ApoE4.Info

Editing my response, somehow I quoted NF52, but the quote was attributed to me. My representation for responding is different than usual, so either there's a ghost in my machine or there's something odd going on with our host software.

So to quote NF52
"The FDA has not yet ruled on the request for accelerated approval for lecanemab for MCI/early AD, so I think it's too early to say that it echoes the findings regarding the FDA approval of aducanumab."

The findings of the Congressional investigation determined that in the aducanumab process Biogen was not completely forthcoming with their information on safety issues. From the recommendations, "4. Biogen and Other Drug Sponsors Should Communicate Safety and Efficacy Concerns to FDA"

The article that I quoted questioned Eisai's communication on their safety risks. Requoting from the article quote above, "The change to the form also raises questions about how effectively Eisai and its clinical trial partners communicated updated warnings to trial participants and how transparent the company has been about the risks of its product, which the U.S. Food and Drug Administration (FDA) has said it could approve for sale by 6 January 2023." Of note Eisai's primary partner is Biogen.

Just because the drug hasn't been approved by the FDA doesn't mean Eisai hasn't been evasive with the FDA, a similar behavior exhibited by Biogen when trying to get Aducanumab approved. Certainly any obfuscation would come before the approval of the drug. Whether Eisai has been evasive or not, I have no first hand knowledge, but there certainly is motivation for Eisai not being completely forthcoming when communicating risks with the FDA since they anticipate their bottom line to benefit if the FDA approves their drug.

My motivation in sharing this was not to bash Eisai, but to emphasize that consideration for taking this drug should not be taken lightly by APOE4s, our primary audience, I should hope you would support that.

You said, we all make our own assessments. Precisely! I want any readers who are considering pursing a drug for cognitive decline, to be able to make informed decisions. Especially when there are options that go beyond slowing cognitive decline, which is all lecanemab does. Requoting what I quoted above for APOE4s, "In the completed core phase of the lecanemab trial, participants who carry at least one copy of the gene variant suffered a much higher rate of brain swelling and bleeding." Compare that to the Bredesen ReCODE protocol, which is benign when it comes to side effects and exhibited IMPROVED (not slowed) cognition in 84% of the clinical trial participants.

TheresaB wrote: ↑Mon Jan 02, 2023 1:32 pm...
My motivation in sharing this was not to bash Eisai, but to emphasize that consideration for taking this drug should not be taken lightly by APOE4s, our primary audience, I should hope you would support that. ...

Theresa, we are in agreement that those with ApoE4 should have the most current and accurate information about possible side effects and risks. My inclusion of consent wording and formatting, along with the process for distributing updated consents in a trial, was to provide information on the process to those who have not been through this experience and to show a typical example of what someone would receive.

None of my comments suggest a cavalier attitude towards those risks, especially since I have friends with ApoE 4 who have been enrolled in this or similar trials, and other friends who have decided against enrolling for a variety of valid reasons. Being in a clinical drug trial does not preclude someone from following the Bredesen protocol, as I know of people doing that also.

I fully agree with Dr. Karlawish's comment in the article that any approval of lecanemab should carry a black box warning for those taking anticoagulants, and should require both careful monitoring and reporting of events as well as requirements for providers to have experience in administering these drugs for the foreseeable future.

In addition to that strong support of a black box warning, I also support required disclosure of ApoE4 status. Everyone in the current lecanemab trials undergoes genetic testing, even if they know their ApoE4 status, and has a specific step in the screening process to give consent to have that status released to them. People have to know if they have a positive amyloid blood and/or PET scan, since it is a requirement to be in the trials. But they can elect not to be told their ApoE4 status. [Currently they are not told of the results of the tau PET, since interpretation of tau results is still at a fairly new stage.]

I look forward to learning more about the FDA approval process this month.
.

Thanks to Theresa and NF52 for this important discussion.

