Celebration Thread: Lecanemab Primary Completion!

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J11
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Celebration Thread: Lecanemab Primary Completion!

Post by J11 »

It appears that I neglected to include a countdown for the Lecanemab Phase 3 Clarity Primary Completion date.

From all that we know about Aducanumab and the dataset that has accumulated for the anti-amyloid mabs, it is not unrealistic to expect a celebration sometime after the primary completion when the results are reported.


https://www.timeanddate.com/countdown/p ... font=serif
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Re: Celebration Thread: Lecanemab Primary Completion!

Post by J11 »

The Core completion date for the Lecanemab Clarity trial is now September 15th.
Party delayed by a week.


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Re: Celebration Thread: Lecanemab Primary Completion!

Post by J11 »

Lecanemab given priority review with PDUFA of January 6, 2023. Insurrection day?
Well, if there's going to be an Alzheimer's revolution, I suppose it might as well be on Insurrection day.

There is also mention that full approval could be sought in March of 2023. I am not sure of what particular relevance that would be once accelerated approval were granted.

Will everyone just wait it out for months and months after the readout on Clarity? It's not that difficult to guess that Clarity will report a strong result; if they have everything set-up properly with amyloid and tau selection, then the results could be very strong.

I do wonder if the result were strong whether there could be a preauthorized Right to Try as of the day of the Clarity readout announcement. At some point the plan seemed to have been that approval for leca could have been before readout of Clarity (e.g., possibly March, 2022). Time has drifted forward and forward and now it seems that time will drift forward even more-- This despite the strong safety and impressive efficacy reports that are already known. Why not allow these patients who have waited patiently for so many years an immediate right to choose once topline results are in. Why wait? or Why wait anymore?

https://www.alzforum.org/news/research- ... nuary-2023
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Re: Celebration Thread: Lecanemab Primary Completion!

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J11 wrote: Thu Jul 07, 2022 5:41 pm Lecanemab given priority review with PDUFA of January 6, 2023. This is likely to be approval based on documented safety and efficacy of the outcome of reducing biomarkers of AD pathology: amyloid beta and tau
There is also mention that full approval could be sought in March of 2023. I am not sure of what particular relevance that would be once accelerated approval were granted. "Full approval" would mean that the drug also met pre-set outcome measures of clinical benefit due to statistically significant slowing of clinical decline compare to the placebo group--something that only one of the two aducanumab trials showed. Full approval would remove the need for a 'confirmatory trial", I believe.

