The problem with Leqembi

Lane Simonian

The FDA will most likely approve Leqembi in July and Medicare has then indicated that it will extend coverage (to those in research settings).  But my own opinion is that neither should happen.  

Every other recent anti-amyloid trial has shown that these drugs only modestly slow down the disease in APOE4 carriers.  In Leqembi's phase 2b trial the results were the following: APOE4 carriers declined 63 percent less and non-carriers declined 7 percent less (on Alzheimer's Disease Composite Scores).  However, for it phase 3 trial, Biogen and Eisai reported the following results for Clinical Dementia Ratings-Sum of Boxes scores: non-carriers declined by 41 percent less, APOE4 carriers with one copy of the gene progressed by 30 percent less, and APOE4 carriers somehow worsened by 22 percent while on Leqembi.

How did Biogen and Eisai flip the numbers?  They did so by comparing the drug group to the combined placebo mean rather than to the mean for each group.  Here is how this changes the numbers:

Difference from the combined mean placebo group:

4.83 - .75=4.08 (non-carriers)

4.83 - .5=4.33 (APOE4 carriers with one copy of the gene)

4.83 + .22= 5.11 (APOE carriers with two copies of the gene)

Difference for the combined mean for each group (APOE4 carriers progress more rapidly during the early stages of Alzheimer's disease.  The following numbers closely match studies on the different rates of progression).

4.3 - .22= 4.08 (non-carriers)

5 - .67= 4.33 (APOE4 carriers with one copy of the gene)

5.6 - .49 = 5.11 (APOE4 carriers with two copies of the gene)

The slowing down in progression in non-carriers is neither statistically nor clinically significant.  Families or the government paying for this treatment for non-carriers is a unnecessary burden.  The slowing down in progression in carriers is statistically significant but probably has very little real-life effects, except that carriers can suffer from brain bleeds and brain swelling from the drug.  

Ed1937

Lane, thank you for staying on top of this stuff. Your posts are important.

Lane Simonian

Thank you, Ed.   And thank you for your helpful posts.

Iris L.

"Slowing down" over what period of time?  And for how long?

I would like to know, does slowing down mean no pathological changes seen on MRI or only changes in function?

I was offered a clinical trial for a drug that was to slow things down.  Keep in mind that I don't have Alzheimer's Disease.   But I followed Best Practices and the progession of my illness (cognitive impairment not otherwise specified) was slowed down.  I had ten good years.   In 2019, shortly before the pandemic lockdowns, I noticed more general difficulty in functioning, although I believe my memory is about the same.  My computer-generated cognitive testing, ordered by my neurologist, shows that I am about the same as a few years ago.                                                                                   

So, if I had been given this drug 10 years ago as an APOe4 positive person with MCI, my slow progress would have been attributed to the drug.  But the drug is not at all a factor.

It is a very tough choice to make, Best Practices versus Leqembi, to get possibly the same results.  I hope I am understanding this correctly.

Iris

Ed1937

Iris, I don't remember if you are on meds for that or not. But if do, so you credit your success to that, or do you think Best Practices is the best answer for you?

Iris L.

Ed,  I have been on Exelon patch and memantine since mid-2009.  Taking medications as prescribed is part of Best Practices.  I also take blood pressure medications, since I believe elevated BP contributes to my cognitive impairment.  So to answer your question, I believe all of Best Practices, including the medications, along with avoiding stress and getting restful sleep contribute to my slow progress.  I have even tried aromatherapy (thanks Lane!).

Iris

Michael Ellenbogen

Did you watch ICER’s revised evidence report review public meeting on March 17 by the California Technology Assessment Forum (one of ICER’s independent evidence appraisal committees)  I thought it was sad on how these folks come to the conclusion. That was a first for me to see one of those live.  Its no wonder the patient always ends up getting screwed.

Lane Simonian

Thank you, Michael, for alerting me to the California Technology Assessment Forum, but then I forgot to watch it.  Maybe there will be a write-up on it or a video posted later.

All the following comments are for Alzheimer's disease.  They may or may not apply to other forms of dementia/cognitive impariment.  Most treatments seems to work better when started early (Namenda/memantine seems to be an exception).  Aricept appears to delay the conversion from mild cognitive impairment due to amyloid by more than a year.  

https://www.brainandlife.org/reports/a-new-diagnosis-called-mild-cognitive-impairment-is-a-warning

For mild Alzheimer's disease, Aricept stalls decline by one year.  At two years, the decline is a little less than placebo.  Aricept has little impact on moderate Alzheimer's disease.  Those taking conventional medicines and Chinese herbs (including panax ginseng) did the same as those taking conventional medicines alone (such as Aricept and namenda) at one year, but they stayed near baseline at two years for mild Alzheimer's disease.  For moderate Alzheimer's disease, those taking Chinese herbs and conventional medicines stayed near baseline for one year, but dropped at the same rate as those taking a placebo at two years.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729264/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/

For Leqembi, the modest slowing down of the disease in non-carriers was at 18 months.  Those taking Leqembi and conventional Alzheimer's medications did a little bit better than those not taking Alzheimer's medications.  

