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

[J11]

Fc1345linville, thank you for your comment.

I especially appreciate your posting of the article that I recited above concerning the longer term benefit of aducan.
It is very unclear to me how if there were to be a negative decision on June 7 it could possibly be seen as definitive given the claims made in the article. A majority of patients treated with high dose aducan were ~stable for a long time is somewhat beyond what I had expected could be possible (even though this was the result reported for the long term extension of 103).

Everything possible seems to have been done to make the decision into a passion play and not a thoughtful analysis of the data set. In fact, the aducan dataset that has accumulated for years and years after the phase 3 has largely been hidden from view. What possible justification can there be for not reporting this data given it is of pivotal importance to the approval process? If we did not have such an advantage here, perhaps we would not even want to know the truth. Yet, the evidence is in our favor. Full public disclosure!

{The old fallback chestnut, oh it's a placebo effect really doesn't hold much water for me. We tried the green goo (whatever it was), it looked terrible it tasted terrible, if there was going to be a placebo effect the green goo should have been off the chart; nothing. Have they ever even shown a placebo effect in Alzheimer's? Or is this just an assumption? With cognitive impairment issues you really wonder if placebo effects could even manifest. Don't you need a certain level of cognitive functioning for a placebo effect.}

[J11]

floramaria, thank you for presenting a view from the nays. There are some highly qualified professionals who do not consider that the positives outweigh the negatives with aducan. The adcomm opinion from November was especially negative. One of the comments in the NYT article noted that a transcript from the adcomm is posted on FDA.gov. Anyone know the exact url? The idea that modern democracy can be reduced merely to the parliamentary antics of yeas and nays is absurd. The internet gives us the potential for a richer form of engagement. If you believe aducan isn't effective, fine -- win the argument on its merits on a blog or a transcript. The widespread engagement in the aducan approval discussion is an encouraging sign that the public can be a constructive part of the process.

How could the adcomm not even call the Emerge as a positive trial when it achieved a 1% result on the primary topline?
"1 yes, 8 no, and 2 uncertain on the question, “Does Study 302 (EMERGE), viewed independently and without regard for Study 301 (ENGAGE), provide strong evidence that supports the effectiveness of aducanumab for the treatment of Alzheimer’s disease?”
That was the Emerge result without any data massage. How can you argue against a clean read-out from the top-line?
The results that we then saw with the dona phase 2 replicated almost exactly the aducan results. Now tau selection is on the table and Alzheimer's trials could report statistically significant results in months in small selected samples.

[J11]

This url has all the info from the adcomm meeting for aducan.

https://www.fda.gov/advisory-committees ... ee-meeting

[Fc1345linville]

floramaria,
I too read the NYTimes oped by Drs. Greicius and Alexander, and not having seen your own post, I duplicated it a separate post. Sorry to others for any confusion.
Coincidentally, I have been a volunteer subject in a AD study at Stanford since 2016, for which Dr. Greicius was the creator and Director until about two years ago. I have had several good conversations with him about their work and was very impressed. I personally think his and Dr. Alexander's well supported arguments against a June release should be addressed, even if it means delaying the decision.

FC

[floramaria]

floramaria,
I too read the NYTimes oped by Drs. Greicius and Alexander, and not having seen your own post, I duplicated it a separate post. Sorry to others for any confusion.
Coincidentally, I have been a volunteer subject in a AD study at Stanford since 2016, for which Dr. Greicius was the creator and Director until about two years ago. I have had several good conversations with him about their work and was very impressed. I personally think his and Dr. Alexander's well supported arguments against a June release should be addressed, even if it means delaying the decision.

FC

Hi, FC, remarkable that you know and have interacted with one of the authors directly. That is quite a coincidence! Before this article, I hadn’t read much about the arguments against aducanumab approval, other than the side effects. So I appreciate getting broader insight into what drives the opposition.

[NF52]

floramaria,
...Coincidentally, I have been a volunteer subject in a AD study at Stanford since 2016, for which Dr. Greicius was the creator and Director until about two years ago. I have had several good conversations with him about their work and was very impressed. I personally think his and Dr. Alexander's well supported arguments against a June release should be addressed, even if it means delaying the decision.

FC

Hi, FC, remarkable that you know and have interacted with one of the authors directly. That is quite a coincidence! Before this article, I hadn’t read much about the arguments against aducanumab approval, other than the side effects. So I appreciate getting broader insight into what drives the opposition.

