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.

Post by J11 »

The excitement is building!
We could have news any day!

I have now stocked up for the approaching party.
I have bought up cashews, a chocolate bar and I want to have some sparkling grape juice (grape juice and pop) in the wine cellar for the big celebration. I think a fine specimen of Camembert would also be in order for the occasion. Load up while you still can everyone!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Extremely exciting!

Lecanemab has been filed with the FDA!
This might be worthy of a first round of celebration.

The original filing will be under accelerated approval and they have asked for priority review.
The Clarity trial apparently has last patient visit early in September and potentially a readout as early as ~~late September/early October.

I can't wait for the FDA briefing document for Lecanemab and any new data presentation formats that they have thought up.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

These countdown timers are great!

Here is one for the primary completion date of Clarity.
Yeah, retirement!

https://www.timeanddate.com/countdown/r ... nt=cursive
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

The phase 2 crenezumab trial in PSEN1 E280E patients reported out negative. I posted earlier on thread about positive signals that crenezumab reported in earlier trials. It is hard not to see benefits to patients on the high dose with Mild AD in those trials, exactly those patients who would be expected to benefit. The patients that did not benefit were the ones not expected to benefit.

Making the executive decisions in AD trials is so difficult because there are so many twists and turns in the logic.
Assuming that Alzheimer's is Alzheimer's across genotypes and demographics is an assumption that I would not want to make: Leaping to broad assertions of generaliziability is best avoided. My strategy would be to take an initial win and then narrowly replicate the result under very similar demographics etc.. In that way non-replication in an outgroup would then be seen not so much as evidence against the rule as an exception to the rule. If I had to guess, then I would think that if the right patients could be found at the right dose, then it would be effective. Yet, at this stage in AD development, probably the right corporate call is to call it a day.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

There appears to have been a significant breakthrough in the understanding of clinical Alzheimer's. The link below
reports that combining amyloid and tau biomarkers creates a highly predictive model for AD progression.

"Over an average of 3.5 years of follow-up, people with plaques and tangles as measured by PET had a 15 to 20 times higher risk of developing mild cognitive impairment or dementia."

This is very dramatic. In the Aducan trial there was a large amount of uncertainty with many of the patients whether they even truly had AD; some of the placebo patients actually improved over the course of 18 months of "treatment".
AD clinical trials still have a large amount of noise that obscures the underlying signal. This new research might help remove much of the noise. It will be fascinating to see the next generation of research that incorporates this result. For example, it was noted earlier on thread that many of those on placebo had their amyloid levels decrease in time and even more surprising there were a surprisingly large proportion of patients who had large tau reductions. Without
such confusions the reported benefit from treatment could be quite a bit bigger.

Note however that this latest research follows closely on the logic reported in the Phase 2 Donanemab trial. In that trial when they included both amyloid and tau selection the readout moved right into focus. I will be very interested to see whether the Clarity trial might have been able to add on a tau measure. Such an addon possibly even if it were done now would greatly clarify those likely to most benefit.

This latest research also largely ends the discussion about amyloid and/or tau. It is fairly obvious that we are all baptists and tauists now. Continuing to debate the amyloid hypothesis is no longer that helpful. anti-amyloid treatment has been firmly established on the causal pathway of Alzheimer dementia now linking
reduced amyloid --> cognitive benefit.


https://www.alzforum.org/news/research- ... impairment
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by NF52 »

J11 wrote: Fri Jul 01, 2022 6:55 pm There appears to have been a significant breakthrough in the understanding of clinical Alzheimer's. The link below
reports that combining amyloid and tau biomarkers creates a highly predictive model for AD progression.

"Over an average of 3.5 years of follow-up, people with plaques and tangles as measured by PET had a 15 to 20 times higher risk of developing mild cognitive impairment or dementia."

