Donanemab and Lecanemab

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Cvd
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Donanemab and Lecanemab

Post by Cvd »

Hi all,

My loved one and I just went to her neurologist, and he said that lecanemab is available now and donanemab will likely be available by the end of this year/early 2024.

Lecanemab requires either a amyloid PET scan or spinal fluid for biomarkers. Donanemab requires consistent imaging, and right now it is not certain if Medicare will pay for constant PET scans.

Lecanemab is 2X a month for 18 months, Donanemab is based on amyloid threshold, so will likely be for less than a year with monthly infusions.

Both have less benefit for e4/e4, and donanemab has a slightly higher chance of ARIA than lecanemab.

Apologies for perhaps missing info on other threads, but does anyone think that one mab is preferable to the other for e4/e4? Has anyone had a positive/negative experience with either?

Thank you!
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Re: Donanemab and Lecanemab

Post by NF52 »

Cvd wrote: Wed Aug 09, 2023 2:51 pm Hi all,

My loved one and I just went to her neurologist, and he said that lecanemab is available now and donanemab will likely be available by the end of this year/early 2024.

Lecanemab requires either a amyloid PET scan or spinal fluid for biomarkers. Donanemab requires consistent imaging, and right now it is not certain if Medicare will pay for constant PET scans.

Lecanemab is 2X a month for 18 months, Donanemab is based on amyloid threshold, so will likely be for less than a year with monthly infusions.

Both have less benefit for e4/e4, and donanemab has a slightly higher chance of ARIA than lecanemab.

Apologies for perhaps missing info on other threads, but does anyone think that one mab is preferable to the other for e4/e4? Has anyone had a positive/negative experience with either?

Thank you!
Hi Cvd,

I remember your posts about your mother's participation in the ALZ-801 trial and your role as her study partner, I believe.
We do have several conversations that have been going on about lecanemab (Leqembi) and to a lesser extent, donanemab. As her neurologist said, the FDA approved Leqembi in early July for people with Mild Cognitive Impairment (MCI) and mild stage dementia. Here's a PDF published in March 2023 for the FDA review of: Lecanemab: Appropriate Use Recommendations. The FDA has its own guidance, which includes testing for ApoE 4, which you already know, and for personalized discussion about known risks, likelihood of side effects, the types of clinical benefit seen in the CLARITY trial of people with MCI/Mild AD and the individual medical, social, lifestyle and other factors that may make someone more or less able or willing to start this drug. [For example, the safety monitoring requires several MRIs in the first 6 months, and then occasional MRIs may be needed later, so someone who is claustrophobic may not be able to tolerate that.]

Donanemab recently reported results of a trial similar to CLARITY, although the participants had slightly different criteria (including tau and amyloid) and were given monthly doses, not biweekly as in lecanemab. One advantage of donanemab appears to be that most people were able to be removed from the drug within 12-24 months when blood tests combined with a PET scan showed their brain levels of amyloid plaque had dropped below 20 centiloids (considered "amyloid negative") and they seemed to both continue to show clinical benefit and continue to stay amyloid negative. Lecanemab kept people on for 18 months and also showed that almost all people went to "amyloid negative" status. Both drugs looked at from all participants showed a slower rate of decline in cognitive skills (memory, language, visual-spatial skills) of between 27-35% approximately compared the those on the placebo. Both drugs also showed a statistically significant slowing (or maintaining) of functional daily living skills of about 35-45%. People at the earlier stage of MCI appeared to have better results than people whose cognitive scores and functioning was close to the moderate Alzheimer's stage, presumably because other types of changes to brain neurons and vascular issues were accelerating changes.

Both drugs carry a risk of ARIA-E (Edema) and ARIA-H (micro-hemorrhage) as well as a small (about less than 1% it appears) risk of a larger macro-hemorrhage or severe brain bleed. People in the donanemab study with ApoE 4/4 had a 50% likelihood of edema, usually within the first 6 months and usually able to be managed by pausing doses and treating with oral or IV steroids. Lecanemab had a smaller rate of ARIA-E of about 39% in ApoE 4/4 carriers, I believe.


