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

[J11]

https://www.sciencedirect.com/science/a ... 1311#f0020

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[J11]

These are some highly informative figures about amyloid. The first shows the density of cognitively normal people with different levels
of amyloid in centiloids. I will need to double check the assumptions here, though it appears that few cognitively normal people have even much more than ~5 centiloids. Perhaps this relates to the sample that is under consideration as a significant fraction of seniors can have amyloid burdens without clear impairment. Young controls have centiloid measures of ~0.

The bottom figure illustrates how amyloid level acts as feedback for more accumulation of amyloid, The more there is the faster it accumulates. This suggests that a good strategy would be to stay to the left of the top of the hill and move leftward. Consider a person with 20 centiloids (x-axis). If this person could remove 10 centiloids, then annualized rate of change would change from ~3 centiloids per year to ~0. That would seem to be the sweet spot. Keeping amyloid controlled between 0-10 might avoid the runaway accumulation that would otherwise occur. It offers a possible reason why so little aducan is needed in those who generate it naturally: If you keep it at a minimal level there will be minimal annualized accumulation. However, if you allow it to enter a runaway stage >20 centiloids a large amount of amyloid then begins to accumulate which will require extensive treatment to reverse.

I am not clear whether those with ~100 centiloids of amyloid (i.e., those with MCI/Early AD) would need to climb the hill from the right and then move down the hill as they decreased amyloid below 40 CL.

[floramaria]

Waiting until the brain is fully saturated with amyloid does not seem to be the best possible strategy.

That’s for sure!

[DoubleBond]

Just in: Aducanumab has been approved by FDA
https://www.cnbc.com/2021/06/07/fda-app ... cades.html

[J11]

DoubleBond, thank you very much for posting the great news!
I have been so happy today celebrating this wonderful development; very happy and also extremely lethargic (perhaps too much happiness).

June 7, 2021 (Alzheimer Liberation Day) is the start of the journey back to normal life for the global amyloid dementia community. Graduate high school, say good bye to your friends, put on your I am a grown up sticker and then start your eternal 24/7 shift at your home dementia ICU doesn't have to be the blueprint for life anymore. The anti-amyloid anti-body revolution offers us the chance for liberation from such a life. My impression is that quite a few people outside of the dementia experience really do not have a grasp of what happened today. ALD-- the day that changed everything. This is a once in a century day that will redefine the 21st Century. In future posts to the thread I can comment upon some of these redefinitions.

Immediately after FDA approval of Aduhelm today a new era in Alzheimer's began. A revaluation of anti-amyloids companies occurred within an instant along with a certain refocusing of one's state of consciousness. The race for the finish line is on and the approval now has motivated everyone to run faster; the connection between input --> output has been made more apparent.

Biogen has a critical first to market advantage with the accompanying cash flow. There would seem to now be so many opportunities that are there just to be plucked (ground lying fruit?). I will be very interested to see whether they will pursue the microdosing lifestyle medicine idea. Basically, potentially population scale microdosing of Aduhelm (200 million people). Avoiding questions of efficacy entirely and thinking more in terms of removing amyloid and striving for the highest non-ARIA dose for safety could make microdosing truly a ground lying fruit scoop.

[J11]

flora, after today I sincerely hope that people with known amyloid and dementia issues do not think that they have more time then they do before they have entered the point of no return for ongoing dementia decline. That will probably be the focus for the thread going forward. I will get up on the stump and just highlight the importance of stopping the process while it can be stopped -- time is brain.

I certainly understand how there is a tendency to wait for problems to become real problems before doing anything about fixing the problems -- by then the problem is typically much bigger, seldom is it smaller. One of the observations that needs to be restated a few times is that even with the aducan phase 3s where the patients were selected right at the start of symptoms apparently for some it was already too late-- the dona phase 2 found that upwards of a half of the patients with earlish AD had too much tau for any benefit. This needs to be made clear to many asymptomatic patients-- waiting until you have even early symptoms might already be too late. Being treated early could prevent the cruel tragedy of having an effective medication at the earlish stages yet an ineffective treatment for somewhat later stages.

[J11]

The approval today for Aduhelm included a condition for a confirmatory follow-on study. I find this to be ethically troubling because randomizing patients to placebo could then mean that these patients would advance into the event horizon of dementing illness and have no treatment options available to stop progression. The phase 2 dona trial demonstrated the power and speed of tau selection in achieving results in AD, perhaps a similar study could be done with Aduhelm. Statistically significant results might be available in only ~40 with only a modest sized trial. Further, selection by suspected demographic risk enhancers could highlight treatment effects.

