AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by NF52 »

Julie G wrote: Tue Oct 25, 2022 5:37 am ...Perhaps because of the media storm proclaiming "historical" results with Lecanemab, I don't see a discussion about its efficacy.

1) Lecanemab does not improve cognition and does not stabilize Alzheimer’s. It simply slows decline in the early stages.
2) The slowing of decline was in between that of aducanumab (22% slowing in its best trial, none in another trial) and donanemab (32% slowing).
3) As mentioned by other posters, the side effects include brain microhemorrhage and brain edema. Thus some people may actually get worse instead of slowing their decline.
Hi Julie,

Detailed results on lecanemab's CLARITY trial in about 1800 participants with confirmed clinical diagnoses of MCI/Mild AD with elevated amyloid on PET scans will be presented at the CTAD conference on 11/29 and may address the issues you raise

The comment below by Dave Morgan from Michigan State in the Comments section of the 9/28 issue of AlzForum https://www.alzforum.org/news/research- ... ne-results puts the clinical slowing in perspective as expected from a single focus on amyloid and may support the need to address elevated levels in some ApoE 4 individuals, in addition to insulin resistance, mold, inflammation, etc. :
The 25-40 percent reduced rate of decline is similar to the contribution of amyloid to cognitive decline variation in the pathology studies from the ROSMAP cohorts.
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NOTE: Additional of information on the source of the data mentioned in AlzForum:
The ROSMAP study is a combined cohort from the Religious Orders Study (ROS) started in 1994 and the Rush [Chicago] Memory and Aging Project (MAP), started in 1997. They have often been combined as one cohort to identify resilience and risk factors for cognitive decline, dementia, and other health outcomes. Religious Orders Study and Rush Memory and Aging Project.

Below is an excerpt from a 2018 analysis of the autopsied neuropathology findings from the ROSMAP study. ApoE 4 status is not addressed in this analysis; possibly because recruitment occurred in the 1990's The AD/Alzheimer's pathology referred to below included "neuritic plaques, diffuse plaques and neurofibrillary tangles" based on autopsies. Bolded sections are added by me Person-specific contribution of neuropathologies to cognitive loss in old age
Characteristics of study participants

Participants [N=1079] were followed annually for up to 22 years (mean=8.3, Standard deviation (SD)=4.8) and died at a mean age of 89.7 years (SD=6.5). All had undergone brain autopsies...Considerable decline in cognition was observed over the course of follow up; this was evident from the difference between the starting level of cognition (mean=−0.10, SD=0.62) and the level proximate to death (mean=−0.84, SD=1.11). By the time of death, 459 participants (43.2%) were diagnosed with the clinical syndrome of AD dementia, 18 (1.7%) with another primary cause of dementia, 261 (24.6%) with mild cognitive impairment, and 324 (30.5%) had no cognitive impairment ...

Neuropathology was ubiquitous, with 94% of participants having 1+, 78% having 2+, 58% having 3+, and 35% having 4+. AD was most frequent (65%) but rarely occurred in isolation (9%). Although AD accounted for an average of about 50% of the observed cognitive loss [across the cohort], the proportion accounted for at the individual level ranged widely from 22% to 100%...the fact that considerable variability remains unexplained suggests that the true impact of any specific neuropathology is actually much less than what was observed here.... An increased focus on resilience may facilitate the identification of novel therapeutic targets that can be applied much more broadly and may have an even greater impact on cognitive outcomes than interventions targeting specific disease mechanisms.
This does seem to show that while focus on AD pathology may account for 50% of cognitive impairment on average, other factors may well help individuals to either be resilient or to show continued cognitive decline.

I have seen no data to date that shows that trial participants who received lecanemab showed a greater rate of cognitive decline as a result of ARIA-E or ARIA-H greater than those taking lecanemab who did not experience ARIA. This of course will be important to see in detail at CTAD and will presumably be of great importance to the FDA in looking at risk/benefit analyses. To date, no reports of deaths due to lecanemab have been reported.

