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>>> Aducanumab


https://en.wikipedia.org/wiki/Aducanumab


Monoclonal antibody
Type Whole antibody
Source Human
Target Amyloid beta

Aducanumab, sold under the brand name Aduhelm, is a medication used to treat Alzheimer's disease (AD).[1][2] It is an amyloid beta-directed monoclonal antibody.[1][2]

Aducanumab targets aggregated forms of Amyloid beta (Aß) found in the brains of people with Alzheimer's disease to reduce its buildup.[3]

Aducanumab was approved for medical use in the United States in June 2021, and it represents a first-of-its-kind treatment approved for Alzheimer's disease.[1] It is the first new treatment approved for Alzheimer's since 2003, and is the first therapy that targets the fundamental pathophysiology of the disease.[1] Aducanumab's approval is controversial due to ambiguous clinical trial results surrounding its efficacy.[4] In November 2020, a panel of outside experts for the U.S. Food and Drug Administration (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.[5] 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.[1][6]


Contents
1 Medical uses
2 Adverse effects
3 History
4 Society and culture
4.1 Controversy
4.2 Economics and cost
5 Research
6 References
7 External links
Medical uses


Aducanumab is indicated for the treatment of Alzheimer's disease.[1][2]

Adverse effects

Amyloid-related imaging abnormalities (ARIA) are monitored by magnetic resonance imaging of the brain 1-2 times a year.

The most serious adverse reactions reported in at least 2% of patients:

ARIA-E Edema of brain (35%) - Symptoms may include headache, changes in mental state, confusion, vomiting, nausea, tremor and gait disturbances.[2]

Headache (21%)[2]

ARIA-H microHemorrhage or bleeding of brain (19%) - Symptoms can include headache, one-sided weakness, vomiting, seizures, decreased level of consciousness, and neck stiffness.[2]

ARIA-H superficial siderosis (Hemosiderin) (15%)[2]

Fall (15%)[2]

Diarrhea (9%)[2]

Confusion/Delirium/Altered Mental Status/Disorientation (8%)[2]

History

Aducanumab was developed by Biogen Inc., which licensed the drug candidate from Neurimmune, its discoverer.[7]

Interim results from the second Phase I study of the drug were reported in March 2015.[8][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 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] showed that the drug reduced clinical decline in patients with early Alzheimer's disease when given at higher doses.[20] In the first "EMERGE" trial (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]

Researchers evaluated the efficacy of aducanumab in three separate studies representing a total of 3,482 participants.[1] The studies consisted of double-blind, randomized, placebo-controlled dose-ranging studies in participants with Alzheimer's disease.[1] Participants receiving the treatment had significant dose-and time-dependent reduction of amyloid beta plaque, while participants in the control arm of the studies had no reduction of amyloid beta plaque.[1]

Aducanumab was approved for medical use in the United States in June 2021.[1][6]

Society and culture

Controversy

The approval of the medication is controversial. In November 2020, a panel of outside experts for the U.S. Food and Drug Administration (FDA) concluded that a pivotal study of aducanumab failed to show "strong evidence" that the drug worked and suggested that the FDA not approve aducanumab, citing questionable efficacy and multiple "red flags" found with the data analysis.[5][24][4]

The drug is considered controversial as clinical trials gave conflicting results on its effectiveness.[25][26] 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.[27][4] Three members of the FDA review panel — Aaron Kesselheim, David Knopman and Joel Perlmutter — resigned after FDA approval for the drug.[28][29][30][31] Public Citizen[32] and the Institute for Clinical and Economic Review criticized the approval.[33] Senator Joe Manchin heavily criticized the decision and called for the acting director of the FDA, Dr. Janet Woodcock, "should be quickly replaced."[34]

Patient advocacy groups lobbied heavily for the approval of the drug because of its novel status for a debilitating condition with very few therapy choices.[26] Advocacy groups such as Alzheimer's Association,[35] Alzheimer Society of Canada,[36] and Alzheimer's Foundation of America[37] were also in favor of the decision.

