Lecanemab and the FDA

Lane Simonian

The FDA may make a decision on the anti-amyloid drug lecanemab on January 6th.  This drug has about the same effectiveness as aducanumab/Aduhelm which the FDA approved last year but which Medicare refused to cover due to concerns over cost, effectiveness, and safety (especially the risk for brain bleeds and brain swelling in APOE4 carriers).

https://www.evaluate.com/vantage/articles/events/conferences-trial-results/ctad-2022-lecanemab-data-hold-big

Both drugs are produced by Eisai and Biogen, although after the Aduhelm fiasco, Eisai is the one out front on lecanemab.

In every other recent anti-amyloid drug trials (including lecanemab's phase 2b trial), the drug has only slowed down the progression of Alzheimer's disease in non-APOE4 carriers.  And yet this time lecanemab slowed down Alzheimer's most in non-carriers.  How did Biogen and Eisai flip these results?  It did so by combining carriers and non-carriers into a composite mean placebo score.  But since non-carriers progress more slowly than carriers, non-carriers are going to be below that placebo score and carriers are going to be above it.  The actual mean placebo numbers for non-carriers are very close to the mean numbers for the drug group.

If the FDA approves the drug for all early stage Alzheimer's patients, non-carriers will be taking an expensive drug involving biweekly or monthly injections that do them almost no good.  Carriers would be taking a drug that would decrease their progression rates closer to non-carriers but which may not produce clinically significant results and may on fairly rare occasions cause brain bleeds and swelling (especially in patients also taking blood thinners). 

In the larger picture, amyloid is the product of many other factors that initially trigger Alzheimer's disease and only reach high enough levels to add to the disease in individuals with one or two copies of the APOE4 gene.  When the FDA, pharmaceutical companies, and the Alzheimer's Association will stop going down this rabbit hole is anybody's guess, but with any luck at all it will be this year.  

dayn2nite2

No cure because they won’t change their thinking.  Sad.

Lane Simonian

The FDA did grant accelerated approval to lecanemab/Leqembi based on the removal of amyloid.  The agency will allow the drug to be sold at around $26,500 a year, but it will be months before Medicare will likely cover it if ever.  In the meantime, further examination of the drug's efficacy may take place.  When (if) subgroups in the placebo and drug groups are ever compared it is likely the drug has almost no effect on ApoE4 non-carriers and modestly slows down the progression of the disease in carriers closer to non-carriers.  ApoE4 carriers, though, can suffer from brain bleeds and swelling from the drug.

Eisai Co. and Biogen Inc. developed the newly approved Alzheimer’s disease drug Leqembi.

A sweeping Medicare rule issued last year will keep the newly approved Alzheimer’s disease drug Leqembi out of reach of most U.S. patients for months to come.

The Food and Drug Administration on Friday approved Eisai Co. and Biogen Inc.’s Leqembi, known generically as lecanemab, for the treatment of people with early-stage Alzheimer’s disease, the vast majority of whom are insured by Medicare. However, Medicare won’t pay for the drug unless patients are enrolled in government-sanctioned clinical trials, and no such studies are ongoing or planned.

The Alzheimer’s Association patient-advocacy group asked the Centers for Medicare and Medicaid Services in December to reconsider its policy, a process that could take as long as six to nine months if it chooses to do so.

As many as 85% of patients who could benefit from Leqembi are insured by Medicare, said Ivan Cheung, Eisai’s global Alzheimer’s disease officer. Eisai projects that 100,000 patients could be using the drug by its third year on the market, assuming that Medicare officials lift coverage restrictions, Mr. Cheung said.

CMS said Friday it “is examining available information and may reconsider its current coverage based on this review.”

Biogen and Eisai priced Leqembi at $26,500 a year for the typical patient.

“It’s clear there won’t be coverage on day one and that’s never been true of any FDA approved drug before,” said Robert Egge, chief public policy officer of the Alzheimer’s Association. “It’s going to be very difficult if not impossible for Medicare beneficiaries to get coverage.”

The holdup stems from the unusual move by Medicare officials last year to issue a rule restricting routine payment of drugs that target the protein amyloid in the brains of Alzheimer’s patients.

They made the move following the approval in 2021 of Aduhelm, also made by Biogen and Eisai, based on uncertain clinical trial evidence that it was effective at slowing progression of Alzheimer’s.

The agency had said its policy leaves drugmakers enough time to organize clinical trials that will answer questions the agency has about the safety and effectiveness of their drugs in Medicare patients, who tend to have more health problems than patients who enroll in industry studies.

Drugmakers and patient-advocacy groups criticized the rule for prematurely deciding the fate of similar drugs still in testing. Aduhelm was a unique scenario because Biogen officials had mistakenly ended two large clinical trials early, and were left with inconclusive results, some companies and doctors say.

Medicare officials moved too fast in judging medicines such as Leqembi based on the Aduhelm results, said Stephen Salloway, a professor of neurology and psychiatry at Brown University.

“It seemed unusual they’d make a coverage decision about future drugs when they haven’t seen the results,” said Dr. Salloway, who has been a paid consultant to drugmakers including Eisai and Biogen.

The FDA granted so-called accelerated approval to Leqembi based on a small, mid-stage study showing the drug significantly reduced levels of the protein amyloid in the brains of people with early Alzheimer’s.

The agency says reducing amyloid is likely to predict a clinical benefit in patients, but the approval is conditioned on the benefit being proven in a follow-up study.

Eisai, which has led Leqembi’s development, says it obtained the proof late last year from a large confirmatory study published in the New England Journal of Medicine showing that the drug slowed cognitive decline by 27% compared with a placebo. The company plans to file for full approval based on the study.

