Will this new drug change the way we manage and understand Alzheimer’s?

Written by Diana Ortega Cruz

In June of 2021, the US Food and Drug Administration (FDA) approved aducanumab, the first drug for the treatment of Alzheimer’s Disease (AD) that targets the condition’s underlying biology (Tampi et al., 2021). This would not be so remarkable if existing treatments could modify the course of AD, or if any of the other thousands of promising drug candidates tested in clinical trials in the last decades had been successful (Cummings et al., 2019). Despite its FDA approval, a surprising twist to this story is that trials for aducanumab did not show a great clinical improvement. Questions emerge effortlessly: Why was this drug approved? Will it benefit people suffering the disease? Will it mark a turning point in the way we manage and understand AD?

As many know, Alzheimer’s is the most common type of dementia, with memory loss its most salient symptom. As the disease progresses, memory problems worsen and other problems related to orientation and speech appear, resulting in a strong dependence on others. As for most human diseases, there is not a single cause for AD, but the probability of developing it is influenced by some known factors. Age is the strongest risk factor for AD, and in the face of an aging population, the number of people suffering from this disease is increasing (Alzheimer’s Association, 2020). From a neurobiological perspective, AD is characterized by the accumulation of two types of proteins in the brain: plaques of the protein amyloid-beta and neurofibrillary tangles of the protein tau (you can learn more details in this previous post).

Aducanumab belongs to a specific class of drugs known as monoclonal antibodies (mAb), which can be identified by the last three letters of their name. Drugs of this type have been developed to treat numerous diseases in the past 30 years. But, what exactly is a monoclonal antibody? Antibodies are proteins produced by our immune system that specifically recognize and bind foreign substances in order to neutralize them. Scientists have harnessed this property to develop antibodies that target specific substances. When applied to therapy, antibodies can be designed to bind a protein responsible for a specific illness to guide immune cells to its destruction. Monoclonal antibodies are a set of antibodies produced by a single clone of cells, meaning that all antibodies will be identical.

mAbs have been approved to treat rheumatoid arthritis, multiple sclerosis, some types of cancer, and even to prevent transplant rejection (Singh et al., 2018). Aducanumab, the mAb starring in this post, was designed to treat AD by removing amyloid-beta plaques, whose presence has been associated with cognitive symptoms of Alzheimer’s (Snitz et al., 2015; Sperling et al., 2019). However, a direct relationship between cognitive symptoms and the amount of amyloid present in the brain has not been found, whereas a stronger link to tau pathology has been suggested (Huber et al., 2018). Several monoclonal antibodies targeting amyloid or tau proteins have been developed as drug candidates (Doody et al., 2014; Hoskin et al., 2019; Vandenberghe et al., 2016).

How did aducanumab make it past this line? Biogen, the drug developer, performed two separate trials enrolling approximately 3300 participants (Tampi et al., 2021). Patients were between 50 and 85 years of age, showed symptoms of early AD and had amyloid plaques (confirmed using a medical imaging technique called Positron Emission Tomography, or PET). Both studies showed a clear reduction of amyloid across the brain in treated patients. However, only one study found an improvement in cognitive performance, albeit one too small to be noticed by the patient’s caregivers (Andrews et al., 2019). Aducanumab was originally rejected due to the conflicting results between both studies. Approximately one year later, its evaluation was reopened and aducanumab received an “accelerated approval”, a pathway applicable to drugs targeting serious diseases that provide a meaningful advantage over existing treatments. However, the unclear cognitive effects of this drug and its side effects — mainly headache and small cerebral bleeding — together with the unfavorable evaluation given by most committee members has prompted numerous reactions from the scientific community, many against this approval.

Although the circumstances surrounding this approval seem confusing, this decision could also open positive perspectives. First, considering the chronic character of AD, such that the pathology begins developing years before symptoms appear (Masters et al., 2015), this anti-amyloid treatment could confer long-term benefits that may not be detectable in a short-term clinical trial. Aducanumab is currently indicated for people in the early stages of AD — the population studied in the trials — and its continued use will reveal whether it delays cognitive worsening through the years. If that were the case, it could open the possibility of treating people at advanced ages with amyloid plaques but without cognitive problems, in order to prevent these from appearing in the first place. Moreover, this treatment paves the way for the approval of similar drugs targeting other disease mechanisms, such as tau pathology. Given the complexity of this disease, a personalized and combined treatment against several pathologies may be key to stopping its progression.

