What's Holding Back an Alzheimer's Breakthrough?

Throughout my life, I have been inspired by science’s unique ability to transform and improve lives. We see evidence of this power every day. A century ago, influenza and pneumonia were America’s leading causes of death: Today, we possess the potential to eradicate cancer deaths for people under 80 by 2050. This is stunning progress.

Unfortunately, for all that science has accomplished, it has yet to achieve substantial breakthroughs in the devastating area of Alzheimer’s disease. For instance, by simply examining ClinicalTrials.gov, Jeffrey Cummings, director of the Cleveland Clinic Lou Ruvo Center for Brain Health, and his colleagues found a mere 0.4 percent success rate for Alzheimer’s drug candidates during the 2002 to 2012 period.   Accordingly, since 2004, while no new Alzheimer’s drugs have been approved by the FDA, the number of Alzheimer’s patients has swelled to 5.4 million in the United States alone.

As somebody whose career is devoted to developing Alzheimer’s treatments, I am often asked about this slow progress. As the FDA approves dozens of new medicines each year, naturally, people wonder why so few are indicated for a disease that impacts so many.  There are many reasons why developing new treatments for Alzheimer’s disease has been exceptionally challenging, but to help clarify the situation, I have tried to identify five that stand above the rest:

1. The brain is the human body’s most complicated organ.

According to the Tufts Center for the Study of Drug Development, medicines aimed to treat brain disorders take 35% longer to develop, while achieving roughly half the approval rate of molecules intended for other therapeutic areas. This is because the brain is an incredibly complex instrument. While it is finely tuned to preserve its own health, sometimes its natural guards prove to be its own worst enemies as it relates to drug development. For instance, humans naturally employ a “blood-brain barrier.” This barrier serves an important function, as it acts as a gatekeeper to our central nervous system, allowing in blood, water, glucose, and critical amino acids while blocking the arrival of many hazardous neurotoxins. Unfortunately, at times this means that potentially beneficial drugs are unable to reach their intended targets. Because of this, we are too often shooting in the dark and only hoping that the medicines we have formulated are actually arriving at their planned destinations.

2. There are multiple pathways which lead to Alzheimer’s disease, and it likely requires a combination of treatments.

When society faces disease epidemics, our natural impulse is to focus on a cure. As humans, one of our great gifts is optimism, and we are bullish on our capability to solve any problem in one fell swoop. While I share the belief that we can ultimately mitigate Alzheimer’s disease, it is increasingly clear that because the disorder has no single cause, there’s likely no single solution. Instead, because Alzheimer’s disease stems from a devastating combination of accumulation of beta amyloid plaques between neurons and neurofibrillary tangles inside neurons, neuroinflammation, neurodegeneration, and synaptic dysfunction, it will almost certainly require therapies that work in concert to simultaneously modify the disease’s path and also reduce its symptoms. Adapting a combination approach to drug development will ultimately accelerate our effectiveness.

3. Alzheimer’s diagnoses tend to arrive at later stages of the disease.

Aging is complicated. We all know that as we get older, certain faculties – including memory and cognitive function –are prone to natural decline. For many people, as these symptoms build, due to either a lack of awareness, willful denial, or stigma, Alzheimer’s disease is written off as simply getting older. While age is certainly a common risk factor in the development of any dementia, in millions of cases, there is a more twisted pathology at work. Alzheimer’s disease offers only a window at its early stages (preclinical, prodromal and mild stage) where we might be able to delay, slow, or stall its progression, and when these delayed diagnoses happen, our ability to study the kinds of breakthrough disease modifying treatments we all hope to accomplish diminishes exponentially.

4. Clinical trial recruitment has proven exceptionally challenging.

Aside from the many inherent challenges we’ve faced in developing good drug candidates for a disease as complicated as Alzheimer’s, one of the biggest impediments to progress has been the difficulty our entire industry has faced in recruiting participants for clinical trials. With diagnoses tending to happen at late stages of the disease, the pool of potential enrollees in studies who are still in the therapeutic window for us to meaningfully test our compounds is unfortunately greatly diminished. Within that dwindled pool, there is intense competition between dozens of concurrent trials to attract participants. We need to take steps to make it easier to find and enroll individuals living in this critical therapeutic window, including developing meaningful biomarkers that identify at-risk individuals before their disease becomes too progressed. Thankfully, groups like the Global Alzheimer’s Platform and Us Against Alzheimer’s are taking important steps towards bringing academic and private research institutions, as well as industry partners, together to build awareness of the importance of these trials and to make the process more effective.

5. We need sensitive tools to measure early stages of Alzheimer’s disease.

Traditionally, we have measured the success of Alzheimer’s drug candidates using what is known as the Alzheimer’s Disease Assessment Scale’s “cognitive subscale” (ADAS-Cog). This test serves an effective purpose for people who are demonstrating clear symptoms of advancing dementia, as it asks questions and poses tasks that only somebody experiencing significant decline would fail (for instance, it tests whether participants can follow commands to fold a letter and stuff an envelope). This test can be administered quickly (critical with elderly patients), easily, and portably, and as subjects’ performance improves, stays steady, or declines, we can see what role drugs are playing. However, today, there is a lot of exciting Alzheimer’s research and drug development work being done to create compounds that treat patients with early pre-dementia (preclinical and prodromal ),  as we try to delay onset or slow the path of the disease. For these patients, who may be years away from experiencing symptoms as severe as losing the ability to stuff an envelope, we need tests that pose greater challenges and offer higher “ceilings,” so that we can monitor the early stages of the disease in a more subtle, sophisticated, and perceptive way.

Despite these challenges, from cancer to HIV, time and again the pharmaceutical industry (and science community at large) has demonstrated an ability to achieve rapid progress. Today, there is more exciting Alzheimer’s research being done – and more exciting drug candidates undergoing trials – than at any point in history. I am very proud that more than a few of those projects are being done right here at Lundbeck

Decades later, I am still as inspired by what science can achieve as I was when I was a young student. While we have faced major hurdles in Alzheimer’s drug development, I have total faith that we will achieve more in the next decade to stem the tide of this terrible disease than we have in the last century.


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