What changed in this filing

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Item 1. Business

2024-03-26 compared with 2023-03-23 · 188 added, 197 removed, 756 unchanged (34% of the section changed)

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

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

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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.

have been diagnosed with AD, and the World Health Organization estimates that AD affects as many as 35 million people globally.

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

Approximately 6.5 million people in the United States have been diagnosed with AD, and the World Health Organization estimates that AD affects as many as 35 million people globally.

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 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.

We are continuing to enroll patients in the Phase 2 COG1201 (SHIMMER) study of CT1812 in mild-to-moderate dementia with Lewy bodies, or DLB.

Enrollment concluded in the Phase 2 COG0201 (SHINE) study of CT1812 in mild-to-moderate AD.

Preliminary results from an interim analysis of the first 24 patients demonstrated a statistically significant decline in the presence of Aβ monomers and a positive trend on cognitive function as measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, or ADAS-Cog, in patients receiving CT1812 compared to placebo.

We anticipate top-line results in mid-2024 after the last participants have completed six months of treatment.

As of November 21, 2023, approximately 278 subjects with dementia have received CT1812 in our clinical trials, including subjects with AD and DLB.

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 $171.0 million in cumulative grants awarded primarily by the National Institute of Aging, or NIA, a division of the National Institutes of Health.

Food and Drug Administration, or FDA, for AD.

Our clinical trials have been funded by approximately $171 million in cumulative grants awarded primarily by the National Institute of Aging, or NIA, a division of the National Institutes of Health, or NIH.

Our awards include a grant award of approximately $81 million from the NIA to fund our Phase 2 START (COG0203) study of CT1812 in patients with early-stage AD.

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.

We received clearance from the FDA to proceed with the START clinical trial and recruitment has commenced.

We intend to enroll 540 adults with mild cognitive impairment, or MCI, due to AD or mild AD who have elevated levels of Aβ as determined by a clinical diagnosis of AD confirmed with amyloid biomarkers positron emission tomography, or PET, imaging and/or cerebrospinal fluid, or CSF, biomarkers.

Participants are being 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 open sites during the first half of 2023.

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.

We expanded our CT1812 pipeline to include geographic atrophy, or GA, secondary to dry age-related macular degeneration, or dry AMD as an additional indication.

GA is an advanced form of dry AMD, an eye disease that results in the deterioration of the macula, causing distortion, loss of central vision and eventual blindness.

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 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 and we announced dosing of the first patient in our Phase 2 COG2201 (MAGNIFY) study in July 2023.

We intend to enroll up to 246 adults in this study.

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

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Mild-to-Moderate AD

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 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.

Phase 2 COG0201 (SHINE) clinical trial, is designed to evaluate safety, dosing and potential efficacy for CT1812 as a treatment for mild-to moderate AD and enrolled 158 adults with mild-to-moderate (MMSE 18-26) AD.

In SHINE, the largest of our trials, we are assessing CT1812’s ability to alter disease progression and cognition.

Top-line results are expected in mid-2024 after the last participants have completed six months of treatment.

In addition, we completed the Phase 2 COG0202 (SEQUEL) study and presented complete results in October 2023 at the Clinical Trials on Alzheimer’s Disease (CTAD) conference.

The SEQUEL trial included evaluations of CT1812’s ability to engage with the S2R complex enabling the restoration of synaptic function as measured by quantitative EEG, or qEEG.

Early-stage AD

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.

We received clearance from the FDA to proceed with our Phase 2 START (COG0203) clinical trial to evaluate CT1812 in up to 540 adult patients, which is designed to investigate the potential for CT1812’s use at an earlier stage of AD.

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 million from the NIA.

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 evaluating CT1812 in a 120-patient Phase 2 COG1201 SHIMMER clinical trial to investigate the potential for CT1812’s use as a disease-modifying agent in adults with mild-to-moderate DLB.

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).

