Celebration Thread: Gantenerumab!

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J11
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Celebration Thread: Gantenerumab!

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Graduate 1 & 2 are moving towards their convocations. It's time that they had a celebration thread for the big day!

The Gantenerumab phase 3s treat out to 116 weeks, with subq dosing and a 9 month titration interval. These are interesting features that will add complexity to interpreting the topline readouts.

An alzforum article suggested that the topline could reach 0.87 on CDR-sb!! Clearly that would be a big result, though it does follow the general trend of our past regressions.
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Re: Celebration Thread: Gantenerumab!

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Sad news today; Gantenerumab reported out negative.

https://www.roche.com/media/releases/med-cor-2022-11-14

The people who have been following AD trials over the longer term know that they all fail.
There has been a 100% failure rate (before Aducanumab, Lecanemab and Donanemab) over the last 2 decades.
If you're not grumpy, then you're a novice.

Failure is the Bayesian prior probability for all AD trials.
Even when you know exactly what needs to happen (remove amyloid), it doesn't mean that enough amyloid will be removed. With Gante there was no clear idea from phase 2 evidence how much amyloid would actually be removed.
All we had was the regression line and a rough idea of the dosing level used. 0.31 was actually one of the most successful AD trial results ever reported, though obviously Lecanemab has moved the yardsticks much farther upfield for an official victory.

From this perspective, we can then see that Donanemab has a reasonably good chance of achieving its topline in comparison to the Gante results because Dona actually went through a phase 2 and it achieved a positive readout.

The problem seems to be partly related to too little amyloid clearance.
Counterintuitively, such a result might wind up enhancing support for the amyloid hypothesis not detracting from it.

The Gantenerumab phase 3 trials added in several innovative features such as longer dosing (out to 116 weeks), longer titration and subQ dosing which could have all contributed valuable insights if the trial had been more positive on the top line. It is also somewhat disappointing that this opens up the field almost entirely to Lecanemab; more competition is better for patients.

https://www.desmos.com/calculator/ibtgnenjb8

The Gantenerumab trials were not that easy to call because there was so little phase 2 to work with. My guesses were more about extrapolating the Lecanemab result forward, though this seems to have been a misguided idea. I had thought that Gante would have pushed towards 0.30 SUVR clearance and then this would have had substantial cognitive effects. What seems possible is that uptitration was so gradual that the benefit only accumulated gradually through time.

I will be very interested to see where the numbers line up in CDR-sb SUVR space. It would be very informative if Gante were to largely hit the regression line but just be short on amyloid clearance. One problem that arose was the placebo seemed to progress very aggressively; Graduate 2 placebo progressed ~2.07 CDR-sb over 18 months which is on the highish side (vs Leca of 1.67). The patient mix might have been more Mild AD. The Aducanumab/Lecanemab placebo have been in the 1.6-1.75 range which for whatever reason (perhaps early enough before tau dominance) seem to be more treatable.
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Re: Celebration Thread: Gantenerumab!

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Re: Celebration Thread: Gantenerumab!

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JulieG, thank you for posting!

It was an egregious error on my part to go along with the suggestions that Gantenerumab was going to readout out with flying colors. The problem was that there was no phase 2 to go by. There was really no good idea how much amyloid Gante would remove. It does appear though that it should be reasonably close to where it should be expected to given the amount of amyloid removed.

I find it notable that it appears that media no longer appear to be questioning the amyloid-cognition relationship. That was the basis for accelerated approval and decades of argument. They now see the topline miss of Gante more related to not removing enough amyloid, than that there is no connection.
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Re: Celebration Thread: Gantenerumab!

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Hello,

I was part of the Gantenerumab study and got the active vaccine for only a couple of months.

In spite of the short time I saw clear decrease in memory capacity after the vaccinations were stopped late November. Conversely the last memory test was just amazing.

One could ask why Roche and other companies testing anti beta amyloid vaccines say they don't work.

Perhaps the reason is that most participants have a fairly advanced Alzheimer's as opposed to me.

I understand that in this case, the market is much smaller but would still be a gift to people early Alzheimers.

Best Regards,
Thomas

https://www.alzheimer-europe.org/news/r ... ntenerumab
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Re: Celebration Thread: Gantenerumab!

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Thomas wrote: Fri Dec 30, 2022 2:19 pm Hello,

I was part of the Gantenerumab study and got the active vaccine for only a couple of months.

In spite of the short time I saw clear decrease in memory capacity after the vaccinations were stopped late November. Conversely the last memory test was just amazing.

One could ask why Roche and other companies testing anti beta amyloid vaccines say they don't work.

Perhaps the reason is that most participants have a fairly advanced Alzheimer's as opposed to me.

I understand that in this case, the market is much smaller but would still be a gift to people early Alzheimers.

Best Regards,
Thomas

https://www.alzheimer-europe.org/news/r ... ntenerumab
Welcome, Thomas.

It must be very discouraging to have benefitted from this trial, only to have it canceled. Rest assured, even though overall the results of the study were insignificant, that doesn't mean that you didn't have the positive effect you perceived. As the daughter of a mom who recently passed after struggling with this disease, I also find it disheartening at times that so many treatment studies that show such promise and provide positive results for some participants end up coming to naught. While I can't offer any information on alternative treatments, or studies, I am sure there will be plenty of members who will do so.

