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.

Postby J11 » Sat May 08, 2021 7:45 pm

The lecanemab phase 2 covariates confirmed the results from the aducan Emerge trial.
The above figure from the FDA Briefing Document showed a large benefit to APOE+ (APOE-) , and Mild AD (vs MCI) on CDRsb.
These findings were duplicated in the lecanemab phase 2 ( 4 posts up first figure and 3 posts up first figure).

The APOE+ result is especially noteworthy (3 posts up first figure).
Well they are basically so compelling that I`ll just repost them below.
First of all, the n for APOE+ is large here n=419 treatment versus n=168 placebo; APOE- n=168 and n=70 placebo.
The first 3 for APOE- are heading in the wrong direction, the 10mg/kg monthly is ~14 times smaller and the 10 mg/kg bimonthly is ~8 fold smaller than the corresponding APOE+ dosages. The magnitude of advantage in the EMERGE for APOE+ was similar. For the APOE+ in the leca trial the benefit was approaching 50% in the highest dose, while the APOE- only had a 7.5% benefit on this dose.

APOE + -.GIF




Treating all of the subgroups as somehow equal does not seem justified. The APOE+s appear to benefit considerably more than do the APOE-s. There might be some confounding due to the side effects removing some of the APOE+s, though the evidence does suggest that there truly is a difference. The APOE+s create almost all of the advantage in the combined group. This would not be entirely unexpected as APOE-s have much greater heterogeneity of disease origin etc.. Subgrouping by APOE status seems the best idea for future reporting. This would be yet another way to magnify the results. (in addition to conditioning on tau).

Similar observation for Mild AD versus MCI. Large large benefit on CDRsb for Mild AD in the leca phase 2 (~ 1.1; n=35; 51% reduction vs placebo) vs MCI( ~ ~0.16; n=49; 14% reduction vs. placebo). Once again this roughly duplicates the magnitude of advantage found for Mild vs MCI in aducan Emerge.

CDRsb phase 2.GIF



Other covariates that added advantage in Emerge were >75 years of age, male, Asian. These covariates do not appear to have been included in the leca results. Reporting results by these covariates as a topline results could be misguided as it might simply be chasing after data noise, though it would not seem unreasonable to consider APOE conditioning and possibly others. Nevertheless,
these subgroups differences might be largely entangled with tau staging; there might be little if any residual left to explain after accounting for tau.
Aducan Variables 5.gif



For me, the above highlights how much of the patient benefit continues to be obscured by the data presentation. The Emerge topline primary result of 22% could be highly unreflective of the different subgroups. Obviously many APOE 44s would be especially interested in how their subgroup might fare. It would not be entirely unexpected that 44s would do even better, as single 4s are also a somewhat heterogeneous group. The overall finding for APOE+ in leca was ~50% improvement. Yet, this still does not consider conditioning on tau and possibly other covariates. It's not easy to guesstimate, though the benefit of anti-amyloid for some subgroups such as APOE+ might have been under-reported. [Note : In the clarity trial, all of the treated patients will receive the highest dose from the phase 2.] Adding in a stratification component into the Clarity trial could help to clarify the benefits that different subgroups received from treatment. Perhaps different demographics could be adaptively assigned stratifcation weights based on a prior estimate of their likely response to treatment and as these different demographics achieved statistical significance then the weightings could be changed to favor other especially advantaged demographics.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Sat May 08, 2021 9:40 pm

APOE + - stat 1.GIF
APOE + - stat 2.GIF
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Sat May 08, 2021 10:02 pm

The statistical appendix for aducan made great note of the fact that APOE+ patients outperformed the APOE- patients. As seen in the above post 2 of the comparisons of the cognitive measures (total of 8) achieved statistical significance, 2 others were borderline significant, and 3 others were not that far off. Only the ADAScog hi seems left to hand wavy argument. Yet, strangely even here the APOE+ scored a notable p-value versus placebo. In fact all of the high doses for APOE+ were statistically significant. Only ADCSadl lo missed by a bit and MMSE lo missed by quite a bit (while APOE- only achieved nominal significance on MMSE lo).