A Mediterranean diet which is part of best practices reduces the risk for Alzheimer's disease and slows down its progression.  

https://pubmed.ncbi.nlm.nih.gov/16622828/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673956/

I  am glad that aromatherapy seems to be helping you Iris, as better of Best Practices.  Here are the results from two clinical trials using aromatherapy for Alzheimer's disease:

Results: All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.[aromatherapy with rosemary, lemon, orange, and lavender essential oil with a diffuser].

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1479-8301.2009.00299.x

Results: The Pittsburgh Sleep Quality Index and the Neuropsychiatric Inventory–Brief Questionnaire Form scores decreased, the Quality of Life-Alzheimer’s Disease score improved (P<0.05), the malondialdehyde (MDA) content in serum was slightly reduced, superoxide dismutase (SOD) activity was enhanced (P<0.05), and TNF-α and IL-6 levels were significantly reduced (P<0.05) in the aromatherapy group, compared to those of the control group. 

Conclusion: Aromatherapy can improve sleep, alleviate psychobehavioural symptoms and improve quality of life in patients with AD, which may be related to reducing the level of oxidative stress in patients and inhibiting inflammatory factors; it is a non-drug intervention that can be widely applied. [aromatherapy with lavender, sweet orange, and bergamont essential oils with a diffuser].

https://assets.researchsquare.com/files/rs-1392290/v1/f79b84f0-ba44-49fd-ace1-57fbb9eac13d.pdf?c=1652156064

Essential oils can also be inhaled directly and indeed that might be even better method than using a diffuser for some essential oils at least.

Leqemib removes one of the factors that cause oxidative stress: amyloid whose levels are highest in APOE4 carriers.  Aricept besides inhibiting acetylcholinesterases also inhibits a factor that leads to oxidative stress (intracellular calcium release) and memantine inhibits another factor that leads to oxidative stress (overactivation of NMDA receptors).  "Chinese" herbs such as panax ginseng, a Mediterranean diet, and essential oils via aromatherapy not only inhibit the production of oxidants, they scavenge them, and partially reverse their damage.  Almost any Alzheimer's drug works better if it is paired with direct antioxidants.

Iris L.

Michael, I do not watch anything complicated on TV or on the internet.

Lane, thanks for posting. I wish more PWDs could begin Aricept or Exelon earlier to give them more good time.

As an aside, I was prescribed Chinese herbs by an Asian-American infectious diseases doctor.  It was his own proprietary blend.  After six months, I notice no change, neither positive or negative.  

Iris 

Cherjer

Like you, Iris, my husband has been on namenda and the exelon patch since 2015. DH is now on hospice but I continue to use namenda and the patch. I remember his neurologist Dr. Shankle telling me to continue this...and I have. I have DH at home with caregivers to help me...he sleeps well at night and basically his day is walking and sitting. He eats well but cannot converse but we do think he knows what is going on with conversation. He has the APO4 gene. Iris I am in Huntington Beach, CA and if you ever want to contact me I would love it!

Iris L.

Hello Cherjer, yes we do live nearby each other.  I'm sorry to learn your husband is on hospice.  He sounds comfortable, and you are taking good care of him.

To clarify about my meds, I believe the two meds are stabilizing my short term memory and my speech.  My long term memory seems to be slowly fading away.  So far, so good.

Iris

Larrytherunner

There are a lot of unanswered safety questions about Leqembi which relates not only to microbleeds but also to why do Leqembi patients show greater brain shrinkage compared to placebo patients. Maybe having leakier blood vessels while using Leqembi is not a good thing.

Larrytherunner

There are a lot of unanswered safety questions about Leqembi which relates not only to microbleeds but also to why do Leqembi patients show greater brain shrinkage compared to placebo patients. Maybe having leakier blood vessels while using Leqembi is not a good thing.

Jan Piraino

My husband is newly diagnosed with Alzheimer’s. We’re interested in knowing how people have reacted to it and if it has helped

M1

Hi Jan, you will likely get more replies if you start a new discussion. I'm not aware however that there is anyone on the boards who has experience with this drug yet---too new.

ElaineD

Today, the announcement came, full FDA backing of Leqembi. Medicare will cover 80% of the cost...here's hoping you have a good supplement to cover the 20%.

And it mostly money down the drain, and out of taxpayers pockets. At best the drug slows the progress, by 5 months over an 18 month period. I really don't believe this.

We are just beginning the journey to seek good practice medical advice. My DH is interested in Memantine (when he can remember it). We will be seeing a neurologist who is part of a large memory clinic at Duke University.

I've already been reading up on things my DH can do to address his cerebral small vessel disease. I hope to be his recording memory as we find ways to help him. I realize that I must make every effort to go with him to his doctor's appointments.

this topic has provided many great posts about coping mechanisms and medications and supplements. Thanks to all of you who posted.

Elaine

Iris L.

How is his blood pressure? Are any arteries clogged? Improving cardiovascular health may slow vascular dementia. But the prognosis is the same.

Iris