CTAD 2022 -- Endgame for AD

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J11
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Re: CTAD 2022 -- Endgame for AD

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The CTAD presentation for Clarity last night exceeded my expectations. I was worried that it was going to be cringe; I have been to enough vacation slide shows to know how much the audiovisual side can obstruct all attempts at effective communication. Yet, with the phase 3 Lecanemab everything was clearly audible, all the slides were easily visible directly from the slide deck (providing the slide deck on the site afterwards was a great bonus) and there were few if any awkward problems in comprehension. It was a very good idea to make it open access; the presentation was simply too important for too many people to keep it pay walled.

There are a few other presentations that they probably should also open up at CTAD. The taurx phase 3 and the blarcamesine phase 2b/3 would certainly fit the bill (possibly others). They should also post the slide decks as soon as possible.
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Re: CTAD 2022 -- Endgame for AD

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Re: CTAD 2022 -- Endgame for AD

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Interpreting sub-groups obviously can often produce erroneous and contradictory results. However, when we compare the Clarity and Emerge subgroups we begin to see convergence in some of the demographics. It would be helpful if someone were to calculate the combined subgroups.

One of the best examples of this convergence is with the Clinical Subgroups: MCI vs Mild AD.

MCI CDR-sb diff % diff Placebo
Clarity nplacebo=544; nleca=528 -0.35 28% -1.25
Emerge nplacebo=446; nadu =438 -0.306 20% -1.53

With ntreatment~950, CDR-sb diff = ~ -0.33


Mild AD
Clarity nplacebo=331; nleca=331 -0.62 27% -2.30
Emerge nplacebo=102; nadu =109 -0.95 33% -2.88

With ntreatment~430, CDR-sb ~~ 0.75 with a quite consistent ~30% slowing.


This general result of those with more advanced illness declining faster is seen in other subgroups
(notably the >75 age subgroup) and is grounded in strong intuitive logic. Focusing excessively on the topline
averaged results would overlook this finding.

Other subgroups of note include the APOE4 Genotype, Female/Male, and Age. For whatever reason, the noncarriers performed exceptionally well in Clarity and completely overturned the regressions posted earlier for the CDR-sb vs SUVR response. These previous results suggested that noncarriers in Clarity would post ~0.15 gain; the actual gain was 0.75. The FDA Briefing Documents did suggest that this would be true, though the uncorrected results for Emerge etc. did not seem to confirm their modeling.

The heterozygotes came in as expected ~0.5, though the homozygotes were truly a great mystery. 0.28??? Homozygotes were 0.28 CDR-sb worse than placebo? I did not see that one coming. The homozygote placebo however was somewhat sluggish. Reasonably homozygotes should benefit more from mab treatment because they are canonical AD patients with almost certain AD pathology. Other genotypes can be more of a mixture of non-pure Alzheimer dementia phenotypes.

I do start to wonder whether phase 3 trials should include more of an adaptive design to investigate these subgroups concurrent with the main trial. Perhaps what could happen is the main trial could accrue patients and then certain subgroups who were prospectively (or during the trial) identified as having "different" response could accumulate in a parallel sample. These overflow samples could help us escape the distorted impression that Clarity readout homogeneously across subgroups at 0.45 CDR-sb benefit; this is untrue- some subgroups probably did do better than others.
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Re: CTAD 2022 -- Endgame for AD

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Re: CTAD 2022 -- Endgame for AD

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The numbers in the presentation readout mostly clean which is great because you do not want to be distracted by small errors that do not add up. One problem that I did find though was with the topline CDR-sb result. In the top figure the topline is reported as 0.451 (boxed in red). However, when I added up the subscores on the figure on box left ( boxed in green) the topline was 0.446; not a large difference, though perhaps it arises from using different patient populations (perhaps ITT vs. OTC etc.).
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Re: CTAD 2022 -- Endgame for AD

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Re: CTAD 2022 -- Endgame for AD

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Something I had not been aware of is that patients on anticoagulants were excluded from the aducanumab trials. The Clarity inclusions were deliberately designed to reach out to help patients with more extensive comorbidities. Managing these comorbidities (especially those on anti-coagulants) has become one of the more difficult considerations in clinical management with Lecanemab.
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Re: CTAD 2022 -- Endgame for AD

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Re: CTAD 2022 -- Endgame for AD

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Mortality is obviously a hot button issue in beta amyloid mab clinical trials and this slide directly addresses the mortality that occurred during the randomized phase of Clarity. As seen in the top row there was actually less mortality in Lecanemab treated patients 6 (0.7%) versus placebo patients 7 (0.8%) during the randomized blinded
part of the trial.

Placebo patients experienced fatalities due to acute respiratory failure, myocardial infarction, metastases to bone, intracranial hemorrhage and COVID-19. It would be of interest to learn more of the placebo patient fatality due to intracranial hemorrhage. Might this have been a result of CAA? I continue to think that as patients especially e4+ and more especially those with e44 begin to more fully appreciate the underlying risk of the CAA that often cooccurs in AD that BA mabs might become to be seen as a potential preventative treatment for CAA. Notably, the patients enrolled into Clarity were likely selected on the basis of having lower than average stroke risk, other AD patients in the community probably have risk.

It needs to be remembered that the potential future AD patients who did not survive their coexisting CAA or became too debilitated by its consequences would have been selected against inclusion in Clarity. I do not think this has been recognized or discussed enough. The most prominent headlines with the BA mabs have been of the patients who have experienced ARIA, though the many people who experience intracranial hemorrhage due to untreated beta amyloid pathology are never mentioned. Having a brain clogged with beta amyloid clearly poses substantial risk of serious vascular events.

I will be very interested in future research that reports on the longer term risk of intracranial hemorrhage for those on Lecanemab. The clear suspicion is that after Lecanemab has cleared out the CAA, patients will then have lower risk of ARIA events than those on placebo and this will be a long lasting benefit. The nature of the clinical trial design disguises this benefit. Placebo patients will if anything have increasing risk of hemmorrhaic stroke while the Lecanemab patients might have substantially reduced risk of this type of stroke.

The second line that is highlighted in red above lists the fatalities in the Lecanemab arm of Clarity in the randomized phase. The list of cause of fatalities in the Lecanemab arm is: cerebrovascular accident, myocardial infarction, respiratory failure, metastases to meninges, and COVID-19. At least one of the patient fatalities is from a cerebrovascular accident. It would also be of interest to have a more detailed report for this patient. Nevertheless, above on the same line it is clearly stated that none of these deaths were deemed related to ARIA. Even still a description of the evolution of the fatality from cerebrovascular could be informative. For example, did this patient receive TPA in the context of an ischemic stroke? The recently reported fatality in the OLE did receive TPA and this did not turn out well. Perhaps the above patient was treated with thrombectomy. In that instance there would then seem to not be any reasonable connection to Lecanemab treatment.
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Re: CTAD 2022 -- Endgame for AD

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