by Roshan Chikarmane
Ph.D. Candidate in Johns Hopkins School of Medicine
Pharmacology & Molecular Sciences program
Memories have a curious way of rising to the surface. Some memories are so salient that even the most subtle sensations – the aroma of freshly baked bread, a wafting perfume, a chorus of light rain – involuntarily catapults those memories into the forefront of one’s consciousness. Other memories are so elusive that they escape one’s grasp, even when pressed to retrieve them. Though many have experienced the latter situation from time-to-time, patients with Alzheimer’s Disease find themselves confronting such experiences with accelerating frequency. Alzheimer’s Disease is an age-related neurodegenerative disorder that occurs in about 17% of people age 75-84 and 32% of people age 85 or older, though it’s associated with a far more rapid decline in cognitive function than the forgetfulness often found in typical ageing1. Disabilities associated with the condition exert a burden on both patients and their caretakers, as shown by a 60 Minutes special report that documented a couple’s experience with Alzheimer’s Disease over a 10-year timespan2. Despite its high prevalence and devastating effects, there are no treatments that either slow or reverse its progression. Or, at least it seemed so until Michel Vounatsos, CEO of the biotechnology company Biogen, surprised the world in late 2019 by announcing the company’s intention to file a request for FDA approval of its Alzheimer’s drug, aducanumab3. Let’s explore why the filing surprised so many people in the drug development industry and the implications that aducanumab might have on the treatment of Alzheimer’s Disease.
On the morning of October 22, 2019, Biogen hosted a routine conference call in which they presented their quarterly financial results and business updates, as do all public companies4. This call, however, was far from routine. It outlined a path by which the company would file for FDA approval of their Alzheimer’s drug, aducanumab, in early 2020. If approved, it would be the first drug to be brought to market for the treatment of Alzheimer’s Disease. Both the timing and the nature of the announcement caught listeners off-guard. Flabbergasted analysts inundated Biogen’s executive team with questions about aducanumab during the concluding Q&A portion of the call; the answers further inflamed their curiosities. Why was the announcement so widely unanticipated?
Seven months prior to the call, an independent data monitoring committee had conducted a statistical assessment of two pivotal Phase 3 clinical trials, which aimed to measure the safety and efficacy of aducanumab across a large and diverse Alzheimer’s patient population. Their analysis forecasted that neither of trials would demonstrate meaningful improvements in key clinical parameters of the disease, so on March 21, 2019, the company announced that it would discontinue both clinical trials6. Given that the two Phase 3 trials, called ENGAGE and EMERGE, were critical in the procurement of FDA approval, it seemed extremely unlikely that aducanumab would enter the marketplace. So, what changed between March and October?
Samantha Budd Haeberlein, Vice President of Late Stage Clinical Research at Biogen, explained the company’s more recent analysis of the two clinical trials. It focused on results seen in a cohort of patients from the EMERGE study that had been treated with the highest dose of aducanumab and contextualized those results with trends seen in another patient cohort in the ENGAGE study. Patients treated with higher doses in the EMERGE trial displayed a 23-46% slower rate of cognitive decline, as determined by four different cognitive tests. However, these findings were inconsistent with the results of the almost identical ENGAGE trial, which actually suggested an increased rate of cognitive decline in treated versus untreated patients in two out of the four cognitive tests. The inconsistencies were explained to be caused by adjustments made to the trial protocol. Nevertheless, the company argued that the ENGAGE data “trended positive” and, therefore, supported the findings of the EMERGE trial.
Biogen’s announcement elicited polarizing reactions. Panelists at the Clinical Trials on Alzheimer’s Disease Conference (CTAD), held roughly two months after Biogen’s initial announcement, adopted an optimistic posture7. One panelist, Dr. Paul Aisen, Director of the Alzheimer’s Therapeutic Research Institute, referred to the EMERGE trial data as a “hugely important result”. In contrast, life science analysts largely regarded Biogen’s move as unlikely to garner FDA approval, citing conflicts between the success of aducanumab in one trial and the failure of the drug in the other8. Biogen’s gauntlet, their biggest challenge as it relates to convincing FDA officials that the drug slows the progression of Alzheimer’s Disease, depends on their ability to reconcile the findings of both clinical trials. While the drug’s marketing approval hangs in the balance, so too does the state of a central theory of Alzheimer’s Disease.