We all make our risk assessments of whether a <1% risk is acceptable in anything. The observed risk was 0.6% in those treated with lecanamb and 0.4% in the placebo arm of CLARITY before the OLE, so the provided estimated risk appears to be both accurate and transparent to AHEAD participants.

It's important to point out that that low risk is taking the entire dataset into account. When you tease out ApoE status, the risk is considerably higher for E4s. One researcher in the quoted article, said 50% of AD patients have CAA, and we know that percentage is even higher in those with E4, with homozygotes being at the highest risk. In terms of risk/benefit assessment, we also can't forget that to date lecanamb offers ZERO benefit to those with 4/4.

Doctors in areas distant from major medical centers will face formidable challenges diagnosing CAA in potential lecanemab recipients, he notes. The condition makes brain swelling and bleeding more likely in combination with antiamyloid drugs such as lecanemab...

This is exactly what we've been trying to pinpoint in our discussion. It's concerning to me that those in more remote locations apparently do not have access to the proper diagnostic MRIs for CAA prior to participation in the study. Please, be careful, friends.

While, study coordinators are acknowledging that the combination of CAA + lecanamab + blood thinners increases risk of a serious adverse event, the combo of CAA + lecanamb presents a similar risk. I'm on the frontlines of personally observing the damage that a CAA brain hemorrhage can do, and my mom is one of the "lucky" ones. Many do not survive.

Another thought, by focusing on just the deaths, we are missing those who were severely disabled by lecanamab. I decided to research how many hemorrhagic strokes occurred during Clarity and learned that 13 people experienced this disabling side effect. See Heralded Alzheimer’s drug works — but safety concerns loom. The article doesn't separate these by E4 status, but I feel confident that all (most) were E4 carriers. Homozygotes especially, need to understand that this is a very real risk for no benefit.

During Clarity AD, 13 people taking lecanemab developed symptomatic bleeding in the brain — or strokes — whereas only 2 people in the placebo group did, according to the conference presentation. This represents just 1.4% of the treatment group, Howard says, but “that’s not a trivial risk profile”.

Julie G wrote: ↑Tue Jan 03, 2023 3:39 pm Another thought, by focusing on just the deaths, we are missing those who were severely disabled by lecanamab. I decided to research how many hemorrhagic strokes occurred during Clarity and learned that 13 people experienced this disabling side effect. See Heralded Alzheimer’s drug works — but safety concerns loom....

During Clarity AD, 13 people taking lecanemab developed symptomatic bleeding in the brain — or strokes — whereas only 2 people in the placebo group did, according to the conference presentation. This represents just 1.4% of the treatment group, Howard says, but “that’s not a trivial risk profile”.

Julie, it would absolutely be disturbing news if 13 people with MCI/mild AD had hemorrhagic strokes and were left "severely disabled" by Lecanemab. I would assume that major news media and medical sources would cover it. Especially because a "stroke" is defined by the American Stroke Association as:

a weakened vessel that ruptures and bleeds into the surrounding brain.

However, ARIA-H is not a blood vessel that "ruptures". It can only be seen with specialized MRIs listed by Biogen in 2020 and is "invisible" even on conventional MRIs, as you have noted previously :

• ARIA-H are thought to represent hemosiderin deposits
• ARIA-H are detected on appropriately weighted MRI sequences, such as GRE/T2 [gradient-recalled echo] or SWI [susceptibility weighting imaging] sequences
– Without such sequences, the small amounts of blood product cannot be detected [emphasis added]
▪ They are invisible on T1, T2, and FLAIR imaging owing to use of rephasing pulse gradients

ADVANCE ™ Biogen Alzheimer's Education: Detection and management of ARIA

[ I'm still expecting an update from an MD affiliated with the ACTC on specific MRI sequences used early next week.]

The incidence of 13 cases of symptomatic ARIA-H cited in the article came from the slide below. If you click on it, you can see the detail better. Neither the slide nor the presenters said the 13 people in the blue circle had a stroke. In fact, from the New England Journal of Medicine article on ARIA-H: Lecanemab in Early Alzheimer’s Disease published Nov. 29, 2022.