Eisai has been in talks with CMS officials in the lead up to the FDA approval decision, and the company plans to seek a reconsideration of the payment policy after it files for full approval, Mr. Cheung said.

If CMS changes course, Leqembi’s use would be limited, Mr. Cheung said, because many Alzheimer’s patients are never clinically diagnosed by a doctor, and patients with early-stage disease can be more difficult to identify than sicker patients.

“People think there are going to be a lot of people on these drugs and there’s not,” Mr. Cheung said.

Eli Lilly & Co. is also expecting an FDA decision on its anti-amyloid drug donanemab early this year. The company is preparing to introduce the drug in the U.S., but is expecting slow uptake unless the CMS coverage decision is liberalized, said Anne White, president of Lilly’s neuroscience division.

SHARE YOUR THOUGHTS

How will a new Alzheimer’s drug transform your life or the lives of people you know? Join the conversation below.

“The use is going to be very limited in the short term,” said Ms. White. “Without Medicare coverage, I think we have limited expectations.”

Doctors, meanwhile, are fielding increasing calls from patients asking about Leqembi. Richard Isaacson, a preventive neurologist and researcher at the Institute for Neurodegenerative Disease of Florida, said that Leqembi requires a significant amount of effort and time on the part of patients and their family members.

Patients will need to come to a doctor’s office every two weeks to get a drug infusion, as well as frequent magnetic resonance imaging, or MRI, scans in the first months of treatment to monitor for the risk of brain bleeding and swelling. Patients also need to know that they are at higher risk of such side effects if they carry a gene variant called APOE4 that is linked to Alzheimer’s disease.

“This isn’t just a pill you take everyday,” said Dr. Isaacson.

The FDA and the Alzheimer's Association are pushing a drug that has little to no clinical efficacy with risk of serious side effects that may result in death.

Larrytherunner

Lane, I find your posts very long and confusing. It seems like you are quoting different articles but you are not saying where they are coming from. It is difficult for me to separate your own ideas from what others are writing. Lane, I think you can do better.

ImMaggieMae

Lane, thank you for posting these articles on aducanumab/Aduhelm. While it’s good to see the research being done on drugs for Alzheimer’s, it does seem like they’re rushing these to market. The pricing is astronomical. I would like to see drugs developed that would aid more advanced stages.

Lane Simonian

Sorry for the confusion, Larry.  It was just one long article from the Wall Street Journal.  I borrowed from someone else who has access to the article (which is also why I did not provide a link).  My own comments are in bold.

I appreciate your comments day2nite2 and MaggieMae.  Too much time has been spent on anti-amyloid "treatments" for Alzheimer's disease.  These treatments only seem to slightly help those with one or two copies of the ApoE4 gene during the early stages of Alzheimer's disease.  The thinking that anti-amyloid treatments are of small benefit to some during the early stages of Alzheimer's disease has been generalized to the notion that all treatments only work during the early stages of Alzheimer's disease.  The earlier one starts the better, but some treatments may also help those with moderate or perhaps even severe Alzheimer's disease.

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

Michael Ellenbogen

This is from a email I sent out to a few doctors yesterday. I belive it say it all. 

From:

Sent: Friday, January 6, 2023 4:45 PM
To: Michael Ellenbogen 
Cc: 
Subject: Re: FDA Approves Lecanemab for Treatment of Early Alzheimer’s

Totally agree.  CMS should hopefully pay for it starting ASAP. 

On Fri, Jan 6, 2023 at 3:45 PM Michael Ellenbogen  wrote:

FYI - I was surprised to see this happen.  I thought they would become gunshy.  Thank God they are doing the right thing. 

---------- Forwarded message ---------
From: Alzheimer's Drug Discovery Foundation 
Date: Fri, Jan 6, 2023, 3:16 PM
Subject: FDA Approves Lecanemab for Treatment of Early Alzheimer’s
To: Michael Ellenbogen  

View this email in your browser

January 6, 2023

Dear Colleagues,

This is a promising day for the entire Alzheimer’s community with the FDA’s announcement that lecanemab (Leqembi) has been granted accelerated approval for the treatment of patients with early-stage Alzheimer’s.

The accelerated pathway allows the FDA to approve drugs that fill an unmet medical need based on strong early clinical trial data while the drugs continue to be studied. In the coming weeks, Eisai will share more information on when the drug will be available for patients.

Based on data already collected in a phase 3 study showing that lecanemab slows cognitive decline, Eisai also plans to file for “full” traditional approval, which evaluates drugs based on their clinical benefit, later this year.

While this is an exciting development, heralding a new era for Alzheimer’s research guided by the biology of aging, we know that amyloid drugs alone will not cure this disease. We will need multiple drugs aimed at the whole host of underlying causes that contribute to Alzheimer’s so that we can combine them in personalized treatment approaches based on each patient’s unique disease pathology. And we are well on our way.

Diagnostic biomarker tests like those supported by the ADDF’s Diagnostics Accelerator are also vital to improve outcomes for patients with Alzheimer’s. Biomarkers will allow us to ensure the right drugs are given to the right patients at the right time, providing the greatest benefit possible.

We celebrate today while remaining focused on our mission to discover drugs for novel targets that will one day allow us to prevent, treat and cure Alzheimer’s disease. Thank you for your continued support and dedication to our mission.

Howard Fillit, MD
Co-Founder and Chief Science Officer

Mark Roithmayr
Chief Executive Officer

Copyright © 2023 Alzheimer's Drug Discovery Foundation, All rights reserved.