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Discovery & Development Drug Discovery, Trends & Forecasts

Top Treatment Prospects: Alzheimer’s Disease

Credit: Authors supplied

The significance of memory cannot be overstated; it constitutes the majority of our experiences as humans – the aggregate of our joy and suffering, the conflict between our shared and individual ideologies, our comprehension of history.

Aeschylus, an ancient Greek tragedian, once said, “Memory is the mother of all wisdom.” Now, imagine losing it. Without an understanding of the past, we cannot function in the present nor think about the future. Without remembering what we did yesterday, how can we plan for tomorrow? This is the reality for patients suffering with Alzheimer’s disease (AD).

To find out if the era of R&D disappointments can be confined to the past and to understand what the future holds, we spoke with several AD experts.

The Experts

Jayne Hornung, Chief Clinical Officer at MMIT, a Norstella company.
Sam Clark, CEO and co-founder at Terran Biosciences.
Paul Song, CEO at NKGen Biotech.
Chris Ward, CSO and co-founder of StrataStem
Ashley Barnes, CSO at Axol Bioscience
Howard Fillit, CSO and co-founder of the Alzheimer's Drug Discovery Foundation

What are the biggest treatment prospects for AD?

JH: A study from Penn Medicine stands out for its potential to change our approach to AD and other dementias. The study, which is currently in preclinical stages, has shown a reversal of AD symptoms in mice using phenylbutyrate (PBA) – a compound already on the market for a different metabolic condition. What sets this study apart is PBA’s ability to effectively cross the blood-brain barrier. Though it is crucial to acknowledge the challenges ahead in translating the findings from mice to human patients, the study presents a unique avenue for future therapeutic intervention. Could reversing the disease’s progression be a tangible reality? With improvements in this area: possibly.

SC: Despite the contentious approvals of Aduhelm in 2021 and Leqembi in 2023, I believe the consistent setbacks in trials for drugs targeting beta-amyloid have prompted drug developers to explore alternative avenues. By examining the connection between beta-amyloid and tau toxicity, there is a potential to intervene effectively and halt the progression of neuroinflammation and degeneration. Personally, I think altered norepinephrine signaling could be the “missing link” in the beta-amyloid/tau cascade; the available evidence is compelling.

PS: Though the primary emphasis in AD therapy has centered on reducing amyloid plaques, the outcomes, thus far, have yielded modest clinical effects in the earliest stages of mild cognitive impairment. And though cognitive improvement hasn’t been observed, there has been a statistical reduction in the rate of progression compared with placebo. Current treatment, however, has not been without drawbacks as 25–37 percent of patients receiving recently approved amyloid-targeting antibodies developed amyloid-related imaging abnormalities (such as brain swelling or bleeding).

Merely eliminating amyloid proteins is insufficient. Today, there is increasing recognition that other proteins, such as p-tau and alpha-synuclein, also contribute to AD pathology, eliciting downstream neuroinflammation. For me, I think more companies are shifting their focus towards methods of removing these additional proteins and/or mitigating neuroinflammation. Meanwhile, others are concentrating on repairing damaged neurons or promoting neural growth.

CW: If we want to move the needle on the 99.6 percent failure rate for AD drug discovery, we need more human-relevant models. Though animal models have offered some insights, there is still a translational gap. After all, mice don’t get AD. The increased adoption of human iPSC-based AD models is an exciting future prospect in this regard. Driven by the FDA Modernization Act 2.0, researchers can now use cells derived from patients to probe disease mechanisms which would then hopefully lead to testing potential therapies. 

HF: The emergence of monoclonal antibodies targeting amyloid represents a significant development for AD as these drugs will serve as the first class of disease-modifying treatments for patients. These new anti-amyloids have the potential to be more widely adopted for patients who qualify, but the more pressing question is: will they become the standard of care or not? I think these monoclonals will eventually become the standard of care, but if you consider the various other treatment prospects, we’re beginning to redefine the traditional standard of care for Alzheimer’s. For instance, we can now combine existing cholinesterase inhibitor treatments used for symptomatic therapy with the available monoclonal antibodies. The next phase for anti-amyloid drugs is subcutaneous administration, which decreases economic and time-based burdens on patients, and is already being explored by major pharmaceutical companies. This would be a major improvement over the current delivery methods that require bi-weekly visits to infusion centers.

I should note that, though these monoclonal antibodies remove amyloid plaques on the brain, they only slow the rate of cognitive decline by around 30%, making them modestly effective.  Consequently, there has been a shift in drug development focus from primarily targeting amyloid or tau pathology to addressing the broader mechanisms related to the biology of aging. This includes exploring other avenues associated with aging such as inflammation, autophagy failure, vascular dysfunction, metabolic disturbances, and more. For instance, drugs like GLP-1 agonists are being studied to address insulin resistance and ensure proper glucose utilization in the brain, which is crucial given the brain’s high energy demands. The future management of AD will involve a combination of symptomatic treatments and drugs targeting the various aging pathways, culminating in a personalized medicine approach based on individual biomarker profiles, like in cancer. 

