Lecanamab: Efficacy, Side Effects, and More

[NF52]

It seems reasonable to me that seeking to maintain insulin resistance, cardiac health, low oxidative stress, etc. is not inconsistent with recognizing a genetic predisposition to one (not the only) key pathogen seen in AD and looking for therapies to eliminate that toxin from the brain one it is evident. One is not incompatible with the other.

...CLARITY didn't test that nuanced hypothesis. We can presume that many who received the drug did have unaddressed risk factors for AD.

AT CTAD, Dr. Sharon Cohen, a neurologist and Director of the Toronto Memory Program (who noted receiving only institutional research fees, not personal consulting fees) spoke about the planned inclusion of people with common health factors in CLARITY to assess both the benefit and risks of lecanemab based on comorbidities.

Dr. Cohen noted in her talk that 50% of participants had two or more co-morbidities. Given the totals of 898 people on lecanemab, the slide shows that 95.7% had at least one of the following risk factors; of 898 on the placebo, it was 97.5 %. Yet analysis by types of comorbidity of CDR-SB scores favored lecanemab for each of the conditions, with the largest results (52% less decline) in those with heart disease. [I hope to see more detailed analysis by ApoE 4 sub-type by comorbidity at some point.]

Those at risk of progression of both MCI/mild Alzheimer's dementia, who also risk serious illness from obesity, diabetes, high blood pressure and heart disease may regret choices they made earlier in life-and so may have been more than willing to enroll in CLARITY and to continue in the Open-Label Extension, whether they were on placebo or lecanemab in the original phase. They may view that given their prognosis, they cannot let "the perfect to be the enemy of the good." Sadly, these are probably not typical of the people who enrolled in Dr. Bredesen's pilot study, and comparisons between outcomes may be comparing people at two very different levels of pathology and risk.

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[J11]

JulieG, not to be difficult, though I think I will avoid quoting due to my own idiosyncrasies.

I also enjoy thinking more about life in terms of science than the more day to day commercial, however with science questions we can never expect there to be a forthcoming answer possibly for decades. In 1906, Dr. Alzheimer noticed there there were 3 clear neuropathological divergences in his dementia patient: tau tangles, amyloid plaques and something else (cholesterol globules?). Over 100 years later some are still arguing about amyloid. This despite having decades of lab evidence confirming how dangerous amyloid is to the human brain. Amyloid is a known neurotoxin.

So, I will be very cautious about answering any why questions. For example, Why is there amyloid in the brain? Probably best and most accurate is to say we do not know. My reflexive response was that it can have to do with oral infection. The Cortexyme gingivitis trial had strongish results. Treating such underlying causes of AD could help enhance the anti-dementia effect of Lecanemab. Yet, as you mentioned there can clearly be other mechanisms involved. It would seem worthwhile to methodically eliminate these different causes of amyloid formation so that we could have some ultimately basal form of amyloid dementia. The less pathological noise the better. It still impresses me though how well the Clarity trial has kept the clinical entity of Alzheimer's in general in place. There are not that many other disease categories left which involve the potential treatment of tens of million of people. This is possibly one of the last undivided mass patient population left. From here on out it might be more in terms of hundreds of thousands of cancer site specific patients etc.. Yet, when they do additional amyloid mab studies they likely will find that a very wide range of typical AD patients do benefit.

Yes, I agree about looking for the underlying causes, though there is the truth I noted above that the process of science is more an accretion that collects over decades. It might be a fun moment in the sunshine now when there is finally something to (for some reluctantly) celebrate. Yet, for here on out it might be decades before there is much woohooing or high fiving.

In terms of operationalizing lecanemab, yes it needs to be carefully considered. There are 50 million e34s; there are 10 million e44s. Most of them would be decades before dementia onset. They have time to observe; they have time to wait. amyloid mabs are now in motion. We can look back a year ago and we had Aducanumab; we look now and we have IV Lecanemab -- Where will be in even a year from now? Subq Leca is now thought to be multiple times safer than IV Leca. Downdosing Leca from the label dose is know to enhance safety. Lowering amyloid without ARIA side effects is already in phase 3 with gamma entrainment. IV Lecanemab is clearly the starting point of the journey.

Of course, the one big positive with Leca is that they went through the clinical trial process; they can quantify safety they can quantify efficacy.
There are so many other treatments such as curcumin which probably lower amyloid but by how much and at what dose and under what clinical dosing conditions? These questions might never be answered. I remember even years ago reading an article about curcumin in AD and being impressed. They showed how curcumin went into mouse brain and directly attached to amyloid and lit up a radiotracer. Yet even still, I have never been able to consistently take curcumin over the long term because they never did the needed human research. If the science is done and I know that all I have to do is take this medicine and there will be this result then I can probably accept that. It is when you really are not sure what the result is that it becomes difficult to maintain chronic dosing.

