Lecanamab: Efficacy, Side Effects, and More

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Re: Lecanamab: Efficacy, Side Effects, and More

Post by J11 »

Percentiles 1a.png



TheresaB, thank you very much for responding. I am glad to hear different perspectives. On my thread it is mostly a monologue and an echo chamber. Always good to hear other voices.

I have reposted the figure from my previous post. Carefully consider this figure. What does it show? For a substantial proportion of the Lecanemab patients in the phase 2 the benefit is likely much more than the average 0.45 benefit. 0.45 and 27% are only averages. Yet, AD patients really are not somehow clones.

The pharma companies have done their best to create this idea that there is Alzheimer's in general; "You have amyloid dementia?" "OK, that's Alzheimer's. Here's a mab". Organizing treatment in this way means that there is a maximal homogeneous market to sell to. AD is in a league of its own in modern medicine. There are no other diseases where there are potentially tens of millions of genetically similar patients to treat. This is the final frontier of medicine. After AD all that's left are highly fragmented patient groups exhibiting a constellation of indistinct syndromes with likely genetically heterogeneous causes.

[For me now I am hoping that whatever we've got that causes dementia that it is Alzheimer's. People with AD are now the lucky ones. All the other patients that have some other neurodegenerative illness that is similar to AD are in a much worse position. There are so many people who might go to their doctor's office on Monday morning and ask for Lecanemab that will be told that they do not actually qualify for treatment. This would be very hard to cope with. If it isn't AD but only something AD like, then I am very unclear what the next line of treatment would be--- honestly, there probably isn't another line.

As much as we might like complaining about the price, and the possibility of side effects and the modest size of average benefit, having something that is on the shelf and potentially there for you if you need it changes everything. I remember when we prayed for anything year after year and nothing ever arrived. We were supposed to invent our own treatment?


Yet here we are and AD has this near euphoric buzz. AD is a once in a century medical breakthrough. AD could essentially be cured over the next year or two. Lecanemab is only the first man on base. There is a whole team of heavy hitters that are ready to step up to the plate.]

Yet, from Clarity and other large AD trials, this "Alzheimer's in general" framework has actually worked out quite well. With Clarity, almost every subgroup's 95% confidence interval showed benefit on treatment (for CDR-sb) except oddly APOE e4s (I am not sure whether this truly holds when you look at the totality of the results on the secondaries, though). Of interest in Clarity, the African and Hispanic patients while still having ~0.5 point gains, actually had large percentage benefit due to their slow placebos. It will obviously be of interest to see if this is replicated in further trials. It is possible then for some subgroups that 0.5 CDR-sb would itself have a large effect.

Look at the above figure. The red vertical bars are 1 CDR-sb benefit between the bottom blue line (high dose) up to the placebo (black line). 1 CDR-sb is a substantial treatment benefit! As can be seen, those on treatment (blue line) declined by about 0.5 for most of the middle range of percentiles; for the placebo in much of this range, they declined by 2- 3 CDR-sb. For these middle percentile patients the patients did not receive a 27% benefit on CDR-sb, but more like ~50%. They benefited a lot!

For patients this sort of data presentation could make their treatment choice much easier. If the percentile cognitive distributions for treatment and placebo are similar, then clearly treatment is obviously the way to go. It is surprising how few of the treated patients actually entered into a catastrophic down turn (~10%). Further, clinical trials do not capture the real world effect of patients who do not respond to treatment selecting against further treatment. It is notable that if the ~20% of the rapid responders on Lecanemab stopped treatment due to futility, then essentially all of those on treatment would derive substantial treatment benefit. Clinical trials do not allow for this. Patients who are simply not responding will continue to receive treatment even when it is obviously futile. From a doctor's perspective, they will see all the patients that were the responders in their offices and they will all do well. These patients will all be stable and those patients without adequate insurance or on a wait list control will endlessly progress into severe dementia. From their simple observational perspective, Lecanemab will obviously become seen as the go to best clinical practice.

The media and much of the online chatter about Lecanemab seems so uninformed to me. All they ever contribute is the 27% reduction in decline topline. If anything, I have encountered "27% reduction in decline" more than quadrillions of times. I am sure that there are trained pigeons that could do better. However, there is more to it than the 27%.

