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
AHFS/Drugs.comMonograph
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][3] 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.[4] In 2021 Europe voted against approval.[5] In the United States it costs about 56,000 USD per year as of 2021; though in December of that year they decreased the price to 28,200 USD.[5][6] 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.[7]

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][8]

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.[9][10]

Interim results from the second Phase I study of the drug were reported in March 2015.[11]

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.[12] 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.[13][14] Phase III trials followed the conclusion of Phase I studies. Phase III clinical trials were ongoing in September 2016,[12] but were canceled in March 2019 after "an independent group's analysis show[ed] that the trials were unlikely to 'meet their primary endpoint.'"[15]

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.[16][17][18]

On 22 October 2019, Biogen announced that it would be restarting the FDA approval process for aducanumab stating that analysis of a larger dataset[19][20][21] claimed that the drug reduced clinical decline in patients with early Alzheimer's disease when given at higher doses.[22] 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.[23][24][25] The FDA accepted Biogen's aducanumab Biologics License Application (BLA) on 7 August 2020 with a Priority Review.[26]

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.[27][28]

Aducanumab was approved for medical use in the United States on 7 June 2021.[2][8][4] 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.[27][29][28][30][31] 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.[32][28]

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.[33][29][34][35] 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.[33][29][34][36][37] Kesselheim said that the FDA move was "probably the worst drug approval decision in recent U.S. history".[34][38]

Public Citizen[39] and the Institute for Clinical and Economic Review criticized the approval.[40]

Senator Joe Manchin heavily criticized the decision and said that the acting director of the FDA, Janet Woodcock, "should be quickly replaced."[41] 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."[42]

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".[43][44]

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.[43][7] 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".[45]

