Donanemab and Lecanemab

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
NF52
Support Team
Support Team
Posts: 2953
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

Re: Donanemab, Lecanemab & Remternetug

Post by NF52 »

J11 wrote: Tue Dec 19, 2023 9:21 pm... patients even with the seemingly low amyloid level of 60 centiloids amyloid already are 40% intermediate/high tau.
Unfortunately, an Amyloid PET centiloid level of 60 is far from low.

The AIBL studyin Australia has followed more than 3000 people for the last 17 years, and produced a wealth of research on factors associated with outcomes in people with normal cognition with and without amyloid. Their six areas of research include Lifestyle One of their studies asked the question: How many people with an average age of 72 and normal cognition, with different levels of amyloid, progress to a diagnosis of MCI or AD over an average of 5.3 years (+/- 1.7 years)?
Association of β-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals
A total of 534 CN individuals from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study with at least 3 years of clinical follow-up after an Aβ PET scan were identified...Aβ level was classified according to 5 categories: <15 CL [centiloids] negative; 15–25 CL uncertain; 26–50 CL moderate; 51–100 CL high, >100 CL very high. The category limits were chosen prior to data analysis based on published CL information.......At baseline, the mean age was 72 ± 6 years, 55% were women, 28% were APOE ε4 positive, and 27% were Aβ scan positive using a threshold of 25 CL. During the follow-up period of 5.3 ± 1.7 years, 57 participants (11%) progressed to MCI or dementia....Greatest risk was seen with high and very high Aβ levels (H.R. [hazard ratio] 5.2 and 8.1, respectively). An uncertain or moderate Aβ PET result did not affect the risk of clinical progression by 4.5 years (HR 1.3 and 0.9, respectively)....

At 4.5 years, carriage of APOE ε4, HA [hippocampal atrophy], and positive Aβ scan were associated with significant increase in risk of clinical progression (table 3). Greatest risk was seen with high and very high Aβ levels..
Twenty-right percent (28%) of the 504 people in this specific study were ApoE 4 carriers, about the typical percentage for Apoe 3/4 and 4/4 in a population with European ancestry. Of those who were clinically stable at the end, 24% were Apoe 4 carriers. But 55% of the 57 people who progressed to MCI or AD were ApoE4 carriers, and the average time to progression was 3.6 years, ranging from 1.4.-7.6 years.

Amyloid plaques are not an immediate or sufficient cause of Alzheimer's, it appears. But once levels are high, it signals many other factors: tau, inflammation, hippomampal atrophy. So earlier treatment would seem to be better.
4/4 and still an optimist!
User avatar
Julie G
Mod
Mod
Posts: 9205
Joined: Sat Oct 26, 2013 6:36 pm

Re: Donanemab, Lecanemab & Remternetug

Post by Julie G »

I like that better testing may further protect E4 carriers, but suspect that it will be reserved for trials as opposed to being offered to regular folks using Lequembi because of the high cost.
While that may not hold true for everyone with Apoe 4, it suggests that moving even further back--before the MCI stage, as the AHEAD and TRAILBLAZER ALZ 3 trials do, might be the most beneficial. Time will tell on that prediction.
Given that the PrecivityAD2™ Blood Test is intended for those with symptoms of cognitive decline, do you have any idea how these trials will identify participants before the MCI stage? Will they use the blood test "off-label" and perhaps rely more heavily on the E4 status part of the algorithm?

Also, any more chatter about how the reduction in brain volumetrics is affected by length of time on the medication? I've read that higher doses have a more severe impact, but presumably this is a drug that will need to be taken for life or maybe I'm wrong about that.
People in two large lecanemab trials on the highest drug dose—which is the one the U.S. Food and Drug Administration (FDA) approved—recorded, on average, a 28% greater brain volume loss relative to placebo after about 18 months. This translated to a loss of an extra 5.2 milliliters (mL) in brain matter.
Apparently brain swelling (more likely to affect E4 carriers) is associated with this reduction in volume.
NF52
Support Team
Support Team
Posts: 2953
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

Re: Donanemab, Lecanemab & Remternetug

Post by NF52 »

Julie G wrote: Wed Dec 20, 2023 9:49 am I like that better testing may further protect E4 carriers, but suspect that it will be reserved for trials as opposed to being offered to regular folks using Lequembi because of the high cost....Given that the PrecivityAD2™ Blood Test is intended for those with symptoms of cognitive decline, do you have any idea how these trials will identify participants before the MCI stage? Will they use the blood test "off-label" and perhaps rely more heavily on the E4 status part of the algorithm?
The AHEAD trial of lecanemab has already started using the PrecivityAD2™ blood test, and I assume the TRAILBLAZER trial has or will also. Because the test is being used as part of clinical research, it can be used to identify people with normal cognition who are likely Ab positive.