As we can see above when you actually start to look under the hood the numbers start to jump around quite a bit. So, from these admittedly smallish n values, I could reasonably say something like at least 30% of the phase 2 treated Lecanemab patients had a 1 point CDR-sb or more benefit over placebo. This would make people sit up and take notice. 1 CDR-sb benefit is what the critics claim is the minimally needed clinical benefit for people to notice a benefit. Well, there it is! At least ~30% of patients would notice this benefit. Such a benefit clearly would be clinically beneficial for them. As a dementia caregiver, I would clearly have noticed such an effect.


In terms of Lecanemab safety I will add this url
https://www.desmos.com/calculator/acvb8xqzut
Drag the slider on equation line 43 on the left.
When the purple and black moving lines to the top "close the scissors" at around 15.7 months then
treatment and placebo have equal ARIA-E risk. As you move further forward in treatment, treatment becomes increasingly less risky than placebo.


What this shows is the simulated rate of ARIA with Lecanemab which is close to that observed in Clarity.
The purple tangent to the top is showing the marginal rate of ARIA for those treated with Lecanemab.
The corresponding bottom purple curve shows the slope of this line.

What I found of interest is that after around 15 months the rate of ARIA for those on treatment and those on placebo equalizes. From that point forward those on treatment would have a lower ARIA-E rate. Clearly this will of interest to have verified in the long term extension. Why would such a result occur? As I noted previously, not treating ARIA-E in placebo does not mean it will go away. One expects ARIA-E in placebo to continue at a constant if not increasing rate forever. However, those on Lecanemab once they have cleared out their CAA might then have a future largely without all of that CAA pathology. Even that benefit might be enough to encourage people to receive micro-dose Lecanemab. Once Lecaneamb is on the market all of those pre-AD patients do not have to wait to be on the officaial label to start treatment. Lecanemab will naturally become safer spontaneously as patients will become lower and lower risk through time. At some point in the future newly on label Lecanemab patients might no longer experience any ARIA.



dona 2a.gif
This is where it gets even more interesting. I never got around to posting much about Donanemab due to the rejection by the FDA of its accelerated approval. However, as the figures above show, Donanemab would have begun the conversation about the validity of the 27% mantra. Donanemab is rotating to ADAS-cog and iADRS as the psychometric instruments of record for Trailblazer. I can see that these are better measures than CDR-sb.

The point of interest is that when you do move to objective tests such as ADAS-cog the benefit is even larger than CDR-sb. It seems like a weak argument to say "Well we do not like CDR-sb because it's a subjective test" "OK, let's use an objective test like ADAS-cog which is an objective test. Oh, and the benefit is even greater on it than with CDR-sb."

ADAS-cog is an objectively measured cognitive test that will have more forward reaching predictive power than CDR-sb which would have more of a back reaching power. Basically, with ADAS-cog, a question would be can you remember these 10 items versuses How has your loved one been able to perform activities over the last 3 months and how has this changed. ADAS-cog while more volatile gives deeper insight into cognitive performance at the time of the test.

In the bottom figure above, notice that moving from CDR-sb to ADAS-cog changed the reported treatment benefit from 23% to 39%. This has been a consistent feature of the last few AD trials. The benefit of treatment is typically quite a bit more on ADAS-cog. If you linearize Clarity, then it also posted a high 30ish% result on ADAS-cog, though it shows more volatility.

Now go to the figure one up. What happens when you add in tau selection as was done with Trailblazer? The result is no longer 39% but 50%! I do not think people are adequately prepared for an AD treatment effect of 50%. 27% -- it doesn't seem that much. 50% cannot be dismissed. And it is not so much that Donanemab is all that much better of a treatment, it is simply that they chose the patients by dual amyloid-tau. Lecanemab should also show this same effect.


