Lecanamab: Efficacy, Side Effects, and More

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Julie G
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Lecanamab: Efficacy, Side Effects, and More

Post by Julie G »

As promised in this thread, I'm creating a dedicated place where we can discuss all things Lecanamb. This seems to be a balanced report for those who are unfamiliar:

After promising data, experts say many questions remain over an experimental Alzheimer’s drug.

I look forward to learning more.
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Re: Lecanamab: Efficacy, Side Effects, and More

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Julie G wrote: Thu Nov 03, 2022 2:22 pm I look forward to learning more.
I found this entire recent article to be very interesting. Why Isn’t There an Effective Alzheimer’s Treatment Yet? It is an interview about the recent developments in Alzheimer’s drugs, specifically aduhelm (aducanumab) and lecanemab, and the future of what Alzheimer's drug research may hold. Regarding lecanemab, some excerpts from the article that helped me understand its efficacy (or lack thereof):

Patients who got lecanemab did 27 percent better on cognitive tests than those who got the placebo. But there are some important caveats. This trial focused on early-stage disease and all the patients had some degree of decline on what’s called the clinical dementia rating: an 18-point scale that determines cognitive function. Zero means you have no signs of cognitive decline; 18 is severe dementia. In practical terms, the trial meant that patients who got the drug did about half a point better on the scale than those who didn’t. What does all this mean in real life?

The debate immediately among clinicians is, what is half a point on the CDR scale over the course of 18 months? Does that mean someone who might have had to give up driving doesn’t or does so less quickly than someone else? Does it mean it’s easier to have longer conversations, recall the names of grandchildren? It’s difficult to tie these sort of conceptual, numerical outcomes to the everyday lives of people with Alzheimer’s disease. There was a pretty good study published where researchers looked at thousands and thousands of patients’ medical records and talked to the physicians who administer these scores, basically asking them: What is the smallest difference on the CDR that you would classify as a clinically relevant difference for a patient? People generally said between 1 and 1.5 points, but the minimum was about 0.5 points. So that would suggest that this drug is kind of doing the bare minimum that clinicians would say actually makes an observable difference in someone’s life. (I added the bold font for emphasis)
then at the end of the interview:
...even if lecanemab turns out to work as well as the company says it does, we’re still leaving behind the vast majority of patients with Alzheimer’s disease. There is still so much more work to do.
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Re: Lecanamab: Efficacy, Side Effects, and More

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Julie G wrote: Thu Nov 03, 2022 2:22 pm As promised in this thread, I'm creating a dedicated place where we can discuss all things Lecanamb. This seems to be a balanced report for those who are unfamiliar:

After promising data, experts say many questions remain over an experimental Alzheimer’s drug.

I look forward to learning more.
The presentation on the completed, open-label CLARITY Phase 3 trial of lecanemab in about 1800 people with MCI or mild AD is Nov 29 at the CTAD conference, and is likely to be well-covered by science reporters. Presumably the FDA is already analyzing the results of CLARITY and will issue a detailed report on safety, including ARIA-E and ARIA-H prevalence and severity among ApoE 3/4 and 4/4 participants, and efficacy across a broad range of cognitive and daily functioning measures . We should see that before or by their expected Jan 6 ruling on accelerated approval (approval with continued data required before full approval.)

One area that is getting interest is the expectation that for better safety and availability, they may soon switch to subcutaneous dosing:
A Phase 1 study compared the concentration of lecanemab in the blood after subcutaneous and IV dosing and found that, when administered under the skin, it was absorbed over a longer duration, reaching its peak concentration after 72 hours compared with one hour for IV dosing.
In this [Phase 3 CLARITY] study, researchers compared the safety and effectiveness of a fixed subcutaneous dose of lecanemab (720 mg weekly) with the IV dosing strategy of 10 mg/kg biweekly.

...Subcutaneous lecanemab...showed a good safety profile and was predicted to cause a lower incidence of ARIA-E because its peak concentration in the blood was lower than IV lecanemab. This lower ARIA-E incidence was observed regardless of ApoE4 status, a known genetic risk factor for late-onset Alzheimer’s.
https://alzheimersnewstoday.com/news/al ... emab-dose/
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Re: Lecanamab: Efficacy, Side Effects, and More

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I agree with earlier comments that lecanemab results should be peer-reviewed. For the CLARITY trial, that will happen after the completed data is released at the CTAD conference and should also be available through FDA documents.

