Warning: Avoid Brain Injury in mAb Clinical Trials.

Gosh. I have 2 of the APOE genes, discovered from testing for a drug study. I didn't qualify for the study so I guess I'm lucky? I am sorry that you had such a dreadful reaction.

Thank you for your posting. You are a brave individual, volunteering for a clinical trial.

I've completed my 12th Leqembi infusion, my final MRI will be after my 13th infusion on Monday. I've had zippo reactions from the Leqembi / infusions.

Prior to starting Leqembi, I carefully studied the Phase 3 Leqembi drug trial paper published in the New England Journal of Medicine (link below). I'm an APOE4 heterozygote (one gene). For this group, 10.9% of the total participants in the Leqembi Phase 3 trial experienced ARIA-E, vs 1.9% on placebo. For APEO4 homozygote (two genes), 32.6% of the participants experienced ARIA-E, vs 3.8% on placebo. I believe these numbers are based on test results identifying ARIA-E. They also separately reported symptomatic ARIA-E, only 1.7% of APOE4 heterozygote's apparently experienced symptoms of ARIA-E, and 9.2% of APOE4 homozygotes experienced symptoms of ARIA-H.

Given my family history (both my parents had dementia), and after watching my Mom slowly fade away from the disease, and given I have only one of the two dreaded genes, after talking this over with my neurologist and my wife, I elected to start Leqembi. I am glad I made that decision, as I feel it is buying me more quality time with my family, albeit with a slight risk for ARIA. There is also a risk I will die in a fatal car accident on my way to the gym, or get shot walking around my city, or get cancer. Life is full of risks, I judged that the incremental risk from Leqembi was low. But I respect that others might come to a different conclusion.

Finally, I remain hopeful that in the next couple of years, drugs which address tau that are currently or will soon start clinical trials will prove successful, be authorized by the FDA, and then can be added to my arsenal.

Here is a link to the Leqembi Phase 3 trial
https://www.nejm.org/doi/full/10.1056/NEJMoa2212948

I understand your concern, and I respect any decision you make.

I feel for people like Genevieve Lane, the 79-year old resident of the Villages in Florida who died in Sept 2022 after 3 doses of Leqembi in the Phase 3 trial. Her autopsy showed she had 51 microhemorrhages. She had two copies of APOE4 and she also had four previous microbleeds before starting on Leqembi (increasing her likelihood of brain bleeding when taking Leqembi). She was unaware of these two risks. She started on placebo, then switched to Leqembi when she had the opportunity at the conclusion of the initial trial. She had a headache after her first infusion, another headache after her 2nd infusion, and another after her 3rd. It was after dinner following her 3rd infusion that she slumped over and became unresponsive, dying in the hospital five days later.

The NYT article indicates participants were unaware of the dangers of the trial when they agreed to participate in the Phase 3 trial for Leqembi.

I would challenge that assertion.

Let us take a quick review of the Phase 1 & Phase 2 trials with Leqembi. In the Phase 1 clinical trial, nobody died. There were zero cases of symptomatic ARIA-E, and zero cases of ARIA-E detected in the MRIs. As one example of how the Phase 1 trial was conducted, they started with a single dosage of 0.1 mg/kg (our dosage today is 10 mg/kg, so they started at 1% of what we now receive). By "single dosage", I really do mean a single dosage. These participants received one dose of 0.1 mg/kg of Leqembi and they were done with the clinical trial. There were 8 people in this portion of the trial, 6 receiving Leqembi and 2 on placebo. Blood draws were taken immediately after dosing, then at 30 minutes, 1 hour, 2H, 4H, 8H, and 24H. They also did blood work at 10, 21, 28, 90, and 180 days after dosing. All of this blood work was done presumably to determine how the concentrations of Leqembi in the bloodstream change over time.

After perhaps a month or so they checked up on the status of those who had received the 0.1 mg/kg dosage and they were find. They then then repeated the process at a dosage of 0.3 mg/kg (3% of what we now receive). Again a single dose, again all of the blood work, again wait around a month after testing to see how people did.

This process was repeated till they got to 10 mg/kg dosage as a single dosage test. In parallel, they also started multiple dosage tests, with the first starting at 0.3 mg/kg every 4 weeks (compared to our biweekly infusions). After they found people did ok with this dosage level, they started a new group of 8 people with a higher dosage administered every 4 weeks. The last group they tested was for our standard conditions of 10 mg/kg with bi-weekly infusions.