Regarding the differential effects of Lecanemab in Clarity offering more benefit for older versuses younger and men versuses women, I think there are explanations. With the older patients, they would be typically more in the clear decline stage of the illness. For some of the younger patients it is more that they have not yet reached the endless decline stage. I suspect a fair few of these patients were more motivated by Lecanemab treatment as a preventative than as a true clinical anti-dementing agent. Part of the reason why ADAS-cog is likely a better measure in the trials is that is able to pick up on the subtler forms of cognitive impairment that was present. These subtleties would not be captured by tests such as CDR-sb. The patients might fake bad on a test such as CDR-sb, though it is not possible to fake good on the ADAS-cog. Also of importance is that men did better on Lecanemab probably because men are bigger than women (i.e. heavier). Lecanemab is dosed by mg/kg. Men have more kg to work with. Research supported this idea. Women can weigh in at 50 kg; men can weigh in at 100 kg.
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Last edited by J11 on Sat Jan 21, 2023 10:35 pm, edited 5 times in total.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by karelena »

TheresaB wrote:There’s an alternative with BETTER results, benign side-effects, and no deaths vs the 3 deaths that have been alleged to leqembi.
Screenshot 2023-01-21 153935.jpg
I don't think we can directly compare the data from the article cited in the bar graph above (by Toups etal) with the lecanemab study. For the Toups study there were only 25 participants and no control group. (Clarity had 1795 participants (898 received the study drug and 897 were controls)). For the Toups study they cited "historical controls" from other articles with different demographics and inclusion/exclusion criteria. In the Toups study they excluded anyone with a MoCA score < 19. The range in their participants was MoCA 19-30, where > 25 is normal. The average baseline MoCA score in their study was 24.6. The final mean score was 27.6, so presumably that is the metric they are using in the graph, although it looks like the top of their arrow is higher than 3. If so, it is very very misleading since they are comparing MoCA scores to CDR-sb which are completely different tests. The other measures in the Toups study were Alzheimers questionnaire; they required a score of 5, and 4 or less is normal, CNS VS score < 50%ile (50% of the normal population has scores in this range) or NCI < 70%ile. They did not use any of the measures in the lecanemab study: CDR-sb, ADASCog-14, ADCOMS or ADCS MCI-ADL It just looks like many of the small number of Toups participants were mildly affected and may have just had age related cognitive decline and were not on the spectrum of AD. They probably did not use CDR-sb because they would have had normal or near normal scores, since it is similar to the AQ. It is just not the same as a real scientific study so the conclusions one can make are very limited. I wish they had done a larger and better study. I also wish they had not presented that graph because it is not an accurate representation of data.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by karelena »

The graph from TeresaB's post on page 4 of this thread:
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by Julie G »

I don't think we can directly compare the data from the article cited in the bar graph above (by Toups etal) with the lecanemab study.
Completely agree. These are apples and oranges: one is a small proof-of-concept clinical trial that used a personalized multifactorial approach without a control group, whereas CLARITY was a large monotherapuetic trial with a control group.
In the Toups study they excluded anyone with a MoCA score < 19. The range in their participants was MoCA 19-30, where > 25 is normal.
Re. cognition, I think the dataset was pretty similar although completely different cognitive measures were used. For CLARITY, an MMSE between 22 and 30 (top end) was accepted, with >25 being normal. Their mean was 25.6 which would be considered normal.
They did not use any of the measures in the lecanemab study: CDR-sb, ADASCog-14, ADCOMS or ADCS MCI-ADL It just looks like many of the small number of Toups participants were mildly affected and may have just had age related cognitive decline and were not on the spectrum of AD. They probably did not use CDR-sb because they would have had normal or near normal scores, since it is similar to the AQ.
Lots of speculation here. Given that the AQ and CDR correlate so well, it's worth noting that the Toups team DID use the AQ with >5 as inclusionary (5-14 = MCI , whereas CLARITY used a CDR score of 0.5-1.0 as incluclusionary (0.5 = questionable, 1 = present). From the Toup's paper:
The AQ-21 is an informant-based subjective assessment with sensitivity and specificity for amnestic MCI and Alzheimer's disease of over 90% [15], answered by the significant other or study partner, with scores ranging from 0 (no problems noted) to 27 (all positive responses to questions regarding impairment). A score of 5–14 is compatible with mild cognitive impairment, and 15–27 is compatible with dementia. Twenty-two of the patients in this study had AQ-21 of 6–14 and three had AQ-21 of 15–18.
The graph that Theresa shared appears to be PR and wasn't used in the paper, but I'm glad that you question the MoCA score there.
The average baseline MoCA score in their study was 24.6. The final mean score was 27.6, so presumably that is the metric they are using in the graph, although it looks like the top of their arrow is higher than 3
Toups and team address that here:
Third, the MoCA score improvements reported here suffered from a ceiling effect, because several patients with MCI who met the entry criteria based on cognitive complaints, AQ-21 >5, and qualifying CNS Vital Signs scores had MoCA scores of 28–30 at baseline. With the inclusion of those 7 patients, the mean change in MoCA score was +2.96, whereas removing those patients increased the mean MoCA change to +3.89. Nonetheless, even with the inclusion of those patients, the improvement in MoCA scores was significant. Furthermore, the more sensitive CNS Vital Signs test [19] provided a dynamic range for these 7 patients with baseline MoCA of 28–30 (despite clear cognitive complaints and AQ-21 >5), and 6 of the 7 improved their NCI, with the other remaining unchanged.
The Toup's team does have a larger clinical trial underway with a control group.
It is just not the same as a real scientific study so the conclusions one can make are very limited. I wish they had done a larger and better study.
For us 4/4s especially, science moves too slowly. I look forward to more results from both camps, but (like everyone else) would prefer to take an infusion if it yielded a similar result without risk of harm.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by J11 »

