Approval of Aduhelm (aducanumab), what went wrong

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
Post Reply
User avatar
TheresaB
Mod
Mod
Posts: 1676
Joined: Wed Feb 03, 2016 9:46 am
Location: Front Range, CO

Approval of Aduhelm (aducanumab), what went wrong

Post by TheresaB »

This article published by STAT FDA, Biogen, and an Alzheimer’s drug approval: 8 key takeaways from congressional investigation is a summation of the congressional investigation.

The 8 major points from the article are:
  • 1. FDA officials failed to document communications with Biogen
    2. Internal clashes caused last-minute chaos at the FDA
    3. Collaboration between the FDA and Biogen was ‘atypical’
    4. Biogen was banking on a blockbuster
    5. The company was ‘pushing the limit’ on price
    6. Biogen knew Aduhelm would be a budget-breaker
    7. The FDA proposed allowing Aduhelm for all Alzheimer’s patients
    8. Biogen aimed to target communities of color with marketing, not clinical data
Congressional investigators sorted through more than 500,000 pages of documents from the Food and Drug Administration and Biogen to chronicle how a controversial Alzheimer’s disease drug was approved. The 45 pages with 122 footnotes of the congressional investigation can be read in its entirety here:
The High Price of Aduhelm’s Approval: An Investigation into FDA’s Atypical Review Process and Biogen’s Aggressive Launch Plans

From the conclusions paragraph
The findings in this report raise serious concerns about FDA’s lapses in protocol and
Biogen’s disregard of efficacy and access in the approval process for Aduhelm. The findings
also justify experts’ and stakeholders’ concerns about FDA’s accelerated approval of Aduhelm.
The criticism surrounding Aduhelm’s approval may have been avoided had FDA adhered to its
own guidance and internal practices. FDA must take swift action to ensure that its processes for
reviewing future Alzheimer’s disease treatments do not lead to the same doubts about the
integrity of FDA’s review.221 Biogen, which currently has another Alzheimer’s drug under
review by FDA, must provide more transparency into its pricing and analyses of clinical benefit
to ensure that new drugs are effective and available for those who need them
Recommendations from the congressional report:
  • 1. FDA Must Fully Implement Its Own Internal Review Recommendation and Ensure All Substantive Interactions with Drug Sponsors Are Properly Memorialized
    2. FDA Should Follow Through on Its Internal Review Recommendation and Establish a Protocol for Joint FDA-Drug Sponsor Briefing Documents for Advisory Committees.
    3. FDA Should Provide Updated Guidance for Industry Regarding Development and Review of New Alzheimer’s Drugs.
    4. Biogen and Other Drug Sponsors Should Communicate Safety and Efficacy Concerns to FDA
    5. Biogen and Other Drug Sponsors Should Consider Value and Patient Access When Setting Prices.
My editorial comment: So very sad.
-Theresa
ApoE 4/4
User avatar
TheresaB
Mod
Mod
Posts: 1676
Joined: Wed Feb 03, 2016 9:46 am
Location: Front Range, CO

Re: Approval of Aduhelm (aducanumab), what went wrong

Post by TheresaB »

ApoE4s are at greater risk for brain arterial disorders (for more info refer to the ApoE4.info wiki article ApoE ε4 and health conditions besides (or maybe contributing to) Alzheimer’s)

I’ve written here in these forums before that this susceptibility poses a greater risk for us ApoE4s with these -mab drugs (aducanumab/aduhelm, lecanemab/leqembi, donemab).

Recently, a paper published in Neurology on December 28, 2023 Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies adds to the pile of findings identifying a strong, significant link between apolipoprotein (APOE) carrier status and the risk of amyloid-related imaging abnormalities (ARIA).
Discussion: We identified a strong, genome-wide significant association between APOE and risk of ARIA. Future, larger studies may be better powered to detect associations beyond APOE. These findings indicate that APOE is the strongest genetic risk factor of ARIA incidence, with implications for patient management and risk-benefit treatment decisions.
A summation of that paper was covered by an article in Neurology live published on January 18, 2024: Phase 3 Trials of Aducanumab Highlight High Risk of Amyloid-Related Imaging Abnormalities in APOE Carriers

