Celebration Thread! Biogen is going to the FDA with Aducan.

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J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

We are now within 1 month of the primary completion date for the Clarity trial!
This is now super-exciting, though as this is now largely uncontested there is not much of a celebratory spirit. We are just waiting for the clock to tick down.

Nevertheless, I think it is time to reengage with the anti-amyloid story and cheer us over the finish line.

One item that caught my attention regarding beta-amyloid mabs was the European withdrawal decision for Aduhelm.
https://www.ema.europa.eu/en/medicines/ ... ns/aduhelm

The decision is from December 2021, so is somewhat dated, yet it is still of interest to see how others have chosen to regulate Aduhelm.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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The European Aduhelm review closely follows the FDA briefing Document for Aducanumab, though it adds in some interesting features. I am not sure whether the FDA included a figure as the one below though this is a good one and it highlights the importance of diagnostic testing that is now moving to the clinic.

These figures showing AD progression provide a great deal of insight how pre-patients can manage their dementia risk even decades ahead of time. The whole disease management strategy of waiting for symptom onset clearly will soon make very minimal sense (i.e., in the era of BA anti-mabs, etc. (i.e., effective pre-symptomatic treatment)). In the figure we see that CDR-sb detects disease progression 10 years before clinical onset!!! That is startling. The patients in the mab trials might have been coping with more subtle cognitive issues years before it is formally diagnosed.

I also like the hippocampal series. I had read about this before though it is nice to have it in the figure. What we see is that the hippocampal signal appears to be sent right at the same time as CDR-sb starts to indicate decline. I have wondered for a while now whether this hippocampal neuroimaging result could be a biomarker for mabs. The CDR-sb result might be difficult to establish in a clinical trial, though as with PET SUVR beta-amyloid, hippocampal degeneration might offer a strong objective result. Even more so than even beta amyloid, it would be highly dubious whether a convincing argument could be made that degeneration in the hippocampii could be dismissed as not being clinically relevant.

Possibly even more remarkably is the long term brain glucose decline that is present even 30 years from onset. We really have not said enough about Alzheimer's as a metabolic disease. I recently found an article online that talked about reactivating OXPHOS 1 with nutritional supplements. Frustrating I am unable now to locate this article. Perhaps once the first wave of mabs are on the market a shift to AD metabolics might be helpful.

Finally there is the beta amyloid accumulation that is shown in the figure. Notable for me is that beta amyloid actually begins to decline after the age of onset. We saw this in the Aducan trials where ~a third of patients had decreased amyloid levels. What the figure suggests to me is that it would be best to conduct the trials more in the ascending phase of amyloid to avoid that problem. You do not want to select the patients who are already in the decline stage of amyloid as this is the mode of action of the beta amyloid mabs! Some of those on placebo with strong natural amyloid removal might enjoy clinical benefit from such removal. Avoiding these patients by moving back in the disease progression would then seem to be a good idea.

AD Progression.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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These subgroup plots suggest that there are patients who respond especially well. What I notice is that the AD patients who are more "typical"-- APOE e4, older, more advanced, etc. usually had larger benefit. Here we see that the APOE e4s carried almost all of the treatment benefit in high dose 302. The mild AD patients also did quite a bit better than did the MCI patients. With the Mild AD patients the CDR-sb benefit approached 1 point which is fairly largish.

This is not cherry-picking because similar results were posted for the APOE e4s and milds in the other Aducanumab, lecanemab etc trials. This is one exciting aspect of the Clarity readout to look forward to: What happens when we see another strong result for the APOE e4s? Perhaps of even greater interest will be the e44 readout for Clarity. The entire narrative that anti-AB mabs have only modest clinical effects will likely be clearly disproven in Clarity subgroups.
302 Subgroups.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I have been fixated on the correlation approach with the amyloid mabs throughout this thread. I was confused almost right from the start when the low dose of aducanumab was described as missing its p-value versus placebo when the result was often exactly on a regression line with the high doses. Such use of statistics made no sense to me. The main takeaway from these plots for me was more that there was a strong dosing effect and the only question of interest was how to get to a higher dose.

In the table below, the European Briefing Document gives a table with the main mabs (excluding Gante). The table shows a very strong correlation of amyloid removal and CDR-sb. These numbers are broadly in agreement with the numbers that I have posted to this thread. Their numbers improve quite a bit when the clearly questionable 301 high dose numbers are removed.

The top figure below shows their regression when they include the phase 3s in one regression and the phase 1 in another. For me this merely highlights how far off the 301 high result was. The light blue regression winds up pointing to nowhere in particular and simply averages out two heterogeneous results. It is difficult to call a regression of hot and cold to give you on average luke warm a valid approach. The phase 1 trial though does show a very strong dosing effect.

mab Corr Table.PNG
Adu Corr 2.PNG
Adu Corr 1.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Why didn't they call J11? J11 is here to help! The above figure is from an earlier thread post. All of these figures are now posted and ready to be referenced when needed. I can coast now!

What we see in the above figure is an even more informative figure than that given in the European Briefing Document. The main results for the mabs are for leca and aducan. The dona result was also strong though it does not seem as directly comparable as it used tau selection. In the figure above the result is further subdivided by APOE genotype. When we averaged everything, the regression slope was ~1.4. However, we consistently saw that the APOE e4s did much better in the trials. In the above regression, we now have a slope of ~1.9 (CDR-sb vs. SUVR). The slope of the non e4s is much less at ~~0.4. In this regression the CDR-sb is no longer in the mediocre range of ~0.39 but possibly upwards of ~0.7 !!!?. The Clarity number could be a great surprise to many when they finally realize how large the benefit could be for subgroups such as APOE e4s especially when you can move towards 0.3 SUVR as the ARIA concerns are now largely addressed.