For an expert view of both drugs, by Dr. Jason Karlawish, Director of the University of Pennsylvania's Penn Memory Center and director of the Ethics Unit in the NIA-funded Alzheimer's Clinical Trial Consortium (ACTC) I recommend this upcoming webinar:
An Update on Anti-Amyloid Treatments for Alzheimer's Disease

Dr. Karlawish is often quoted in articles on safety, working with patients to support their values and preferences, and takes a nuanced view of how and when. to use these drugs.

Finally, FWIW, I am in the AHEAD study of lecanemab for people with elevated amyloid and normal cognition. Today I had my 49th infusion, came home and did some overdue weeding, called a long-distance friend, had a 90-minute Zoom call and sent some info to another friend. In other words, being in the study, in which I have had mild side effects, has not kept me from enjoying life. But I also went into it knowing that I was ready to take a risk for "time saved".

My very best wishes for you and your mother to get great support from her doctors as you decide on whether to use the drugs.

Nancy
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Re: Donanemab and Lecanemab

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Cvd wrote: Wed Aug 09, 2023 2:51 pm Hi all,

My loved one and I just went to her neurologist, and he said that lecanemab is available now and donanemab will likely be available by the end of this year/early 2024.

Lecanemab requires either a amyloid PET scan or spinal fluid for biomarkers. Donanemab requires consistent imaging, and right now it is not certain if Medicare will pay for constant PET scans.

Lecanemab is 2X a month for 18 months, Donanemab is based on amyloid threshold, so will likely be for less than a year with monthly infusions.

Both have less benefit for e4/e4, and donanemab has a slightly higher chance of ARIA than lecanemab.

Apologies for perhaps missing info on other threads, but does anyone think that one mab is preferable to the other for e4/e4? Has anyone had a positive/negative experience with either?

Thank you!
Both drugs have controversy, especially for 4/4s.

You’ve likely heard the issue of ARIA (amyloid related imaging abnormalities) with the -mab (monoclonal antibody) drugs (aducanumab/aduhelm, lecanemab/leqembi, donanemab). The lecanemab drugmaker itself determined that there is an elevated risk of side effects for people with one copy of the ApoE4 gene variant, and a more significant risk for people with two copies. (source: At AAIC, We Tracked Down Answers to Readers’ Alzheimer’s Drug Questions)

Why? Because APOE4s are more susceptible to brain arterial disorders such as cerebral atherosclerosis, small vessel disease, and cerebral amyloid angiopathy. All three disorders can lead to bleeding in the brain.

From this article Will unpredictable side effects dim the promise of new Alzheimer’s drugs? published by the highly respected publication Science.
The side effect—amyloid-related imaging abnormalities, or ARIA—remains mysterious. “We don’t really understand what it is, what causes it, and what we can do about it,” says neurologist R. Scott Turner, director of the Memory Disorders Program at Georgetown University.
and
These trials and others of similar antibodies have helped identify risk factors for ARIA, in particular having a gene variant, APOE4, that also heightens risk of Alzheimer’s. Anticoagulants that treat or prevent blood clots appear to increase ARIA risk as well.
and
Researchers are especially eager to help people with two copies of APOE4. They are at higher risk for ARIA but also develop Alzheimer’s at a younger age. Many doctors are unsure about prescribing the antibodies to these patients (lecanemab data suggest they may also benefit less than patients without APOE4), and the Department of Veterans Affairs has said it won’t typically cover antiamyloid treatment for them, but will consider requests for exceptions. But, “Just saying, ‘Oh, sorry,’” isn’t good enough, Wilcock says. “We need to figure this out so we can treat those people without the risk.”
So one needs to weigh the risks vs the benefits. For 4/4s, the lecanemab/leqembi manufacturer’s (Eisai) US chairman himself stated the clinical trial revealed no benefit for 4/4s. Specifically his quote, "For that small group of (APOE4) homozygous patients, when it comes to CDR-SB, (rate of decline on a clinical dementia scale) we don't see a signal favouring lecanemab" suggesting that the 4/4s given a placebo fared better.

