ARTICLE | Guest Commentary

We must reframe the discussion on Alzheimer’s disease

We’re at a pivot point in Alzheimer’s drug development, and we mustn’t let history slow us down

September 11, 2023 4:21 PM UTC
BioCentury & Getty Images

Recent progress in Alzheimer’s disease research has created a unique opportunity.

We now have the chance to pave the way to two goals that seem plausible for the first time: halting the progression of this insidious disease and preventing it from developing in the first place. But achieving these revolutionary goals will require changing attitudes among investors, physicians, payers and the public.

The debate about the clinical meaningfulness and safety of the first anti-β-amyloid therapies to reach the market is a distraction that threatens to slow the progress needed to get to the next generation of therapies. Rather than continue to let the conversation be mired in historical baggage, industry should take a leading role in reframing the discussion.

This means providing a unified front when it comes to the need for early and routine testing, the power of lifestyle intervention, and yes, the need for treatment and broad coverage of those treatments.

The anti-β-amyloid mAbs that have demonstrated success in clinical development are not cures for Alzheimer’s, but the data show they have benefit. The amyloid hypothesis has finally been validated, and as we celebrate the development — a truly important breakthrough in the war against dementia — we should also consider this a new starting point.

Can we now dare to view the road ahead objectively, with fresh eyes? Can patients afford for us not to?

Let’s remember that every three seconds, someone around the world is diagnosed with dementia. It affects around 55 million people, with over 300 million at risk of developing clinical symptoms of Alzheimer’s disease in the coming years. Without successful intervention, the number of patients will double every 20 years, reaching 139 million in 2050. It is a slow, silent pandemic and addressing it is an urgent moral and economic imperative.

Active immunotherapies and combination regimens are needed to combat this public health crisis. We should rally behind progress in these areas and not let endless debate about first-generation anti-amyloid antibodies dominate the conversation.

A springboard to accelerate progress

The recent positive clinical data from two new Alzheimer’s disease treatments — Leqembi lecanemab from Eisai Co. Ltd. (Tokyo:4523) and Biogen Inc. (NASDAQ:BIIB), and donanemab from Eli Lilly and Co. (NYSE:LLY) — should be hugely welcome, as they promise to bring some measure of relief to early-stage patients and their families.

The magnitude of their benefit relative to their side effect profile continues to fuel heated debate among physicians and the public, but that misses the point. Whether modest or profound, the results from two large, well-controlled trials are clear on one thing: the clinical efficacy of these therapies is real. This creates an inflection point, a chance to accelerate progress.

Next-generation diagnostic and therapeutic solutions are already in view, and we could soon have the knowledge and tools to move to the next level: preventing rather than treating Alzheimer’s and other neurodegenerative diseases.

The success and speed with which industry developed vaccines against COVID-19 showed what can be done when we work with urgency. Given the suffering, increasing incidence, and societal cost of neurodegeneration, shouldn’t we apply similar urgency to neurodegeneration?

Those who work in this field understand that in the long term, antibody therapeutics are not ideally suited for Alzheimer’s prevention; they have high costs, require frequent administration and have a side effect profile that may require chronic safety monitoring that is both costly and challenging to implement.

But antibody products, particularly first-generation intravenously infused products, are not the end of the story — they are a new beginning.

The etiology of this multifactorial disease remains shrouded, meaning a true cure might still be hard to imagine. Nevertheless, the positive data from passive immunization with mAbs inspires genuine hope that combination therapies and active immunotherapies will be able to halt disease progression or prevent the emergence of clinical symptoms.

We can already identify people with genetic predisposition and even detect signatures of β-amyloid and tau pathologies in the brains of people many years before they display any clinical symptoms. Our diagnostic tools are rapidly improving in sensitivity, accuracy and accessibility. While most approved tests are cerebrospinal fluid-based, a handful of plasma and blood tests are now commercially available, and researchers continue to discover new blood-based biomarkers to detect Alzheimer’s as well as techniques to pinpoint biomarkers.

We also now know that diet, exercise and other lifestyle changes can delay onset, or, in some cases, perhaps even prevent the cascade of events leading to Alzheimer’s disease — much like the medical prognosis for people at risk of developing Type II diabetes. Identifying and educating those who will benefit from lifestyle changes and starting the right therapeutic interventions at the right times should respectively ward off or slow neurodegeneration in more and more people.

We can all help hasten this future: whether it’s as researchers and drug developers, or simply as citizens raising awareness and conducting advocacy to ensure that dementia is treated by governments and payers as the public health crisis that it is.

A new age of Alzheimer’s prevention

It is not hard to imagine a medical system that engages timely use of genetic testing and new diagnostics, and advises patients to work towards avoiding disease progression through lifestyle changes and use of active immunotherapies to provide long-term protection against Alzheimer’s disease. One doesn’t have to be an economist to work out that this would yield tremendous savings for the overburdened medical systems of the world — palliative care for the increasing numbers of late-stage dementia patients already is a heavy burden on global healthcare systems and economies.

