An Alzheimer’s Drug Rises from the Ashes

Originally published on April 11, 2020 in Hopkins Biotech Network’s newsletter The Transcript (link)

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 ageing (Alzheimer’s Association). Disabilities associated with the condition exert a burden on both patients and their caretakers, as shown by a 60 Minutes special report, which documents a couple’s experience with Alzheimer’s Disease over a 10-year timespan. 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, aducanumab (Biogen press release). 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.

Biogen’s Gauntlet

On the morning of October 22, 2019, Biogen hosted a routine conference call during which they presented their quarterly financial results and business updates, as do all public companies. 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 disease-modifying 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 trials. 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 posture (FierceBiotech). 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 other (Reuters). 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 maturity (The Structure of Scientific Revolutions). 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 plaques (Brain). 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 (Eli Lilly press release). 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 Disease (Eli Lilly press release, Roche press release). 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 efficacy.

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 (Nature Reviews Neurology). 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.

Update #1: Since the article was originally published, the FDA accepted Biogen’s BLA for aducanumab, with a PDUFA date of March 21, 2021(Biogen press release). There are mixed signals as to whether the drug will ultimately get approved. A document released on November 4, 2020 revealed that FDA staff scientists largely endorse approval of aducanumab, while the FDA advisory committee (composed of outside experts) who met on November 6, 2020 largely voted against its approval (STAT).

Update #2: On June 7, 2021, the FDA approved Aduhelm (aducanumab) to treat patients with Alzheimer’s disease using the Accelerated Approval pathway. The agency has stated the following:

“In determining that the application met the requirements for Accelerated Approval, the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy. […] Approval is based on a surrogate or intermediate clinical endpoint (in this case reduction of amyloid plaque in the brain). […] FDA will continue to monitor Aduhelm as it reaches the market and ultimately the patient’s bedside. Additionally, FDA is requiring Biogen to conduct a [phase 4 confimatory] clinical trial to verify the drug’s clinical benefit. If the drug does not work as intended, we can take steps to remove it from the market.” Dr. Patrizia Cavazzoni, Director, FDA Center for Drug Evaluation and Research, 6/7/2021 (FDA press release)

In an interview with CNBC’s senior health and science reporter Meg Tirrell, the CEO of Biogen Michel Vounatsos remarked that company could take up to nine years to satisfy the FDA’s post-approval requirement (CNBC interview, STAT).

I anticipate — as of June 9, 2021 — that books, movies, and at least one 60 Minutes segment will be created in response to this historic outcome and I am looking forward to hearing the diverse perspectives of industry scientists, academic/clinical researchers, physicians, patients/patient advocacy groups, and Alzheimer’s/dementia-related foundations.

Update #3: On June 24, 2021, Derek Lowe — a Director of Chemical Biology Therapeutics at Novartis Institutes for Biomedical Research (NIBR) & author of the “In the Pipeline” column run by the journal Science — published a perspectives piece entitled “Open the Floodgates” in which he suggested that the FDA approval of Aduhelm would set off a domino effect within the biotech industry. The more permissive regulatory environment might encourage other biotech & pharma companies that have been developing anti-amyloid beta therapeutics over the past few decades — like Eli Lilly, Merck, Genentech/Roche — to likewise file for approval based on the amyloid-lowering surrogate endpoint, which they have already demonstrated in large-scale clinical trials. Indeed that appears to be the case:

• Lecanemab (Biogen/Eisai), an investigational anti-amyloid beta (Aβ) protofibril antibody for the treatment of Alzheimer’s disease (AD), was granted FDA Breakthrough Therapy designation on June 23, 2021 (press release).
• Donanemab (Eli Lilly), an investigational antibody that targets a modified form of beta amyloid called N3pG for the treatment of Alzheimer’s disease (AD), was granted FDA Breakthrough Therapy designation on June 24, 2021 (press release).

Update #4: On June 29, 2021, STAT News released a detailed investigational report that described how Al Sandrock — Biogen’s Head of Research & Development — collaborated with Billy Dunn —FDA’s Director of the Office of Neuroscience — to utilize the FDA’s Fast Track Approval process as a regulatory shortcut and advance Aduhelm to the market.

Update #5: On July 9, 2021, the FDA Commissioner called for a wide-ranging federal investigation into the approval of Biogen’s treatment for Alzheimer’s disease just one month after a decision that sparked the ire of lawmakers, doctors, and public health advocates (STAT). In a letter, acting Commissioner Janet Woodcock asked the independent Office of Inspector General to investigate how agency staff interacted with Biogen in the run-up to the June 7 approval of Aduhelm. The agency cited STAT’s reporting that FDA officials worked hand in hand with Biogen executives to get the drug on the market, including an off-the-books meeting and an unprecedented decision to approve Aduhelm through a regulatory shortcut. This federal action prompted Biogen’s Head of R&D Al Sandrock to publish an open letter on July 22, 2021 to correct so-called “misinformation and misunderstanding that has been outside the boundaries of legitimate scientific deliberation”. The letter discusses (1) the >250 drugs approved by FDA’s Fast Track Approval pathway, (2) the FDA’s data-driven approach to the Aduhelm decision, and (3) how the Aduhelm approval is “paving the way for more innovation and competition in Alzheimer’s disease”.

Update #6: On November 15, 2021, STAT leaked the news that Al Sandrock — Biogen’s Head of R&D and “the face of its years-long campaign to develop a treatment for Alzheimer’s disease” — was retiring from the company after more than 23 years at the company. STAT reporters characterize the timing of this high profile departure as follows:

“Sandrock is departing a company in decline. Biogen’s revenues are on a steady annual descent, with 2021 projected to come in about 20% below the prior year. Aduhelm, predicted to become a blockbuster medicine, brought in just $300,000 in the third quarter, coming dramatically short of Wall Street’s expectations. Biogen doesn’t expect demand for Aduhelm to improve until next year, when Medicare is set to decide whether to cover the medicine.

Sandrock’s research division, responsible for restocking the Biogen pipeline, has struggled in recent years. Since Spinraza’s approval in late 2016, Biogen has [attempted] to develop multiple gene therapies, treatments for Alzheimer’s, and a therapy for amyotrophic lateral sclerosis. The company has more than 30 medicines in clinical trials, but investors and analysts have low expectations for their potential value. Biogen’s strongest prospects are a follow-on treatment for Alzheimer’s called lecanemab, developed by Biogen’s partner Eisai, and zuranalone, a treatment for depression licensed from Sage Therapeutics.”

Update #7: On July 21, 2022, Science reported an expose detailing apparent research fabrication (ie. blatant image tampering) by leading Alzheimer’s professor Sylvain Lesné & Karen Ashe at UCSF, going back to their seminal 2006 work establishing the causal role of amyloid beta in rats. This revelation calls into question 16 years of foundational research on the Aβ*56 toxic oligomer and casts a dark shadow over the Alzheimer’s field.