With Lecanemab it is fairly clear what happens to amyloid levels in treated patients. There is a highly consistent and established distribution of amyloid removal. With mainstream medicine you have high confidence that a desired result (here amyloid removal) will occur as expected.

The curcumin research you quoted does seem encouraging, though it almost never has the scale of human clinical evidence that people want. After all of these many decades Lecanemab has finally made it over the bar. I suppose considering the expenses involved some might be motivated to include a range of enhancers such as curcumin, gamma entrainment etc. to Lecanemab, though for many Lecanemab might be the go to off the shelf treatment choice perhaps especially for some particularly when thinking in terms of nanodosing ahead of onset.

The pre-dosing approach opens up a new horizon in prevention. Waiting for people to have full onset of MCI or early AD is late in the illness course. Then they treat with upwards of a gram of Lecanemab; it is not ideal. Moving this to a lifestyle medicine with close to zero risk; fairly inexpensive; paid out of pocket and convenient dosing (i.e., subq) would make this almost a population scale treatment. It would be a treatment for everyone. This framing of Leca is now more how I see it. Of the tens of millions of those at genetic risk for AD only a very small proportion are actually experiencing cognitive onset.

If we could freeze that river of dementia or that conveyor belt of AD upstream of onset, then AD could largely end over the medium term. There will no longer be a steady flow of people progressing forward into cognitive decline: We could stop the entire progressing process! This is very exciting.

On the Celebration thread I order of magnitude estimated that this would have $5 trillion in net present value. When you through around trillion dollar savings people start to take notice. Wheels start turning; people start getting on side. A tax credit for Lecanemab pre-treatment would seem a good idea. Perhaps even a double tax credit. AD causes so much social dysfunction; you want people to prevent even early symptoms of cognitive impairment-- it costs too much not to do something.

[TheresaB]

but this is a place for many opinions.

You can say that again. The discussions in this thread here covered quite the spectrum, which has been interesting but it is to the point I'm questioning if we're losing track of what's most important. This website/organization’s mission is dedicated “to understanding the APOE-ε4 allele and how it affects health” and this thread specifically asks about efficacy and side-effects. So, with respect to APOE4 health and lecanemab/leqembi:

Efficacy
*For E4/4s - none per Eisai's US chairman (the drug manufacturer)
*Single 4s – unknown
*For the collective of all genotypes - a 27% slower decline or less than half a point improvement on a 18 point scale based on subjective measure. But results were inconsistent. It works better in those over 65, and better in men with no significant effect in women and as noted above no improvement for 4/4s.

Side-effects
*Death - three deaths in the trial have been attributed to leqembi's use, admittedly we will never know with absolute certaintly
*Brain swelling -- About 12.6 % of patients (full trial population – all genotypes) who got leqembi in the clinical trial developed brain swelling, compared with 1.7% of those in the placebo group.
*Brain bleeds -- About 17% of the leqembi group (full trial population – all genotypes) experienced brain bleeds, compared with 9% in the placebo group.

We don’t know the breakdown of brain bleeds by genotype, but it is important to note that 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, thus indicating APOE4s are at greater risk for brain bleeds on lacenemab/leqembi.

So, as Dr. Richard Isaacson, director of the Alzheimer’s Prevention Clinic in the Center for Brain Health at Florida Atlantic University’s Schmidt College of Medicine said to CNN,

“I will prescribe this drug in the right person, at the right dose and in a very carefully monitored way, but this drug is not for everyone … I would do genetic testing for APOE4 first. I would have a frank discussion with my patients.

(I added bold font in that quote added for emphasis)

[karelena]

When I was being evaluated for the study they said I qualified to have a brain amyloid PET scan based on my amyloid blood test (amyloid 42/40 ratio). My PET scan result was < 20 centiloids so I did not qualify to proceed further in the study, as I mentioned in an earlier post. But I was worried about the blood test result, and they said they cannot give me the quantitative result, so I asked my doctor to order the test from Quest along with a bunch of other labs I was having. The test takes about 2.5 weeks to result and my result was "lower risk." The interpretation is "lower risk" or "higher risk." There is a number also but I don't know what to make of it. I have been looking for a table of norms, but I could not find one. Are there norms by age? Most of the papers about this test are using cohorts who have had PET amyloid scans or CSF amyloid testing, in order to see how this test correlates. This population is mainly older and there is a lot of MCI and AD in these subjects. Is there a number that, in addition to APOE4/4 status, predicts brain PET amyloid positivity or the risk of becoming brain PET amyloid positive in the future? I read that the test by itself predicts PET positivity as well as the risk of conversion to positivity in the next 4 years. So I'm not sure how to interpret my result. Would it still be "lower risk" if they took my APOE 4/4 status into account? I am happy it is not low though.