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.[31] Advocacy groups such as Alzheimer's Association,[46] Alzheimer Society of Canada,[47] and Alzheimer's Foundation of America[48] 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.[49][50] 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."[51][52] For patients with applicable health insurance and/or Medicare, the drug is a Tier 5 Specialty drug[53][54] and the copayment for such therapy would be about $11,500 annually.[55][34] 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,[56][57] and as of 2018, can cost $2,250 – $10,700.[58] 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.[52][49]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 "Aduhelm- aducanumab injection, solution". DailyMed. Archived from the original on 14 June 2021. Retrieved 14 June 2021.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "FDA Grants Accelerated Approval for Alzheimer's Drug". U.S. Food and Drug Administration (FDA) (Press release). 7 June 2021. Archived from the original on 8 June 2021. Retrieved 7 June 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ↑ "Aducanumab Monograph for Professionals". Drugs.com. Retrieved 27 October 2022.
  4. ↑ 4.0 4.1 "Drug Approval Package: Aduhelm (aducanumab-avwa)". U.S. Food and Drug Administration (FDA). 22 June 2021. Archived from the original on 2 September 2021. Retrieved 1 September 2021.
  5. ↑ 5.0 5.1 "Aducanumab". SPS - Specialist Pharmacy Service. 1 January 2016. Archived from the original on 19 November 2021. Retrieved 19 November 2021.
  6. ↑ Khandekar, Amruta (20 December 2021). "Biogen halves price of Alzheimer's drug to $28,200". Reuters. Archived from the original on 20 December 2021. Retrieved 20 December 2021.
  7. ↑ 7.0 7.1 Gumbrecht J (9 July 2021). "Acting FDA commissioner calls for independent investigation into approval of Alzheimer's drug". CNN. Archived from the original on 13 August 2021. Retrieved 1 September 2021.
  8. ↑ 8.0 8.1 "FDA's Decision to Approve New Treatment for Alzheimer's Disease". U.S. Food and Drug Administration (FDA). 7 June 2021. Archived from the original on 8 June 2021. Retrieved 7 June 2021.
  9. ↑ Zacks R (20 November 2007). "Biogen Inks $380 Million Deal with Swiss Company". Xconomy. Archived from the original on 30 October 2019. Retrieved 19 November 2021.
  10. ↑ "Approval for New Alzheimer's Drug Developed at UZH". University of Zurich. 7 June 2021. Archived from the original on 17 November 2021. Retrieved 16 November 2021.
  11. ↑ Sevigny J, Chiao P, Williams L, Chen T, Ling Y, O'Gorman J, Hock C, Nitsch RM, Sandrock A (July 2015). "O4-04-05: Aducanumab (BIIB037), an anti-amyloid beta monoclonal antibody, in patients with prodromal or mild Alzheimer's disease: Interim results of a randomized, double-blind, placebo-controlled, phase 1b study". Alzheimer's & Dementia. 11 (7S_Part_6): P277. doi:10.1016/j.jalz.2015.07.367. S2CID 54339030.
  12. ↑ 12.0 12.1 Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. (September 2016). "The antibody aducanumab reduces Aβ plaques in Alzheimer's disease". Nature. 537 (7618): 50–6. Bibcode:2016Natur.537...50S. doi:10.1038/nature19323. PMID 27582220. S2CID 205250312.
  13. ↑ Karlawish J (30 May 2021). "If the FDA approves Biogen's Alzheimer's treatment, I won't prescribe it". STAT. Archived from the original on 7 June 2021. Retrieved 7 June 2021.
  14. ↑ Belluck P, Robbins R (5 June 2021). "Alzheimer's Drug Poses a Dilemma for the F.D.A." The New York Times. Archived from the original on 19 November 2021. Retrieved 7 June 2021.
  15. ↑ Li Y (21 March 2019). "Biogen shares plunge nearly 30% after ending trial for Alzheimer's drug Aducanumab". CNBC. Archived from the original on 7 June 2021. Retrieved 19 November 2021.
  16. ↑ Ducharme J (21 March 2019). "Biogen Halts Promising Alzheimer's Drug Trials Due to Disappointing Results". Time. Archived from the original on 2 June 2019. Retrieved 21 March 2019.
  17. ↑ Li Y (21 March 2019). "Biogen posts its the worst day in 14 years after ending trial for blockbuster Alzheimer's drug". CNBC. Archived from the original on 7 June 2021. Retrieved 19 November 2021.
