BIOGEN FILES NEW DRUG APPLICATION FOR ADUCANUMAB IN JAPAN
If approved, aducanumab would become the first treatment to meaningfully change the course of Alzheimer’s disease
CAMBRIDGE, Mass. and TOKYO, [December 10, 2020] (GLOBE NEWSWIRE) – Today, Biogen (Nasdaq: BIIB) and Eisai, Co., Ltd. (Tokyo, Japan) announced that Biogen has submitted a Japanese New Drug Application (J-NDA) to the Ministry of Health, Labor and Welfare (MHLW) for aducanumab, an investigational therapy for Alzheimer’s disease. Aducanumab, an amyloid beta-targeting antibody, has been shown in clinical trials to remove amyloid beta in the brain and significantly slow clinical decline in patients with Mild Cognitive Impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease dementia.
“Japan is the third market where we have applied for regulatory approval for aducanumab, and the filing represents continued progress on our commitment to bring this therapy to patients around the world,” said Michel Vounatsos, Chief Executive Officer at Biogen. “Japan has met the challenges of a rapidly-aging population by demonstrating global leadership in setting policies that aim to increase support for Alzheimer’s disease patients and caregivers. We look forward to the regulatory review of aducanumab with the hope that, if approved, it could help further manage the impact of this devastating disease.”
“As Japan has the oldest population in the world, it is anticipated that the social burden of Alzheimer’s disease will continue to grow,” said Dr. Haruo Naito, Chief Executive Officer at Eisai Co., Ltd. “For more than 30 years, Eisai has been dedicated to dementia research and development, and working with people living with Alzheimer’s and their caregivers to fight this disease. The filing of the application is an important step in serving patients and their families as aducanumab may help reduce clinical decline and potentially maintain the ability to live an independent life for as long as possible. Aducanumab also has the potential to help address the public health challenges our aging population faces in Japan.”
The Japanese regulatory authority will review the application through the standard review process. In addition to the filing in Japan, aducanumab is under Priority Review with the U.S. Food and Drug Administration, with a Prescription Drug User Fee Act (PDUFA) action date of March 7, 2021 and is also under review with the European Medicines Agency.
About Aducanumab
Aducanumab (BIIB037) is an investigational human monoclonal antibody studied for the treatment of Alzheimer’s disease. Based on clinical data from patients with Mild Cognitive Impairment due to Alzheimer’s disease and mild Alzheimer’s disease, aducanumab has the potential to impact underlying disease pathophysiology, slow cognitive and functional decline and provide benefits on patients’ ability to perform activities of daily living, including conducting personal finances, performing household chores, such as cleaning, shopping and doing laundry, and independently traveling out of the home. If approved, aducanumab would be the first treatment to meaningfully change the course of the disease for individuals living with Alzheimer’s.
Biogen licensed aducanumab from Neurimmune under a collaborative development and license agreement. Since October 2017 Biogen and Eisai Co., Ltd. have collaborated on the development and commercialization of aducanumab globally.
EMERGE and ENGAGE were Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group studies designed to evaluate the efficacy and safety of aducanumab. The primary objective of the studies was to evaluate the efficacy of monthly doses of aducanumab as compared with placebo in reducing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. Secondary objectives were to assess the effect of monthly doses of aducanumab as compared to placebo on clinical decline as measured by the Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13) and Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI).
About Alzheimer’s Disease
Alzheimer’s disease is a progressive neurological condition that impairs thinking, memory and independence, leading to premature death. The disease currently cannot be stopped, delayed or prevented and is a growing global health crisis, affecting those living with the disease and their families. According to the World Health Organization (WHO), tens of millions of people worldwide live with Alzheimer’s disease, and the number will grow in the years ahead, outpacing the healthcare resources needed to manage it and costing billions of dollars.
According to the Health, Labor and Welfare Ministry, it is estimated approximately 4.6 million people live with dementia and about 4 million people live with Mild Cognitive Impairment (MCI) in Japan (2012). Alzheimer’s disease is suspected to represent around 60-70% of dementia cases.