In the meantime, here is a meta-analysis by French researchers that appears to have undergone extensive peer-review:
Received 18 February 2022, Revised 25 April 2022, Accepted 15 June 2022, Available online 29 September 2022
in Revue Neurologique available through Google Scholar on Science Direct:

High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 1: Meta-analysis and review of efficacy and safety data, and medico-economical aspects
The main difference between this new generation of anti-amyloid clinical trials and the previous ones is their ability to induce a high clearance of amyloid load in the brains of patients selected on their clinical-biological profiles...we performed a meta-analysis of the high-dose groups from lecanemab and donanemab phase 2 trials and the aducanumab phase 3 trials.We performed this meta-analysis on the effect of the drug on the shared cognitive tests used in these three trials (CDR-SB and ADAS-Cog;; MMSE was only performed with the donanemab and aducanumab trials’ results)... on the planned 18-month endpoint, and only on the highest dose group (i.e., the groups used for approval application or ongoing phase 3 trial...Briefly, this meta-analysis...proved a significant global effect of high-clearance anti-amyloid immunotherapies on the progression of CDR-SB, ADAS-Cog, but not of MMSE (Fig. 1). The results were also significant on the same scales when using Fixed-Effect models...We confirmed these findings using a generic inverse variance approach, i.e., entering directly the difference estimates and their error intervals as calculated in the original articles using multivariate models... Finally, we performed a Bayesian meta-analysis...which gave very similar results... showing a benefit of high clearance anti-amyloid immunotherapies were the most convincing on the ADAS-Cog (BF10 = 36.1) while being significant (but anecdotal) for the CDR-SB (BF10 = 1.2) and slightly in favor of the null hypothesis for the MMSE (BF10 = 0.6) (Online material Supplementary Fig. S3). Such a meta-analysis should not substitute the agency gold standards for drug approval, i.e., two positive phase 3 randomized-control trials, and should not add any confusion to this debate. Nonetheless, it confirms the trend regarding the clinical efficacy of high-clearance anti-amyloid immunotherapies and offers the opportunity to estimate the magnitude of the clinical effect of high-clearance anti-amyloid immunotherapies
When researchers who are not involved in the trials crunch data through many different statistical tests and still find a "convincing" trend of efficacy in the Phase 2 lecanemab results, I look forward to hearing the larger and extended Phase 3 CLARITY data.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by Julie G »

One area that is getting interest is the expectation that for better safety and availability, they may soon switch to subcutaneous dosing.
Thanks for sharing, Nancy. I've been reading about this. This is good news indeed as E4 carriers have about a 25% likelihood of developing ARIA with the IV method.
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Re: Lecanamab: Efficacy, Side Effects, and More

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According to this paper published by Science on 27 November 2022 Second death linked to potential antibody treatment for Alzheimer’s disease a second fatality has been reported in the clinical trial of lecanemab. From the article:
A 65-year-old woman who was receiving a promising experimental treatment to slow the cognitive decline caused by her early Alzheimer’s disease recently died from a massive brain hemorrhage that some researchers link to the drug. The clinical trial death, described in an unpublished case report Science has obtained, is the second thought to be associated with the antibody called lecanemab. The newly disclosed fatality intensifies questions about its safety and how widely lecanemab should be prescribed if ultimately approved by regulators.
Also from the article:
Rudolph Castellani, a Northwestern neuropathologist who studies Alzheimer’s and conducted an autopsy at the request of the patient’s husband, ...“It was a one-two punch,” Castellani says. “There’s zero doubt in my mind that this is a treatment-caused illness and death. If the patient hadn’t been on lecanemab she would be alive today.”
There's more, read the article.
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Re: Lecanamab: Efficacy, Side Effects, and More

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I am just so surprised by this. They treated with T-P-A ??? when they knew that Lecanemab would likely cause ARIA symptoms? That is ARIA ~= hemorrhagic stroke. That was thought to be low risk? Perhaps I am missing something here. It is probably best not to make hasty responses to these sorts of patient reports, though as a knee jerk reaction, I would think that TPA would be highly contraindicated with Lecanemab. One lesson here might be that there should be a 24/7 1-800 number to call for emergency medical advice for management of patients on anti-amyloid mabs. Leaving it to be figured out by itself does not seem the best idea.