[floramaria]

It is all too easy to say that aducan is not an ideal drug. In some sense that is clearly true. Yet, the question truly is what is an ideal drug that patients might access on Monday? If you do not have a few years to wait, then aducan is one of the few choices. There are others for example: semaglutide, reduced methylene blue, gamma frequency, plasma exchange/albumin, etc.; they do offer potential and for those desperate enough they clearly have strengths, though they could be a ways off from FDA approval. Perhaps an ideal workaround would be to simply accelerate lecanemab's approval. leca is a second generation anti-amyloid. The phase 2 result was strong and the phase 3 is already quite mature. Possibly with tau selection statistical significance might already have been achieved; an added benefited is that it has substantially lower ARIA. The problem with that idea is that typically everything develops upon a fixed schedule
and leca might take years for approval.

I am very grateful to the pharmaceutical industry for their efforts and the benefits that it will provide for me. The potential market for anti-dementing drugs is simply so large that pharma will be able to offer patients compelling products and generate substantial revenues, while at the same time giving patients affordable options..

Hi J11~ well, 575 posts into the Aducanumab Celebration Thread, the FDA has approved it. I was reading back on this earlier post about lecanumab, because what you mentioned is one of the reasons behind opposition to approving aducanumab. Repeatedly, the argument has been made that once aducanumab is available, out of desperation people will sign up for it..demand it, in fact. And this will make it more difficult to recruit people for double-blind clinical trials of other, potentially safer and more effective treatments. It might be almost impossible to even get the recruits for the Phase Four Aducanmumab trial. Who will be willing to get the placebo when the drug can be administered outside of the clinical trial setting?
“a bird In the hand....”

as for generating substantial revenues, I’ll say! $56,000 a year price tag, plus the cost of monitoring for ARIA. Not what I consider “an affordable option”. If it reversed AD, that would be a different story. I truly hope this turns out to be a boon for those who need help now, not just for those who own stock in Biogen.

[NF52]

The approval today for Aduhelm included a condition for a confirmatory follow-on study. I find this to be ethically troubling because randomizing patients to placebo could then mean that these patients would advance into the event horizon of dementing illness and have no treatment options available to stop progression. The phase 2 dona trial demonstrated the power and speed of tau selection in achieving results in AD, perhaps a similar study could be done with Aduhelm. Statistically significant results might be available in only ~40 with only a modest sized trial. Further, selection by suspected demographic risk enhancers could highlight treatment effects.

Hi J11,

Just a bit of clarification. A Phase IV study, like an OLE (Open Label Extension) study, doesn't involve a placebo arm. It is instead a monitoring study of long-term safety, similar to what is being done with COVID-19 vaccines currently, using a much larger sampling size. Since Aduhelm was approved for all stages of Alzheimer's disease, this seems prudent for patient safety.

A Phase IV trial is also known as a postmarketing surveillance trial or drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test.[1] Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives regulatory approval to be sold.[6] Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials).[2][6] The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials.[6] Harmful effects discovered by Phase IV trials may result in a drug being withdrawn from the market or restricted to certain uses; examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).

https://en.wikipedia.org/wiki/Phases_of ... h#Phase_IV

[floramaria]

Just a bit of clarification. A Phase IV study, like an OLE (Open Label Extension) study, doesn't involve a placebo arm. It is instead a monitoring study of long-term safety, similar to what is being done with COVID-19 vaccines currently, using a much larger sampling size.

Thanks for the clarification, N52. From articles that I had read about the effect that aducanumab approval might have on other clinical trials, I had gotten the wrong idea. Or now, based on your post, I think I had the wrong idea, anyway. Here are some sources of my confusion. ( bold type emphasis added by me).
This from the article about FDA approval in yesterday’s NY Times: “ If the new trial, called a Phase 4 trial, fails to show the drug is effective, the F.D.A. can — but is not required to — rescind its approval.....
Several experts expressed skepticism that Biogen would be able to recruit many participants in the United States for a post-market trial because patients who can get a drug from their doctors are often reluctant to take the chance of receiving a placebo in a clinical trial.
“Once the product is approved, the cat’s out of the bag, the horse is out of the barn,” said Dr. G. Caleb Alexander, a member of the F.D.A. advisory committee, who is an internist, epidemiologist and expert on drug safety and effectiveness at the Johns Hopkins Bloomberg School of Public Health. “There’s no way to recover the opportunity to understand whether or not the product really works in the post-approval setting.”

Companies can conduct post-market trials with participants from other countries, but may face similar challenges recruiting participants if those countries approve the drug before trials are completed. “

This is from the NIA website, from article titled “ NIA Statement on FDA Approval of Aducanumab for Alzheimer’s Disease”.
The FDA also stated that “approval is based on a surrogate or intermediate clinical endpoint (in this case reduction of amyloid plaque in the brain).” Additionally, “drug companies are required to conduct post-approval studies to verify the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial does not verify the drug’s anticipated clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.”

Neither of these say that the Phase 4 trial is limited to safety.