How pharma is targeting advances in Alzheimer’s treatments

Neurodegenerative disorders

Cognition Therapeutics recently completed the enrolment of its Phase II SEQUEL trial for patients with mild-to-moderate Alzheimer’s disease. The focus of the trial is to test Cognition Therapeutics’ experimental drug, CT1812 for patients with dementia with Lewy Bodies and dry age-related macular degeneration. Reece Armstrong speaks to Lisa Ricciardi, CEO of Cognition Therapeutics, to learn about what the company hopes to achieve with CT1812.

RA: Why have neurodegenerative conditions such as Alzheimer’s and dementia with Lewy bodies proven so challenging to treat?

LR: The history of Alzheimer’s disease (AD) as a clinical target is largely the story of the amyloid beta hypothesis. For decades, companies both large and small targeted removal of a-beta plaques as a means to prevent cognitive loss, and the industry experienced universal failure in these trials. More recent studies have moved the field ahead by identifying the need for a certain volume of plaque removal in order to demonstrate improved cognition relative to placebo. In addition, the field is also catching up with other key findings, notably decades-long research on the role of the toxic species of amyloid, that is, oligomers and protofibrils. By targeting these sub-species, we are finally seeing advances in treatment. All researchers and clinicians would likely agree that multiple mechanisms – not just one – are at work in these dementia conditions. Companies are focused on neuro-inflammation, micro-glial activation and on other approaches. At Cognition Therapeutics, we are focused on the key toxins, oligomers, and understand that more approaches will be elucidated as companies like us progress their trials.

Alzheimer’s disease and DLB are complicated conditions that typically require lengthy trials and sizable patient populations. Clinical insights from trials take a meaningful amount of time. And the patients are not homogeneous. Alzheimer’s disease is a highly prevalent condition with an estimated 6 million patients in the US. While Dementia with Lewy Bodies or DLB is smaller, estimated 1.5 million patients, the conditions have some similarities which can lead to a slower differential diagnosis. So, in summary, there is not a single reason for the industry challenges but rather, a set of clinical and operational realities which have to be dealt with on top of evolving information about targets.

RA: Do you see CT1812 being used alongside therapies such as lecanemab as a multi-drug approach to Alzheimer’s?

LR: We believe that when we complete our clinical trials and upon FDA approval, our drug will be used as a single agent for the treatment of Alzheimer’s disease as well as in the treatment of DLB. Given the oral route of administration and convenient once-daily dosing, we believe CT1812 will be a desirable candidate to study in combination therapy. The goal will be to study multiple therapies to determine synergy and additive effects slowing disease progression to a greater extent than any one treatment can alone. With a potential 6 million patient population, there is likely great variability across disease severity and physicians will need multiple choices to effectively treat their patients.

From a mechanism perspective, lecanemab has been shown to slow disease progression by binding to soluble oligomers and protofibrils, which are the toxic forms of the protein, beta-amyloid. CT1812 also targets oligomers, clearing them from binding sites and ensuring that with proper drug saturation levels, no new oligomers bind to neurons. We believe this approach represents a considerable potential advance in treatment for AD patients.

RA: Could you explain the mechanism of action behind CT1812?

LR: Our approach with CT1812 is to target sigma-2 receptors on cells, specifically neurons, which are responsible for our ability to create and retain memories. These sigma-2 receptors function like a damage control mechanism on cells. By binding to the sigma-2 receptor, CT1812 prevents the toxic amyloid beta oligomers from binding to neurons, essentially protecting neurons from their toxicity. In addition to neurons, these sigma-2 receptors are prevalent on cells in the retina as well, which has led us to conduct a separate study of CT1812 to treat geographic atrophy connected with dry age- related macular degeneration. We believe CT1812 has a protective role in cell health and function by targeting the sigma-2 receptor.

RA: Why might sigma-2 receptors be important in the treatment of Alzheimer’s and other neurodegenerative diseases?

LR: Cognition’s scientific team and colleagues recently published a paper on this topic in the International Journal of Molecular Sciences. Sigma-2 receptors govern pathways in age-related diseases and are known to regulate signaling, protein trafficking, oxidative stress, as well as amyloid-beta and alpha-synuclein toxicity. Importantly in our effort to address Alzheimer’s disease, targeting the sigma-2 receptor is an approach distinct from that of treatments that bind directly to forms of amyloid beta. We believe that having multiple approaches to treat Alzheimer’s disease will be required to ultimately manage this and other neurodegenerative conditions.