Neurologists and memory centers providing Leqembi also have to confirm positive amyloid before prescribing, and are strongly recommended to confirm ApoE status also. I would expect that they have the same clinical and time-saving incentive to use that test in initial eligibility screening.

It's possible that "regular folks" above the age of 55 might be able to have their primary care provider order a PrecivityAD2™ test, with symptoms of "subjective cognitive decline." I would hope both doctor and patient have talked about how the results might affect the person and their family members. Unless ordered through a FM doctor or someone who agrees to not enter the result in an electronic health record using an ICD-10 code for SCI, it would likely go in their medical record. That can't affect access to health insurance under GINA, but would likely affect access to long-term care insurance, even without ApoE 4 status. (My AHEAD data does not go into my electronic health record.) Multiple presenters at CTAD and AAIC said that "primary prevention" should soon include genetic, lifestyle, and multiple blood-based biomarkers for personalized risk prediction so that people can make decisions about how to address each of those factors.
Also, any more chatter about how the reduction in brain volumetrics is affected by length of time on the medication? I've read that higher doses have a more severe impact, but presumably this is a drug that will need to be taken for life or maybe I'm wrong about that.
None of these drugs is currently recommended to be taken for life. The longest duration I know of is someone who was in multiple aducanumab trials over 7 years, although probably not for a total of 7 years--maybe more like 4-5 years, including the post-FDA Phase 4 trial. That person is amyloid negative, still at the "mild AD" stage of cognition and continuing lots of healthy lifestyle measures.

Donanemab moved people off the drug in trials as soon as they have become amyloid negative. I assume their FDA submission will be similar, with some researchers predicting re-testing every 2-4 years for changes in amyloid levels and a return to time-limited dosing if needed. I believe that Leqembi use will be similarly reliant on PET scan results. I think some suggested movement to monthly dosing for those who were at the highest centiloid levels for a period of time, to see if they are "fast accumulators". It is also recognized that with people who have a diagnosis of mild AD, especially those over 75, it's likely that tau, alpha-synuclein (Lewy body disease), vascular disease may become more relevant to disease progression, so that continuing with anti-amyloid therapies may have diminishing returns over time. The hope was expressed by clinicians at AAIC and CTAD for combination therapies and interventions, for example aggressive control of insulin resistance and T2D, hypertension, coronary artery disease.

I really wish there was a clearer answer on the volumetric MRI results! It seems like the three leading theories, not mutually exclusive are:
  • Actual reduction in either total brain volume or hippocampal volume from the treatment, for reasons not yet identified
  • "Pseudo-atrophy" from removal of amyloid throughout the brain, leading to a loss of overall volume, but not of cognitive skills.
In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aβ or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo...We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years (range 63–87). Thirty-four participants (27%) exhibited an initial high-Aβ burden on PET imaging. Faster HV [hippocampal volume] atrophy was correlated with faster cognitive decline (R2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aβ and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers.
4/4 and still an optimist!
J11
Contributor
Contributor
Posts: 3357
Joined: Sat May 17, 2014 4:04 pm

Re: Donanemab, Lecanemab & Remternetug

Post by J11 »

genotype by time 3a.png
https://www.desmos.com/calculator/r0ccjjfqx7

This is another result from CTAD of interest. It shows amyloid removal by e3/e4 genotype. Firstly, we can see that ALL the patients on the relatively low side of baseline amyloid (~50 centiloids or less) became amyloid negative by 76 weeks. NF_52 noted that 50 centiloids is quite a bit of amyloid which is quite true, though given the current clinical reality even over 200 centiloids can be present with AD and 100 centiloids is the reference point for the typical AD patient. The TB-2 trial had an average baseline amyloid centiloid of 107. Also of note is that as baseline amyloid increases in the above figure we see a significant fraction of the e44s who become non-clearers. This might perhaps relate to ARIA and perhaps other side effects. It would be of interest to have a dose response curve for e44s specifically so that we could see how they actually responded to amyloid removal and not to other possible confounders. It also highlights how when you move back the disease stage that e44s can do quite well. This gives more confidence that they could perform well in comparison to other genotypes in the context of the 95% slowing for those with early stage MCI as noted above.

