The differential diagnosis for neurological symptoms can be broad and include potentially serious disorders, managing and assessing these symptoms can be particularly difficult in the community. The most prevalent form of dementia, Alzheimer's disease starts with modest memory loss and may progress to a lack of communication and environmental awareness. The latest therapeutic agent for the management of Alzheimer's is the novel disease-modifying treatment aducanumab.

1. The Aduhelm (Aducanumab) Controversy – The
new ‘wonder drug’ for Alzheimer's
Done by: Sree Divya

3. Introduction
On June 7, the FDA approved aducanumab, the first novel Alzheimer's disease therapy in nearly two decades—
and, more importantly, the first drug with a recognized disease-modifying action, notably elimination of β-
amyloid (or Aβ) plaques from the brain. Aducanumab's acceptance has caused a global discussion, with opposing
viewpoints splitting the scientific community.
FDA authorized Accelerated Approval based on the evident effect on the biomarker, the potential clinical effect
demonstrated in one trial, and the imperative need in this area of medicine. The FDA has granted the ‘accelerated
approval’ under ‘Subpart H’ (CDER Drug approval) based on surrogate endpoints.
Two-phase III randomized clinical trials ‘ENGAGE and EMERGE’ with aducanumab yielded mixed findings,
with contradictory evidence of therapeutic benefits. These when present, were of dubious clinical benefits.1
Instead, the FDA cited a coherent and persuasive decrease in the brain -amyloid plaques (as measured by PET
scanning) in a dose- and time-dependent manner, as well as some proof for changes in putative downstream
biomarkers, and indicated that "the decline in plaques is justifiably likely to lead in clinical benefit”.2

4. Heralded therapy for Alzheimer’s under scrutiny
Alzheimer's disease is the most common form of dementia and one of the leading causes of
mortality in the United States. It affects about 50 million people worldwide and is expected to
double by 2050. Beta-amyloid (often called amyloid-beta) peptides (beta 40 and 42) are
thought to be the most prevalent disease mechanism in Alzheimer's. Before this, there was no
effective treatment. Only two FDA-approved classes of medications, which
include cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, were
authorized for curative relief, with only minimal efficacy.
Aducanumab's approval under the FDA's Accelerated Approval Program is being viewed by
some as a step in this direction, but it is not without controversy. It has been shown that
Aducanumab, marketed as Aduhelm by Biogen, reduces beta-amyloid plaques in the brain.3
According to Biogen, this will help patients with Alzheimer's disease to improve their
cognition and function.

5. Stage 1: Rejection of Aduhelm
When Biogen petitioned for approval of aducanumab (Aduhelm) to the FDA's Peripheral and
Central Nervous System Drugs Advisory Committee in November 2020, it was almost
collectively denied. Aduhelm was disapproved by the committee because it used amyloid plaque
reduction as a surrogate objective.
The results of two previous Biogen clinical trials assessing the efficacy of Aduhelm in
Alzheimer's disease were determined to be unsatisfactory by the committee.4 Despite the fact
that both studies were discontinued midway due to ineffectiveness, a following retroactive
analysis revealed positive results, allowing the medicine to be reconsidered.

6. Stage 2: Reconsideration and Approval of Aduhelm
Regardless of the ongoing issues, the FDA issued a statement on June 7, 2021,
authorizing Aduhelm via the Accelerated Approval Pathway, despite the continued
disputes and unfavorable evaluations. Following this, some committee members
resigned in disgrace of the decision. Biogen must now complete phase 4 trials and
produce evidence of clinical efficacy as anticipated by the surrogate endpoint as part of
the FDAAccelerated Approval Program.5
The FDA will give the medication a traditional approval if these trials provide proof of
the projected clinical value. Eventually, the FDA will commence regulatory proceedings
to remove the drug from the market. Under the terms of the Accelerated Approval
Program, Biogen can commercialize Aduhelm for decades before phase 4 research data
is accessible.

7. Stage 3: Criticism from Health Experts
The FDA employed an 'accelerated approval pathway' to approve this medicine, which is intended
for therapies for life-threatening conditions that "offer a considerable therapeutic advantage over
current treatments." According to health experts, Something that this medicine does not supply.
Scientists are split on whether the medicine was approved too quickly without enough evidence
that it delivers.
They believe that the approval of aducanumab is a catastrophic mistake that will only harm
patients and their families, and that it will stall the current quest for effective dementia treatments
for years. Surprisingly, the FDA has ignored accessible clinical trial results that indicate the drug is
unlikely to work.6
The cost of the treatment has also been a source of criticism. Aduhelm must be delivered
intravenously every month at a clinical facility, and the business estimates that it will probably cost
$56,000 per year.

