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.

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CDRsb phase 2.GIF
Figure 18 page 239.GIF
103 Cog.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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One aspect of the anti-amyloid trials that has not been highlighted enough to date is how large the treatment effects have been in certain responding sub-groups; for whatever reason this has largely been overlooked and instead the focus has been directed almost exclusively on the top-line primaries. Of course the most restated of these memorable numbers are -0.39 CDR-sb and 22% reduced decline for the high dose Aducanumab result in the 302 study.

However, as seen in the above figures there are some considerably larger numbers that have also been reported. For instance, the 10 mg/kg dose for the 103 study reported a -1.26 CDR-sb benefit versus placebo which was a 67% relative gain. Not only was this dose arm impressive so were most of the others: the titration arm had a -1.19 benefit with -63% less decline; also 6 mg/kg had a -0.80 with -42% and even 3 mg/kg had a -0.56 advantage and 30% less slowing. These 103 treatment arms had large CDR-sb gains from treatment and this was not based on small treatment samples; collectively there were 97 patients in these dose groups.

In the middle figure above we see the results for the patients that received "adequate" dosing with aducan in the 301 and 302 studies. In the three treatment arms shown with over 300 patients, all of the treatment groups were approaching a benefit of ~40%. Remarkably this was true even in the 301 high dose where the top line was negative.

Another strong result is shown at the top of the previous post. Here the mild AD on the highest dose of leca had over a -1 CDR-sb (n=35) gain. There are yet other examples. The APOE e4 on the highest and second highest leca dose in the phase 2 also posted strong results with the APOE e4s on the highest dose having a nearly 50% advantage. Also in the dona phase 2 when selected for tau, there was a 50% gain on treatment.

The entire dialogue surrounding anti-amyloids has been so dominated by the top-line results of 20-25% that it has obscured the very substantial gains that have been repeatedly seen in large subgroups across multiple trials. The results in the 103 study were overlooked because the randomization was thought wanting; With the Aducan trials the ARIA side-effects and the change in the dosing schedule mid-way through created confusion about whether these results were simply cherry-picked... . The leca phase 2 gave a cleaner readout because of the reduced side-effects, though even here the results were posted to the supplementary appendix.

With the substantially sized phase 3 trials that are expected to readout next year we should expect to see some big benefits demonstrated for various sub-groups. Those patients with the most favorable treatment outcome profile (e.g., APOE e4, perhaps mild AD etc.) the treatment gain might be ~60% or more. For the APOE e4s, it would not be unexpected to see 40-45% benefit. Perhaps the only limitation might be the size of the trials; even 3 categories would divide the treatment arm into eighths.

Such treatment gains when they become more widely appreciated would help end the discussion about funding. Many have questioned the clinical relevance of a therapy with ~20% cognitive benefit. However, the gains noted above are much more than 20%. Slowing cognitive decline in dementia by ~50% has clear and indisputable clinical importance. This will be even more true as future treatments offer yet more therapeutic benefit.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Anti-Amyloids.png
Amino 3a.png
PDB Aducan.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Until now I have stayed away from the chemistry of the amyloid beta mabs, though I have finally taken a look and in the above post are some of the things that I found notable.

The first highlight from the top figure in the post above is how extremely similar the chemical formulae for the four different mabs were. I had not realized that they were that similar. I had expected that they might even possibly be entirely different molecules.

This turned out to be completely untrue. In the middle figure we have the amino acid sequence for the chain B of gantenrumab (5CSZ_2), and underneath the Chain A of aducan ( 6CO3_1). The amino acid letters that have been highlighted in red are the differences between the two sequences. It is remarkable how few changes there are between the two mabs. Of more interest is that in the bottom half of these sequences there are no differences; presumably this is where the important binding occurs with beta amyloid. On the right I noted what changes were made as one went from gantenerumab to aducan in terms of the functional impact on the amino acid.

Of the 27 amino acids changes, fully 12 were not actually changes at all. These changes would change one hydrophobic amino acid for another hydrophobic amino acid: not really much of a change -- as a first guess such changes might have somewhat subtle effects on the protein. The most consistent change that is noted is the change from a hydrophobic group on gantenerumab to a polar group on aducan. This happened 8 times. This might be no accident as I vaguely recall that abeta mabs with more hydrophobic quality could be helpful in disrupting the amyloid structure. So the order really should have been from aducan --> gantenerumab not the other way round as, the basic scaffold of aducan was likely taken and then tweaked where thought appropriate.

Given the above insights it might be expected that the anti-amyloids that are now near or have achieved approval will likely have similar effects. However, as we are all too aware with e.g. APOE e4, even a single letter substitution can create differing biological effects.

The url below provides a very wide range of annotations for the C chain. Funnily enough acetylcholine function is prominently mentioned.
https://www.rcsb.org/annotations/6CO3
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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CDR-sb gant 2.GIF
SUVR gant.GIF
Ganten CDR-sb.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Good to keep track of the references.
The above figures are from PMID: 29221491. These were the Scarlet Road and Marguerite Road studies with low doses of Gantenerumab. I included these doses in my correlation plots.


They extended out the Scarlet and Marguerite Road studies in OLE with high dose Ganten of 1200 mg monthly reported in this article PMID: 31831056. It was somewhat confusing because it was not easy finding the SUVR values for amyloid reduction; they reported the results mostly in terms of centiloids. It was basically a lot of centiloids (~59), though I am still somewhat unclear of the exact comparison into SUVR. My best understanding is that it was ~~0.30 SUVR. If so, then this should put ganten alongside aducan on the regressions at ~-0.40 CDR-sb improvement. As a note they were 90% APOE e4 in the Scarlet Road OLE which is somewhat of an overweight from other trials. Strangely, 7(37%) on Scarlet Road OLE had a negative baseline amyloid scan. Non-Alzheimer's Alzheimer's?
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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

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The above are tables from the second referenced article cited above which provide the CDR-sb and amyloid removal for Ganten for high dose 1200 mg monthly in the OLEs. It will take some time to figure out these tables. I will also want to see if the SUVR are reported.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Corr.GIF
All Amyloids 1 Edit 1.jpg
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I have been intending to confirm the Ganten results that I plotted on the correlation for some time. As can be seen from the above post in the bottom figure of the Aducan FDA Briefing Documents 2 (i.e., the next round of FDA Briefing Documents after the first round), Ganten is shown as having a worsening of cognition with the low and high doses of the Roads studies. They also seem to have smaller amyloid clearance than I plotted with the cross on the right actually showing a gain in amyloid. My plot in the above figure shows different result. The discrepancy can be explained by the middle figure 5 posts up. I used the week 60 amyloid results of -0.03 and -0.11, whereas the FDA Document used the week 100 result. I wanted to keep the comparison as close to possible to that used with the other amyloids (i.e., week 78). I'll have to think about how where my CDR-sb numbers are derived from. They do not appear to relate to the 0.10 or 0.18 reported above or the result from the figure 5 posts up.

The FDA document does not show the Gantenerumab results as being consistent with Aducanumab, lecanemab or donanemab, though my plot has shown Ganten to be very much in line. The high dosing OLE noted in the post 2 up found a ~1.64 CDR-sb decline with high dose Ganten over a year interval. There was no placebo comparison so it is not easy to tell whether this is in line with expectations, though there were a substantial number of the patients who appeared to develop runaway AD during the OLE so the
reported decline might be a reasonably strong result.
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