Lecanamab: Efficacy, Side Effects, and More

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Julie G
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by Julie G »

They are going to give me my amyloid PET scan results, and also do some blood tests for "biomarkers" and I will find out exactly what those are, and ask about the MRI sequences they are using to detect ARIAs.
Thank you, karalena. I'm so grateful that you and chicagogirl are sharing your experience. As you know, it's so important that they do the necessary MRI sequences to thoroughly search for past micro-hemorrhages as they're way too easy to overlook with a less in-depth MRI. I want to make sure that you're safe. After my mom's experience, I'm beginning to think that CAA is much more prevalent among E4 carriers than we previously thought.
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Re: Lecanamab: Efficacy, Side Effects, and More

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Article from ALZFORUM site regarding the Lecanemab results reported at the Clinical Trials on Alzheimer's Disease held on November 29th. Data published in the New England Journal of Medicine the same day.

https://www.alzforum.org/news/conferenc ... ws-disease

I will leave it to you to read and draw your own conclusions.
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Julie G
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Re: Lecanamab: Efficacy, Side Effects, and More

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Article from ALZFORUM site regarding the Lecanemab results reported at the Clinical Trials on Alzheimer's Disease held on November 29th. Data published in the New England Journal of Medicine the same day.

https://www.alzforum.org/news/conferenc ... ws-disease

I will leave it to you to read and draw your own conclusions.
Thank you for sharing, Chicagogirl. While an average of the sub-groups showed about a 25% slowing of decline (not improvement), the benefit appears to be mixed for E4 carriers. Heterozygotes received less slowing of decline than non-carriers, while homozygotes received none. Lecanamab appears to be the least effective for younger (<65), female, black, homozygotes. And, they report that 1/3 of E4 carriers (more than I had previously seen reported) do experience ARIA. Some describe the lack of effect for E4s as "noise" suggesting that we need a longer term intervention to really draw a definitive conclusion.

Off topic, but from every Pharma study that I'm learning about ALZ-801 seems to hold the most promise for E4s, particularly homozygotes because it shows an actual IMPROVEMENT in symptoms, similar to Dr. Bredesen's approach.
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Re: Lecanamab: Efficacy, Side Effects, and More

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A third death?

According to this article published in Science Scientists tie third clinical trial death to experimental Alzheimer’s drug
As enthusiasm mounts for a new experimental antibody that appears to slow cognitive decline in some Alzheimer’s patients, a third death linked to the drug during its clinical testing may amplify concerns about its safety. Science has obtained medical records showing a 79-year-old Florida woman participating in an ongoing trial of the antibody died in mid-September after experiencing extensive brain swelling and bleeding, as well as seizures. Multiple neuroscientists who reviewed the records at Science’s request believe her death was likely caused by the antibody, lecanemab.
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Julie G
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Re: Lecanamab: Efficacy, Side Effects, and More

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Thanks for sharing, Theresa. One thing that I found startling from this article is the statement that 50% of people who have AD also have CAA ...and we can certainly expect that number to be much higher for E4 carriers. All of this underscores the importance of getting a pre-treatment MRI with a microhemorrhage sequence (MP-RAGE), which can reliably find current and prior bleeds. I understand that this type of an MRI is more expensive than those with less slices, but incredibly important especially for E4 carriers. Huge thanks to karalena, (a physician) whose agreed to determine and share the exact type of MRI that will be used in this trial. I care deeply about the safety of all of our E4 family.
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Re: Lecanamab: Efficacy, Side Effects, and More

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Hi, I did ask about the MRI sequences used in the study and the study coordinator did not know the exact sequences, he just said he was sure they would be the most sensitive to detect hemorrhages, so the question of whether MP-RAGE is being used is still unanswered. NF52 is working on an answer to that.

I went for my appointment for my amyloid PET scan results and I do not have enough amyloid to continue in the AHEAD study, meaning less than 20 centiloids. Unfortunately my study center does not get exact results, so all I know is it was less than 20. They gave me a copy of the images on a disc so I can have it read independently if I want. They still wanted to do additional blood tests for other biomarkers for AD, but they did not know the exact markers that were being tested.

The study coordinator said, from their experience, it is not uncommon for participants who have a qualifying blood amyloid score to have a amyloid PET scan with < 20 centiloids. Overall they only get about 10% of those screened who qualify for the study which is why they are still actively recruiting. Perhaps the correlation of the blood test with brain amyloid is not as strong as previously thought, or at least not as strong for preclinical populations. They said they are looking for more information about that, and that is part of the reason they wanted more of my blood for the biomarkers, even though I was no longer in the study.

Before volunteering for this study I also volunteered for TRAILBLAZER-3 study (donanemab) but I did not qualify on their screening blood test which is a Tau test.