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Geographic Atrophy Secondary to Dry AMD

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

We are also evaluating the use of CT1812 to treat GA secondary to dry AMD in Phase 2 COG2201 (MAGNIFY) study.

We are assessing the change in GA lesion size over the treatment duration, as measured by fundus autofluorescence (FAF) imaging, as well as CT1812’s safety and tolerability.

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.

Preclinical data suggest that modulating the S2R complex can 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 GA secondary to dry AMD.

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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.

and we announced the initiation of dosing in July 2023.

Discovery Initiatives

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Our START (COG0203) clinical trial in patients with mild dementia associated with early-stage AD has been funded by a grant of approximately $81 million awarded from the NIA.

● 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.

● Advance clinical development of CT1812 for GA secondary to dry AMD .

We are evaluating 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.

We are currently evaluating CT1812 in a 246-patient Phase 2 study of CT1812 in patients with GA.

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

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Where appropriate, we may use strategic collaborations or partnerships to accelerate development and maximize the commercial potential of our programs.

We and our key opinion leaders believe CT1812 also can be used in combination with other therapeutics targeting AD biologies and thus may have many partnering opportunities.

We and our key opinion leaders believe CT1812 also can be used in combination with other therapeutics and thus may have many partnering opportunities.

● Continue to pursue non-dilutive funding opportunities .

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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 modulators, such as CT1812.

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

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.

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

It is the leading cause of blindness in people over 60 years of age and afflicts approximately 11 million Americans, including an estimated 12% of all U.S.

adults over 80 years of age.

An estimated 18 million adults in the United States have some form of AMD, which is the leading cause of vision loss in people over 60 years of age.

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.

Preclinical data suggest that modulation of the S2R complex can 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.

We submitted an IND application to the FDA at the end of 2022;

it was cleared by the FDA at the end of January 2023;

and we reported that the first participant was dosed in the Phase 2 COG2201 (MAGNIFY) study in July 2023.

We intend to enroll approximately 246 adult patients who will be randomized to receive once-daily oral CT1812 or placebo for 24 months.

The Sigma-2 Receptor Complex

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Biomarker and Imaging-Driven Evidence

Biomarkers have become increasingly important in the development of treatments for neurodegenerative diseases for a number of reasons, including monitoring drug activity in patients, assessing changes in disease pathology during treatment and identifying responder populations for clinical studies.

Given that biomarker-enabled therapeutics have a higher rate of success at gaining product approval, we elected to employ biomarkers in our programs to mitigate clinical development risk.

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Our Lead Product Candidate:

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;

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

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.

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Continued functional decline ultimately results in the patient’s death.

Due to the size of the affected population and the current lack of effective disease modifying therapies, we believe that AD is one of the most significant unmet medical needs of our time.

Due to the size of the affected population, we believe that AD is one of the most significant unmet medical needs of our time.

Nearly six million Americans have been diagnosed with AD and disease prevalence is expected to more than double by 2050.

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Absent the development of meaningful intervention in the course of the disease, the number of people diagnosed with, and dying from, AD is anticipated to escalate appreciably as lifespans lengthen, since prevalence increases significantly with age.

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 as of December 2022 AD affects as many as 35 million people globally.

The Centers for Disease Control listed AD as the sixth leading cause of death among all adults and the fifth leading cause for those aged 65 or older.

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

Currently Approved AD Therapeutics

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:

acetylcholinesterase inhibitors, or AChEIs, and glutamatergic modulators and an orexin receptor antagonist.

Only two disease-modifying therapeutic options have been approved by the FDA:

Biogen’s Aduhelm, which received accelerated approval on June 7, 2021 and Eisai’s Leqembi, which received complete approval in July 2023.

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

Other therapies approved for AD are indicated to treat the symptoms of AD:

acetylcholinesterase inhibitors, or AChEIs, antipsychotics, glutamatergic modulators and an orexin receptor antagonist.

