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Francisco Lopera 1951-2024

Francisco Lopera (June 10, 1951 – September 10, 2024), a professor and neurologist at the University of Antioquia in Medellín, Colombia,  identified and studied the world’s largest extended family

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BIOGEN DUMPS ADUHELM

On June 7, 2021, the US Food and Drug Administration (FDA) approved aducanumab  (branded Aduhelm by Biogen), the first new drug in 18 years for the treatment of patients with Alzheimers disease (AD). On January 31, 2024, Biogen announced it would stop making Aduhelm and also stop a clinical trial, dubbed ENVISION, a confirmatory trial which` the FDA had ordered to find out whether Aduhelm could in fact slow the disease progression and cognitive decline in AD patients. In the words of Christopher Viehbacher, CEO of Biogen: “When searching for new medicines, one breakthrough can be the foundation that triggers future medicines to be developed. Aduhelm was that groundbreaking discovery that paved the way for a new class of drugs and reinvigorated investments in the field.What happened here, the topic of this news and views, provides an example of bad science, sloppy trials and misconduct of the FDA management and regulatory bodies, which became the subject of a Congressional investigation.

Aducanumab is an anti-Aβ monoclonal antibody, originally cloned by Neurimmune from the blood of an elderly cognitively intact individual, and licensed to Biogen for further development and one clinical trial that showed aducanumab reduced amyloid in the brain, as seen in amyloid PET scans, and slowed cognitive decline of AD patients.  At the time (2016) this made the headlines in newspapers and popular media, and the cover story in Nature.

 

The approval of aducanumab in 2021 was based on two identical clinical trials (sponsored by Biogen) on patients with mild to moderate AD, one showing aducanumab slowedcognitive decline, and one showing it did not. Remarkably, these studies and the results were not published in a peer-reviewed journal until 14 months after the FDAs decision to approve aducanumab. It is also peculiar that an article in the Boston Globe, 3 days after the approval, prominently featured a picture advertising Aduhelm (the brand name of aducanumab) packed in the box and ready to be shipped to 600 locations in the USA.

At the time,  the Aduhelm approval received considerable media attention, generated commentaries and fierce debate in medical journals, and resulted in two investigations at the Congress concerning the unusual business relations between Biogen and the FDA.

On November 6, 2020, 11 members of the advisory committee for the FDA voted 8 to 1 (2 undecided) that data from the positive study was not sufficient to show the drug works, and voted 10 to 0 (1 undecided) that the positive study should not be considered as the evidence for the drugs approval, because the negative study had shown no effect, and if anything, the drug had enhanced cognitive decline. Nevertheless, the FDA approved aducanumab for the treatment of AD patients based on the reduction of brain amyloid, and infamously concluded that the reduction in plaques is reasonably likely to result in clinical benefits.”  

In the spring 2021, several members of the advisory committee expressed their concern on aducanumab in writing. On March 30,  Alexander, Emerson, and Kesselheim published a commentary in JAMA on the contradictory results of the two identical trials on the efficacy of aducanumab in slowing cognitive decline. On April 7, Knopman, Jones, and Greicius published a paper in Alzheimers & Dementia demonstrating convincingly there was no evidence in the Biogen data to showbrain amyloid lowering slows cognitive decline. In contrast, on May 10, Cummings and colleagues wrote in Alzheimers Disease & Therapy: aducanumab achieves the stan- dard of meaningful efficacy with adequate safety in early ADand We support providing persons with AD . . .  a first-generation drug with aducanumabs risk- burden/benefit profile.

On June 10, 2021, Kesselheim (Harvard Medical School and Brigham and Womens Hospital) resigned from the FDA advisory committee he had been serving for six years, following the resignation of Perlmutter (Washington University School of Medicine) and Knopman (Mayo Clinic).

On June 16, 2021, Michael A. Carome, Director of the Public Citizen Health Research Group, sent a letter to Xavier Becerra, Secretary of the US Department of Health and Human Services (HHS) saying The FDAs decision to approve aducanumab for anyone with Alzheimers disease, regardless of severity, showed a stunning disregard for science, eviscerated the agencys standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.