A total of 2.8% of the participants in the lecanemab group had symptomatic ARIA-E; commonly reported symptoms were headache, visual disturbance, and confusion. The incidence of isolated ARIA-H (i.e., ARIA-H in participants who did not also have ARIA-E) was 8.9% in the lecanemab group and 7.8% in the placebo group. The incidence of isolated symptomatic ARIA-H was 0.7% in the lecanemab group and 0.2% in the placebo group. The most common symptom associated with isolated symptomatic ARIA-H was dizziness.

They did acknowledge, both in the presentation, (red circle on slide) and NEJM article that:

Macrohemorrhage occurred in 5 of 898 participants (0.6%) in the lecanemab group and 1 of 897 participants (0.1%) in the placebo group with a higher risk for ApoE 4 carriers. ... ARIA-E and ARIA-H were numerically less common among ApoE ε4 noncarriers than among carriers, with higher frequency among ApoE ε4 homozygotes than among ApoE ε4 heterozygotes

Presenters noted that macrohemorrhages appeared to occur independently of ARIA-H in at least some people.

Here's some info on the 69% of both placebo and lecanemab arms who were ApoE4 carriers in CLARITY (620 out of 1795 participants).

• ApoE 4/4 carriers were approximately 7 times their normal population distribution: 132 people on placebo (15.1% of total) and 136 on lecanemab (15.8% of the total).

I am not trivializing the impact on 5 people with MCI or AD who had macro hemorrhages. Yet even if ALL were among the 690 people who were ApoE4 carriers, that's a risk of slightly less than 1 in 100, almost exactly what was shared with the updated June consent.

I fully expect that the FDA will require and release more info on the macrohemorrhages and the deaths. And like you, I fully believe that ApoE 4 members should know as much as possible about any clinical trial in which they enroll.

Julie, it would absolutely be disturbing news if 13 people with MCI/mild AD had hemorrhagic strokes and were left "severely disabled" by Lecanemab. I would assume that major news media and medical sources would cover it.

Agreed! From the slide you’ve shared, it looks as though the Nature reporter confused microhemmorhages with macrohemmorhorages.

However, ARIA-H is not a blood vessel that "ruptures". It can only be seen with specialized MRIs listed by Biogen in 2020 and is "invisible" even on conventional MRIs, as you have noted previously.

To clarify, ARIA-H is indeed a microhemmorhage, a rupture of a blood vessel, that can be accompanied by hemosiderin. (Hemosiderin deposition is the consequence of recurrent or persistent hemorrhage.) This condition can lead to a macrohemmorage or a hemorrhagic stroke. These are not separate phenomenon, but rather gradients of the same phenomenon.

I'm still expecting an update from an MD affiliated with the ACTC on specific MRI sequences used early next week.

I appreciate that! From other reporting, it appears as though not all study participants (especially those in “remote” locations) have access to MP-RAGE to best identify both ARIA-H and CAA. This is a 3D magnetization-prepared rapid gradient-echo sequence that provides structural brain imaging. The sequence captures high tissue contrast and provides high spatial resolution with whole brain coverage in a short scan time. I look forward to learning more.

Interesting information and interview on lecanemab here: https://howonearthradio.org/archives/8819

The interview starts with various experts sharing pros and cons about the drug. Then Dr Dale Bredesen (more info: https://wiki.apoe4.info/wiki/Bredesen_Protocol ) shares his criticisms of lecanemab and gives recommendations for better ways to improve cognition

Of note from the trial results on lecanemab: nobody got better, nobody even stayed the same cognitively. People just get worse more slowly on lecanemab.

Per Dr Bredesen, the results on lecanamab are:
“Clinically insignificant, neurologically dangerous, and financially unsustainable.”

He points out that amyloid acts like a scab, and eliminating the amyloid too soon can be dangerous. He gives analogies explaining why targeting amyloid is misdirected and provides recommendations on better ways to improve cognition.