AChEIs are designed to slow the degradation of the neurotransmitter acetylcholine, helping to preserve neuronal communication and function temporarily.

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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.

Several therapeutics in this class have recently been approved by the FDA, including Aduhelm and Leqembi, which are monoclonal antibodies designed to reduce Aβ plaques and protofibrils, approaches that are distinct from but potentially complementary to our small molecule approach of targeting the S2R to prevent Aβ oligomer toxicity at the synapse.

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:

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CT1812 Uses a Differentiated Mechanism of Action to Selectively Target Aβ Oligomers

Our proprietary CT1812 clinical candidate employs a novel and fundamentally different mechanism which through alteration of S2R activity selectively facilitates removal of neurotoxic Aβ oligomers.

Our proprietary CT1812 product candidate employs a novel and fundamentally different mechanism which through alteration of S2R activity selectively facilitates removal of neurotoxic Aβ oligomers.

Experimental evidence suggests that Aβ oligomers likely occupy binding sites contiguous to the S2R complex.

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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

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.

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.

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

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.

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CT1812 Clinical Results in AD

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.

We have completed multiple clinical trial evaluations of CT1812, in both healthy volunteers and patients with mild-to-moderate AD, with two clinical trials ongoing (SHINE, which has concluded enrollment, and START, which is currently recruiting).

The clinical trials we have conducted to date have enabled us to evaluate the safety profile of CT1812, as well as validate its mechanism through proof-of-concept trials and to conduct initial assessments of its therapeutic potential.

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

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COG0201 — Phase 2 (SHINE) Clinical Trial

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.

Our ongoing COG0201 SHINE study is a randomized, double-blind, placebo-controlled Phase 2 clinical trial to evaluate the safety and potential efficacy of CT1812.

A total of 153 adult participants were enrolled and divided in two CT1812 dose groups (100 mg or 300 mg) and one placebo group, dosed daily for six months.

Endpoints include safety and biomarker evidence of disease modification as well as cognitive function, as measured by the ADAS-Cog 11-item version, or ADAS-Cog 11.

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

Top-line results are expected in mid-2024 after the last participants have completed six months of treatment.

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

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

These data were consistent with findings from earlier clinical studies.

These data were consistent with findings from earlier clinical trials.

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.

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Preliminary data showed 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

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

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p=0.1295), while the treatment difference relative to placebo that observed for the reduction in CSF Aβ 42 protein at the 300 mg dose was significant (p<0.05;

Proof-of-Concept Clinical Trials for the Mechanism of CT1812

We have conducted and are continuing to conduct a series of clinical proof-of-concept trials intended to assess target engagement and the impact of CT1812 on synaptic activity.

COG0203 — Phase 2 START Clinical Trial

Our COG0203 study, referred to as START, is a randomized, double-blind, placebo-controlled Phase 2 clinical trial designed to enroll 540 patients with early-stage AD and powered to show a change in the rate of cognitive and functional decline.

We are currently recruiting patients with MCI due to AD or mild AD who have elevated levels of Aβ as determined by PET imaging or as measured in CSF.

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 million from the NIA to fund this trial.

Completed Proof-of-Concept Clinical Trials for the Mechanism of CT1812

We have conducted a series of clinical proof-of-concept trials intended to assess target engagement and the impact of CT1812 on synaptic activity.

These proof-of-concept trials are presented in more detail below.

COG0202 — Phase 2 (SEQUEL) Trial

COG0202 — Phase 2 SEQUEL Clinical 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 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.

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

The other half of the participants receive placebo daily for 29 days.

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

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

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

After a 14-day wash out period, these participants received placebo for an additional 29 days.

The other half of the participants received placebo daily for 29 days.

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

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

We completed enrollment in the first quarter of 2023 and presented results in October 2023.

Results showed that CT1812-treated participants exhibited a statistically significant change in relative theta in the central region of the brain and consistent trends of improvement across all prespecified EEG parameters, reflecting improved synaptic function after just a matter of weeks.