The paper documenting the results of the Phase 1 trial states "Leqembi was safe and well tolerated in mild to moderate AD. The incidence of ARIA on MRI was comparable to placebo. On the basis of these findings, a Phase 2b efficacy study has been initiated in early AD."

There were 7 deaths during the Phase 2 trial for Leqembi. But first, note that like the Phase 1 trial, the Phase 2 trial utilized different dosage levels of Leqembi: 2 on placebo, 2 on 2.5mg/kg biweekly, 1 on 5/mg/kg biweekly, and 2 on 10 mg/kg monthly. There were zero deaths in the Phase 2 trial for those on 10mg/kg biweekly.

The publicly available paper documenting the results of the Phase 2 trial for Leqembi states the following in the "Safety" section: "Leqembi was generally well-tolerated with ARIA-E incidence <10% at the highest doses for the overall population and 14.3% for APOE4 positive subjects. … 37 of the 48 ARIA-E cases (2 for placebo, 46 for Leqembi) were in APOE4+ subjects. There were 5 cases of symptomatic ARIA-E. Most ARIA-E (60%) occurred within the first 3 months of treatment and were mostly mild-to-moderate in radiologic serverity. All ARIA-E caess resolved, with a typical time course of 4-12 weeks. There were no symptomatic cases of ARIA-H. As seen for the incidence of ARIA-E, the incidence of ARIA-H on Leqembi was higher in APOE4 carriers (13%) than in APOE4 non-carriers (5%)."

All of this data supported the Phase 3 trial, which showed that Leqembi resulted in 27% slowing in cognitive decline compared to placebo based on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) score. The published Phase 3 trial contains additional statistics regarding ARIA incidence rates.

Eli Lily has published similar data for their anti-amyloid drug Kisunla.

This data seems to generally indicate the amyloid hypothesis is correct, in that reducing amyloid does result in a small slowing in cognitive decline. Are there risks with anti-amyloid drugs? Yes, and anyone considering taking Leqembi / Kisunla should be aware of the possible issues with ARIA.

Last point.

By my estimates, there are over 50,000 people in the U.S. currently receiving Leqembi (this is based on the Leqembi sales reported by Eisai in the company earning's reports on their website). I'm not sure how many people outside the U.S. are taking Leqembi. If huge numbers of people were having problems with Leqembi, I presume that there would be lots of postings to groups like this about problems with Leqembi, and articles in newspapers, and the FDA would be issuing warnings. ARIA isn't something to take lightly, and there are other dangers with Leqembi. But the alternative is to let "nature take its course" and have a faster rate of cognitive decline. I can understand why others may make a different decision than I did, but I'd suggest individuals considering Leqembi / Kisunla might want to read both sides of the story regarding the pros/cons of the drug.

LBC83, thanks for the info on the NYT article that seems to be ignoring the care of the Leqembi researchers and what they did to protect the trial participants.

My message to jojorurus64 and others taking Leqembi is not to give up hope! I continue to believe those of us receiving Leqembi infusions to slow down the progression of AD may have a chance at actually beating the disease, albeit living the rest of one's life with some degradation in cognitive capability. I am an Engineer by training, and this hope is not based on some fantasy about a miracle drug that will one day cure AD. Rather, my hope is science-based, reviewing the data available in the open literature.

As I understand today's grand theory of AD progression, things start going haywire in our brains a decade or so before any symptoms show up. For reasons still unknown to our Doctors, amyloid plaque begins to form in our brains. This plaque can cause minor damage, but it isn't the key driver in cognitive decline. Rather, large accumulations of amyloid plaque seem to trigger the generation of tau proteins in our brains. It is the accumulating tau that drives the cognitive decline.

Thus, while Leqembi (and Kisunla) reduce the amount of amyloid plaque, they aren't targeting the tau which is the real problem.