For me personally it is good not to qualify however I know I am at high risk due to APOE 4/4. These measurements at this one point in time may be reassuring for now but not for the long term. I am glad they are studying these treatments, and others, in preclinical people who they are most likely to see a difference in treatment vs. placebo groups.
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Re: Lecanamab: Efficacy, Side Effects, and More

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For me personally it is good not to qualify however I know I am at high risk due to APOE 4/4. These measurements at this one point in time may be reassuring for now but not for the long term. I am glad they are studying these treatments, and others, in preclinical people who they are most likely to see a difference in treatment vs. placebo groups.
Very good news, karelena!!! Congratulations and thank you for generously sharing your experience. Despite the hype around blood tests for amyloid, I suspect that they are still pretty inaccurate as evidenced by your experience.
Hi, I did ask about the MRI sequences used in the study and the study coordinator did not know the exact sequences, he just said he was sure they would be the most sensitive to detect hemorrhages, so the question of whether MP-RAGE is being used is still unanswered. NF52 is working on an answer to that.
Huge thanks to you both for trying to figure this out as it gets to the heart of protecting E4s who participate in the study.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by J11 »

JulieG, they should have ADCOMMed it. It looked like there was not that much to talk about, and then there is.
I had not realized that with Lecanemab they changed the inclusion to allow for those on anticoagulants to be treated-- the Aducanumab phase 3s did not allow anticoagulant use.

My overall impression is that there is still a great deal of low hanging fruit that could be harvested to further reduce risk from treatment with beta amyloid mabs. Either the FDA or CMS could play a facilitating role in advancing this additional risk reduction. Perhaps the conditionalities for an accelerated approval could shift from an efficacy focus (which has now largely been definitively established) more to a safety enhancement focus. We already know of several risk reduction strategies that likely would be successful.

From what we know as of now the patients that have experienced negative reactions to Lecanemab typically have been in a very high risk subsample.

The patient with the MCA stroke had considerable specific risk.
This patient was epsilon 44, a woman, had hidden moderate to severe CAA, was on anticoagulants, had an MCA stroke, was then treated with tPA. That pretty much hits all of the risk categories. This patient would have been well within the top 1% on a prospective risk assessment. Such an assessment would have been a great addition to the Clarity design. Perhaps those patients in the top 5% of prespecified risk could then have been placed in a parallel trial analysis and have had a different treatment algorithm.

The most recent fatality while seeming to not be in the high risk subsample actually could have been on the exclusion list for treatment. In the below second from bottom MRI for this patient, three arrows point to the microhemorrhages present before treatment started. It is hard to say but there would seem to be 4 microhemorrhages present in the three arrows and I have boxed in orange other possible microhemorrhages (or admittedly just imaging noise). It is not that clear that this patient should have ever been treated with Lecanemab. There has been online chatter along these lines; it is very unclear whether the patient was reevaluated for exclusions when she went into the long term extension. It is an important question that would be well worth addressing. I am not that good at reading these MRIs, though I wonder whether some of the cloudiness that is present on the second to bottom figure is actually mild radiographic ARIA-E.

The top figure shows MRIs for two additional patients that experienced severe negative reactions to Lecanemab. The MRI on the far right shows a truly massive lesion resulting from ARIA (~7 cm). It would be helpful to carefully review all the patients that have had moderate/severe negative responses in order to consider how to reduce risk and have a better understanding of the risks. The text for the top figure notes that both of these patients were e4 carriers without stating whether they were e44. It would also be informative if additional risk factors were present for example whether they were on anti-coagulants etc..

I have thought of an interesting possible workaround for these high risk patients; I am not sure whether it would be realistic etc., though I'll just add it to the conversation for consideration. What if instead of waiting for symptoms or radiographic imaging abnormalities to emerge in high risk patients, PET amyloid feedback were used in those at high risk? The idea here is that you could take the highest ~1%-2% and initially use low dose for the first treatment or two and measure the amyloid response. If there were a large amyloid response, then you would know that you had a superresponder and the dose would then be set below the threshold of initiating ARIA. What has been the strategy to date is to largely treat even high risk patients and then wait for symptoms to emerge. The problem is that for a small percentage of these patients the first symptom that emerges is a severe ARIA event. Perhaps PET amyloid could avoid ARIA from ever manifesting.