COG0105 — Phase 1 SPARC Clinical Trial

The COG0105 SPARC study is a randomized, double-blind, placebo-controlled Phase 1 clinical trial of 23 patients with mild-to-moderate AD.

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Most adverse events were mild-to-moderate in severity with no deaths and no treatment-related SAEs reported.

We observed mild and transient elevations of liver enzymes without any other indications of liver injury in two patients in the 300-milligram group.

We observed mild and transient elevations of liver enzymes without any other indications of liver injury in two patients in the 300 mg group.

The patients were discontinued from the study and the liver enzyme levels returned to normal.

Topline results from the analyses of secondary endpoints demonstrated that after 24-weeks of treatment, there were no significant treatment differences on the ADAS-Cog 11 change from baseline.

Top-line results from the analyses of secondary endpoints demonstrated that after 24-weeks of treatment, there were no significant treatment differences on the ADAS-Cog 11 change from baseline.

In addition, there were no significant treatment differences on SV2A signal change compared to baseline.

However, vMRI showed a trend (p=0.0641) towards a significant reduction in the loss of composite brain volume in CT1812- treated patients (pooled) compared to placebo.

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.

COG0104 — Phase 1 (SNAP) Trial

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.

LS Mean Change from Baseline in vMRI (composite) over Time by Treatment

COG0104 — Phase 1 SNAP Clinical Trial

Our COG0104 SNAP study was a randomized, double-blind, placebo-controlled Phase 1 clinical trial that enrolled three patients with mild-to-moderate AD to measure the effects of CT1812 on displacement of Aβ oligomers.

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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.

Results of this clinical trial revealed an increase in Aβ oligomer levels in the CSF over the 24-hour period following treatment with CT1812, but not in the patient administered placebo.

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

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

COG0102 — Phase 1 Trial

COG0102 — Phase 1 Clinical Trial

Our COG0102 study was a randomized, double-blind, placebo-controlled, Phase 1 clinical trial of 19 patients with mild-to-moderate AD.

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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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There were no SAEs related to the product candidate or TEAEs leading to withdrawal from the study.

COG0103 - Phase 1 trial

COG0103 — Phase 1 Clinical Trial

Our COG0103 study was a Phase 1 clinical trial of 15 healthy volunteers designed to evaluate the potential effects of CT1812 on select CYP isoenzymes:

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Based on the small magnitude of change in PK parameters of the probe drugs observed in this study for the isoenzymes CYP2D6 and CYP3A4, clinically meaningful interactions are unlikely.

Clinical Development Plans and Future Trials

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

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.

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 fund this trial.

In all blinded and unblinded clinical trials, several patients experienced asymptomatic, reversible elevations in serum liver chemistries prompting harmonization of monitoring, increasing frequency where appropriate, across our clinical trials.

Preclinical Results

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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 death.

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

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.

We submitted an IND application to the FDA at the end of 2022 to initiate a Phase 2 clinical trial of CT1812 in this indication;

it was cleared by the FDA at the end of January 2023;

and we announced in July 2023 that participant dosing had commenced in the Phase 2 COG2201 (MAGNIFY) study.

CT1812 will be given orally, once daily for 24 months to

determine if it can slow disease progression.

Approximately 246 patients will be randomized to receive once-daily oral CT1812 or placebo for 24 months.

We are assessing the change in GA lesion size over the treatment duration, as measured by fundus autofluorescence (FAF) imaging, as well as CT1812’s safety and tolerability.

We believe that well-characterized clinical endpoints and a defined regulatory path make dry AMD an attractive indication.

Overview of the Disease

AMD is the leading cause of blindness in people over 50 years of age in the United States, afflicting approximately 11 million people in the U.S., including an estimated 12% of all U.S.

