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

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
J11
Contributor
Contributor
Posts: 1356
Joined: Sat May 17, 2014 4:04 pm

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

Postby J11 » Fri Oct 25, 2019 3:27 pm

A futile futility analysis?
Are they kidding?

What if the futility analysis wasn't futile after all?
For me, I have to draw the line-- that would be too nuts.
Life can only be so weird, and not more.
I'm going to stick with the futile futility analysis interpretation.

Well we'll take a win no matter how the billiard ball wound up in the right pocket.


This is amazing!
Where is everyone on this?
As a forum elder, I cannot remember any AD news being this big over at least the last 5 years; actually I am unable to remember any AD news that has ever been this promising.

After being a member of the dementia underclass for the last 10,000 years, I wake up and find that I have been promoted to the upper class? Not bad.

I think this calls for and deserves some celebration.

Of course, it is not unreasonable to expect that the 3 thousand + patients in the phase 3 trials and those who had started the EVOLVE phase2, and those on the phase 1b extension will be able to provide more clinically important cognitive data once they get back on site. If it takes a while for the amyloid to clear, then might not the last 7 months have given those who received active treatment a chance to make further cognitive gains relative to those who were on placebo? It is still something of a mystery as to why they have taken 7 months to finally disclose this. The news reports appear to indicate the analysis team had concerns within weeks after the futility analysis was announced. Wouldn't it have been better to then use the precautionary principle and relaunch the trial? The online data at 78 weeks for the Emerge trial look fairly strong, why would it have been necessary for both to have demonstrated efficacy at this stage?

My hunch would be that this treasure trove of clinical information that will be gleaned when the patients return to the clinical trial sites will definitively answer the question of efficacy, so that there would be no lurking uncertainty. However, that would have to be one of those higher levels calls as at least for this round once you would have to pre-specify the outcome and the ball would really have to drop in the right pocket (perhaps after a little hesitation on the rim). I hope that is the game plan that the FDA has in mind, though it might take a little bit longer than a month or two to extract all of this important information from the cancelled trials.

For those on the forum, this is enormous news. If there is an actual product with efficacy then a self-sustaining Alzheimer research economy can emerge. It is so difficult when a problem is seen as an endless money pit with no clear endpoint. Unending exhortations for yet more money with little actual evidence of progress eventually wears down everyone. If we finally have something in which the financial resources of the dementia community can flow into, then a self-sustaining wealth base could emerge that will progressively move the research agenda forward.

The market potential is obviously large and one would have to think that rolling back treatment to those with MMSE equivalent to ~40 would be the next step as this would increase the potential customer base enormously while also likely reducing the risks associated with maxing out dosage as this is already known to cause ARIA especially in epsilon 4s. Hopefully this roll back will begin sooner instead of later as we have all seen how years can become decades with clinical research, only to find that the futility analysis or something was incorrect.

Very very pleased with this news.
Clearly it is somewhat premature to party, but would it really be sinful to celebrate without definitive evidence?
I seem to recollect other instances on this forum in which we have celebrated results which might best be described as
wishful thinking. The results from Biogen are clearly much more than that.
Last edited by J11 on Wed Oct 30, 2019 5:34 pm, edited 2 times in total.

NF52
Support Team
Support Team
Posts: 1376
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

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

Postby NF52 » Sat Oct 26, 2019 7:36 am

J11 wrote:...A futile futility analysis?...
This is amazing!
Where is everyone on this?...
Unending exhortations for yet more money with little actual evidence of progress eventually wears down everyone. If we finally have something the financial resources of the dementia community can flow into researching an effective treatment.
Hi j11,

"A futile futility analysis" is a great phrase! I agree that at least a few dance steps are warranted with this news. By the way, Biogen plans to ask the FDA for approval to offer aducanumab to all participants who had been in the two trials. That would be consistent what clinical trials call the Extension arm, when completed trial participants are offered the active drug, without being told (I believe) whether they had been on the active drug or a placebo in the actual trial. Doesn't require the enormous approval process of a new trial, and allows for continued monitoring and up to a doubling in size of the treatment group.

We haven't been ignoring the story; just posting a couple of different places (as happens on a forum!) Check out this thread: halting Phase III trials of aducanumab
And check out these links from Biogen:

https://investors.biogen.com/news-releases/news-release-details/biogen-plans-regulatory-filing-aducanumab-alzheimers-disease has a good summary of the 59 pages in this report:

https://investors.biogen.com/static-files/5a31a1e3-4fbb-4165-921a-f0ccb1d64b65
Enjoy an oasis in the desert!
4/4 and still an optimist!

