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.

Postby J11 » Thu Jul 09, 2020 8:20 pm

tau imaging

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

Postby J11 » Thu Jul 09, 2020 8:40 pm

These tau imaging results from EMERGE and ENGAGE are great!
I find them to be very insightful about what occurred during the trials.
(I am confused though by how low in the brain the red areas (what I suspect are the hippocampi.
Is the hippocampus really that low in the brain? I though it should be more towards the center
of the coronal image.)


What these images show is that the amyloid antibody actually modified tau pathology.
I had not fully appreciated this point before seeing these images.

When you look carefully, you can see on the second set of tau images that all three of the placebo patients
clearly progressed through time, while all three treated patients clearly regressed (in terms of tau) through time.
At the same time, the treated patients still maintained much of the low level tau.

What this highlights for me is that by itself (i.e., monotherapy) an anti-amyloid antibody will only have a somewhat limited range of clinical benefit when given after clinical cognitive impairment has emerged. This doesn't mean that aducan should be withheld from the market because of this.

No, it is a simple recognition that endless reductionism is bad science and bad medicine. This same problem emerges repeatedly. Life is complicated; and then people try to conceptualize it with a single idea. It is absurd. Multivariate problems needs multivariate solutions. We could wait an eternity if we try to solve our problems with such a flawed conception of reality.

From the first figure, I am impressed by the idea that the real comparison should not be between treatment and placebo but treatment and healthy. There would be no problem with placebos that did not behave properly. A healthy tau scan should be a constant. What you are then seeking is to move the AD brain towards the healthy brain. Notably this is exactly what is illustrated in the figures in the second post above.

From what I understand by looking at these figures, I do not want to wait until my brain lights up red with tau. tau is a known neurotoxin. I do not want neurotoxins in my brain. Given the opportunity, I would immediately inject .1 mg/kg aducan. A world of near universal aducan treatment will be a world in which your friends, family and community are always there for you, and not endlessly receding into neuropathology.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Fri Jul 10, 2020 5:15 pm

Oh my! Whoa! Very interesting!
I think I might have stumbled across something of relevance regarding the Biogen
phase 3 trials that has not been widely recognized.

Given the success of my riddle on another thread, I think that another one is in order.
Yet, if it becomes overly frustrating, then I will just be more explicit.
This one is somewhat more obscure than the last one.

Biogen isn't even looking at its cards anymore.
It isn't bothering to rebut critics.
Are they that confident?

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

Postby J11 » Fri Jul 10, 2020 6:46 pm

OK, then, I went to go back to some of my recent posts and for some revisioning.
I could just edit the posts, though it will be much more transparent if I actually
just repost my edits here.

My first egregious error is from my July 08, 8:55 post where I wrote of the probable
decline of the treatment group while they were off treatment after the futility analysis.
My suggestion that these patients could achieve absolute stasis in cognitive scores
was clearly untrue. Even when the patients were at full dose they still did not achieve
stasis. One should expect that once the treatment is stopped then continued decline
would likely resume. However, one interesting note is that the half life of the treatment
is quite long. ~21 days. It is thus possible that patients could actually drift for some time
without immediate cognitive deterioration, thought this would probably not last for
a year (?). Nevertheless, some widening (though probably a smallish amount) in the difference
from treatment to placebo might have occurred during the break. The big item to account
for is the big hidden placebo understatement that would need to unwind at some point.
[Edit: A big question that I have now relates to the nature of the driving force of AD pathology.
In particular, the high dose patients after ~78 weeks of treatment in the EMERGE trial were
had such minimal amyloid levels that they were approaching the limits of detection. If amyloid
has been so throughly removed from the brain, then would tau continue to accumulate? Isn't
amyloid a necessary, though insufficient condition for AD progression? The current aducan
extension should help resolve this question.]