At this early stage in the development of mabs it is probably an error to follow the bouncing ping pong ball too carefully. As seen above in the earlier stage setting e44s can respond quite well treatment. This observation possibly applies to other demographics who might have seemed to underperform to date.
You do not have the required permissions to view the files attached to this post.
User avatar
TheresaB
Mod
Mod
Posts: 1676
Joined: Wed Feb 03, 2016 9:46 am
Location: Front Range, CO

Re: Donanemab, Lecanemab & Remternetug

Post by TheresaB »

J11 wrote: Wed Dec 20, 2023 8:58 pmThis is another result from CTAD of interest. It shows amyloid removal by e3/e4 genotype.
But is that a good thing?

I'm not saying I don't recognize the toxic effects of amyloid, however, the amyloid hypothesis has been questioned for years and such questions only grew when it was revealed that 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: BLOTS ON A FIELD? (Charles Piller, Science, 21 Jul 2022)]

As I highlighted before in one of my previous posts citing the findings of Dr Rudolph Castellani, Director and Professor of the Neuropathy Core, Northwestern University Feinberg School of Medicine, who participated in the autopsy of one of the patients who died in the Lecanemab trial, while these drugs target soluble proto fibrils, there was also an attack on the insoluble amyloid which destroyed the blood vessels. In other words, these drugs are stimulating an immune response to amyloid, which it is supposed to do, but it is also attacking the blood vessel wall.

His findings were separately supported in the paper that I previously posted in this thread, Fatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer’s disease (Elena Solopova et al, Nature Communications, 12 Dec 2023)
-Theresa
ApoE 4/4
User avatar
TheresaB
Mod
Mod
Posts: 1676
Joined: Wed Feb 03, 2016 9:46 am
Location: Front Range, CO

Re: Donanemab, Lecanemab & Remternetug

Post by TheresaB »

As I have written before in these forums, the scientific community has critical voices about drug manufacturers not being completely forthcoming with information from their clinical trials. Here’s another one this one referring to Donanemab with ApoE4 at the center of the target.

Published two days ago (19 December 2023) in the Journal of the American Medical Association
Use of Donanemab in Early Symptomatic Alzheimer Disease (Nunzio Pomara MD and Bruno Pietro Imbimbo PhD, JAMA 19 Dec 2023)

The write-up is addressed to Dr John R Sims of Eli Lilly, the manufacturer of Donanemab. The first two quotes excerpted to set the preface, the third quote is the request to Dr Sims.
During donanemab treatment, amyloid-related imaging abnormalities of edema/effusion were observed in only 15.7% of APOE ε4 noncarriers but in 22.8% of heterozygous carriers and 40.6% of homozygous APOE ε4 carriers.
Increased amyloid burden associated with APOE ε4 and a more pronounced immune response have generally been suggested as factors contributing to the increased amyloid-related imaging abnormalities associated with this genotype. However, there is evidence that the APOE ε4 genotype may also be associated with a disruption of the blood-brain barrier.4 Breakdown of the blood-brain barrier may result in increased drug entry into the central nervous system that could have important safety implications because adverse events are generally dose-dependent.
We would be grateful if Dr Sims and colleagues could discuss any data or insights they may have on the possible role of higher CSF donanemab levels in the increased risk for amyloid-related imaging abnormalities associated with the APOE ε4 genotype.
Certainly there’s established research supporting Blood Barrier Breakdown in older ApoE4s. To read some of these papers, see the write-up: Blood Brain Barrier (BBB) Breakdown/Leakage which can be found in the ApoE4.info wiki article, ApoE4 and Health Conditions besides (or maybe contributing to) Alzheimer’s.

