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.

Postby J11 » Mon Oct 04, 2021 6:36 pm

Sorry, everyone for the extended off-topic comments about PTSD; it has just been quite a big shock for me over the last few months that this had gone unrecognized for so long --- basically forever. No one in my family (or anyone in my community for that matter) had ever guessed that PTSD was driving the problem behavior we had encountered chronically. For me the genetics diagnosis largely is a cure. Knowing what the problem is can sometimes be that helpful. Perhaps for other family members it will take some more time.

When I look at the Merck Manual's chapter on Psychiatric Disorders almost all of the categories seem to apply to us at some level. There is a daliesque morphing of reality that can occur with mental health problems; if you have one, then you can have them all. From my current vantage point, I have none of them. With my realization of the presence of PTSD, I feel that I can turn the page on all these problems. Bye bye obsessive-compulsive, bye bye Munchausen's; bye bye cults ... . It's going to be quite dull without all of you. With AD largely fading, moving on to other unfinished business such as PTSD is almost too easy. Until now we have been so preoccupied with AD, that these other problems that were further down the list were never addressed. They can now all be put into the outbox.

My main motivation for posting this to the thread was in the hope that it would be helpful for others. Knowing this right from the start of life would have made things so much easier for me (and I hope for others on their way up). From my recollection I had pretty much always known (subjectively anyways) that something like PTSD was in play, though it has been a long struggle against others (including my parents etc.) to try and convince them the environment that they were providing did not fit me. For me it has not been so much about a triumph of overturning the system, but instead largely aging through it. It seems so tragic that nominal compliance could be seen as some sort of victory. What happens when compliance can no longer be enforced? Almost anything else would be an improvement.

I greatly hope that my experience can help to motivate change. I'll say it: it's wrong to do this to children. It is simply an attack on children. It is an act of genocide and is recognized as such under international law. Those who stand by are complicit in the crime. It is no great leap of imagination to realize the significant social harm must be done with the current model. It clearly would not be surprising to me to learn that this PTSD feature is deeply involved as a precipitating factor in acts of violence; it would be hard to imagine that this would not occur. The actual risk at the individual level is probably reasonably small, though when seen at a higher level it would not be that surprising if PTSD were a contributor. Locking people into environments that they do not want to belong to and then waiting until they cause social disruption can then be seen as especially counter-productive. The simple workaround of virtualizing has already emerged during the COVID pandemic and apparently is being made a permanent option for those with different needs.

Creating the momentum for needed social change on this issue does not strike me as a high hurdle to leap over. There are very few (if any) vested interests that would rejoice in making life worse for everyone. PTSD behavior simply causes an endless tearing of the social fabric without anyone being better off. A range of potential strategies seem available; boycotting institutions that exhibited no interest in complying with criminal law would be a good place to start.
Last edited by J11 on Mon Oct 04, 2021 9:56 pm, edited 3 times in total.

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

Postby J11 » Mon Oct 04, 2021 8:07 pm

Time to get back to AD! Great thing is that when you really know what AD is like, everything else is pretty much a zero. It is great being able to frame life in this way.

This could be a fairly long wait for the leca adcomm. There is not that much out there to talk about related to the submission; I thought perhaps things might need to go silent for a while -- but no! There is the phase 2 leca clinical trial that was published not so long ago.
https://pubmed.ncbi.nlm.nih.gov/33865446/

With all of this time we can read through this very carefully. Typically, there is a tendency to sort of skim through readings and then often miss out on some quite important points of interest. For example, here even in the abstract there is the clarification that the primary miss for leca (the 64% instead of 80% probability of being better than placebo by 25%) was for the 12 month readout.
The 12 month read-out? What 12 month readout? Isn't the readout meant for 18 months? Apparently not! Goal posts have been moved! Success is now defined as an 80% probability of being 25% better than placebo at the 12 month mark? 64% missed the success. Hmm, what was the probability of being 25% better than placebo at the 18 month mark? Well I had to read through for that one. It was only 76%! Another miss ... by 4%. To be clear this was Ed90 dose (i.e., the highest dose of 10mg/kg biweekly). Oh, I almost forgot the probability of straight superiority to placebo at 12 months was 97.6% (n=143)-- and as we have seen the leca phase 2 has a very high correlation to a linear regression line.

