Decision Time for the FDA and Aducanumab
Will the controversial Alzheimer's drug from Biogen gain FDA approval next week?
A mind is a terrible thing to waste, so the adage goes.
Alzheimer’s Disease the most common type of dementia, which progressively decays parts of the brain that control thought, memory, and language. The disease begins with mild memory loss but evolves into the loss of being unable to carry a conversation or respond to one’s environments; ultimately being the sixth most prevalent cause of death in the US. Nearly 5.8 million Americans were living with Alzheimer’s Disease in 2020, and this figure is projected to nearly triple to 14 million by 2060. Currently, there is no US Food and Drug Administration (FDA) approved treatment today that alters the course of the disease as opposed to merely treating symptoms.
This could change come June 7th, 2021.
Monday, June 7th, is the (FDA) deadline to announce whether or not Biogen’s Alzheimer’s treatment drug, aducanumab, merits approval and wide clinical use. This marks the first time in nearly twenty years that the FDA has considered approving a potential Alzheimer’s treatment. 99% of all trials in for potential new Alzheimer’s treatments have failed over the past 15 years, and the opportunity for adding a treatment for those suffering from the degenerative disease is an immense one.1
However, the drug has not come without its fair share of controversy. Many critics of the drug in the medical field argue that the poor efficacy as well as questionable data and halted trials should not be overlooked simply because of the need for a treatment. Proponents of the drug argue that even with mild efficacy, the drug would allow for delays of further cognitive impairment from the disease. This would allow for loved ones to have more time in a cognitive state of mild dementia versus severe dementia.
Ultimately, the FDA decision has massive consequences not only for public health but also for investors. The decision has been crowned “the mother of all binary events” by a JPMorgan Chase & Co. analyst, and considering the stock could move nearly 50% in either direction based upon the FDA’s ruling; this is a defining binary event for the biotech sector.
Aducanumab Overview
Aducanumab is a human monoclonal antibody that was developed by Biogen for the treatment of Alzheimer’s Disease. The antibody targets peptides of amino acids known as β-amyloid. These are the main component of amyloid plaques found in the brains of those with Alzheimer’s Disease, and research has suggested that such plaques may be causative agents in the development of Alzheimer’s disease, and the removal of which would slow the mental decline of patients.2
Two of Biogen’s Phase 3 trials: ENGAGE3 and EMERGE4, aimed to evaluate the efficacy of the drug over 78 weeks of treatment. Biogen launched these trails in conjunction with Japanese medical company Eisai. Each trial had the goal of determining what the rate of change was in Clinical Demential Rating-Sum of Boxes (CDR-SB), which is a holistic method of measuring functional and cognitive abilities for things like home activities, problem solving, and communication. The total sum of the enrollment was nearly 3,300 people with mild cognitive impairment or mild Alzheimer’s. Once the trials had completed, Biogen submitted the data from these two Phase 3 trials to the FDA.
During the FDA’s review period in March 2019, the advisory committee determined the data did not support the claim that the drug was effective in treating the disease. This was a multi-billion dollar setback for Biogen, and for a period of time, marked the death of aducanumab’s viability. Biogen announced in 2019 a halt to its clinical development as a result of the independent advisory committee’s assessment of interim data.5
When all hope seemed lost, the firm submitted additional analyses and clinical data per FDA request. In the new data presented, Biogen factored in data generated after the cutoff for the interim assessment, arguing that with the new data set, the EMERGE trial resulted in statistically significant changes on a clinical dementia scale (22% slowing of decline).
Yet, the other trial, ENGAGE, resulted in data with much to be left desired. The high dose of aducanumab performed worse than placebo on the clinical dementia scale. Biogen argued that the divergence between the data compiled from both studies was due to greater exposure of the high dose of the drug in the EMERGE trial; arguing that the better results were a direct effect of the drug dosage.6
Upon initial review in late 2020, many FDA panel members were left unsatisfied with the results of the trials as well as the methodology:
“There is a suggestion of an effect, but there are enough red flags in terms of the changes to the protocol, concerns about unblinding and the observation of efficacy in the final 78-week analysis without a full cohort of patients being able to contribute to that analysis, for me, doesn’t add up to a strong evidence,” - Aaron Kesselheim, M.D., an associate professor at Harvard Medical School.7
Even with the committee’s doubts, the final FDA assessment including the updated dataset concluded that “exceptionally persuasive” data showed the drug slowed cognitive decline caused by Alzheimer’s.
