This year, Biogen is expected to submit a Biologics License Application to the FDA for its anti-amyloid antibody, aducanumab. If approved, it will be the first new drug available to patients with Alzheimer’s disease in 16 years.
Administered intravenously once a month, aducanumab clears some of the plaque materials that may cause cell death and tissue loss in the brain caused by Alzheimer's disease, according to Barry Reisberg, MD, one of the clinical investigators who developed the Alzheimer’s drug memantine, which was approved back in 2003.
Although it is not curative, aducanumab could be a valuable addition to the clinician’s armamentarium, according to Sharon A. Brangman, MD, chair of the geriatrics department and director of the Center for Excellence for Alzheimer’s Disease at Upstate Medical University in New York.
“Aducanumab is exciting in terms of adding more information to our knowledge of Alzheimer’s disease and maybe offering potential treatment, but it is not a cure,” she said.
Reference: The Alzheimer's Association.
The Alzheimer’s Association estimates that 5.8 million Americans live with Alzheimer’s, and the disease cost the country about $290 billion in 2019. Healio Primary Care discussed aducanumab with several experts to see where the drug fits in the treatment landscape and what its approval could mean for patients.
What is aducanumab?
The mechanism behind aducanumab, an anti-amyloid antibody, is different than donepezil, rivastigmine, memantine and galantamine — which are cholinesterase inhibitors or glutamate modulators and the three currently approved medications to treat patients with Alzheimer’s dementia.
Researchers have previously reported that aducanumab is a human monoclonal antibody that selectively binds to amyloid fibrils and soluble oligomers. Donepezil is a centrally acting, reversible, rapid inhibitor of acetyl cholinesteras that binds reversibly to acetylcholinesterase and impedes the hydrolysis of acetylcholine. Memantine is an antagonist of the N-Methyl-D-Aspartate subtype of glutamate receptors in the central nervous system, while donepezil. rivastigmine and galantamine are cholinesterase inhibitors and reversibly inhibit acetylcholine esterase and improve the intrinsic action of acetylcholine on cholinergic receptors.
According to Biogen, aducanumab was evaluated in two, phase 3 randomized controlled trials — EMERGE (n = 1,638) and ENGAGE (n = 1,647). Although the EMERGE trial met its primary endpoint showing a significant reduction in clinical decline, the trials were discontinued in March 2019 following the results of a futility analysis, which the company said “relied on an earlier and smaller data set.”
Biogen then conducted an additional analysis with a larger data set that yielded positive results.
“They found that there was a subgroup of patients who had mild cognitive impairment but did not meet the criteria for Alzheimer’s disease or any dementia who got higher doses, [and those patients] did have improvement in their cognition,” Brangman said. “Then, when Biogen did a PET scan, these patients did not have amyloid buildup. So, the thinking is that if you remove this amyloid, you may be treating their Alzheimer’s disease.”
The price of aducanumab could be a factor in whether or not patients request or adhere to the medication.
The authors of a recent Neurology study found that a $50 increase in out-of-pocket costs was associated with a 12-percent decrease in the time that a person had access to medication. For example, in 2015, when the cost of the drug donepezil was about $3 for a 30-day supply, patients filled those prescriptions about 70% of the time. Patients prescribed rivastigmine, which cost about $100 for a 30-day supply in 2015, filled their prescriptions about 45 percent of the time.
Biogen declined to answer questions about the price of the drug for this story.
Likelihood of approval
Reisberg, who is now director of the Fisher Alzheimer’s Disease Education and Resources Program at New York University’s Alzheimer’s Disease Center, said the FDA may approve aducanumab based on the current unmet need for effective therapies to mitigate the progression of Alzheimer’s disease.
He added that Biogen will submit its BLA based on the data it has, namely from the EMERGE trial and the secondary analysis of both studies.
“The secondary review is very much ex post facto reasoning, which the FDA does not like. The FDA wants pre-specified endpoints in each study,” he said. “But under the circumstances — the toll Alzheimer’s disease takes, the very limited symptomatic-only treatments currently available — there's a good chance that the FDA will approve aducanumab.”
Rebecca M. Edelmayer, PhD, the director of scientific engagement at the Alzheimer’s Association said that the organization “looks forward to the FDA’s rigorous review of aducanumab.” But she suggested that the drug is not a “one-size-fits-all treatment,” so even if Biogen does get clearance to market it, more Alzheimer’s drugs are needed.
“Therefore, we must continue to develop new ideas, test those ideas in large scale clinical trials to better understand whether or not they're going to be effective,” she said. – by Janel Miller
Alzheimer’s Association. 2019 Alzheimer’s facts and figures. https://www.alz.org/media/documents/alzheimers-facts-and-figures-2019-r.pdf. Accessed Feb. 12, 2020.
Alzheimer’s Association. Inside the brain. https://www.alz.org/alzheimers-dementia/what-is-alzheimers/brain_tour_part_2. Accessed Feb. 12, 2020.
Kumar A, Sharma S. StatPearls. Donepezil. Accessed Feb. 14, 2020.
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Disclosures: Brangman reports that her center is serving as a clinical trial site for the drugs gantererumab and troriluzole as well as the Long-term Nicotine Treatment in Mild Cognitive Impairment (MIND) study. Edelmeyer reports no relevant financial disclosures. Healio Primary Care could not confirm Reisberg’s relevant financial disclosures at time of publication.