Insider interview

Alexander Gebauer from Galimedix Therapeutics talks to Pharmafocus about the link between the two diseases and what the treatment landscape for both could look like in the future

Pharmafocus: How prevalent are Alzheimer’s disease (AD) and age-related macular degeneration (AMD) both individually and as comorbidities?

Alexander Gebauer: Alzheimer's Disease (AD) is the most common cause of dementia. The prevalence of AD increases with age, and it is estimated that about 5-8% of people aged 65 and older have AD worldwide. As the population ages, the number of individuals with AD is expected to rise.

Age-related macular degeneration (AMD) is a degenerative eye disease that affects the macula, the central part of the retina responsible for sharp, central vision. It can be classified into two main types: dry AMD and wet AMD, with dry AMD affecting approximately 80-90% of individuals with AMD. AMD is the leading cause of severe vision loss in individuals over the age of 50. Alongside AD, it is a disease of the elderly and, therefore, its prevalence increases with age. According to estimates, approximately 8.7% of the global population aged 45 and older has some form of AMD.

Current research on the comorbidity of AD and AMD is still limited. However, some studies suggest that there may be a higher prevalence of AMD among individuals with AD compared to the general population. Also, a recent study suggested that people who get AMD, cataracts and diabetes-related eye disease may have a higher risk for dementia.1 In addition, detection of deposited amyloid beta in the retina is more and more accepted as a diagnostic marker for AD.

Pharmafocus: What are the symptoms of AMD and how can these symptoms be used as indicators for specific neurodegenerative diseases such as AD?

AG: Symptoms of AMD may include:

• Blurred central vision: Objects in the centre of the visual field appear blurry, making it difficult to read, recognise faces or perform detailed tasks

• Distorted vision: Straight lines may appear wavy or bent, which is known as metamorphopsia. This can affect the perception of shapes and cause objects to appear distorted

• Dark or empty areas in the central vision: A blind spot or a dark spot may develop in the centre of the visual field, causing a loss of clarity and detail

• Reduced colour perception: Colours may appear less vibrant or washed out

• Difficulty adjusting to low light levels: The ability to adapt to changes in lighting may be reduced, leading to difficulties in seeing in dim environments.

These symptoms are specific to AMD and are related to the degeneration of the macula. It's important to note that they alone are not indicative of other specific neurodegenerative diseases such as AD. AMD primarily affects vision, while AD is a complex neurodegenerative disorder that primarily affects cognitive function. However, there is growing research interest in the potential links between the eyes and AD. The retina, located at the back of the eye, is considered an extension of the central nervous system and shares similarities with brain tissue. Therefore, studying changes in the retina may provide insights into AD pathology and offer opportunities for early detection and monitoring of the disease and the other way around: Alzheimer’s research can provide insights into retinal degeneration.

Pharmafocus: What is the current standard of care for AD and how can ophthalmic treatment options help in expanding the treatment of AD?

AG: The current standard of care for AD involves a combination of pharmacological and non-pharmacological approaches to manage symptoms and slow disease progression.

On one hand, the primary pharmacological approach involves the use of cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and an NMDA receptor antagonist (memantine). These drugs can help manage cognitive symptoms, such as memory loss and confusion, by modulating neurotransmitters in the brain.

Importantly, recent positive results with amyloid beta-targeting therapies have validated the importance of Aβ in treating AD. In June 2023, Lequembi, the first disease-modifying drug to treat AD was approved in the US, marking a new era in treating this disease. Aduhelm was previously approved but showed limited efficacy and significant side effects. Both of these drugs have to be infused, making their usability complicated. On the other hand, non-pharmacological interventions aim to improve the overall quality of life for individuals with AD. They include cognitive stimulation, physical exercise, social engagement and the creation of a supportive and structured environment. An increasing body of literature suggests that the same cell death mechanism – Aβ toxicity – is involved in both AD and retinal diseases. It therefore seems likely that a therapeutic approach showing a marked effect in one disease could also be of benefit against the other.