Quotes from that Neurology live article:
The sample observed had a mean age of 70.3 years, with all participants of European ancestry. When compared with ε3/ε3 homozygotes, results showed a dose-dependent association between APOE ε4/ε4 and ARIA. All told, participants homozygous for APOE ε4 exhibited 4.28 greater odds of experiencing AIRA-H, 4.58 greater odds of experiencing ARIA-H microhemorrhage, and 7.84 greater odds of experiencing ARIA-H superficial siderosis.
(bold font added for emphasis)
Continued stratification of the effect of APOE on the risk of ARIA showed that APOE ε4/ε4 genotypes were significantly associated with mild, moderate, and severe radiographic ARIA. The effect was stronger among ε4/ε4 homozygotes than ε3/ε4 heterozygotes and showed a larger effect in severe (ε4/ε4 OR, 7.04–24.64; P ≤ 2.38 × 10−6) vs mild (ε4/ε4 OR, 3.19–5.00; P ≤ 1.37 × 10−5) cases. Despite APOE being associated with both symptomatic and asymptomatic ARIA, no association was seen for APOE when comparing symptomatic vs asymptomatic cases (P >.05).
-Theresa
ApoE 4/4
User avatar
Tincup
Mod
Mod
Posts: 3592
Joined: Fri Aug 08, 2014 2:57 pm
Location: Front Range, CO

Re: Approval of Aduhelm (aducanumab), what went wrong

Post by Tincup »

TheresaB wrote: Mon Jan 22, 2024 8:05 am Quotes from that Neurology live article:
The sample observed had a mean age of 70.3 years, with all participants of European ancestry. When compared with ε3/ε3 homozygotes, results showed a dose-dependent association between APOE ε4/ε4 and ARIA. All told, participants homozygous for APOE ε4 exhibited 4.28 greater odds of experiencing AIRA-H, 4.58 greater odds of experiencing ARIA-H microhemorrhage, and 7.84 greater odds of experiencing ARIA-H superficial siderosis.
(bold font added for emphasis)
Continued stratification of the effect of APOE on the risk of ARIA showed that APOE ε4/ε4 genotypes were significantly associated with mild, moderate, and severe radiographic ARIA. The effect was stronger among ε4/ε4 homozygotes than ε3/ε4 heterozygotes and showed a larger effect in severe (ε4/ε4 OR, 7.04–24.64; P ≤ 2.38 × 10−6) vs mild (ε4/ε4 OR, 3.19–5.00; P ≤ 1.37 × 10−5) cases. Despite APOE being associated with both symptomatic and asymptomatic ARIA, no association was seen for APOE when comparing symptomatic vs asymptomatic cases (P >.05).
Theresa, thank you for pointing out the vastly increased risks of the -mab drugs for ApoE4 carriers. It is a good counterpoint to all of the "Celebration" posts here that neglect to point out these vastly increased risks for our main audience - ApoE4 carriers.
Tincup
E3,E4
User avatar
TheresaB
Mod
Mod
Posts: 1676
Joined: Wed Feb 03, 2016 9:46 am
Location: Front Range, CO

Re: Approval of Aduhelm (aducanumab), what went wrong

Post by TheresaB »

Just announced (1/31/2024) in this article: Biogen to cease production of controversial Alzheimer’s drug
Drugmaker Biogen will discontinue development and marketing for Aduhelm, a landmark Alzheimer’s disease treatment that also provoked controversy over conflicting data around its efficacy, the company said Wednesday.

The FDA granted accelerated approval to the drug, which targets amyloid plaques in the brain that are thought to contribute to the disease, in 2021. That endorsement was contingent upon Biogen completing a follow-up study confirming that the treatment’s benefits outweigh the risks.
While Aduhelm and Leqembi were applauded as breakthroughs in Alzheimer’s care, their clinical trials showed modest benefits for patients — along with potentially dangerous side effects like brain bleeding and swelling.

Medicare has limited coverage of Alzheimer’s drugs with accelerated approval to only patients participating in a randomized clinical trial, of which none were enrolling. Both Aduhelm and Leqembi have price tags exceeding $25,000 a year, making access challenging.