There have been other inconsistencies with regard to results for lecanemab. It works better in those over 65, and better in men with no significant effect in women. It is only advised for those early in the disease process and there’s very little data on efficacy in minorities despite the fact they experience Alzheimer’s at a greater rate (blacks 2 times the rate of whites and Hispanics 1 ½ times more than whites). These minorities were screened out of clinical trials because they did not have enough amyloid to qualify. (source: Insight: Promising new Alzheimer's drugs may benefit whites more than Blacks). This suggests that Alzheimer’s Disease is driven by factors other than amyloid. Certainly there’s been a growing swell of scientific opinion that the amyloid hypothesis for Alzheimer’s disease is obsolete. Remember these are not anti-Alzheimer drugs, these are anti-amyloid drugs and they were approved based on proxy, that by removing the amyloid fibrils this aids issues of cognition decline.

Then there’s the issue of if it is even beneficial in real life. Ideally a drug should be approved for being both statistically significant and clinically significant. A drug can be statistically significant but not clinically significant and vice versa. Unfortunately, the FDA has come under criticism for this. (source: FDA increasingly approves drugs without conclusive proof they work . The result from the lecanemab trial indicated statistical significance, but, alas, another controversy of the drug is that it is said to be not clinically significant.
Satistically Significant
the numbers from a study are reliable
Clinically Significant
the change experienced during a study is meaningful to the patient or caregiver

I'm borrowing the below graphic from this piece, These New Alzheimer’s Drugs Are a Travesty (interesting read beyond the graphic). Look at the representation on the far left under “Measurement and Meaning” (you can click on the graphic to see it better). That small gap represents the 27% slower decline. Remember, there was no improvement in cognition during the 18 month clinical trial. Both the lecanemab group and the placebo group had decline in cognition, it was just the lecanemab group got worse a little slower, and even that is up to interpretation. The lecanemab group scored on average 1.21 on the clinical dementia scale and the placebo group scored 1.66, a 0.45 difference, less than half a point! But it sounds much better as a percentage: a 27% slower rate of decline. Percentages are often used to make results sound more impressive than they really are.
Lecanemab results graphic2.png
But just how precise is that 27%? It relies on how cognition was measured, which was subjective. For each category, patients are on a 5-point scale: 0 is normal, 0.5 is questionable dementia and 1, 2 and 3 are mild, moderate and severe stages of dementia, respectively. The rating method is “very subjective,” said Dr. Ronald Petersen, a neurologist at the Mayo Clinic in Rochester, Minnesota, because the scores are based on questions the researchers posed to patients. (source: 3 unanswered questions about the newly approved Alzheimer's drug Leqembi

And just how relevant is that 27%? Remember that number is from over 18 months of the clinical trial, the 27% does not extend over the many years of cognitive impairment and Alzheimer’s Disease.

So getting back to being clinically significant, referring again to the graphic, the middle section, "Findings and Interpretation", It can reasonably be argued that lecanemab is not clinically significant. No one improved, all worsend or were harmed and note the quote, "A 9% less decline is imperceptible."

So what about donanemab, your doctor is correct, it is likely to be approved soon. Results from the Phase 3 Trial of Donanemab were recently presented at the Alzheimer's Association International Conference (AAIC) in Amsterdam. The trial enrolled 1736 patients across eight countries, although more than 91% of the participants were white. They were randomized to get either the antibody or a placebo. Both groups got intravenous infusions every 4 weeks for 18 months. Only 1320 of the participants completed the trial, 622 of whom were on the treatment; dropouts were attributed to side effects, changes in caregiver circumstances, and other reasons. Results showed donanemab appears to come with higher risks than lecanemab. In the donanemab trial, almost 37% of people getting the antibody developed ARIA (amyloid-related imaging abnormalities). One-quarter of participants had brain swelling. Three people died from brain swelling or bleeding attributed to the treatment. (source: Alzheimer’s trial shows clear benefits and significant risks of Eli Lilly antibody)

So bottom line for me, these drugs may provide benefit to some, but it is clearly not for everyone. With the greater risk, an ApoE4 carrier should especially do a great deal of research before going forward. You may want to watch this Alzheimer International Society- webinar - FDA's Upcoming Controversial Full Approval of Lecanemab . It's just over an hour and a half long, but very interesting.

I am a 4/4 and I personally would want to have nothing to do with any of the -mab drugs (aducanumab/aduhelm, lecanemab/leqembi, donanemab). My siblings are currently suffering from dementia, and I would not want my loved ones to have anything to do with them either.
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Re: Donanemab and Lecanemab

Post by TheresaB »

Cvd wrote: Wed Aug 09, 2023 2:51 pm Donanemab requires consistent imaging, and right now it is not certain if Medicare will pay for constant PET scans.
A couple more references since I last replied here.