It’s disturbing to me that these -mab drugs appear to be adding an accelerant to ApoE4 weaknesses. Again I must express my concern for our lack of knowledge on the long-term affects.
-Theresa
ApoE 4/4
User avatar
Julie G
Mod
Mod
Posts: 9205
Joined: Sat Oct 26, 2013 6:36 pm

Re: Donanemab and Lecanemab

Post by Julie G »

I really wish there was a clearer answer on the volumetric MRI results! It seems like the three leading theories, not mutually exclusive are:
* Actual reduction in either total brain volume or hippocampal volume from the treatment, for reasons not yet identified
* "Pseudo-atrophy" from removal of amyloid throughout the brain, leading to a loss of overall volume, but not of cognitive skills.
* Continuing atrophy from other causes; which might co-exist with either causes 1 or 2. See the excerpt below, just published in November 2023 in Neurology: Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults
Thank you for this thoughtful reply. I appreciate that this is being further explored based on current understanding that a reduction in volumetrics is typically associated with cognitive decline.
None of these drugs is currently recommended to be taken for life. The longest duration I know of is someone who was in multiple aducanumab trials over 7 years, although probably not for a total of 7 years--maybe more like 4-5 years, including the post-FDA Phase 4 trial. That person is amyloid negative, still at the "mild AD" stage of cognition and continuing lots of healthy lifestyle measures.

Donanemab moved people off the drug in trials as soon as they have become amyloid negative. I assume their FDA submission will be similar, with some researchers predicting re-testing every 2-4 years for changes in amyloid levels and a return to time-limited dosing if needed. I believe that Leqembi use will be similarly reliant on PET scan results. I think some suggested movement to monthly dosing for those who were at the highest centiloid levels for a period of time, to see if they are "fast accumulators". It is also recognized that with people who have a diagnosis of mild AD, especially those over 75, it's likely that tau, alpha-synuclein (Lewy body disease), vascular disease may become more relevant to disease progression, so that continuing with anti-amyloid therapies may have diminishing returns over time. The hope was expressed by clinicians at AAIC and CTAD for combination therapies and interventions, for example aggressive control of insulin resistance and T2D, hypertension, coronary artery disease.
Super interesting! So, the idea is to remove as needed. I greatly appreciate the interest in addressing chronic disease as that may render removal to be needed less frequently or not at all (?) My guess is that those (like you) who are addressing root causes may have the most successful experience. I'd love to see this trialed in a systematic way.
It's possible that "regular folks" above the age of 55 might be able to have their primary care provider order a PrecivityAD2™ test, with symptoms of "subjective cognitive decline."
Yes, it’s available now, see here. Per the test manufacturer’s: The Precivity™ tests are innovative new blood tests intended for use in patients with cognitive impairment. So, using it in an asymptomatic population as in the AHEAD Trial is off-label and experimental. As we know, many people have significant levels of both amyloid and tau and never show symptoms. See They have AD Brains, but no symptoms. Why?
About 30% of older adults have brains littered with enough amyloid or tau, or both, to qualify for an Alzheimer’s diagnosis but without so much as a hint of dementia, said neuroscientist Timothy Hohman of Vanderbilt University Medical Center, who is leading the largest-ever study to identify genetic explanations for that resilience.
“You can have abundant plaques and tangles without having Alzheimer’s disease,” agreed neurologist Rudy Tanzi of Massachusetts General Hospital. “The challenge is to figure out how. If we can, then the goal would be to mimic what these resilient people have with some kind of a drug.”
As many have surmised, cognitive reserve and a clean lifestyle like many here practice may be big contributors to staying symptom-free, despite pathology. As I've mentioned before, my biggest fear is that E4 carriers who would never have experienced symptoms will participate in one of these trials with devastating consequences. I recognize that participating earlier should help to protect them... but what if the long term loss of brain volumetric ends up contributing to decline. There are still so many unknowns.

I know I repeatedly say this, but I mean it from the bottom of my heart. You (and others) participating in these trials are brave pioneers helping us better understand the science and hopefully carving out a path for future E4 carriers. I appreciate your generous sharing of your deep knowledge in this area. We are grateful. Happy holidays, my friend,.
NF52
Support Team
Support Team
Posts: 2953
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

Re: Donanemab and Lecanemab

Post by NF52 »

Here is some recently published analysis about the risk of ARIA-H for ApoE 4 carriers, from the 18-month CLARITY trial of lecanemab in people with confirmed PET amyloid and a diagnosis of MCI or Mild Alzheimer's dementia. It refers to isolated ARIA-H, (i.e. microhemorrhages, superficial siderosis or macrohemorrhages) that occurred in trial participants on the placebo or the drug, without ARIA-E (edema) occurring at the same time. It is also noted that less than one percent (0.6%) of people taking lecanemab experienced a macrohemorrhage (defined as >10mm in size), while 0.2% of people on the placebo also experienced a macrohemorrhage.