AMD is the leading cause of blindness in people over 50 years of age in the United States, afflicting approximately 11 million people in the United States, including an estimated 12% of all U.S.

adults over 80 years of age.

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

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

There is currently one approved therapeutic for dry AMD.

Advanced dry AMD, or GA, affects approximately two million people in the United States.

There are currently two approved therapeutics for dry AMD, both of which are intravitreal injections designed to regulate the complement system.

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

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Limitations of Current Treatments

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.

In addition, cell and gene therapy approaches are being evaluated to regenerate RPE cells and rescue the loss of photoreceptors.

Small molecule visual cycle modulators are also under evaluation to maintain retinal integrity.

Most of these approaches require invasive administrations.

There are currently two FDA-approved therapeutics for dry AMD:

Apellis Pharmaceuticals’ SYFOVRE and Astellas Pharma’s Izervay, both of which are designed to inhibit complement factors.

In addition, there is considerable development activity ongoing involving numerous targets.

Beyond complement inhibitors, other areas of ongoing interest include cell and gene therapy approaches to regenerate RPE cells and rescue the loss of photoreceptors.

Small molecule visual cycle

modulators are also under evaluation to maintain retinal integrity.

Most of these approaches require invasive administration.

Rationale for S2R Mechanism of Action

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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 modulators, such as CT1812.

Further investigation of the role of the S2R complex in dry AMD is ongoing.

Unbiased Analysis of Clinical Trial Sample Proteomics Data:

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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.

Pathway analysis of transcriptomic data suggests 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

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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.

Planned Phase 2 Clinical Trial Design

COG2201 — Phase 2 MAGNIFY Clinical Trial

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.

We submitted an IND application to the FDA at the end of 2022 to initiate a Phase 2 clinical trial of CT1812 in this indication;

it was cleared by the FDA, and we announced that the first participant was dosed in July 2023 in the Phase 2 COG2201 (MAGNIFY) study.

CT1812 will be given orally, once daily for 24 months to determine if it can slow disease progression.

Approximately 246 patients will be randomized to receive once-daily oral CT1812 or placebo for 24 months.

We are assessing the change in GA lesion size over the treatment duration, as measured by fundus autofluorescence (FAF) imaging, as well as CT1812’s safety and tolerability.

S2R Modulators for the Treatment of Synucleinopathies

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

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

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Synucleinopathies are second only to AD in terms of neurodegenerative disease prevalence.

In the United States, as many as one million people suffer from PD and an estimated 1.4 million from DLB.

In the United States, as many as 1 million people suffer from PD and an estimated 1.4 million from DLB.

According to the Parkinson’s Foundation and the Lewy Body Dementia Association, the direct healthcare costs for patients with PD and DLB are estimated to be approximately $25 billion and $31 billion per year, respectively.

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

The S2R 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 and 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.

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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.

Fox Foundation, α-synuclein oligomers were found to bind to brain cells in culture and are

internalized as indicated by the red dots in the image to the left below.

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

CT1812 blocked the binding and internalization of α-synuclein oligomers in 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.

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

COG1201 — Phase 2 SHIMMER Clinical Trial

We are actively enrolling participants in our Phase 2, SHIMMER (COG1201) clinical trial, which is studying the use of CT1812 to treat adults with mild-to-moderate DLB.

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

We intend to enroll approximately 120 patients 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.

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Additional Product Candidates

Many degenerative disorders likely involve a dysfunctional cellular damage response mechanism and significant evidence is emerging which highlights the importance of the S2R complex and its components in regulating this response.

Many degenerative disorders are likely to involve a dysfunctional cellular damage response mechanism and significant evidence is emerging which highlights the importance of the S2R complex and its components in regulating this response.

The complex likely contains a number of relevant binding sites that may allow for multiple disease intervention approaches, making it an attractive therapeutic target.

Accordingly, we are actively engaged in a number of earlier-stage discovery programs which are built upon our identification of five structurally distinct chemical series.

