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

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

Post by Julie G »

Julie G, aducanumab was discovered through Reverse Translational Medicine™. Anti-amyloid antibodies from those people who did not develop AD were screened and aducanumab was found to be the most potent antibody studied. In effect, it was known from the start that aducanumab was safe and effective because it was safe and effective in the healthy cognitive agers studied.
From what I understand, anti-amyloid antibodies were found in the brains of heathy elderly with slowly progressing dementia. It is an enormous leap in logic to suggest that aducanumab can do the same and therefore clinical trials are unnecessary. Humans are very complex organisms. What other protective systems (insulin sensitivity, low inflammation, appropriate trophic support, etc.) were in place for this subset? Is a combination of factors necessary to stave off dementia? And, are there healthy elderly who don't develop amyloid or dementia? What are the protective factors for that subset? I still think we have much to uncover.

The aducanumab story is fascinating. I agree that it has been shown to effectively bind to brain amyloid, but whether it will truly slow progression of cognitive decline (at a level commensurate with it's risk and costs) is the unanswered question that I hope is resolved in the Phase 4 study.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I have a lot of familiarity with this drug and I have physically manufactured it in the lab with my own hands (along with several other anti-Abeta antibodies). I've read dozens of the research papers on this antibody. I think this is a horrible precedence by the FDA, because they've approved it not based on cognitive efficacy (the only thing that really matters), but instead based on an biomarker endpoint (amyloid beta - a controversial hypothesis). This drug was resoundingly disapproved by the advisory committee. 10 of 11 experts in the panel voted to not approve, and the 11th was "uncertain". Did Biogen or some other entity "buy" this FDA approval? It sure seems that way to me. 2 of the advisory committee members just quit because they saw this approval as a sign that the FDA "foreordained" the approval regardless of the science or advice.

https://www.biospace.com/article/2-fda- ... -approval/

Also, $56,000 a year for a drug with no proven efficacy? Those are healthcare dollars that could be spent instead on actual life saving treatments. I really hope sales are zero for this thing.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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broiler_x wrote:I have a lot of familiarity with this drug and I have physically manufactured it in the lab with my own hands (along with several other anti-Abeta antibodies). I've read dozens of the research papers on this antibody. I think this is a horrible precedence by the FDA, because they've approved it not based on cognitive efficacy (the only thing that really matters), but instead based on an biomarker endpoint (amyloid beta - a controversial hypothesis). This drug was resoundingly disapproved by the advisory committee. 10 of 11 experts in the panel voted to not approve, and the 11th was "uncertain". Did Biogen or some other entity "buy" this FDA approval? It sure seems that way to me. 2 of the advisory committee members just quit because they saw this approval as a sign that the FDA "foreordained" the approval regardless of the science or advice.

https://www.biospace.com/article/2-fda- ... -approval/

Also, $56,000 a year for a drug with no proven efficacy? Those are healthcare dollars that could be spent instead on actual life saving treatments. I really hope sales are zero for this thing.
Update to the biospace.com article : Third member of advisory committee quits over aducanumab approval

https://www.cnbc.com/2021/06/10/third-m ... -drug.html

Maybe the celebration thread isn’t the best place to be posting this :o
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Alzheimer's is changing

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There's lots and lots of scribbling to catch up with. I thought that after approval my logophilia might abate somewhat; probably the opposite.

At the top of the list of ideas that I want to expres is that with approval Alzheimer's disease is even now in a dramatic process of redefinition. If we were to time port ten years forward, most diseases will remain recognizably similar to what they are right now; the presentation of pathology (while probably not treatment etc.) will not be far different for most maladies than from what it is today. This could be true for mostly everything except Alzheimer's. What we can call Alzheimer's (2021) or Alzheimer's 1.0 will probably be very different from Alzheimer's (2031).

Such a radical change in the typical clinical presentation will arise from the very fact that patients will seek early (probably very early treatment). [In our instance, we reached 20 MMSE before even bothering much with treatment options; actually there weren't any with disease modifying effect. Soon after we hit 18 and the legal loss of mental competence of our loved one and from then on anytime we wanted a roll of toilet paper we had to send in a form to our financial advisor.] What we should expect in the future is that AD patients will first present at the clinic with MMSE's of ~30. In the aducan phase 3 trials patients were recruited with MMSE's down to 24 with massive amyloid burdens that required near emergency dosing to quickly reduce such burdens in order for the anti-amyloid to have a chance at effectiveness.

Over the next year or two all of those people with mild cognitive impairment with the means could receive aducan treatment. The great urgency to receive treatment and the weighing of risks of aggressive amyloid against the risks of imminent neurodegenerative would then fade somewhat into the background as patients would not be placed in such a desperate circumstance. The reason there
now appears to be such a rush for treatment is exactly because patients until now have only been able to watch while cognitive impairment progressively intensified without any meaningful treatment option. Once this rush stage is over, patients will have the opportunity to be much more relaxed about treatment which might be years and years away from being critically necessary. My idea of induction dosing also seems possible. Why not pre-dose before the time of disease onset so that when needed high dose treatment can be started with minimal ARIA risk. The FDA Briefing Document clearly shows that this is possible. Once the induction phase of dosing was completed, the level of ARIA approached 0% even while the patients received multiple high doses.