All patients in the trials are informed of any MRI that shows ARIA-H and their dosing is paused until a follow-up MRI at least a month later show resolution of the ARIA-H. Patients and study sites are not aware of the assignment to placebo or drug, so people on both arms would have been "paused" until it was viewed as safe to re-start dosing.
Results
Overall, the incidence of isolated ARIA-H was similar in the lecanemab (8.9%) and placebo (7.8%) groups. Incidence of microhemorrhages was 6.0% vs 6.2%, superficial siderosis was 2.1% vs 1%, and macrohemorrhages was 0.6% vs 0.2%, for lecanemab and placebo, respectively. The incidence of isolated ARIA-H increased with number of APOE4 alleles in both placebo (noncarriers:3.8%; heterozygotes:7.3%; homozygotes:18.0%), and lecanemab-treated subjects (noncarriers:8.3%; heterozygotes:8.4%; homozygotes:12.1%). For APOE4 homozygotes, the incidence of isolated ARIA-H was less on lecanemab (12.1%) than on placebo (18%). Isolated ARIA-H events (microhemorrhages, superficial siderosis, and macrohemorrhages) in both the placebo and lecanemab groups were infrequent and distributed at a steady rate over 18 months of treatment.
Isolated ARIA-H in patients treated with lecanemab in the phase 3 clarity AD study in early Alzheimer's disease

While this is a separate issue from the risk of ARIA-E, the results suggest that with lecanemab, it may be possible to take the drug without additional risk of isolated ARIA-H and with less than a 1% risk of a macrohemorrhage, even with ApoE 4/4. Given the requirement for monitoring MRIs during the firs six months, and 12-month monitoring recommended for ApoE4 carriers, it seems that patients taking Leqembi might have MORE information about their vascular health than they would have learned if they simply had silent, isolated microhemorrhages with no MRIs and no possible benefit from this drug.
4/4 and still an optimist!
User avatar
Julie G
Mod
Mod
Posts: 9205
Joined: Sat Oct 26, 2013 6:36 pm

Re: Donanemab and Lecanemab

Post by Julie G »

Thank you for sharing this, Nf52. Did you purchase the paper? I see it is behind a paywall.

Also, have you seen this thoughtful article from STAT News? While it goes beyond just discussing just ARIA-H, it points out a disturbing lack of openness about the severity of side effects from the manufacturer of Lecanemab. I'm hopeful that the request for more information about adverse events will be honored given what many consider to be a premature FDA approval.
Both scientific publications reporting clinical trial results as well as drug manufacturer-sponsored awareness campaigns targeting physicians tend to portray brain swelling and bleeding due to ARIA as mostly mild or even asymptomatic, typically observed during the first few weeks of treatment, and often resolving spontaneously. Moreover, the narrative goes, in the majority of patients who show mild symptoms, they simply have to go on a temporary hold until brain scans show that ARIA have resolved, at which point the medication can be safely continued.

However, this message largely ignores the worrying reality that 1-2% of patients treated with these drugs experience serious symptoms due to ARIA including headache, seizures, delirium, impaired speech, problems with vision, and muscle weakness. Alzheimer’s clinical trials typically run for 18 months — what happens to the memory and functional abilities of these patients after these trials end? Do they fare worse when compared with patients who do not experience any ARIA symptoms or to those with only mild symptoms?

The drug manufacturers that have sponsored trials of the three FDA-designated “breakthrough” drugs have not addressed these obvious questions in peer-reviewed publications. But we do know that 12 patients in the Phase-3 trial of lecanemab developed serious adverse events due to ARIA.

The only peer-reviewed scientific publication that examined a potential link between ARIA and worsening memory in these patients was written by a team of physicians in France whose hospital was one of the centers for this clinical trial. The researchers, who are not affiliated with the drug manufacturer, looked more closely at two of the 12 patients who developed ARIA during the Phase 3 trial of lecanemab. Both had mild Alzheimer’s.