This is very dramatic. In the Aducan trial there was a large amount of uncertainty with many of the patients whether they even truly had AD; some of the placebo patients actually improved over the course of 18 months of "treatment".
AD clinical trials still have a large amount of noise that obscures the underlying signal. This new research might help remove much of the noise. It will be fascinating to see the next generation of research that incorporates this result. For example, it was noted earlier on thread that many of those on placebo had their amyloid levels decrease in time and even more surprising there were a surprisingly large proportion of patients who had large tau reductions. Without
such confusions the reported benefit from treatment could be quite a bit bigger.

Note however that this latest research follows closely on the logic reported in the Phase 2 Donanemab trial. In that trial when they included both amyloid and tau selection the readout moved right into focus. I will be very interested to see whether the Clarity trial might have been able to add on a tau measure. Such an addon possibly even if it were done now would greatly clarify those likely to most benefit.

This latest research also largely ends the discussion about amyloid and/or tau. It is fairly obvious that we are all baptists and tauists now. Continuing to debate the amyloid hypothesis is no longer that helpful. anti-amyloid treatment has been firmly established on the causal pathway of Alzheimer dementia now linking
reduced amyloid --> cognitive benefit.

https://www.alzforum.org/news/research- ... mpairment
Thanks for posting this J11. It is great news for researchers trying to find how to identify which people are most likely on the amyloid/tau/neuropathology pathway to Alzheimer's.

And since few people might want to learn of a significant risk of MCI/AD within 4 years with no likelihood of help, it's just as important to share the good news: The newest generation of anti-amyloid therapies--developed after aducanumab--appear to show significant ability to be safe and effective in clearing amyloid, reducing tau spread and preserving cognition. Both donanemab, which first showed this from their AHEAD studies and lecanemab (AHEAD studies) are now measuring tau in blood plasma (which occurs much earlier than in the brain so an earlier intervention point) and in PET scans. Here's some good news from last summer; I expect we'll hear more about these groups this month at the 2022 AAIC conference and the November CTAD conference:
At the July 2021 AAIC, the company showed additional data from TRAILBLAZER-ALZ. Donanemab led to rapid amyloid reduction in the first six months of treatment, which was sustained to the end of the trial. Participants who cleared amyloid below a brain-wide threshold, and were switched to placebo, did not reaccumulate amyloid after one year. People with amyloid clearance also showed a reduction in tau burden in the temporal, parietal, and frontal lobes, and a significant decline in the biomarker plasma ptau217. At end of the trial, ptau217 concentrations fell by 24 percent in the treated group, while rising 6 percent in placebo (see Aug 2021 conference news).
https://www.alzforum.org/therapeutics/donanemab

Demonstrating an intervention for the amyloid/tau pathway is important, possibly especially so for ApoE4 carriers, who have a high likelihood of early amyloid formation. It would still leaves lots of need for continued research into synapse support, vascular disease, and early lifestyle prevention and intervention for high blood pressure, coronary artery or cerebral vascular disease, metabolic causes (T2D, obesity, high LDL cholesterol), neuroflammation (infection, auto-immune issues),toxins (mold, heavy metals, air, water or soil pullution), mental health issues, and systemic lack of societal supports. It also leaves people who develop mixed dementias (common after age 80) and other dementias (Lewy Body, FTD, PSP etc.) still vulnerable.

As someone who has been in clinical trials, the "informed disclosure" of an imminent risk better be done with sensitivity! People who join trials know they have a 50% of being the placebo person who has to prove the benefit. Doesn't mean they can't do everything others do on this forum to stay healthy; they're also agreeing to put theories to the test for 4 years or so.
4/4 and still an optimist!
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Re: 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.

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NF52, thank you for responding.

This duo amyloid and tau story has been emerging for quite some time. As you noted the Donanemab phase 2 greatly brought the potential of A+ T+ into focus. The problem with science stories is that there is often not an easy to find nice crisp date when a new idea has firmly been established; often it is more of an accretion process.

