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arsenal09490 t1_iybcye3 wrote

The full trial can be found in today's issue of NEJM: van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. NEJM. 2022;387(22):E-pub ahead of print. DOI: 10.1056/NEJMoa2212948

Overall, this does appear to be a promising treatment. Upon reading the study, my biggest criticism is that the primary endpoint is not a tool validated for measuring Alzheimer's progression. CDR-SB is mainly used for initial staging and diagnosis. However, the secondary endpoints that better assess progression were also significant, which does point toward an efficacious medication.


Relevant_synapse OP t1_iybev6a wrote

What do you think about the rates of ARIA and the potential interaction with anticoagulants?


arsenal09490 t1_iyboubb wrote

The rates of ARIA were concerning, but they were pretty localized in patients with ApoE ε4 carrier. Still high in non-carriers, but at least that has a better risk-benefit profile. Additionally, only 0.8% of ARIA cases were considered severe. That being said, the risk of ARIA leading to discontinuation will make it difficult to identify ideal candidates until more data comes out.

I do not think lecanemab should interfere with any DOACs or antiplatelets? However, patients on these medications may be at an increased risk of ARIA and/or brain bleeds (especially if the have a stroke and need tPA). So the potential additive blood thinning effect may further limit the population this drug could be used in.


Relevant_synapse OP t1_iybp4zt wrote

Did you see the reports of the two patients who had massive brain hemorrhages and died during the open label extension? One was an E4 noncarrier who was heparinized for an MI and the other was an E4 homozygote who got tPA for a stroke.

Presented here:


arsenal09490 t1_iybpqh3 wrote

No, I have not had a chance to look at those reports yet. Are they published or just announced in the press release?


Kooky_Edge5717 t1_iycfqht wrote

I’m not familiar with the various tools/scores, and I won’t be able to check the full paper for a while. Do you happen to know the minimum clinically important difference in any of the scores?


Relevant_synapse OP t1_iycgkru wrote

In general, the MCIDs for the measures they reported are larger than the effect size of this drug.

1-2 for the CDR sum of boxes:

3 points on the ADAS-Cog (70 point scale), not sure about the Cog14 (90 point scale)

0.05 points for MCI and 0.1 for dementia on the ADCOMS (range from 0 to 1):

Looking into the other measures later


SghnDubh t1_iybm5oq wrote

Wasn't the whole amyloid link found to be bunk? Or at least likely a dead end?


Relevant_synapse OP t1_iybndjq wrote

The falsified data involve one amyloid oligomer, not the entire theory. You can read more about the scandal here:


Sarcastinator t1_iyc16pu wrote

Before the fraud was discovered several studies were stopped because Amyloid therapies had disappointing results in human trials.


Relevant_synapse OP t1_iycd88b wrote

The amyloid hypothesis is by no means the whole story and the -mabs may be barking up the wrong tree altogether. Does not mean that the whole amyloid link is bunk, as the comment I responded to suggests. Mutations in the amyloid precursor protein often lead to dominantly-inherited, early-onset AD, for example, so the link should not be casually dismissed.


Darkhorseman81 t1_iycgvkq wrote

Amyloid and tau build up in everyone with age. It's just a side effect of loss of nutrient sensing and epigenetic quality control, leading to a build-up of cholesterol and fatty acids between cells, instead of feeding those cells.

A single gene is responsible MOF.

The Max Planck institute have already worked out what causes Alzheimers and all vasculature dementia.


Relevant_synapse OP t1_iych9ko wrote

If there is no amyloid link, then please explain the changes in CSF amyloid/tau/p-tau composition in AD patients that predate clinical symptoms by years and are now being used as part of AD diagnostic criteria:

Note: CSF beta amyloid decreases as AD disease severity progresses, not increases as your hypothesis seems to suggest.


Darkhorseman81 t1_iychxsz wrote

That happens to everyone, and is a part of ageing and loss of epigenetic quality control/epigenetic drift.

The reason it happens faster in APOE4 variants is because that gene is linked to superior cholestrol efflux across the blood brain barrier, which is also linked to higher IQ, and cognitive resilience in children in 3rd world countries who suffer starvation, chronic dirahhea, or toxic metal exposures.

They don't lose IQ like most do during hardship, due to superior brain cholesterol metabolism. They are cognitive powerhouses.

They want to treat the amyloid build-up as a prescription model to make money, and have you on drugs the rest of your life, while it is little more than a side effect of the core dysfunction of ageing.

Fixing MOF repairs the blood vessels and nutrient sensing, so fatty acids and cholestrol don't build up between cells. It also repairs cellular waste management and repair, which prevents the build-up of TAU and Amyloid in the first place.

Study the effect of MOF(Myst1/Kat8) on blood vessels, cellular waste management and repair, chromatin structuring, the integrated stress response, and neural metabolic imbalance.

