cells in culture and are internalized, indicated by the red dots in the image to the left below.

With the addition of S2R antagonist CT1812, the binding and thus internalization of the α-synuclein oligomers is inhibited as indicated in the image to the right below.

CT1812 blocks the binding and internalization of α-synuclein oligomers the neuronal synapses

The potential for S2R antagonists to reverse the deleterious cellular effects of α-synuclein oligomers is also reflected in the in vitro analysis of LAMP2A expression presented below.

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.

CT1812 blocked the binding and internalization of α-synuclein oligomers the neuronal synapses

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.

LAMP2A is a critical component of chaperone-mediated autophagy, one of several processes that eliminate damaged cellular proteins.

Its expression, noted in orange, is upregulated in the presence of the toxic α-synuclein oligomer, likely a compensatory mechanism in response to the cellular insult.

S2R antagonists, which block membrane trafficking deficits caused by α-synuclein oligomers, are observed to inhibit the upregulation of LAMP2A, as evidenced by the dark and light gray in the below chart.

S2R modulators, which block membrane trafficking deficits caused by α-synuclein oligomers, are observed to inhibit the upregulation of LAMP2A, as evidenced by the dark and light gray in the below chart.

As these antagonists are selective for the S2R complex, their ability to reverse the effects of α-synuclein on LAMP2A expression provides compelling evidence of the S2R complex’s importance in the regulation of this autophagy pathway.

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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.

S2R antagonists reverse the effects of α-synuclein oligomers on LAMP2A expression and trafficking

Proposed Phase 2 Clinical Trial in Dementia with Lewy bodies (DLB)

We are evaluating sites for our Phase 2 clinical trial studying the use of CT1812 to treat patients diagnosed with DLB.

S2R antagonists reversed the effects of α-synuclein oligomers on LAMP2A expression and trafficking

Phase 2 Clinical Trial in Dementia with Lewy Bodies (DLB)

We are actively enrolling sites for our Phase 2 clinical trial studying the use of CT1812 to treat patients diagnosed with DLB.

The design of this trial is a double-blind, randomized trial involving three dose groups, two active treatment cohorts and a placebo group.

We expect to enroll 120 patients in a six-month study, with equal participant numbers in each of the three dose groups, with daily (QD) dosing.

Eligibility requirements will 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.

We are enrolling 120 patients in a six-month study, with equal participant numbers in each of the three dose groups, with daily (QD) dosing.

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.

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.

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Taken together, the company has been awarded approximately $171.0 million in cumulative grants for the advancement of our pipeline programs.

Of this, approximately $128.5 million in cumulative non-dilutive grants have been awarded by the NIA to fund development of CT1812 for the treatment of Alzheimer’s disease.

Of this, approximately $81.0 million in cumulative non-dilutive grants have been awarded by the NIA to fund development of CT1812 for the treatment of AD.

As of December 31, 2022, we had approximately $89.3 million available from NIA funds for applicable expenses to be incurred in the future.

National Institute on Aging (NIH)

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Only costs that are allowable under the grant award, certain government regulations and the NIH’s supplemental policy and procedure manual may be claimed for reimbursement, and the reimbursements are subject to routine audits from governmental agencies from time to time.

While these NIA grant do not contain payback provisions, the NIA or other government agency may review our performance, cost structures and compliance with applicable laws, regulations, policies and standards and the terms and conditions of the applicable NIA Grant.

While these NIA Grants do not contain claw back provisions, the NIA or other government agency may review our performance, cost structures and compliance with applicable laws, regulations, policies and standards and the terms and conditions of the applicable NIA Grant.

If any of our expenditures are found to be unallowable or allocated improperly or if we have otherwise violated terms of such NIA Grant, the expenditures may not be reimbursed and/or we may be required to repay funds already disbursed.

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As of March 1, 2023, our intellectual property portfolio contained nine issued U.S.

patents, fifty one issued foreign patents as well as one pending U.S.

provisional applications, four pending U.S.

patent applications, two pending PCT applications and twenty one 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.

patents, sixty seven issued foreign patents as well as one pending U.S.

provisional application, four pending U.S.

patent applications, two pending

Patent Cooperation Treaty applications and twenty four 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.

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.

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We expect to file additional patent applications in support of current and new product candidates as well as new platform and core technologies.

We are the exclusive owner of five patent families that include several granted U.S.

We are the exclusive owner of six patent families that include several granted U.S.

patents and pending U.S.