An FDA spokesperson said patients currently on Aduhelm can continue treatment until Nov. 1 and should discuss options with their providers.
-Theresa
ApoE 4/4
User avatar
TheresaB
Mod
Mod
Posts: 1676
Joined: Wed Feb 03, 2016 9:46 am
Location: Front Range, CO

Re: Approval of Aduhelm (aducanumab), what went wrong

Post by TheresaB »

A short recap on the controversial history of Aducanemab/Aduhelm.

Aducanemab/Aduhelm was the first of the two -mab (monoclonal antibody) drugs approved by the FDA (Lecanemab/Leqembi was the 2nd, the final determination on Donanemab is currently under consideration. Gantenerumab, Solanezumab and Crenezumab failed in clinical trials).

The FDA approved Aducanemab based on proxy, i.e. not that it is an anti-Alzheimer drug, rather because it is an anti-amyloid drug with the assumption that the amyloid hypothesis as the cause of Alzheimer’s is valid.

With Aducanemab, controversy began with two identical phase III studies, EMERGE and ENGAGE. The trials were terminated in March 2019 when a futility analysis determined aducanumab was unlikely to outperform placebo at completion. In October 2019, Biogen reversed its position, saying a review of previously unavailable data showed the drug reduced cognitive decline in EMERGE, but not in ENGAGE.

Aducanumab/aduhelm was approved by the FDA, despite its advisory committee soundly recommending disapproval in Nov 2020. The committee cited insufficient evidence that the drug actually slowed cognitive decline. Three committee members resigned in protest over that decision.

Then in 2022 there was a scathing Congressional investigation into the FDA’s approval process citing their conduct as "rife with irregularities" and that the agency's actions "raise serious concerns about FDA's lapses in protocol" in its "atypical collaboration" with the drug maker.

Additionally, there was the issue of cost, Aducanemab/aduhelm initially was priced at an exorbitant $56,000 annually. Medicare limited coverage. The drug maker eventually reduced the price to half, $28,000.

With respect to ApoE4, all "mabs" require monitoring for ARIA a risk that is higher for us ApoE4s. In December 2023, Neurology published a paper Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studiesciting: “We identified a strong, genome-wide significant association between APOE and risk of ARIA.” Participants homozygous for APOE ε4 exhibited 4.28 greater odds of experiencing AIRA-H, 4.58 greater odds of experiencing ARIA-H microhemorrhage, and 7.84 greater odds of experiencing ARIA-H superficial siderosis.

Then on Jan 31, 2024, the drug manufacturer, Biogen, announced it was discontinuing Aduhelm
-Theresa
ApoE 4/4
Indywoman
Contributor
Contributor
Posts: 62
Joined: Sat Mar 03, 2018 8:58 am
Location: Indianapolis

Re: Approval of Aduhelm (aducanumab), what went wrong

Post by Indywoman »

Thank you Theresa for all your hard work and research, and to everyone who delves deeper on these drugs, keeps abreast, and gives a variety of views on these drugs.

The problems seem to involve ARIA as one of the biggest concerns for anyone with one or two ApoE 4 genes, along with underlying problems with the whole FDA process of approval, cost of the drug, and efficacy for women compared with men. The question is also whether these drugs can meaningfully change the quality of life, with a change that would be clinically significant such that the person and family would see a benefit in day to day life.

I have many friends who know that I have two ApoE 4 genes, and say, "you must be so happy to know these drugs are out there and now available" I think when someone hears, "slow cognitive decline-even for four months" the person hears that it is making an improvement.

Yet, can the drug improve patients’ quality of life, and is slowing decline without a noticeable and clinically significant alteration of cognition--improvement? And, is it possible to keep buying this level of medical care?

Perhaps I feel calmer about all this because I have plans to end my life in Switzerland if I get Alzheimer's or any form of dementia, and have had many good talks with my doctors about this choice. So, I wonder how people define improvement (perhaps quantity of days) and I wonder who ultimately picks up the tab for these drugs?
4/4. Do something today that your future self will thank you for.
Post Reply