Dr. Mia talks about the newly released preliminary results of anti-amyloid drug: lecanemab, the context of this newest drug development, and more questions than answers going forward.
News release of clinical trial Clarity AD (lecanemab) trial results
Biogen & Eisai's 50/50 relationship for lecanemab
Other trials including lecanemab
Biogen's recent $900 million lawsuit settlement due to improper physician payment
ARIA (Amyloid-related Imaging Abnormality): key side effects in lecanemab
Transcript & more at www.miayangmd.com
*Disclaimer: views expressed are Dr. Mia Yang's solely and do not represent her employer, National Institute of Health (NIH), or Patient-Centered Outcomes Research Institute (PCORI). Dr. Mia has no pharmaceutical company funding.
Music & disclaimer
Transcripts on www.miayangmd.com.
Opinions expressed are exclusive of Dr. Mia Yang and not reflective of her or guest speaker's employers or funders.
Dr. Mia: [00:00:00] Welcome back to Ask Dr. Mia podcast. This is Dr. Mia, and today I am excited to talk to you about lecanemab, a new monoclonal antibody against amyloid protein. The news release was just out as of last week. And there is a lot of excitement about this new drug, and I also have a lot of questions, so I thought it would be good for me to go through my thinking process with you all here.
So lecanemab is targeting the abnormal protein called amyloid. We think if one of the mechanisms causing Alzheimer's disease. For those of you who are new to this podcast, I would encourage you to go back to episode number four where I talked about the two types of Alzheimer's disease and [00:01:00] the mechanisms leading to what we clinically call Alzheimer's disease, which at times may be different from how researchers or what the actual cells and neurons look on the microscope after someone passes away.
But in lecanemab, this is a newly released result from a phase three clinical trial, meaning this was done in real people. Actually, a lot of people this time, 1,906 people. And it was a trial done by two companies, and Biogen, and it was an international trial with many participants from the United States.
This trial was done during the pandemic and the news release said that 25% of its participants are black and Hispanic. The significant primary outcome [00:02:00] for the trial indicated that those who were randomized digital arm had a 0.5 point difference on an 18 point scale called Clinical Dementia Rating Scale, or cdr.
This is a test that is oftentimes done in the research setting, but not so much in the clinical setting. There are some subjectiveness to the scoring of cdr, but basically a study coordinator would ask the participant, usually someone with some mild memory loss to describe recent events, answer some questions, doing a little bit of short term memory tests, like remembering the address in a particular city, and then they would interview the study partner, someone who knows to participant well.
[00:03:00] Separately and see of the answers between the study partner and the participant correspond.
This was also, press release also showed that the side effects or aria or amyloid related imaging abnormalities or A R I A were 21.3% in the group that receive lecanemab and 9.3% in the group that received placebo. Because this is a drug that's given via IV infusion once every two weeks. I would assume that a placebo is some sort of saline IV infusion, and when people are blinded, It means that the participants, the people conducting the study, the physicians who see the participants [00:04:00] and the people who are involved in the study that measure outcomes like conducting the cdr, were looking at MRIs, none of them knew which drug the patient was receiving.
Before I go further into the study results, I do wanna give a little bit of context because I think those of you who do not follow the Alzheimer's drug development as closely may not know about a similar drug called Aducanumab, which was fDA approved last year, by Biogen, and it was also a monoclonal antibody against amyloid, but a slightly different mechanism compared to lecanemab.
There were two trials done by Biogen, Engage and Emerge Trials, which initially, both trials were stopped because of futility, [00:05:00] but after the trials were stopped, the results were analyzed again, and a subgroup of one of the trials did show a slight improvement in cdr. Uh, a slight improvement in the group who received aducanumab. FDA approval process was highly controversial. There were NPR and other media reports about it. Apparently, the FDA external advisory Committee almost unanimously recommended not approving Aducanumab, but it was approved. There is a congressional investigation into the relationship between Biogen and the FDA that is currently ongoing.
After the FDA surprisingly approved of Aducanumab, there was a lot of public discussion about the drug [00:06:00] and Medicare decided to not pay for Aducanumab outright, but recommended for Biogen to do another clinical trial in which Medicare will pay for those participants in the additional clinical trial.