J11
Contributor
Contributor
Posts: 1356
Joined: Sat May 17, 2014 4:04 pm

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

Postby J11 » Sat Oct 26, 2019 9:03 am

Thank you for replying NF52!

Yes, I did not want to post over the existing threads, though I was just not feeling the joie de vivre.

One of the great ironies here of course is that the Alzheimer epidemic has actually now gotten worse.
Extending out the time caregivers need to care for those with clinical dementia adds to their burden.

The great benefit, though, for what has been reported is that it will force stake holders to double down.
Partial solutions in Alzheimer's will only make it worse, we need a full commitment that broadly effective treatments
for dementing illness will be developed. This is one of those counter-intuitive times when it is not the time to hit
the breaks on the Alzheimer research efforts, but the accelerator.

There is already a massive potential payout lurking here. If those who are well before clinical onset could take these anti-amyloids as an effective preventative, then as they aged through and reached their age of onset and did not develop AD the cost savings for the health care system would be $200-$300 billion+ per year (in today's dollars). This is big money. Hopefully the enormity of the financial payback will help drive the process forward efficiently.

Of course, as a lifestyle medicine we could avoid maxing out dosing to 10mg/kg to see results; it might have been needed in an 18 month study, though treating younger people with mild amyloid burdens should not require such drastic measures. From what I remember aducan was based upon an anti-body that was naturally found in humans and was associated with AD prevention. Thus, in a sense we already know (now at least) that this anti-body is in fact effective as a preventative. It was surprising to me that a treatment with such strong logic and actual real world human efficacy did not show efficacy, though of course treating after a large buildup up of amyloid and conversion to cognitive impairment presented unique obstacles to success.

I notice in the Biogen url that you included that the low dose and high dose in Emerge and Engage had exactly the same amyloid
trajectories until week 26. I find it odd that they would continue giving the high dose during this time. What this seems to be telling me is that the brain can only process so much amyloid over the first few months no matter how high the dose. If this is true, then why would a patient want to take the high dose and perhaps expose themselves to ARIA without any benefit?
https://investors.biogen.com/static-fil ... ccb1d64b65 (page 15)

However, I suppose that once efficacy has been conclusively established, slower dosing schedules will be adopted along with seeking out patients with even milder clinical symptoms. Concerns about ARIA among these next cohort patients might then not even be present.
Last edited by J11 on Wed Oct 30, 2019 5:36 pm, edited 7 times in total.

NF52
Support Team
Support Team
Posts: 1376
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

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

Postby NF52 » Sat Oct 26, 2019 9:14 am

J11 wrote:One of the great ironies here of course is that the Alzheimer epidemic has actually now gotten worse.
Extending out the time caregivers need to care for those with clinical dementia adds to their burden.
I notice in the Biogen url that you included that the low dose and high dose in Emerge and Engage had exactly the same amyloid
trajectories until week 26. I find it odd that they would continue giving the high dose during this time. What this seems to be telling me is that the brain can only process so much amyloid over the first few months no matter how high the dose. If this is true, then why would a patient want to take the high dose and perhaps expose themselves to ARIA without any benefit?
Great question on the 26-week effect! If only we could get in the room and ask the researchers!! Check out pp 21 and 22 of the report. They seem to show a turning point for tau reduction and also for reduction in the rate of decline on the CDR-SB (a measure of AD progression) around week 26 also. Here's a wild speculation: It takes about 26 weeks to reduce the level of beta-amyloid in the brain to a sufficient level that other compensatory mechanisms, including reduction in tau, better cerebral metabolism, preservation of neurons, etc. can begin to exponentially improve.

Or, if they only measure twice a year (which was true in my clinical study) they are seeing a similar effect, then a big effect. Who knows when the divergence really starts: could be week 26, or week 40? As scary as ARIA sounds, it appears that it was a time-limited effect, seen only on imaging and not in clinical or daily functioning. I would imagine they'd try to further tweak the dosing regimen (start high, then go low, or vice versa) to reduce the risk.

And this or other drugs that greatly slow the rate of decline may not increase the length of caregiver burden. If my mother and her 4 sisters had stayed at the MCI or early AD level for 6 years, they would have died of heart failure in their mid to late 80's without ever having to leave their homes and without needing anything more than periodic support from available family members. You don't have to run out the clock forever.
4/4 and still an optimist!

