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: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Thank you Flora!
I appreciate your kind words.

Yes, while trying to think through (to the best of my ability) the meta-analysis of the AD research (and the conclusion that anti-amyloids are effective in AD treatment) has been at times challenging, trying to access my emotional self (through visualization, etc.) is tougher. That's why I only reach for this inner truth a few times a year (e.g., often during the end of year beginning of year holidays). Given how taxing emotional contact can be, I think I'll stick mostly with more correlation plots etc..

Best Wishes, Flora for 2022!
Last edited by J11 on Sat Jan 01, 2022 6:50 pm, edited 3 times in total.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Big news (or at least big rumors)!
Biogen is to be bought out by Samsung?

I thought this would be a great time for some lake time before my big end of the year assessment.
Relax J11 take it easy... it's a nice quiet contemplative time of year when nothing much happens...
... and then Biogen is being bought out?

Probably be a good idea for some more lake time.
Can you take holidays to recover from the stress of holidays?

I am trying to analyze what is happening with anti-amyloids, though all these things keep popping up
that are very difficult to anticipate (before they happen). It somewhat defeats the entire purpose of
analysis when all you can do is shrug when something else odd occurs.

Biogen's anti-amyloids have to be worth at least $40 billion by themselves. This is one of the few times that I can think of where the potential of a product was holding back its commercial success. The fear has been that the anti-amyloids could bankrupt the American healthcare system (along with many others in the world). Perhaps this is the underlying reason why Aducan has not been more of a success. If the financial side (and others) could be worked through, then it would seem that the sky is the limit.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

2021 has been a monumental year in the Alzheimer's clinic.
The FDA's accelerated approval of Aducanumab is clearly a turning point in the more than century long struggle to develop effective anti-dementing agents.

The evidence supporting the efficacy of Aducanumab is conclusive. While the FDA still requires additional clinical results to confirm the benefits of Aducanumab, the many hundreds of posts on this thread have convinced me that there exists definitive support for Aducanumab's efficacy. For me the numerous scatter plots of CDR-sb versus SUVR for the large clinical trials of Aducanumab, Lecanemab, Donanemab and Gantenerumab offer the strongest supporting evidence. Surprisingly, the linear correlations calculated for many of these plots approached 100%. Not approving Aducanumab in the light of these scatter plots would have been to dismiss extremely strong evidence: The graphical representations of the results are too powerfully persuasive for an observer to easily ignore or rebut.

The evidence favoring Aducanumab only strengthens when APOE epsilon 4s were considered alone and not the unselected trial populations of a mix of epsilon 4s and non-4s. Specifically, the reduction in decline versus placebo of Aducanumab (lecanemab) increased from ~21% (with mixed APOE epsilon 4 and non-4s) to ~40%-50% (with only APOE epsilon 4s). For epsilon 4s, Aducanumab is offering a functional cure. Anti-amyloids clearly have anti-dementing effects and the large phase 3 clinical trials for anti-amyloids that are to complete next year will help to confirm the extent of such benefits.

If efficacy is proven, then why has the clinical uptake been so restrained? Typically an FDA approved drug that has cleared all the hurdles is then accepted as the standard of care. With Aducanumab this has not been true.

One of the lingering issues holding back Aducanumab has been safety. While Aducanumab has been found to be reasonably safe in the clinical trials (~0.3% of patients had a serious response to treatment- depending upon patient demographics) an even safer product would be appreciated by patients and their caregivers. Yet, as the clinical trial patients were not allowed to have the often extensive comorbidities of typical community dementia patients, real world treatment exists in a higher risk environment. Various approaches to reduce risk of anti-amyloid treatment could be tried. Lecanemab apparently might be a safer anti-amyloid which has used a more rapid uptitration and might be approved next year. Other strategies could include a slower uptitration, possibly investigating anti-beta amyloid autoantibodies, inter alia.


For me personally the approval of Aducanumab offers the potential for very early treatment with an anti-amyloid at low very safe doses (at a possibly highly affordable price) years ahead of symptom onset. It is worth repeating from an earlier post that the risk that today's Aducanumab patients are facing is a result of their waiting decades to access an anti-amyloid. The original research found that naturally occurring Aducanumab in homeopathic doses did not cause side effects, though helped to prevent the onset of dementia. It is only within the context of a clinical trial where a lifetime of amyloid needs to be removed over the course of a few months that safety concerns become so prominent.