The Amyloid Hypothesis
In his influential 1962 book, The Structure of Scientific Revolutions, author Thomas Kuhn coined the term ‘paradigm shift’ to describe a three-step process through which scientific fields have historically attained maturity9. In the first step, which he refers to as ‘normal science’, the majority of research efforts revolve around a set of fundamental rules that comprise a central paradigm. It’s practically taken for granted that the central paradigm is true. In maturing scientific fields, a second step often arises that throws ‘normal science’ off balance. Certain experiments present anomalies that disagree with the central paradigm, so the scientific community enters a period of crisis. The third step is the one in which a ‘paradigm shift’ occurs and a new set of fundamental rules replace the old rules.
For instance, the now obsolete ‘miasma theory’ attributed toxic air derived from rotting matter to epidemics like cholera and tuberculosis. This theory persisted up until the late 1800’s, when the German physician Robert Koch identified microorganisms as the root cause of both diseases. Dr. Koch was awarded the 1905 Nobel Prize in Physiology or Medicine for his findings and the medical field replaced ‘miasma theory’ with ‘germ theory’ as the central paradigm for explaining infectious disease.
Some argue that the ‘amyloid hypothesis’, which aims to explain one of the root causes of Alzheimer’s Disease, has reached a similar turning point. The hypothesis proposes that toxic aggregates of amyloid beta (Aβ) proteins cause cognitive deficits seen in patients with Alzheimer’s Disease by disrupting neuronal signaling in areas of the brain that are responsible for memory formation and retrieval. Several pieces of evidence support the amyloid hypothesis. Brain tissue from patients with Alzheimer’s Disease often contain Aβ plaques11. Furthermore, people with heritable mutations in the gene APOE4 and individuals with Down syndrome harbor genetic changes that lead to increased levels of Aβ proteins and, coincidently, have an increased risk of developing Alzheimer’s Disease.
If Aβ plaques indeed cause the neurodegenerative disorder, it stands to reason that removing those plaques could either halt or reverse declines in cognitive function. Biogen’s drug, aducanumab, is an antibody that has been demonstrated to effectively bind and clear Aβ plaques from the brain, as corroborated by brain images of treated patients in both the EMERGE and ENGAGE clinical trials. Yet, those same patients fail to display consistent improvements in cognitive function. In 2016, the pharmaceutical company Eli Lilly announced that their Aβ-targeted antibody failed to demonstrate cognitive improvements in patients with mild Alzheimer’s Disease 12. In early 2020, both Eli Lilly and Roche reported that neither of their Aβ-targeted antibodies demonstrated cognitive improvements in patients with a rare, inherited form of early-onset Alzheimer’s Disease13, 14. Furthermore, a handful of drugs designed to inhibit proteins that lead to the formation of Aβ, like γ-secretase and β-secretase, similarly failed to demonstrate efficacy15.
These anomalies have inspired questions as to whether Aβ plaques play the role of an innocent bystander, as opposed to being the direct cause of the neurodegenerative disease. Additionally, another protein, tau, also forms fibrillary tangles in areas of the brain affected by Alzheimer’s Disease, and there is reasonable speculation that targeting amyloid beta alone will not be a sufficient disease-modifying therapeutic approach. Consequently, the FDA’s assessment of Biogen’s aducanumab could serve as a cornerstone event that molds the scientific consensus surrounding the amyloid hypothesis. In an effort to remove uncertainty related to Biogen’s already completed Phase 3 clinical trials, FDA officials might ultimately suggest that the company conduct a third Phase 3 clinical trial that more definitively demonstrates the ability of aducanumab to delay cognitive decline in patients with Alzheimer’s Disease. Nevertheless, the scientific field of neurodegenerative diseases might be due for a ‘paradigm shift’. The field ought to reorient around other promising theories of what causes Alzheimer’s Disease in order to devise novel therapeutic strategies that improve clinical outcomes for the millions of patients around the world that need it.
- https://edge.media-server.com/mmc/p/3dsvh8oa (Slide 6, aducanumab announcement)
- https://investors.biogen.com/static-files/40565136-b61f-4473-9e58-9be769bbac6c (Slide 6, aducanumab announcement; Slides 10-24, clinical trial analysis)
- Kuhn, Thomas S. The Structure of Scientific Revolutions. University of Chicago press, 2012.
- The Nobel Prize in Physiology or Medicine 1905. NobelPrize.org. Nobel Media AB 2020. Fri. 3 Apr 2020. <https://www.nobelprize.org/prizes/medicine/1905/summary/>
- Robinson, John L., et al. “Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.” Brain 141.7 (2018): 2181-2193.
- Giacobini, Ezio, and Gabriel Gold. “Alzheimer disease therapy—moving from amyloid-β to tau.” Nature Reviews Neurology 9.12 (2013): 677.