J11
Contributor
Contributor
Posts: 1356
Joined: Sat May 17, 2014 4:04 pm

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

Postby J11 » Sat Oct 26, 2019 11:42 am

Aducan.PNG
You do not have the required permissions to view the files attached to this post.
Last edited by J11 on Sat Oct 26, 2019 11:44 am, edited 2 times in total.

J11
Contributor
Contributor
Posts: 1356
Joined: Sat May 17, 2014 4:04 pm

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

Postby J11 » Sat Oct 26, 2019 11:43 am

NF52, what report are you referring to with pages 21 & 22? The Biogen url that you cited only went to page 17.

After perusing the report more carefully, I do not see how the FDA could reasonably not approve it.
To simplify only look at pages 10 & 11 of https://investors.biogen.com/static-fil ... ccb1d64b65
everything else is too much information.

These readouts scream out a clear message: Approve!
Read no more of the report and take a coffee break.

Delving further into the report only needlessly distorts what is already clear: This should be approved.
How could you turn down an application that hit a p-value of 0.0002 on the ADL-MCI with N=340 in the high dose
OTC population and a 46% benefit over placebo? Or a p value of 0.001 with N=547 in the high dose and a 40% benefit
over placebo?

We fought to get into the bapi trial and it turned out that the significant result (i.e., p~ 0.05) that was claimed was for an N=5 subgroup of apoe-4 positives without correcting for multiple comparisons. They did not report the confidence bands on the p-values, though I suspect 0.0002 does not include say 0.01 in the 95 or 99% Confidence intervals. All of which is to say that we now live in a very blessed time.

We really need more study for 2 chances in 10,000? Um, relax a little? The high dose was pre-specified so this is not
cherry-picking. It also appears that ADL-MCI is the most sensitive (and for caregivers and families probably the most
relevant) of the measures; so the other measures probably did not score even lower simply because they did not have
the validity to do so.

It is remarkable that on pages 10 & 11, EMERGE high dose hit every measure except MMSE on ITT.
This occurred even when only 60% of EMERGE was included in the Larger Dataset OTC (page 9).
ITT is only intent to treat not actual treatment, so even the MMSE miss is hardly relevant.

Ignoring the results from ENGAGE is probably the best policy, because otherwise you need to start
selecting patients after the fact. With EMERGE you are using a clean dataset that has not been massaged.

Yes, NF52 I am also trying to think through what is happening during those first 26 weeks. The analogy
of driving on the freeway might be handy. When the flow of traffic is 50 miles per hour, it does not matter
what you do, you will move with this flow and travel at 50 mph. Possibly same with amyloid, you can
go low dose you can go high dose, though for the first 26 weeks it does not appear to matter you will
have the same amyloid reduction. In fact, I suggested that it might be worse to go high dose during this
time because just as on the freeway if you try to push through the flow of traffic all that happens is
you increase danger without actually increasing your speed (with amyloid this would mean ARIA).

Now that anti-bodies have been shown to be effective, my thinking would be that clinical trials should
dose down. Strangely, in the media reports that I saw, there was word about this vindicating high dosing;
I do not really see it that way. What I understand for the result from this trial is that patients need more
drug exposure, that is not equivalent to higher dosing, one might argue that what this really should imply
is lower dosing combined with a longer trial, say 30 months instead of 18 might become the standard.
This observation is supported by the EMERGE low dose results on page 10 & 11. The ADL-MCI (the most sensitive
of the measures used) is moving in the right direction. We also see this in the figures on page 13. It really is not that
low dose was not effective, it was more that the blue lines had not yet caught up with the green lines in amyloid reduction.

[Edit: My understanding is evolving as I read more about this aspect of the clinical response. In the Figures that I post on the next thread page, it appears that my traffic analogy really does not apply to the human brain: Apparently those who are in a big rush can get there somewhat quicker. To pull out another slogan: Time is brain. The Figure on the next page those on a higher aducan dose appear to maintain more of a cognitive benefit than those who were on the lower dose. The common sense explanation here is that with a neurodegenerative process you want to stop it as soon as you can. If you are not aggressive, then cognitive ability is lost that cannot be recovered.

I would still want to hedge on my new interpretation as the different treatments even after 3 years did not appear to have maxed out their amyloid lowering potential (except for the 10 mg/kg dose). The numbers involved are also small and it is not totally clear how selection might skew results for the 10 mg/kg considering that this arm might have been especially influenced by drop outs form ARIA.]