  18. ↑ Annett T. "Biogen Plunges More Than 25 Percent on Alzheimer's Setback". Bloomberg News. Archived from the original on 8 June 2021. Retrieved 19 November 2021.
  19. ↑ Roberts M (22 October 2019). "First drug to slow Alzheimer's may be available soon". BBC News. Archived from the original on 5 December 2019. Retrieved 22 October 2019.
  20. ↑ Foster L (26 October 2019). "Drug 'could be biggest Alzheimer's development'". BBC News. Archived from the original on 19 December 2019. Retrieved 26 October 2019.
  21. ↑ Kunkle F (6 December 2019). "Biogen's potential new drug for Alzheimer's disease gets cautiously optimistic review following presentation". The Washington Post. Archived from the original on 2 January 2020. Retrieved 19 November 2021.
  22. ↑ Howard J, Gumbrecht J (23 October 2019). "Drugmaker to seek approval for Alzheimer's treatment". CNN. Archived from the original on 24 August 2021. Retrieved 23 October 2019.
  23. ↑ McNamara D (28 May 2020). "Mixed Results for Aducanumab in Two Phase 3 AD Trials". Medscape. Archived from the original on 8 June 2021. Retrieved 19 November 2021.
  24. ↑ Herper M (22 October 2019). "In shocking reversal, Biogen to submit Alzheimer's drug for approval". STAT. Archived from the original on 26 May 2021. Retrieved 22 October 2019. In one study, called Emerge, patients on the high-dose aducanumab had a 23% reduction in their rate of decline compared to those on placebo; those who were on the low dose were 11% lower than placebo, but that result was not statistically significant. But in the second trial, Engage, the decrease was only 2% in patients on the high dose.
  25. ↑ "Biogen Plans Regulatory Filing for Aducanumab in Alzheimer's Disease Based on New Analysis of Larger Dataset from Phase 3 Studies". Biogen. 22 October 2019. Archived from the original on 29 May 2020. Retrieved 22 October 2019.
  26. ↑ "FDA Accepts BLA for Biogen's Alzheimer's Drug, Grants Priority Review". BioSpace. 7 August 2020. Archived from the original on 2 September 2021. Retrieved 1 September 2021.
  27. ↑ 27.0 27.1 Marchione M, Perrone M (6 November 2020). "FDA panel urges rejection of experimental Alzheimer's drug". Associated Press. Archived from the original on 17 November 2021. Retrieved 19 November 2021.
  28. ↑ 28.0 28.1 28.2 McGinley L (22 June 2021). "FDA releases fresh details on internal debate over controversial Alzheimer's drug". The Washington Post. Archived from the original on 19 November 2021. Retrieved 19 November 2021.
  29. ↑ 29.0 29.1 29.2 Ault A (5 May 2021). "FDA Reviewers: Why We Are Against Approval of Aducanumab for Alzheimer's". Medscape Medical News. Archived from the original on 10 June 2021. Retrieved 9 June 2021.
  30. ↑ "US approves first new Alzheimer's drug in 20 years". BBC News Online. 7 June 2021. Archived from the original on 30 September 2021. Retrieved 19 November 2021.
  31. ↑ 31.0 31.1 Belluck P, Robbins R (7 June 2021). "F.D.A. Approves Alzheimer's Drug Despite Fierce Debate Over Whether It Works". The New York Times. Archived from the original on 14 November 2021. Retrieved 19 November 2021.
  32. ↑ McGinley L (17 June 2021). "Furor rages over FDA approval of controversial Alzheimer's drug". The Washington Post. Archived from the original on 19 November 2021. Retrieved 19 June 2021.
  33. ↑ 33.0 33.1 "Third member of FDA expert committee resigns over Alzheimer's decision". STAT. 10 June 2021. Archived from the original on 2 September 2021. Retrieved 1 September 2021.
  34. ↑ 34.0 34.1 34.2 34.3 "3 Experts Have Resigned From An FDA Committee Over Alzheimer's Drug Approval". NPR. 11 June 2021. Archived from the original on 11 June 2021. Retrieved 11 June 2021.
  35. ↑ Belluck P, Robbins R (10 June 2021). "Three F.D.A. Advisers Resign Over Agency's Approval of Alzheimer's Drug". The New York Times. Archived from the original on 14 November 2021. Retrieved 19 November 2021.
  36. ↑ McGinley L (9 June 2021). "Two members of an FDA advisory committee quit after approval of controversial Alzheimer's drug". The Washington Post. Archived from the original on 10 June 2021. Retrieved 9 June 2021.
  37. ↑ Langreth R (10 June 2021). "Harvard Expert Quits FDA Panel as Furor Over Biogen Drug Grows". Bloomberg. Archived from the original on 10 June 2021. Retrieved 10 June 2021.