But essentially since last year, almost no one has received aducanumab because of the controversy, which I think was a good idea because I think that the results were questionable. So within the context of all of that, I would say my trust in Biogen is very little. Another interesting news release that came out about a week ago was that Biogen had decided to settle for 900 million, by a whistle blower within Biogen that said that the company was too aggressively pushing for some of their multiple sclerosis drugs and was getting a kickback from physicians and [00:07:00] prescribers and basically paying for people to promote and prescribe the drug, which they're not supposed to do. So I will link the links for these and the show notes within the context of all of this.
I think it's reasonable to say that everyone should have a healthy dose of skepticism when it comes to the motivations of Biogen. But lecanemab study was, done by a company called Eisai. Uh, it's a Japanese company, but there is some relationship between Eisai and Biogen where they decide to uh, split lecanemab profit and losses 50 50 according to those who watch these type of pharmaceutical company mergers.
And basically Biogen will be the manufacturer for lecanemab while Eisai is the developer. So the final results of the trial is not going to be released until probably [00:08:00] November, which hopefully will be shortly afterwards, the full study results will be published in a peer reviewed academic journal. It is interesting that despite aducanumab's approval last summer, the full trial results have yet to be published.
If we have a big assumption that the results are, as they indicate it in the press release, then it seems like, lecanemab is a slightly more efficacious drug compared to aducanumab. And by slightly, let's go back to the primary outcome, which is the CDR or Clinical Dementia Rating Scale.
And those who were randomized to the lecanemab arm had an improvement of 0.49 on this 18 point scale. Now, this might be clinically significant for people who are in the mild stage dementia [00:09:00] or if they have mild cognitive impairment. A CDR sum boxes of 0.5 might mean that someone is having a little bit of cognitive impairment, but they are still able to maintain their daily functions.
Versus a CDR sum boxes of one might mean that someone is starting to need some assistance with some of the more difficult instrumental activities of daily living, such as doing their taxes, managing their complex medication regimen or driving , but they're still able to do a lot of what they need to do on a daily basis.
So a, a CDR sum boxes of 0.49 might be clinically significant if you catch people at the early part of the disease, which, , was the study population that was recruited for the CLARITY AD trial, which was the name of the trial that studied lecanemab. And this was done in [00:10:00] 1,906 people. One thing that is an improvement of lecanemab Clarity ad trial compared to the aducanumab trials is that it is a lot more racially and ethnically diverse.
It said that it recruited 25% black and Hispanic participants, which is great as it, it is more representative, the United States population. But like I said, the full results are to be released and I think despite the potential for more efficacy, there is still a lot of questions that we don't have.
For example, we don't know how clinically we would determine which patients have amyloid in their brain and which people do not have amyloid in their brain. Despite very smart clinicians, myself included, we're not always correct when we diagnose someone as having [00:11:00] alzheimer's disease, their history may suggest that it's a slow progressing disease that, started out with short term memory problems first, and then started involving other domains of memory, like I mentioned in episode five of this podcast.
But when people look at folks' brain under the microscope after autopsy or under an amyloid PET scan, which is currently still only available within a research setting, it's difficult to say who truly has amyloid in their brain. We think that amyloid builds up for decades before people start having symptoms.
And if I had the choice, of picking whether to have amyloid or not have amyloid In my brain, I certainly will pick not having amyloid, but is amyloid the only reason why people develop what we call clinically call Alzheimer's disease? I don't think so. I think [00:12:00] the picture is much more complicated than that.
And I think that there's a lot of overlap, in our population with vascular disease, with effects of small blood vessel disease in the brain, such as from longstanding high blood pressure, hypertension, other vascular risk factors, high cholesterol, and there are a lot of other potential pathologies as well, including infections, covid, long covid, for example, or immune system malfunction or the gut brain microbiome connection.
Basically, I say all that to say that what we clinically call Alzheimer's disease, or to 6 million Americans who currently have Alzheimer's disease, I am sure 6 million of them do not all have amyloid in their brain or that at least should probably not be receiving lecanemab because Clarity AD Trial only recruited people who were [00:13:00] in that very mild stage in the mild cognitive impairment or mild ad stage.
So going back, how do we determine who actually has amyloid in their brain? Right now, no insurance is paying for an amyloid PET scan. There was a very large clinical trial that looked at whether or not the results of amyloid PET scan would significantly change a dementia specialist plan of care.
That was an interesting study called IDEAS. I can link that result in the show notes below as well. But basically, amyloid PET scans are very expensive and, while there may be other tests like a blood work that checks for a molecule called phosphorolated tau, it is not something that we routinely widespread use in memory clinic or certainly not in primary care clinics.