The research, though, undermines the coverage decision of the CMS. The CMS reported its final anti-amyloid coverage decision on April 7th, 2022. On May 24th, 2022 the article containing the above figures showing the importance of the amyloid and tau combination in AD was posted to medariv. The CMS' final decision was sooo scientifically weak. This was obvious throughout their consultation process. The final decision maintained credibility for barely a month? Now, their decision can no longer be reasonably considered as scientifically valid. In fact as mentioned above, tau + amyloid had been in the AD literature for quite some time even before their decision (i.e., at least from the Dona phase 2 release). As suggested previously, it would have been strategically wiser to have limited their final decision to Aducanumab. This would have allowed for new research to be open for a new analysis for the rest of the class and isolate the ruling to Aducan.

My interpretation of the pre-clinical potential of treatment is quite optimistic. It now feels to me that we have already crossed over the bridge to where more early knowledge of impending clinical decline will help lead the clinical treatment infrastructure to advance therapies quicker through the system. There are all of these anti-amyloid mabs (Lecanemab, Gantenerumab, Donanemab) that are within the short term window for readouts. These are powerful anti-amyloid treatments. Patients are told they have impending onset of AD clinical decline --> concerned patients ---> .... yet ... we have this anti-amyloid that could help. Bingo! The alternative of --> well let's wait until you progress into moderate AD ... yeah no thanks.

In fact, more knowledge has constantly helped the AD community advance their agenda. I remember a number of years ago how difficult and expensive it was to receive an APOE epsilon 4 genotyping. There was debate at the time whether it should even ethically be provided to people. Yet, over the years it has become standard and is even included on the 23 and me and other genotyping arrays. The widespread knowledge of epsilon 4 genotype in the community has had a large influence on the development of a sociopolitical movement to address AD. It is always interesting to see what a few million committed people (here e44 especially) can achieve. Also consider this forum namely the APOE4 forum. We have had a fair number of crisis type arrivals on forum after posters received surprising news of a epsilon 44 genotype. This knowledge has clearly helped to more rapidly move treatments through the clinical trial process. The 21st Century has brought us into the unusual era in which a substantial percentage of the population have become dedicated health advocates for themselves, their loved ones and sometimes the broader the community.

The new knowledge about impending AD clinical decline will almost certainly be another win for us. In our experience, clinical AD drifted for years and years. Without an effective treatment there did not seem to be that much of a rush to confirm a diagnosis that was already obvious to us given our extensive family history. My impression is that we are now very close to a turning point in the well-being of our communities. Until now we have had substantial numbers of people with varying levels of cognitive impairment who have caused considerable unrecognized harms to the general welfare. In my particular family instance, it now seems clear that we developed with some level of parental cognitive impairment through most of our adolescence. Navigating through these years as a parent requires high level cognitive ability; without such ability very negative results can result. I am so happy to realize that we are now on the threshold where such childhood experiences will no longer occur. Teenagers without parents with cognitive impairment from AD will be such a positive.

What I am also very positive about is that the yard sticks now seem to have moved to 4 years before clinical onset. That is startling! If treatment were to begin at such an early time point, then progression into even a minimal level of dementia might be entirely prevented. My End of Alzheimer's thread might have called it right: We might soon see the rapid disappearance of those progressing into and forward into AD. If you can firmly stop the AD conveyor belt at the starting point of dementia and also stop progression all the way along on the line into severe dementia, then dementia essentially stops!

When patients are given the knowledge of impending AD progression it is not that difficult to imagine what they might choose to do even if conclusive clinical trial evidence were not in support of early treatment. In fact, further, amyloid is present for decades before clinical advance, it is also not that difficult to imagine that many pre-patients might be interested in amyloid removal as a precaution.


One thing that I am not overly clear about is whether Clarity has actually screened for tau. I have been somewhat lazy about this and have not carefully checked on this, though when I perused clinical trials gov there did not appear to be a tau PET inclusion criteria. It would clearly be very disappointing if duo amyloid and tau selection were not used in the Clarity trial. With both as selectors there is a dramatic enhancement in selecting the correct patients. As shown in the figure above, selecting patients with amyloid + and tau + had ~40 times selection over only amyloid alone. If tau had not been included up till this point then perhaps even now tau could be added in. The figures show that those who were only amyloid positive did not convert to MCI/AD over a period of years. So the strategy could be to PET tau them and retrospectively find those without tau and then exclude them from the primary analysis. That could be a fairly good workaround if needed.