Below is an excerpt of the data posted by Biogen on 9/27. [emphasis added]:
The incidence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), an adverse event associated with anti-amyloid antibodies, was 12.5% in the lecanemab group and 1.7% in the placebo group. The incidence of symptomatic ARIA-E was 2.8% in the lecanemab group and 0.0% in the placebo group. The ARIA-H (ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis) rate was 17.0% in the lecanemab group and 8.7% in the placebo group. The incidence of symptomatic ARIA-H was 0.7% in the lecanemab group and 0.2% in the placebo group.
LECANEMAB

From what Chicagogirl has posted and materials presented at AAIC and CTAD presentations, the AHEAD prevention trial informed consent, approved by each study site Institutional Review Board (IRB) presents risks in detail. Titration to full dosing takes 8 weeks and dosing is paused and an additional MRI done if someone experiences suspected symptoms of ARIA-E or ARIA-H. The trial doesn't require that someones stop taking supplements that would be consistent with the Bredesen protocol or change their diet, exercise and social and intellectual engagement.

To paraphrase a comment from one neurologist, not speaking specifically of any treatment, said at AAIC that stuck with me: "Patients with mild dementia and their families don't ask what the CDR score will be, or what the P-value is: they ask how long they will be able to play with their grandchildren or keep driving or do other things of meaning in their lives. An extra 6-12 months is very meaningful to them."
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by Julie G »

The 25-40 percent reduced rate of decline is similar to the contribution of amyloid to cognitive decline variation in the pathology studies from the ROSMAP cohorts.
I look forward to diving into the data on the ROSMAP, but your link doesn't seem to work. Could you please check it?
I have seen no data to date that shows that participants in the lecanemab trials showed cognitive decline as a result of ARIA-E or ARIA-H, especially since most is transient and asymptomatic.
I think you mean to suggest that the cognitive decline may still be slowed despite the side effects that can occur. That may be true; I look forward to learning more. My point is that the side effects have been quite significant for some and those folks certainly got worse (for instance, several have even died with aducanumab) as a result. I appreciate the safeguards that will be put in place for this trial.
To paraphrase a comment from one neurologist, not speaking specifically of any treatment, said at AAIC that stuck with me: "Patients with mild dementia and their families don't ask what the CDR score will be, or what the P-value is: they ask how long they will be able to play with their grandchildren or keep driving or do other things of meaning in their lives. An extra 6-12 months is very meaningful to them."
I couldn't agree more. Every additional day is a blessing. I just think that E4s, especially homozygotes, could do better with other pharmaceutical options, such as tramiprosate/ALZ-801 which has shown actual cognitive improvement vs. a slowing of decline without the potentially serious side effects.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by NF52 »

Julie G wrote: Tue Oct 25, 2022 9:05 am...
I look forward to diving into the data on the ROSMAP, but your link doesn't seem to work. Could you please check it?
...I think you mean to suggest that the cognitive decline may still be slowed despite the side effects that can occur. That may be true; I look forward to learning more. My point is that the side effects have been quite significant for some and those folks certainly got worse (for instance, several have even died with aducanumab) as a result. I appreciate the safeguards that will be put in place for this trial. ...I just think that E4s, especially homozygotes, could do better with other pharmaceutical options, such as tramiprosate/ALZ-801 which has shown actual cognitive improvement vs. a slowing of decline without the potentially serious side effects.
Hi Julie,

I fixed the broken link; thanks for checking it--which I should have done. I've added a source link and excerpt to my post above from a 2018 analysis of the ROSMAP data and edited my post to add the name of the person quoted in AlzForum about ROSMAP.