So I [00:14:00] think if lecanemab is FDA approved and if it is covered by insurance, there also needs to be some coverage of some sort of biomarker test. Whether it is a blood test or a amyloid PET scan, it probably will end up being whatever is the cheapest and has the best detection. Because you really cannot just give out a monoclonal antibody against amyloid to everyone who may not have amyloid in their brain.
Within the context of the clinical trial, they also excluded people who have significant, vascular risk factors such as, history of strokes, or if they had high risk of having brain bleeds, if they have significant psychiatric illness, other reasons why they might have memory loss. The study was recruited and enrolled during the pandemic, so I think it would be [00:15:00] interesting to see once the final results come out, whether there were any unbalanced dropout rates between the arm that received lecanemab with the arm that received placebo.
And the main side effects that we need to talk about with all monoclonal antibodies against amyloid is this concept called aria, a r i a or amyloid related imaging abnormalities. It is basically two phenomenon that are detected on mri. One is small areas of swelling in the brain, and the other ones is small areas of bleeding in the brain.
And most of these ARIAs are asymptomatic, meaning that it's only seeing on MRI, which within the clinical trial was done every three months to look for these ARIAs. That's another question: how often will doctors actually need to scan people who are receiving lecanemab in the real world? We don't know.[00:16:00] Most ARIAs are asymptomatic, but symptomatic could range from something as minor as headaches and confusion to seizures and brain bleed and death.
So the symptomatic ARIA rates are significantly lower than those who are asymptomatic. So the news release said that ARIA E, which is the edema side effect, is 2.8% in the lecanemab group and 0% in the placebo group, which is great. Because you, hopefully you should not have brain bleed if you're just getting, IV saline.
And then for ARIA H or the hemorrhage, type of ARIA, the rate is, 0.7 versus 0.2. This is for symptomatic, so for the percentages are more about 17 to 20 percent, total.
So I think it also [00:17:00] depends on how widely this drug could potentially be given to patients and how long this drug needs to be taken. It is an infusion that is once every two weeks, but does that mean that someone who is 60, who has mild cognitive impairment need to be on lecanemab for the rest of their lives?
We don't know. We know that amyloid protein can build up for decades in someone's brain before they have symptoms, but we don't know how long the drug is safely should be given, and the trial was only done for 18 months.
So with all that said, if all of those questions could be potentially answered and at least discussed, and Medicare decides to pay, we don't know how much the companies will charge for this drug. When Aducanumab, the other monoclonal antibody was approved by the [00:18:00] FDA last year, the initial price that was released by Biogen was $56,000, per year, and it was a once a month infusion. Lecanemab is twice a month infusion. Interestingly when no one really bought aducanumab, biogen had given it a 50% sale, pricing at $28,000, which is still a significant amount that very few people could outright pay. So I think this also leads to a larger discussion about the entire field of dementia research.
A part of me is a little worried that if lecanemab is indeed efficacious, at least statistically efficacious, possibly mildly, clinically efficacious, what would it mean for Medicare and for our country's healthcare system? Unfortunately, [00:19:00] healthcare expenditure is not something that is sustainable if it's continued to grow, and I worry that other potentially equally important breakthroughs in Alzheimer's pathology could be potentially not funded or not that interesting because people think that now we have a cure, quote unquote, for Alzheimer's disease in lecanemab. And I hope that doesn't happen. But I wouldn't be surprised if we do, because we tend to be a country that is very focused on the pharmaceutical treatments for diseases when a lot of times families and care partners for people living with dementia need support and, guidance through the healthcare system, probably more so than any specific pill or infusion they receive. What does it mean for the people who have much later stage of disease now and [00:20:00] are not eligible to receive lecanemab?
Where is the funding for comprehensive dementia care where people could get, a more tailored, experience in all the changes that come with dementia, Not only for the person experiencing memory loss, but also for their families. So I think this is my initial thoughts, surrounding lecanemab. It's definitely an exciting new development. But I'm not sure if it's going to have the significant benefit that some proponents are thinking. I think the reality is going to be much more complicated in terms of expanding lecanemab potentially from just a clinical trial population to the larger population. [00:21:00] So if you have enjoyed this episode, please leave me a review on Apple Podcast or any other podcast platform of your preference. This will really help other people in finding this information and finding this podcast. Thank you so much and see you next time.