After an extension of the FDA’s review period for aducanumab, the deadline is Monday to issue a ruling on the application for approval.
A New Hope
Supporters of approving the drug argue that even with limited efficacy in slowing cognitive decline, those previous months could mean the chance for “more time” for those suffering with the disease.8
Dr. Maria Carrillo, the Chief Science Office for the Alzheimer’s Association, supports approval of the drug and believes that the hope of a potential treatment should be available to patients should they choose.
“We think that research is actually paying off, and that this is a time where it should be a message of hope… We know that, for those individuals that could be eligible for this treatment — would be eligible, let’s say, if there is approval — the drug could mean more time with family. One of the most important things we wanted to do was to make sure that people understood what this means.“ remarked Dr. Carrillo .
People facing Alzheimer’s are facing a progressive and fatal disease, and would give anything to have ‘More Time,'” the association stated in an email. “To deny millions of people days, weeks, months or even years of active life, particularly with early diagnosis, is inhumane.
In the eyes of the Alzheimer’s Association and Carrillo, current trial data supports aducanumab’s safety. While there were side effects reported as a result of taking the drug, such as brain swelling (cerebral edema), Carrillo believes the side effects associated with the drug can be effectively managed in a clinic.9
Not only would approval of the drug spark hope in patients suffering from it, but also in other firms researching and testing new treatments for Alzheimer’s. The first new approval of a drug for this disease in 20 years would be very promising to smaller biotech firms working on their own technology to cull the degenerative effects of the disease.
Firms such as:
Cassava Sciences (SAVA)
Ymanity Therapeutics (YMTX)
Longeveron (LGVN)
Cyclerion Therapeutics (CYCN)
Alector (ALEC)
and many other are actively working on treatments in various clinical stages for Alzheimer’s. The approval of Biogen’s aducanumab would re spark interest in a stagnant biotech sector, and incentivize investors to invest in the potential of these early stage treatments. Approval would also shine investor spotlight to fund newer trials for therapeutic companies not currently exploring working on treatments due to the historical difficulty of gaining FDA approval.
This Isn’t the One
There are also an equal amount of medical professionals who believe the dataset from the EMERGE and ENGAGE trials are not convincing, and that the drug should not be given special treatment simply because Alzheimer’s treatments are in dire need.
Dr. Michael Greicius, professor of neurology at Stanford and Director of the Stanford Center for Memory Disorders, and Dr. Caleb Alexander, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, recently wrote an op-ed in the New York Times overviewing why aducanumab should not be approved. The title of the op-ed was “People Want an Alzheimer’s Drug. This Isn’t the One.” Dr. Alexander also served on the FDA advisory committee that evaluated aducanumab, making him a knowledgeable source of information on the drug and its efficacy.
The doctors argue that the drug has not been truly shown to work, and the questionable differences in the two trials do not support the claim that the drug causes a statistically significant response.
The article also emphasizes how nearly 25 clinical trials have tested the “amyloid cascade” hypothesis, and not a single one has been successful.10 Biogen’s own trial was initially considered a failure until it did everything it could to “explain away the uncomfortable and disappointing fact this product has not been proved to work.” While Dr. Carrillo argues the side effects can be managed, Dr. Greicius and Alexander note that three out of ten patients had brain swelling as a complication, and this was asymptomatic; only being detected through rigorous safety screens and routine M.R.I scans as a part of the trials. If a patient is taking aducanumab outside of a controlled experimental environment, would they be able to catch the swelling prior to any further complications? Or could this side effect on its own become more harmful to patients than the disease itself? The swelling led to confusion, disorientation, and falls; symptoms oftentimes associated with Alzheimer’s itself. Would medical professionals be able to distinguish these side effects as inherent or due to aducanumab? This could be a costly experiment to find out with already vulnerable patients suffering.
The op-ed also argues that approving a questionably effective drug would disincentive new drugs for the disease as opposed to incentivize development. Approving a drug with questionable procedures and data would slow progress in a new drug that is unequivocally safe and effective. Alzheimer’s patients may be hesitant to enroll in new trials due to already taking aducanumab; others may be ineligible due to the difficulty of determining whether adverse effects were from aducanumab or a new investigational drug.11
“As millions of Americans know all too well, there is an urgent need to identify new treatments for Alzheimer’s. But there is no fundamental conflict between that challenge and maintaining the standards that have earned the F.D.A. the respect of regulatory agencies around the world. Our patients and their families deserve nothing less, and approving aducanumab without persuasive evidence that it actually works will only slow the discovery of what we need most — treatments that we can be confident actually work.” -excerpt from NYT op-ed
To many medical professionals, approving aducanumab without trial data that fully justifies its statistical efficacy simply because a treatment is badly desired, would mean one step forward and two steps backwards for a proven treatment.