Economics and 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.[38] For patients with applicable health insurance and/or Medicare, the drug is a Tier 5 Specialty drug [39][40] and the copayment for such therapy would be about $11,500 annually.[41][30] An initial Brain positron emission tomography (PET scan) is required to detect the presence of amyloid beta; it is not currently covered by Medicare since 2013 [42][43] and can cost $2,250 – $10,700.[44]

Research
Aducanumab is a human IgG1 monoclonal antibody that primarily binds to Aß aggregates, soluble oligomers and also insoluble fibrils and has been studied for the treatment of Alzheimer's disease (AD).[8][45] However, it does not seem to target Aß monomers.[medical citation needed] Aducanumab analogue can cross the blood-brain barrier and engage its target efficiently, thus clearing amyloid beta toxicity.[medical citation needed] The effects can be monitored by positron emission tomography (PET).[45]

References
"FDA Grants Accelerated Approval for Alzheimer's Drug". U.S. Food and Drug Administration (FDA) (Press release). 7 June 2021. Retrieved 7 June 2021. This article incorporates text from this source, which is in the public domain.
"Aduhelm- aducanumab injection, solution". DailyMed. Retrieved 14 June 2021.
Toyn J (May 2015). "What lessons can be learned from failed Alzheimer's disease trials?". Expert Review of Clinical Pharmacology. 8 (3): 267–9. doi:10.1586/17512433.2015.1034690. PMID 25860157. S2CID 35158630.
McGinley L (22 June 2021). "FDA releases fresh details on internal debate over controversial Alzheimer's drug". The Washington Post.
Marchione M, Perrone M (6 November 2020). "FDA panel urges rejection of experimental Alzheimer's drug". Associated Press.
"FDA's Decision to Approve New Treatment for Alzheimer's Disease". U.S. Food and Drug Administration (FDA). 7 June 2021. Retrieved 7 June 2021.
Zacks R (20 November 2007). "Biogen Inks $380 Million Deal with Swiss Company". Xconomy.
Fox C (28 April 2015). "The Story of Biogen's Alzheimer's Drug, Aducanumab". Drug Discovery and Development. Archived from the original on 1 July 2015.
Herper M (20 March 2015). "Biogen Drug Could Inspire New Hope For Alzheimer's Treatments". Forbes.
Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. (September 2016). "The antibody aducanumab reduces Aß plaques in Alzheimer's disease". Nature. 537 (7618): 50–6. Bibcode:2016Natur.537...50S. doi:10.1038/nature19323. PMID 27582220. S2CID 205250312.
Karlawish J (30 May 2021). "If the FDA approves Biogen's Alzheimer's treatment, I won't prescribe it". STAT. Retrieved 7 June 2021.
Belluck P, Robbins R (5 June 2021). "Alzheimer's Drug Poses a Dilemma for the F.D.A." The New York Times. Retrieved 7 June 2021.
Li Y (21 March 2019). "Biogen shares plunge nearly 30% after ending trial for Alzheimer's drug Aducanumab". CNBC.
Ducharme J (21 March 2019). "Biogen Halts Promising Alzheimer's Drug Trials Due to Disappointing Results". Time. Retrieved 21 March 2019.
Li Y (21 March 2019). "Biogen posts its the worst day in 14 years after ending trial for blockbuster Alzheimer's drug". CNBC.
Annett T. "Biogen Plunges More Than 25 Percent on Alzheimer's Setback". Bloomberg News.
Roberts M (22 October 2019). "First drug to slow Alzheimer's may be available soon". BBC News. Retrieved 22 October 2019.
Foster L (26 October 2019). "Drug 'could be biggest Alzheimer's development'". BBC News. Retrieved 26 October 2019.
Kunkle F (6 December 2019). "Biogen's potential new drug for Alzheimer's disease gets cautiously optimistic review following presentation". The Washington Post.
Howard J, Gumbrecht J (23 October 2019). "Drugmaker to seek approval for Alzheimer's treatment". CNN. Retrieved 23 October 2019.