The confusion about the labeling of the time points in the PRIME and the two phase 3s is worth
reiterating. The phase 3s really only treated for 52 weeks. AD trials have almost always typically
been 18 month treatment trials. PRIME showed that at the 24 week mark there was almost
no difference between placebo and treatment. It is something of a mystery as to why at the
52 week of active treatment (week 78 in the phase 3s) there did not appear to be more benefit.
With thousands of patients one might think that such evidence should be highly visible. The problem
seems to have been a lack of placebo decline. At 78 weeks, a 4.5 point decline in MMSE is expected,
EMERGE reported 3.3. 1.2 more MMSE points to the treatment effect would give 1.8; close to the 2.2
figure reported in PRIME.

Instead of a 3 1/3 point decline in placebo over a 3 year period (=10), a more conservative 3 gives us 9.
For the extra weeks to bring us up to week 164, add 0.5. So the placebo decline expected to week
164, is ~9.5 MMSE points. Now instead of a 6 point treatment gain in MMSE, we have a gain of 5.5.
That is still very large. That would be of clearly apparent and highly relevant to those caring
for someone with dementia.

From my first post, I was confused about how large the treatment difference seemed to be between
PRIME and the phase 3s, apparently this related to slow placebo decline.

-----
For my second post I suggested that 2.7/3.3 was a ~19% decline. In fact this is a 22.9% decline almost exactly the
23% figure reported. I only included 2 decimal places from the online app so I might have hit 23% exactly. This
shows how accurate the online tool is for extracting coordinates.


The comment about non-AD patients in the phase 3s is perhaps misplaced. All the patients underwent amyloid measurement and were required to be positive, thus the patients should be ~ true AD.

Using the patient registry idea would have made so much sense.
Being able to characterize patients before they arrived on site would have been a big plus in the phase 3s.
-----


Post Three -- Hmm, I can also take the correlation between the SUVR and CDR-sb for ENGAGE. I was quite impressed with the 98.5% correlation with EMERGE. Yet, I was nagged by the idea that ENGAGE correlation would not be as strong. If so, is ENGAGE even accurate?

Go back to page 15 of the third link of the second post of this thread; right hand side ENGAGE.
Correlation between ENGAGE CDR-sb change and SUVR: -0.97 (p=0.15?). There were only 3 points involved!
This is an apples to apples comparison (i.e., those who received 10 or more injections in EMERGE and ENGAGE). There is nearly 100% correlation between amyloid reduction and change in cognitive score during the course of the trials.

These calculations were based upon large subgroups including 340-550 for ENGAGE placebo, 300-550 for EMERGE placebo
and 100-120 ENGAGE with sufficient high dose treatment and 130 150 EMERGE with sufficient high dose treatment. The claim that ENGAGE did not show efficacy is entirely unsupported by ... the evidence. If it is reasonable to group all the data points into an average and then find the correlation, then knowing the level of amyloid removal nearly perfectly predicts the decline in CDR-sb.

In fact, one could use the amyloid decline from either of the phase 3 trials and with near perfect foresight predict
the cognitive scores in either trial. The predictor is invariant to treatment sample: a near universal regression law
of amyloid neuropathology for AD. It probably can also be derived from the PRIME trial. Such a strong predictor
definitively proves that the trials were a success. The top line numbers for ENGAGE were largely only noise.
The logic is not entirely closed, though it is close. There could be 100% correlation and yet no significant treatment effect. Yet, we know that there was a significant treatment effect for EMERGE. That should do it.

A final note: strangely, even the placebo decline for the CDR-sb apparently is off. From my perusal of the evidence, the typical placebo decline for the CDR-sb at 78 weeks is 2.7! On page 15 on the right look up -- way up. 2.7 is off the chart! That is where the placebo is expected to have been. Apparently the CDR-sb placebo was just as far off as the MMSE placebo. This true placebo decline should probably be included with these figures. The "true" p-values must be massive for both trials. I want to double check this, though it does seem that the expected placebo result at week 78 does not even fit onto the chart.
Last edited by J11 on Sun Jul 12, 2020 8:59 am, edited 3 times in total.

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

Postby J11 » Sat Jul 11, 2020 9:26 pm

First 52 weeks of PRIME.

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

Postby J11 » Sat Jul 11, 2020 9:45 pm

There are a great many more exciting insights that I want to add to this thread.
It might take a while to post my entire magnum opus.