One developed severe seizures that are believed to have triggered heart failure. Eleven months later, her memory score dropped by nine points on a commonly used 30-point assessment scale of memory. The other patient developed a “massive (7 cm)” bleed in the brain and, seven months after the event, experienced persistent loss of vision as well as a 12-point decrease in her memory score. This patient is now in a nursing home and unable to speak.

To put these changes in perspective, the average decline in memory scores on this scale in patients with mild Alzheimer’s is approximately one to two points per year. These cases suggest that Alzheimer’s patients with serious ARIA may experience a significant and irreversible worsening of their memory and functional abilities.
NF52
Support Team
Support Team
Posts: 2953
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

Re: Donanemab and Lecanemab

Post by NF52 »

Julie G wrote: Tue Jan 02, 2024 10:12 am Thank you for sharing this, Nf52. Did you purchase the paper? I see it is behind a paywall.

Also, have you seen this thoughtful article from STAT News? While it goes beyond just discussing just ARIA-H, it points out a disturbing lack of openness about the severity of side effects from the manufacturer of Lecanemab. I'm hopeful that the request for more information about adverse events will be honored given what many consider to be a premature FDA approval.
Both scientific publications reporting clinical trial results as well as drug manufacturer-sponsored awareness campaigns targeting physicians tend to portray brain swelling and bleeding due to ARIA as mostly mild or even asymptomatic, typically observed during the first few weeks of treatment, and often resolving spontaneously. Moreover, the narrative goes, in the majority of patients who show mild symptoms, they simply have to go on a temporary hold until brain scans show that ARIA have resolved, at which point the medication can be safely continued.

However, this message largely ignores the worrying reality that 1-2% of patients treated with these drugs experience serious symptoms due to ARIA...

The drug manufacturers that have sponsored trials of the three FDA-designated “breakthrough” drugs have not addressed these obvious questions in peer-reviewed publications. But we do know that 12 patients in the Phase-3 trial of lecanemab developed serious adverse events due to ARIA. ...

These cases suggest that Alzheimer’s patients with serious ARIA may experience a significant and irreversible worsening of their memory and functional abilities.
Julie, the excerpt I shared is about 95% of an abstract (not a full article) published with other abstracts and available for $31 for 24-hour access, although I was able to print out a copy. I have seen "abstract only" articles used sometime to share information previously presented in conferences, although I don't know if in this case a more complete article will be coming.

I have read the STAT article and while I value the author's commitment to providing clear information to potential patients, it seems to me that he is finding fault with factual information, namely that
ARIA [is] mostly mild or even asymptomatic, typically observed during the first few weeks of treatment, and often resolving spontaneously. Moreover, the narrative goes, in the majority of patients who show mild symptoms, they simply have to go on a temporary hold until brain scans show that ARIA have resolved, at which point the medication can be safely continued.
ARIA is in fact mostly mild or asymptomatic. Except in about 1% of patients, it did resolve. And there is a recommended monitoring protocol that is not "simple" or a "narrative", rather it has been part of Lecanemab: Appropriate Use Recommendations published in the Journal of Alzheimer's Prevention in March 2023. [ J. Cummings, L. Apostolova, G.D. Rabinovici, et al. Lecanemab: Appropriate Use Recommendations. J Prev Alz Dis 2023; http:// dx.doi.org/10.14283/jpad.2023.30 ]

I think it's important to understand that what might be shared in a brief blurb from an article about Leqembi or a medical center offering it, is far different than the extensive screening process that any potential patient and support partner would experience. Here is just some of the detailed information about risks and deaths and counseling patients from that 16-page AUR (Appropriate Use Recommendations):
Patients with AD identified by their physicians as potential candidates for treatment with lecanemab must
understand the potential benefits and potential harms of treatment. Care partners and family members of patients
considering treatment with lecanemab must understand the benefits being sought, the occurrence of ARIA and
its possible consequences,
the possibility of infusion reactions, the need for twice monthly intravenous
infusions, and the requirement for MRIs at baseline (if not done within the past 12 months) and 3 or 4 scans in the first year of therapy for the safe management of ARIA. Patients seeking treatment with lecanemab will be informed that APOE genotyping is recommended, there must be confirmation of amyloid pathology in the brain with either amyloid PET or CSF studies, and an MRI scan taken within the past 12 months must be available or obtained to ensure that they do not have vascular or other types of pathology incompatible with lecanemab therapy (described above)...