From these series we have multiple leads which will be optimize each of our lead series.

From these series we have multiple leads which will be optimized from each of our lead series.

Each of these leads has demonstrated favorable potency with variable selectivity in early preclinical testing and each of the molecular series possesses distinct bioavailability and PK properties, including differences in half-life and blood-brain and blood-retina permeability.

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We would also study α-synuclein pathology and motor deficits in two mechanistically distinct in vivo models of synucleinopathies.

parallel, these studies will elucidate the mechanism of action by which S2R modulators are efficacious in PD and DLB and provide essential data to support potential biomarker nomination for PD and DLB.

these studies will elucidate the mechanism of action by which S2R modulators are efficacious in PD and DLB and provide essential data to support potential biomarker nomination for PD and DLB.

Grant Funding

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Ten Preclinical Programs

Each of the grants awarded to us relate to agreed-upon direct and indirect costs for specific studies or clinical trials, which may include personnel and consulting costs, costs paid to CROs, research institutions and/or consortiums involved in the grant, as well as facilities and administrative costs.

Each of the grants awarded to us relates to agreed-upon direct and indirect costs for specific studies or clinical trials, which may include personnel and consulting costs, costs paid to CROs, research institutions and/or consortiums involved in the grant, as well as facilities and administrative costs.

These grants are cost plus fixed fee arrangements in which we are reimbursed for our eligible direct and indirect costs over time, up to the maximum amount of each specific grant award.

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Company Owned Intellectual Property

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

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.

As of March 1, 2024, our intellectual property portfolio contained ten issued U.S.

patents, forty five issued foreign patents as well as five pending U.S.

provisional applications, three pending U.S.

patent applications, one pending Patent

Cooperation Treaty applications and forty five foreign pending patent applications directed to the composition of matter of, pharmaceutical compositions of, methods of use of, and methods for selecting subsets of patients for treatment with our chemical structures, including our lead 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 six patent families that include several granted U.S.

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

patents and pending U.S.

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This patent family also includes a pending U.S.

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

patent application and pending application in certain foreign jurisdictions including India and the European Union.

This patent family has a natural expiration date in 2035 subject to any adjustment or extension of patent term that may be available in in a particular jurisdiction such as PTE following approval of the New Drug Application, or NDA, in the United States or extension of patent term via a Supplementary Protection Certificate, or SPC, following EMEA marketing authorization.

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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 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.

We also own seven families of pending patent applications directed to methods for selecting subsets of patients with AD for treatment with CT1812, methods of modulating amyloid beta monomer and oligomer levels using CT812, methods of treating GA secondary to dry AMD with CT1812 and methods of treating various neurologic diseases including PD and synucleinopathies with CT1812, as well as a pending provisional application directed to treating certain subsets of AD patients with CT1812 and treating Niemann-Pick disease.

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

expiration between 2038 and 2044, subject to any adjustment or extension of patent term that may be available such as PTE following NDA approval in the United States as well as any term limitations based upon earlier expiring patents.

Additional Product Candidates

We are the exclusive owner of three patent families that include several pending U.S.

patent applications, as well as pending patent applications in numerous foreign jurisdictions directed to additional product candidates, including CT2168 and CT2074, among others.

We are the exclusive owner of four patent families that include several pending U.S.

patent applications, as well as pending patent applications in numerous foreign jurisdictions directed to additional product candidates.

These patent families have expirations no earlier than 2038 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.

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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 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.

CT1812 drug product is manufactured via conventional pharmaceutical processing procedures, employing commercially available excipients and packaging materials.

The procedure and equipment employed for manufacture and analysis are consistent with standard organic synthesis or pharmaceutical production, and are transferable to a range of manufacturing facilities, if needed.

The procedure and equipment employed for manufacture and analysis are consistent with standard pharmaceutical production, and are transferable to a range of manufacturing facilities, if needed.