You and I both have high hopes for ALZ-801, the prodrug of tramiprosate. As an oral drug it could be administered to people in rural and under-served settings with high risk of developing amyloid beta or those with validated a-beta and tau. But the Phase 3 APOLLOE4 trial of ALZ-801 in participants having both ApoE 4/4 and a diagnosis of "early AD" will not read out until 2024. Depending on safety and efficacy data, lecanemab and donanemab may be the only drugs to have both FDA and Medicare approval for people with confirmed amyloid pathology and clinically diagnosed MCI/mild AD before ALZ-801 results come out. The Alzheon website projects a Phase 3 trial in asymptomatic ApoE 4 carriers with normal cognition sometime in 2023, although most trials seems to start a year after their projected dates. https://alzheon.com/pipeline/alzheon-alz-801/ More trials may mean more knowledge about who is in most need of which interventions or in what combination.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by Julie G »

Nancy, you are a wealth of information about all pharmaceutical clinical trials- thank you for generously sharing. I appreciate an opportunity to also discuss the efficacy/safety of each as this is ultimately the most important information for our community.
More trials may mean more knowledge about who is in most need of which interventions or in what combination.
Yes, more trials provide more information, but what I care most about are the best outcomes for our members now. It's important to put lecanamb into perspective. All we have is self-reported data from Eisai and Biogen about it's efficacy with very exuberant media reporting. To date, there have been no peer-reviewed papers on the phase 3 data. Based on what we know, lecanamb is supposedly more effective than aducanumab and less effective than donanemab. All three have demonstrated slowing of cognitive decline (that still progresses) whereas tramiprosate in peer-reviewed papers has already demonstrated actual improvement in cognitive decline. Anyone (with DXed MCI/early stage AD) interested in pursuing tramprosate can consider a trial opportunity here.

Those who don't qualify, may be interested in pursuing this independently as homatuarine is available OTC; see this thread. If we have enough interested folks, we could consider putting together our own informal study.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by J11 »

karalena, thank you for your reply.

I find it especially interesting that they are using full genome sequencing in the AHEAD trial. The price of full sequencing has dropped so much that this could become the standard. This could be a big win for the AD community as if they were to do in house GWAS perhaps they could find more of the AD genetics puzzle.

Yes, NF52's advice about off label does make a great deal of sense. There are still so many uncertainties about mab treatment. Yet, it is intriguing to consider what implications a recent court ruling might have for Lecaneamb once it is approved. In this recent ruling, it was found that CMS was liable for coverage of an FDA treatment even for off label use. If that were to apply to Lecanemab, then there might be interest by those on Medicare who have the amyloid though are still somewhat off from a clear AD diagnosis.

I am so happy for you that you are able to access the AHEAD trial before cognitive symptoms have become present. When the on label period arrives you will then be assured of being treated with the active treatment and all the while you will receive the best clinical care available.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

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Julie G, I do not want to thread squat so I will only make brief comments here (but more boring and long winded comments will be posted to the Aducan Celebration thread).

1. Anti-amyloid mabs do seem to stabilize some AD patients. This was seen in the long term extensions with Aducan.
There are a core group of responders constituting ~1/3 to 1/2 that appear to do very very well. The topline numbers do not make this point clearly.

2. After all of the hundreds of posts to the Aducan Celebration thread, I would characterize the treatment response of all the anti-amyloid mabs as being essentially the same; they all seem to fall on the same regression line. It is more that some mabs allow for more dosing due to lower ARIA risk which has allowed for more efficacy to be reported. With Donanemab, they reported 23% benefit on CDR-sb which is almost identical to the Emerge result for Aducanuamb.
the 27%, 23% etc. also need to be considered cautiously. 27% is the average over the 18 month treatment period for Lecanemab. By the 18 month mark the marginal benefit has likely reached closer to 50%. The e4s of course did even better on average even with the average. e4s with Clarity probably had ~40% slowed decline versus placebo. It is not certain, though the e44s likely did even better than the e4 average.