In the post above I show the first 54 weeks of the PRIME trial.
This was considered a highly successful trial and allowed Biogen to move directly
to phase 3 without the need for a full phase 2.

I included only the first year of the trial because in the EMERGE and ENGAGE trials
there were really only 52 weeks of high level dosing (the first 24 weeks were needed
to titrate up). As we can see in the figure, there is almost no separation in response
in PRIME for the first 26 weeks. It is only during the next 30 weeks that a separation occurs.
A true placebo is used for the first 54 weeks and it behaves exactly as expected with a change in
CDR-sb of ~2.

The main take away is that there is admittedly a somewhat modest cognitive benefit to treatment
after 54 weeks in PRIME. ~1 point benefit on CDR-sb could be claimed to be of limited clinical meaning.
As the CDR-sb isn't an everyday instrument that non-researchers would be familiar with, the corresponding
difference for the MMSE is ~2.5 points. Here again some might question the clinical relevance
of even 2.5 MMSE points (?). However, when as PRIME matures, the benefits begin to magnify.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Sat Jul 11, 2020 10:08 pm

Now with the 78 week data added.

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

Postby J11 » Sat Jul 11, 2020 10:42 pm

This next figure dramatically illustrates how through time the cognitive gain widens.
At week 54, there might be room for discussion about how relevant the gain is.
This is no longer even plausible at week 166. The gain has went from ~1 CDR-sb point
to ~ 3.

The entire online discussion has focused exclusively on the reported figures
from the phase 3 results that only have ~52 weeks of true treatment with no
mention of PRIME and the long term extension. It is quite obvious why: the
PRIME study ends the debate: There is no longer anything meaningful to argue
about as the gains accumulate.

In MMSE terms, the treatment advantage extends to ~5.5 at week 166. This is too
large a difference to be even worthy of rebuttal.

Looking carefully at the previous figure, one can see that the length from the mean to
the 95% CI is ~1 CDR-sb at week 166. Even with ten patients on high dose this was statistically
significant. In the EMERGe trial at week 78, this distance for the high dose is only 0.1 CDR-sb.
Extreme levels of statistical significance should be reached with the large patient sample
of the phase 3 extension trials.

Only 10 patients are required to demonstrate statistical significance after ~3 years?
Thousands of patients were enrolled in the aducan phase 3s starting in 2015? We have too little
information? No, we have too much information!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Sat Jul 11, 2020 11:00 pm

There are a great many additional comments that I would like to make about aducan.
As a preview (and reminder for myself) here are some topics that I want to cover in future posts:

- the placebo problem -- There really does seem to be a very substantial problem with the placebo in EMERGE and ENGAGE.
The placebo did not decline. This difference is almost too large to believe. I will have to double check/
I already have, though I want to double check again. There has to be a mistake; how could such a large
placebo discrepancy even be possible. I do not recall this being mentioned elsewhere.

-- End of Alzheimer's -- We are now only months away from a fundamental transition to a non-dementing society and world.
This shift could happen much more rapidly than many currently expect. As soon as we stop
yet millions and millions of more victims from descending into dementia, the entire crisis could
resolve rapidly.

Once approved, those who might be decades away from cognitive impairment could begin treatment.
Without the big rush that was seen in the trial, the risk of treatment almost disappears. If you
have not 1 year to demonstrate amyloid reduction but perhaps 10 years, then ARIA and the other
side effects would never happen. The endless discussion about side effects would seem misplaced,
as after the first wave of patients are treated, these side effects should never recur.


-- The high correlation of SUVR and CDR-sb that I found in the PRIME results (consistent with EMERGE and ENGAGE).
Last edited by J11 on Sun Jul 12, 2020 9:14 am, edited 1 time in total.

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

Postby roxanne » Sun Jul 12, 2020 4:53 am

Hi J11: Thank you J11 for all your hard work in trying to make this topic easier to understand.

I do hope that they approve it, although from what I'm reading in the news, it's going to be difficult.

Just wanted to mention that even if we don't comment, we are noticing and reading.

Roxanne


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