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.

Post by J11 »

I am feeling very optimistic about the upcoming Leca readout. Recently there has been an attempt at lowering expectations for the readout which is of course a good idea; there is some chance I suppose that this will not go to plan, though there seems to be so much padding in Clarity that even a nominal miss on the top line really would not be a miss. As mentioned above, the trials to date have largely ignored the e4/non-e4 treatment effect difference.

If necessary we could simply rotate to a prespecified e4 subgroup win. If they were to hit a ~0.34-0.39 topline on CDR-sb (~~ matching Aducanumab's Emerge high dose) which admittedly would now be seen as luke-warm, but still reported a number ~0.55+ on APOE e4s, then it would be difficult to see how e4s would be happy with anything but an approval. With Aducanumab the readout was so confusing-- patients on different doses and substantial rates of ARIA etc.; with Leca subgroups should cleanly readout and the statistics will be more credible.

One of the possible snags that I have encountered online regarding Leca is that under the current accelerated approval framework apparently it is ruled by the final CMS decision. That is Lecanemab would only be provided through CMS in a restricted clinical trial/registry process. I found this somewhat surprising. Did they really think that such a funding stance should be applied to leca? If you go through their final decision, then what part of their argument remains valid in the context of Leca?

Once again I am very unclear how this would work at the sociopolitical level. The concerns that CMS raised about Aducan related to safety and efficacy do not seem to have clear applicability to Leca. It would have been much better if CMS had simply decided on Aducan as a beta-amyloid mab 0.1. Generalizing their ruling across all mabs does not now seem realistic. Leca is a ba mab 2.0 and reasonably patients would likely expect to be given broad access to it once the top-line is announced within the next month. The CMS has put itself into the highly awkward potential position of watching the party balloons popping, and J11 swinging from the chandeliers with a healthy dose of cashews and my new secret weapon chocolate covered almonds-- the biggest party in the history of the universe ever, and having to be the one to tell everyone to turn down the music... real party pooppers. I am not sure how this will all play out in the court of public opinion. The Clarity readout could have some very strong subgroup readouts (for example, for Asians, mild AD etc. that we have also seen in earlier trials (e.g., Aducan etc.)) that could reach to and perhaps beyond 1.0 CDR-sb benefit. That would be massive! I am not seeing how this could then be denied broad funding by CMS. One additional wrinkle here is that private insurers might feel obligated to provide coverage for Leca even if CMS is not onboard. This would then have the unpleasant optics of people having a private insurance route to coverage. I am not entirely clear if it would actually work out that way, however once the results are posted one might wonder whether private insurance coverage for AD treatment might then enter into the discussion.

We have also had signals that Leca could have a more flexible pricing model. Aducanumab did have the feeling that if universal coverage were provided that the entire Medicaid financial model could collapse. If you opened treatment to all, the liability could almost be unlimited. For Leca, the lesson learned appears to be that bankrupting the government's plan is not on the table. Wisely, the signals to date suggest that Leca will coexist responsibly within the global budget of the plan.
Last edited by J11 on Tue Aug 23, 2022 10:52 pm, edited 1 time in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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We've been in the data wilderness for about a year and a half! No new news; only not new news. Without any readouts to point to we have had to keep our heads down and wait it out for the big trials that are now on the short term time horizon. Without any actual new evidence to point to all we have had is endless criticisms from the anti-amyloids. Yet, with a wave of results approaching the anti-amyloids no longer have an empty net shot on goal. It is reasonably clear that strongish results are on the way. These readouts are all lined up and it will be exciting to wait for their reports. Of course, with success we will have more and more exciting results in the years ahead. With all of these trials about to report, the opposition has given up. No Adcomm for Leca! It does not even seem worthwhile to spend time arguing about Leca because there clearly is not much to argue about.

This is the medical public health advance in a century and they do not even want to talk about it? Could always have a celebration with cashews and chocolate covered almonds catered by J11. Where was I, oh yes, data wilderness ... from here on out no more wilderness. Pharma really needs to ramp up the mab confirmatory pipe. It is disappointing to me that there are not more Leca trials already in process. Why wait? Last I counted there were about 30 anti-Ache trials and anti-Ache did not have much if any treatment effect. Good to start projecting forward to a post-approval clinical trial stance.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I have to admit that it has been difficult trying to become excited about scribbling for the Clarity trial when it all seems so mostly settled even before the readout. No one is interested to even pretend to argue about it.

Fortunately, alzforum to the rescue with some updates from this year's ICAD.

The most eye-popping of which was a simulation for Gante out to 5 years. The simulation called it as 0.87 benefit at 27 months and 5.2 CDR-sb at 5 years. 0.87, yes, that is a massive number that I had not been expecting; 5.2 is massively massive. I have stayed away from Gante predictions because it does have that uncertainty of what happens when you extend out the trial to ~2 years.

