Aducanumab
Aducanumab, sold under the brand name Aduhelm, is a medication designed to treat Alzheimer's disease (AD). It is an amyloid beta-directed monoclonal antibody that targets aggregated forms of amyloid beta (Aβ) found in the brains of people with Alzheimer's disease to reduce its buildup. It was developed by Biogen and Eisai. Aducanumab was approved for medical use in the United States by the Food and Drug Administration (FDA) in June 2021, in a controversial decision that led to the resignation of three advisers to the FDA in the absence of evidence that the drug is effective . The FDA stated that it represents a first-of-its-kind treatment approved for Alzheimer's disease and that it is the first new treatment approved for Alzheimer's since 2003. Aducanumab's approval is controversial due to ambiguous clinical trial results surrounding its efficacy. In November 2020, a panel of outside experts for the FDA concluded that a pivotal study of aducanumab failed to show "strong evidence" that the drug worked, citing questionable efficacy and multiple "red flags" found with the data analysis. Nevertheless, the drug was approved under the FDA's accelerated approval pathway, and the FDA requires  Biogen to perform a follow-up study to see if the drug helps treat symptoms of Alzheimer's. The Office of Inspector General, U.S. Department of Health and Human Services has been asked to investigate interaction between the drug company and the FDA prior to the drug's approval. Aducanumab has since been approved by the Ministry of Health and Prevention in the United Arab Emirates as of 3 October 2021, making it the second country in the world to approve the treatment. Medical uses. Aducanumab is indicated for the treatment of Alzheimer's disease. In July 2021, the U.S.  Food and Drug Administration (FDA) limited the indication to people with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. Adverse effects. Amyloid-related imaging abnormalities (ARIA) are monitored by magnetic resonance imaging of the brain one to two times per year. The most common serious adverse reactions reported are: History. Aducanumab was developed by Biogen Inc., which licensed the drug candidate from Neurimmune, who discovered it with the University of Zurich. Interim results from the second Phase I study of the drug were reported in March 2015. A Phase  Ib study was published in August 2016, based on one year of "monthly intravenous infusions" of aducanumab, with brain scans to measure amyloid plaques. Phase II trials were not required by the FDA and were not conducted by Biogen for aducanumab, a decision that received criticism from some experts. Phase III trials followed the conclusion of Phase I studies. Phase III clinical trials were ongoing in September 2016, but were canceled in March 2019 after "an independent group's analysis show[ed] that the trials were unlikely to 'meet their primary endpoint.'" Biogen halted development of the drug in March 2019 , after preliminary data from two phase III trials suggested it would not meet the primary endpoint. On 22 October 2019, Biogen announced that it would be restarting the FDA approval process for aducanumab stating that analysis of a larger dataset claimed that the drug reduced clinical decline in patients with early Alzheimer's disease when given at higher doses. In the first trial, "EMERGE",(NCT02484547), an analysis split by dose indicated that high doses reduced rate of decline by 23% versus placebo. A second identical trial, "ENGAGE", failed to replicate this, with a non-significant 2% reduction in decline compared to  placebo. The FDA accepted Biogen's aducanumab Biologics License Application (BLA) on 7 August 2020 with a Priority Review. In November 2020, a panel of outside experts on the FDA's Peripheral and Central Nervous System Advisory Committee concluded that a pivotal study of aducanumab failed to show "strong evidence" that the drug worked, along with potential safety issues, and suggested that the FDA not approve aducanumab, citing questionable efficacy and multiple "red flags" found with the data analysis. Aducanumab was approved for medical use in the United States on 7 June 2021. Aducanumab was rejected for medical use in  Europe on 17 December 2021 by the European Medicines Agency (EMA) but it will be left pending as Biogen will be allowed to ask for a re-examination. Society and culture. Controversy. The June 2021 approval of the drug by the U.S. Food and Drug Administration (FDA) is considered controversial because clinical trials gave conflicting results on its effectiveness. Specific criticisms of the approval included: insufficient evidence of efficacy, that the drug offers false hope, and that the high cost will adversely impact patient finances and Medicare budget. Ten of the eleven outside experts that had served on the FDA 's Peripheral and Central Nervous System Advisory Committee voted in November 2020 against approving aducanumab. Soon after the approval was announced in early June 2021, three of the panelists who had voted against aducanumab's approval—Joel S. Perlmutter, MD, David S. Knopman, MD, and Aaron Kesselheim, MD, JD, MPH—resigned in protest. Kesselheim said that the FDA move was "probably the worst drug approval decision in recent U.S. history". Public Citizen and the Institute for Clinical and Economic Review criticized the approval. Senator Joe Manchin heavily criticized the decision and said that the acting director of the FDA, Janet  Woodcock, "should be quickly replaced." According to "The New York Times", the review process for the drug "took several unusual turns, including a decision for the FDA to work far more closely with Biogen than is typical in a regulatory review." A 29 June 2021 "STAT" article reported that in the months prior to Aducanumab's FDA approval, FDA officials had met with "Biogen executives" using "back channels". On 9 July 2021, the FDA's Acting Commissioner, Janet Woodcock, requested that the Office of Inspector General, U.S. Department of Health and Human Services conduct an independent review of interactions between  FDA officials and Biogen representatives prior to the FDA's 27 June approval of aducanumab. It was reported in August that the OIG will also investigate the "accelerated approval pathway, the regulatory mechanism" the FDA used to approve Aducanumab in spite of "conflicting data over whether it could actually slow Alzheimer's patients' mental decline". Patient advocacy groups had lobbied heavily for the approval of the drug because of its novel status for a debilitating condition with very few therapy choices. Advocacy groups such as Alzheimer's Association, Alzheimer Society of Canada, and Alzheimer's Foundation of America were also  in favor of the decision. Economics and cost. Drug treatment is estimated to cost per year, and Biogen's CEO stated that they would maintain this price for at least four years. In their 10 June 2021 article, Kaiser Family Foundation (KFF) researchers said that a conservative estimate of the cost to Medicare would be $USD29 billion in one year. This is based on 500,000 Medicare patients potentially receiving Aduhelm. To put this in perspective—in 2019, "total Medicare spending for all doctor-administered drugs reached $37bn." For patients with applicable health insurance and/or Medicare, the drug is  a Tier 5 Specialty drug and the copayment for such therapy would be about $11,500 annually. An initial brain positron emission tomography (PET scan) is required to detect the presence of amyloid beta; since 2013, it has not been covered by Medicare, and as of 2018, can cost $2,250 – $10,700. A 15 July 2021 article in "The Economist" reported that the annual price of Aduhelm and the controversial 2021 FDA approval process resulted in the launch of an investigation by the United States House of Representatives, the Committee on Oversight and Reform, and the Committee on Energy  and Commerce, making Aduhelm the "poster-child" for the Elijah Cummings Lower Drug Costs Now Act (H.R.3) campaign. Sales. Sales of the drug have been far lower than analyst's predictions. As of September 2021, only about 100 patients had received the drug, far short of the 10,000 that would be needed by the end of 2021 to meet Wall Street expectations for Biogen's revenue.