The problem with ARIA type responses is that I do not know if there is really any clear treatment response to try. It is Monday morning quarterbacking, though the immediate and extreme response of the patient to TPA is largely what one would logically expect from giving a strong blood thinner to a patient with ARIA.

I am also unclear of the timeline involved. The last placebo visit for Clarity was on ~ September 15th. 2 1/2 months ago. When did the patient in this recent report have the incident? Was this possibly months and months ago? And it was reported the day before the big CTAD meeting?
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Re: Lecanamab: Efficacy, Side Effects, and More

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It is not clear whether the patient had ARIA. From what I read it was a stroke. When TPA is used after a stroke, it is only for non-hemorrhagic strokes and a CT or MRI is required before giving TPA, to exclude any hemorrhage because that would be a contraindication to TPA. So it would have been an ischemic stroke, with no hemorrhages prior to TPA. In the setting of stroke TPA can cause brain hemorrhage especially if it is given after 4.5 hours from symptom onset. Ideally it is used within 3 hours of symptom onset but it can be used until 4.5 hours with some increased risk of hemorrhage. But even if it was an ischemic stroke with duration under 3 hours, if they had taken the recent start of treatment with lecanemab into account (she was on the open label trial extension for 1 month and they believe she had likely had placebo before) as a risk factor for bleeding then maybe the safer option would have been thrombectomy (if the stroke was from a large artery occlusion in the anterior cerebral circulation). In any case I don't think it was a "one-two punch" as the neuropathologist says. It was more like 1-4 punch with stroke + TPA + CAA + lecanemab.
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Re: Lecanamab: Efficacy, Side Effects, and More

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Julie G wrote: Thu Nov 03, 2022 2:22 pm As promised in this thread, I'm creating a dedicated place where we can discuss all things Lecanamb.
I ran across another couple of interesting articles today. In this first one, Anti-amyloid drugs and the mystery of treatment-associated brain shrinkage the author is interested in seeing whether the brain shrinkage seen in the Phase 2 trial remains and is addressed in the Phase 3 trial. In the phase 2 clinical trial, whole brain volume in participants treated with lecanemab was greater compared to the placebo group. From the article:
It’s important to fully understand this phenomenon and its long-term implications, because in people with Alzheimer’s disease, brain shrinkage, typically measured on MRI scans as a reduction in brain volume or an increase in the volume of the brain’s fluid-filled spaces (known as ventricles), has been consistently associated with progression of the disease rather than slowing of symptoms. Brain shrinkage also correlates with severity of pathological changes in the brain due to Alzheimer’s assessed at autopsy.
I propose four questions that should be pursued in the clinical trial data about lecanemab and other amyloid-targeting antibodies. These are:
• Does the loss of brain volume track with worsening cognitive performance or other side effects such as headache, confusion, and dizziness?
• Is there a relationship between brain volume loss and frequently observed amyloid-related imaging abnormalities (ARIA) that cause brain swelling or microbleeds in patients treated with these drugs?
• Is loss of brain volume related to higher levels of biomarkers of neurodegeneration?
• Are patients who show brain volume loss on MRI scans more likely to develop long-term worsening of cognitive decline?
The other article, Breakthrough drug marked as 'beginning of the end for dementia' which ails a million Britons in doubt over brain bleed risks, expert warns says:
• One in ten patients in the most recent lecanemab trial suffered brain swelling
• One in six experienced brain bleeds
The ramification of the brain bleeds means anyone taking lecanemab would need regular MRI scans, which would increase the burden and expense of the therapy. Those who were found to experience brain bleeds were taken off the drug.
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Re: Lecanamab: Efficacy, Side Effects, and More

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From this article, Alzheimer's drug slowed cognitive decline overall in trial, but with major side effects for some
"For that small group of (APOE4) homozygous patients, when it comes to CDR-SB, (rate of decline on a clinical dementia scale) we don't see a signal favouring lecanemab," said Ivan Cheung, Eisai's U.S. chairman, in an interview. He suggested that could be because homozygous study patients who were given a placebo fared better than expected.

The APOE4 carriers did show improvement on the trial's secondary goals, including other measures of cognition and daily function. Overall, lecanemab patients benefited by 23 per cent to 37 per cent compared with a placebo on these secondary trial goals.
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