I am not clear of the timeline for a clinical roll-out of anti-amyloids as a preventative, though such a market must be something that pharmas have considered. It is not entirely clear to me whether off-label would be allowable for such an indication, though the FDA's initial label for Aducanumab appeared to be highly inclusive for those with varying cognitive abilities. In our family experience cognitive impairment was present for decades before an AD/MCI diagnosis. A short clinical trial that established the safe pre-MCI treatment dose could give those considering off label use great comfort. How much clinical evidence and how long clinical evidence will be required to accumulate for an on label preventative indication?
Last edited by J11 on Sat Jan 01, 2022 6:57 pm, edited 1 time in total.
User avatar
floramaria
Support Team
Support Team
Posts: 1423
Joined: Tue Jul 04, 2017 11:22 am
Location: Northern New Mexico

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

Post by floramaria »

J11 wrote: Wed Dec 29, 2021 6:12 pm Big news (or at least big rumors)!
Biogen is to be bought out by Samsung?
Interesting rumor! After reading this I looked up recent info on this and found this from Business Insider:

Biogen stock dropped 8% on Thursday after Samsung denied it was seeking to buy the drugmaker. 
​
Samsung Biologics said in filing it wasn't true that it was aiming to buy the Massachusetts-based company. 



Time will tell. I’m following the news about whether or not MediCare will approve coverage.

Meanwhile…I hope you get that lake time!! Happy new year !
Functional Medicine Certified Health Coach
IFM/ Bredesen Training in Reversing Cognitive Decline (March 2017)
ReCODE 2.0 Health Coach with Apollo Health
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Thank you for replying Flora.

Yes, I did not know what to make of the rumor.
My immediate response to the rumor was surprise that such very short term thinking could be thought plausible.
Not commenting on the rumors tended to add credibility to them, though I suppose that if one were to make a habit of denying rumors then there would be not much time left to do anything productive.

Good to get in the lake time while I can because 2022 looks like we could all be swamped with Alzheimer's news. Could there be even more than 3 AD approvals in 2022? 2021 was the dress rehearsal: 2022 will be show time. We have all seen the tricks that can crop up in the analysis of the results and we know what the rebuttals are. I am eagerly awaiting what new curve balls that we might see from the next round of the analysis. Very excited to see what 2022 will bring.

Best Wishes for the New Year Flora and others on the APOE4 forum.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

2021 was such an enormous year.
The FDA approval of Aducanumab was clearly massive.

The sequencing of my full genome along with receiving polygenic scores for a wide range of health and behavior traits was another top 2021 highlight (for me anyways). The polygenic scores have offered me extremely powerful insights into understanding what makes me me. Several of these idiosyncratic aspects of my personality were part of my mental landscape though I had been unable to express them in a coherent sentence.

It is not difficult to guess that many are far far behind the curve on this technology. The popular discussion is so locked into futile debates about eugenics etc. that the benefits of knowing oneself at the level of base pairs of DNA has been lost for them. Even more unfortunately, it is typically the most disadvantaged people who are the very ones who develop these technophobias even when the technologies could often greatly benefit them.

Looking at my polygenic scores I can trace out all of the major problems that have occurred in my life. All the major health risks are clearly evident (except AD) as are many behavioral quirks. Also with my sequence it is clear to me that the social responses that my parents, my schools and others used in attempting to modify these quirks were largely counterproductive. The sheer magnitude of the harm that the community inflicts on others because of this ignorance is something that I do not want to think about. My genome revealed to me a list of largely hidden genotypes that would have been entirely unknown to highly informed professionals even a few years ago. Polygenic insights might take some time to percolate through society.

What is of particular interest is that many of the important drivers of my behavior can not be found in medical texts. Much of the traditional vocabulary that surrounds abnormal psychology does not actually correspond to the various other layers of underlying polygenic traits that help to form one's personality. In fact, I found it immediately liberating having such a vocabulary and with it I felt able to tune into my core personness and be more me.

A social revolution related to this genetic knowledge over even the near term should not be unexpected. Having good insight into one's own polygenics and that of one's friends would quite likely create much more stable friendships and harmonious communities. Ignoring the multiple dimensions of polygenetics that can now be calculated has given us our endlessly dystopian world. Given that the genetic technology to fully sequence genomes is now so affordable, there is no obvious reason for a social revolution (based on this technology) not to begin at any time.

Probably the best way to frame this is in terms of identical twins. Identical twins can often have extremely close relationships exactly because they share so much in common genetically. Research has even found that in a school environment those friendships that are stronger are also those friendships in which there is more genetic similarity.
Genetics does matter and ignoring it simply results in endless conflicts. It will be fascinating to watch as genetically organized communities emerge and the social patterns are reported.

