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Discovery & Development Drug Discovery

The Chance to Stop – or Even Prevent – Neurodegenerative Diseases

After all these years, why are neurodegenerative disorders still so difficult to treat? Neurodegenerative diseases are generally slow to progress, difficult to accurately diagnose, and have wrongly been considered part of aging.

For these reasons, many of the early studies were done with comparatively little information and should really be classified more as clinical science than industrial drug development. Many of these yielded invaluable data, which has significantly enhanced our understanding of, and how we might best treat or even prevent, neurodegeneration. Thanks to this knowledge accumulation, the industry has made steady progress – and my hope is that this generation is the last to face untreatable Alzheimer’s disease.

We have finally seen definitive validation of the amyloid hypothesis by amyloid beta antibodies. Specifically, the full FDA approval of lecanemab, which was further strengthened by recent positive phase III donanemab data. These drugs have confirmed that clearing amyloid beta plaques at early stages of the disease is a valid strategy that can lead to clinically meaningful outcomes. 

And this is only the beginning. This progress opens up the possibility of two goals that now appear achievable for the first time: halting the progression of Alzheimer’s disease, and even preventing it from developing in the first place. Prevention is far superior to treating Alzheimer’s after it has already progressed, as by then much of the damage has already been done.

The progression of care in Alzheimer’s will move further towards precision medicine, where diagnostics will play a key role to help guide treatment, and eventually prevention. Diagnostics are rapidly improving and we are continuing to discover new blood-based biomarkers to detect Alzheimer’s, and techniques to pinpoint the most appropriate stage to intervene in the disease. We can already build on improved and earlier diagnosis with active immunotherapies – vaccines – and combinations of treatments, tailored to the needs of individual patients. To this end, we are developing vaccines against toxic forms of both, amyloid beta and tau, which are progressing well in phase II clinical development.

We should not be disappointed with increased understanding

Many trials of drugs for neurodegenerative diseases have had negative readouts, but we have learned from each of them. Now we know a lot more about the biology of neurodegenerative disease, about the strengths and limitations of therapeutic candidates in development, and biomarkers that could be used to predict disease progression and/or monitor therapeutic impact. 

In terms of successes, we now have biomarkers that have been shown to be predictive of disease progression. These biomarkers are key for future and accelerated drug development because they can be used to reduce risk in clinical trials by improving patient selection and measuring clinical efficacy, shortening clinical development timelines and reducing costs. For example, amyloid beta plaque measurement using positron emission tomography (PET) has now been recognized by the field as a clinically relevant biomarker and surrogate for clinical efficacy.

Another protein involved in Alzheimer’s is tau. When this protein misfolds and forms tangles, it causes cell damage and ultimately neuronal death. It is hypothesized that abnormal tau protein then spreads between neurons, gradually involving more areas of the brain and leading to clinical disease progression. It has been shown that tau-PET imaging is more predictive of cognitive decline than amyloid beta-PET. The next step is to validate tau as a second surrogate biomarker.

Notably, we are developing a tau-targeting PET tracer in collaboration with Life Molecular Imaging (LMI); it recently entered phase III testing. We believe tau-PET will ultimately be a widely accepted corollary for diagnosing and determining disease stage, as well as measuring progression and clinical benefit. In addition, with support from the Michael J. Fox Foundation, we were the first to show live images of alpha-synuclein in the human brain, using our PET tracer. We believe this could ultimately be used to diagnose Parkinson’s and related diseases, as well as monitor the efficacy of therapeutics.

With such biomarkers, we have the ability to identify people at risk of developing Alzheimer’s 15-20 years before symptoms develop. Once symptoms appear, the disease has already done irreversible damage to the brain. We need to identify patients at risk – especially those in early pre-symptomatic stages of disease. From here, we can begin to think about long-term prevention strategies, such as vaccines.

Example efforts

As with cancer, I believe that precision medicine based on early and accurate diagnosis, identification of the underlying pathologies, and then targeted mono- or combination therapies will be the most promising approach to prevent and treat neurodegenerative diseases in the future.

At AC Immune, we discover and develop optimal diagnostics and therapeutics, spanning all modalities, including antibodies, vaccines, and small molecules; afterall, while some targets or stages of disease may require intracellular targeting, while others may be better served by extracellular mechanisms of action to prevent the spread of disease.

We believe a vaccination approach is a particularly promising strategy to prevent rather than treat neurodegenerative diseases. We have two Alzheimer’s vaccines in mid-to-late-stage clinical development; one targets toxic species of amyloid beta, and the other targets toxic species of tau. Besides these, we are also advancing an anti-a-syn vaccine in Parkinson’s disease, which might very well become relevant to target a frequent co-pathology – a-syn accumulation – in Alzheimer’s. Our vaccines have already shown that they generate high titers of antibodies against these validated proteinopathies.

We are looking forward to the first clinical amyloid beta-PET biomarker data from our anti-amyloid beta vaccine next year, to confirm earlier findings that showed this vaccine generates high levels of antibodies against amyloid beta oligomers and pyroGlu Abeta – the two toxic species of Abeta targeted by lecanemab and donanemab. Our partner Janssen Pharmaceuticals recently selected our anti-Tau vaccine for further clinical development and we look forward to the next clinical trial being initiated soon. 

The priorities

The recent successes in drug development for Alzheimer’s disease were made possible by the advent of accurate diagnostics and biomarkers, which enable the more precise characterization of pathology and stage of disease. These are having a huge impact on all neurodegenerative diseases, not just Alzheimer’s. Clinicians now have the tools to ensure the right patient receives the right treatment at the right stage of the disease before being enrolled in a clinical study. We need to carry on innovating in this area.

We also need to boost awareness about emerging biomarkers and educate people so that they understand that treatment and lifestyle changes can help delay or even prevent the progression of the disease. The population is aging and the incidence of neurodegenerative diseases is growing; this is already a major public health crisis and it will only accelerate if we don’t act now.

The best strategy to prevent that is to seek to preserve patients’ cognitive abilities before damage. That will require all of us in dementia to work in tandem to prove the importance of  detection and intervention, at the earliest possible stage, to regulators, healthcare providers and public.

One topic that is close to my heart is AC Immune’s work with the Down syndrome community. Today, people with Down syndrome have a life-expectancy beyond 60 years of age, but amyloid beta plaque pathology can be found in virtually all individuals living with Down syndrome in their 40s, which, unfortunately, means that almost all of them will go on to develop Alzheimer’s disease. In our opinion, the lack of treatment options to address amyloid pathology in Down syndrome needs urgent attention, as this community represents the largest population with early onset Alzheimer’s disease. The individuals themselves together with their families are searching for therapies to help improve their quality of life and, as our first clinical study with a vaccine approach has shown, are willing to participate actively in the development of a solution. An effective vaccine could potentially offer a means of prevention or reduction of disease severity and have a major positive impact on the lives of people living with Down syndrome.

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About the Author
Andrea Pfeifer

Co-Founder and CEO of AC Immune

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