It should not be overlooked that due to the regulatory intervention to prevent APOE's from continuing to enrol in the highest dose that there was a weighting to the APOE non-4s in this highest dose: split was 107 non-e4, to 45 e4 as seen in Supplementary Table S16 which for whatever reason is not equal to the Table 2 finding of 143. Of further note is that the non e4s on the highest dose did not demonstrate much benefit. They showed a 0.011 benefit on benefit on ADCOMS (n=107) versus the baseline placebo of 0.146 (n= 70) with a 63% probability of numerical superiority to placebo and a 29% of clinical superiority (i.e., 25% difference) to placebo.

It is the APOE e4s that really carry the load in the dose result. They show a massive 0.084 benefit on ADCOMS (n=45) versus the placebo (n=168) baseline of 0.180 with a 99.2% probability of numerical superiority to placebo and 93.6 % probability of clinically significant benefit versus placebo. This isn't going to even be close in the phase 3. The highest dose used in the phase 2 was the dose chosen for the phase trial. Yet, even the second highest dose of 10 mg/kg monthly in the phase 2 in particular the APOE e4s also showed strong results for the probabilities (95.5% numerical,67.9% clinically significant with (n=218) for treatment and (n=168) for placebo).

The supplementary appendix runs through various similar results for ADCOMS / CDR-sb / ADAS-cog 14 for Bayesian and MMRM at 12 and 18 months. The ADAS-cog 14 Bayesian result in Table S8 appears to be especially strong. I am not entirely clear why the results do not appear much improved at the 18 month versus the 12 month mark.

There should be ~ 1200 patients who have been in the phase 3 now for at least 12 months. Table S4 notes that the 10 mg/kg biweekly dose with n=152 showed a p-value of 2.7% on ADCOMS versus the placebo (n=238) at 12 months. It would then be highly instructive if the rolling submission were to include an interim glimpse of how the 1200 patients might be doing. Prespecifying APOE e4 might be all the more instructive (remember that only 45 e4s were needed to establish 99.2% probability of numerical superiority). If such analysis were to be included in the FDA Briefing Document, then that would remove most of my enthusiasm from posting to the thread. At some time in the not too distant future questioning the efficacy of anti-amyloids (especially lecanemab) might no longer be felt productive. This is not even going to be close.

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

Postby J11 » Mon Oct 04, 2021 8:32 pm

One of the few complex aspects of the leca trial was the definition of "simplest".

“Simplest” means the earliest in the order of convenience (5 mg/kg monthly, 10 mg/kg monthly, 2.5 mg/kg biweekly, 5 mg/kg biweekly, 10 mg/kg biweekly).

Hmm, seems a little complicated. What do they mean by order of convenience?

Yes, I kid you not after explaining what simplest meant then they described the futility conditions.

"Monitoring for futility was initiated at the first interim analysis (IA) and was based on the dose identified as the most likely
ED90. The trial would have stopped early for futility at any of the first three IAs if there was a <5% posterior probability that the most likely ED90 is superior to placebo by the clinically significant difference (25%). From the 350-subject IA until the completion of the trial, the futility criterion was increased to 7.5%. Interim monitoring for early success occurred at each IA beginning when 350 subjects had been enrolled, where a .95% posterior probability that the most likely ED90 is better than placebo by the CSD was required. The trial was designed to continue to full completion if neither futility nor early success was achieved according to criteria. At full study completion, the study was considered a success if an 80% probability that the most likely ED90 was better than placebo by the CSD was achieved. In this phase 2 trial, success is defined as a drug effect that exceeds the placebo rate by ≥25%, rather than only being
superior to placebo. ..." Interestingly they monitored for futility throughout the trial and continued it till completion.


Another aspect of the trial of interest is the safety results. In a recent post I speculated that perhaps a prolonged dosing titration might be of help with leca. However, what I have found of interest in the leca article is that only the highest doses of 10 mg/kg monthly and 10 mg/kg biweekly appeared to report radiologic severity for symptomatic patients. It would seem that those on lower doses with presumably the same titration schedule do not actually experience the same rate of symptoms as those on the higher doses. This was not true with Aducan. With Aducan the peak doses for severe symptoms of ARIA occurred with the second dose of 3 mg/kg during titration. The obvious workaround that I suggested was to simply slow the uptitration. This idea might not be that effective with leca because the titration period appears to be largely clear of symptomatic ARIA. We will need to see some more of the safety results to get better insight into this. This also means that side effects in the higher dose arm especially for those with APOE e4 might be higher than we might originally expected. The high dose was where the ARIA occurred prominently in the e4s yet in the phase 2 leca these e4s were largely not enrolled into the high dose arm. There were only n=45 e4s in the high dose arm and they appear to have accounted for quite a bit of the ARIA. This will need to be clarified.