[NF52]

... I have been looking for a table of norms, but I could not find one. Are there norms by age?...
Is there a number that, in addition to APOE4/4 status, predicts brain PET amyloid positivity or the risk of becoming brain PET amyloid positive in the future? I read that the test by itself predicts PET positivity as well as the risk of conversion to positivity in the next 4 years.

My understanding is that the test was designed not to predict conversion to amyloid positivity within 4 years; only to predict with about 81% accuracy those with "positive" amyloid PET scans who might show changes in cognition over the next 4 years (i.e. the range of prevention clinical trials).

The good news is that you are amyloid negative; the frustrating news is that is will probably be a few years before screening data from the AHEAD (lecanemab) and Trailblazer (donanemab) trials show what the results are in people in their mid-to late-50's vs those 60-65. It just hasn't been used enough and even in older populations, they are comparing Person A, age 60 with Person B age 65 to predict conversion to positivity, rather than following people for years.

But here are some charts that address your specific question:

APOE, Age &amp; Amyloid PET SUVR.png

You can see that at age 65 about 80% of those in this study were at what AHEAD would call the "intermediate" stage of 120-130 centiloids (or 20-30).
Association Between Apolipoprotein E ε2 vs ε4, Age, and β-Amyloid in Adults Without Cognitive Impairment
https://doi.org/10.1001%2Fjamaneurol.2020.3780

Big caveats: The mean age of these participants in the A4 trial was 71, significantly older than you, with a range from 65 to 85 and all had a family history of AD.

From talks I've heard, in prevention trials, the goal isn't to capture people likely to be diagnosed with MCI or mild AD within 4 years, but to use an array of cognitive tests sensitive enough to capture the very earliest signs of cognitive changes BEFORE a diagnosis of MCI or mild AD. A comparison might be to IQ tests and TBI: a score of 85-115 is considered within one standard deviation (S.D) and falls under "average IQ". But if someone with an IQ of 130 has a moderate brain injury, they may show specific deficits in planning and organization or language skills, and might now test as having an IQ of 117. While still "above average", they have a statistically significant change in performance and likely feel that even with a "cognitively normal IQ".

In a prevention trial, most may continue to have normal cognition at the end of 4 years, but if those on placebo overall show a decrease of 15% from their own baseline level, even if still cognitively normal,(with some perhaps in MCI), while those on the drug show only a slight changes in scores, the amyloid positivity test has accurately identified people who would benefit from an anti-amyloid drug at the pre-impairment stage.

[karelena]

Thank you NF52 for your reply. Those are some scary charts for E44s, 80% amyloid positivity at age 65. So much higher than the other groups. Do you happen to know the conversion formula from SUVR to centiloids? Also, I was asking about the amyloid blood test, The AB42/40 ratio in blood (plasma). For the Quest test it says > or = 0.160 is "lower risk" and < 0.160 is "higher risk." I was looking for data about norms by age for those values. I was > 0.160, but not sure what it means because maybe I am still low for my age. Is the mean value in the normal population in their late 50s 0.18, 0.2, 0.3, etc? I could not find that info.

[NF52]

Thank you NF52 for your reply. Those are some scary charts for E44s, 80% amyloid positivity at age 65. So much higher than the other groups. Do you happen to know the conversion formula from SUVR to centiloids? Also, I was asking about the amyloid blood test, The AB42/40 ratio in blood (plasma). For the Quest test it says > or = 0.160 is "lower risk" and < 0.160 is "higher risk." I was looking for data about norms by age for those values. I was > 0.160, but not sure what it means because maybe I am still low for my age. Is the mean value in the normal population in their late 50s 0.18, 0.2, 0.3, etc? I could not find that info.

The algorithm for the "low risk" result does take into account your age and 4/4 status, which I forgot to include in my earlier reply. I've heard that explained in conference presentations and found that in this physician reference: https://precivityad.com/healthcare-providers-faqs

The PrecivityAD® test uses mass spectrometry to quantify plasma concentrations of amyloid beta 42 and 40 (Aβ42 and Aβ40) and to determine the presence of Apolipoprotein E proteotype (equivalent to ApoE genotype)...The Aβ42/40 ratio and ApoE genotype, as well as the patient’s age, are incorporated into the test’s statistical algorithm to estimate an Amyloid Probability Score (APS)—the test result.

I wonder if your "low risk" score of ≥ 0.160 is consistent with this 2019 study High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis by the researchers who developed the PrecivityAD® test : [Note: it's behind a paywall, but available for $39.]