As noted in the statistical appendix "All of these trends suggest bigger effects in APOE+ as compared to APOE-."
For eight out of eight APOE+ is better. This is one of those times where you have to agree. Yes, APOE+ likely did do better.
APOE+ is a relatively homogeneous group of patients; APOE- not so much.

"There is a statistically significant interaction for MMSE between APOE and treatment groups, p=0.0065,
i.e., the treatment effect(s) is not the same across APOE subgroups."

{Admittedly, page 79 of the Briefing Document does add some caution to the idea that there is a real difference
between APOE+ and -.}

This appears to have been confirmed in hundreds and hundreds of patients in the leca phase 2.

Ok, we concede. APOE+ do better. Now what?

Doesn't this mean that the APOE-s are mostly dragging down the average?
Isn't the level of significance then actually understated for the APOE+ patients? APOE- largely obscured the strong result of the APOE+. The Emerge CDRsb for APOE+ then shows a benefit of 0.53 (0.19) over placebo (p=0.0053) while APOE- only had a benefit of 0.06(0.27) p-value =0.8366. The p-value here for the difference was 0.1537. One third of the arms of 302 at baseline were noncarriers. More carriers probably were non-completers due to side effects; so there was a fair amount of weighting to noncarriers who had minimal treatment effect (hmm, using 0.53 + , 0.06 -, 0.39 : x=70% APOE+ 1-x =30% APOE-).

Yeah! Declare defeat and then join the victory party!

Stat 2.GIF
Stat 1.GIF
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Mon May 10, 2021 8:15 pm

The neutral and negative reviews online to aducan are not easy to align with the current evidence. I am very unclear how others are seeing the cup half empty. From what I currently understand, the effectiveness of aducan is beyond reasonable argument. This will only be strengthened further as additional selection by tau etc. is reported.

When you examine the subgroups underneath the topline, it seems reasonably likely that some did substantially better than the average. This result has been replicated in the leca phase 2 that was recently published. APOE+, Mild AD, etc. have shown strong results. With Mild AD, the reports indicate a >+1 CDRsb benefit (that is even before selecting on tau). >+1 CDRsb would clearly have a significant real world impact on the lives of AD patients.

It is not easy to understand why adaptive clinical trials are not the norm when such results are observed. Basically, plug the expected covariates into the trial computer and let it adapt patient selection to find those who are the top responders. Given the enormous computational power of modern computers, perhaps the trial computer could even be instructed to look out for additional covariates. As it is, there are some large potential treatment effects in some subgroups, though they also usually have large error bars. With more personalized subgrouping a positive result for a top performing subgroup might have been published years ago.

It is disappointing that more homogeneous grouping was not pre-specified in the analyses for aducan (at least I think it was not prespecifed). Assigning all AD patients into one category is questionable. APOE+ is a substantial fraction of all AD and has shown in the aducan trial and elsewhere better than average treatment effects. Simply prespecifying on APOE+ would have substantially enhanced the result (as noted in a recent post). Selection on tau along with APOE (perhaps others) might be highly informative.

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

Postby J11 » Sun May 16, 2021 7:42 pm

Yeah!
We've been waiting for 5 years for this one to move forward.


Semaglutide has 2 phase 3 trials about to enroll with ~3700 patients!
The AD treatment landscape is opening up everywhere.

[This is for liraglutide]
"Oh, and there is (a) savings card, pay no more than $25 out of pocket for a prescription.
https://www.victoza.com/get-started-usi ... -card.html"
A near generic for Alzheimer's with a coupon and only a $25 copay?
Life is good. Life is very good.

There is just so much money out there for pharma to grab and at the same time this will be such a huge win for the dementia community.

Oh, yeah; semaglutide in the AD trials will be an oral (not injectable) formulation.

So much is happening in AD treatment now. 2021-2022 is the time that everything changes in AD therapy.

viewtopic.php?f=4&t=2204&p=80556#p80556


Only clouds I am seeing here is that they do not appear to have included tau imaging or even APOE genotyping.
Given the current knowledge base 3,700 patients really might not be even needed to demonstrate efficacy.
With tau selection and perhaps selection on covariates you might get to down ~50 in the treatment arm.
Why not do this right and have the answer for us in 50 weeks and not 5 years?