I'm telling you, fix the acetylation patterns of MOF, a single treatment would do it, and the condition is fixed.

Maybe have to do it again once every 30-40 years, if we don't find a way to correct epigenetic drift, but it's a quick fix.

Dementia and Parkinsons are even easier. Dementia is the integrated stress response alone, parkinsons is the ISR + PGC1A gene, which regulates mitochondrial quality control, becoming dysfunctional.

MOF is slightly upstream from all of them. A spectrum of the same condition.


Sarcastinator t1_iycszoc wrote

Could I get a link to this?


Darkhorseman81 t1_iydbteu wrote

Type brothers in arms, the brain and its blood vessels, or janus faced MOF, into a search engine. Good starting point.

On a phone atm, so it's annoying to post links, until I get back to the PC.


Sarcastinator t1_iycu4jl wrote

It's not casual dismissal when human trials fail and the ground laying research included forgery.


Relevant_synapse OP t1_iycuijf wrote

It’s important to understand what the extent of the forgery was before making sweeping pronouncements. It’s a common misconception that the forgery invalidates the field. Holding such a frequently-parroted opinion has unfortunately become a litmus test for being uninformed in this space. You can read about the scandal yourself here:


Sarcastinator t1_iycwwgt wrote

It's not just about the forgery but don't take it from me:

> At the same time, though, news like this needs to be examined carefully. As the world knows, the anti-amyloid clinical landscape for Alzheimer's is absolutely littered with failures in every direction: anti-amyloid antibodies of various types, attempts to inhibit beta-secretase and gamma-secretase enzymes, attempts to prevent aggregation, you name it. Nothing has worked. The presumption at this point is that such therapies will not succeed, so if lecanemab has indeed worked, the question is what makes it different. There's a ready answer (up to a point) because antibodies can indeed be quite different (that's their point!) and if you do manage to hit exactly what needs to be hit, you could expect efficacy when apparently similar attempts have led to nothing.

So being skeptical towards amyloid therapies isn't unwarranted, or casual dismissal.


Relevant_synapse OP t1_iycyb3d wrote

Being skeptical is not the same as dismissing the entire connection as “bunk”. Derek is a much respected voice in the field. I actually agree with his take, and he is spot on with the quote you provided.

What makes lecanemab different? Compared to other drugs in its class that we’ve seen thus far, it has much higher affinity for amyloid fibrils and soluble oligomers than plaques.


masshiker t1_iycazcn wrote

Most people have brain plaques but not all get dementia.


[deleted] t1_iybfxk3 wrote



Relevant_synapse OP t1_iyba9fe wrote

TL:DR - Modest benefit and potential severe interactions with blood thinners including standard-of-care treatments for atrial fibrillation and ischemic stroke:

Primary endpoint: adjusted least-squares mean change on the Clinical Dementia Rating Sum of Boxes (an 18-point scale measuring cognitive function) from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P<0.001).

2 deaths associated with the drug in the open-label extension, both with massive brain hemorrhages: an 87 year old man previously on Eliquis who was heparinized for an acute myocardial infarction, and a 65 year old woman who received tPA for acute ischemic stroke.


Relevant_synapse OP t1_iybfnq4 wrote

Other select findings:

Greater reductions in brain amyloid burden with lecanemab than with placebo on PET (difference, −59.1 centiloids; 95% CI, −62.6 to −55.6) in a subset of 698 participants.

Adjusted mean change from baseline at 18 months in the 90-point ADAS-cog14 score (another measure of cognitive function) was 4.14 in the lecanemab group and 5.58 in the placebo group (difference, −1.44; 95% CI, −2.27 to −0.61; P<0.001).

The most common adverse events (affecting >10% of the participants) in the lecanemab group were infusion-related reactions (26.4% with lecanemab and 7.4% with placebo); amyloid-related imaging abnormalities (ARIA) with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (ARIA-H; 17.3% with lecanemab and 9.0% with placebo); ARIA-E (12.6% with lecanemab and 1.7% with placebo).


sockalicious t1_iyd0m0d wrote

From the Science artice you linked:

>Still, one reason to think lecanemab contributed to the woman’s death is that her autopsy revealed widespread cerebral amyloid angiopathy (CAA), a condition in which amyloid deposits gradually replace the smooth muscle of blood vessel walls. Castellani, Nicoll, and others who reviewed her case suspect CAA made her blood vessels vulnerable to weakening when lecanemab did what it is expected to do: strip amyloids from the brain. The tPA treatment then likely ruptured those weakened vessels, leading to serious ARIA—and apparently fatal brain bleeding, according to the Northwestern report authors and independent CAA or Alzheimer’s experts.