Biogen
If approved, aducanumab is projected to gross billions of dollars for Biogen annually, and could move the stock price nearly 60-100+ points next week based on the FDA’s final ruling.
Analysts on Wall Street have mixed views as to the potential for aducanumab to be approved, some giving it a 50% chance, others viewing it as a longshot with chances well below 50%. Mizuho Securities analyst Salim Syed commented in a recent research note that, “If the FDA approves aducanumab, [Biogen] could go to circa $400, and if not, to circa $200”. Bank of America Securities analyst Geoff Meacham had a more pessimistic outlook on approval, stating that he put the odds at 75% that the approval would not go through for the drug. “If the FDA does approve, I think it could signal probably more regulatory flexibility,” said Meacham.12
Biogen is also roughly a 3% weight in the iShares Nasdaq Biotechnology ETF (IBB), meaning that volatility in Biogen’s stock will have market wide implications for the sector.
A rejection may actually be bullish for companies with competing treatments in research or undergoing trials. RBC Capital Markets analyst Brian Abrahams said that a rejection by the FDA could spike shares of Biogen acquisition targets on the premise that their treatments would rise in value and Biogen would need to make acquisitions to salvage its pipeline.13
Even if approved, sales estimates for the drug have varied over the past few months, with 2023 sales of aducanumab down $400 million to $1.6 billion from the $2 billion estimate made in late March 2021. The Institute for Clinical and Economic Review issued a report in early may calculating a cost-effectiveness analysis could support an annual price for aducanumab at between $2,560 and $8,290 - multiples below the $50,000 per year price some market analysts had expected leading up to potential approval.14
However, with approval of the drug Biogen would hold the only drug approved for non-symptomatic Alzheimer’s treatment. The worldwide need for this drug to become viable would make aducanumab immensely valuable due to the exceeding demand for it, regardless of those that question its efficacy.
A Controversial Decision
The FDA is left with the most controversial drug treatment decision in recent history. If the drug is denied approval, millions of patients suffering from Alzheimer’s will be unable to have a potential opportunity at a treatment, while new treatments are years away from a potential approval decision. While on the other hand, approval of the drug would set a precedent for lowering the bar needed to attain FDA approval and potentially expose millions to an under proven drug that could leave asymptomatic side effects with patients.
Regardless of which way the FDA’s decision leans on Monday, the decision will be extremely impactful in the lives of millions of those suffering from this awful disease and their families; as well as for investors placing their bets for what could be the “mother of all binary events”.
I, for one, err on the side of optimism, and hope that an approval could excite the sector and give a drop of hope to those who need it so dearly due to this disease.
https://www.fiercebiotech.com/biotech/biogen-and-eisai-rocked-as-aducanumab-turns-out-to-be-a-dud
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772133/
https://clinicaltrials.gov/ct2/show/NCT02477800
https://clinicaltrials.gov/ct2/show/NCT02484547
https://alzheimersnewstoday.com/2019/03/22/phase-3-trials-aducanumab-alzheimers-halted/
https://investors.biogen.com/static-files/5a31a1e3-4fbb-4165-921a-f0ccb1d64b65
https://www.fiercebiotech.com/biotech/fda-panel-slams-biogen-s-controversial-alzheimer-s-med
https://www.npr.org/sections/health-shots/2021/06/04/1003350956/fda-poised-for-decision-on-controversial-alzheimers-drug
https://alzheimersnewstoday.com/2021/06/03/alzheimers-association-aducanumab-biogen-means-more-time-merits-approval/
https://pubmed.ncbi.nlm.nih.gov/30610216/
https://www.nytimes.com/2021/05/28/opinion/alzheimer-treatment-FDA-aducanumab.html
https://www.reuters.com/business/healthcare-pharmaceuticals/investors-patients-await-fda-decision-biogen-alzheimers-drug-due-monday-2021-06-04/
https://www.barrons.com/articles/biogen-alzheimers-drug-fda-decision-51622757204
https://icer.org/wp-content/uploads/2020/10/ICER_ALZ_Draft_Evidence_Report_050521.pdf