Below is a link to an opinion essay published May 30 in STAT news, (a Boston Globe Media publication) by Dr. Jason Karlawish. Dr. Karlawish has 18 years of experience in both direct patient care and in running clinical AD research trials as director of the University of Pennsylvania Neurodegenerative Disease Ethics and Policy Program, co-director of the Penn Memory Center, director of the Healthy Brain Research Center at Penn and a board-certified geriatrician. I've read Dr. Karlawish's recent book--a sensitive look at the stigma and family needs associated with an Alzheimer's diagnosis--and I've talked with someone who was his patient. His opinion is one that bears consideration--even from those desperate for approval.

If the FDA approves Biogen’s Alzheimer’s treatment, I won’t prescribe it

One of its risks is small bleeds in the brain, a risk that is heightened in those with the APOE4 gene, a gene associated with late-onset Alzheimer’s disease. Families will be drawn into these risk-benefit discussions, because treating a parent’s Alzheimer’s with aducanumab may well mean their children will learn their genetic risk of developing the disease. I have little doubt that these at-risk individuals will push the margins of when to begin prescribing aducanumab...
Skipping a key phase of research and performing a futility analysis weren’t scientific decisions; they were business decisions about the pace of research to discover an effective Alzheimer’s treatment and how much a company will spend to sustain that pace... It hasn’t been properly studied, and so the FDA has incomplete data to form a judgment. The cause of this is a series of decisions that were good for business but bad for science and patient care.

[floramaria]

If the FDA approves Biogen’s Alzheimer’s treatment, I won’t prescribe it

.....
The cause of this is a series of decisions that were good for business but bad for science and patient care.

Oh my! Harsh words and another strong “nay” vote. The FDA decision is coming soon. I am curious to see what they decide and what arguments they use to support that decision.

[J11]

Amyloid.GIF

[NF52]

Amyloid.GIF

I’ve seen this chart, along with the suggestion that the crucial window for anti-amyloid therapy is before tau aggregation accelerated and before any cognitive impairment has occurred.
I wonder if current and future drug trials of BAN2401 and ALZ-801 designed for this “window” will be able to reduce ARIA-E and show biomarker evidence alone to gain approval with “progression-free-survival” in the study group even if it’s not hugely different than placebo at this earlier stage.

Have to recruit lots of ApoE4s who will have to learn what this chart means for their risk curve.

[J11]

We are moving towards the decision and I want to make some last minute posts. What I have realized is that some fairly important issues have largely been overlooked here and in most of the other commentary that I have read online about aducan. You always think that someone else will mention it and yet here we are and some quite important issues have remained highly obscure.

Probably at the top of this list is off-label dosing. This truly is a mystery to me: How could this not have been so overlooked? When you read back introductions on this forum it is not unusual for a poster to speak of the mental health crisis that they experienced upon learning that they were APOE 44 and how they had found this forum after a frantic internet dive into APOE and Alzheimer's. It is not that unheard of for posters who had no known family history of Alzheimer's to wake up to their diagnosis. The leaders on the forum typically reassure these posters by relating how they too responded with desperation, though with time it gets better.

{I read one account where a poster was screened for APOE, though the clinical significance of the 44 genotype was never made known to them. How could that possibly make sense? They did not even appear to provide informed consent to being APOE genotyped. If you test for it, then this creates some obligation of disclosure within the rights of people not to know. It is surprising that a more sensitive (and ethical) approach to APOE genotyping has not developed.}

There are ~10 million 44s in America! 10 million often desperate 44s. aducan approval will obviously be a red flag moment for them.
A near instant black market in aducan microdoses is not some far-fetched speculation. aducan would give people at very high risk of AD a pro-active and quite plausible strategy for managing their risk. Microdosing would actually seem to make much more sense approach than maximally reducing amyloid just on the edge of symptomatic decline. Where was the political voice of all of these millions of 44s?

Why was this not a more prominent aspect of the approval process? Basically, June 7 approval-- 10 million 44s seeking a black market source of aducan. That would not be entirely unreasonable either. Micro-dosing on aducan and paying ~$1,000 per year out of pocket would not be a clearly bad strategy. Given available evidence it realistically could be described as the optimal current strategy. However, the onlabel dose of 10 mg/kg for many (who might be decades from symptoms) would not be sensible.

Nevertheless this issue has not been entirely overlooked. In fact this was the first question asked at the adcomm meeting.
(I have read through the adcomm meeting and there are some interesting comments that can be made about it. Notably the voting that was reported needs to be understood within the context of the specifications given by the members of the advisory committee.)

