CTAD 2022 -- Endgame for AD

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J11
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Re: CTAD 2022 -- Endgame for AD

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As noted in the above post the as randomized phase of Clarity the Lecanemab arm had a lower number of fatalities and a lower rate of fatalities as compared to placebo. Given the higher dropout rate in the Lecanemab arm this is perhaps understated. Perhaps providing the aggregate patients exposure months to treatment/placebo would be an even more accurate way of assessing the risk involved.

In the OLE phase it has been noted that there were two fatalities of Lecanemab treated patients. Both of these patients were using anti-coagulants. The first patient noted is 65F e44 treated with tPA for left MCA occlusion (OLE). The CTAD Clarity safety presentation gave me the impression that tPA would not be the recommended treated for those on Lecanemab experiencing a MCA occlusion. This is what had been speculated on forum. It probably would be for the best to formalize this learning even now for those still undergoing treatment in the OLE. Thrombectomy might not be readily available in all medical contexts, so patients could be alerted to which hospitals have 24/7 capability to perform this procedure. While tragedies can and do happen, it is doubly tragic when lessons to prevent further such outcomes are not heeded.

The other OLE phase fatality was in a 87M e4- patient. A previous description for this patient noted an extensive list of medical events occurring that probably contributed to the fatality. The lesson from this patient might be to suspend Lecanemab treatment in patients who appear to be entering a terminal phase. Lecanemab can help patients years into the future, when patients begin to experience serious medical challenges, then it is probably for the best to first concentrate on stabilizing the patient over at least the time frame of months.
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Re: CTAD 2022 -- Endgame for AD

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I wish there were mora data on the E 4/4s to try to explain the unexpected finding that they did worse than placebo. Were they more MCI and less early AD? What about age/sex/race/national origin? I also think the result is surprising.
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Re: CTAD 2022 -- Endgame for AD

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Dis they compare the outcome of the E 4/4 with lecanemab to the E 4/4s on placebo? Or are they only compared to the placebo group as a whole?
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Re: CTAD 2022 -- Endgame for AD

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karelena wrote: Thu Dec 01, 2022 3:51 pm Dis they compare the outcome of the E 4/4 with lecanemab to the E 4/4s on placebo? Or are they only compared to the placebo group as a whole?
The comment on this during the presentation was that the 4/4s on placebo had unexpectedly stable cognitive performance. I’ve seen previously (have to find the reference) that even in trials enriched for 4/4s, they show a higher degree of variability in progression than other groups, so that researchers are looking to identify “slow progressors” and “fast progressors” for what is only an 18 month trial. One indication mentioned in a presentation today was about of spatial tau outside of the medial temporal cortex being a strong signal of progression within 3 years much more so than simply amyloid beta or tau in medial temporal lobe.
4/4 and still an optimist!
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Re: CTAD 2022 -- Endgame for AD

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Re: CTAD 2022 -- Endgame for AD

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Re: CTAD 2022 -- Endgame for AD

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Re: CTAD 2022 -- Endgame for AD

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Karalena, I was fortunate on my Aducanumab thread that I avoided chasing after the subgroups. If you stay with the big Ns, then you will mostly stay on track: the insights that you notice will probably be valid. It is when you start going off road and trying to make sense of subgroups and various anomalies that you can get really lost. With Aducanumab I was able to stay on course and saw that Aducanumab did have anti-dementing effects.

I was able to recognize the topline result for Aducanumab, though for the fine grain analysis it is still murky to me. For instance I agreed with the Statistical appendix's interpretation that the non-APOE carriers did not seem to benefit from Aducanumab. I found this assertion convincing. The non-carriers did not do well in any of the arms of Emerge or Engage and they did not do well in the Lecanemab phase 2b. First figure in the second post above shows that the non-4s did not do well on any of the cognitive measures in Emerge. The regression line for the e4-s seemed clear: mabs do not work for them. Yet, Clarity reported the non-4s as benefiting by 0.75 on CDR-sb. Without the non-4 contribution Clarity might have read out negative.

The FDA did extensive modeling (two posts up second and third uploads) with Aducanumab. What they found was that APOE 4 is not a significant covariate for response. I did not believe this and I went with the non-4s had an inferior response to treatment. The FDA was right; Clarity showed that the CDR-sb went from 0.078 with Emerge high --> 0.75 Clarity. It is surprising though it appears that the subgroups can really jump around quite a bit even when the ns involved can be largish (~200).

Apparently, the only covariates that they could find for progression in their final model was baseline MMSE. Perhaps they could rerun the established model from Aducanumab on the Clarity dataset. It would be reassuring if the model still does not see any difference by APOE genotype.

Notice in the first post that the e44 homozygotes had a placebo decline of only 1.27. Non-declining placebo has typically been a problem in AD trials. For example, Engage declined by ~0.20 CDR-sb less than Emerge and this probably contributed to it missing. If the placebo does not decline as expected, then it is very difficult to show a treatment effect. With mabs, it seems that there is about 1 CDR-sb decline that is locked in; treatment only has about 0.75 CDR-sb that is susceptible to intervention. e44 is perhaps even more sensitive to this effect. Possibly it is more like 1.25 CDR-sb that is locked in for e44. In this scenario a non-declining placebo becomes an even more difficult barrier to overcome.

I found it quite strange that the e44 results for Engage and Emerge were never disclosed. The baseline demographics reported heterozygote and homozygote numbers. Why did they not report the cognitive scores? In the Clarity study they are reporting ns down to ~20. There were ~100 e44s in the Aducanumab trial's high dose arms.

Notice that the e4 carriers in Emerge high dose had a 0.52 benefit on CDR-sb. The heterozygotes had a 0.50 benefit in Clarity on CDR-sb. Taking the Clarity result as our best estimate of response in Emerge, then the homozygotes would have also had a response close to 0.5 CDR-sb in Emerge. When you move down to the subgroup level it becomes much less clear what is happening.
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Re: CTAD 2022 -- Endgame for AD

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This year's CTAD has been truly epic!
Such positive energy.

From what I understand many of these previous conferences have been fairly depressing- one report after another bemoaning endless trial failures. This time it seems that there have been so many successes. There are even a few more successes that were not even reported at the conference that are expected over the next month or two.

One schmuncher after another; just startling.
This has a fin de siècle feel to it- fin de démentia.

I suppose that the best ideas always pop up ex post, though when I thought about it CTAD 2022 would have been an ideal time to bring the people in. Instead of thinking of this purely about the science it could have been more about the lived experience of millions of people -- basically, go to the SanFran ball park and turn it into scientific opera on a massive scale. Somewhat surprised that this idea did not pop up. Basically, 70,000 people from the world dementia community, add in some of the top science presenters who could handle being a rock star for a day and it could have been magical. Perhaps this could be the game plan for the next iteration of the AD science conference roadshow. It seems somewhat surprising that people were satisfied with reading it in the headlines and not making the headlines.

Hmm, AD/PD 2023 is in Gothenburg, Sweden
AAIC 2023 is in Amsterdam, Netherlands
CTAD 2023 is in Boston

{October 2023 might be a bit long for some to wait for the big celebration.}

Considering how profoundly significant the recent announcements have been some sort of mass celebration does seem appropriate. There are so many millions of people that have been affected by dementing illness, it really would not take that much to make this largely a within the community type event.
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