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, dry AMD, PD, and synucleinopathies.

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.

As of March 1, 2022, 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, China, the European Union, Hong Kong, Israel, Japan, Mexico, South Korea, Russia and South Africa.

As of March 1, 2023, 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.

This patent family also includes a pending U.S.

patent application and pending application in certain foreign jurisdictions including Brazil, Canada, the European Union, India, and New Zealand.

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 NDA approval in the United States or extension of patent term via a Supplementary Protection Certificate, or SPC, following EMEA marketing authorization.

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 ,” which we refer to as the Orange Book.

These patents complement the regulatory exclusivity by providing the basis for an additional waiting periods prior to the FDA’s approval of an abbreviated new drug application, or ANDA, or 505(b)(2) applicant.

patent application and pending application in certain foreign jurisdictions including Canada, India, the European Union and Hong Kong.

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.

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.

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.

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).

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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.

We also own three 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, and methods of treating dry AMD with CT1812, as well as one pending provisional patent application directed to methods of treating various neurologic diseases including Parkinson’s disease and synucleinopathies with CT1812.

Any of these applications, if issued, will have a natural expirations between 2038 and 2042, 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.

We also own four 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.

Any of these applications, if issued, will have a natural expiration between

2038 and 2043, 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 continue to develop a commercial route for CT1812 API and to meet all requirements for our planned clinical trials.

We plan to transfer the API manufacture to a larger third-party manufacturer once the commercial route is developed.

We plan to transfer the API manufacture to a larger third-party manufacturer to support the commercial launch of the product, if approved.

The current API manufacturer is able to supply all of our needs for the planned clinical studies.

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We face substantial competition from multiple sources, including large and specialty biotechnology and pharmaceutical companies, academic research institutions and governmental agencies and public and private research institutions.

Our competitors compete with us on the level of the technologies employed, or on the level of development of product candidates.

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.

Our competitors compete with us on the level of the technologies employed, or on the level of development

of 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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We consider our relationship with our employees to be good.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and new employees, advisors and consultants.

We are dedicated to conducting business with the highest standards of corporate responsibility.

Our goal is to build a culture of diverse 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.

We believe that a diverse, equitable, and inclusive workplace allows our company to best fulfill our mission.

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.

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.

During 2022, the Company has taken proactive steps to enhance and improve our policies related to employee welfare and engagement.

Government Regulation

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requirements at any time during the product development process, the approval process or after approval may subject an applicant to administrative or judicial sanctions.

These sanctions could include the FDA’s refusal to approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions,

fines, refusals of government contracts, restitution, disgorgement, or civil or criminal penalties.

Any agency or judicial enforcement action could have a material adverse effect on us.

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● submission to the FDA of an IND, which must become effective before human clinical trials may begin;

● approval by an independent IRB ethics committee, either centralized or with respect to each clinical site, before each clinical trial may be initiated;

● performance of adequate and well-controlled human clinical trials in accordance with GCP requirements to establish the safety and efficacy of the proposed drug for its intended use;

● approval by an independent institutional review board, or IRB, or ethics committee, either centralized or with respect to each clinical site, before each clinical trial may be initiated;

● performance of adequate and well-controlled human clinical trials in accordance with good clinical practices, or GCP, requirements to establish the safety and efficacy of the proposed drug for its intended use;

● submission to the FDA of an NDA after completion of all pivotal trials;

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● satisfactory completion of an FDA advisory committee review, if applicable;

● satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with cGMP requirements to ensure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality, and purity, and of selected clinical investigation sites to assess compliance with GCPs;

● satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with current good manufacturing practices, or cGMP, requirements to ensure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality, and purity, and of selected clinical investigation sites to assess compliance with GCPs;

● FDA review and approval of the NDA to permit commercial marketing of the product for particular indications for use in the United States;

● compliance with any post-approval requirements, including potential requirements to conduct any post-approval studies required by the FDA or the potential requirement to implement a REMS;

● compliance with any post-approval requirements, including potential requirements to conduct any post-approval studies required by the FDA or the potential requirement to implement a risk evaluation and mitigation strategy, or REMS;

● compliance with the Pediatric Research Equity Act, or PREA, which requires either exemption from the requirements or may require conducting clinical research in a pediatric population.

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and any available human data or literature to support the use of the investigational product.

An IND must become effective before human clinical trials may begin.

The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises safety concerns or questions about the proposed clinical trial.