Alzheimer’s disease is characterized by changes in the brain, including the abnormal accumulation of toxic amyloid beta plaque, which begins approximately 20 years before patients exhibit symptoms of the disease. MCI due to Alzheimer’s disease is one of the earliest stages of the disease when symptoms start to be more visible and can be detected and diagnosed. Current research efforts are focused on catching and treating patients as early as possible for the best chance of slowing or stopping the progression of Alzheimer’s disease.
About Biogen
At Biogen, our mission is clear: we are pioneers in neuroscience. Biogen discovers, develops and delivers worldwide innovative therapies for people living with serious neurological and neurodegenerative diseases as well as related therapeutic adjacencies. One of the world’s first global biotechnology companies, Biogen was founded in 1978 by Charles Weissmann, Heinz Schaller, Kenneth Murray and Nobel Prize winners Walter Gilbert and Phillip Sharp. Today Biogen has the leading portfolio of medicines to treat multiple sclerosis, has introduced the first approved treatment for spinal muscular atrophy, commercializes biosimilars of advanced biologics and is focused on advancing research programs in multiple sclerosis and neuroimmunology, Alzheimer’s disease and dementia, neuromuscular disorders, movement disorders, ophthalmology, immunology, neurocognitive disorders, acute neurology and pain.
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About Eisai Co., Ltd.
Eisai Co., Ltd. is a leading global pharmaceutical company headquartered in Japan. Eisai’s corporate philosophy is based on the human health care (hhc) concept, which is to give first thought to patients and their families, and to increase the benefits that health care provides to them. With a global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to realize our hhc philosophy by delivering innovative products to target diseases with high unmet medical needs, with a particular focus in our strategic areas of Neurology and Oncology.
Leveraging the experience gained from the development and marketing of a treatment for Alzheimer’s disease, Eisai aims to establish the “Eisai Dementia Platform.” Through this platform, Eisai plans to deliver novel benefits to those living with dementia and their families through constructing a “Dementia Ecosystem,” by collaborating with partners such as medical organizations, diagnostic development companies, research organizations, and bio-ventures in addition to private insurance agencies, finance industries, fitness clubs, automobile makers, retailers, and care facilities. For more information about Eisai Co., Ltd., please visit https://www.eisai.com.
Biogen Safe Harbor
This news release contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, about potential regulatory discussions, submissions and approvals and the timing thereof; the potential clinical effects of aducanumab; the potential benefits, safety and efficacy of aducanumab; the treatment of Alzheimer’s disease; the anticipated benefits and potential of Biogen’s collaboration arrangements with Eisai; the potential of Biogen’s commercial business and pipeline programs, including aducanumab; and risks and uncertainties associated with drug development and commercialization. These statements may be identified by words such as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “intend,” “may,” “plan,” “possible,” “potential,” “will,” “would” and other words and terms of similar meaning. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early stage clinical trials may not be indicative of full results or results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements or the scientific data presented.
These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including without limitation actual timing and content of submissions to and decisions made by the regulatory authorities regarding aducanumab; regulatory submissions may take longer or be more difficult to complete than expected; regulatory authorities may require additional information or further studies, or may fail or refuse to approve or may delay approval of Biogen’s drug candidates, including aducanumab; unexpected concerns that may arise from additional data, analysis or results obtained during clinical trials; the occurrence of adverse safety events; risks of unexpected costs or delays; the risk of other unexpected hurdles; uncertainty of success in the development and potential commercialization of aducanumab; risks relating to the potential launch of aducanumab, including preparedness of healthcare providers to treat patients, the ability to obtain and maintain adequate reimbursement for aducanumab and other unexpected difficulties or hurdles; failure to protect and enforce Biogen’s data, intellectual property and other proprietary rights and uncertainties relating to intellectual property claims and challenges; product liability claims; third party collaboration risks; and the direct and indirect impacts of the ongoing COVID-19 pandemic on Biogen’s business, results of operations and financial condition. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from Biogen’s expectations in any forward-looking statement. Investors should consider this cautionary statement as well as the risk factors identified in Biogen’s most recent annual or quarterly report and in other reports Biogen has filed with the U.S. Securities and Exchange Commission. These statements are based on Biogen’s current beliefs and expectations and speak only as of the date of this news release. Biogen does not undertake any obligation to publicly update any forward-looking statements, whether as a result of new information, future developments or otherwise.