Julie G, I am interested in your take on possibly pre-dosing with Lecanemab. Lecanemab is now on the market. Would it make sense to you to think more in terms of reducing CAA risk than even the AD risk? In the phase 2 trials, the risk of ARIA decreased quite a bit as the dosing declined. Many epsilon 44s have latent CAA pathology that has never been treated. This CAA is in fact what drives the ARIA problems.

I realize that I asked you this exact same question on December 2nd, as a hypothetical. This time it is not so hypothetical. Lecanemab is now on the market. One could remove the question of risk by continuing to reduce the dose. The dose that one could choose could almost be homeopathic yet it would still remove amyloid. 1 mg/kg dosing still removes quite a bit of amyloid fairly fast-- this is what drives ARIA. What you really want for CAA clearance is fairly modest amyloid outflow from the brain over time. This basic strategy would seem to have some place where marginal risk = marginal benefit even for those who are highly risk avoidant. This is all the more true when one realize that doing nothing when there exists so much lurking amyloid in many of those at risk for AD also has significant risk potential.
Also at such nano-dosing the actual potential out of pocket cost could be minimal. Some people simply do not want to think in terms of the possibility of taking on any external risk from treatment, while the risk of ARIA-E in Clarity in placebo was ~7%.


We are already seeing evidence that Lecanemab could reduce ARIA-E and possibly other brain risks. Below is from one of my other posts. Even after ~16 months of Lecanemab treatment ARIA-E risk is lower than placebo when on full treatment. Clearly, will also want to see a longer term result of this for confirmation.

"In terms of Lecanemab safety I will add this url
https://www.desmos.com/calculator/acvb8xqzut
Drag the slider on equation line 43 on the left.
When the purple and black moving lines to the top "close the scissors" at around 15.7 months then
treatment and placebo have equal ARIA-E risk. As you move further forward in treatment, treatment becomes increasingly less risky than placebo."
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by TheresaB »

J11 wrote: Mon Jan 23, 2023 7:10 pm I realize that I asked you this exact same question on December 2nd,
Another reminder to you that if you direct a question or comment to a specific person, you need to learn to quote them, otherwise the individual won’t realize the question/comment exists unless they just happen to stumble upon it.

In the meantime, here’s an op-ed piece by Adriane Fugh-Berman, a professor in the departments of Pharmacology and Physiology and in the Department of Family Medicine at Georgetown University Medical Center, where she’s also the director of PharmedOut, a research and education project that promotes evidence-based prescribing. Published in the Baltimore Sun.

I added bold font to the op-ed piece for emphasis to areas of interest to us APOE4s.

Too soon to celebrate new Alzheimer’s drug | GUEST COMMENTARY
https://www.baltimoresun.com/opinion/op ... story.html

A treatment that improves Alzheimer’s disease would be a great advance, but Leqembi (lecanemab), which recently received accelerated approval from the FDA, is not that drug. Yes, lecanemab slows decline to an extent detectable on a test, but not to an extent that a relative or caretaker would notice. This drug doesn’t actually make anything better. It just slows the rate that someone goes downhill over 18 months — by less than half a point on an 18 point scale. And we don’t know whether things get better or worse after that.