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

Postby J11 » Tue Oct 05, 2021 5:34 pm

It's one of those times when you see something, you're not paying attention and you let it float by-- it is only later that it hits you. The phase 2 from leca has been out there for months now and it is only now that it has hit me: the APOE epsilon 4s had a large response to leca on the highest dose. On the 10 mg/kg biweekly dose the epsilon 4s (n=45) had a change from baseline of 0.096 points on ADCOMS versus a 0.180 change for placebo (n=168). A 47% reduction in decline at 18 months for the e4s? That is more than I had expected might be possible for an anti-amyloid.

Table 2 from the article noted that there was a 97.6% probability of superiority against placebo after 12 months for the highest dose arm. The e4s were the subgroup that contributed most to the treatment effect. All ~1800 patients in the phase 3 Clarity leca trial will have been on trial for 12 months by March of next year. Considering how large the treatment effect could be especially for the e4s, I am starting to wonder whether it would be reasonable to think of next March as a potential transition point for the Clarity trial. What might happen is the epsilon 4 patients results could be part of the rolling submission and when the expected large result for them is confirmed perhaps the epsilon 4 patients on the placebo arm could then be titrated up and lecanemab approved for epsilon 4s? The non-e4s might then continue on with the trial.

Lecanemab has shown very impressive results with e4 patients and we should prepare now for the celebration. This is the APOE epsilon 4 forum if I am not mistaken! Not much room for the party-poopers to grumble with this one.

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

Postby J11 » Tue Oct 05, 2021 6:15 pm

lumia, sorry I have not posted until now about your comment on August 5 about the OIG investigation into the approval of Aducan. There are not many posters to the thread, so I should in theory be able to keep the inbox clear. Problem is that when you wait a few months the news reported back in August has developed in new directions. Increasingly the OIG investigation would appear to be of less relevance.

Indeed any investigation might be more about investigating right-doing than wrong-doing. A new generation of anti-amyloids which began with Aducan will help tens of millions of people avoid a devastating neurodegenerative illness that typically develops into profoundly severe disability: Is helping desperate people a crime? The political optics no longer look favorable. It would certainly complicate any potential to find wrong-doing when tens of millions of people in the dementia community would consider those who made difficult choices related to Aducan to be heroes.

The next wave of anti-amyloids --e.g., lecanemab -- has arrived and they only add yet more evidence that the approval process for Aducan was based on solid science. As I noted above lecanemab appears to have especially strong treatment benefits for epsilon 4 carriers. If anything with such impressive results an investigation (or perhaps another FDA patient listening panel) might be considered to determine why lecanemab has not been approved yet. The treatment effects for leca could realistically be described as substantial. As a reminder there are ~10 million e44s in America. I suspect quite a few of them would be more than happy to have early access to leca.

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

Postby J11 » Wed Oct 06, 2021 8:10 pm

APOE plus minus.PNG
APOE 302 plus minus 2.png
Leca APOE plus-minus 1.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Wed Oct 06, 2021 8:48 pm

The phase 2 Lecanemab results for the APOE epsilon 4s were stunning. Admittedly this is a delayed headline (almost reading history than your newspaper as this result was published in April), though it is still worthwhile to highlight these results.

The bottom figure from the above post is an attempt to convey the information in Supplementary Table 16 of the article in a more easily understandable graphical format. What we can see is that the APOE epsilon negatives did not appear to have much of a response relative to placebo on ADCOMS for any of the doses. However, the APOE epsilon positives appeared to have a quite large % response versus placebo. At the highest SUVR on the left ~ -0.31, the percentage reduction in decline was ~50%. That is worth repeating:

There was a ~50% reduction in decline on ADCOMS at 18 months for APOE epsilon 4s in the phase 2 clinical trial for the highest treatment arm of 10 mg/kg twice monthly (n=45 treatment; n= 168 placebo).

Slowly Alzheimer's progression in epsilon 4s by ~50% in this population of early mild AD patients constitutes a near functional cure. This represents a substantial treatment advance. Extrapolating this result forward one could imagine that with such a magnitude of slowing of progression the most severe stage of AD would likely not manifest for those somewhat younger than their expected age of cognitive decline onset. It is startling to recognize that for the ~50 million American epsilon 34s, the vast majority could have a clinically proven treatment option that would prevent their manifesting AD.