Actively heralding the rapidly approaching availability of new technologies may seem unwise, even rash, given the highly publicized challenges we’ve faced in Alzheimer’s drug development in past years.  However, I am concerned that all the debate around amyloid, the safety, the costs and the persistent doubts about antibodies providing a meaningful clinical benefit may be preventing us from taking the next steps with the urgency patients deserve.

We should re-focus the discussion around building momentum after having finally established the first biomarkers to serve as surrogates for disease modification. This crowning achievement can now be leveraged thanks to the emerging cheaper, faster and more accurate diagnostic tools. For example, CMS, the single largest payer for healthcare in the U.S., now covers more than one amyloid PET scan per lifetime to monitor plaque burden.

This means that pre-symptomatic individuals can already be more easily identified, diagnosed and stratified using validated biomarkers and offered the first potential benefits of investigative precision medicines. Many of the biomarkers used in the Phase III trials of Leqembi and donanemab are being developed as additional markers of Alzheimer’s disease and co-pathologies. These include a variety of cerebrospinal fluid biomarkers as well as plasma biomarkers Aβ42/40 ratio, pTau181, pTau217, GFAP and NfL.

PET will likely continue to play an important role as the gold standard for confirming diagnoses and determining appropriate treatment strategies. At the same time, using PET for chronic monitoring to identify those at risk of disease or for regular safety monitoring is cumbersome for patients and healthcare systems, and financially challenging. More effective biofluid markers, especially blood-based, are vitally needed. They will be essential for precision medicine and active immunotherapies to be used successfully for prevention. 

Considering that the neuronal damage of Alzheimer’s disease is irreversible, the best treatment strategy is to preserve a patient’s cognitive abilities and function, and thereby reduce overall societal healthcare costs. Tremendous energy, both public and private resources, must now rapidly be re-directed to education. Everyone in the field of dementia — including companies, researchers, key opinion leaders, public health officials and those in ancillary organizations — should be working to prove to both healthcare providers and the public the importance of detection and intervention at the earliest detectable stage of disease. We need to highlight the benefits so that there is a market “pull” from payers and clinicians for new technologies that enable the precision medicine approach to work.

To achieve this goal, payers and medical practitioners should be presented data-driven arguments urging them to pursue accurate diagnoses at the earliest stages of disease. Precedents already exist for Type II diabetes, where pre-diabetic patients are identified through biomarkers and offered education and treatments; breast and prostate cancer detection practices also come to mind.

Experience shows that changing medical practice from palliative care to prevention will not happen automatically, especially in light of the misguided but heavily entrenched attitude that dementia is an unavoidable part of aging. It will require those of us in the industry who can see the horizon to speak out boldly — unburdened by our past — as we work to catalyze patient advocacy, drive new regulatory guidance, inspire payers to invest and foster the adoption of new medical practices.

Whether we prepare the way now or not, I believe these changes will ultimately be achieved through the successful development of effective therapeutics and diagnostics. The question is whether patients should be made to wait for healthcare systems to adapt to the new reality.

Active immunotherapies are ideally suited to be the core components of the precision medicine approach to Alzheimer’s disease, as well as many other neurodegenerative conditions. This modality does not require long infusion sessions and is highly differentiated by its strong potential for improved safety, ease of administration, and cost-effectiveness, making it the most suitable therapeutic strategy for both chronic treatment and prevention. We at AC Immune S.A. (NASDAQ:ACIU) are not alone in pursuing investigational active immunotherapies and are encouraged to see peers increasingly joining the field.

To date, despite the high antibody titers observed against hallmark proteinopathies, no ARIA-E cases have been reported with any active immunotherapy currently in clinical development for neurodegenerative diseases. The convenience and low frequency dosing — not to mention the benefits in manufacturing, storage and distribution — promise to significantly improve global access.

I believe that by the end of this decade, the first active immunotherapies targeting toxic forms of β-amyloid, tau, ɑ-synuclein and potentially other proteinopathies will reach the market. Simply put, we are on the cusp of being able to prevent neurodegeneration before neuronal loss occurs. This would transform the future, allowing many more people to remain and feel productive and independent as they age. Our industry can and will prevent this type of human suffering and, importantly, alleviate a very significant financial burden on our healthcare systems at the same time.

Effective treatments for neurodegeneration are here and more are coming. The time to start building the new mindset and capabilities required to prevent rather than merely treat these diseases is now.  The discussion needs to change to accelerate these solutions and meet the urgency of the moment.

Andrea Pfeifer is CEO of AC Immune S.A., a biopharma company focusing on precision medicine for neurodegeneration. AC Immune has been granted fast track designation from FDA for ACI-24.060, an anti-β-amyloid active immunotherapy for Alzheimer’s disease.

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