Celebration Thread: Solanezumab A4

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J11
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Celebration Thread: Solanezumab A4

Post by J11 »

Yes, sorry everyone, it might be too much celebrating and not enough sticking to the knitting, though it appears there
is yet another near term readout we need to be aware of.

Solanezumab has a phase 3 trial (the A4) with a primary end date in December.
https://clinicaltrials.gov/ct2/show/NCT ... w=2&rank=5


This has a reasonable chance of having a convincing topline.
However, it is somewhat less clear how this will fit into the regression as Sola engages amyloid on the monomer side -- away from the plaques. Sola could have zero effect on SUVR while having good cognitive benefits. Without our regression crystal ball there is no good way to know how good the cognitive benefit will be. One can see that it is always wise to consider each amyloid mab individually and not as a class.

Lilly also has Remternetug which was unknown to me until recently, even though it is in phase 3.
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Re: Celebration Thread: Solanezumab A4

Post by floramaria »

J11 wrote: Thu Oct 06, 2022 7:21 pm Yes, sorry everyone, it might be too much celebrating and not enough sticking to the knitting, though it appears there
is yet another near term readout we need to be aware of.

Solanezumab has a phase 3 trial (the A4) with a primary end date in December.
https://clinicaltrials.gov/ct2/show/NCT ... w=2&rank=5


This has a reasonable chance of having a convincing topline.
However, it is somewhat less clear how this will fit into the regression as Sola engages amyloid on the monomer side -- away from the plaques. Sola could have zero effect on SUVR while having good cognitive benefits. Without our regression crystal ball there is no good way to know how good the cognitive benefit will be. One can see that it is always wise to consider each amyloid mab individually and not as a class.

Lilly also has Remternetug which was unknown to me until recently, even though it is in phase 3.
Oh NO!! Is your regression crystal ball broken?? :D
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Re: Celebration Thread: Solanezumab A4

Post by J11 »

flora, please!

I have conquered Mount Olympus;
I have communed in Xanadu

Without my regression crystal ball
I will be flightless.

How the mighty have fallen.


Solanezumab is now a mystery to me.
There will be no three decimal accuracy.
There is no obvious dose response relationship to recognize.
I am very unsure how A4 will readout.
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Re: Celebration Thread: Solanezumab A4

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J11 wrote: Fri Oct 07, 2022 6:24 pm flora, please!

I have conquered Mount Olympus;
I have communed in Xanadu

Without my regression crystal ball
I will be flightless.

How the mighty have fallen.


Solanezumab is now a mystery to me.
There will be no three decimal accuracy.
There is no obvious dose response relationship to recognize.
I am very unsure how A4 will readout.
J11 ~ :lol:
Like a phoenix, you will rise again!
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Re: Celebration Thread: Solanezumab A4

Post by J11 »

I will dodge the slings and arrows of outrageous mockery once again to remind everyone of the now imminent A4 readout. This is a sleeper, though everyone could be startled by the result. I will be fairly ambivalent about an actual pre-readout prediction, though this is one where the cognition vs. amyloid clearance does not seem to be applicable.

Basically, 1150 patients treated for 336 weeks ? (nobody does a 336 week trial!) tested on PACC for pre-symptomatic AD. They have quite a few good elements here to make this a winner. PACC is a good one. Check. 336 weeks is a good one. Check.

The primary completion date was December 27th, 2022. They could report on this within days! Remember Sola had little if any ARIA in other trials. I will need to look online for some reasonably priced cashews for more celebrating! Last time I looked though it appeared that there are other party participants who are cornering the market.

This could potentially be a massive massive topline. It would obviously move the game a great deal up field. It would then offer those with pre-dementia a treatment choice. This is just so gigantic and there is no online chatter about it.
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Re: Celebration Thread: Solanezumab A4

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Disappointing that the A4 Solanezumab phase 3 did not work out. When the reports noted that patients continued to accumulate amyloid while being treated with Sola, it did not give me a good feeling. The neurodegenerative effects of amyloid would continue to accumulate even with Sola treatment.

I have still not internalized the idea that Alzheimer's has a 100% failure rate. With AD you can predict that a trial will not be successful and will be correct almost 100% of the time. I was so lucky to only start paying close attention with Aducanumab and Lecanemab, my Bayesian prior is 100% success. However, this is not aligned with the century of one failure after another. There would not have been that much opportunity for celebrations during the first century of AD clinical research. Good that I was able to avoid all of that.

https://investor.lilly.com/news-release ... reclinical
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Re: Celebration Thread: Solanezumab A4

Post by NF52 »

J11 wrote: Thu Mar 09, 2023 6:20 pm Disappointing that the A4 Solanezumab phase 3 did not work out. When the reports noted that patients continued to accumulate amyloid while being treated with Sola, it did not give me a good feeling. The neurodegenerative effects of amyloid would continue to accumulate even with Sola treatment.