To learn from the experience with aducan, perhaps they could use an adaptive selection mechanism.
Once they achieved convincing evidence for the most favored demographic, the FDA could grant that demographic
approval. The trial could continue along with rolling approvals. AD is a somewhat heterogeneous illness. Why not
simply acknowledge that and give the advantage to the patient community? Averaging everything out makes it more difficult
to rapidly identify the super-responders.


Not completely sure if this relates to aducan, though the whole point is that as soon as you remove the driver of the pathology then other add-ons such as sema could act as amplifiers. Once we have aducan approved then they could start doing the combinations trials. However, I am not entirely clear on this point. If you remove the upstream AD drivers of neuropathology --i.e., amyloid and tau -- would their actually be anything left to treat? Doesn't everything else largely happen downstream?

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

Postby J11 » Sun May 16, 2021 8:43 pm

You really have to start to wonder: What if sema could help dampen down the inflammation that can arise with aducan treatment?
It's almost hard to believe: Could sema actually solve (or at least diminish) aducan's (another anti-amyloid anti-bodies) problem with brain inflammation? That is what tends to happen once the ball moves forward -- it keeps moving forward. Some might call it inertia.

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

Postby J11 » Sun May 23, 2021 9:32 pm

This link is from Fc1234linville's aducan thread. viewtopic.php?f=16&t=7663

Very startling claims are made in the below article.
https://www.beingpatient.com/aducanumab ... erimental/


"Because the first trial lasted for a year against placebo and then everyone would continue on active medicine, we’ve had many people at our center who’ve been on aducanumab for more than five years and on active treatment.

The good news is that the majority of people that were on it actually stayed pretty stable over a pretty long period of time, which is not typical for Alzheimer’s because Alzheimer’s gets gradually worse. Preserving quality of life in early stages of Alzheimer’s is worth a lot, and families who at least had this stability really appreciate it."

This is a very dramatic statement about the efficacy of aducan. I have been quite unsure myself of how long the treatment effect might last. Oftentimes you have the impression that companies will only report trial results over the period of time they feel there might be patient benefit. For current AD medications with acetylcholinesterase modes of action this was typically about 6 months. aducan extends benefit out to ~5 years ( "a pretty long time") in the majority of treated patients and the patients are largely non-progressors ("pretty stable")? That constitutes a functional cure (in my book anyways).

I have not gotten around to taking that law class, yet that would seem to me be a material representation of fact and it would seem highly reasonable to me that a data lock of all aducan dosed patients (that is reasonably current) should occur and that the dataset uploaded to bioarchiv etc.. Perhaps that should be a condition of approval. Wouldn't have to be a lot of pretty words, but having confirmation of the majority of patients are non-progressors over the long-term would essentially end all discussion. This is a red flag claim for the dementia community and if verified would require aducan approval.

How could this extended dataset have been withheld up till now? Clearly it does make a difference how patients do over the longer term. How would a nay vote then even be plausible with extended benefit?

Lately, I had been wavering somewhat in my enthusiasm. The benefits might be smallish; they might be shortish; the side effects might be troubling in larger less well-managed patient settings; there are other AD and amyloid treatments that are emerging etc. .
Yet, as we have seen the benefits are largish for at least some subgroups; apparently the benefits can be longish; side effects typically are manageable and with earlier treatment and possibly co-treatment with other anti-amyloids (e.g. gamma light {I recently bought one of these lights}) perhaps can be made even more manageable; and the other AD treatments that are emerging might not see FDA approval for years. A non-approval of aducan would be devastating for the tens of millions of AD patients.

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

Postby J11 » Tue May 25, 2021 5:42 pm

Still letting the "we’ve had many people at our center who’ve been on aducanumab for more than five years and on active treatment. The good news is that the majority of people that were on it actually stayed pretty stable over a pretty long period of time" comment percolate. That is very very startling. Of importance here is that once the long-term extension is underway there is no blinding to treatment. All those at the clinics would have a clear view of the treatment effect because all the patients in the extension would be on active dose and they would all be receiving the high dose.