Pharmafocus: Given that there appears to be a connection between AMD and AD, when do you expect current research into AMD to have a decisive impact on research into AD treatments and how would this be implemented?

AG: Both AMD and AD are age-related neurodegenerative diseases and there is a growing body of evidence suggesting that the neurodegenerative processes in the retina and the brain are very similar, potentially identical. Also, clinical epidemiological data points in this direction, showing that individuals with AMD may have an increased risk of developing AD or experiencing cognitive decline. Research into AMD and AD often share common ground due to the involvement of similar underlying mechanisms. Advances in understanding these shared mechanisms could potentially lead to insights and therapeutic strategies that may be beneficial for addressing both diseases.

If current research into AMD were to have a decisive impact on AD treatments, it would likely occur through the identification of shared pathways or targets. For example, a breakthrough in developing effective treatments for AMD that target a specific mechanism, such as reducing the formation of toxic amyloid beta oligomers and/or removal of existing toxic oligomers, could identify a promising therapeutic strategy for AD, too.

Pharmafocus: How do you see the treatment landscape for dry AMD and AD developing in the next five years?

AG: Dry Age-Related Macular Degeneration (dAMD):

As one of the major factors for retinal cell death in dry AMD appears to be formation of toxic amyloid beta oligomers, therapeutic strategies that directly prevent the formation of these species and additionally remove existing oligomers, are seen as a highly promising approach. Nevertheless, clinical proof of concept still needs to be shown.

Another interesting approach that is being explored as a potential treatment is the use of complement inhibitors. These drugs aim to control the over-activation of the complement cascade, a part of the immune system suggested to have a role in dAMD. Large clinical trials have demonstrated that complement plays a certain role in the pathophysiology. The first anti-complement drug Syfovre has recently been approved by the FDA for the treatment of geographic atrophy secondary to AMD.

A second drug, Zimura, is expected to be approved by FDA this summer, with European approvals also expected soon. However, these drugs are applied by intraocular injection, which is burdensome for patients, and not acceptable for all. Therefore, a safe and effective non-injectable drug would offer a great improvement for patients. Ongoing clinical trials will provide insights into the efficacy and safety of these therapies in the coming years.

Alzheimer's Disease (AD):

Efforts to develop disease-modifying therapies for AD are ongoing. Several antibody drugs targeting beta-amyloid species and tau tangles are currently in clinical trials or have recently been approved, as previously mentioned. Within the next five years, we believe that we will gain a better understanding of the potential impact of these treatments on AD progression. However, even though big pharma is focused on the development of antibody therapies, they come with major and frequent side effects, such as headaches, changes in mental state and confusion, due to antibody-typical brain swelling and micro-bleedings (ARIA) seen in brain imaging, that limit their therapeutic window. Also, antibody-based therapeutics are expensive. Alternatively, small molecules might offer a certain advantage regarding patient safety and could be economically more accessible for patients.

Early detection and intervention is key for the treatment of AD. Researchers are currently focused on identifying biomarkers and developing reliable diagnostic tools to detect AD at its earliest stages. This may enable intervention before significant neuronal damage occurs. Advances in neuroimaging, blood tests and cerebrospinal fluid analysis may contribute to improved early detection methods.

References:

1. Visit: health.harvard.edu/mind-and-mood/ eye-diseases-linked-to-a-higher-risk-ofdementia#:~:text=People%20who%20 get%20age-related%20macular%20 degeneration%20%28AMD%29%2C%20 cataracts%2C,13%2C%202021%2C%20 in%20the%20British%20Journal%20of%20 Ophthalmology

Alexander Gebauer is co-founder and executive chairman of Galimedix Therapeutics. A medical doctor by training, Gebauer has spent over 30 years in the pharmaceutical industry in various R&D leadership roles at international pharmaceutical companies, including Sun Pharmaceuticals, Hoechst AG, Aventis, Sanofi and Merz Pharmaceuticals. During his time at Merz, he served as CSO, head of Global Research & Development and was directly involved in developing GAL-101 and GAL-201, which are now being further advanced at Galimedix.