June is recognized as ‘Alzheimer’s & Brain Awareness Month’, and is used to raise awareness about this disease. What better timing that the first week of this month to get approval for a new Alzheimer’s drug! Notably, this is the first new drug to treat this condition to be approved since 2003. The Alzheimer’s drug that is approved is an antibody aducanumab, tradename Aduhelm® produced by the biotechnology company Biogen.
Alzheimer’s Disease – What is it?
Alzheimer’s disease is considered to be the most common form of neurodegenerative dementia in the United States. With almost 50 million people affected worldwide, approximately 5.8 million Americans aged 65 and older are currently living with Alzheimer’s dementia. Importantly, Alzheimer’s disease is the sixth-leading cause of death in the United States, and the fifth-leading cause of death for those age 65 and older. The long duration of this disease contributes significantly to the financial public health impact of Alzheimer’s disease. In addition to the physical and psychological impact on the patient and family members, the costs of health care and long-term care are substantial. The total costs in 2020 (excluding informal caregiver costs) for individuals with Alzheimer’s disease are ~$305 billion.
Disease Pathophysiology
While the exact cause of Alzheimer’s disease is unknown, extensive research in this area has shown that in the brains of patients with this condition, there is accumulation of:
a protein called beta-amyloid in the form of beta-amyloid plaques outside the neurons, and
an abnormal form of the protein called tau in the form of tau tangles or neurofibrillary tangles inside neurons
These plaques and tangles affect communication between neurons and lead to neurodegeneration. Clinically, there are three stages of this disease:
Preclinical Alzheimer’s
Mild cognitive impairment, and
Alzheimer’s dementia
Similarly, Alzheimer’s disease can be described as either mild, moderate, or severe.
Alzheimer’s Disease Therapeutics
Before the current approval of aducanumab, there were 4 approved drugs for Alzheimer’s disease. Three of these drugs belong to a class of drugs called cholinesterase inhibitors: donepezil, galantamine, and rivastigmine. The fourth drug is a blocker of the receptor protein NMDA and is named memantine. In addition, one combination is approved as well (memantine + donepezil).
None of the previously approved drugs are curative against Alzheimer’s disease. The need for development of an effective therapeutic against this condition is paramount. Unfortunately, the failure rate for Alzheimer’s drug development has been more than 99%. On the backdrop of this staggering failure rate, the past few years were notable. There was excitement in the field as many pharmaceutical and biotechnology companies had promising candidates in clinical testing. However, as most of these compounds failed in studies, experts were expectantly looking at the last two companies standing, locked in a race for approval of their respective drugs against Alzheimer’s disease – Eli Lilly for donanemab and Biogen for aducanumab. Both of these drugs targeted the beta-amyloid protein to stop disease progression. Unfortunately, the data for donanemab was not good enough for the drug to be approved for clinical use, which meant all eyes were now on aducanumab.
Aducanumab – The Newest Anti-Alzheimer’s Drug
Aducanumab is a human monoclonal antibody that was originally developed by Biogen and their Tokyo-based partner Eisai. Aducanumab binds to the beta-amyloid protein and disrupts plaque formation. Through two clinical trials, Biogen tested this drug in Alzheimer’s patients. Unfortunately, in preliminary analyses, these studies did not show clinical improvement in patients and were stopped. However, in a stunning reversal, following more data analysis and additional dosing, Biogen detected some clinical improvement in Alzheimer’s patients in one of these studies and also showed reduction of beta-amyloid buildup in the brain.
To review the results from this study, the U.S. Food and Drug Administration (FDA) convened an independent advisory committee of experts, including neurologists and biostatisticians. After careful review, the committee voted overwhelmingly that the data from the study did not demonstrate evidence of the drug being effective. However, in a shocking disagreement with its expert panel, the FDA proceeded to conditionally approve aducanumab against Alzheimer’s disease. The FDA’s explanation for this decision was that they saw “substantial evidence that the drug reduce(d) beta-amyloid plaque, and that this reduction is reasonably likely to predict clinical benefit.” Furthermore, in a statement following this controversial approval, Patrizia Cavazzoni, M.D., Director of the FDA’s Center for Drug Evaluation and Research said, “currently available therapies only treat symptoms of the disease; this treatment option is the first therapy to target and affect the underlying disease process of Alzheimer’s. As we have learned from the fight against cancer, the accelerated approval pathway can bring therapies to patients faster while spurring more research and innovation.” As a next step, Biogen is now required to demonstrate and confirm in a large clinical trial that removing the beta-amyloid plaque has definitive cognitive benefits. For now, Biogen has placed a undiscounted price of $56,000 per year for treatment of patients with Alzheimer’s disease. While this requires a much bigger discussion, it cannot be overstated that this price tag has huge implications for patients, their families, payers, and the healthcare system in general. It remains to be seen what discounts will be applied and how Biogen and the insurance companies will work together to agree to compensate Biogen. In fact, Wall Street had predicted an undiscounted price of $25,000 per year. While their prediction is not necessarily relevant, it does reflect a large difference of opinion regarding reasonableness.
What’s Next for Alzheimer’s Drug Research?
What is the impact of the FDA’s decision on the field of drug development, particularly in Alzheimer’s disease? Experts are divided on Cavazzoni’s claim about the effect of such an approval on research. Irrespective of the effectiveness of this drug (to be determined in a later study), some experts in the field are enthusiastic while others are disappointed and fear a negative impact. There are researchers who feel that the FDA’s decision on aducanumab will drag down innovation in the Alzheimer’s space, and others have minced no words expressing that this was a disgraceful decision by the FDA. Matthew Herper at StatNews thinks, “the Food and Drug Administration is rewriting its rulebook, an enormously risky move that could accelerate the public’s access to medicines but upend the future of drug regulation, forcing the 114-year-old agency to do the equivalent of redesigning a fighter plane in mid-flight.” Some scientists express apprehension that individuals with Alzheimer’s who are on other clinical trials might withdraw in order receive aducanumab as a therapy. There are scientists who also worry that drug developers might abandon other targets to focus on beta-amyloid alone.
On the other hand, many patient groups, disease advocates, and nonprofits are confident that this approval will spur more innovation in this field and provide the much-needed impetus to innovate further. In addition to this news driving up the stock price for Biogen, some researchers and neurologists viewed this development with a positive outlook. Many patient advocacy groups such as Us Against Alzheimer’s and The Alzheimer's Association are excited by this development.
Exactly how effective this drug turns out for patients will become clearer in the next few years. But now it is time for some cautious optimism as we look forward to seeing detailed results on aducanumab, while we keep our sights trained on the horizon for other candidates that may yet revolutionize the Alzheimer’s ecosystem.
Written by: Sandeep Pingle, MD PhD
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