Not sure why my post got deleted. -emab is hamster

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.

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.

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.

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.

https://www.frontiersin.org/articles/10.3389/fnins.2022.848215/full

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: https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease

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:

https://www.nature.com/articles/s12276-019-0250-2

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

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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690415/

3 points on the ADAS-Cog (70 point scale), not sure about the Cog14 (90 point scale) https://pubmed.ncbi.nlm.nih.gov/22019547/

0.05 points for MCI and 0.1 for dementia on the ADCOMS (range from 0 to 1): https://pubmed.ncbi.nlm.nih.gov/35513767/

Looking into the other measures later

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.

Not sure about the first case. Per this article in Science Insider, the second case has at least been written up?

https://www.science.org/content/article/second-death-linked-potential-antibody-treatment-alzheimer-s-disease

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: https://twitter.com/JacobPlieth/status/1597770771606429698?s=20&t=EUU4CuKWkmzyva1QQH9d3g

The falsified data involve one amyloid oligomer, not the entire theory. You can read more about the scandal here: https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease

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).

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

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.

https://amp.cnn.com/cnn/2022/10/28/health/alzheimers-drug-lecanemab-trial/index.html

https://www.science.org/content/article/second-death-linked-potential-antibody-treatment-alzheimer-s-disease