In the modified figure below I extrapolate the low dose (blue line) decline in amyloid for Emerge. It reaches the same level as the high dose (green line) by week 130. This might turn out to be the new accepted approach for the clinical application of these antibodies. APOE epsilon 4s have especially high ARIA occurrence with high dose anti-body use and this was one of the reasons that the futility analysis turned out to be futile; they tried to avoid aggressive dosing of APOE 4s in the early stages which left the futility analysis underpowered. Why not simply drive the limit? Might be cheaper and safe to dose it this way.

The entire discussion about ARIA would seem almost moot now because this side effect only seems relevant within the context of aggressive dosing used to prove treatment efficacy. Would the epsilon 4s on forum now really consider overclocking the antibodies for no particularly good reason?


Aducan.PNG



This is totally true about the long term payback from this research, though I was thinking of it more over the short-run. It should not be unexpected over the next few years to have headlines saying that the dementia epidemic has actually intensified. The current results have proven that those with existing cognitive decline from amyloid can have this decline slowed, though possibly a 23% decline will extend out the dementia somewhat. Of course, it would not be unexpected now for additional gains to materialize. All those other add-ons that those on the forum have been trying could have a better chance at being effective without having to compete against a relentless neurodegenerative process. It will be the next wave of research that allows for even earlier treatment that will result in a noticeable inflection of the dementia crisis.
You do not have the required permissions to view the files attached to this post.
Last edited by J11 on Mon Oct 28, 2019 4:53 pm, edited 3 times in total.

J11
Contributor
Contributor
Posts: 1356
Joined: Sat May 17, 2014 4:04 pm

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

Postby J11 » Sat Oct 26, 2019 12:40 pm

Thank you for clarifying the url.

The AD clinical trial registry was such a great idea and it is unfortunate that it did not appear to meaningfully contribute to the success reported. Having a large registry of patients gives you a large placebo group with small confidence bands and a permanent resource that would withstand trial cancellations etc. If it had been drawn upon, then we would even now have a better idea about the cognitive trajectories after the trial was halted.

It is disappointing though that adaptive designs are not included in these trials. One pages 10 & 11, the low and high dose groups show very large differences in effects and p-values. Why are these discrepancies allowed to occur in modern clinical trials? This is not the first time that we have seen this even with AD trials. It might seem like hindsight bias, yet those differences did not emerge yesterday; they would have probably grown monotonically for the years in which the trial was underway.

When patients enroll in clinical trials they expect that the maximum information will be gleaned from their participation. However, this can clearly be seen to be untrue in the readout from the trial. Why did not an adaptive clinical trial design allow a computer to continuously monitor the flow of results and change the dosing arm allocations as this data accumulated? Patients would then be offered treatment (given priors) which would use all available information in the trial which is consistent with international human rights legislation.

As it was, the low dose patients clearly did not receive optimal treatment. How could they have received optimal treatment when the clinical treatment plan had no mechanism to recognize it even if it had been apparent? The great irony is that on site investigators did not want the trial to end because they could see for themselves that it seemed to be helping their patients. What kind of a clinical science is this when gross personal observation is somehow more sensitive and perceptive than the clinical trial mainframe? This is a pre-modern emprical type science instead of a modern age of instruments type science. Modern science is about observing what is beyond our perception. It is difficult to accept that this trial not only did not observe what mere humans could see but also managed to futilely override these correct observations.

Why are we in such awe of computers that are programmed without any regards to receiving input?
It was not so much GIGO, as there was no Garbage In.
It was more only GO: Garbage Out.

Further, adapting the trial would have forced the answer sooner. It wasn't merely the futility analysis that was futile, more importantly considering the human rights of the patients in these trials was that the low dosing arm was also futile relative to the high dosing one. Alzheimer dementia patients can develop profound levels of dementing illness; it is the moral responsibility of the community (specifically us) to look out for their interests and advocate for their human rights; current clinical trial designs do not fulfill these obligations.
Last edited by J11 on Sat Oct 26, 2019 9:15 pm, edited 1 time in total.

NF52
Support Team
Support Team
Posts: 1376
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

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

Postby NF52 » Sat Oct 26, 2019 5:49 pm

Thanks for these thoughts; I added my brief reactions in green.
J11 wrote:NF52, what report are you referring to with pages 21 & 22? The Biogen url that you cited only went to page 17.
Sorry about that! I copied the wrong url. Here's the correct one:
https://investors.biogen.com/static-files/40565136-b61f-4473-9e58-9be769bbac6c

The high dose was pre-specified so this is not cherry-picking. It also appears that ADL-MCI is the most sensitive (and for caregivers and families probably the most relevant) of the measures; so the other measures probably did not score even lower simply because they did not have the validity to do so.

