Leqembi infusions

I just had my 33rd Leqembi infusion. Here is one data point: I had the Montreal Cognitive Assessment (MoCA) performed twice: a few months before starting on Leqembi and after about 10 months on Leqembi. I scored the same on both tests.

I'd suggest you aren't quite reading the study results correctly. Cognitive decline is a common characteristic of AD. In the respective Phase 3 clinical trials for Leqembi & Kisunla, they both slowed the cognitive decline by about the same percentage. Some folks have converted this percent slowing of cognitive decline into time, as that is seemingly easier for us common folk to understand.

Thus, in general, neither drug "helps with ST or LT memory gain." Rather, both drugs help slow ST/LT memory loss.

There is one exception. In the Phase 3 trials for both drugs, they did a subgroup analyses for those with no/low levels of tau in their brains. As a reminder, the two hallmarks of AD are amyloid plaques which exist outside of neurons and tau tangles which are inside neurons. It is the tau tangles which drive the cognitive decline associated with AD. Unfortunately, no anti-tau drugs are currently available (some are undergoing clinical trials right now). The two drugs that have been approved by the FDA (Leqembi & Kisunla), are anti-amyloid drugs.

Back to the no/low tau groups. For this subset, the drugs stopped cognitive decline in a significant fraction of this group, and a small fraction in this group actually did experience a slight improvement in cognition during the clinical trial.

Yes, ARIA is a concern with these drugs. I was well aware of the risk. Both of my parents had dementia. My Dad died quickly from cancer, but my Mom lingered on while AD slowly robbed her of all of her memories.

Thus, I was very aware of what it was like to experience this disease, so for me it was a simple decision to start on Leqembi (that was the only drug available at the time). I was also considering joining a clinical trial with an anti-amyloid drug and an ant-tau trug. But that trial was delayed, so I started on Leqembi.

I respect that others may make a different choice.

What is the centiloid value most saw when diagnosed? My DH is in the gray area at 24 (age 64) right now. One doctor wanted him to wait for 2 years before being tested again - that was a hard NO from us. Next beter doctor said 6 months; try infusion; and PET again to see where he is in 6 mns using 30 as a positive value.

How many people out there would decide to get the infusions who are past 80 yrs. old or older???? AND are in the mild stage of Alzheimerl's? I am reconsidering the infusions after all the research, etc. I am now thinking " No " to the infusions that are available to me. Opinions??

Thank you for sharing..

The subcutaneous injection option for Leqembi is currently only approved by the FDA for "maintenance dosing". This term refers to completing the initial 18 month Leqembi bi-weekly infusion protocol. After that, Eisai (the company primarily responsible for Leqembi) recommended switching to infusions every four week for "maintenance dosing". Now, with FDA approval of the subcutaneous version of Leqembi for maintenance dosing, patients have a two options after completing the initial 18 month period of bi-weekly infusions: continue with infusions every 4 weeks (note the change in frequency), or switch to a weekly subcutaneous injection.

The Leqembi vs Kisunla tradeoff can get complicated. At a high level, you are comparing bi-weekly infusions for Leqembi with infusions every four weeks for Kisunla. Regarding treatment duration, we just covered the 18-month recommended length for Leqembi. In the phase 3 trial for Kisunla, participants were taken off the drug if amyloid PET scans showed amyloid plaque clearance. As the sole purpose of Kisunla is to remove amyloid plaque, it doesn't make much sense to continue treatment after all of the plaque is gone. Specifically, in the Kisunla Phase 3 trial, 17% of those taking Kisunla stopped taking the active drug at 6 months, 47% at 12 months, and 69% at 18 months. The concept of stopping Kisunla treatment after amyloid clearance seems somewhat controversial, with some Doctors recommending continuing treatment. Then there is the practical question of how one determines the amyloid level, to figure out if treatment can be terminated. Repeat lumbar punctures or amyloid PET scans are costly (and the former not exactly a joyful experience). Some of the new blood tests to check for amyloid might help solve this problem at some point in the future.

Eisai likes to note that Leqembi is "dual-acting", as it removes both amyloid plaque and amyloid protofibrils. The latter can damage neurons which is presumably bad for cognition. So one rationale for continuing with Leqembi dosing after 18 months is to continue to remove amyloid protofibrils (side note: Kisunla does not address amyloid protofibrils).