Leqembi is similar to Aduhelm (aducanumab), approved last year by the FDA, despite its advisory committee soundly rejecting it. Leqembi is slightly more effective — although it had no significant effect in women, those under age 65 and people who have two copies of APOE4, a gene variant that increased Alzheimer’s risk. Both Aduhelm and Leqembi cause brain bleeds, which can be fatal.

Leqembi and Aduhelm destroy amyloid plaque, a kind of protein that patients with Alzheimer’s have more of in their brains. It’s not clear whether amyloid causes Alzheimer’s, because many patients with brains full of amyloid have no symptoms of dementia. Amyloid may be a harmless marker of disease — or may even be a protective effort by the body to repair damaged cells. In any case, amyloid can fuse to blood vessel walls, and when the amyloid is attacked by a drug, the blood vessels in the brain may leak, sometimes catastrophically. Small bleeds are common; Aduhelm caused brain bleeding or swelling in 40% of patients; Leqembi is slightly less harmful, at about 21.5%, but that’s still one out of five patients.

Three people died from bleeding while taking Leqembi in studies done before the drug was approved. That’s especially concerning, because people in experimental trials tend to be healthier than people in the general population, so problems that show up in people who volunteered for a clinical trial are likely to be much greater in the general population. Bleeding is also likely be more common in those on anticoagulant drugs — blood thinners — which are given to elders with atrial fibrillation (a common condition) to reduce the risk of stroke. Two of three of the deaths during lecanemab treatment were in patients on blood thinners.

People with the APOE4 allele are more likely to have Alzheimer’s disease — and are also the most likely to bleed from amyloid-busting drugs. Black patients are more likely to have APOE4 variations, and thus more likely to have risks of bleeding. Only 2.6% of the subjects in the lecanemab trials were Black, only slightly better than the less than 1% of Black subjects in the Aduhelm studies. Nonetheless, Biogen and Eisai, collaborating companies for both Leqembi and Aduhelm, have targeted organizations of color to promote their drugs.

Biogen/Eisai have promoted a “Brain Guide” that reinforces the notion that mild memory changes must be addressed medically, unecessarily worrying elders. The companies also promoted a test for mild cognitive impairment that anyone would fail (do you ever lose your “train of thought or the thread of conversations, books, or movies”?) on a now-defunct website called “It’s Time We Know.” The website seemed designed to make anyone who misplaced their keys think that they had mild cognitive impairment (MCI), an ill-defined condition that is a risk factor for Alzheimer’s. In fact, MCI is often due to medications, fatigue or depression. And even when MCI is not caused by these factors, it often remains stable, regresses and can disappear entirely.

The Alzheimer’s Association, which takes money from Biogen, called the approval of Aduhelm a “victory for people living with Alzheimer’s and their families.” Of Leqembi, the Association claims that this treatment addresses “the underlying biology of Alzheimer’s and changes the course of the disease in a meaningful way for people in the early stage” and, again without evidence, that “individuals will have more time to participate in daily life and live independently.” UsAgainstAlzheimer’s calls the accelerated approval of Leqembi “tremendous news and a true milestone in the fight against Alzheimer’s.”

Instead of promoting drugs that don’t improve functioning, we should focus on preventing dementia through exercise, smoking cessation and treating high blood pressure, high cholesterol and diabetes — all of which reduce cognitive decline- and many other chronic diseases. Hearing aids also lower the risk of dementia.
The Alzheimer’s Association, predictably, has been pressuring the Centers for Medicare and Medicaid Services (CMS) to have Medicare cover Leqembi. There’s no reason to think that Leqembi will be marketed any more responsibly than Aduhelm. It’s up to physicians, patients, and CMS to reject an expensive drug that improves no symptoms and puts users at risk of fatal bleeds.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by NF52 »

Theresa, I took the liberty of adding quotes to Dr. Fugh-Berman's op-ed, so that members can see it self-contained and respond, if desired. I happen to disagree with several of her points, but this is a place for many opinions.
TheresaB wrote: Wed Jan 25, 2023 5:43 am...
In the meantime, here’s an op-ed piece by Adriane Fugh-Berman, a professor in the departments of Pharmacology and Physiology and in the Department of Family Medicine at Georgetown University Medical Center, where she’s also the director of PharmedOut, a research and education project that promotes evidence-based prescribing. Published in the Baltimore Sun.

