As I read the findings about drugs targeting beta amyloid proteins that were released during the annual Clinical Trials in Alzheimer’s Disease conference in Boston earlier this month, I thought of a favorite old quote, “99 percent of success is built on failure.” But that only holds true if we are learning from our mistakes.
Trials of drugs targeting beta amyloid — which makes up the plaques common in the brains of people with Alzheimer’s — continue to get the lion’s share of attention and funding, even though many such trials have failed in recent years. But rather than pivot to other targets, many companies are choosing to try again with the same drugs, testing them at higher doses or in patients at earlier stages of the disease. It’s time to devote at least the same amount of attention to other approaches that could slow, prevent, or even reverse Alzheimer’s.
Bill Gates announced this week a $100 million investment in Alzheimer’s research and outlined an agenda for it. “We need more approaches to stopping the disease,” he wrote. Gates went on to acknowledge that most investments have focused on beta amyloid and tau, another toxic protein that comprises tangles. “A more diverse drug pipeline increases our odds of discovering a breakthrough,” he concluded.
A recent analysis published in Nature Reviews Drug Discovery also raises questions about continuing to pursue drugs that target beta amyloid, particularly at the expense of other approaches. The authors reviewed 10,107 unique drugs that were in development for a variety of diseases between 1996 and 2016. They determined the number of drugs that were successful or discontinued for specific approaches to treating diseases. (Drugs may be discontinued for many reasons, including lack of effectiveness, safety issues, and strategic or business considerations.)
The authors found that 83 percent of treatment approaches were abandoned after just a single program was discontinued. Among disease targets that never resulted in an FDA-approved drug, only 2 percent had five or more clinical trial attempts. But that picture looks very different for Alzheimer’s disease: Four of the top five targets with the most discontinued drug trials — but which are still being tried in ongoing trials — are all beta amyloid drugs. Together, these beta amyloid targets have been discontinued 93 times. Despite this, beta amyloid remains the most common drug target in Alzheimer’s clinical trials, representing about 25 percent of the current clinical pipeline in Alzheimer’s, according to a recent report from my organization, the Alzheimer’s Drug Discovery Foundation.
I couldn’t agree more with Gates or with the authors of the Nature Reviews Drug Discovery analysis, who argued that reducing the odds of more trial failures will require more and better drug targets.
And such targets do exist. Alzheimer’s drugs aimed at neuroinflammation, genetics and epigenetics, neuroprotection, and metabolic and mitochondrial dysfunction are now in clinical trials or nearly there. We need to pursue all of these targets, and look for new ones. That’s why our foundation funds a diverse pipeline of drug targets beyond beta amyloid.
Alzheimer’s is a complex disease with multiple, interrelated causes. An effective treatment will likely involve taking several drugs that target more than one of its causes. This approach is already the standard of care in diseases such as diabetes, HIV/AIDS, and high blood pressure. Alzheimer’s researchers can and should follow these examples.
Everyone in the field hopes that the search for an Alzheimer’s drug will be successful in the next few years. If it’s a beta amyloid drug, we will all rejoice. But even if that happens, to effectively treat Alzheimer’s, we will still need other drugs that target other causes. To get there, we must invest in more diverse drug targets now.
Howard M. Fillit, M.D., is the founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation. He also serves as a clinical professor of geriatric medicine and palliative care, medicine, and neuroscience at the Icahn School of Medicine at Mount Sinai.
Editor’s note: The author did not initially disclose having received payments for consulting work in pharmacoeconomics for Hoffmann-La Roche; Genentech; Eli Lilly; Otsuka; Lundbeck; and Merck Sharp & Dohme.
We also need to remember that amyloid plaque deposition is not always associated with Alzheimer’s. Additionally, the ‘Einstein Aging Study’ (a longitudinal study) showed that psychological stress lead to cognitive impairment. So, lifestyle changes and interventions directed at stress reduction can go a long way in preventing the manifestation of Alzheimer’s.
Reference: Katz, M. J., et al. (2016). Influence of Perceived Stress on Incident Amnestic Mild Cognitive Impairment: Results From the Einstein Aging Study. Alzheimer disease and associated disorders, 30(2), 93-98.
Research investigations have shown increased activity of the Default Mode Network (DMN) of the brain is significantly associated with amyloid plaque deposition [1]. Increased activity in DMN is a result of engaging in undirected thinking (e.g. proliferating thoughts, cultivating thoughts related to regrets, anxiety, rumination, etc.). So, any intervention that can decrease the activity of DMN (i.e., decrease proliferating thoughts, etc.) can go a long way in preventing AD and stopping the progression of the disease as well. In this regard, studies have shown that meditation practices lead to significantly reduced activity in the DMN [2]. Studies have also shown that meditation practices prevent the development of the disease [3], and can also stop the progression of the disease [4, 5].
References:
1. Bero, Adam W., et al. neuronal activity regulates the regional vulnerability to amyloid-(beta) deposition, Nature neuroscience 14.6 (2011): 750-756.
2. Garrison, Kathleen A., et al. “Meditation leads to reduced default mode network activity beyond an active task.” Cognitive, Affective, & Behavioral Neuroscience 15.3 (2015): 712-720
3. Larouche, Eddy, Carol Hudon, and Sonia Goulet. “Potential benefits of mindfulness-based interventions in mild cognitive impairment and Alzheimer’s disease: an interdisciplinary perspective.” Behavioural brain research 276 (2015): 199-212.
4. Quintana-Hernández, D. J., et al. (2016). Mindfulness in the maintenance of cognitive capacities in Alzheimer’s disease: a randomized clinical trial. Journal of Alzheimer’s Disease, 50(1), 217-232.].
5. Hanson, L. R., Barclay, M., Kashyap, B., Somerville, B., Kreitzer, M. J., Stuck, L., & Barclay, T. R. (2017). Mindfulness for early Alzheimer’s Disease: A Pilot Study. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 13(7), P1410-P1411.