Regarding the broader pathophysiology of AD, perhaps the best approach might be to simply limit amyloid/tau has the primary drivers of pathology in AD. These are the specific features of core AD. Other aspects such as neuroinflammation etc. could be thought of more as generic aspects of neurodegenerative diseases. With this strategy you might be able to have more of a pan-dementia style clinical trial that would capture the disease process in a range of related and mixed dementias.

With respect to placebo, we might now be moving somewhat beyond clinical trials with pure placebos. The standard of care might now rapidly move to a multi-drug regimen that targets amyloid and tau processes. What is especially exciting about this is that we might now be near an era in which disease reversal becomes viable.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Recently, Eisai announced that they would not pursue a maximal price strategy for Lecanemab. This clearly is a very wise approach. An effective Alzheimer treatment clearly will have enormous financial implications for payors such as Medicaid and insurance companies. Ignoring such truth is not helpful. As we have seen payors have resisted the possibility of their plans moving towards bankruptcy by denying coverage, using political tactics etc.. Admittedly, this thread has at times embraced the somewhat manical tone of a near infinite money drop. At that time it was more in the spirit of encouraging the capitalist system to recognize the enormous payday that was presented to them.

Alzheimer's in this respect in very fortunate: so many other illnesses have no payday to offer. There is no excitement of unlimited markets with massive payouts. In fact, oftentimes the potential payback in developing a treatment for an orphan illness is so minimal that special incentives must be provided to biotechs to move ahead. When they do proceed they are then often heaving criticized for charging what seems to be exorbitant prices.

What we have seen with aducan is that the actual willingness to pay out of pocket for an anti-amyloid mab is minimal.
I find this somewhat surprising. Aducan can only generate ~ $2 million per year in revenue when people have to reach into their own pockets??? The trial found that with only amyloid selection (and not tau coselection) earlish stage AD patients have ~1/3-1/2 chance of becoming long-term non-progressors. That is not worth more than $2 million in revenue? It is surprising.

Lecanemab is being advanced under the logic of respecting the financial integrity of the payors. They are signaling that there will not be an unlimited AD liability. My guess is that there is a tacit agreement that has been arrived at that there is ceiling of ~$30 billion per year in revenue available. Anything over the ceiling would simply trigger price reductions. This approach will ultimately benefit everyone: patients, pharma and payors.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I wondered about the ADCOMM; Will lecanemab have an ADCOMM? From what I understand now no; no ADCOMM.
That is actually fairly strange. We have argued on this thread for 2 years about the results for Aducan: Whether it was effective? Whether it was safe? Whether it should have been approved? Whether the ADCOMM made the right call?

And now nothing? No Contest!?

The FDA gave Lecanemab breakthrough status based upon the surrogate biomarker of beta amyloid
( CDR = f(beta amyloid) ~= a + b* (beta amyloid)) ... then recently it gave Lecanemab priority review (This means that it will only take 6 months to decide and not 10 months) ... Then it decides an ADCOMM is not even needed!?
They don't even want to argue about the surrogate biomarker? After all of this empty debate, at the end of the day they have completely capitulated? Basically, keep arguing and then when you're not interested anymore stop and completely fold?

Lecanemab is a highly similar mab to Aducanumab. I do wonder whether maybe there should be an ADCOMM afterall.
ADCOMM do not always have to be as dramatic as the Aducan meeting. Lecanemab appears to have a clean ride to its accelerated approval. However, it might be of value to go through with the ADCOMM so that it is clear to all what is now thought to have changed to allow Lecanemab essentially an uncontested approval. It would seem a great opportunity to add transparency to the process.
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