Therefore, a quick response to our titular question could be that we don’t yet know whether aducanumab will change our perspective on AD management. The longer answer is that aducanumab’s FDA approval needs to be understood within the context of the societal challenge that this disease poses. Even more so, if we consider not only AD, but also other pathologies related to dementia that often coexist with AD pathology, the scene becomes trickier. We aim to reach a future with patient-specific diagnosis and treatment of AD and other dementias, a goal that we are pursuing in cancer as well. Having an approved treatment against one of the pathologies underlying AD could represent a first step towards that goal. In the future, we will see whether aducanumab is an adequate tool to change the course of AD, and we will hopefully witness the approval of new treatments acting on other disease fronts.

~~~

Written by Diana Ortega Cruz

Illustrated by Sarah Barron

Edited by Lauren Wagner and Carolyn Amir

Translated by Diana Ortega Cruz

~~~

Become a Patron!

Image made using www.Biorender.com

References
Alzheimer’s Association. (2020). 2020 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia, 16(3), 391–460. https://doi.org/10.1002/ALZ.12068

Andrews, J. S., Desai, U., Kirson, N. Y., Zichlin, M. L., Ball, D. E., & Matthews, B. R. (2019). Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer’s disease clinical trials. Alzheimer’s & Dementia (New York, N. Y.), 5, 354–363. https://doi.org/10.1016/J.TRCI.2019.06.005

Cummings, J., Feldman, H. H., & Scheltens, P. (2019). The “rights” of precision drug development for Alzheimer’s disease. Alzheimer’s Research & Therapy 2019 11:1, 11(1), 1–14. https://doi.org/10.1186/S13195-019-0529-5

Doody, R. S., Thomas, R. G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., Raman, R., Sun, X., Aisen, P. S., Siemers, E., Liu-Seifert, H., & Mohs, R. (2014). Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer’s Disease. New England Journal of Medicine, 370(4), 311–321. https://www.nejm.org/doi/10.1056/NEJMoa1312889

Hoskin, J. L., Sabbagh, M. N., Al-Hasan, Y., & Decourt, B. (2019). Tau immunotherapies for Alzheimer’s disease. Expert Opinion on Investigational Drugs, 28(6), 545–554. https://doi.org/10.1080/13543784.2019.1619694

Huber, C. M., Yee, C., May, T., Dhanala, A., & Mitchell, C. S. (2018). Cognitive Decline in Preclinical Alzheimer’s Disease: Amyloid-Beta versus Tauopathy. Journal of Alzheimer’s Disease, 61(1), 265–281. https://doi.org/10.3233/JAD-170490

Masters, C. L., Bateman, R., Blennow, K., Rowe, C. C., Sperling, R. A., & Cummings, J. L. (2015). Alzheimer’s disease. Nature Reviews Disease Primers 2015 1:1, 1(1), 1–18. https://doi.org/10.1038/nrdp.2015.56

Singh, S., Tank, N., Dwiwedi, P., Charan, J., Kaur, R., Sidhu, P., & Vinay, K. (2018). Monoclonal antibodies. A review. Current Clinical Pharmacology, 13(2), 85–99. https://doi.org/10.2174/1574884712666170809124728

Snitz, B. E., Weissfeld, L. A., Cohen, A. D., Lopez, O. L., Nebes, R. D., Aizenstein, H. J., McDade, E., Price, J. C., Mathis, C. A., & Klunk, W. E. (2015). Subjective Cognitive Complaints, Personality and Brain Amyloid-beta in Cognitively Normal Older Adults. The American Journal of Geriatric Psychiatry, 23(9), 985–993. https://doi.org/10.1016/J.JAGP.2015.01.008

Sperling, R. A., Mormino, E. C., Schultz, A. P., Betensky, R. A., Papp, K. V., Amariglio, R. E., Hanseeuw, B. J., Buckley, R., Chhatwal, J., Hedden, T., Marshall, G. A., Quiroz, Y. T., Donovan, N. J., Jackson, J., Gatchel, J. R., Rabin, J. S., Jacobs, H., Yang, H. S., Properzi, M., … Johnson, K. A. (2019). The impact of amyloid-beta and tau on prospective cognitive decline in older individuals. Annals of Neurology, 85(2), 181–193. https://doi.org/10.1002/ANA.25395

Tampi, R. R., Forester, B. P., & Agronin, M. (2021). Aducanumab: evidence from clinical trial data and controversies. Drugs in Context, 10. https://doi.org/10.7573/DIC.2021-7-3

Vandenberghe, R., Rinne, J. O., Boada, M., Katayama, S., Scheltens, P., Vellas, B., Tuchman, M., Gass, A., Fiebach, J. B., Hill, D., Lobello, K., Li, D., McRae, T., Lucas, P., Evans, I., Booth, K., Luscan, G., Wyman, B. T., Hua, L., … Black, R. S. (2016). Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimer’s Research and Therapy, 8(1), 1–13. https://doi.org/10.1186/s13195-016-0189-7