Donanemab and Lecanemab

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
Indywoman
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Re: Donanemab and Lecanemab

Post by Indywoman »

As I headed to my pharmacy this morning, seeking something to supplement my antibiotic for a sinus infection, I entered the aisle with a bold sign that read “Cold and Severe Flu Remedies”.

I was stunned to see boxes and boxes of oral Sudafed along with liquid and tablet DayQuil lining the aisle underneath that sign. But, wait, hadn’t the FDA recently said the main ingredient-phenylephrine- in these items was ineffective and no better than a placebo, and this had been known for years? Why were these products still on the shelf?
This is an excellent article showing many issues with the FDA that are germane to our discussion of approval of drugs. https://medicine.yale.edu/news-article/ ... symptoms

This is the same FDA agency where 10 of the 11 advisory panelists to the FDA voted against approval of Aducanumab (Aduhelm) in 2020 (and 3 of the advisors resigned in 2021) but the FDA still approved it. The FDA’s solution for Lecanemab/Leqembi was simpler, cutting the advisory panel to 7, (one of whom recused himself for conflict of interest) and then approving it. https://www.fiercepharma.com/pharma/fda ... dy-shows

I know this is a Donanemab and Lecanemab thread. As a 4/4, I am among the many here who want solutions to dementia and feel the Cinderella clock ticking. Yet, to get there, I don’t want falsification of research (e.g.Marc Tessier-Lavigne, former president of Stanford, retracting his 2009 Alzheimer’s paper five days ago) or rushed conversations about the safety and efficacy of drugs. https://stanforddaily.com/2023/12/31/bl ... esistance/

And, increasingly the FDA seems less rigorous about efficacy, though mostly still careful about safety. https://www.fiercepharma.com/pharma/fda ... dy-shows

As people have said on this site, the past few years have been full of blockbuster steps in Alzheimer’s research. I wonder though, if this research needs to have longer time to see if the research is sound, longer time to be replicated, longer time to be thoroughly gone over by outside experts, more followup after studies. Journals and articles need to quit rushing to circulate ‘findings’ to the public, and do some serious fact checking.

People doing the research need to quit feeling like they have to produce certain outcomes in a short amount of time. And, in my view the government needs to fund alternative research that looks at other causes of Alzheimer’s whether that involves autoimmune causes, which can include amyloid, but ultimately broaden the lens beyond that Amyloid Hypothesis. As my neurologist says, "We just don't know what to target. It's that simple. We are behind cancer in research, but also Alzheimer's just seems to be more complex."

Lastly, I echo what Julie said. Kudos, kudos to those of you who are involved in the trials of these drugs or excited about trying them! None of this takes away from what you have believe or have chosen--- or feel strongly about. Your knowledge and vast assimilation of information equals that of any neurologist or Alzheimer's researcher in the best of labs. We hear the same information, but we come to different conclusions.
4/4. Do something today that your future self will thank you for.
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TheresaB
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Re: Donanemab and Lecanemab

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 before repeatedly 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
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TheresaB
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Re: Donanemab and Lecanemab

Post by TheresaB »

Just announced, the FDA is delaying its approval of Donanemab. Excerpt from the New York Times,
The Food and Drug Administration has decided to delay action on a closely watched Alzheimer’s drug, donanemab, which the agency was widely expected to approve this month. The F.D.A. will instead require donanemab to undergo the scrutiny of a panel of independent experts, the drug’s maker, Eli Lilly and Company, said Friday.
“The F.D.A. has informed Lilly it wants to further understand topics related to evaluating the safety and efficacy of donanemab, including the safety results in donanemab-treated patients and the efficacy implications of the unique trial design,” the company said in a statement.
For those who do not subscribe to the NY Times, here's an article from USAToday,
FDA delays action on promising Alzheimer's drug donanemab, drugmaker Eli Lilly says
-Theresa
ApoE 4/4
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Re: Donanemab and Lecanemab

Post by NF52 »

TheresaB wrote: Fri Mar 08, 2024 8:00 am Just announced, the FDA is delaying its approval of Donanemab. Excerpt from the New York Times,
The Food and Drug Administration has decided to delay action on a closely watched Alzheimer’s drug, donanemab, which the agency was widely expected to approve this month. The F.D.A. will instead require donanemab to undergo the scrutiny of a panel of independent experts, the drug’s maker, Eli Lilly and Company, said Friday.
“The F.D.A. has informed Lilly it wants to further understand topics related to evaluating the safety and efficacy of donanemab, including the safety results in donanemab-treated patients and the efficacy implications of the unique trial design,” the company said in a statement.
For those who do not subscribe to the NY Times, here's an article from USAToday,
FDA delays action on promising Alzheimer's drug donanemab, drugmaker Eli Lilly says
As noted in the NYT, this was a surprise announcement, but appears to focus on two issues that may help craft "Appropriate Use Recommendations":
Donanemab’s trial had two unusual aspects that the F.D.A. indicated it would ask the advisory committee to evaluate, said Dr. John Sims, a medical director with Lilly and the leader of the donanemab clinical trials.

One feature would be particularly appealing to patients: Participants in the trial stopped receiving donanemab after their amyloid plaques were cleared to a certain level — about a year for half the participants who started off with donanemab — and their cognitive decline kept slowing. Lilly scientists have estimated it would take nearly four years for amyloid levels to bump up over the threshold again.
Dr. Sims said he believed the F.D.A. wanted to understand more about stopping treatment because “it’s very unique” and regulators might want to explore whether other anti-amyloid drugs could be halted at a certain point.
...
The other unusual feature of the trial involved another protein, tau, which forms tangles in the brain after amyloid accumulates. Higher tau levels are more closely associated with memory and thinking problems.

The donanemab trial divided participants into groups with high tau levels and intermediate tau levels. People with intermediate tau levels had more slowing of cognitive decline — supporting a widespread theory that treating patients as early as possible in the disease process provides a better chance of slowing symptoms.
Dr. Sims said ...that the F.D.A. had not indicated “the specifics of what they want to talk about” involving tau, just that it was a subject the advisory committee would consider.
https://www.nytimes.com/2024/03/08/heal ... nemab.html From my admittedly outside perspective, but having listened to a number of presentations, here is my take on what may be issues the FDA would like guidance on:
  • Whether treatment can be started and stopped using one or more blood plasma tests instead of more costly and less accessible PET scans.
  • Whether those same blood tests should be used on a periodic basis after treatment is stopped to monitor levels of amyloid and/or tau for possible resumption of the drug, similar to monitoring PSA levels or biomarkers of coronary artery disease.
  • Whether people need to have both positive amyloid PET scan and a positive tau PET scan as was required for the Phase 3 trial, or could have a only positive Amyloid PET (i.e. elevated levels of amyloid plaques) or amyloid blood test, similar to Leqembi.
  • Whether people with Apoe 4/4 who have 2-4 pre-existing microhemorrhages on a screening MRI should be precluded from taking the drug, or have a "black box" warning. Donanemab had a high rate (about 82%) of ARIA-E (edema) for people with that profile, significantly higher, I believe, than lecanemab.
  • Whether those in the low-medium tau group, who showed a significantly higher likelihood of staying at the same level or even improving compared to placebo should be specifically defined as the population most likely to see significant clinical benefit, about 30-45% in memory and daily living skills).
I hope that this decision is seen as the FDA taking their responsibility seriously and giving this the time needed to arrive at a recommendation that can be viewed as credible.
4/4 and still an optimist!
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