An IND must become effective before human

clinical trials may begin.

The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises safety concerns or questions about the proposed clinical trial or drug candidate.

In such a case, the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.

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Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical study.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness

criteria to be evaluated.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments.

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Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the clinical trial is unlikely to meet its stated objectives.

Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which may review data and endpoints at designated check points, make recommendations and/or halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.

There are also requirements governing the reporting of ongoing clinical studies and clinical study results to public registries.

Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, or DSMB, which may review data and endpoints at designated check points, make recommendations and/or halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.

There are also requirements governing the registration of ongoing clinical studies and posting of clinical study results to public registries.

Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

The product candidate is initially introduced into healthy human subjects or patients with the target disease or condition.

The product candidate is initially introduced into a limited number of healthy human subjects or patients with the target disease or condition.

These studies are designed to test the safety, dosage tolerance, absorption, metabolism, and distribution of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

In the case of some products for severe or life-threatening diseases, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing;

The product candidate is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages, and dosing schedule and to identify possible adverse side effects and safety risks.

Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning;

In the case of some product candidates for severe or life-threatening diseases, especially when the product candidate may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing;

The product candidate is administered to a limited patient population with the target disease or condition to evaluate the preliminary efficacy, optimal dosages, and dosing schedule and to identify possible adverse side effects and safety risks.

Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning Phase 3 trials;

Phase Three :

The product candidate is administered to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites.

These clinical trials are intended to establish the overall risk.

These clinical trials are intended to establish the overall risk relative to potential benefit and generate the data used by FDA and other regulatory agencies to evaluate suitability for marketing authorization.

Post-approval clinical trials, sometimes referred to as Phase 4 studies, may be conducted after initial marketing approval.

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In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

The FDA or the sponsor may place a clinical trial on a 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.

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.

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.

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.

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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These points may be prior to submission of an IND, at the end of Phase 2, and before an NDA is submitted.

Meetings at other times may be requested.

Meetings at other times may be requested by the sponsor.

These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide advice, and for the sponsor and the FDA to reach agreement on the next phase of development.

Sponsors typically use the meetings at the end of the Phase 2 clinical trial to discuss Phase 2

clinical results and present plans for the pivotal Phase 3 clinical trials that they believe will support approval of the new drug.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

Sponsors typically use the meetings at the end of the Phase 2 clinical trial to discuss Phase 2 clinical results and present plans for the pivotal Phase 3 clinical trials that they believe will support approval of the new drug.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug candidate and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality, and purity of the final drug.

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NDA Review and Approval Process

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development nonclinical and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product.

The submission of an NDA is subject to the payment of substantial user fees;

a waiver of such fees may be obtained under certain limited circumstances.

Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

Additionally, no user fees are assessed on NDAs for product candidates designated as orphan drugs, unless the product also includes a non-orphan indication.

The FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality, and purity.

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For example, the FDA may approve the NDA with a REMS to ensure the benefits of the product outweigh its risks.

A REMS is a safety strategy to manage a known or potential serious risk associated with a medicine and to enable patients to have continued access to such medicines by managing their safe use.

A REMS is a safety strategy to manage a known or potential serious risk associated with and approved drug and to enable patients to have continued access to such drug by managing their safe use.

It could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries, and other risk minimization tools.

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In addition, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could impact the timeline for regulatory approval or otherwise impact ongoing development programs.

Changes to some of the conditions established in an approved application, including changes in indications, labeling, or manufacturing processes or facilities, require submission to and FDA approval of a new NDA or NDA supplement before the change can be implemented.

An NDA supplement for a new indication typically requires clinical data similar to that in the original application, and the FDA uses the same procedures and actions in reviewing NDA supplements as it does in reviewing NDAs.

As with new NDAs, the review process is often significantly extended by the FDA requests for additional information or clarification.

Expedited Development and Review Programs

The FDA has a fast track designation program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria.

Specifically, new drugs are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

With regard to a fast track product, the FDA may 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.

CT1812 was awarded Fast Track designation by the FDA in 2016.

Any product submitted to the FDA for approval, including a product 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.

A product is eligible for priority review if it has the potential to provide safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement in the treatment, diagnosis, or prevention of a disease compared to marketed products.

The FDA will attempt to direct additional resources to the evaluation of an application for a new drug designated for priority review in an effort to facilitate the review.

The FDA has a Fast Track designation program that is intended to expedite or facilitate the process for reviewing new drug candidates that meet certain criteria.