The problem that the high risk patients often have is that they have a great deal of amyloid burden and then with treatment there is a flood of amyloid that is removed from their cerebral blood vessels --> ARIA-E and ARIA-H. Why turn superresponders into those with the most side effects? Once it is established that these patients remove a great deal of amyloid, one could simply personalize treatment so that they do not remove a dangerous amount of amyloid. These patients would then be expected to go onto having a good treatment response. Interestingly, those on anticoagulants did appear to have better than average CDR-sb benefit.
Clinical ARIA 2.PNG
ARIA 1.png
3rd Aria 2.jpg
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Re: Lecanamab: Efficacy, Side Effects, and More

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Julie G wrote: Wed Dec 28, 2022 7:03 am Huge thanks to you both for trying to figure this out as it gets to the heart of protecting E4s who participate in the study.
More to the story on emphasizing the need to protect us 4s, from this article published in Science on Dec 30, 2022 Revised clinical trial form for Alzheimer’s antibody warned of fatal brain bleeds

Excerpts from the article:
Earlier this year, the developer of a promising antibody designed to slow Alzheimer’s disease strengthened a key warning given to participants in an ongoing trial of the experimental drug. Taking the antibody alongside blood clot medications, the Japanese biotech company Eisai cautioned, increases the risk of possibly fatal brain hemorrhages. That revision of its informed consent form, revealed in a 14 July version obtained by Science, appears to challenge the company’s contention that the antibody, known as lecanemab, played no role in the recently revealed deaths of two people who suffered dramatic brain bleeds while concurrently taking the drug and blood thinners.

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.
Sam Gandy, a neurologist and neuroscientist at the Icahn School of Medicine at Mount Sinai, also worries about people with cerebral amyloid angiopathy (CAA), a common condition among Alzheimer’s patients in which amyloid replaces blood vessel lining. 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, contributing to risks of using blood thinners with the antibody.
(bold font added)
Gandy agrees the agency should assess the need for a black box warning that could include every class of drug—such as anticoagulants, tPA, and antiplatelet treatments—that can cause or increase the risk of brain bleeding. He also favors genetic testing of potential lecanemab recipients to ensure they know their APOE4 status. 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.
(bold font added)

The question posed in the article about Eisai's communication to trial participants and its transparency about the risks of its product echoes some findings of the Congressional investigation into Biogen and the FDA's approval of aducanumab/aduhelm. You can read the highlights of that investigation (with a link to the entire Congressional investigation) here: viewtopic.php?t=8352
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Re: Lecanamab: Efficacy, Side Effects, and More

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Julie G wrote: Wed Dec 28, 2022 7:03 am Huge thanks to you both for trying to figure this out as it gets to the heart of protecting E4s who participate in the study.
TheresaB wrote: Sun Jan 01, 2023 7:15 pm More to the story on emphasizing the need to protect us 4s, from this article published in Science on Dec 30, 2022 Revised clinical trial form for Alzheimer’s antibody warned of fatal brain bleeds

Excerpts from the article:
...Taking the antibody alongside blood clot medications, the Japanese biotech company Eisai cautioned, increases the risk of possibly fatal brain hemorrhages....
The question posed in the article about Eisai's communication to trial participants and its transparency about the risks of its product echoes some findings of the Congressional investigation into Biogen and the FDA's approval of aducanumab/aduhelm...
In response to Julie's comment, as a member of the Alzheimer's Clinical Trial Consortium (ACTC) Research Participant Advisory Board, I have asked for specific information about the MRI sequences used in both the CLARITY core study (completed) and its Open-Label Extension (OLE) (ongoing) for people with MCI/Mild AD and for the AHEAD trials (ongoing) in people with normal cognition and intermediate or elevated amyloid. I have been advised that an MD will reply by early next week.

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.

However, I believe that the title itself: Taking the antibody alongside blood clot medications, the Japanese biotech company Eisai cautioned, increases the risk of possibly fatal brain hemorrhages is evidence of prompt transparency in communication, and is consistent with what I've experienced as a clinical trial participant. Consent forms are updated as new information is assessed by the outside safety and data monitoring group while the trial is running. Updating consents is a key safety feature for clinical trial participants.

As one such participant, I signed several updated consent forms, each of which was approved by the study site's Institutional Review Board. IRBs act independently, so an updated consent may take weeks to reach each participant, and is shared at an individual visit, not over the phone or by email.

Each time the Nurse Practitioner/Coordinator explained in detail the changes to me, and I indicated that I understood those changes and signed that I consented to continue in the study. I haven't seen the CLARITY consent form, but have been able to see the updated AHEAD consent form, which reflects a lower observed risk of macrohemorrhage at that earlier stage of disease. This isn't a screen shot, but it is accurate from the June 27, 2022 AHEAD revision. [Note that no deaths have been reported in AHEAD, nor has it been running long enough to have reported more than screening demographics at CTAD] The forum uses this warning graphic on several points, not just macrohemorrhages :
Warning!.png
Cerebral macrohemorrhages and superficial siderosis...Areas of large bleeds in the brain (known as macrohemorrhages) and areas of bleeding on the surface of the brain (known as superficial siderosis) were also seen in participants with AD who were treated with [lecanemab]. They may both be associated with symptoms and may not require treatment. The risk of these types of bleeding abnormalities at the dose and frequency used in this study is low (less than 1 in 100 people).

MRI scans will be done at regular intervals to check for bleeding abnormalities.

If you take medications which prevent blood clots from forming, you may continue with these medications, but you and the study doctor should discuss the risk of bleeding.
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.

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.
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