I do wonder if the result were strong whether there could be a preauthorized Right to Try as of the day of the Clarity readout announcement... Why wait? or Why wait anymore? I would not expect that to translate to a "right to try", since the AHEAD-3/45 studies in people with normal cognition who have positive amyloid PET scans is still recruiting and unlikely to have final results until 2027 (hopefully interim results sooner.) About 75% of ARIA-E and H cases appear to be asymptomatic, and resolve without cognitive impairment, this drug or donanemab MAY have a much greater chance of both FDA and Medicare approval for MCI/mild AD individuals. When scientists are criticized for moving too slowly, they point to the need to slowly move from Phase 1 safety in a small group of healthy people to Phase 2 safety across a range of doses, to determine the dose with the greatest safety/efficacy, and then to Phase 3 trials with hundreds or thousands of people followed long enough to ensure a significant and robust measure of safety and efficacy. For the current AHEAD trials in preclinical AD, Eisai and its partners have screened more than 29000 people to enroll 10% of that as of Spring 2022. So we can't fault research for moving slowly to get strong results and then question the results they spent years gathering.
This AAIC talk appears to me to be an example of transparency around safety and risk, particularly for ApoE 4/4 carriers. Yesterday, AAIC (remember, this is the Alz. Assn.) had great talk by several neurologists who provide comprehensive care (checking multiple biomarkers Dr. Bredesen would approve of ) saying that they recommend people considering a trial get ApoE4 genotyping so that if they are already in early-stage AD (beyond MCI) they can
consider whether the burden of the trial providing a 30% reduction in slowing makes sense to the individual and their choices of priorities.
https://www.alzforum.org/news/research- ... nuary-2023
Here's an excerpt from the abstract of a talk to be presented by Eisai on Wednesday at AAIC. FWIW, I am optimistic that the CLARITY results to be released in fall will be strong both in significant slowing of cognitive decline (in a group with expected cognitive decline due to MCI/AD).
Background: Lecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species with activity at insoluble fibrils. A multicenter, double-blind, placebo-controlled phase 2 study (Study 201 Core) was conducted in 856 patients with early [stage] Alzheimer’s disease (EAD). Amyloid related imaging abnormalities — edema/effusion (ARIA-E) was a main adverse event of special interest. Incidence of ARIA-E was lecanemab dose-dependent and greater in APOE4 carriers. A previously presented logistic model found steady-state Cmax was a predictor of ARIA-E incidence and more likely in APOE4 carriers (Hussein, 2019).
Results: Model-predicted ARIA-E rates for APOE4 homozygous carriers treated with lecanemab 10 mg/kg Q2W were 22.5% (versus 6.8% in heterozygous or 5.4% in noncarriers) and comparable to the observed 25% incidence in newly-treated homozygous carriers (1/4) in the OLE study, and less than the 50% incidence in homozygous carriers (5/10) in the Core.
Conclusions: The incidence of ARIA-E in subjects treated with lecanemab appears highest in APOE4 homozygous subjects. No statistically significant difference in ARIA-E incidence was found between non-carriers and heterozygous carriers. Data from the larger CLARITY-AD study will be needed to confirm these findings. Modeled Impact of APOE4 Genotype on ARIA-E Incidence in Patients Treated With Lecanemab
Modeled Impact of APOE4 Genotype on ARIA-E Incidence in Patients Treated With Lecanemab
4/4 and still an optimist!
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Re: Celebration Thread: Lecanemab Primary Completion!

Post by J11 »

NF52, thank you for replying. It's great to have someone on the ground (or here online) at AAIC. It has a fin de siècle
feeling to me-- it is astonishing the entire AD conveyor belt might soon STOP. I noted in my End of AD thread that such a medical revolution does not happen every day. In fact, this is more on the scale of a once in century or less type medical breakthrough. Once there is a disease modifying treatment for a disease such as AD which evolves over decades, then the potential exists that prevention could translate into a functional cure. This is extremely exciting and I will follow what happens over the next few days very carefully. I suppose though when it is announced we will
all know soon afterwards.

The big surprise lately for me with Lecanemab was the complete capitulation of the anti-amyloids. They just gave up? I don't suppose it is dignified to start trash talking the other side, but they aren't even going to show up for Round 2?
Get in the ring! They ran away? Completely routed? Priority review? Check. ADCOMM? Yeah, no; No check. What's the point? It's all too obvious to everyone that Lecanemab is already over the line.

What is also surprising is that this admission is in the context of actually no new evidence. It's basically admitting to the evidence that was published over a year ago. The phase 2 Leca trial that was published last year is the basis for the current assessment. Apparently it is now felt that this evidence essentially conclusively proves Lecanemab's safety and efficacy. Even with that they have unconditionally surrendered? The final CMS ruling had the same published evidence regarding Leca as we have now and they were not able to make the assessment about Leca that is now obvious to all?

If this is all so obvious to the thought leaders, then why wasn't Leca approved months ago? Before the change in FDA leadership this did appear to be the policy stance. The phase 2 trial would be enough for accelerated approval and then Clarity could be a confirmatory study. I had wondered on thread about this: could they have simply received approval for Leca in March or April and then have the confirmatory readout for Clarity afterwards? The confirmatory trials with Aducan were designed in such a post-approval manner.