Scientists torn over Biogen’s new Alzheimer’s drug
The FDA approved Aduhelm based on its ability to lower amyloid-β plaques in the brain. Many researchers think it was the wrong decision.
by Ryan Cross
An effective drug for Alzheimer’s disease has long eluded doctors and the patients they treat who have this memory-robbing condition. After nearly 20 years with no new treatments for the disease, a novel Alzheimer’s drug would seem like cause for celebration. Instead, the US Food and Drug Administration’s historic and controversial approval of Biogen’s Alzheimer’s therapy, Aduhelm, left neurologists exasperated. Many believe that the drug doesn’t work and that, even if it does, its benefits are marginal at best.
“I suspect there was a lot of pressure to approve, but I was quite disappointed,” says Mary Sano, director of the Alzheimer’s Disease Research Center at Mount Sinai School of Medicine. “It will be very interesting to see what will happen internationally. I am not convinced it will get approval in other countries.”
Alzheimer’s by the numbers:
13.5 Years
Biogen spent developing Aduhelm before FDA approval
$56,000
Estimated average annual cost of Aduhelm before insurance
6.2 million
Estimated number of people 65 and older with Alzheimer’s in the US
145%
Increase in deaths due to Alzheimer’s between 2000 and 2019
$355 billion
Projected cost of caring for people with Alzheimer’s and other dementia in the US in 2021
120
Number of Alzheimer’s drug candidates in clinical studies
Sources: Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation.
Others are more optimistic. “It is a step forward,” says Oscar L. Lopez, director of the Alzheimer’s Disease Research Center at the University of Pittsburgh. “You have a drug that slows down progression. It is not a cure, but it opens the door to better treatments in the future.”
Aduhelm, also known as aducanumab, is a monoclonal antibody that targets amyloid beta (amyloid-β) plaques that aggregate in the brains of many—though not all—people with Alzheimer’s disease. Neuroscientists have long thought that getting rid of these plaques, which are tied to brain cell death, could slow or halt the progression of Alzheimer’s disease. This so-called amyloid hypothesis has dominated Alzheimer’s research for decades. Yet study after study has shown that drugs targeting amyloid-β don’t seem to alter the course of the disease.
Biogen’s drug was set to change that. In 2015, the company demonstrated that aducanumab dramatically lowered amyloid-β plaques in the brains of people with early Alzheimer’s disease. That small trial prompted Biogen to launch two larger, and nearly identical, clinical trials to see if the drug could also slow cognitive decline.
In March 2019, Biogen pulled the plug on those studies; an early analysis of the data suggested that there was no hope the drugs would work. But the firm reversed course that October, saying additional data indicated the drug was slowing cognitive decline in one trial, though not the other.
Even though the FDA normally requires two positive trials for drug approval, Biogen argued that Aduhelm should be approved based on data from its single positive trial. For many scientists, the conflicting results between the two trials was a nonstarter.
“You have to look at both studies, and there is no logical reason to focus on one study and not the other,” says David S. Knopman, a clinical neurologist at the Mayo Clinic and a site investigator for one of the Biogen trials. He says he was “completely taken by surprise” when the FDA granted Aduhelm an accelerated approval based on its ability to lower amyloid-β plaques in the brain, rather than a standard approval based on proving that the drug slows cognitive decline.
After 18 months of treatment, Aduhelm reduced amyloid-β plaques by 71% in one trial and by 59% in a second, as measured by positron emission tomography (PET). “There is no doubt that this drug removes amyloid from the brain—that was really obvious from PET imaging,” says Elizabeth Mormino, an Alzheimer’s imaging researcher at Stanford University. “This drug really brings people down to the normal level, and it does so quite quickly.”
But Mormino and others note that the amyloid hypothesis has been called into question for the very reason that dramatic reductions of amyloid-β plaques don’t consistently correlate with a slowing of Alzheimer’s. By approving Aduhelm based on the amyloid data, the FDA “skirted the question” of whether or not the drug actually makes a meaningful difference for people with Alzheimer’s, Sano says. “They have created a pathway for approval that doesn’t require any symptomatic benefit, and that is pretty distressing.”