TheresaB, the bottom figure is from a recently published Lecanemab article. The two figures above are my derived results from the dataset.

As you can see in the phase 2 trial (top figure) ~30% of the Lecanemab patients did have improved cognition. Disclosure: There was no control for covariates so caution is warranted. Of course, it then needs to be also noted that 20% of the placebo improved. The problem is still that patient selection is not optimal. 20% of placebo should not improve over 18 months. Placebo that improve over 18 months are not AD patients.

As they move to dual amyloid-tau patient selection the benefits of mab treatment will only amplify versus what has been reported in Clarity (as for example with Donanemab which has shown 50% cognitive improvement on iADRS.). It's not that mab treatment will actually be better, it is that Clarity underreported the benefits to typical patients due to the way patients were selected. We saw this also with Aducanumab in Emerge and Engage high dose. There was a large group of patients who were given a full round of treatment who had 1 CDR-sb or more benefit (That is what the critics are saying needs to be reported for a minimally clinical significant result. Well, there it is!)

What I actually find quite impressive is how few of the high dose patients (the blue line) progressed that much. Notice that even up to the 75th percentile, the highest dose patients are nearly stable on CDR-sb with only a ~0.5 point decline. The typical decline for AD patients is ~1.7 CDR-sb points. When you stay away from the debatable claim
of the small n's of the 10% upper and lower tails of high dose versus placebo favoring treatment, but instead focus on the broad middle of the distribution 40%-80% with a fairly largish n, it becomes difficult not to accept that treatment helped treated patients -- probably helped these patients quite a bit. This will be brought into
focus when the same data view is published for Clarity.

It is only when you reach to the upper ~10th percentile treated patients that you see this runaway decline into clinical decline. Here again this likely a consequence of not selecting patients with dual amyloid-tau. While ~30% of the patients were too early and did not decline even on placebo, towards the top 10-20% you see patients who are too late. They are already past the mab frontier of benefit. mab treatment can be much more effective when the patients are selected more carefully. When this insight is reported on the topline of a trial people are likely going to be quite surprised.

The FDA has had this more realistic viewing point for mab trials and this is probably one of the reasons they had confidence in stepping ahead of the reported toplines (for example, with Aducanumab). The FDA have known for quite some time that mabs. The one thing that the FDA has also known for quite some time is that mabs do not merely work but for a wide range of median patients -- they work a lot. This is something that is yet to reach mainstream consciousness. The figure illustrates just how much this benefit actually is. It is quite a bit.

As it is now, all we hear is 27% reduced decline with Lecanemab repeated 100 quadrillion times in headlines and we never hear about how those in the wide 50% median of typical patients actually appear to do quite a bit better than placebo. As seen in the top figure, those from the 50th -80th percentiles gain from ~1 - ~3 CDR-sb points on Lecanemab versus placebo (subtract the top black line(placebo) from the bottom blue line (high dose Lecanemab).
The sample sizes here are admittedly small, though Clarity , given the already reported topline results, will almost by the force of logic have to report a similar finding. This would entirely reframe the conversation. People would no longer be focusing on the 27%; They would focus on the fairly surprising and unexpected result that about 80% of lecanemab treated patients actually do quite well (even surprisingly well). I am not even completely sure how mathematically it is possible for them to do this well. How can so many patients have a 1 CDR-sb benefit while the reported topline in the phase 2 was only ~0.4 on CDR-sb?

J11 wrote: ↑Sat Jan 21, 2023 12:52 pm TheresaB, the bottom figure is from a recently published Lecanemab article.

You should learn to use quotes if you direct issues to a specific person, I just happened to see your post.

You celebrate this drug and other amyloid targeting drugs. You insist it’s a good drug. I beg to differ. We all have opinions.

Everything you’ve cited addresses the population en masse. That obfuscates the efficacy and safety issues affecting the primary audience in these forums, APOE4 carriers.