Somewhere in the back archives of this thread I noted that by about this time a placebo extrapolation would have the patients from the aducan trials now entering profound levels of disability: They would be ~0 MMSE scores; bed bound and mute. The care-giving burden for these patients would be substantial. From my understanding the bed sores and other disabilities that typically present never heal properly in ordinary care settings. While it does not take that much effort to provide the necessary treatment to overcome these challenges, many quasi-medical environments do not provide such treatment. Necrotic bed sores probably cause extreme levels of pain.

For us, when minor bed sores occurred on occasion it was fairly easy to simply apply a dressing and allow them to heal in a day or two. Bed sores weren't really that big of a challenge for us. The main problem that we did have was from time to time the g-tube would open up and it could cause a serious and large bed sore. There was no easy way to prevent that from happening. A sensor that could detect such dampness with an attached alarm would be such a blessing for many dementia patients who face that risk.

The bigger challenges that we faced were the seizures that apparently are quite common in AD. Such seizures were not present before the AD diagnosis and perhaps were a consequence of AD progression or possibly a result of the acetylcholinesterase drugs. The other challenge that we faced was the muscle stiffening that occurred after prolonged bed boundness. We bought one of those "muscle shaker" machines which did seem to help somewhat, though a more comprehensive solution probably would be better.

Against this image of essentially complete disability, we can imagine patients who are essentially long term non-progressors?
Possibly going about their business blissfully unaware of what the placebo arm would be like? The visual difference between the two groups would be overwhelming. It is possible that some on treatment might still retain legal mental competence. Of course, the ~10 million AD patients in America are also in the placebo group. Until now the only clue that we had of the longer term effect was with the 103 trial which has reported out to ~48 months of treatment; they also maintained cognitive function quite well through time.
Now there is a very large dataset of aducan treated patients that could offer very detailed results over the long-term. These results should be disclosed. How could any valid decision possibly be made without it?

What is the back story here? What is going on? It's a coverup. That is my best guess as of now. Biogen would be all too willing I am quite sure to make a full disclosure on the trial extension. They have the top card, why haven't they played it? The only explanation that I can think of is that they are not allowed to throw it down and claim the pot. "the majority of people that were on it actually stayed pretty stable over a pretty long period of time" that statement if proven is a debate ender. And it is also an automatic free pass to an immediate appeal if a negative decision were reached. It is very surprising to me that such a large dataset has been allowed to lurk in the background of the decision for so long. Is this really the standard procedure for such decisions?

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

Postby Fc1345linville » Wed May 26, 2021 7:29 am

J11, thank you for your thorough and thoughtful coverage of this subject, which could represent a major breakthrough on AD treatment.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby floramaria » Fri May 28, 2021 10:08 pm

J11 wrote:
Very startling claims are made in the below article.
https://www.beingpatient.com/aducanumab ... erimental/
Lately, I had been wavering somewhat in my enthusiasm. The benefits might be smallish; they might be shortish; the side effects might be troubling in larger less well-managed patient settings; there are other AD and amyloid treatments that are emerging etc. .
Yet, as we have seen the benefits are largish for at least some subgroups; apparently the benefits can be longish; side effects typically are manageable and with earlier treatment and possibly co-treatment with other anti-amyloids (e.g. gamma light {I recently bought one of these lights}) perhaps can be made even more manageable; and the other AD treatments that are emerging might not see FDA approval for years. A non-approval of aducan would be devastating for the tens of millions of AD patients.

Hi J11 and others following this thread. I listened to the Being Patient interview yesterday and then today came across this article in The NY Times presenting a case against approval.
About the authors: “Dr. Greicius is a professor of neurology at Stanford, where he directs the Stanford Center for Memory Disorders. Dr. Alexander is an internist and professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health. He served on a Food and Drug Administration advisory committee evaluating aducanumab, the subject of this essay.”
People Want an Alzheimer’s Drug. This Isn’t the One.
https://www.nytimes.com/2021/05/28/opin ... ticleShare

I am posting this here not because I believe that the opinion of the authors is the correct opinion, but rather because this thread is where the merits of approving aducanumab are being presented and discussed.
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