While genetic selection as a vehicle to create stronger friendships, better marriages and healthier communities might be viewed as somewhat benign, the next step of selecting embryos based on polygenics traits is proving more contentious. What I found somewhat surprising (and disturbing) when looking through my scores was how seemingly simple it would be to have selected a much much better version of me. If I am a typical person, then everyone might have the chance to select children who are geniuses in their own way. The genetic evidence is fairly conclusive that I am within a step or two of being a genius in my own way. Get ready-- a world of such geniuses might now be on the way in the next generation.

My impression had been that IQ (as genetically determined) would be the central trait that would dominate selection pressure. You would have a single roll of the genetic dice with everything riding on the outcome. What if that single roll didn't work out well? Well, that's that. Those with maximal IQ would develop enormous power in the next generation. Yet, from what I understand now this might not actually be the outcome. When I examined my genome I noticed that there were several traits that would be valued aside from stratight IQ; a stark division of the world into the winners and the non-winners might not be the result. In this view, everyone could be seen as having a valued gift and could make a contribution to society.

The scientific community has asked for an urgent conversation about these issues related to genetics; to no avail.
While the conversation has been absent, the consequences will not be.
JD2020
Contributor
Contributor
Posts: 185
Joined: Mon Dec 30, 2019 4:22 pm

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

Post by JD2020 »

The Wall Street Journal has a long article about this drug and its journey through the testing and approval process. What a mess. There is also a picture of a 54 year old woman, a former attorney, who is taking this drug because, to paraphrase, she will do anything to give herself a little more time. I wonder if she is familiar with ReCode. This disease is tragic.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

JD2020, thank you for posting!

I have not read the WSJ article that you cited, though I guess it reviews the storyline of Aducanumab which this thread has also closely followed.

Aducanumab's clinical results to date have demonstrated substantial anti-dementing effects for those with MCI/early AD and APOE epsilon 4 genotype. The hundreds of posts to this thread have built-up a convincing evidence base for this assertion (at least I am convinced). I have considered the research to the best of my ability and my nearly final assessment (with some wiggle room) is that anti-amyloid treatment is a reasonable approach to help those with early amyloid dementia. This year several large clinical trials complete that might validate this assertion.

Given the devastating effects of progressive dementing illness, the ~~1% risk of serious adverse effects as reported in the clinical trials (varying by dosage, geographic location, genotype, comorbidity etc.) does not seem unreasonable. Consider that for epsilon 44s the probability of dementia onset likely exceeds 90%. For 44s, measurable cognitive impairment might even be present in their 50s. However, there are clearly some patients who would likely be at very high risk of side effects and a good amount of clinical judgment would be in order.

I do not feel overly comfortable making rhetorical statements suggesting what other people should do; I am not (nor are others in the immediate family) in the position of needing near-term anti-amyloid treatment for MCI/early AD. I feel fairly comfortable waiting and watching to see how all of this sorts out over the next year or two. There are a wave of anti-dementia treatments approaching that will be safe, effective and possibly even quite reasonably priced. I feel so blessed that after all these years of research treatments for AD are finally arriving. However, I realize that there are millions of others who are much closer to age of onset that might feel the need to be more proactive and are unfortunately in a higher risk decision environment. It would be very difficult for us if there were a serious side-effect with treatment. Nonetheless, in our particular experience, there would be few if any comorbidities to consider; pretty much straight AD.

Even still, a range of safety enhancing measures for Aducanumab perhaps could still be considered. For example, ARIA GWAS, slowed uptitration, perhaps limiting by comorbidities, improved ARIA treatment, ... Possibly above all applying sound clinical judgment on those who would be right for the treatment. Indiscriminately dosing every eligible senior with MCI with maximal Aducanumab is not reasonable. It is surprising, though, that more have not benefited from treatment. There must be a large group of early patients who would derive significant benefit with highly reasonable risk.

Notwithstanding my above comments, right now the population scale logic would seem to me to be shifting towards waiting for Lecanemab. We have almost reached the point where if a patient were to start up Aducanumab they would be no further ahead than if they waited for Lecanemab's approval. The titration for Aducanumab is 6 months versus Lecanemab's 2 months, while the rate of ARIA for Lecanemab has been reported to be much lower. The thread has previously speculated that the best result might be for Lecanemab to be the first wide scale anti-amyloid to reach market (over Aducanumab); this scenario seems increasingly plausible. The strategic logic of having two anti-amyloids (in development/on market) escapes me. The market could largely reject Aducanumab and then embrace
lecanemab (the second generation Aducanumab). Even still for my purposes, Aducanumab has a low dose preventative anti-amyloid might still be plausible.