Of course, if some sort of social arrangement to supply aducan at population scale (which does seem highly feasible financially) might be reached {possibly in the 2022 political cycle} then Alzheimer's (2023) or Alzheimer's 2.0 might be postponed to more like Alzheimer's (2025). Yet, Alzheimer's 2.0 would clearly be a very different sort of illness. For most, amyloid could be largely cleared early on in the pre-AD stage.

Pushing the treatment window back ~5 years from onset and using a titration phase that extended over a year or two would mean side effects likely would be minimal. Considering the known neurodegeneration that occurs even in this "asymptomatic" stage such earlier dosing would also offer the potential of greater efficacy.

This background on how Alzheimer's will evolve over the short-medium term presumably will have importance in shaping how any phase IV trials are conducted. Making the assumption that all that needs to be done is to somehow replicated the phase 3s would seem to be misguided. Alzheimer's 2.0 will mostly be a non-amyloid illness; aducan will have removed all of the pathological amyloid load. Enrolling those with MMSE 24 no longer might be seen as reflective of the AD patient population. This could pose problems as it is these very mild AD patients who demonstrated the strongest benefit. It could be much more difficult to prove benefit in a trial limited to MCI patients.

Beginning 2-3 years in the future the safety and efficacy of aducan should become much more apparent as the most desperate patients with the latest stages of illness move through the clinical treatment process.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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ARIA 4- Edit 2.gif
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Last edited by J11 on Thu Jun 10, 2021 9:02 pm, edited 1 time in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

I thought it was worthwhile to highlight how dramatically lower the risk for ARIA can be once the initial stage of early dosing has been completed. The figure above from the FDA Briefing Document shows exactly that. I removed some of the information to help focus attention on how potentially small the risk of ARIA might be. At week x, ARIA is reported as 18.1%. 16 weeks later after 4 * 10 mg/kg doses it is 19.7%. 1.6% of the patients experienced ARIA after receiving these 4 marginal doses. At week x +32 21.0% of patients had experienced ARIA this is a 1.3% increase from 16 weeks before during which an additional 4 10 mg/kg doses were received. Finally at week x+48 with another 4 10 mg/kg, a marginal .4% experienced ARIA. Patients would have received 12 * 10 mg/kg of dosing and much of the amyloid lowering would have occurred during this time and yet almost magically only 3.3% of patients actually experienced ARIA.

The impression that high levels of ARIA are somehow an inherent feature of aducan treatment is misguided. High dosing of aducan is consistent with surprisingly low ARIA rates even with a large amount of amyloid removal. As noted above, there was only 3.3% ARIA rate over that 48 week interval. The one cheat here is that this is for APOE -s. Nonetheless, the lower initial amyloid burden in these negatives illustrates what might be possible with a greater emphasis on a prolonged titration phase. For the negatives, it might not even take that much of an extension to reduce risk as there would seem not be as much excess amyloid as there is with APOE +s.
Last edited by J11 on Thu Jun 10, 2021 9:12 pm, edited 2 times in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by broiler_x »

floramaria wrote:
Update to the biospace.com article : Third member of advisory committee quits over aducanumab approval

https://www.cnbc.com/2021/06/10/third-m ... -drug.html

Maybe the celebration thread isn’t the best place to be posting this :o
Wow, thanks. I really hope I'm wrong, but this just looks like a pharma company trying to extract any profit that they can from multiple, expensive failed drug trials. And also preying on desperate patients, and additionally putting a burden on health care costs. This is all very suspect. I'm glad these people left the committee, good for them.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by broiler_x »

"Dr. Aaron Kesselheim, a professor of medicine at Harvard Medical School, said the agency’s decision on Biogen “was probably the worst drug approval decision in recent U.S. history,” according to his resignation letter obtained by CNBC."

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

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ARIA 4- Edit 3.gif
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

I want to emphasize how large this induction effect is on ARIA risk. As seen in the edited version of the figure, the initial 40 mg/kg caused 18.1% of the ARIA, while the next 120 mg/kg of aducan dosing caused 3.3% ARIA. Three times more dose and six times less ARIA? That seems like a good deal.

This demonstrates that the dosing schedule that was required for an 18 month clinical trial probably does not minimize ARIA risk. ARIA risk quite likely could be greatly reduced by simply expanding out the initial titration phase. Hopefully, patients will be given the flexibility to choose the dosing that they feel comfortable with. If given this option, then they could be more directly involved in shaping the risk profile of their treatment. Gaining better insight into how the titration phase can be adjusted to reduce ARIA risk would seem to me to be a research priority for aducan.
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