  38. ↑ "Harvard Expert Quits FDA Panel as Biogen Drug Furor Grows". Bloomberg. 10 June 2021. Archived from the original on 10 June 2021. Retrieved 1 September 2021.
  39. ↑ "Statement: FDA's Decision to Approve Aducanumab for Alzheimer's Disease Shows Reckless Disregard for Science, Severely Damages Agency's Credibility". Public Citizen. 7 June 2021. Archived from the original on 11 June 2021. Retrieved 11 June 2021.
  40. ↑ "ICER Issues Statement on the FDA's Approval of Aducanumab for Alzheimer's Disease". ICER. Archived from the original on 11 June 2021. Retrieved 11 June 2021.
  41. ↑ Edney A (17 June 2021). "Key Democrat Manchin Bashes FDA Leader on Alzheimer's Approval". Bloomberg News. Archived from the original on 2 July 2021. Retrieved 19 November 2021.
  42. ↑ Belluck P, Kaplan S, Robbins R (20 July 2021). "How Aduhelm, an Unproven Alzheimer's Drug, Got Approved". New York Times. Archived from the original on 4 August 2021. Retrieved 5 August 2021.
  43. ↑ 43.0 43.1 Rosenbaum L (9 July 2021). "FDA Commissioner Calls For Inspector General Probe Into Biogen Alzheimer's Drug Approval". Forbes. Archived from the original on 19 November 2021. Retrieved 1 September 2021.
  44. ↑ Feuerstein A, Herper M, Garde D (29 June 2021). "How Biogen used an FDA back channel to win Alzheimer's drug approval". STAT. Archived from the original on 2 September 2021. Retrieved 1 September 2021.
  45. ↑ Jason M (4 August 2021). "HHS extends Aduhelm investigation into the accelerated approval pathway, wading into a brewing controversy". Endpoints News. Archived from the original on 2 September 2021. Retrieved 1 September 2021.
  46. ↑ "It's a New Day in the Fight Against Alzheimer's — Aducanumab Approved". Alzheimer's Association. Archived from the original on 10 June 2021. Retrieved 11 June 2021.
  47. ↑ "First new treatment for Alzheimer's disease approved in nearly two decades offers hope for people living with dementia". Alzheimer Society of Canada. 7 June 2021. Archived from the original on 10 June 2021. Retrieved 11 June 2021.
  48. ↑ "Alzheimer's Foundation of America Statement on FDA Approving First New Alzheimer's Medication in Nearly 20 Years". Alzheimer's Foundation of America. Archived from the original on 11 June 2021. Retrieved 11 June 2021.
  49. ↑ 49.0 49.1 Cunningham PW (16 June 2021). "The Health 202: The pricey new Alzheimer's drug adds to the pressure for drug price controls". Archived from the original on 19 November 2021. Retrieved 1 September 2021.
  50. ↑ "Biogen CEO: committed to gathering new data on FDA-approved Alzheimer's drug". Archived from the original on 7 June 2021. Retrieved 19 November 2021.
  51. ↑ "FDA's Approval of Biogen's New Alzheimer's Drug Has Huge Cost Implications for Medicare and Beneficiaries". Kaiser Family Foundation (KFF). 10 June 2021. Archived from the original on 1 September 2021. Retrieved 1 September 2021.
  52. ↑ 52.0 52.1 "Aduhelm may not cure Alzheimer's, but it might help fix drug prices". The Economist. 15 July 2021. ISSN 0013-0613. Archived from the original on 1 September 2021. Retrieved 20 July 2021.
  53. ↑ How do drug tiers work? Archived 15 June 2021 at the Wayback Machine. Blue Cross Blue Shield of Michigan. Retrieved 14 June 2021.
  54. ↑ What Medicare Part D drug plans cover Archived 19 November 2021 at the Wayback Machine. US Centers for Medicare & Medicaid Services. Retrieved 14 June 2021.
  55. ↑ "Medicare Copays For New Alzheimer's Drug Could Reach $11,500 Annually". NPR. Associated Press. 10 June 2021. Archived from the original on 10 June 2021. Retrieved 11 June 2021.
  56. ↑ National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N) Archived 28 June 2021 at the Wayback Machine. 27 September 2013. Centers for Medicare & Medicaid Services (CMS). Retrieved 19 June 2021.
  57. ↑ New Alzheimer's drug could be 'devastating' for Medicare Archived 27 June 2021 at the Wayback Machine 15 June 2021. Politico. Retrieved 19 June 2021.
  58. ↑ How much does a PET scan cost? Archived 24 June 2021 at the Wayback Machine. 31 July 2018. New Choice Health. Retrieved 19 June 2021

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