Aducanumab

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Aducanumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetAmyloid beta
Names
Trade namesAduhelm
Other namesAducanumab-avwa, BIIB037, BIIB-037
Clinical data
Main usesAlzheimer's (AD)[1]
Side effectsBrain swelling, headache, bleeding in the brain, falls[1]
Routes of
use
Intravenous
External links
US NLMAducanumab
Legal
License data
Legal status
Pharmacokinetics
Elimination half-life24.8 days[1]
Chemical and physical data
FormulaC6472H10028N1740O2014S46
Molar mass145912.34 g·mol−1

Aducanumab, sold under the brand name Aduhelm, is a medication used to treat Alzheimer's disease (AD).[1] Benefits are unclear, with only decreased amyloid plaque shown in mild disease.[1] It is given by injection into a vein.[1]

Common side effects include brain swelling, headache, bleeding in the brain, and falls.[1] Other side effects may include angioedema.[1] It is a monoclonal antibody directed against amyloid beta (Aβ).[1]

Aducanumab was approved for medical use in the United States in 2021.[3] In 2021 Europe voted against approval.[4] In the United States it costs about 56,000 USD per year as of 2021.[4] The Office of Inspector General, U.S. Department of Health and Human Services has been asked to investigate interaction between the manufacturer and the FDA prior to its approval.[5]

Medical uses

Aducanumab is a drug can be used for a drug for a serious or life-threatening illness, such as Alzheimer's disease[2][1] to provide a meaningful therapeutic advantage over existing treatments. However, 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.[1]

Efficacy was studied in three trials representing a total of 3,482 patients. The studies consisted of double-blind, randomized, placebo-controlled dose-ranging studies in patients with Alzheimer’s disease. Patients receiving the treatment had significant dose-and time-dependent reduction of amyloid beta plaque, while patients in the control arm of the studies had no reduction of amyloid beta plaque. These results support the accelerated approval of Aduhelm, which is based on the surrogate endpoint of reduction of amyloid beta plaque in the brain—a hallmark of Alzheimer’s disease. Amyloid beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology.

The FDA has urged Biogen to perform additional follow-up studies measuring the drug's efficacy in treating symptoms of Alzheimer's.[2][6]

Dosage

It is given at a dose of 10 mg/kg every 4 weeks.[1]

Side 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:[1]

  • ARIA-E edema of brain (35% of patients treated with Aduhelm vs 3% of patients treated with placebo) – Symptoms may include headache, changes in mental state, confusion, vomiting, nausea, tremor and gait disturbances.[1]
  • Headache (21% vs 16%)[1]
  • ARIA-H microhemorrhage or bleeding of brain (19% vs 7%) – Symptoms can include headache, one-sided weakness, vomiting, seizures, decreased level of consciousness, and neck stiffness.[1]
  • ARIA-H superficial siderosis (hemosiderin) (15% vs 2%)[1]
  • Fall (15% vs 12%)[1]
  • Diarrhea (9% vs 7%)[1]
  • Confusion/delirium/altered mental status/disorientation (8% vs 4%)[1]

History

Aducanumab was developed by Biogen Inc., which licensed the drug candidate from Neurimmune, who developed it with the University of Zurich.[7][8]

Interim results from the second Phase I study of the drug were reported in March 2015.[9]

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.[10] 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.[11][12] Phase III trials followed the conclusion of Phase I studies. Phase III clinical trials were ongoing in September 2016,[10] but were canceled in March 2019 after "an independent group's analysis show[ed] that the trials were unlikely to 'meet their primary endpoint.'"[13]

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.[14][15][16]

On 22 October 2019, Biogen announced that it would be restarting the FDA approval process for aducanumab stating that analysis of a larger dataset[17][18][19] claimed that the drug reduced clinical decline in patients with early Alzheimer's disease when given at higher doses.[20] 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.[21][22][23] The FDA accepted Biogen's aducanumab Biologics License Application (BLA) on 7 August 2020 with a Priority Review.[24]

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.[25][26]

Aducanumab was approved for medical use in the United States on 7 June 2021.[2][6][3] 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.[2] It is the first therapy that targets the fundamental pathophysiology of the disease. The drug was approved under the FDA's accelerated approval pathway.

Aducanumab has since been approved by the Ministry of Health and Prevention in the United Arab Emirates as of October 3, 2021, making it the second country to approve.

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.[25][27][26][28][29] 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.[30][26]

Ten of the eleven outside experts that had served on the FDA's Peripheral and Central Nervous System Advisory Committee had voted on November 2020 against approving aducanumab.[31][27][32][33] Soon after the approval was announced in early June 2021, three of these 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.[31][27][32][34][35] Kesselheim said that the FDA move was "probably the worst drug approval decision in recent U.S. history".[32][36]

Public Citizen[37] and the Institute for Clinical and Economic Review criticized the approval.[38]

Senator Joe Manchin heavily criticized the decision and said that the acting director of the FDA, Janet Woodcock, "should be quickly replaced."[39] 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."[40]

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".[41][42]

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.[41][5] 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".[43]

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.[29] Advocacy groups such as Alzheimer's Association,[44] Alzheimer Society of Canada,[45] and Alzheimer's Foundation of America[46] were also in favor of the decision.

Cost

Drug treatment is estimated to cost US$56,000 per year, and Biogen's CEO stated that they would maintain this price for at least four years.[47][48] 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 receiving Aduhelm. To put this in perspective—in 2019, "total Medicare spending for all doctor-administered drugs reached $37bn."[49][50] For patients with applicable health insurance and/or Medicare, the drug is a Tier 5 Specialty drug[51][52] and the copayment for such therapy would be about $11,500 annually.[53][32] 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,[54][55] and as of 2018, can cost $2,250 – $10,700.[56] 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.[50][47]

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