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)