Eisai's (the drug company) own U.S. chairman said, "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 those APOE4 homozygotes given a placebo fared better.

J11 wrote: ↑Sat Jan 21, 2023 12:47 pm As it is now, all we hear is 27% reduced decline with Lecanemab repeated 100 quadrillion times in headlines

I don't think it's quite that many times, but that 27% is cited often for good reason, since as a true measure, it's suspect.

At the end of the third trial (18 months) patients in the Leqembi group scored on average 1.21 on the clinical dementia scale and the placebo group scored 1.66, a 0.45 difference. But it sounds much better as a percentage: a 27% slower rate of decline.

But just how precise is that 27%? It relies on how cognition is 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: https://www.nbcnews.com/health/aging/3- ... p7xZlv0oWw )

In real life (not on a spreadsheet) the drug’s effect has been called "modest" and it’s unclear whether it will even lead to noticeable changes in people's daily lives, which I content is the true measure of an effective drug. (source: https://www.nbcnews.com/health/aging/3- ... p7xZlv0oWw )

There are repeated concerns from multiple sources about this drug's safety. These concerns are heightened when it comes to our gene.

We've all heard about the brain bleeds, which likely disproportionately affected APOE4s. About 17% of the Leqembi group experienced brain bleeds, compared with 9% in the placebo group. Those experiencing brain bleeds were taken off the drug, thus their results aren’t included in the final statistics.

About 12.6 % of patients who got Leqembi in the clinical trial developed brain swelling, compared with 1.7% of those in the placebo group.

We've also heard about the alleged 3 deaths, although the drug manufacturer denies a link to Leqembi,

The length of trials were limited. The long term effects are unknown. We don’t know if even more people will experience brain swelling, brain bleeding (or deaths) the longer a person takes the drug,

We also know that brain shrinkage was noted in the Phase 2 trial. Brain shrinkage has been consistently associated with progression of Alzheimer’s disease. We don’t know if those experiencing the brain shrinkage would develop longer-term worsening of cognitive decline.

Lecanemab/Leqembi does not address the root cause of Alzheimer’s, the body produces amyloid in an effort to protect itself. The drug works by removing amyloid from brain cells, but, in the process, it also removes amyloid from the walls of blood vessels, which can make the brain "leaky." Leaky brain is known to cause neuroinflammation. Amyloid can be liken to a scab. Listen to the interview with Dr Bredesen that I cited in my previous post, he offers a very understandable analogy using leprosy as an example. Don't get me wrong, I'm not saying Amyloid is not toxic, it is, but as the cause, the amyloid hypothesis has been in question for years and such questions have only increased after one of the most cited Alzheimer’s studies that underpins a key element of the amyloid hypothesis of Alzheimer’s Disease cited fraudulent/manipulated “evidence”. (Source: https://www.science.org/content/article ... misconduct.)

This drug effects different people differently, not just APOE4s. It works better in older people compared to younger people and better in men than women. I contend this begs the need for more research into what exactly the mechanism of this drug is.

Lecanemab/leqembi is only to be administered to those with MCI or in the early stages of AD.

It’s expensive! $26,500 a year not including the regular MRI scans that should accompany any administration of the drugs, a ramification of the experienced brain bleeds.

This drug is burdensome and not available to everyone. In addition to needing regular MRI appointments, it is administered via infusion necessitating visits to a hospital or clinic every two weeks.

There’s an alternative with BETTER results, benign side-effects, and no deaths vs the 3 deaths that have been alleged to leqembi. So I contend this drug is minimally beneficial for a certain population only, risky-especially in the long run, expensive, burdensome. In my opinion, that's not a good answer.

As a 4/4, I personally wouldn’t touch this drug. I don't recommend it to any ApoE4 carrier. I would advise any non-carriers to consider it’s use VERY carefully. And I hope that as a taxpayer I won't be required to pay for the burden of this drug through Medicare.