From these two images, it looks like people with scores ≥0.16 were at very low risk of a positive PET scan, and also were likely to have a very low, if any, amyloid PET centiloid score, since the scatterplot shows most scores around zero for that group.. They settled on a score of approximately ≤0.12 for a high likelihood of a positive result . It's possible the study organizers for AHEAD 3, looking for those with "intermediate" levels of between 20-40 centiloids, weighted ApoE 4/4 carriers higher in deciding who to refer for a PET scan. That's pure speculation on my part of course!
Nancy

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[NF52]

The Alzheimer’s Disease and Related Disorders Therapeutics Work Group, a group that includes researchers who have been principal investigators (PIs) at various study sites for lecanemab, last week published in The Journal of Prevention of Alzheimer's disease this report: Lecanemab: Appropriate Use Recommendations

The article is available in PDF form for download and notes that:

Appropriate Use Recommendations (AURs) were developed to assist in guiding the use of new agents such as lecanemab into clinical practice and patient care and to anticipate challenges that may arise with use of a new therapy in real-world settings. ... We describe the appropriate patient for treatment with lecanemab; dosing, administration, and monitoring of lecanemab; apolipoprotein E (APOE) genotyping of lecanemab treatment candidates; discussions with patients and care partners concerning lecanemab treatment; and clinician and workflow considerations regarding lecanemab use in practice. We describe AD-related populations for which there is no available information on the safe use of lecanemab.

[p2.]
This is a drug in which more than 2/3 of those on the drug were ApoE4 carriers, providing extensive experience for those seeking information:

In the CLARITY AD trial, 69% of participants had at least one allele; 53% were heterozygotes and 16% were homozygotes (2). The APOE gene produces the APOE protein, and some laboratory tests determine APOE status by assessing the patient’s proteotype. APOE4 carriers (especially homozygotes) are at increased risk for ARIA, symptomatic ARIA, and recurrent ARIA (discussed below; shown in Table 5). They are at increased risk for CAA-ri/ABRA, an additional risk factor for ARIA. We recommend APOE genotyping of all treatment candidates before initiating lecanemab therapy. This information will inform risk discussions and help guide safety considerations.

Below is an example of the kind of data they offer. The last four columns provide data on Apoe4 heterozygous and homozygous carriers in both placebo and lecanemab groups.

ARIA rates reported for Lecanemab CLARITY trial.png

They also provide specific MRI recommendations and probable criteria of cerebral amyloid antipathy (CAA) which may reduce the risk of severe reactions, and recommend against use of "clot-busting" drugs.

MRI criteria for probable CAA-related inflammation.png

[NF52]

This is the url for the ADCOM for lecanemab. https://www.fda.gov/advisory-committees ... ee-meeting The webpage states that the related documents will be posted 2 days before the meeting.

Thanks to J11 for catching the FDA Advisory Committee Hearing on lecanemab (Leqembi™) on June 9, 2023, from 10 a.m. to 5 p.m. Eastern Time. Officially this is called the Peripheral and Central Nervous System Drugs Advisory Committee; Notice of Meeting; Establishment of a Public Docket; Request for Comments

If you are interested in providing comments by mail or online, you can follow J11's helpful link to do so, using the Docket # FDA-2023-N-1114-000. Read the fine print about having your name appear, or not.

As a refresher, the FDA granted "accelerated approval" to lecanemab (Leqembi™) on January 6, 2023. The accelerated approval was based on the Phase 2 trial, with about half the participants in the Phase 3 CLARITY trial. Safety, efficacy in removing amyloid plaques and clinical benefit, and sub-group data on benefits, risks and deaths in both Phase 2 and Phase 3 trials will likely be the focus on the June 9 hearing.

Here's the official FDA statement from January 6: https://www.fda.gov/news-events/press-a ... -treatment

Leqembi was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is an unmet medical need and a drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients...

Researchers evaluated Leqembi’s efficacy in a double-blind, placebo-controlled, parallel-group, dose-finding study of 856 patients with Alzheimer’s disease. Treatment was initiated in patients with mild cognitive impairment or mild dementia stage of disease and confirmed presence of amyloid beta pathology. Patients receiving the treatment had significant dose- and time-dependent reduction of amyloid beta plaque, with patients receiving the approved dose of lecanemab, 10 milligram/kilogram every two weeks, having a statistically significant reduction in brain amyloid plaque from baseline to Week 79 compared to the placebo arm, which had no reduction of amyloid beta plaque. These results support the accelerated approval of Leqembi, which is based on the observed reduction of amyloid beta plaque, a marker of Alzheimer’s disease.
The prescribing information for Leqembi includes a warning for amyloid-related imaging abnormalities (ARIA), which are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur. ARIA most commonly presents as temporary swelling in areas of the brain that usually resolves over time and may be accompanied by small spots of bleeding in or on the surface of the brain, though some people may have symptoms such as headache, confusion, dizziness, vision changes, nausea and seizure. Another warning for Leqembi is for a risk of infusion-related reactions, with symptoms such as flu-like symptoms, nausea, vomiting and changes in blood pressure. The most common side effects of Leqembi were infusion-related reactions, headache and ARIA.

As specified in the prescribing information...Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of disease... The labeling also states that there are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.