Nevertheless, this is somewhat speculative as the highest dose that achieved nearly 50% reduction in decline only had 45 APOE + patients. Nonetheless, the next lower dose of 10 mg/kg once monthly with n=218 recorded a 23% reduction in decline. Table 2 from the article further notes that the Bayesian ADCOMS at 12 months for the combined group of APOE epsilon plus and minus had a 32% decline in progression versus placebo. One has reason to assume that much of this benefit would also be driven by the e4+s as they demonstrated almost all of the benefit at 18 months. 1200 of the Phase 3 patients in Clarity now have 12 months data, though perhaps only half would be epsilon 4s.

This is extremely positive news!

The lecanemab results appear to be driven almost entirely by the epsilon 4s. They are not receiving a benefit of ~20% as reported with Aducan, but closer to 50%. Perhaps with some data filtering these numbers would increase. For example, what were the results for the patients with more amyloid clearance? How could the placebo be corrected for the hidden placebo treatment effect? or the rapid progressors or non-progressor placebo? ...

The upper figures in the previous post highlight the superior performance that was also noted in the 302 Aducan trial for e4+s. It is becoming increasingly unclear whether epsilon 4s actually do receive benefit from anti-amyloids. Combining these two subgroups merely obscures the large difference in response. If Clarity had pre-specified e4+s as a top-line result, the trial might have already been halted for success. The e4 results are large. It does seem that some of the e4-s are likely benefiting though it could take some effort to determine exactly the covariates that determine their response.

Also highlighted in the figure for the 302 results is the consistent statistical significance across all measures for the high dose arms for the e4+s, while all of the high dose arms in the e4-s are far wide off such significance. Also the 0.53 CDR-sb gain versus placebo for the high dose for the e4+s is somewhat better than the overall 0.39 gain for the 302 high dose arm. Yet, 0.53 reflects closer to a 30% gain for Aducan versus ~50% gain for the high dose e4+s on Leca in the phase 2. Perhaps this difference relates to the higher SUVR result for Leca and possibly as well as the cleaner trial results due to reduced side-effects etc..

Given the above, It would be very helpful if we could find an early approval mechanism for leca. There is a large dominance of naysayers in the regulatory process. Considering the near perfect 100% failure rate of AD drugs for almost 20 years this is possibly inevitable. However, the results above suggest that we need some more yea sayers. Leca has shown some large positive benefit for epsilon 4s and realistically this would seem to offer substantial benefit. Perhaps let Clarity run to March which would be 12 months of full enrollment of 1800 patients; then begin the up titration for the epsilon 4s who were on placebo while maintaining randomization and then open up Right to Try on a profit neutral basis until full approval were granted. Of course, Depending upon what the regulatory time line is this might not be needed. It is not clear to me whether the plan is to approve leca even while Clarity is ongoing. The rolling submission for leca only mentioned including safety data for Clarity.

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

Postby J11 » Thu Oct 07, 2021 9:01 pm

As I continue to inform myself about the Lecanemab results the more I realize that this could be a long frustrating wait for approval. The focus has been so exclusively on Aducan's approval that the other anti-amyloids were put into the periphery. Yet, here we are only a few months out from the approval of Aducan and the breakthrough designation for lecanemab has progressed into a rolling submission. When I carefully read the background research for Lecanemab, it increasingly feels notwithstanding the rapid developments over the last few months for lecanemab that the regulatory process is behind the curve.

With the currently published results lecanemab should already have been approved. At first I thought that the plan was to set-up an approval date to coincide with the end of the Clarity trial, though I am not so sure now. Perhaps approval could happen before. There is a certain regulatory etiquette that is good form to follow, though one aggressive strategy that might be considered is to simply rapidly submit and close out the rolling submission with the dataset that exists as of now. Even now there is strong support for the claim. The FDA could set the PDUFA date and then a week before the approval decision an interim look at the Clarity results
could be announced. Fait accompli! It would make any subsequent decision almost superfluous.

Such a strategy would be almost the optimal result for the APOE4 community. Conceivably leca could then be approved by April, 2022. Trying to organize a patient response (e.g., for Right to Try, etc.) would likely be more cumbersome: Finding a way to use the existing regulatory procedures to our advantage would greatly simplify advancing the patient rights of those with dementing illness.