Specifically, new drug candidates are eligible for Fast Track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

Fast Track designation applies to the combination of the drug candidate and the specific indication for which it is being studied.

The sponsor of a fast track designated product has

opportunities for more frequent interactions with the applicable FDA review team during product development.

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.

A drug candidate is eligible for priority review if it has the potential to provide safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement in the treatment, diagnosis, or prevention of a disease compared to marketed products.

The FDA will attempt to direct additional resources to the evaluation of an application for a new drug candidate designated for priority review in an effort to facilitate the review.

The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months for review of new molecular entity NDAs under its current PDUFA review goals.

In addition, a product may be eligible for accelerated approval.

Drug products intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

In addition, the FDA currently requires pre-approval of promotional materials as a condition for accelerated approval, which could adversely impact the timing of the commercial launch of the product.

In addition, a drug candidate may be eligible for accelerated approval.

Drug candidates intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval upon a determination that the drug candidate has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of accelerated approval, the FDA generally requires that the sponsor perform adequate and well-controlled post-marketing confirmatory clinical trials which must be conducted with due diligence to verify and describe the predicted clinical benefit.

Under the Food and Drug Omnibus Reform Act of 2022, or FDORA, the FDA may require, as appropriate, that such confirmatory trials be underway prior to approval or within a specific time period after the date accelerated approval is granted.

Under FDORA, the FDA has increased authority for expedited procedures to withdraw approval of a drug or indication approved under accelerated approval if, for example, the sponsor fails to conduct the required confirmatory trials or if such studies fail to verify the predicted clinical benefit.

In addition, the FDA currently requires, unless otherwise informed by the agency, pre-approval of promotional materials as a condition for accelerated approval, which could adversely impact the timing of the commercial launch of the product.

The Food and Drug Administration Safety and Innovation Act established a category of drugs referred to as “breakthrough therapies” that may be eligible to receive Breakthrough Therapy designation.

A sponsor may seek FDA designation of a product candidate as a “breakthrough therapy” if the product is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

A sponsor may seek FDA designation of a product candidate as a “Breakthrough Therapy” if the drug candidate is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug candidate may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance.

The Breakthrough Therapy designation is a distinct status from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria are met.

If a product is designated as breakthrough therapy, the FDA will work to expedite the development and review of such drug.

Fast track designation, priority review, accelerated approval, and breakthrough therapy designation do not change the standards for approval, but may expedite the development or approval process.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

We may explore some of these opportunities for our product candidates as appropriate.

If a drug candidate is designated as Breakthrough Therapy, the FDA will work to expedite the development and review of such drug candidate.

Fast Track designation, priority review, accelerated approval, and Breakthrough Therapy designation do not change the standards for approval, but may expedite the development, review or approval process.

Even if a drug candidate qualifies for one or more of these programs, the FDA may later decide that the drug candidate no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

We may explore some of these opportunities for our drug candidates as appropriate.

Post-Approval Requirements

Any products manufactured or distributed by us pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record- keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion of the product.

After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval.

approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval.

There are continuing, annual program fees for any marketed products.

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● restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;

● fines, warning letters, or untitled letters;

● clinical holds on post-approval or Phase IV clinical studies, if applicable;

● fines, warning letters, untitled letters, Form 483s;

● clinical holds on post-approval or Phase 4 clinical studies, if applicable;

● refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product license approvals;

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● mandated modification of promotional materials and labeling and the issuance of corrective information.

Under the Pediatric Research Equity Act (PREA) an NDA must contain data to assess the safety and efficacy of the applicant product for indications in applicable pediatric populations.

Under PREA, an NDA must contain data to assess the safety and efficacy of the applicant product for indications in applicable pediatric populations.

It must also contain information to support dose administration for pediatric populations where the drug may be utilized.

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Physicians may prescribe, in their independent professional medical judgment, legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA.

Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances.

Physicians may believe that such

off-label uses are the best treatment for many patients in varied circumstances.

The FDA does not regulate the behavior of physicians in their choice of treatments.

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However, companies may share truthful and not misleading information that is otherwise consistent with a product’s FDA-approved labelling.

Marketing Exclusivity

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.

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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.

The FDCA also permits patent term restoration of up to five years as compensation for a patent term lost during product development and FDA regulatory review process to the first applicant to obtain approval of an NDA for a new chemical entity in the United States.

Patent-term restoration, however, cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date.