We have selected a larger third-party drug product manufacturer and will be executing technology transfer of drug product manufacture to a larger manufacturer.

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In order to commercialize any products that are approved for commercial sale, we must either develop a sales and marketing infrastructure or collaborate with third parties that have sales and marketing experience.

We may to seek third-party support from established pharmaceutical and biotechnology companies for those products that would benefit from the promotional support of a large sales and marketing force.

We may seek third-party support from established pharmaceutical and biotechnology companies for those products that would benefit from the promotional support of a large sales and marketing force.

In these cases, we might seek to promote our products in collaboration with marketing partners or rely on relationships with one or more companies with large established sales forces and distribution systems.

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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.

In addition, many small biotechnology companies have formed collaborations with large,

established companies to (i) obtain support for their research, development and commercialization of products or (ii) combine several treatment approaches to develop longer lasting or more efficacious treatments that may potentially directly compete with our current or future product candidates.

We anticipate that we will continue to face increasing competition as new therapies and combinations thereof, technologies, and data emerge.

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Our commercial opportunity could be reduced or eliminated if one or more of our competitors develop and commercialize products that are safer, more effective, better tolerated, or of greater convenience or economic benefit than our proposed product offering.

Our competitors also may be in a position to obtain FDA or other regulatory approval for their products more rapidly, resulting in a stronger or dominant market position before we are able to enter the market.

Currently available therapies for these diseases are limited, with two approved disease-modifying treatments each for Alzheimer’s disease and geographic atrophy (GA) secondary to dry AMD but no approved treatments for dementia with Lewy bodies.

However, our competitors also may be in a position to obtain FDA or other regulatory approval for their products more rapidly, resulting in a stronger or dominant market position before we are able to enter the market.

The key competitive factors affecting the success of all of our programs are likely to be product safety, efficacy, convenience and treatment cost.

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Generally, before a new drug can be marketed, considerable data must be generated, which demonstrate the drug’s quality, safety, and efficacy.

Such data must then be organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.

data must then be organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.

Drug Development Process

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The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical studies.

The IND also includes results of animal and in vitro studies assessing the toxicology, PK, pharmacology, and pharmacodynamic characteristics of the product;

The IND also includes results of animal and in vitro studies assessing the toxicology, PK, pharmacology, and

pharmacodynamic characteristics of the product;

chemistry, manufacturing, and controls information;

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.

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.

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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.

In addition, an IRB representing each institution participating in the clinical trial must review and approve the

plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review and reapprove the study at least annually.

The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects.

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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.

Sponsors typically use the meetings at the end of the Phase 2 clinical trials 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.

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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.

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.

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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.

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

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.

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

Drug manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP, which impose certain procedural and documentation requirements upon us and our third-party manufacturers.

Drug manufacturers

and their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP, which impose certain procedural and documentation requirements upon us and our third-party manufacturers.

Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented.

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Physicians may 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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The federal government has levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label promotion.

The FDA and other regulatory agencies have also required that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.

The FDA and other

regulatory agencies have also required that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.

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

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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.

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.

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.

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.

Five-year and three-year exclusivity will not delay the submission or approval of a full NDA.

However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to any nonclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

However, an applicant submitting a full NDA would be required to

conduct or obtain a right of reference to any nonclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Pediatric exclusivity is another type of marketing exclusivity available in the United States.

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● 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;

and state laws and regulations that require drug manufacturers to file reports relating to pricing and marketing information, which requires tracking gifts and other remuneration and items of value provided to healthcare professionals and entities;

● the Physician Payments Sunshine Act, implemented as the Open Payments program, and its implementing regulations, requires certain manufacturers of drugs, devices, biologics and medical supplies that are reimbursable under Medicare, Medicaid, or the Children’s Health Insurance Program to report annually to CMS information related to certain payments made in the preceding calendar year and other transfers of value to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;

beginning in 2022, applicable manufacturers are required to report such information regarding payments and transfers of value provided, as well as ownership and investment interests held, during the previous year to physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, and certified nurse-midwives.