What the article doesn't mention is that CAA would be a contraindication to t-PA therapy for stroke, whether someone had received anti-amyloid therapy or not.

Considering t-PA therapy for stroke is always a "chaotic scene" because there is a brief window of time after stroke onset that it can be used, and the standard imaging studies used to see if t-PA is indicated don't detect CAA - you have to look back in the record and see if an MRI has been done, and that lookback isn't always possible in the emergency department setting.


Relevant_synapse OP t1_iyd1dof wrote

If you go back to the trial protocol, the participants’ MRIs had to have <4 microhemorrhages in order to be enrolled. Known CAA would have been a contraindication to even being in the trial. It’s reasonable to believe that there was no indication that this woman had CAA before she received tPA and all hell broke loose, but we obviously won’t know for sure until the case report is published.


sockalicious t1_iyd2z8h wrote

I have rarely seen such a dramatized account of a medical complication in a science journal, by the way. When folks die in cancer trials, is it commonplace to describe their screaming, or the visit of the priest to the bedside?


Relevant_synapse OP t1_iyd3hpx wrote

People don’t tend to die from massive brain bleeds in cancer trials. The priest visit depends on the patient’s religious beliefs, but is pretty commonplace in my experience as an ICU physician.


sockalicious t1_iyd3x66 wrote

I am a neurologist. People do indeed die screaming on the cancer ward, happens all the time. My point was just that it's a little odd to find these details in a science journal article about an investigational drug.


Relevant_synapse OP t1_iyd430n wrote

I am also a neurologist, but my patients tend to die intubated since I’m neurocrit. This piece hit close to home because it’s literally what I do, and unfortunately what you think may be a dramatic description I see in daily life.


Predawnbread t1_iyc1tyw wrote

28% improvement in cognitive decline and the risk of hemorrhages and swelling doesn't seem worth it ??? Like would you even be able to notice such an improvement? Seems a lil risky for basically no benefit I hope it doesn't get approved


sprouting_broccoli t1_iyc7vg1 wrote

The important bit is that targeting amyloid removal appears to have reduced the decline in patients which offers a way forward for other treatment options. Unfortunately this doesn’t seem like the right one but it’s likely this research will lead to much better alternatives going forward.


TreesAreNiceThings2 t1_iyc8hqb wrote

Be patient, these trials are expensive and how to best use these drugs remains up for debate.

This is a breakthrough for more reasons than just “we have a pill ready”. Its an important proof of concept and step forward in developing therapeutic strategies. We have learned a ton from trials the last 2 decades.


CityWizard t1_iyc9f2c wrote

It's too risky, 28% is insignificant for the risk and cost of the drug. You're looking at a $20-30K USD/year and 17% chance for brain hemorrhage.


Predawnbread t1_iyc22g0 wrote

Will be v costly to prescribe too as monitoring is needed and drug infusion times


Katana_sized_banana t1_iydcfkj wrote

I don't know but for some people 28% of the total can be the difference between stupid and vegetable.


sockalicious t1_iycxvyy wrote

People receive therapies for incurable cancers that have far worse side effects. AD is an incurable, terminal disease and some folks would be able to use the extra time this treatment provides.


Gummibando t1_iycwtmo wrote

What does -emab stand for in the mAb naming scheme? (Like -umab = Human, -omab = murine etc.)


SimbaOnSteroids t1_iydfqlu wrote

The ab at the end is for antibody as these are immunotherapies.


Gummibando t1_iydkiyh wrote

Actually, the mab stands for monoclonal antibody. The letter/s directly before the mab refer/s to the “source” (for lack of a better term, I’m not an English native speaker) of the antibody.

omab = murine (mouse), imab = Primates, umab = recombinant human antibodies etc.

But I have never before heard of emab, so I’m curious what this refers to.


Archer_Sterling t1_iydn8fp wrote

Lecanemab looks like a word that's been spelled backwards.


Darkhorseman81 t1_iycgmkn wrote

Alzheimers is caused by loss of nutrient sensing driven by dysregulation in a gene called MOF, which regulates epigenetic quality control in the brain.

Two articles on the Max Planck institute website: Brothers in Arms; the Brain and its Blood Vessels, and Janus Faced MOF will show you the 'real' causes of Alzheimers and how to cure it.

The US and thr FDA are desperate for a prescription model to make money from it, though.

Fixing MOF fixes 8/12 major keystones of ageing, too.

I may have found a way to modulate MOF, but time and Capital restricts me, currently.


Otherwise-Way-1176 t1_iye3gww wrote

Neither the federal government nor the FDA make money from prescriptions. Pharmaceutical companies do.

“Capital restricts me, currently” So you too are desperate to make money from it?


[deleted] t1_iybp263 wrote



[deleted] t1_iybrso5 wrote