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

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One aspect of the Aducan FDA Briefing Document that has bothered me is the differences in treatment response by cognitive subgroups. I do not think I have comprehensively explored this topic previously on thread even though it is of considerable importance.

The first post of figures on this page illustrates the point. In the middle figure of the first post we see on the left that MCI subgroup received much less benefit from Aducanumab then did the Mild AD subgroup. The numbers below this figure in red report that the MCI patients in 302 received 0.295 CDR-sb benefit while the Mild AD patients received 0.947 CDR-sb benefit. What is of importance and should be underlined is that the Mild AD patients received 0.947 CDR-sb benefit. That is quite a bit. That magnitude of cognitive benefit is obviously clinically meaningful. Using the 1.74 placebo decline in high dose Emerge, 0.947 would represent a 54% slowing of decline.

Now go down to the figure directly above this post. Notice that in the 301 trial, all the arms had ~80% MCI patients.
They chose the patients that had the least expected clinical benefit? The MCI patients only received a 0.295 CDR-sb benefit not a 0.947 benefit. Now look at the demographic composition of the 103 trial in the red rectangle. Notice that 59% and 43% of patients in the 10 mg/kg and titration subgroups had mild AD. Also notice that in the titration group
100% were APOE epsilon 4 carriers (versus 71% in the placebo). Ordinarily, epsilon 4s would be expected to have greater cognitive decline than non-e4s, though with treatment e4s would be expected to do much better than e3s.
It is not hard to imagine that under these conditions (namely, substantial Mild AD (with even more in the placebo who would decline much more than MCI, and 100% e4s) that the titration group would do quite well and they did. Also, the 10 mg/kg. This is verified in the first figure in the above post. Here we see -1.26 CDR-sb benefit (p=0.0246) and -1.19 CDR-sb benefit (p=0.0432) in the 10 mg/kg and the titration arms respectively. Not bad for arms that only had n=30 and n=23 respectively. The titration arm did even better when looking at the regression plot.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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The above post highlighted a very strange idea that has not been highlighted enough in the conversation: some of the patients on Aducanumab did very very well. A CDR-sb gain versus placebo
of 0.94 --> 1.26 is massive. It is clearly clinically significant; it represents cognitive slowing ~50-70%. This is something that even someone with only vague understanding of AD would find of interest. Such slowing would mean that the so-called endless goodbye truly could become endless. AD would then no longer be the life-limiting disease that it currently is. I suppose that those who did not know better would still complain that 50% was not enough, though such slowing might largely prevent progression to severe dementia with profound levels of disability and substantial caregiving burdens.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Return to the first post on this page and look at the third figure. Notice in 302 the same 80% MCI to 20% Mild AD split is also present. They heavily weighted the trial with the patients that would largely be non-responders? The MCI patients had a 0.295 benefit not a 0.947 benefit. Why?

Go up one figure and look at the green rectangle on the bottom right.
Here I calculated what the CDR-sb topline would be based on the extracted CDR-sb for MCI and Mild for Emerge
given the percentage given in the table (i.e., 80% MCI, 20% Mild). The calculated figure is 0.425 -- not far off the reported 0.39. (This variation might be partly related to the difference in placebo proportion of Mild and MCI, etc.).
For fun I also calculated what the topline result would have been if there were a 20% MCi and 80% Mild weighting in the trial. With such a weighting Emerge would have reported a 0.82 top line result for CDR-sb. Clearly, we would have a very different conversation if this weighting had been used.

Now go to the second post from the top of the page. this figure is for the phase 2 lecanemab trial. What did the lecanemab trial report for the MCI and Mild AD subgroups? Pretty much the same as 302. The bright green rectangles on the right highlight a -0.159 CDR-sb for MCI and a -1.083 CDR-sb for Mild AD advantage for the highest dose leca over placebo. These results are similar to Aducanuamb's advantage of -0.295 and -0.947, respectively. Notice the light green rectangles on the left highlighting the placebo decline of 1.168 for MCI and 2.125 for Mild AD.
The Mild AD placebo decline is almost twice that of MCI! So using a straight numerical readout with MCI using an 80% creates a very large disadvantage. The MCI and Mild are largely on different scales, yet it is pretended that they are on the same scale.

What is also interesting to speculate is that there might be a 1 point CDR-sb loss that occurs beyond the control of amyloid. So with the MCI figures: placebo declines by 1.168 and the highest treatment is able to slow the decline by 0.159. That is almost 100% of the speculated purely amyloid component. Also, with the Mild AD placebo there is a 2.125 CDR-sb decline and the highest dose prevents 1.083. Here once again almost the entire putative pure amyloid component is saved. Loading up 301 and 302 with MCI patients with potentially limited room to capture substantial cognitive gains setup the trials to post only middling results.