I am not fully clear with Lecanemab, though Clarity has frequently been described online as a confirmatory trial. I am not totally sure about this because Clarity is the first Leca phase 3, so it's not that obvious what exactly it is confirming. The phase 2? Probably gets into the idea of what a registry trial is for Leca; the phase 2 could plausibly described in that way.

Yeah, AD trials have a certain could improve with respect to staying on the field of the clinical trial staging. It probably would have helped so much and would have gotten us to the finish line a great deal quicker if they had just taken it one clinical stage at a time. Jumping from phase 1 directly to phase 3 was such an exciting development for Aducan, though then there were all of the confusions that followed. Leca is one of the few AD drugs that has stayed on course and we might finally have a clean result to work with.

I realize now that many of my posts on this thread were far off base because the Aducan trials were so confusing. For example, the fact that the Aducan Engage high dose was so much in motion should have precluded much of the statistical discussion that followed. They placed the stationary requirement in the statistical plan for good reason: if the numbers are zooming around at data lock then it should be telling you something (namely, the statistical analysis will be tricky). It would be great if they were to include stationarity statistics for the Clarity results. It is not just what the top line result is: it is also how much this was locked in through time. Interestingly, in a properly conducted clinical trial, one would expect that the effect size should be unbiased even from an early time point; it would all just reduced down to how much dampening occurred with greater clinical trial evidence.

Yes, apoe4 testing--- this is one of the bigger mysteries for me with Aducan. I mean, patients are taking possibly a $100,000 yearly treatment, apoe e4 genotype has profound influence on the risk level of ARIA and genotyping is not thought of as being essential possibly even required? I really do not understand that. One might think that the safety protocol would be clearly differentiated by APOE 4 status.

Not just APOE 4 genotype of course. There is also PET amyloid and PET tau. Apparently on the horizon there could also be photoacoustic amyloid imaging that is down to micron level (recently reported on alzforum). That could be amazing! They might be able to have much much better insight into the disease burden of AD patients in a research clinical setting.


Incidence of ARIA-E was lecanemab dose-dependent and greater in APOE4 carriers. A previously presented logistic model found steady-state Cmax was a predictor of ARIA-E incidence ...

There are so many positives with Leca! In Clarity they did not appear to optimize all these positives. Basically they probably knew that they were gong to be so far over the line as it was that it wasn't even worth it to push onto the risk frontier.

What are some of these hidden positives, J11, some might ask? steady-state Cmax was a predictor of ARIA-E incidence Steady state Cmax is strongly determined by dosing. So if you go from maximal once monthly dosing and divide it up into isoequivalent weekly dosing you could reduce Cmax --> reduce ARIA. The move to subcu dosing could allow for this; I think they are studying that approach. Another unclaimed positive was even with the low side effects they decided to stay with the top of the dose. This seemed strange to me because as we saw with Aducan after reaching the top dose as maintenance, we soon saw that the ARIA risk quickly receded: almost all the ARIA risk was present on the uptitration doses. Perhaps patients who showed less than average amyloid response could have had gradual uptitration from the typical maximum dose. However, apparently this was not felt necessary given how rapidly Leca can be uptitrated to the top dose. One other hidden positive here is those patients who were the most desperate to begin anti-amyloid mab treatment are now working through the system those who will begin treatment in the future will be less in a hurry and will probably be lower risk. Anti-AB mabs will become safer simply because it will be more preventative. One of the newer diagnostic tests that I have heard of speaks about being able to diagnosis people 2.5 years ahead of a MCI diagnosis. Wow! Pre-Patients could be amyloid negative before they even show clinical signs? The clinical course of AD is about to undergo a revolution!
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Re: Celebration Thread: Lecanemab Primary Completion!

Post by J11 »

I neglected to include a countdown for the big FDA decision for Lecanemab.
I think the retirement theme works well for this one.


https://www.timeanddate.com/countdown/r ... nt=cursive
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