What single R&D innovation excites you the most – and why?

JH: The creation of the Critical Path for Alzheimer’s Disease (CPAD) will hopefully inspire a shift in the current research methodology. This initiative promotes the sharing of information among pharmaceutical companies, non-profit organizations, and government advisers. Of course, the benefits of data sharing are clear, but this approach could also reduce the time and resources typically required for R&D. If we want to progress as an industry and develop the best possible treatment options for patients, breaking down traditional, secretive silos in the industry is one way we can boost our therapeutic output.

SC: I believe there is significant untapped R&D potential in therapeutic candidates that may have been overlooked or halted in their development for other medical conditions; in other words, many promising therapies may already exist but haven’t been appropriately tailored to address specific conditions. Take the aforementioned norepinephrine “missing link” in the beta-amyloid/tau cascade, for instance. Preclinical studies have shown compelling results with idazoxan, an alpha 2 adrenergic receptor antagonist previously studied for schizophrenia and Parkinson’s disease and now undergoing human trials again. Idazoxan has demonstrated the ability to disrupt beta-amyloid activation of the tau cascade, slow amyloid-beta pathology progression, and normalize cognitive function in AD mouse models. Improving novel drugs like idazoxan, which have undergone clinical trials for other conditions, is an attractive strategy. These drugs are well-understood in terms of safety and tolerability, so it’s essentially a head start.

PS: You’ll have to forgive my self indulgence, but I’m naturally very excited about my own work. My team and I have found that we can expand and activate patients’ own NK cells to cross the blood–brain barrier through a simple peripheral IV and remove amyloid, p-tau, and alpha-synuclein proteins. This approach successfully reduced neuroinflammation without any treatment related side effects.

AB: I’m excited about the concept of  “clinical trial in a dish” (CTIAD) models, using samples from a large, diverse cohort of AD patients to build a cohort-scale in vitro disease model. This model could eventually be used to identify key biomarkers and applied to patient stratification, allowing researchers to test for potential new therapeutics on the CTIAD model to identify the best responders.

HF: Among the various innovative developments underway, two stand out to me as particularly promising. First of all, approximately 28 percent of novel drugs in development are targeting inflammation. We know that many people have amyloid plaques in their brains without exhibiting clinical symptoms, and research leads us to believe the presence of inflammation around these plaques correlates strongly with cognitive decline. Therefore, addressing inflammation could potentially slow down the advancement of the disease significantly. Secondly, there is also growing interest in metabolic interventions. For instance, GLP-1 agonist Semaglutide is currently being explored in AD clinical trials. There is cautious optimism surrounding its potential efficacy, and I believe there’s reasonable chance it may prove to be beneficial for patients.

Make a bold prediction for the future of AD treatment…

JH: As the granddaughter of two individuals who succumbed to AD during a time when our treatment arsenal was limited to memantine (Namenda) and donepezil (Aricept), I am heartened by the progress we’ve made in combating this illness over the past two decades. In that time, we’ve made great strides in better understanding the pathology, genetics, and the impact of lifestyle factors. In the next 20 years, there’s a chance we’ll develop therapies that can effectively halt or even reverse the progression of AD. This will not only improve the quality of life for patients and their families, but could also pave the way towards our ultimate goal: a cure.

SC: I envision a future where AD is more similar to a treatable cancer than the slow, devastating, and inevitable decline that patients face today. Between innovations in the diagnosis of AD pathology, and in the development of treatments that effectively target the mechanisms driving the disease, it is not implausible to believe we can reach this point. With more definitive and accessible diagnostic tools, providers could screen for, diagnose, and intervene in AD before severe cognitive decline. Treatments that halt or even reverse its pathological mechanisms and symptoms could bridge this gap further.

CW: AD is predicted to triple by 2050, with a global cost of over $9 trillion. To tackle these rising numbers, drug discovery will need to address the significant clinical and molecular heterogeneity that has hindered progress thus far. I believe in vitro research and clinical studies will unveil panels of biomarkers and susceptibility factors, which can then be used to aid earlier diagnosis and develop more targeted treatments for specific patient cohorts.

HF: With biomarkers like brain scans, and blood tests, we’ve gained insights into the disease’s preclinical phase where the pathology—plaques and tangles—can accumulate long before symptoms arise, typically around 20 years before disease onset. This gap offers a critical window for intervention and prevention. By leveraging biomarkers, we can identify individuals in the pre-symptomatic phase and conduct clinical trials aimed at preventing or delaying cognitive decline. Studies indicate that even a modest five-year delay in AD onset could halve the number of cases.

Looking to the future, I anticipate a surge in prevention trials that will use new drugs and their corresponding biomarkers alongside validated lifestyle interventions that have shown efficacy in preventing cognitive decline. Similar to approaches in managing heart disease, we’ll adopt a comprehensive strategy involving a combination of lifestyle interventions and tailored therapeutics that address individual risk factors. 

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About the Author
Jamie Irvine

Associate Editor, The Medicine Maker

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