Dementia drug hailed for slowing down Alzheimer's by up to a THIRD may be unsafe for 9 out of 10 patients
The headline is misleading, lacenemab does not slow down Alzheimer’s by a third, it appeared to slow down the progression of mild cognitive impairment or early stage Alzheimer’s in an 18 month timespan. Nevertheless, from the article:
But research warns that there is no data to show the drug is safe for nine out of ten early-stage Alzheimer’s patients. This is because the drug has only been tested on patients who are otherwise healthy.
and
Patients hoping to participate in the lecanemab trial, carried out by Japanese drug firm Eisai, could not take part if they had conditions such as obesity, diabetes, heart problems or a history of cancer.
And despite participants being cleared with a clean bill of health, side effects were experienced by a significant percentage of the participants.
The article goes on to report that the Mayo Clinic found 92% of older adults with mild cognitive impairment or mild dementia have health problems that would have excluded them from the lecanemab trial.
Last quote
Dr Maria Vassilaki, epidemiologist at the Mayo Clinic and study author, said that more research was needed to examine the safety and efficacy of lecanemab before it could be offered to ‘less healthy populations.
I can't answer the donanemab question on paying for imaging, but with regard to lecanemab there's this article and quote:
Insurers view new Alzheimer’s drug as experimental, won’t cover treatment for some customers
Insurers selling coverage in North Carolina, Pennsylvania and New York, among other states, told The Associated Press they won’t cover Leqembi with insurance offered on the individual market and through employers because they still see the $26,000-a-year drug as experimental.
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Re: Donanemab and Lecanemab

Post by NF52 »

TheresaB wrote: Mon Aug 21, 2023 8:31 am
Cvd wrote: Wed Aug 09, 2023 2:51 pm
You both raise important questions and I hope providing some data from the recent AAIC presentation on donanemab and the November 2022 CTAD presentation on lecanemab, as well as a recent CMS (Medicare) notice will address some of them.

PET scans for lecanemab and donanemab are generally required twice: one before beginning the drug, to confirm amyloid beta plaques are at an elevated level in the brain and once to confirm that amyloid is removed, which may be 24 to 48 weeks for donamab (about 9 infusions, given monthly) or about 18 months for lecanemab, given biweekly for elevated amyloid. Recent clinical trials using a combined amyloid/tau blood test that showed 96% accuracy compared to PET scans may within a few years eliminate the need for PET scans.

CMS has proposed changing the current "one PET per patient" rule to provide Medicare coverage when indicated for use with an anti-amyloid therapy, explained here: Proposed Decision Memo: Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease

The Daily Mail statement that lecanemab
has only been tested on patients who are otherwise healthy.
is not accurate. I can't speak to the criteria for the lecanemab trial in Japan, but most patients in the US had one or more comorbidities and were on medications, as shown by these charts, both of which show treatment favoring use of lecanemab.
CDR-SB by medication types.png
Comorbidities in CLARITY.jpeg

Similarly, the statement that
the Mayo Clinic found 92% of older adults with mild cognitive impairment or mild dementia have health problems that would have excluded them from the lecanemab trial
is at best misleading. These were not patients seeking the drug; rather they are in a long-term study of aging in Olmstead County, Minnesota at an average age currently of 80, well above the typical age for diagnosis of elevated amyloid, especially in ApoE 4 carriers. Nor were the majority excluded for health problems: 56 people (24% of the initial group) were in the Moderate AD range (green below) while 48 were below the MCI criteria (blue below). This 44% of the group identified through their electronic records would have been appropriately deemed either too cognitively healthy or too advanced to benefit from a drug designed for the MCI/mild aF stage.
Twenty-one participants were excluded due to their BMI (less than 17, or 35 or greater), 48 due to a CDR global score other than 0.5 or 1.0;[/color] 46 did not meet the WMS-R Logical Memory II scores [score at least 1 SD below age-adjusted mean... In addition, eight people were excluded due to an MMSE score outside the bounds of 22-30, and an additional two were excluded with a CDR memory score < 0.5 (Figure 2).
Eligibility for Anti-Amyloid Treatment in a Population-Based Study of Cognitive Aging

