Why are Alzheimer’s disease drugs failing?

July 30, 2019

Written by: Claudia Lopez-Lloreda

 

The same story seems to keep happening again and again. A new, promising drug seeks to become the cure for Alzheimer’s disease (AD). After drugs prove themselves beneficial in the lab, federal agencies and pharmaceutical companies pour millions of dollars into well-controlled human clinical trials. A few months or maybe years of the trial go by without any improvement to cognitive decline. Even worse, some seem to be actually aggravating decline even further. So, what is happening with drugs that are seeking to target AD?

How do drugs make it from the lab to pharmacy shelves?

First, it is important to highlight that the drug development process is long and arduous, and rightly so. The Food and Drug administration (FDA) regulates the drug development process at five different stages: (1) Discovery & Development, (2) Preclinical Research, (3) Clinical Research, (4) FDA Review, and (5) FDA Post-Market Safety Monitoring1. Starting at the clinical research stage (3), the drug is tested on human subjects in four different phases—clinical trials—which are increasingly demanding in terms of experimental design and number of patients. Safety and efficacy are evaluated and data from each trial must be submitted before obtaining approval to move on to the next one. It takes on average 12 years for a drug to be approved though all stages, if it ever is, pointing to the rigorous nature of this process.

How to target Alzheimer’s disease

Despite the long drug-approval process, a huge effort has been employed to try to cure or at least alleviate the cognitive impairment brought on by AD. The disease has severe impacts on the daily functioning of patients, leading to disability and dependence. These impairments are thought to be due to two distinct traits in the brain: amyloid plaques composed of a protein called amyloid-β and neurofibrillary tangles composed of a protein called tau. These clumps of proteins are thought to lead to neurotoxicity and consequently impairment of cognition. The field has long focused on targeting accumulation of amyloid-β, based on the popular amyloid cascade hypothesis. This idea suggests that the accumulation of amyloid-β causes AD by initiating a domino effect that activates many detrimental pathways2.

To stop the generation of amyloid-β, scientists have sought to target the pathway that produces it. Amyloid-β is produced when a starting protein, amyloid precursor protein (APP), is cut up in a series of steps. APP is first cut up by an enzyme called β-secretase 1 (BACE1) and later by ϒ-secretase (Figure 1). The cutting of APP by BACE1 is the limiting step in creating the toxic amyloid-β. In fact, deleting BACE1 in mouse models of AD reduces the amount of amyloid plaques, rescues neurodegeneration, and diminishes cognitive impairment3,4. Similarly, blocking BACE1 with drugs that inhibit its activity succeeded in lessening learning and memory impairments in mice5. Therefore, researchers decided that BACE1 was a potential therapeutic target for AD patients.

 

APP BACE1 processing
Figure 1. The β-secretase BACE1 and ϒ-secretase cleave, or cut up, APP to release amyloid-β, which then accumulates and is thought to lead to neurodegeneration in Alzheimer’s disease.

 

Why are BACE1 inhibitors failing?

Based on animal studies, targeting BACE1 seemed to be the most logical way to go. However, things have not been as straightforward in human clinical trials. A clinical trial funded by Merck examining the BACE1 inhibitor verubecestat was ended a year early due to adverse effects such as anxiety and insomnia, on top of having only a very modest effect on the amount of amyloid plaques6. Even more recently, two trials by Novartis/Amgen testing the BACE1 inhibitor umibecestat had to be halted when they observed that patients being treated actually had more brain atrophy and worse cognitive impairment than those that were not taking the drug7.

So, what did scientists miss? One hypothesis is that BACE1 inhibitors are being administered too late – by the time patients are treated, they have had amyloid-β plaques for years. Further, although BACE1 seems to have a harmful role in contributing to AD, its normal role in the brain had not been fully explored. In addition to cutting up APP, BACE1 also has other important targets such as neuregulin 1, which plays a role in synaptic plasticity. In exploring BACE1’s normal function, Chatila and colleagues found that it was important in regulating the growth and differentiation of neurons in the hippocampus8. In mice that did not have the BACE1 gene, the neural stem cells which give rise to neurons did not reach maturity in the same manner as normal mice. Therefore, completely blocking BACE1 activity may be having off-target effects that further worsen cognitive decline in AD patients.

Years of targeting of BACE1 have so far been unsuccessful, underscoring the complexity of AD pathology. Further research determining the right time to target BACE1, whether or not to inhibit it completely, or if other proteins like tau should be considered is necessary for the potential discovery of a drug that works to help people with AD.

 

 

 

Images

Cover image. Michael Chen from Flickr.

Figure 1. Ipeltan from Wikimedia commons, public domain.

 

 

References

  1. S. Food and Drug Administration. The Drug Development Process. Retrieved from https://www.fda.gov/patients/learn-about-drug-and-device-approvals/drug-development-process.
  2. Hardy, J., & Higgins, G. (1992). Alzheimer’s disease: The amyloid cascade hypothesis. Science, 56(5054), 184-185. doi:10.1126/science.1566067.
  3. Luo, Y., Bolon, B., Kahn, S., Bennett, B. D., Babu-Khan, S., Denis, P., . . . Vassar, R. (2001). Mice deficient in BACE1, the Alzheimers β-secretase, have normal phenotype and abolished β-amyloid generation. Nature Neuroscience,4(3), 231-232. doi:10.1038/85059.
  4. Ohno, M., Cole, S. L., Yasvoina, M., Zhao, J., Citron, M., Berry, R., . . . Vassar, R. (2007). BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiology of Disease,26(1), 134-145. doi:10.1016/j.nbd.2006.12.008.
  5. Thakker, D. R., Sankaranarayanan, S., Weatherspoon, M. R., Harrison, J., Pierdomenico, M., Heisel, J. M., . . . Shafer, L. L. (2015). Centrally Delivered BACE1 Inhibitor Activates Microglia, and Reverses Amyloid Pathology and Cognitive Deficit in Aged Tg2576 Mice. Journal of Neuroscience,35(17), 6931-6936. doi:10.1523/jneurosci.2262-14.2015.
  6. Merck Announces Discontinuation of APECS Study Evaluating Verubecestat (MK-8931) for the Treatment of People with Prodromal Alzheimer’s Disease. (2018, February 13). Retrieved from https://www.mrknewsroom.com/news-release/research-and-development-news/merck-announces-discontinuation-apecs-study-evaluating-ve.
  7. Novartis, Amgen and Banner Alzheimer’s Institute discontinue clinical program with BACE inhibitor CNP520 for Alzheimer’s prevention. (2019, July 11). Retrieved from https://www.novartis.com/news/media-releases/novartis-amgen-and-banner-alzheimers-institute-discontinue-clinical-program-bace-inhibitor-cnp520-alzheimers-prevention.
  8. Chatila, Z. K., Kim, E., Berlé, C., Bylykbashi, E., Rompala, A., Oram, M. K., . . . Tanzi, R. E. (2018). BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice. eNeuro,5(4). doi:10.1523/eneuro.0067-18.2018.

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