There is also the time effect to consider. Aducan had a 6 month titration interval and then 12 months of maintenance treatment. Titration with Leca is only ~ 2months?? with 16 months of treatment? It is not easy to determine how much final benefit could result with this dosing interval.

One problem that does emerge when trying to subdivide down to e4 genotype is that the SUVR removal is not reported for the genotypes separately. I think that the non4s actually had more amyloid removal than did the 4s so their benefit is even less than suggested by the regression (while the 4 benefit should be somewhat more). Also wonder how much the 44s might benefit. 44s should be a near certain pure AD phenotype that even the 34s would not display. There might be a fair percentage of 34s who do not have simple amyloid dementia and so might benefit less than would the 44s.

What is also of interest in the figure above is that by splitting the APOE 4s and non-4s one no longer sees the discrepancy in the high dose 301 trial for the non-4s. In the above regression, the high dose 301 non 4s are exactly in line with expectation; it is only the 4s that are still out of place. This does suggest that perhaps the problem that occurred was that in the 301 trial they had problems coping with the ARIA side effects that were most prominent in the e4s. As the trial continued and more experience was gained in managing ARIA the e4s were able to show greater cognitive benefit.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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One of the other research updates that has emerged is the idea that the dose response might not actually be linear. Considering that over a thousand posts to the thread were based upon the assumption of linearity, such a revision would diminish much of what has been previously been posted here. However, such an idea was introduced by Biogen in one of their research reports. In their model, ~the first 40% of amyloid reduction would only yield 0.1 CDR-sb benefit, with the next 35% yielding 0.3 CDR-sb. I have tried to simulate such a result above with the pink parabolish line.

This result helps to give insight into why pharmas had so much trouble establishing clinical benefit. Most of the early mabs could not remove ~0.2 SUVR so they would be stuck with a benefit of 0.1 CDR-sb as a ceiling. It was only with Aducan which moved the bar to ~0.3 SUVR reduction that you would reach the more steeply descending phase of the parabola. In this manifestation, the slope is no longer a linear constant m; but instead would be 2ax. We will need to wait for Clarity for this to be confirmed; perhaps they could see how the dose response presented within the overall high dose arm.

When you consider the results as above with e4s subgrouped and possible parabolic effects, beta amyloid mabs could have much larger benefits than is generally reported. there is the possibility that if the SUVR pushed out to 0.35 with a parabolic dose response that all of a sudden the CDR-sb might appear to gap down. The differential would no longer be 1.4 (0.08) but 2*a (0.35)(0.08) -- which could become biggish. Lecanemab now offers these benefits of Aducanumab with greatly enhanced safety. It is not difficult to understand why there is now no longer a debate about Lecanemab. It is uncontested.

Still I am interested in knowing what ARIA numbers will be reported for Clarity. These numbers to date have suggested that APOE e4s have virtually the same ARIA rate as the non e4s at ~5%. That seems almost too good to believe. Perhaps these numbers are only an artifact of the phase 2 trial which stopped dosing the e4s at the highest dose due to ... ARIA concerns (that were later determined to be unfounded). If the true number is 5%, that would be amazing! Perhaps additional research could use an even less aggressive uptitration in which ARIA was almost non-present. Eliminating ARIA risk would be of considerable benefit to patients.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I posted a variant of the figure above to the End of Alzheimer thread. What I continue to find fascinating is the idea that Alzheimer's could essentially "end" over the next year or two as the first wave of treatments are approved. As noted in this previous thread, diseases typically no longer just end anymore. In the post-infectious chronic disease era the most that you can expect is a year by year and decade by decade erosion of at most ~5% decline per year. The leading causes that I posted above and on the End of AD thread all show this erosion type pattern and not more of an extreme slalom. This gradualist model has been dominant for most leading causes for the last century. With AD it could be quite a bit more rapid than that.

My goto metaphor continues to be the conveyor belt. AD treatment could shutdown almost the entire amyloid dementia conveyor belt. Those before onset could have a pre-dose lowish dose mab prevention strategy, those with clinical AD (MCI, mild AD) would have an on label option with the mabs, and then those further along on the conveyor belt could have reduced methylene blue etc.. It would be profoundly amazing to watch the entire pathology process of amyloid dementia just stop in place. Basically, the entire river of dementia could just freeze. Yeah!

With the e4s, mabs (e.g., leca) are expected to slow progression by ~50%. That is a lot! If you have 10 years to severe AD, then 50% slowing might extend this out to 20 years. Of course, additional treatment options are also emerging. Clinical management for AD is beginning to appear fairly impressive. Those on the event horizon of the AD black hole that we have spoken about previously on thread might be just fortunate enough to avoid being drawn inexorably into an irreversible dementia. That is such a difficult part of dementia when trying to cope with it; it creeps up on you and then the caregiving just gets more and more progressively more difficult. You become enveloped in a fog of dementia that relentlessly advances. For those now on this path, the endstage of severe dementia might never be reached. AD could End!!!

Those in the pre-symptomatic stage will know years and years, decades(?) ahead before they reach age of onset. The FDA's original decision for Aducanumab seemed to anticipate the dilemma that this would pose for the worried well with its inclusive label for "Alzheimer's Disease". Alzheimer's disease as the inclusions for the phase 3 for Aducanumab? No, more Alzheimer's in general.

That would be awesome if the FDA were to give the same broad label to Lecanemab. Leca is safer and one could certainly understand those who might want to moderately pre-dose before achieving the official diagnosis as per a strict narrow label. Admittedly, this might require more clinical testing depending on the safety readout for Clarity. Pre-symptomatic treatment would require a wider margin of safety.
Last edited by J11 on Thu Aug 25, 2022 2:37 pm, edited 2 times in total.
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