I have still not internalized the idea that Alzheimer's has a 100% failure rate. With AD you can predict that a trial will not be successful and will be correct almost 100% of the time. I was so lucky to only start paying close attention with Aducanumab and Lecanemab, my Bayesian prior is 100% success. However, this is not aligned with the century of one failure after another. There would not have been that much opportunity for celebrations during the first century of AD clinical research. Good that I was able to avoid all of that.

https://investor.lilly.com/news-release ... reclinical
Even failed trials provide answers, J11! Solanezumab was the very first clinical trial for prevention of cognitive impairment (diagnosis of MCI or mild AD) in people with no cognitive impairment who had elevated levels of toxic beta amyloid plaques on PET scans. The drug did not target or remove amyloid plaques at all. It targeted soluble forms of amyloid oligomers, but not apparently protofibrils. So, as you noted, amyloid plaques continue to increase because upstream forms of beta amyloid also continued to increase. If you don't clear out the hoarder's attic and only focus on keeping the entryway clear, pretty soon the hoarder's bedroom, kitchen, and all other living spaces will be impassible.

As you have pointed out, later formulations of the drugs, including lecanemab and donanemab, selectively target protofibrils but also remove plaques by about 18 months. It has been speculated that plaques are merely cemetery where toxic amyloid is safely buried. This study would seem to strongly show that is not the case. The same was true with the CTAD results on gantenerumab: Not getting rid of plaques quickly and completely (they got to above 50% reduction) gave no benefit.

People on the placebo trial or the ineffective dose of solanezumab, ALL of whom had elevated amyloid with normal cognition, had a 36% risk of progression to MCI/mild AD over 5-6 years. People who were tested for the A4 trial and did not have elevated amyloid, but were followed with the same cognitive tests and scans in the LEARN trial. If similar clinical trial participants, without elevated amyloid, did NOT have that risk, that suggest to me the need to get rid of multiple forms of upstream amyloid and plaques--quickly and safely.

And a deep bow to those who participated for up to 6 years in this trial, going for monthly infusions and numerous lengthy cognitive tests, EKGs, blood draws and MRIs and PET scans. They showed it was possible to ask people with normal cognition to participate based on increased risk to help others.
4/4 and still an optimist!
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Re: Celebration Thread: Solanezumab A4

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All Amyloids 1.JPG
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Re: Celebration Thread: Solanezumab A4

Post by J11 »

Hmm, that one did not turn out all that great.
I think the problem is that if you snip it and then repost it then it starts to get all smudgy.

The Solanezumab is the pinkish purple x near the 0.0 on the x-axis.
Sola did not have any effect on amyloid in the previous trials though interestingly it did possibly seem to have some benefit on CDR-sb when used in the typical mild-moderate AD population. The latest A4 trial treated in the pre-AD stage and showed no benefit. I would still like to see Sola in combination with Leca. It might add in marginal benefit, while adding in possibly minimal ARIA risk.

NF52, that hoarder analogy struck a little too close to home. We are dealing with such a situation currently. What should one do when the DVD are stacked waist high everywhere in a room? Things do start to get someone confining ... and then there is a tendency for tentacles of hoarding piles to spread elsewhere.

Yes, this is true about Sola not clearing amyloid. I think (hope) with the previous results with anti-amyloids that we are now over that hill. Aducan provided the first round of evidence supporting anti-amyloids; then Leca phase 2 and clarity provided further substantial evidence; then Gantenerumab while topline negative actually also strongly confirmed the regression. Now we have Sola and it is out completely on its own with no relationship to amyloid clearance. The anti-amyloid position now has a very firmly established evidence foundation.

I am somewhat uneasy about definitively talking about mechanism of action. Often, such assertions wind up being proven untrue. My guesstimate is along the lines that clearing plaque should shift the amyloid balance in a Le Chateauean manner and then have anti-dementing effect, though I will not be dogmatic about this more a working suggestion. One highly provocative piece of research is with Alzheon, where they found that even without removing plaque they could have large cognitive effects by clearing oligos/protofibrils.
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