McNamara D (28 May 2020). "Mixed Results for Aducanumab in Two Phase 3 AD Trials". Medscape.
Herper M (22 October 2019). "In shocking reversal, Biogen to submit Alzheimer's drug for approval". STAT. 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.
"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. Retrieved 22 October 2019.
Ault A (5 May 2021). "FDA Reviewers: Why We Are Against Approval of Aducanumab for Alzheimer's". Medscape Medical News. Retrieved 9 June 2021.
"US approves first new Alzheimer's drug in 20 years". BBC News Online. 7 June 2021.
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.
McGinley L (17 June 2021). "Furor rages over FDA approval of controversial Alzheimer's drug". The Washington Post. Retrieved 19 June 2021.
McGinley L (9 June 2021). "Two members of an FDA advisory committee quit after approval of controversial Alzheimer's drug". The Washington Post. Retrieved 9 June 2021.
Langreth R (10 June 2021). "Harvard Expert Quits FDA Panel as Furor Over Biogen Drug Grows". Bloomberg. Retrieved 10 June 2021.
"3 Experts Have Resigned From An FDA Committee Over Alzheimer's Drug Approval". NPR. 11 June 2021. Retrieved 11 June 2021.
Belluck, Pam; Robbins, Rebecca (10 June 2021). "Three F.D.A. Advisers Resign Over Agency's Approval of Alzheimer's Drug". The New York Times. ISSN 0362-4331. Retrieved 14 June 2021.
"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. Retrieved 11 June 2021.
"ICER Issues Statement on the FDA's Approval of Aducanumab for Alzheimer's Disease". ICER. Retrieved 11 June 2021.
Edney, Anna (17 June 2021). "Key Democrat Manchin Bashes FDA Leader on Alzheimer's Approval". Bloomberg News.
"It's a New Day in the Fight Against Alzheimer's — Aducanumab Approved". Alzheimer's Association. Retrieved 11 June 2021.
"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. Retrieved 11 June 2021.
"Alzheimer's Foundation of America Statement on FDA Approving First New Alzheimer's Medication in Nearly 20 Years". Alzheimer's Foundation of America. Retrieved 11 June 2021.
"Biogen CEO: committed to gathering new data on FDA-approved Alzheimer's drug".
How do drug tiers work?. Blue Cross Blue Shield of Michigan. Retrieved 14 June 2021.
What Medicare Part D drug plans cover. US Centers for Medicare & Medicaid Services. Retrieved 14 June 2021.
"Medicare Copays For New Alzheimer's Drug Could Reach $11,500 Annually". NPR. Associated Press. 10 June 2021. Retrieved 11 June 2021.
National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N). September 27, 2013. Centers for Medicare & Medicaid Services (CMS). Retrieved 19 June 2021.
New Alzheimer's drug could be 'devastating' for Medicare 06/15/2021. Politico. Retrieved 19 June 2021.
How much does a PET scan cost?. 2018-07-31. New Choice Health. Retrieved 19 June 2021
Ghosh S, Durgvanshi S, Agarwal S, Raghunath M, Sinha JK (October 2020). "Current Status of Drug Targets and Emerging Therapeutic Strategies in the Management of Alzheimer's Disease". Curr Neuropharmacol. 18 (9): 883–903. doi:10.2174/1570159X18666200429011823. PMC 7569315. PMID 32348223.
External links
"Aducanumab". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02484547 for "221AD302 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease (EMERGE)" at ClinicalTrials.gov
Clinical trial number NCT02477800 for "221AD301 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease (ENGAGE)" at ClinicalTrials.gov
Clinical trial number NCT01677572 for "Multiple Dose Study of Aducanumab (BIIB037) (Recombinant, Fully Human Anti-Aß IgG1 mAb) in Participants With Prodromal or Mild Alzheimer's Disease (PRIME)" at ClinicalTrials.gov

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