In the boxes below the post I took the leca CDR-sb results for MCI and Mild and weighted them to that of 301/302.
As can be seen even with the large Mild result in leca there would still have been only 0.34 reported on the topline which is similar to that of Emerge. I also reweighted using the slight difference in the Emerge MCI/Mild proportion
and this time found a 0.33 CDR-sb topline. once again for fun I reweighted the results this time using 20% MCI and 80% Mild (red rectangle on the bottom. Here 0.90 would have been posted.

Notice that the bright blue rectangle on the bottom with a p-value of 0.044 shows that a nominally statistically result was reported for the Milds even with only n=35 in the highest treatment arm.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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The above posts are extremely revealing to me. The patients that did the worst are the ones that were overweighted in the trials. Samples involved are not small: in the 302 high dose arm, n=438 for MCI and n=109 for Mild. These are substantial sample sizes with likely fairly confined confidence intervals (especially for MCI). The middle figure of the first post actually includes the confidence intervals and the MCI CI is quite constricted; the Mild not so much.

The why question certainly lurks here. My guess is that the 103 trial showed such overwhelming efficacy that those on the inside did not feel it overly important to emphasis this finding in a replication. It would have been all to easy to post a 1+ CDR-sb topline benefit and curtail and further argumentation. Instead it appears that the 80% weighting of MCI was used as an opportunity to enroll patients that would not during the 18 clinical trial show that much benefit, though in the long-term extension would be able to demonstrate how the treatment performed over years of followup. If the trials had been weighted more towards the moderate end of Mild dementia, then these patients might not have been able to demonstrate the same longer-term benefits.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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A few ideas follow from the above post.

One is that additional demographic targeting might reveal super-responders.
For example, from the first two figures in the first post, we can see that those aged >=75 did quite a bit better better than other age groups, possibly men more so than women, epsilon 4 more than non-4, and Mild over MCI. Clearly, this could wind up being nothing more than statistical noise, though the logic that those with greater levels of amyloid pathology (i.e., those >=75, e4 over non-4 and Mild over MCI) would on first glance seem compelling. At some point clearly pre-specifying such results would not be unexpected. It is disappointing that adaptive trials have not been used to actively select such patients for maximal clinical efficiency.

It is also notable that the 301 high dose had a placebo decline of only 1.56.
The expected placebo decline using the leca phase 2 MCI and Mild placebo with 80 and 20% weighting gives us:
1.168 (0.8) + 2.125 (0.2) = 0.93 + 0.425 = 1.36
(I could not find the Aducnuamb placebo results)
The problem with such a low placebo could arise from my idea that 1 CDR-sb is essentially baked into the results as an unchangeable aspect of non-amyloid decline. The MCI placebo might only have a small part of the decline that can be stopped by anti-amyloids (0.159 as seen above). As the placebo moves closer to this hard limit of 1 decline, less benefit is open to show treatment benefit. With 302 high dose the decline is 1.74. Unsurprisingly with patients that had more actual decline to work with more treatment was possible. Once again the problem is that 301 and 302 were weighted so heavily with MCI patients that the typical placebo decline of ~2 CDR-sb was not present in the trials. MCI patients have slow decline even on placebo.
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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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Unlike any other anti-Aβ monoclonal antibody in development, aducanumab was derived from
human B-cells collected from healthy elderly subjects with no signs of cognitive impairment and
from cognitively impaired elderly subjects with unusually slow clinical decline. (FDA Briefing Document for Aducanuamb , p.13).

None of the failed anti-Aβ antibodies achieved a clinical proof of concept, i.e., effect on clinical
progression prior to initiating Phase 3 studies. Aducanumab was the first program to achieve
proof of concept prior to Phase 3, as will be discussed in Section 3.1.2. (ibid, p.14).

... aducanumab due to its particular affinity and binding stoichiometry toward
β-amyloid aggregates uniquely among anti-Aβ antibodies directly inhibits the molecular process
through which oligomers form (secondary nucleation),... (ibid, p.15)

Aducanumab was, with Study 103, the first of this generation
of antibodies to demonstrate robust reductions in brain amyloid in clinical trials, and to have
shown a reduction in clinical decline, i.e., the first anti-Aβ program to establish proof of concept
before initiating Phase 3 (results detailed in Section 3.1.2). ... (ibid, p.16)
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