Trivial as it may seem, the aducanumab trials were motivated by the amyloid hypothesis, which proposes AD begins in the brain with Aβ peptides accumulation, aggregation, and amyloid formation. For 30 years, the amyloid hypothesis has almost singularly misguided biomedical research, drug discovery, and clinical development in AD. The FDA approval of Aduhelm never was a proof of the validity of the amyloid hypothesis. In fact, the amyloid hypothesis is not a hypothesis at all, because, in spite of all the observations and facts against the hypothesis, it seems it cannot be proven wrong. The amyloid hypothesis is too good to be true.

By approving useless anti-amyloid therapies associated with significant and serious health risks, including brain bleeding and atrophy, it is clear the FDA does not promote, protect, and ensure the full enjoyment of human rights by persons with disabilitiesas articulated in the UNs Convention on the Rights of Persons with Disabilities (CRPD), May 3, 2008, in force in 186 nations.

Further reading

Perlmutter S (2021) FDAs green light, sciences red light. Science 372: 1371

Kurkinen M, Tran L (2021) Aduhelm: The best hope for Alzheimers patients or the worst decision the FDA ever made? J Alzheimers Dis 84, 969-971

Budd Haeberlein S, Aisen PS, Barkhof F, Chalkias S, Chen T, Cohen S, Dent G, Hansson O, Harrison K, von Hehn C, Iwatsubo T, Mallinckrodt C, Mummery CJ, Muralidharan KK, Nestorov I, Nisenbaum L, Rajagovindan R, Skordos L, Tian Y, van Dyck CH, Vellas B, Wu S, Zhu Y, Sandrock A (2022) Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. J Prev Alzheimers Dis 9:197-210.

Rebecca Robbins: Biogen Abandons Its Controversial Alzheimers Drug Aduhelm. The New York Times, January 31, 2024

Beth Mole: Biogen Dumps Dubious Alzheimers Drug After Profit-Killing FDA Scandal. Ars Technica 1/31/2024, 7:17 PM 

https://arstechnica.com/science/2024/01/biogen-dumps-dubious-alzheimers-drug-after-profit-killing-fda-scandal/

Lecanemab Receives Priority Review Status in Japan

January 29, 2023 18:30 ET | Source: Biogen Inc.

TOKYO and CAMBRIDGE, Mass., Jan. 29, 2023 (GLOBE NEWSWIRE) — Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) and Biogen Inc. (Nasdaq: BIIB, Corporate headquarters: Cambridge, Massachusetts, CEO: Christopher A. Viehbacher, “Biogen”) announced today that an application for manufacturing and marketing approval for lecanemab (generic name, U.S. brand name: LEQEMBI™), an anti-amyloid-β (Aβ) protofibril* antibody, in Japan has been designated for Priority Review by the Japanese Ministry of Health, Labour and Welfare (MHLW). Priority Review in Japan is granted to new medicines recognized as having high medical utility for serious diseases, and once designated for Priority Review, the target total review period is shortened.

In Japan, Eisai submitted the manufacturing and marketing approval for lecanemab to the Pharmaceuticals and Medical Devices Agency (PMDA) on January 16, 2023. This application is based on the results of the Phase III Clarity AD study and the Phase IIb clinical study (Study 201), which demonstrated that lecanemab treatment showed a reduction of clinical decline in early AD.

Lecanemab selectively binds and eliminates soluble, toxic Aβ aggregates (protofibrils) that are thought to contribute to the neurotoxicity in AD. As such, lecanemab may have the potential to have an effect on disease pathology and to slow down the progression of the disease. The Clarity AD study of lecanemab met its primary endpoint and all key secondary endpoints with highly statistically significant results. In November 2022, the results of the Clarity AD study were presented at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference and simultaneously published in the New England Journal of Medicine, a peer-reviewed medical journal.