● the Physician Payments Sunshine Act, implemented as the Open Payments program, and its implementing regulations, requires certain manufacturers of drugs, devices, biologics and medical supplies that are reimbursable under Medicare, Medicaid, or the Children’s Health Insurance Program to report annually to CMS information related to certain payments made in the preceding calendar year and other transfers of value provided to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;

applicable manufacturers also are required to report such information regarding payments and transfers of value provided, during the previous year to physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, and certified nurse-midwives.

Violations of any of these laws or any other governmental regulations that may apply to us, may subject us to significant civil, criminal and administrative sanctions including penalties, damages, fines, imprisonment, and exclusion from government funded healthcare programs, such as Medicare and Medicaid, and/or adverse publicity.

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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.

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.

The Inflation Reduction Act of 2022, for example, 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.

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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.

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.

Among other things, the Affordable Care Act expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum Medicaid rebate for both branded and generic products, expanded the 340B program, and revised the definition of average manufacturer price, or AMP, which could increase the amount of Medicaid rebates manufacturers are required to pay to states.

The legislation also extended Medicaid rebates, previously due only on fee-for-service Medicaid utilization, to include the utilization of Medicaid managed care organizations as well and created an alternative rebate formula for certain new formulations of certain existing products that is intended to increase the amount of rebates due on those products.

On February 1, 2016, CMS issued final regulations to implement the changes to the Medicaid Drug Rebate program under the Affordable Care Act.

These regulations became effective on April 1, 2016.

Since that time, there have been significant ongoing efforts to modify or eliminate the Affordable Care Act.

The legislation also extended Medicaid rebates, previously due only on fee-for-service Medicaid utilization, to include the utilization of Medicaid managed care organizations as well and

created an alternative rebate formula for certain new formulations of certain existing products that is intended to increase the amount of rebates due on those products.

There have been significant ongoing efforts to modify or eliminate the Affordable Care Act.

The Tax Act, enacted on December 22, 2017, repealed the shared responsibility payment for individuals who fail to maintain minimum essential coverage under section 5000A of the Internal Revenue Code of 1986, as amended, or the Code, commonly referred to as the individual mandate.

Other legislative changes have been proposed and adopted since the passage of the Affordable Care Act.

The Budget Control Act of 2011, among other things, created the Joint Select Committee on Deficit Reduction to recommend proposals in spending reductions to Congress.

The Joint Select Committee did not achieve its targeted deficit reduction of an amount greater than $1.2 trillion for the fiscal years 2012 through 2021, triggering the legislation’s automatic reductions to several government programs.

These reductions included aggregate reductions to Medicare payments to healthcare providers of up to 2.0% per fiscal year, which went into effect in April 2013.

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 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.

On January 2, 2013, the American Taxpayer Relief Act was signed into law, which, among other things, reduced Medicare payments to several types of providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

The Budget Control Act of 2011, among other things, created measures for spending reductions by Congress that include aggregate reductions to Medicare payments to healthcare providers of up to 2.0% per fiscal year, which remain in effect through 2031.

The American Taxpayer Relief Act of 2012 further reduced Medicare payments to several types of providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

The American Rescue Plan Act of 2021 eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

These laws and regulations may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

The Affordable Care Act has also been subject to challenges in the courts.

On December 14, 2018, a Texas U.S.

District Court Judge ruled that the Affordable Care Act is unconstitutional in its entirety because the “individual mandate” was repealed by Congress.

On December 18, 2019, the Fifth Circuit U.S.

Court of Appeals held that the individual mandate is unconstitutional and remanded the case to the Texas District Court to reconsider its earlier invalidation of the entire Affordable Care Act.

An appeal was taken to the U.S.

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.

In the most recent challenge, in June 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.

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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.

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

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.

Legal Proceedings

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business