On page 56, the first adcomm question directly relates to the question of aducan treatment for 44 asymptomatic patients.
https://www.fda.gov/media/145691/download

Part 1 of the question asks about the need for amyloid screening for aducan treatment. Biogen's position is that amyloid positivity should be required for treatment. In the context of 44 genotype one wonders whether that is even necessary. Amyloid positivity in 44s is almost a given. Perhaps a simple retinal scan could suffice.

Part 2 of the question asks about treatment in asymptomatic 44s. I am having some comprehension problems here because the phase 3s did not have a strong requirement for cognitive impairment: the inclusion criteria allowed an MMSE score of 30, so it does make the "cognitive impairment" issue somewhat contradictory to me. A new form of AD appears to have emerged in which people with minimal cognitive dysfunction are diagnosed with early "AD"/MCI. This is the direction that treatment clearly is heading, though it makes establishing a benefit of anti-amyloids more difficult. The MCI stage AD patients had CDR-sb gains of ~0.15, while the early AD patients had gains upwards of gains of ~1. The reason why the top line primary was not even more impressive was there was a 80:20 weighting of MCI: Mild.

Biogen's answer to the asymptomatic question was that there is no evidence supporting such treatment at this time.
They went on to clarify that there is evidence of benefit in both epsilon 4 carriers and non-carriers. I am not sure whether this was actually shown in the Briefing document about the non-carriers. Given the research there probably is a subgroup of non-carriers that benefit, though the overall non-carrier result was smallish. It would have been a great opportunity to press on the question of benefit in 44s from the phase 3s. The 4s did better than the non-4s in the trials; it should be expected that the 44s would do better than the single 4s. Many on forum would be highly interested to have the question of genotype specific response clarified. The obvious question of off-label black market dosing is entirely disregarded. It is not realistic to think that millions of 44s will not recognize the potential significance of an FDA marketed anti-amyloid. This aspect of the aducan regulatory process (as well as that of other anti-amyloids in the clinical trial process) should have been/should be addressed.

None of the trials not even the A3- A45 trial have micro-dosed; dosing was in the 1 mg/kg -10 mg/kg range. The mouse studies found that you could dose well below any side effects and still achieve amyloid clearance. What is very frustrating for me is that this research does not appear to have been done. It is fairly obvious that those people who know of their 44 status will be highly motivated to do something proactive about their risk. Yet, the clinical trial process did not in any way consider harm reduction strategies. We can only even guess at the correct dosing and what effect this might have on amyloid.

The problem that has obstructed such innovation is the fixation on medical evidence. How could micro-dosing be justified based on cognitive evidence? It really couldn't -- given patent laws this evidence might never be collected. Regulatory innovation could help bridge this barrier. Anti-amyloids could perhaps be approved as lifestyle medicines. Some people as a lifestyle choice might choose not to have a known neurotoxin lurking in their brains for decades before dementing illness arose. In this lifestyle category, all that would be needed is to provide evidence that amyloid was reduced and the treatment was safe. This would be a low hurdle. given that aducan was reverse engineered from those who themselves were nano-dosed and did not develop AD it would not be overly surprising that microdosing would be effective in preventing AD.

Comments from the 44s on forum?
Forum Survey: Given the chance to microdose on aducan at ~$1,000 and being 10+ years pre-symptom on-set and with likely minimal potential of side-effects, would you microdose?

The Biogen slide above from the aducan adcomm shows the stylized progression of AD pathology. I am somewhat unclear why the phase 3 area in the slide only includes MCI. The phase 3 trials also included mild AD which could possibly move the phase 3 patient population to the right of the red vertical line that I added to the figure. What is especially notable in this figure (stylized or not) is that amyloid accumulation has achieved essentially a maximal saturation. One could already look at this figure somewhat in disbelief, are they really waiting to treat the amyloid once the brain has almost reached total amyloid saturation? This isn't even Neuroscience 101; more like Neuroscience for non-neuroscientists (or even neuroscience for people really uninterested in neuroscience).

The brain can compensate for even substantial insults (and for decades before symptomatic onset, it does), though the stress placed on the brain with all of the neurodegeneration shown eventually leads to the complete systematic collapse of mental processing. When I look at that figure my impression is that profound Alzheimer's dementia should be easily preventable by simply ensuring that the top fraction of brain functioning is preserved. The later stages into profound dementia create extreme caregiving challenges. Greater emphasis should have been placed on this phase of dementia. The existing Biogen long term extension data would provide considerable light on the later stages. If this data set did show such benefits for aducan, then aducan should be approved on that basis alone.