I added bold font to the op-ed piece for emphasis to areas of interest to us APOE4s.
Too soon to celebrate new Alzheimer’s drug | GUEST COMMENTARY
https://www.baltimoresun.com/opinion/op ... story.html
A treatment that improves Alzheimer’s disease would be a great advance, but Leqembi (lecanemab), which recently received accelerated approval from the FDA, is not that drug. Yes, lecanemab slows decline to an extent detectable on a test, but not to an extent that a relative or caretaker would notice. This drug doesn’t actually make anything better. It just slows the rate that someone goes downhill over 18 months — by less than half a point on an 18 point scale. And we don’t know whether things get better or worse after that.

Leqembi is similar to Aduhelm (aducanumab), approved last year by the FDA, despite its advisory committee soundly rejecting it. Leqembi is slightly more effective — although it had no significant effect in women, those under age 65 and people who have two copies of APOE4, a gene variant that increased Alzheimer’s risk. Both Aduhelm and Leqembi cause brain bleeds, which can be fatal.

Leqembi and Aduhelm destroy amyloid plaque, a kind of protein that patients with Alzheimer’s have more of in their brains. It’s not clear whether amyloid causes Alzheimer’s, because many patients with brains full of amyloid have no symptoms of dementia. Amyloid may be a harmless marker of disease — or may even be a protective effort by the body to repair damaged cells. In any case, amyloid can fuse to blood vessel walls, and when the amyloid is attacked by a drug, the blood vessels in the brain may leak, sometimes catastrophically. Small bleeds are common; Aduhelm caused brain bleeding or swelling in 40% of patients; Leqembi is slightly less harmful, at about 21.5%, but that’s still one out of five patients.

Three people died from bleeding while taking Leqembi in studies done before the drug was approved. That’s especially concerning, because people in experimental trials tend to be healthier than people in the general population, so problems that show up in people who volunteered for a clinical trial are likely to be much greater in the general population. Bleeding is also likely be more common in those on anticoagulant drugs — blood thinners — which are given to elders with atrial fibrillation (a common condition) to reduce the risk of stroke. Two of three of the deaths during lecanemab treatment were in patients on blood thinners.

People with the APOE4 allele are more likely to have Alzheimer’s disease — and are also the most likely to bleed from amyloid-busting drugs. Black patients are more likely to have APOE4 variations, and thus more likely to have risks of bleeding. Only 2.6% of the subjects in the lecanemab trials were Black, only slightly better than the less than 1% of Black subjects in the Aduhelm studies. Nonetheless, Biogen and Eisai, collaborating companies for both Leqembi and Aduhelm, have targeted organizations of color to promote their drugs.

Biogen/Eisai have promoted a “Brain Guide” that reinforces the notion that mild memory changes must be addressed medically, unecessarily worrying elders. The companies also promoted a test for mild cognitive impairment that anyone would fail (do you ever lose your “train of thought or the thread of conversations, books, or movies”?) on a now-defunct website called “It’s Time We Know.” The website seemed designed to make anyone who misplaced their keys think that they had mild cognitive impairment (MCI), an ill-defined condition that is a risk factor for Alzheimer’s. In fact, MCI is often due to medications, fatigue or depression. And even when MCI is not caused by these factors, it often remains stable, regresses and can disappear entirely.

The Alzheimer’s Association, which takes money from Biogen, called the approval of Aduhelm a “victory for people living with Alzheimer’s and their families.” Of Leqembi, the Association claims that this treatment addresses “the underlying biology of Alzheimer’s and changes the course of the disease in a meaningful way for people in the early stage” and, again without evidence, that “individuals will have more time to participate in daily life and live independently.” UsAgainstAlzheimer’s calls the accelerated approval of Leqembi “tremendous news and a true milestone in the fight against Alzheimer’s.”