Right now, Eisai (Japanese drug company that developed Leqembi) is recruiting participants for a Phase 2 drug trial paring an anti-tau drug E2814 with Leqembi. I created the table below showing all of the planned locations for the trial, in the US & Japan. The 14 locations in the U.S. that are now enrolling participants are shown in green. I called one of the clinics located within commuting distance from my new home, just to see if I could be eligible. Unfortunately, already being on Leqembi disqualified me from participating in the trial. So I don't believe any of us on Leqembi can participate in this trial. :(

For those unfamiliar with E2814, Eisai began a Phase 1 trial with E2814 (by itself) in Dec 2019. The results of the trial were presented at the July 2023 Alzheimer's Association International Conference. The drug was shown to be safe and well-tolerated in the highest dose in both healthy and AD cohorts, with a particular form of tau declining by 30-70% after treatment in AD patients. Data from a different trial with E2814 was presented at another 2024 AD conference. In this second trial, CSF pTau217 was halved after 2 years of treatment.

The trial with E2814 concurrent with Leqembi is scheduled to run through 2028, so we will have to wait a while for results. If the trial is successful, and if and early readout of results sometime before 2028 shows positive results, and if at that point Eisai starts a Phase 3 trial, and finally if the Phase 3 trial shows positive results, then finally the FDA could approve E2814 and we could all possibly take that in combination with Leqembi.

Lots of "if" statements in that prior sentence, but that is what gives me some hope.

Study Title: A Study of E2814 With Concurrent Lecanemab Treatment in Participants With Early Alzheimer's Disease
https://clinicaltrials.gov/study/NCT06602258

Going back to where we started, with the discussion of amyloid and tau, there is a 2023 paper by Dr Boxer and Dr Sperling with a graphic I've found to be very helpful in understanding the theory of AD progression. The graphic is copied below. The paper is titled "Accelerating Alzheimer's therapeutic development: The past and future of clinical trials."

Here is my understanding of the plot (I'm an Engineer, not a biologist, or a Doctor, or a chemist, so my interpretations may be completely wrong).
Box "A" (at the top, Biomarker cascade). This shows the typical progression of a person with AD and no treatments, from 20 years prior to symptoms showing up to having severe dementia. The dotted red line is showing the soluble amyloid starts to increase at 20 years before symptoms. The next biomarker to increase is the solid red line (amyloid plaque), then soluble tau (dotted blue line), and finally tau tangles (solid blue line) are detectable about 6 years before cognitive decline is detected. Boxer labels this point as a "Ca-tau-strophe", a play on words with tau causing a catastrophe in our brains.

Box B is Boxer's view on what happens to those of us on Leqembi or Kisunla - the amyloids and the soluble tau drop, but the dreaded tau tangles only drop slightly and the cognitive decline is only slightly reduced.

Box C is Boxer's prediction of what might happen if somebody were to take an anti-amyloid drug like Leqembi in conjunction with an anti-tau drug. Note that the blue tau tangle line now drops, but most importantly, note that the black line showing cognitive decline levels off (i.e. cognitive decline is stopped!!!). Again, my hope is that the anti-tau drugs now undergoing testing will be available to those of us on Leqembi soon enough to help our situation, and that these drugs work as predicted by Boxer.

To finish off Boxer's plot, Box D illustrates what he believes might be the result of an existing trial with Leqembi. In this case, the drug is given very early in the progression of AD (way before any cognitive decline, or large accumulation of amyloid in the brain). Boxer's theory is that taken at this very early stage, the control of amyloid results in no large amount of soluble tau, so there is little to no tau tangles, and no cognitive decline. I would quibble with Boxer's illustration for Box D. If I had been asked to review the paper, I would have suggested changing the shape of the black line for cognitive decline in Box D, as I don't think Boxer meant to show that the cognitive decline would start to increase for some weird reason later in life.

Box E is the distant future, perhaps past my lifetime. At that point, perhaps a vaccine will have been developed to prevent amyloid from accumulating, thus again short-circuiting the process of AD.

Source: 2023 paper "Accelerating Alzheimer's therapeutic development: The past and future of clinical trials."

Thank you for all the information.

I had my 1st infusion, a slight headache next day but no other side effects.

Jo

I am APOE 3/4. I decided not to take Leqembi because of the risks. What I did not know at that time, was that a Supplement was later published, that confirmed my decision. The results indicated that females had a 12% slowing of decline, whereas males showed a 43% slowing of decline. I don't know if the difference is statistically significant but, as a female, especially one who carries the APOE4 gene, I believe this information should have been available before all the hoopla.

https://www.nejm.org/doi/suppl/10.1056/NEJMoa2212948/suppl_file/nejmoa2212948_appendix.pdf