Scientists also take issue with the FDA’s approving Aduhelm for anyone with Alzheimer’s, even though Biogen tested it only in people with mild disease who had a PET scan confirming the presence of amyloid-β plaques. “I completely disagree with it being approved,” says David Holtzman, an Alzheimer’s neuroscientist at Washington University School of Medicine in St. Louis. Labeling the drug a therapy for anyone with Alzheimer’s was “definitely not justified at all,” he adds.
The disconnect between the FDA’s broad label and the narrower group of people the drug was tested on raises an ethical dilemma for neurologists who will inevitably face families desperate for a treatment. “We are going to have some difficult conversations with patients, and I suspect we will end up discouraging its use in more people than we end up encouraging it in,” says Jeffrey Burns, the codirector of the Kansas University Alzheimer’s Disease Center. “I am not going to prescribe it unless I have measures that suggest someone has elevated levels of amyloid in the brain,” he adds, and those would have to come from an expensive PET scan or a painful cerebrospinal fluid test. “It is not stated on the label, but I think that is mandatory for this drug, based on its mechanism of action.”
Even though Aduhelm seemed to lower amyloid-β plaques within the first 6 months of treatment, it took longer for tests to reveal cognitive benefits. In Biogen’s positive trial, it took 18 months before a statistically significant difference appeared between the cognitive decline of people who got the drug and those who got a placebo. At that time, the memory and function of people who got Aduhelm was declining about 22% more slowly than those who got a placebo.
Aduhelm’s FDA approval carried an asterisk that Biogen must conduct an additional clinical trial to confirm that it actually slows cognitive decline. Holtzman says that if Biogen can replicate or exceed that 22% slowing of decline in another clinical study, he thinks the approval is warranted. “But it is really right on the border of what you’d want. Anything less than that is pretty marginal,” he says.
Biogen has not announced any details about how it will run that study or when it will start. The FDA has given the company until 2030 to submit the data.
Many scientists say they wish the agency had required that Biogen conduct a confirmatory study before it granted the approval. When the FDA’s advisory committee for neurological drugs met in November 2020 to discuss the Aduhelm data, 10 of the 11 members said Biogen’s single positive study did not provide evidence of aducanumab’s effectiveness. The 11th member voted “uncertain”. Although the panel’s vote isn’t legally binding, scientists were shocked that FDA officials would buck an effectively unanimous recommendation. “I am very surprised that they went against such consistent feedback,” Mormino says.
After Aduhelm’s approval, two scientists resigned from the advisory committee in protest: Joel Perlmutter from Washington University in St. Louis and Mayo’s Knopman, who had recused himself from the panel during the review of aducanumab since he was an investigator in one of the trials. “I don’t wish to be in a position in the future where my role on the advisory committee is treated with such disdain and disrespect that the FDA showed this committee,” he tells C&EN.
In addition to having questionable benefit, the drug is not always safe. Some 41% of people treated with Aduhelm, compared with 10% of those who got a placebo, had a potentially troubling brain scan that neuroscientists call an amyloid-related imaging abnormality (ARIA).
For the most part, ARIA “is relatively benign, and it goes away when you stop or reduce the drug,” Burns says. But it can indicate problems such as brain bleeding and swelling, he adds. About a quarter of people who got Aduhelm and had ARIA developed side effects including confusion, dizziness, headaches, and nausea, and some had severe side effects that included microhemorrhages in the brain.
The FDA requires doctors to check for ARIA with a magnetic resonance imaging (MRI) scan before treating a person with Aduhelm and twice during the first year of treatment.
Biogen estimates that 1–2 million people in the US with mild cognitive impairment or mild dementia would have amyloid-β pathology if they were tested. At an average list price of $56,000 a year, Aduhelm could be a financial windfall for the company even if only a fraction of potential patients are prescribed the drug. Biogen will share profits with the Japanese drugmaker Eisai, which has helped develop the drug since 2017. Neurimmune, a small Swiss biotech firm from which Biogen licensed aducanumab in 2007, will get a $100 million milestone payment for Aduhelm’s approval, plus royalties on sales.
Scientists disagree on whether the approval will spur innovation of better Alzheimer’s therapies or simply lead to a series of marginally effective, or ineffective, amyloid-β-lowering drugs. But researchers largely agree that the approval will have historic repercussions. “For better or worse, it is very exciting that something like this has made it to this point,” Mormino says. “It is a field-changing moment, and we have entered uncharted territory.”
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