Raising awareness: Addressing the lack of treatment for Alzheimer’s disease

Cryo-EM structure of human AA amyloid fibril (PDB ID: 6MST)

written by Claire MacMurray

In light of news published earlier this year, it is evident that the field of Alzheimer’s disease (AD), as a collective, refuses to abandon the “amyloid hypothesis”. I aim to suggest that such inaction is inadvisable, underlines the caveats of human-driven science, and accounts for a large proportion of the failure in AD therapeutic efforts.

The amyloid hypothesis has been favoured as the field’s central hypothesis for numerous decades. The theory proposes that either the increased deposition or reduced clearance of extracellular b-amyloid (Aβ)—a protein present in abnormal amounts in the AD brain— promotes a cascade of neurotoxic events, eventually resulting in cellular and synaptic loss (1). Thus, the hypothesis reasons that removing or altering this toxic species will, ideally, reverse symptoms of AD.

In March of 2019, Biogen and Eisai (two large pharmaceuticals) announced their termination of the phase 3 trial examining an immunotherapeutic compound, aducanumab, designed to clear Aβ (2). The trial was discontinued due to the futility of the effort, meaning the ability of aducanumab to slow/reverse cognitive decline in patients was not observed (3). To emphasize the significance of this announcement, I was first informed of the decision by email, in which my considerate, 70-something, distant uncle shared a popular-science article (published in a tabloid of sorts). And this was the first of many emails throughout the course of the fateful day. As someone who is deeply invested in AD-research, it felt as though “things” were hitting the fan, for lack of a better phrase.

While many participants of the phase 3 trial (i.e. administrators, investors, patients, scientists) were upset (especially considering a phase 3 trial is one step prior to the clinical administration of the compound), it is most intriguing that numerous accounts revealed the lack of surprise voiced by scientists (4). In other words, the inefficacy of the compound was predictable. Upon reading these testimonies, I questioned how a proposed treatment with a likelihood to fail proceeded to phase 3 testing. If this was not enough cause for speculation or worry, only days following the announcement of the termination of aducanumab trials, Eisai published their decision to begin a phase 3 trial of BAN2401 (5). BAN2401, another immunotherapeutic compound*, is remarkably similar to aducanumab, namely in its ability to target Aβ and promote a reduction in detectable levels of the protein (6). My initial reaction to the Eisai announcement? Utter perplexity—the beating of the dead horse was to continue.

Within a span of ten years (2002-2012), 243 therapeutic compounds designed to treat AD have all failed to receive approval by the Food and Drug Administration of the United States (7). “Failure to receive approval” signifies the proposed therapy was ineffective in treating symptoms, led to adverse effects, or could not be accurately measured. This statistic sets the failure rate of AD therapeutic trials higher than any other disease area, including cancer. And yes, many of these therapies were designed to target and somehow alter the aggregation of Aβ.

The drastic number of failed compounds reveals the shortcomings of therapeutic research. However, it is not only revealing, it is demanding of radical change promoted by the research community. Promoting radical change requires an abandonment of the amyloid hypothesis as the guiding factor in therapeutic efforts. Similar sentiments are expressed by others, including Dr. Karl Herrup (8). Herrup, an upcoming Connell lecture guest, will outline what is arguably needed in efforts to abandon the amyloid hypothesis in the “Exploring Solutions” edition of this two-part series.

Esai’s willingness to invest time, funding, and additional resources to evaluate a compound with near-identical therapeutic outcome as aducanumab (as determined in previous mouse and cellular studies) implies their adherence to the amyloid hypothesis. Moving past the initial shock of Eisai’s decision, I sought to answer why the field dare not depart from such a hypothesis. When viewed at large, the BAN2401 trial (and far too many like it) is comparable to expecting different results when performing the same experiment. While on the surface the dilemma seems easily solved—change the experiment, abandon the hypothesis—in reality, things are far from simple.

Conversations with colleagues are quick to bring up the many factors influencing science that aren’t highlighted in the Discussion section of a journal publication. Whose ego will be bruised in learning that their compound failed entirely? Whose money will be lost? Whose life’s work will be “thrown to the wayside”? What amount of published literature will require reconsideration? What, if any, resources exist to help foster a change in scientific approach? Who is willing to start at ground zero or reassess field-specific “doctrines” with less of a dependency towards these theories? Can we really ignore such overwhelming evidence when observing a post-mortem brain? And if not, what is the altered significance of these data and observations? Asking these questions highlights the many obstacles in face of radical change.

I do not doubt Eisai’s ability to justify their decision to proceed to the phase 3 trial. However, I also believe in the value of “big-picture speculation”. Targeting Aβ in hopes of treating the symptoms of the disease aligns with the inferences put forth by the amyloid hypothesis. How many fruitless, amyloid-related endeavors will eventually promote the radical change mentioned above? While current evidence points to the inadvisability in targeting Aβ, it is important to recognize that Eisai’s decision brings to question the limitations of the field, whether classified as institutional, political, or ideological**. Perhaps it is these limitations that need addressing first.

I encourage all to attend Dr. Herrup’s lecture (Oct. 30th), and again, stay tuned for an overview of his thoughts concerning potential solutions to the outlined dilemma.

Notes:

* Both aducanumab and BAN2401 are monoclonal antibodies that bind b-amyloid.

** As of last week (~October 23, 2019), Biogen announced their decision to reboot aducanumab trials, once again upsetting many in the field and confirming the current relevancy of the thoughts I’ve conveyed above.

References

(1) Cairns, N. “Alzheimer’s Disease: Neurodegeneration.” In Handbook of the Neuroscience of Aging. London: Academic, 2009.

(2) Fagan, T “Biogen/Eisai Halt Phase 3 Aducanumab Trials | ALZFORUM.”

https://www.alzforum.org/news/research-news/biogeneisai-halt-phase-3-aducanumab-trials.

(3) Fagan, 2019

(4) Fagan, 2019

(5) “INITIATION OF PHASE III CLINICAL TRIAL OF BAN2401 IN EARLY ALZHEIMER’S

DISEASE | News Release:2019 | Eisai Co., Ltd.”

https://www.eisai.com/news/2019/news201919.html.

(6) Söllvander, Sofia, Elisabeth Nikitidou, Linn Gallasch, Marlena Zyśk, Linda Söderberg, Dag Sehlin,

Lars Lannfelt, and Anna Erlandsson. “The Aβ Protofibril Selective Antibody mAb158 Prevents

Accumulation of Aβ in Astrocytes and Rescues Neurons from Aβ-Induced Cell Death.” Journal

of Neuroinflammation 15, no. 1 (March 28, 2018): 98. https://doi.org/10.1186/s12974-018-1134-4.

(7) Burke, Maria. “Why Alzheimer’s Drugs Keep Failing.” Scientific American, July 14, 2014.

https://www.scientificamerican.com/article/why-alzheimer-s-drugs-keep-failing/.

(8) Herrup, Karl. “The Case for Rejecting the Amyloid Cascade Hypothesis.” Nature Neuroscience 18,             no. 6 (June 2015): 794–99. https://doi.org/10.1038/nn.4017.



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