The efficacy and safety of lecanemab are known only for the type of patients that were included in clinical trials
manifesting early AD with confirmed amyloid positivity (Tables 1 and 2).. The efficacy and safety of lecanemab for patients with AD dementia more severe than those included in the trials are not known, and recommendations for stopping lecanemab therapy when patients progress beyond mild AD dementia will depend on accruing more information...

A history of seizures may be related to symptoms of more severe amyloid related imaging abnormalities (ARIA; discussed in more detail below) including seizures and status epilepticus (6). We recommend excluding patients with any history of seizures until additional data are available.

Cerebral amyloid angiopathy-related inflammation/amyloid beta-related angiitis (CAA-ri/ABRA) increase the risk for ARIA (discussed below) and should exclude patients as treatment candidates....

Patients on anticoagulants are at higher risk for macrohemorrhage associated with lecanemab therapy. We recommend excluding patients from treatment with lecanemab if they are on warfarin, vitamin K antagonists, or direct oral anticoagulants (dabigatran, rivaroxaban, edoxaban, apixaban, betrixaban), or heparinuntil more evidence has accrued regarding the safety of administering lecanemab to patients on anticoagulants in the real-world practice setting. Severe, multi-focal brain hemorrhages leading to death were reported in a patient treated with tPA for acute stroke who had received lecanemab during an open-label extension (17).

Lecanemab may increase the risk of hemorrhage from concomitant administration of thrombolytics (intravenous or intra-arterial), and we recommend that patients on lecanemab not be treated with acute thrombolytics until safety evidence of their combined use is available. Participants with clotting disorders should be excluded...

Patients who are homozygous for the APOE4 gene are at increased risk for ARIA with lecanemab administration, (see below) and the risk may be increased with antiplatelet agents....

A cerebral macrohemorrhage represents a major central nervous system event often with enduring neurological
deficits.
A macrohemorrhage is more likely to occur when patients with pre-existing microbleeds or CAA-ri/ABRA are given anticoagulants (26, 27). Though numbers are small, the rate of cerebral macrohemorrhage in the CLARITY AD double blind and available open label periods was higher in patients on anticoagulation and in those on anticoagulation and lecanemab (Table 6). ARIA events with serious morbidity or mortality with lecanemab treatment are infrequent; three fatalities have been reported in the CLARITY AD open label extension which the site principal investigators attributed to lecanemab. One fatality occurred in an elderly [age 87] APOE4 gene non-carrier with cardiovascular disease on anticoagulation who developed a macrohemorrhage; a second death occurred in a patient homozygous for
APOE4 with a large vessel occlusion and pathologically confirmed severe CAA and vasculitis with multi-focal
hemorrhage following tPA; a third death occurred in a patient homozygous for APOE4 with severe ARIA-E and ARIA-H and a clinical syndrome resembling CAA-ri (16) (Table 6 (28)). We recommend that patients receiving anticoagulants not be treated with lecanemab (detailed above). If patients on lecanemab require treatment with
anticoagulants, we recommend stopping the lecanemab infusions
. ...

Taken together, APOE4 gene carrier status, especially APOE4 homozygosity, CAA-ri/ABRA, and anticoagulation are all risk factors for intracerebral bleeding. Caution should be used when considering lecanemab for patients who have these risk factors.

Recommended Exclusion Criteria:
More than 4 microhemorrhages (defined as 10 millimeter [mm] or less at the greatest diameter); a single macrohemorrhage >10 mm at greatest diameter; an area of superficial siderosis; evidence of vasogenic edema; more than 2 lacunar infarcts or stroke involving a major vascular territory; severe subcortical hyperintensities consistent with a Fazekas score of 3 (60); evidence of amyloid beta-related angiitis (ABRA); cerebral amyloid angiopathy-related inflammation (CAA-ri); or other major intracranial pathology that may cause cognitive impairment
At the very least, I think it is fair to say that information on the possible risks and fatalities is available, whether from STAT or here or the AUR recommendations and is likely to continue to improve with more time in the OLE and more people taking Leqembi.
4/4 and still an optimist!
Post Reply