As a welcome intern, I can introduce you to several resources on this forum which you may find useful. The Primer provides accessible science background and prioritized sensible preventative measures. It was written by a member physician who carries two copies of the APOE-ε4 allele. Other good resources include the search engine on our site, PubMed, and the internet at large in your quest for information.

The WIKI is a searchable compendium of various topics related to ApoE4 and Our Stories gives you access to the experiences of many members of this forum. You are always welcome to post your story, as well.

I wish you all the best in your journey and hope that you find a treatment that works for you. Please feel free to post additional questions or comments as they arise.

Be well,
Kathleen
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Re: Celebration Thread: Gantenerumab!

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Thomas wrote: Fri Dec 30, 2022 2:19 pm Hello,

I was part of the Gantenerumab study and got the active vaccine for only a couple of months.

In spite of the short time I saw clear decrease in memory capacity after the vaccinations were stopped late November. Conversely the last memory test was just amazing.

One could ask why Roche and other companies testing anti beta amyloid vaccines say they don't work.

Perhaps the reason is that most participants have a fairly advanced Alzheimer's as opposed to me.

I understand that in this case, the market is much smaller but would still be a gift to people early Alzheimers.

Best Regards,
Thomas

https://www.alzheimer-europe.org/news/r ... ntenerumab
Welcome, Thomas!

A quick word on your user name: As a Moderator, I'd suggest changing it to Thomas so that you have more privacy on the forum. If you want to do that, just click on Quick Reply below and let us know.

I felt fortunate to be able to watch the detailed presentations about Gantenerumab and the GRADUATE Open-Label Extension (OLE) studies, which were stopped in November. The presenters made a point of thanking the many participants like you who went through the initial randomized trial and then enrolled in the OLE.

No one yet knows for sure why the GRADUATE studies showed only 1/2 the reduction in amyloid plaques seen by gantenerumab in previous studies. Most people never got below an "elevated" level of amyloid, regardless of their baseline cognition. Previous trials of gantenerumab and drugs like donanemab, lecanemab and aducanumab have ALL lowed amyloid beta to below 25 centiloids; similar to a "negative" Amyloid PET scan.

Gantenerumab previously led to statistically significantly less decline in cognitive and daily living skills. GRADUATE trials showed an insignificant difference from the placebo. What the presenters and researchers in the audience seemed to agree on, was that this "failed" trial suggested a clear association between the rate and degree of amyloid lowering and the rate and degree of cognitive benefit. In other words, the benefit to amyloid removal requires getting it down to a level that would be considered insignificant to have a cognitive/functional benefit. Sometimes, a "failed" trial, like a failed experiment, proves a hypothesis by its opposite.

Since then, I've seen some speculation that because Roche, the company involved, went with a different supplier, the drug may have undergone some unrecognized changes in quality, since these are very tricky to produce. Also, the trial introduced (I think) subcutaneous dosing. If the doses were administered incorrectly, or the subcutaneous dose was not sufficient to cross the blood-brain barrier, that also was cited as a possible problem. Since other companies are looking at subcutaneous dosing instead of IVs, your participation may help ensure others get accurate doses in their trials. All of that remains to be seen, and the researchers promised more information as they dig deeper into what happened.

As for your results: researchers say that it's just as important to track the progress of an individual over time as it is to track the average progress of a group of individuals. So you should trust how you did on that cognitive test! If you're looking to try some more, you may want to check out this one, which is free, has no obligation and helps researchers track participants' scores on "card games". I've been in both clinical trials and in APT Webstudy; the online games are much more fun!
https://www.aptwebstudy.org

Best,
Nancy
4/4 and still an optimist!
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Re: Celebration Thread: Gantenerumab!

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ta69901, I was wondering about that: What would happen for those patients like you who were responders? From what I can see Gantenerumab is in the same class as lecanemab and aducanumab and some subset of patients would be expected to be responders. I would have to wonder whether in such circumstances there might be a compassionate use exemption. You even wonder whether on an orphan basis it could even receive funding.

I also considered how perhaps patients might be better suited (for whatever reason) to one mab over another. Possibly a slightly different mab would have less side effects or be more effective.
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Re: Celebration Thread: Gantenerumab!

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Thomas wrote: Fri Dec 30, 2022 2:19 pm I was part of the Gantenerumab study and got the active vaccine for only a couple of months. In spite of the short time I saw clear decrease in memory capacity after the vaccinations were stopped late November. Conversely the last memory test was just amazing.
J11 wrote: ta69901, I was wondering about that: What would happen for those patients like you who were responders? From what I can see Gantenerumab is in the same class as lecanemab and aducanumab and some subset of patients would be expected to be responders. I would have to wonder whether in such circumstances there might be a compassionate use exemption. You even wonder whether on an orphan basis it could even receive funding.

I also considered how perhaps patients might be better suited (for whatever reason) to one mab over another. Possibly a slightly different mab would have less side effects or be more effective.
The presenters at CTAD and Roches itself made clear that they are ending all current trials of gantenerumab and cancelling a planned prevention trial. The evidence from earlier trials had been trending positive, but not as clearly as other "mabs". Because Roche is a Swiss company and has no plans to apply for FDA or European approval, no "compassionate use" would be possible.

It is possible that Thomas might be eligible for one of the other anti-amyloid treatments once they are approved, or for participation in one of the likely anti-tau trials coming in a year or two, or one of the other approaches (ALZ-801, for example.) Assuming his own amyloid dropped dramatically to a level near 25 centiloids, he may have re-set his biological clock by years or decades already.
4/4 and still an optimist!
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