I am unclear about the exact timeline, yet my current guess is that the rolling submission for Lecanemab should close out over the next month or two. This would correspond to an FDA approval just after Clarity ends. 2022 is going to be another big year for Alzheimer's medicine! The results for the phase 3 anti-amyloid trials that complete this year should end any lingering discussion about the effectiveness of this drug class.

Admittedly, some of my statements about Aducanumab have been more enthusiastic than those from the FDA and sometimes even Biogen. I have found this to be somewhat odd; I cited specific quantitative results for all of my assertions. This might have partially been related to Biogen wanting to claim the largest possible treatment population by using the overall blended APOE epsilon 4 and non-4s. The problem with this approach is that it has created this strong impression in casual observers that Aducanumab is only marginally effective (~22% reduction in decline). This is not true. Almost all of the cognitive benefit went to the e4s; very little to the non-e4s. I find it surprising how few realize that Aducanumab likely has a 40-50% reduction in progression in those with epsilon4; that is a fairly large treatment effect.

The difference in outcome between e4s and non-e4s has been a constant feature of AD trials. With e4s, you have a fairly homogeneous patient population; with non-4s there is a large mix of various AD genotypes. Anti-amyloids probably would be effective in some of these genotypes, though it is not yet clear which genotypes these might be.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Corr.GIF
You do not have the required permissions to view the files attached to this post.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

The CMS ruling has been posted and they decided to go with "Coverage with Evidence" meaning that Aducanumab would be covered only within the context of a clinical trial.

I found it interesting that their report had a table for phase 3 clinical trials of anti-amyloids that included Bapineuzumab, Solanezumab etc. and yet the recent phase 2 trial results for Lecanemab or Donanemab were absent.
When these phase 2 results were published last year it appeared to capture the FDA's attention. In fact, after the Donanemab result was published in January of last year the FDA decided that another 3 months would be required for the Aducanumab decision.

As can be seen in the figure above, the modern generation of anti-amyloids which include Aducanumab, Lecanemab, Donanemab and Gantenerumab strongly exhibit collinearity on the CDR-sb vs SUVR axes. Admittedly, Donanemab was not included above because it was somewhat "off the line" though as explained earlier even this deviation appears to be a consequence of their using certain patient selection techniques. Some of the other points were also wiggled into place (e.g. 302 Hi is placed at 0.35 and not 0.39), though the broad result of strong linear correlation was shown repeatedly in these plots.

What I also found unusual was the CMS strategy to search pubmed etc. for research and clinical trials for anti-amyloids and not to focus more on the extensive scrutiny of the clinical trial results for Aducan which were conducted through the FDA. This seemed odd to me because a substantial amount of computer modeling with the actual Aducanumab dataset was presented in the CDER CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) which strongly supported Aducanumab approval.

In fact, this is where the classic line that they ran out of CPU was noted.
Only 10 million clinical trials were simulated.
Only 10 million!

A good rule of thumb is to accept the wisdom of those who are closest to the dataset especially when the
dataset itself is somewhat murky as was true with ENGAGE/EMERGE. In this instance those who did the
simulations found that the trials were convincing.

"When the same scenario was analyzed (4 endpoints, high dose, and week 78), the larger
sample size and more data from earlier visits based on MMRM analysis resulted in an
even smaller false positive rate, 0.000008, compared with 0.00007 when only 300
subjects were simulated in each group only at week 78. When all positive estimates from
4 endpoints, 3 visits and 2 dose levels were considered, the overall false positive rate
was below 1/10,000,000. An accurate false positive rate could not be estimated because
only 10 million clinical trials were simulated due to computation capacity
." p.35

Three phase 3 trials anti-amyloids (2 x Gantenerumab and 1 x Lecanemab (Clarity)) will finish this year. We should soon have a very clear idea of the efficacy of the anti-amyloids. From the figure above the expectation is that the relationship between CDR-sb and SUVR will be defined by: delta(CDR-sb) ~ 1.27 * delta(SUVR) in the top-line result with sub-groups (most notably APOE epsilon 4) expected to show even stronger benefits.

In addition to the anti-amyloids we now also can look forward to the LMTM phase 3 results which could offer additional anti-dementing power through an anti-tau effect.
Post Reply