While the phrase 'slowing of decline" is often cited, the data shows that many patients on donanemab, especially those with MCI and low to intermediate levels of tau, showed stable cognitive and functional skills over 18 months--which then continued as an extended benefit after donanemab was ended, which for many patients was by week 24, when they cleared amyloid. This is the goal of "disease modification": to change the future trajectory of the disease by focusing one key disease component, recognizing that there are many. "Meaningful change" has a specific definition in AD research and the chart below which seems to show step-wise progression below, is actually capturing differences at 6-month assessment intervals. These were shared at the AAIC conference by Dr. Liana Apostolova of Indiana University, who was not a study site doctor for donanemab:
Percent stable on CDR-SB in donanemab Phase 3.png
Meaningful within patient change on donanemab-2.png
The same PBS article that you quoted on a decision to not offer coverage by some plans in some states, also included this:
Their decision stands in contrast to Medicare, which will wind up covering most patients who take the drug...Prominent insurers that will cover the drug for commercial plans include Kaiser Permanente and Elevance Health, the largest provider of Blue Cross-Blue Shield plans in the United States... Because Medicare covers the drug, patients with privately run Medicare Advantage plans will receive coverage, said Juliette Cubanski, of the non-profit KFF, which researches health care issues.
The Penn Memory Center in PA plans to start a pilot of Leqembi this fall to carefully assess the patients for whom it is appropriate, and to require ApoE4 testing before use, with guidance on the risk of ARIA-E and ARIA-H in ApoE 4/4 carriers. More about their process and detailed info from Co-Directors Dr. Jason Karlawish and Dr, David Wolk on the two drugs can be seen here:An Update on Anti-Amyloid Treatments for Alzheimer's Disease

Taking lecanemab is not a decision which can, or should, be made quickly. The Lecanemab: Appropriate Use Recommendations and the CMS Medicare requirement for patients to be enrolled in a registry which will track outcomes in more diverse populations, both suggest to me that considerable thought and caution has gone into the eventual use of lecanemab and potentially donanemab for appropriate individuals with MCI or mild AD.
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Re: Donanemab and Lecanemab

Post by Cvd »

Thank you both for taking the time to link articles and resources. I have not had a chance to go through them all yet, but I will . We have decided, for now, to wait to see what happens with the donanemab approval and to revisit this in a few months.
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Re: Donanemab and Lecanemab

Post by broiler_x »

This was just published today.

https://pubmed.ncbi.nlm.nih.gov/37676096/

Lecanemab (Leqembi) is not the right drug for patients with Alzheimer's disease

"In this 18-month trial, lecanemab did not slow cognitive decline in women. This is especially significant because women have a twofold increased risk of AD compared to men"

"Lecanemab did not slow cognitive decline in APOE4 carriers; rather, it enhanced the decline in study participants with 2 APOE4 genes. "

"These negative results regarding lecanemab's therapeutic value make me wonder if the approval of lecanemab was the worst decision of the FDA up till now"

Clearly not a fan.
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Re: Donanemab and Lecanemab

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broiler_x wrote: Fri Sep 08, 2023 3:40 pm This was just published today.

https://pubmed.ncbi.nlm.nih.gov/37676096/

Lecanemab (Leqembi) is not the right drug for patients with Alzheimer's disease

"In this 18-month trial, lecanemab did not slow cognitive decline in women. This is especially significant because women have a twofold increased risk of AD compared to men"

"Lecanemab did not slow cognitive decline in APOE4 carriers; rather, it enhanced the decline in study participants with 2 APOE4 genes. "

"These negative results regarding lecanemab's therapeutic value make me wonder if the approval of lecanemab was the worst decision of the FDA up till now"

Clearly not a fan.
Clearly not. And yet when I went to the same Appendix Supplementary graphs, which were not "hidden in Figure S1B" as he claimed, but included along with extensive data on reduction in tau, and other protein markers of AD, in the January 2023 article by Dweck et al that Dr. Kurkinen says he reviews "in detail" :Lecanemab in Early Alzheimer’s Disease

So it is hard to know how he decided that the lecanemab didn't slow cognitive decline in women, especially because of. the charts from that Supplementary material shown below, all of which show that the 95% confidence interval of the mean of all results favors lecanemab in women--on cognitive and daily living skills.

