I'm newly diagnosed with Alzheimer's and considering one of the new drugs

Welcome, Shank.

Glad you're here. Lots of knowledgeable people and support! I take donezepil, too. I've only had a few vivid dreams but I hear that taking it in the morning instead of at night helps..

I'm also taking Lequmbi infusions every 2 weeks- doing fine with no side effects . Considered Kunsula but the side effects warned me away from that option ….

Larry

As others have noted, welcome to the 'club' you probably never wanted to join. I've had 46 Leqembi infusions. I followed the standard protocol of bi-weekly infusions for 18 months, then I switched to maintenance dosing every 4 weeks. I had the option of the new IQLIK for maintenance dosing, which utilizes a subcutaneous injection (similar to the delivery method for Ozempic).

At a very high level, reactions to anti-amyloid infusions (i.e. Leqembi or Kisunla) come in two buckets: infusion-related reactions and ARIA (Amyloid-Related Imaging Anomalies, so-named due to brain swelling / bleeding appearing on MRIs). I've had neither type of reaction, which is the most common experience. Infusion-related reactions include flu-like symptoms and headache. Unfortunately, ARIA symptoms also include a headache, as well as confusion and others. Side note: for more details, I suggest you look up the Donanemab Appropriate Use Recommendations (AUR). This document was prepared by a team of Neurologists to serve as a guide to other Neurologist prescribing Kisunla. The document is available for free on the web.

Some infusion centers pre-treat patients with a drug cocktail in an attempt to mitigate infusion-related reactions. I've personally never had a pre-treatment, and again, I've never experienced an infusion-related reaction.

Most cases of ARIA have no symptoms, hence the frequent MRIs you mention, to check for ARIA. If ARIA were found, the Kisunla AUR recommends pausing treatment until ARIA clears. Depending on the ARIA severity (based on the quantity of brain microbleeds / extent of swelling), for cases deemed minor, treatment may resume after a follow-on MRI indicates the ARIA has dissipated. For severe ARIA cases, the recommendation is to treat the ARIA with steroids and not resume anti-amyloid treatment after ARIA is resolved. I forget the recommendation for moderate ARIA (I have AD, give me a break!).

But there are some cases of ARIA where the patients have symptoms, which may include a headache. The AURs also make recommendations on treating these cases.

Genetic testing is usually part of the discussion, specifically APOE4 testing. It turns out that those with two APOE4 genes (i.e. they inherited one from each parent) are the group most likely to develop ARIA. Those with zero APOE4 genes are least likely to develop ARIA, and those with a single APOE4 are only a bit more likely to develop ARIA compared with those with no APOE4 genes. So the risk of ARIA is very high for those with 2 APOE4 genes, very low for those with no APOE4 genes, and low for those with a single APOE4 gene. I happen to have one APOE4 gene, so I wasn't terribly worried about the ARIA risk.

For me, the risk vs reward calculation (I'm a retired Engineer) was simple. While it is true that for the overall group that received Kisunla in the Phase 3 trial, compared to those on placebo, the average person receiving Kisunla had a moderate slowing in cognitive decline. However, within the group of people who received Kisunla, those who started treatment very early in the disease progression (as measured by tau levels) had more significant slowing of cognitive decline. This implies that Kisunla was not as effective for those who started treatment with higher tau levels. If you read up on the Amyloid Cascade Hypothesis, this information should not be a revelation. The hypothesis states that Amyloid starts a chain reaction, which drives the formation of tau tangles within neurons (which damage the neurons), resulting in cognitive decline. Your case seems to be an example of starting treatment early, so the trial data seems to suggest that you might have better performance with the drug.

If you agree to start on Kisunla, you might ask about the treatment duration. In the Phase 3 trial, patients had amyloid PET scans at 6-month intervals. Those on Kisunla who had very low amyloid levels in a single PET scan, or two consecutive moderately low amyloid levels, where blindly switched to placebo. At 6 months, 30% of those on Kisunla were amyloid clear (and thus switched to placebo). At 12 months, 66% were amyloid-clear, and 76% at 18 months. The trial continued, and 91% were amyloid-clear at 36 months (3 years). Note this means that 9% were not amyloid-clear after 3 years of Kisunla infusions. Based on my conversations with those on Kisunla, I've found that Doctors don't seem to be sharing these statistics with patients. Maybe someday, Doctors will be able to predict which patients will be amyloid-clear after 6-months of Kisunla treatments / 12-months, 18-months, and 3-years. Wouldn't that be nice?!?

This raises the question of how to determine when to stop Kisunla infusions. The AUR notes that amyloid PET scans are expensive, and not so practical to perform every 6-months in clinical practice. The AUR suggests that one solution might be to just stop treatments at 18 moths, based on the statistic that 76% of the people were amyloid clear at 18-months in the clinical trial. I personally find that recommendation to be a bit hokey. In today's world, AD blood tests are very cheap, and they do a pretty good job of estimating brain amyloid levels. I had one of the new blood tests, it showed that I was amloid-clear after my Leqembi infusions. This data supported me moving from Leqembi bi-weekly infusions for amyloid clearance to Leqembi every-4-weeks infusions for maintenance dosing.

As if this reply isn't long enough, one more thought. The rationale behind Leqembi maintenance dosing and Kisunla stopping after amyloid clearance is based on the different mechanism of action between the two drugs. Kisunla only targets and removes amyloid plaque, hence the recommendation to stop treatments after amyloid plaque clearance. Some ask about amyloid rebound rates after stopping Kisunla infusions. As noted above, Eli Lilly (the drug company responsible for Kisunla) setup the trial to switch people off Kisunla following amyloid clearance. These folks still received periodic amyloid PET scans, thereby allowing Lilly to calcualte the amyloid rebound rate for those who stop treatment. One researcher estimated that in most people's lifetimes, after achieving amyloid clearance with Kisunla, they would never need to restart infusions.

In contrast, Leqembi targets both amyloid plaque and amyloid protofibrils. The latter are thought to also be damaging to neurons. Hence the recommendation to continue Leqembi maintenance dosing after amyloid clearance. In other on-line forums, I have read posts from those on Kisunla, who switch to Leqembi after amyloid clearance with Kisunla. There is a section in the Kisunla AUR about switching monoclonal anti-body treatements. The AUR simply states that someone on drug A should wait until the drug is almost all cleared from their body before starting on drug B. This seems like a no-brainer recommendation to me, and very easy to implement (the AUR provides the timeframe for the two drugs).

I've seen some Neurologists suggest a head-to-head trial between Leqembi & Kisunla, so we could all learn which drug really is better at reducing cognitive decline. I fully understand the proposal, but my crystal ball says such a trial will never happen. Lilly is currently developing the next generation version of Kisunla (Remternetug), which is administered via subcutaneous injection (similar to IQLIK with Leqembi). So by the time a 3-year trial comparing Leqembi/Kisunla might be over, Kisunla might be a side story with Remternetug the new AD drug from Lilly.