It also would fit into the emerging groove of FDA logic initiated with the Aducan approval. Specifically, if Aducan is worthy of approval, then shouldn't by rights another anti-amyloid that is even better than Aducan by an appeal to the logical principle of equivalence also be approved (i.e., posthaste) ? The logic of the argument is almost unassailable: a treatment for a devastating neurodegenerative illness that results in severe disability that demonstrates strong efficacy should be approved in a timely manner. By March 2022 (though realistically even by October, 2021) there should be overwhelming evidence of leca's strong efficacy in APOE e4s. Players in the regulatory process can simply extend the logic that the FDA has created. Possibly as an extension of such thinking other regulatory agencies could coordinate their national PDUFA dates to conincide with the FDA decision. Typically the FDA is the lead agency to set the global standard; other nations do not typically want to step ahead of the FDA decision. Here perhaps there could be international coordination to sign-off on national approvals conditional on FDA approval. Yet, other nations have not had an Aducan roll-out to prepare them for widescale infusion capability.

With all of the advances in leca and aducan through clinical trials and the regulatory system, we have broken through the main line of the defense for the anti-anti-amyloids. It feels like a rout. The yardsticks are moving so fast upfield that the momentum is developing a sense of inevitability that this is going into the endzone. Arguing against the amyloid hypothesis increasingly seems to be arguing against established factual evidence. How can a 50% reduction in decline be ignored?

I had thought that perhaps there be might months in which the anti-amyloid camp would need to wait silently for new results; all the while the nays would have an unopposed opportunity to cast doubt on amyloid treatment. However, the leca research has provided us with a powerful rebuttal. The phase 2 results for the APOE epsilon 4s were very impressive. The very strong results at the 12 month mark had also been overlooked. The APOE e4s drove almost all the entire benefit: this had been largely obscured by combining the e4 and non- e4s into the treatment arms.

I have found the OLE results and they also appear quite strong. The full OLE enrolled 180 patients for 18 months which completed in August. These results should now be on the way. One prominent finding from the OLE is the runaway decline in cognitive ability in those who had a decline of >1 gCDR during the core study. We saw this also with Aducan; once a certain threshold is crossed there then is frequently very large declines. A very startling difference. The >1 gCDR subgroup declined by nearly ~8 CDR-sb!!!, while the gCDR<1 subgroup only declined by 1.4 CDR-sb. With all of this strong evidence I greatly wish that leca will not be slow walked through the regulatory process; more of a snappy quick walk.

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

Postby J11 » Fri Oct 08, 2021 8:29 pm

Big news everyone!
Gantenerumab has been granted breakthrough designation by the FDA.

Gante has been for me the most obscure of the modern anti-amyloids. Clearly it is out there, though it has been in quiet mode and I wasn't clear when it would exit qm and head for the spotlights. Well it has now just arrived in the big city. It has attained an FDA breakthrough designation.

Nevertheless, my impression in July when Roche appeared to reject an accelerated path for Gante was that they wanted to take this slow and steady. Roche seems to be a very conservative pharmaceutical company; I am sure they were very unamused by the futility analysis that was then decided not to be futile and in fact the drug was then approved. In a current Gante phase 3 AD clinical trial they included almost 30 secondary measures. Basically, they included almost every dementia cognitive test that I had ever heard of and then they added in a few more that I hadn't heard of. I think it is fair to say that their AD clinical trials can be described as rigorous. Probably be reasonable to be somewhat forgiving on correcting for multiple comparisons.

Roche has added $40 billion in market capitalization very recently as the breakthrough designation for Gantenerumab became reflected in their share price. Nothing wrong with being cautious. No siree; Yes, I always say put an extra dose of starch in your collars just to be careful. No harm in being careful and cautious. Government 30 year bonds -- just think 0.5% annual coupons.

I included Gante in my regressions, though I was somewhat uncertain about it because the recent FDA documents related to Aducan placed Gante on the cognition vs amyloid removal figure indicating less cognitive benefit than I had plotted. The clinical reports for Gante seemed somewhat confusing to me; however, the main takeaway from Gante for me is that it is another modern style anti-amyloid in the Aducan class that should stay on the regression line as patients are dosed up.

There are some important features of Gante's clinical development that is especially encouraging. Gante has a deep pipeline with 5 phase 3 trials! The phase 2/3 trials were the early low dose studies that did not show much of an effect. Yet, some of even the more recent studies noted below might also be more related to a homeopathic scale of dosing.