Instead of promoting drugs that don’t improve functioning, we should focus on preventing dementia through exercise, smoking cessation and treating high blood pressure, high cholesterol and diabetes — all of which reduce cognitive decline- and many other chronic diseases. Hearing aids also lower the risk of dementia.
The Alzheimer’s Association, predictably, has been pressuring the Centers for Medicare and Medicaid Services (CMS) to have Medicare cover Leqembi. There’s no reason to think that Leqembi will be marketed any more responsibly than Aduhelm. It’s up to physicians, patients, and CMS to reject an expensive drug that improves no symptoms and puts users at risk of fatal bleeds.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by Julie G »

Julie G, I am interested in your take on possibly pre-dosing with Lecanemab. Lecanemab is now on the market. Would it make sense to you to think more in terms of reducing CAA risk than even the AD risk? In the phase 2 trials, the risk of ARIA decreased quite a bit as the dosing declined. Many epsilon 44s have latent CAA pathology that has never been treated. This CAA is in fact what drives the ARIA problems.

I realize that I asked you this exact same question on December 2nd, as a hypothetical. This time it is not so hypothetical. Lecanemab is now on the market. One could remove the question of risk by continuing to reduce the dose. The dose that one could choose could almost be homeopathic yet it would still remove amyloid. 1 mg/kg dosing still removes quite a bit of amyloid fairly fast-- this is what drives ARIA. What you really want for CAA clearance is fairly modest amyloid outflow from the brain over time. This basic strategy would seem to have some place where marginal risk = marginal benefit even for those who are highly risk avoidant. This is all the more true when one realize that doing nothing when there exists so much lurking amyloid in many of those at risk for AD also has significant risk potential.
Thanks for the tag, Theresa, and for the great question, J11. Safely removing amyloid would ostensibly reduce risk of complications from CAA and microdosing with lecanamb could potentially be helpful in that regard. That said, I think it's important to ask why we have amyloid in the first place before assuming we should just try to remove it. Like many, I believe that amyloid is most likely the body's natural defense system (nature's Band-aid) and, if present, is likely there in response to an insult from any of the known contributors to AD, such as insulin resistance, hypoxia (from sleep apnea), HSV-1, etc. I would first want to remediate the possible reason(s) for the amyloid aggregation before "ripping off the band-aid" to better ensure chances of a successful long term outcome.

Pragmatically, I would need an amyloid-PET for confirmation before beginning even a micro-dosing program and ideally an MRI-RAGE for safety. Perhaps self subcutaneous injections would prevent the need for infusions, which would likely be expensive even with a lower dose. I wonder if simply taking curcumin could achieve a similar effect without the high costs? From this paper:
5. Curcumin and Amyloid Beta
In the last decade, considerable progress has been made on curcumin in AD. Several lines of evidence suggest that curcumin has anti-amyloid properties in AD: 1). Findings from an in vitro study revealed that curcumin inhibits Aβ aggregation as well as disaggregates to form fibrillar Aβ40 [31]. 2) Several in vivo studies revealed that curcumin promote disaggregation of existing amyloid deposits and prevent aggregation of new amyloid deposits, even reduce the size of remaining deposits [31, 50]. 3) Curcumin and its derivatives are reported to inhibit the fibrillar Aβ formation from Aβ monomer and also destabilizes preformed fibrillar Aβ in vitro, indicating that curcumin protective against Aβ toxicity [51]. 4). The levels of Aβ (40%) and Aβ deposits (43%) were reduced in the brains of APP mice treated with low doses of curcumin relative to untreated APP mice. At higher concentration, curcumin binds to amyloid beta and blocks its self assembly [31]. 5) A recent study reported that curcumin destabilizes Aβ40 and Aβ42 [52]. 6) Further, curcumin-derived isoxazoles and pyrazoles bind to the Aβ and inhibit AβPP metabolism [53]. 7) Curcumin protects PC12 cells and normal human embelical endothelial cells from amyloid-β-induced oxidative stress [54]. 8) Curcumin reduced the levels of oxidized proteins and IL1B in the brains of APP mice [55]. 9) Curcumin enhances Aβ uptake by macrophages in AD patients, bone marrow derived dendritic cells may correct immune defects in AD patients and provide immunotherapy approach to AD patients [56]. 10) Curcumin inhibits peroxidase and modulate the cytopathologies in AD patients [57]. 11) Curcumin binds to redox-active metals, iron and copper, it suppresses inflammatory damage by preventing metal induction of Nf-kB [58] (Figure 3).
J11, I'd love to hear your thoughts on WHY the body produces amyloid in the first place? It's really interesting to consider especially in the case of CAA where amyloid is in the brain's arteries themselves.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by NF52 »