In fact lecanemab did show slowing of cognitive decline and slowing of change in functional skills.

But Dr. Kirkunin has a literal investment in an alternate theory of "neurogenesis" of hippocampal neurons, using a drug called NA-831 developed by NeuroActiva the company he works for, which has so far conducted a Randomized Double-Blind Placebo-Controlled Phase 2A Clinical Trial of NA-831 in Patients with MCI and Mild and Moderate Alzheimer’s Disease on 32 patients with mild cognitive impairment and 24 patients with mild and moderate Alzheimer’s disease. As of May 2023, they sought out JP Morgan to seek acquisition by a larger Pharma company, apparently because they have not been able to get NIH or other funding for a larger trial of NA-831. https://www.biomedind.com/news-JPMorgan.html
.
Adjusted mean difference in ADCS-MCI-ADL vs placebo.png
Adjusted mean difference in ADCOS Lecanemab vs Placebo.png
Adjusted Mean Difference ADAS-COG14 lecanemab vs placebo.png
Adjusted Mean Difference ADAS-COG14 lecanemab vs placebo.png
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Re: Donanemab and Lecanemab

Post by J11 »

Yes, I was not all that impressed either with this newest article.
I wasn't able to make it through the abstract without arguing about several of the summary points -- actually all of the non-literal statements made.

Below is my color highlighting of the abstract. Anything in red are items that I feel approach being factually incorrect.

There is so much in red that I am not sure whether I want to even start analyzing everything.
On the first point about not slowing cognitive decline in women, the rebuttal is that the trial was not powered to do so. The Clarity trial was powered to show that it helped "Alzheimer's in general" across a wide range of cognitive abilities, comorbidities etc.. Saying that it did not work for women would seem not be corrected for multiple comparisons. One needs to be extremely careful about these bold claims of non-effectiveness when the standards to make claims of efficacy are so high. Of course, one of the reasons why treatment might have been less effective was that women tend to weigh less and Lecanemab was administered on a fixed mg/kg basis. the subQ dosing is going to use a fixed mg dose so in this treatment women might be expected to overperform men.

I think that I should post a true gratitude post to the main aducan thread. I think my gratitude to pharma for rescuing me from centuries of dominant Alzheimer's dementia has not been expressed with enough directness.
Basically, Thank you! Thank you! Thank you! Thank you! Thank you!
Thank you! Thank you! Thank you! Thank you! Thank you!!!!!
If you want more of the above, please await my stump speech on the aducan thread.




Abstract

On July 6, 2023, the U.S. Food and Drug Administration (FDA) approved lecanemab (Leqembi) for the treatment of Alzheimer's dementia (AD) patients. In 2 clinical trials, lecanemab reduced amyloid in the brain and slowed cognitive decline. Here, I review in detail the clinical trial by van Dyck et al. (2023) entitled "Lecanemab in early Alzheimer's disease", published in The New England Journal of Medicine on January 5, 2023. In this 18-month trial, lecanemab did not slow cognitive decline in women. This is especially significant because women have a twofold increased risk of AD compared to men, that is, there are 2 times more women than men living with AD. Lecanemab did not slow cognitive decline in APOE4 carriers; rather, it enhanced the decline in study participants with 2 APOE4 genes. This is bad news for AD patients, 60-75% of whom carry at least 1 APOE4 gene. These negative results regarding lecanemab's therapeutic value make me wonder if the approval of lecanemab was the worst decision of the FDA up till now, after the approval of aducanumab on June 7, 2021.

Keywords: APOE4; Alzheimer; clinical trial; immunotherapy; lecanemab.
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Re: Donanemab and Lecanemab

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NF52 wrote: Fri Sep 08, 2023 6:42 pm So it is hard to know how he decided that the lecanemab didn't slow cognitive decline in women, especially because of. the charts from that Supplementary material shown below, all of which show that the 95% confidence interval of the mean of all results favors lecanemab in women--on cognitive and daily living skills.
When I look at the charts you posted, the error bars for both homozygotes and women cross the 0 line (except for women in the first chart and it is hard to tell if it just touches 0 or crosses it). This means the result is not statistically significant.
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