During the NCE exclusivity period, the FDA may not approve or even accept for review an ANDA or an NDA submitted under Section 505(b)(2) (505(b)(2) NDA), submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval.

However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed in the FDA’s publication Approved Drug Products with Therapeutic Equivalence Evaluations , which we refer to as the Orange Book, with the FDA by the innovator NDA holder.

During the NCE exclusivity period, the FDA may not approve or even accept for review an ANDA or an NDA submitted under Section 505(b)(2), or a (505(b)(2) NDA), submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval.

However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed in the Orange Book, with the FDA by the innovator NDA holder.

Upon approval of an NDA, each of the patents listed in the application for the drug is then published in the Orange Book.

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(2) the patent has expired;

(3) the date on which the patent has expired and approval will not be sought until after the

patent expiration;

(3) the date on which the patent has expired and approval will not be sought until after the patent expiration;

or (4) the patent is invalid or will not be infringed upon by the manufacture, use, or sale of the drug product for which the application is submitted.

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If the drug has NCE exclusivity and the ANDA is submitted four years after approval, the 30-month stay is extended so that it expires 7 1∕2 years after approval of the innovator drug, unless the patent expires or there is a decision in the infringement case that is favorable to the ANDA applicant before then.

The FDCA alternatively provides three years of marketing exclusivity for an NDA, or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages, or strengths of an existing drug.

are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages, or strengths of an existing drug.

This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for drugs containing the active agent for the original indication or condition of use.

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These laws include:

federal Anti-Kickback Statute, which prohibits, among other things, persons or entities from knowingly and willfully soliciting, offering, receiving or paying any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, lease, order, or arranging for or recommending the purchase, lease or order of, any good or service, for which payment may be made, in whole or in part, under federal healthcare programs such as

Medicare and Medicaid.

A person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;

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● state laws and regulations, including state anti-kickback and false claims laws, that may apply to our business practices, including but not limited to, research, distribution, sales and marketing arrangements and claims involving healthcare items or services reimbursed by any third-party payer, including private insurers;

state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the U.S.

state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s

voluntary compliance guidelines and the relevant compliance guidance promulgated by the U.S.

federal government, or otherwise restrict payments that may be made to healthcare providers and other potential referral sources;

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The FCPA also requires public companies to make and keep books and records that accurately and fairly reflect the transactions of the corporation and to devise and maintain an adequate system of internal accounting controls.

Our industry is heavily regulated and therefore involves significant interaction

with public officials, including officials of non-U.S.

Our industry is heavily regulated and therefore involves significant interaction with public officials, including officials of non-U.S.

Additionally, in many other countries, the health care providers who prescribe pharmaceuticals are employed by their government, and the purchasers of pharmaceuticals are government entities;

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Violations could result in fines, criminal sanctions against us, our officers, or our employees, the closing down of our facilities, requirements to obtain export licenses, cessation of business activities in sanctioned countries, implementation of compliance programs, and prohibitions on the conduct of our business.

Enforcement actions may be brought by the Department of Justice or the Securities and Exchanges Commission (“SEC”), and recent enacted legislation has expanded the SEC’s power to seek disgorgement in all FCPA cases filed in federal court and extended the statute of limitations in SEC enforcement actions in intent-based claims such as those under the FCPA from five years to ten years.

Enforcement actions may be brought by the Department of Justice or the SEC, and recent enacted legislation has expanded the SEC’s power to seek disgorgement in all FCPA cases filed in federal court and extended the statute of limitations in SEC enforcement actions in intent-based claims such as those under the FCPA from five years to ten years.

Coverage and Reimbursement

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In addition, third-party payors are increasingly reducing reimbursements for pharmaceutical products and related services.

government and state legislatures have continued implementing cost-containment programs, including price controls, restrictions on coverage and reimbursement and requirements for substitution of generic products.

Third-party payors are increasingly challenging the prices charged, examining the medical necessity and reviewing the cost effectiveness of pharmaceutical products, in addition to questioning their safety and efficacy.

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Decreases in third-party reimbursement for any product or a decision by a third-party payor not to cover a product could reduce physician usage and patient demand for the product.

On August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 into law.

This legislation contains substantial drug pricing reforms, including the establishment of a drug price negotiation program within the U.S.

Department of Health and Human Services that would require manufacturers to charge a negotiated “maximum fair price” for certain selected drugs or pay an excise tax for noncompliance, the establishment of rebate payment requirements on manufacturers of certain drugs payable under Medicare Parts B and D to penalize price increases that outpace inflation, and requires manufacturers to provide discounts on Part D drugs.