...ITT is only intent to treat not actual treatment, so even the MMSE miss is hardly relevant. Good point; I noticed that also. Even for people who did not complete the 78 week trial, and even including those who dropped out at any point, the benefits appear similar. Maybe the occur primarily in the first year (52 weeks). Figuring out how long someone needs to be on the drug, especially if it is approved for prevention, not treatment, is a significant need.

...I am also trying to think through what is happening during those first 26 weeks. The analogy
of driving on the freeway might be handy. When the flow of traffic is 50 miles per hour, it does not matter
what you do, you will move with this flow and travel at 50 mph. Possibly same with amyloid, you can
go low dose you can go high dose, though for the first 26 weeks it does not appear to matter you will
have the same amyloid reduction....if you try to push through the flow of traffic...you increase danger without actually increasing your speed (with amyloid this would mean ARIA). I like this analogy; you have to manage the congestion before the efficiency of any traffic system is evident.

... What I understand for the result from this trial is... this really should imply lower dosing combined with a longer trial, say 30 months instead of 18 might become the standard...It really is not that low dose was not effective, it was more that the blue lines had not yet caught up with the green lines in amyloid reduction. Another great observation!

...All those other add-ons that those on the forum have been trying could have a better chance at being effective without having to compete against a relentless neurodegenerative process. It will be the next wave of research that allows for even earlier treatment that will result in a noticeable inflection of the dementia crisis.
4/4 and still an optimist!

J11
Contributor
Contributor
Posts: 1356
Joined: Sat May 17, 2014 4:04 pm

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

Postby J11 » Sat Oct 26, 2019 8:24 pm

Amyloid 2a.PNG


The numbers are starting to make a great deal of sense to me.

Firstly, as seen in the figure above the low dose arms for both Emerge and Engage had very similar trajectories for amyloid removal. Given that these trials were reportedly based on the same design this is what one would expect, and this was especially true for the low dose arms as concerns about ARIA were less and the protocols for both the trials were administered in a more similar manner (versus the high dose).

Now when you look at the cognitive readouts for the low dose arms in Emerge and Engage on pages 10 & 11 of the Biogen presentation, you see that for the ITTs they are reasonably similar. In fact the ITTs appear so similar that combining them into one group would be the best way to analyze them (The largest difference is with MMSE which ranges over 9%.) Using the ITT as a focus of analysis instead of the OTC allows one to look at the centroid of the data and avoids becoming confused with whatever differences of dosing happened with the OTC.

The big difference that emerges from the figure above is the amyloid clearance in Emerge trial over Engage in the high dose arms.
Emerge moved down to ~ -0.27 while Engage went to ~ -0.24 ( versus ~ -0.16 for both low dose arms). This might help to account for why the results were different for the high dosing arms of the trials. Perhaps this region around ~0.15 - -0.20 is a sweet spot for amyloid removal which needs to be reached in order for brain healing to begin. What is particularly interesting is that if you draw lines along -0.20 on both of the trials, you see that Emerge spent twice as long below this line till week 78 than did the Engage trial and there was approximately twice the cognitive benefit on ADAS-COG and ADL-MCI the most sensitive measures used. The seemingly small differences might actually cause significant differences in the readouts. This is painting the bulls-eye after the fact, though it does at least have a slight chance of plausibility.

I also wonder whether the increase in the amyloid level in the placebo group in the Emerge trial might have further driven some of the changes. Here again I am not sure why the placebo was not simply combined for the two trials.

It was disappointing that there was discussion about differences in epsilon 4 versus non-epsilon 4 in the trial. We have seen this in so many other trials that one might have thought that the lesson had finally been learned to conduct separate trials; apparently not. We have seen in other trials that a fair number of the non-4s did not even have Alzheimer's, even if amyloid scans were done on all patients it would seem best to simply have different trials.
You do not have the required permissions to view the files attached to this post.

J11
Contributor
Contributor
Posts: 1356
Joined: Sat May 17, 2014 4:04 pm

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

Postby J11 » Sun Oct 27, 2019 2:18 pm

Study 1c.PNG


Study 1b.PNG


Study 1a.PNG
You do not have the required permissions to view the files attached to this post.


Return to “Prevention and Treatment”

Who is online

Users browsing this forum: No registered users and 12 guests

 

 

cron