3. With ARIA it needs to be remembered that those with mild ARIA tended to do better; mild ARIA is evidence that considerable amyloid is being removed -- the more amyloid removed the better. Removing those who experienced ARIA would simply be one way of removing the responder group.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by Julie G »

With ARIA it needs to be remembered that those with mild ARIA tended to do better; mild ARIA is evidence that considerable amyloid is being removed -- the more amyloid removed the better. Removing those who experienced ARIA would simply be one way of removing the responder group.
It's also important to remember that ARIA is more likely to occur with E4 carriers as described in this paper. Sadly, the first death has been reported with lecanemab following a brain bleed; see Death of patient in closely watched Alzheimer’s trial raises concern about risk for some groups.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

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Julie G, thank you for your reply. I will again only make limited and brief comments in response to your comment above. For those who want the full reply please go to the Aducan Celebration thread.

Firstly, yes, ARIA in amyloid mab treatment is typically related to e4 carriage. Notably, with Lecanemab such ARIA on initial reporting (e.g., in the phase 2 trial) appears to be much lower in comparison to Aducanumab. Even more notably, the ARIA rates for those with e34 appear to be quite similar to that of the e33s (again in the readout from the phase 2).

Secondly, about the fatality reported I was somewhat unclear about this as this has been mentioned online for months. After 5 months of investigation they still seem very unclear about the circumstances involved.

For me, this patient report opens up a great number of questions. Foremost among these questions was why a patient that seemed so medically unstable was even on mab treatment (or for that matter even still eligible to be in the long term extension). The report noted: " ...the patient had experienced multiple falls, a heart attack, a respiratory infection, and mini-stroke-like event. The patient who died was also taking a commonly prescribed anticoagulant at the time." Another report characterized the comorbidities as “multiple falls, a heart attack, a respiratory infection, and mini-stroke-like events". It was not made clear in the online reports how proximal these other medical events were to the brain bleed or the fatality.

Online probably isn't the best place to argue about the patient report as the causal mechanism is no doubt highly involved and complex; Being able to develop meaningful understanding considering the technical complexity involved might not be possible for casual observers. Nevertheless, the problem is that without an ADCOM these patient reports might never be fully disclosed. With Aducanumab the FDA Briefing Documents (round 2) had patient level descriptions for those who experienced serious side effects. Similar level of disclosure would be helpful for Lecanemab.

There is much more related to the safety of Lecanemab and mabs that should be added, though I will add these comments to the Aducan thread.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

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Last edited by Chicagogirl on Tue Nov 01, 2022 7:08 pm, edited 2 times in total.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

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Firstly, yes, ARIA in amyloid mab treatment is typically related to e4 carriage. Notably, with Lecanemab such ARIA on initial reporting (e.g., in the phase 2 trial) appears to be much lower in comparison to Aducanumab. Even more notably, the ARIA rates for those with e34 appear to be quite similar to that of the e33s (again in the readout from the phase 2).

Yes, great news for E3/4s, but those in our group who are participating are 4/4s, who have a 25% chance of developing ARIA per data presented at AAIC.
To see more of J11 comments and analysis please see the Prevention and Treatment. Forum under the topic of:
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Post by J11 » 30 Oct 2022 21:19 page 121
Thank you Chicagogirl and huge thanks for sharing your journey with the community! We all look forward to learning with you and wish you well. FWIW, I think it's a good idea to share the benefits and side effects on lecanamb here and the benefits and side effects of aducanumab in the other thread. I, for one, am not reading both.
Secondly, about the fatality reported I was somewhat unclear about this as this has been mentioned online for months. After 5 months of investigation they still seem very unclear about the circumstances involved.
I think this incident occurred during the phase 3 trial. Per the company:
There is at least a reasonable possibility lecanemab may have contributed to the” hemorrhage but ultimately concluded that other factors made it difficult to nail down.
From everything I've read including Eisai's Alzheimer's hopeful lecanemab may have contributed to patient death: report it appears that taking a blood thinner may have been a big contributor. I hope that our members who are participating are aware that omega-3s, curcumin, and even aspirin could have a similar effect. Be careful, friends.
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