The Inflation Reduction Act of 2022 also caps Medicare beneficiaries’ annual out-of-pocket drug expenses.

Substantial penalties can be assessed for noncompliance with the drug pricing provisions in the Inflation Reduction Act of 2022.

Additional drug pricing proposals could appear in future federal legislation.

At the state level, there are also new laws and ongoing ballot initiatives that create additional pressure on drug pricing and may affect how pharmaceutical products are covered and reimbursed.

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Healthcare Reform

The United States and many foreign jurisdictions have enacted or proposed legislative and regulatory changes affecting the healthcare system.

The United States government, state legislatures and foreign governments also have shown significant interest in implementing cost-containment programs to limit the growth of government-paid healthcare costs, including price controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription products.

The United States and many foreign jurisdictions have enacted or proposed legislative and regulatory changes affecting the healthcare system, including implementing cost-containment programs to limit the growth of government-paid healthcare costs, including price controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription products.

In recent years, Congress has considered reductions in Medicare reimbursement levels for products administered by physicians.

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Therefore, any reduction in reimbursement that results from federal legislation or regulation may result in a similar reduction in payments from private payers.

The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Affordability Reconciliation Act, or collectively the Affordable Care Act substantially changed the way healthcare is financed by both governmental and private insurers, and significantly impacts the pharmaceutical industry.

governmental and private insurers, and significantly impacts the pharmaceutical industry.

The Affordable Care Act is intended to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against healthcare fraud and abuse, add new transparency requirements for healthcare and health insurance industries, impose new taxes and fees on pharmaceutical and medical device manufacturers, and impose additional health policy reforms.

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Subsequent legislation extended the 2% reduction, on average, to 2030 unless additional Congressional action is taken.

However, pursuant to the Coronavirus Aid, Relief and Economic Security Act, or CARES Act, the 2% Medicare sequester reductions were suspended from May 1, 2020 through December 31, 2021 due to the COVID-19 pandemic.

However, pursuant to the Coronavirus Aid, Relief and Economic Security Act, or CARES Act, the 2% Medicare sequester reductions were suspended from May 1, 2020 through March 31, 2022 due to the COVID-19 pandemic.

As of July 2, 2022, the 2% sequester reduction resumed.

The sequester will remain in place through 2030.

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Supreme Court.

On June 17, 2021, the Supreme Court ruled that the plaintiffs lacked standing to challenge the law as they had not alleged personal injury

traceable to the allegedly unlawful conduct.

On June 17, 2021, the Supreme Court ruled that the plaintiffs lacked standing to challenge the law as they had not alleged personal injury traceable to the allegedly unlawful conduct.

As a result, the Supreme Court did not rule on the constitutionality of the ACA or any of its provisions.

Further changes to and under the Affordable Care Act remain possible but it is unknown what form any such changes or any law proposed to replace or revise the Affordable Care Act would take, and how or whether it may affect our business in the future.

We expect that changes to the Affordable Care Act, the Medicare and Medicaid programs, changes allowing the federal government to directly negotiate prices and changes stemming from other healthcare reform measures, especially with regard to healthcare access, financing or other legislation in individual states, could have a material adverse effect on the healthcare industry.

We expect that changes to the Affordable Care Act, the Medicare and Medicaid programs and changes stemming from other healthcare reform measures, especially with regard to healthcare access, financing or other legislation in individual states, could have a material adverse effect on the healthcare industry.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

We expect that additional federal, state and foreign healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in limited coverage and reimbursement and reduced demand for our products, once approved, or additional pricing pressures.

could result in limited coverage and reimbursement and reduced demand for our products, once approved, or additional pricing pressures.

Legal Proceedings

We are not currently a party to any material legal proceedings.

From time to time, we may become involved in other litigation or legal proceedings relating to claims arising from the ordinary course of business.

Corporate Information

We were incorporated under the laws of the State of Delaware on August 21, 2007.

Our principal corporate office is located at 2500 Westchester Avenue Purchase, NY 10577, and our telephone number is (412) 481- 2210.

Our website address is www.cogrx.com.

Our website and the information contained on, or that can be accessed through, the website will not be deemed to be incorporated by reference in, and are not considered part of, this Annual Report on Form 10-K.

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.

What changed 10-K

Item 1. Business