We believe that removal of amyloid is a sound approach to treating AD and recent studies have confirmed this strategy can slow disease progression. Modulating the sigma-2 receptor and thereby reducing the affinity of amyloid oligomers for their receptor is a more traditional pharmaceutical approach to addressing amyloid toxicity. CT1812 is a small molecule, orally delivered drug that reaches the brain in sufficient concentrations to reduce the affinity of oligomers to their receptors in a magnitude that is very similar to the reduced affinity of oligomers that carry the ‘Icelandic’ mutation. The Icelandic mutation is a single nucleotide substitution (A673T) in the amyloid precursor protein (APP) gene which leads to reduced APP production, reduced affinity of amyloid oligomers and reduced incidence of developing AD.

RA: You’ve recently finished enrolment in your Phase II SEQUEL trial. What data do you hope to generate from this study regarding CT1812 and Alzheimer’s/ other neurodegenerative conditions?

LR: SEQUEL was designed to assess CT1812’s tolerability and to measure the impact of CT1812 on the electrical activity in the brain, specifically looking at brainwaves or electrical impulses called theta waves, which are measured by electroencephalography (EEG), a widely available and non-invasive tool. In individuals with AD, a greater proportion of wave bands in the EEG patterns are theta waves. An analysis of theta wave proportion may indicate how well the brain is processing information. In addition to causing long-term neurodegeneration, bound oligomers have an acute effect on synapse activity. Displacement of oligomers may have an acute effect on synapse activity in individuals with AD which may be measurable with EEG. If successful, our trial will show that treatment with CT1812 normalises the theta wave patterns of people with Alzheimer’s disease, which would further support the role of CT1812 in protecting synapses from the toxicity of amyloid beta oligomers. We anticipate reporting top-line data from SEQUEL midyear 2023.

RA: Could you discuss how you’re using quantitative electroencephalogram (qEEG) to measure theta waves and how this could act as a biomarker on disease progression and treatment effect?

LR: Researchers at the Amsterdam University Medical Centers are looking at the use of quantitative EEG to measure theta waves, which are a useful tool to measure how Alzheimer’s disease impacts processes in the brain. By extension, we may be able to use theta wave patterns as an indicator of how Alzheimer’s disease patients respond to treatment. Measuring theta waves by a quantitative EEG is non-invasive and could have a more economical impact on tracking outcomes and disease progression. Advanced imaging technologies have an important role in the care of patients with neurodegenerative diseases but they may not be available in every medical centre. Tools that are widely available, compact and non-invasive will hopefully allow more patients to be diagnosed and monitored appropriately.

RA: You’re expecting topline results from the SEQUEL trial in the middle of 2023. What does the future timeline look like for CT1812?

LR: Cognition has two additional Phase II studies ongoing. The SHINE trial of CT1812 for mild-to-moderate Alzheimer’s disease and the SHIMMER study of CT1812 for mild-to-moderate dementia with Lewy bodies are both anticipated to complete enrollment in 2023r. Both are supported by grant awards from the National Institute on Aging (NIA), which is part of the NIH. Pending completion of enrollment, we anticipate data from these trials next year.

In addition, Cognition and the Alzheimer’s Clinical Trials Consortium (ACTC) are preparing to enroll patients in the Phase II START trial for those with early Alzheimer’s disease, and clinical trial sites are expected to start opening sites and enrolling patients in mid- 2023. This will be Cognition’s largest study to date. We plan to enroll 540 participants, who will be treated for 18 months. This is also supported by an award from the NIA.

Lastly, we received FDA clearance to start the Phase II MAGNIFY study of CT1812 for geographic atrophy associated with dry age-related macular degeneration. As I mentioned earlier, sigma-2 receptors are found in the eye – on cells called retinal pigment epithelial (RPE) cells – as well as the brain. In the eye, RPE cells are responsible for supporting the health of photoreceptors, which transmit the signals coming into the eye to the brain, enabling us to see. Work conducted by Cognition and our collaborators suggests that sigma-2 receptors may have a role in protecting RPE cells in the eye. The science led us to this indication, and we’re excited to explore CT1812’s impact on this disease, which affects more than one million people in the United States alone.

DDW Volume 24 – Issue 3, Summer 2023

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