In the U.S., lecanemab was granted accelerated approval as a treatment for AD by the U.S. Food and Drug Administration (FDA) on January 6, 2023. On the same day, Eisai submitted a Supplemental Biologics License Application (sBLA) to the FDA for approval under the traditional pathway. In Europe, Eisai submitted a marketing authorization application (MAA) to the European Medicines Agency (EMA) on January 9, 2023 and accepted on January 26, 2023. In China, Eisai initiated submission of data for a BLA to the National Medical Products Administration (NMPA) in December 2022.

Eisai serves as the lead of lecanemab development and regulatory submissions globally with both Eisai and Biogen co-commercializing and co-promoting the product and Eisai having final decision-making authority.

* Protofibrils are large Aβ aggregated soluble species of 75-500 Kd. 1,2

Lecanemab Receives Priority Review Status in Japan
January 29, 2023 18:30 ET | Source: Biogen Inc. …

TOKYO and CAMBRIDGE, Mass., Jan. 29, 2023 (GLOBE NEWSWIRE) — Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) and Biogen Inc. (Nasdaq: BIIB, Corporate headquarters: Cambridge, Massachusetts, CEO: Christopher A. Viehbacher, “Biogen”) announced today that an application for manufacturing and marketing approval for lecanemab (generic name, U.S. brand name: LEQEMBI™), an anti-amyloid-β (Aβ) protofibril* antibody, in Japan has been designated for Priority Review by the Japanese Ministry of Health, Labour and Welfare (MHLW). Priority Review in Japan is granted to new medicines recognized as having high medical utility for serious diseases, and once designated for Priority Review, the target total review period is shortened.

In Japan, Eisai submitted the manufacturing and marketing approval for lecanemab to the Pharmaceuticals and Medical Devices Agency (PMDA) on January 16, 2023. This application is based on the results of the Phase III Clarity AD study and the Phase IIb clinical study (Study 201), which demonstrated that lecanemab treatment showed a reduction of clinical decline in early AD.
Lecanemab selectively binds and eliminates soluble, toxic Aβ aggregates (protofibrils) that are thought to contribute to the neurotoxicity in AD. As such, lecanemab may have the potential to have an effect on disease pathology and to slow down the progression of the disease. The Clarity AD study of lecanemab met its primary endpoint and all key secondary endpoints with highly statistically significant results. In November 2022, the results of the Clarity AD study were presented at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference and simultaneously published in the New England Journal of Medicine, a peer-reviewed medical journal.
In the U.S., lecanemab was granted accelerated approval as a treatment for AD by the U.S. Food and Drug Administration (FDA) on January 6, 2023. On the same day, Eisai submitted a Supplemental Biologics License Application (sBLA) to the FDA for approval under the traditional pathway. In Europe, Eisai submitted a marketing authorization application (MAA) to the European Medicines Agency (EMA) on January 9, 2023 and accepted on January 26, 2023. In China, Eisai initiated submission of data for a BLA to the National Medical Products Administration (NMPA) in December 2022.
Eisai serves as the lead of lecanemab development and regulatory submissions globally with both Eisai and Biogen co-commercializing and co-promoting the product and Eisai having final decision-making authority.
* Protofibrils are large Aβ aggregated soluble species of 75-500 Kd. 1,2

Contacts
MEDIA CONTACT:
Eisai Co., Ltd.
Public Relations Department
TEL: +81-(0)3-3817-5120

Eisai Inc. (U.S.)
Libby Holman
+ 1-201-753-1945
Libby_Holman@eisai.com

INVESTOR CONTACT:
Eisai Co., Ltd.
Investor Relations Department
TEL: +81-(0)03-3817-5122
MEDIA CONTACT:
Biogen Inc.
Natacha Gassenbach
+ 1-857-777-6573
public.affairs@biogen.com

INVESTOR CONTACT:
Biogen Inc.
Mike Hencke
+ 1-781-464-2442
IR@biogen.com

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