8. Figure: Interpretation on how strongly do physicians agree or disagree with FDA’s
approval of aducanumab (Sy Mukherjee, 2021)7
Note: This survey was conducted between June 14th – 23rd, 2021

9. Reason behind the ‘Controversy’
A rift among the agency is one cause of controversy surrounding Aduhelm. FDA statisticians
claimed the data from the two clinical trials cited to justify the approval did not match statistical
requirements, but agency authorities rebuffed them, according to records. Another point of
contention is that Aduhelm gained accelerated approval, which is a different regulatory process
aimed to expedite the release of pharmaceuticals.
The FDA has a history of accelerating approvals based on evidence from modest early-stage trials.
Since Aduhelm was tested in two fairly large phase 3 trials, the issue is not the size of the trials, but
whether those trials merited an FDA approval.6 Despite the uncertainty about whether these
markers translate into improved symptoms and outcomes, approvals based on surrogate markers are
controversial.
The FDA initially granted Aduhelm a broad label, allowing Biogen to profit from nearly 6 million
Americans living with Alzheimer's. Aduhelm's label was quickly lowered to patients with milder
forms of the disease after the agency came under fire.

10. Stage 4: Future Implications
In a way, Aduhelm is truly a trial run for the future of dementia
therapies. There are several additional alternatives to AD therapies
that are slowly being examined via Phase 1 and 2 testings. These
approaches are substantially different from manipulating amyloid
levels. Despite the suggestions from some that Aduhelm’s approval
will pique the pharmaceutical industry's interest, I believe that
passion for discovering treatments with clinical advantages already
exists. However, because of Aduhelm’s fast approval, Lilly
(donanemab), Eisai-Biogen (lecanemab), and possibly Roche
(gantenerumab) have filed for a similar "accelerated approval”. 8

11. Conclusion
Aducanumab's future impact is yet unknown; it is not yet available in the United Kingdom or
Europe. Nonetheless, aducanumab represents a ray of light in a never-ending hunt for
medicines for Alzheimer's disease, as it is the first medication in a long time. The need for
innovative life-changing medicines is only growing in the UK, where dementia research has
been chronically underfunded. As it stands now, aducanumab is far from a cure for
Alzheimer's disease, and there are still many more hurdles to surmount. As a result of the
controversy surrounding its approval, many doubt the FDA's Accelerated Approval Program.
The FDA mandated a phase IV post-marketing randomized controlled trial to confirm
therapeutic benefit, with a final report due in February 2030. Even with a new and potentially
promising molecule in the fight against AD, the immediate future, at least, appears bleak.
However, it is undeniably a momentous moment that represents a watershed point in
dementia research.

12. References
1. Biogen. (2020, August 7). A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to
Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer’s Disease. Clinicaltrials.gov.
https://clinicaltrials.gov/ct2/show/NCT02477800
2. Office of the Commissioner. (2021a, June 7). FDA Grants Accelerated Approval for Alzheimer’s Drug. FDA.
https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
3. Noah Higgins-Dunn. (2021, July 8). Biogen, FDA walk back controversial Aduhelm label after weeks of fierce criticism.
FiercePharma. https://www.fiercepharma.com/pharma/facing-pushback-biogen-and-fda-agree-to-narrow-aduhelm-s-broad-
label
4. Mari Devereaux. (2021, July 20). Health systems’ rare rejection of Alzheimer’s drug sparks questions about FDA approvals.
Modern Healthcare. https://www.modernhealthcare.com/policy/health-systems-rare-rejection-alzheimers-drug-sparks-
questions-about-fda-approvals
5. Biogen. (2021). FDA grants accelerated approval for ADUHELMTM as the first and only Alzheimer’s disease treatment to
address a defining pathology of the disease | Biogen. Investors.biogen.com. https://investors.biogen.com/news-releases/news-
release-details/fda-grants-accelerated-approval-aduhelmtm-first-and-only
6. Emma Betuel. (2021, August 5). Aduhelm approval sparks HHS watchdog review of FDA’s accelerated approval pathway.
TechCrunch. https://techcrunch.com/2021/08/05/aduhelm-approval-sparks-hhs-watchdog-review-of-fdas-accelerated-
approval-pathway/
7. SY MUKHERJEE. (2021, July 8). Doctors refuse to prescribe Biogen’s Alzheimer’s drug. Fortune.
https://fortune.com/2021/07/08/biogen-aduhelm-aducanumab-alzheimers-doctors-disapprove/
8. Rachel Arthur. (2021, June 8). Biogen: “Aduhelm will be the catalyst to a new era of innovation for Alzheimer’s
disease.” Biopharma-Reporter.com. https://www.biopharma-reporter.com/Article/2021/06/08/Biogen-Aduhelm-will-be-the-
catalyst-to-a-new-era-of-innovation-for-Alzheimer-s-disease