You have to be careful when comparing Kisunla & Leqembi ARIA rates. Comparing the Phase 3 trial data for Kisunla & Leqembi, Leqembi did have lower ARIA rates. However, since the Phase 3 trial for Kisunla, Eli Lilly (drug company responsible for Kisunla) has gotten FDA approval for a revised dosing strategy. Originally, dosing for Kisunla started with two vials of Kisunla for doses #1-#3, doubling the dosing to four vials of Kisunla for infusion #4 and all subsequent infusions. A brilliant person at Eli Lilly figured out that if you shift one vial from infusion #2 to infusion #4 (so you have one vial for infusion #1, two vials for infusion #2, three vials for infusion #3, and four vials for infusion #4 and all subsequent infusions), then this might reduce ARIA rates. Sure enough, in a trial, the ARIA rates for Kisunla improved greatly. Leqembi still has a slightly lower ARIA rate, but the difference in ARIA rates between Kisunla & Leqembi are now much smaller. Much of what you might read on the web could be comparing the old Kisunla ARIA rates with Leqembi.

In terms of slowing cognitive decline associated with AD (perhaps the whole point of taking one of these drugs), using a the same measure for cognitive decline (specifically the Clinical Dementia Rating - Sum of Boxes, which is a comprehsive test assessing memory, time/place orientation, judgement / problem solving, community affairs, home & hobbies, & personal care), in the Phase 3 trial, Kisunla slowed cognitive decline by 29% compared to 27% slowing for Leqembi. A bigger number is better (more braking of cognitive decline), so Kisunla was slightly better at slowing cognitive decline compared with Leqembi. This teeny-tiny difference would perhaps not be noticable if you could somehow start on Leqembi for a year, take a cognitive test, then Quantum-Leap back in time and start on Kisunla instead for a year, then take another cognitive test and compare results.

Unfortunately, there is much confusion over tau. You are correct, tau tangles seem to be a major contributor to the cognitive decline associated with Alzheimer's. At a high level, the difference between amyloid plaque and tau tangles is simple: as in real estate, the key is location, location, location: amyloid plaque exists outside of neurons, while tau tangles exist inside neurons.

With regards to the effects of the current medications, below is an illustration from an Eisai presentation (the drug company responsible for Leqembi). The red line is showing amyloid-ß plaque, the blue line tau tangles. The graphic shows what happens when this person starts on Leqembi at a specific point in their AD journey, when amyloid plaque and tau tangles are high but not yet at their maximum levels. As you would expect, following treatment with Leqembi, the red line is showing the reduction in amyloid plaque. The dotted red line shows how amyloid plaque levels might have increased had the person not started on Leqembi.

Similar story for tau. Leqembi (and presumably Kisunla) slows down the accumulation of tau tangles, but does not completely stop tau. Thus, the solid blue line bends downward slightly, compared with the dashed blue line (what tau would have looked like without starting on the anti-amyloid drug).

Then finally we get to cognitive decline. The dashed green line is showing the cognitive decline curve without treatment. There is region color coded in green, showing "high risk" and "low risk" people for cognitive decline. For both groups, taking Leqembi (again this presumably also applies to Kisunla) reduces the cognitive decline. But unlike the amyloid plaque and tau, the change in cognition differs between "high risk" and "low risk" people, with everybody else somewhere in the green region between these two limits. I haven't seen any materials from Eisai elaborating on how any of us might figure out if we are "high risk" or "low risk" people.

You mentioned your blood test included tau levels. That is another whole can of worms, with confusing terminology. Generally speaking the tau that is measured in the currently available blood tests is used as a biomarker indicator for amyloid plaque, not for tau tangles. For example, a common blood-based biomaker is called ptau-181, which stands for Phosphorylated tau strand #181. Studies have shown this correlates very well with amyloid plaque levels. But ptau-181 is not a biomarker for tau tangles. As I understand it, blood-based biomarker testing has yet gotten to the point of being able to detect tau tangles. There are studies that have shown that something called MTBR tau when measured in the blood can accurately correlate with tau tangles. But as I understand it, none of the AD blood tests that are commercially available today detect MTBR tau.