Phase 1 NCT03236844 December 15, 2017 114
Phase 3 NCT03443973 September 30, 2022 982
Phase 2 NCT04592341 October 27, 2023 192
Phase 3 NCT04339413 April 27, 2023 116
Phase 3 NCT03444870 May 31, 2022 1016
Phase 1 NCT02882009 March 22, 2017 48
Phase 1 NCT02711423 September 28, 2016 18
Phase 3 NCT04374253 October 4, 2024 2032
Phase 3 NCT02051608 April 16, 2021 389
Phase 1 NCT02133937 September 2014 31
Phase 3 NCT01224106 September 10, 2020 799
Phase 1 NCT01656525 March 2014 28
Phase 1 NCT01636531 October 2012 120
Phase 1 NCT00531804 September 2010 60
Phase 2|Phase 3 NCT04623242 December 2012 194
Phase 2|Phase 3 NCT01760005 December 2012 490


But wait! There's more!

The phase 3 NCT03443973 study second from the top in the above table is listed with a primary completion date of September 30, 2022. What is actually exciting about this is that the patients in the trial are being treated on trial for 116 weeks? 2 years of treatment in a randomized trial for AD? Nobody's does that! Unless ... unless, you're very very cautious.

What does this mean? Well 116 - 78 = 38. If you subtract 38 weeks from September 30, 2022 you wind up with ~ Friday January 7, 2022. Yeah! The NCT03443973 phase 3 with 982 patients will reach the GRAAD (Generally recognized as acceptable (end) date) for an Alzheimer's trial in January? Time for a celebration if you're not too busy practicing accounting for fun. This is great! They could submit essentially the entire 78 week data in the next month or two and let the "The correlation between the extent of Aβ plaque reduction and effect on clinical endpoints ... further supports Aβ as a surrogate endpoint that is reasonably likely to predict clinical benefit logic that was established during the accelerated approval of Aducan displace any doubts.

Another pleasant surprise is that Gante has been tested for sub-cutaneous dosing. Great! The easier and more convenient treatment can be the more likely people will receive the help they need. Being hooked up to an IV every month (or possibly every 2 weeks) for the next 10 years is something that many people would prefer to avoid. Gante treatment doesn't require all of that hassle.

Yet, another innovation is their brain shuttle technology. Very little of the anti-amyloids that are administered ever wind up in the place in the brain that they are needed. It is a remarkably small amount ~0.1%. Brain shuttle moves this up 8 fold to ~0.8%. This should allow much lower doses and possibly lower side effects. They are conducting early stage clinical trials with this technology now. Only problem might be that it uses transferrin has a transport protein. From what I remember I have transferrin mutants; hopefully this would not interfere with using transerrin has an anti-amyloid shuttle.

The Gantenerumab breakthrough designation is very good news!
There are 3 anti-amyloids that have now been granted this designation and they will provide a wave of clinical evidence validating this target. Our regression line will soon have overwhelming clinical support. My wish is that this will allow us to move the yard sticks further upfield in a timely manner.

The clinical results that are already datalocked would be more than sufficient to end any argument and allow the patients who need treatment access. With all of this great news, I recommit myself to advocating the position that we should do the right thing and swiftly move the products through the regulatory process. Perhaps the "supports Aβ as a surrogate endpoint that is reasonably likely to predict clinical benefit" logic allows Aβ to be the primary endpoint for regulatory purposes and then all of the mountains of cognitive results that is now on track to reach shore will provide the irrefutable evidence possibly concurrent with regulatory approval. My hope is that the filings can go somewhat early and allow the clinical trials to mature in the background. This will be a big payoff for the approval of Aducan: the second generation of treatment would then have arrived considerably earlier than it would have without Aducan approval.

January 7, 2022!!

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

Postby J11 » Mon Oct 11, 2021 6:25 pm

The United Arab Emirates approved aducanumab on October 3rd. Supplies of aducanumab were not expected to arrive in the UAE for possibly months.

This approval should be understood in the context of a more restrained treatment environment that has evolved as the new anti-amyloids have been granted breakthrough designation. These new anti-amyloids are already exerting their covert presence. For starting treatment now with aducanumab might offer minimal treatment treatment benefit versus waiting ~8-12 months for lecanemab. This is true because aducanuamb has an ~8 month time interval to reach therapeutic dose versus a ~2 month time interval for lecanemab. Waiting would have the expected benefit of considerably less side effects with lecanemab. Thus, any sense of urgency for need of treatment could be misplaced.

The UAE has apparently recognized this more subdued treatment context by stipulating that treatment with aducanumab be restricted for those aged 65 and over. It would also seem reasonable to explore less aggressive up titration schedules. We have noted on thread that even some of the earlier doses in the titration (most prominently the second 3 mg/kg dose) can cause side effects. Finding a better titration scheme would be of considerable benefit.


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