J11 wrote:
Julie G wrote: Wed Jan 25, 2023 11:53 am...I think it's important to ask why we have amyloid in the first place before assuming we should just try to remove it. Like many, I believe that amyloid is most likely the body's natural defense system (nature's Band-aid) and, if present, is likely there in response to an insult from any of the known contributors to AD, such as insulin resistance, hypoxia (from sleep apnea), HSV-1, etc. I would first want to remediate the possible reason(s) for the amyloid aggregation before "ripping off the band-aid" to better ensure chances of a successful long term outcome.
J11, I'd love to hear your thoughts on WHY the body produces amyloid in the first place? It's really interesting to consider especially in the case of CAA where amyloid is in the brain's arteries themselves.
Julie, the question of "why we have amyloid in the first place", and whether it is the brain's "natural defense system" and the interactions between amyloid beta toxicity and insulin resistance, neuro-inflammation and other factors depend on which type of amyloid (healthy monomers), misfolded amyloid or amyloid beta plaques are being discussed.

Plaques may be nature's attempt at a bandaid in the midst of a major battlefield in the brain. Here's an explanation from an open-access article that covers many forms of amyloid pathogenesis. Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression Full disclosure: The authors are employees of Alzheon, which is currently testing the oral pill ALZ-801 in ApoE 4/4 carriers with MCI/mild AD, which has been discussed on the forum here:
ApolloE4 Study.
The formation of insoluble fibrils and plaques appears to be a protective mechanism that mitigates and reduces oligomer toxicity...This process has been shown to protect adjacent neurons and, by sequestering toxic oligomers into plaques, microglia may play a protective role in AD brains
If all toxic oligomers were able to be safely sequestered, we would seem to be safe from their effects. Yet the same article explains why the plaques are not sufficient as bandaids. To continue the analogy, a bandaid won't work if you have a systemic infection.
Aβ oligomers are highly heterogeneous and... different types of oligomers have been shown to elicit distinct mechanisms of neuronal injury... Aβ oligomers directly induce mitochondrial dysfunction and oxidative stress, leading to massive calcium influx into brain cells and resultant toxicity...oligomers were found to affect memory and learning by directly blocking hippocampal long-term potentiation (LTP), the first step of memory formation. In addition, Aβ oligomers trigger a redistribution of critical synaptic proteins and induce hyperactivity... which result in calcium overload, tau hyperphosphorylation, insulin resistance, oxidative stress, and synaptic loss. Notably, this Aβ oligomer-dependent hyperactivity precedes amyloid plaque formation and is present at early stages of the disease, long before the appearance of clinical symptoms, further supporting the causative role of oligomers in AD pathogenesis....AD patients who are APOE4 carriers show several-fold increased concentrations of Aβ oligomers in their brains compared with non-carriers, likely driving the earlier onset and faster progression of AD...Levels of Aβ oligomers in brains of AD patients with the APOE4/4 genotype were approximately three-fold higher than in APOE4 non-carriers .
Accumulation of amyloid beta oligomers in ApoE 4 carriers as a specific risk group may explain how an anti-amyloid trial (CLARITY) had 69% of participants with ApoE 4, and 15% of ALL participants with ApoE 4/4, even though the global percentages are closer to 25% and 2%: [As a comparison of how rare 7 times the population average is for a trait, World Redhead Day (May 26 this year) celebrates that 13% of my Scottish genetic cousins are redheads, while only about 1-2% of global populations have red hair.]

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.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by Julie G »

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.
Thanks for weighing in, NF52. You know that we are in agreement re. this, but CLARITY didn't test that nuanced hypothesis. We can presume that many who received the drug did have unaddressed risk factors for AD. I would love to see low dose lecanamab (or something similar) trialed in patients who've already identified and addressed modifiable AD risk factors.
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