For whatever reason, mostly everyone settled on an 18 month AD trial, though it really is not that clear that 18 months is truly the best time to assess benefit. We saw with some of the aducan results in the LTE that the benefits do tend to grow with time. The memorable figure showed how those on treatment phase 3 aducan patients who did not clear amyloid well during the treatment phase, tended to progress into irreversible and rapid dementia during the LTE. The LTE for the phase 1 Aducan also showed how cognitive benefit magnified through time.

We could reasonable be expected to see large cognitive benefit for those treated over the long haul on anti-amyloids. I hope that with Clarity and the other trials that the LTE research is published at the time of or soon after the top-line results. I suppose there would be no reason why they could not data lock the LTE for Clarity on September 1st and then begin to analyze the results. It would be difficult to overlook LTE results no matter what the topline from Clarity might be.

0.87 ... that would be a large readout. It is simply not easy to develop a good feel for Gante because we did not have a high dose phase 2 to work with. The benefit of letting the cognitive benefit accrue over almost another year is also not easy to estimate. With many of the shorter anti-amyloid trials, sometimes adding in the next 3 month cognitive testing can move the result back below significance. At 18 months, there can still be a certain amount of noise in the numbers. When going out to 24+ months, this noise would be diminished and the treatment signal would be more prominent. For Graduate, 0.7 ... 0.8 that does seem to be in the right ball park; nevertheless it is still a substantial benefit, though this would still be in the ~~25% reduction in decline window.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

On further examination of the alzforum article it is notable that the above noted ICAD presentation suggested that anti-amyloids would offer ~0.24 CDR-sb benefit when considering Lecanemab, Aducanumab, Donanemab etc.. I would tend to go more with ~0.40 CDR-sb on the low end with 80-20 MCI mild mix at 18 months along the average regression slope (not the apoe4 slope). I suppose this could be more in the category of downtalking the upcoming results.

Clarity has 1900+ patients, 50-50 placebo and 1 high dose treatment arm; might have been worthwhile to have went 30-70. Almost 1,000 patients on high dose? That's quite a few. ~70% e4? We could see strong sub-group performance with narrow confidence intervals. It is somewhat of a concern that the patient mix is different from the phase 2 (this does add in some level of added risk), though there is also the sense that the weak performers in the phase 2 were replaced with potentially stronger performers in the phase 3.

The dona result was included in the 0.24 estimate, though as has been previously noted on thread dona really should be considered in terms of its own unique scale as it combined amyloid with tau selection. The number to watch with dona seemed to be more the 50% reduction in decline number moreso than the somewhat lowish CDR-sb result. On thread, I winded up relying mostly on the leca & aducan results for the cognitive benefit assessment. Gante was also on the regression line though it was more towards the lower dosing side. For whatever reason, the new analysis called Scarlet Road (Gante) a fail. I do not recall that being true. From what I remember any Gante fail was more a dosing problem than an actual off-the regression line problem.

Of additional note the FDA was present at ICAD and their off the record remarks are of interest to gain insight into their regulatory deliberation process. It is interesting that the FDA also thought along the lines of a comprehensive assessment of aducanumab, gantenerumab, lecanemab, crenezumab, bapineuzumab, and solanezumab trials in formulating their stance. Hey, how about donanemab?

They did say at the time, though it would be interesting to know what their thought process was when the donanemab results broke. That was around January 2021 and it was also about the time that the FDA called a 6 month time out to think some more about their decision. If they had been wavering with only aducanumab, lecanemab and ganetenerumab as being strongly on the regression line, then donanemab might have been what pushed them over the line.

On thread, I was not as clear about crenezumab, bapineuzumab, and solanezumab. These mabs did not have the same correlation to the regression line. One of the more insightful features of this thread was being able to quickly appreciate how aducan, leca and gante formed a remarkably persuasive dosing response relationship. The big question that troubled everyone else was: What about high dose Engage? Without all the other confirming clinical research it would have been more difficult to toss the high dose Engage result out; you can't merely select the results that do not confirm your hypothesis. However, Engage clearly was the outlier and once removed all the other results fit almost perfectly a linear relationship.

What is particularly impressive is that the FDA pretty much has to get it right, most of the time. As a global scale regulator, you need consistently make the right calls in order to maintain moral and intellectual legitimacy. Increasingly Aducanumab can be seen as a difficult call that was called right. Anti-amyloids clearly have a cognitive benefit and there are now a queue of results that likely will confirm this. Ergo, crickets from critics about Lecanemab etc..

Admittedly, Aducanumab was still one of the murkier FDA decisions in recent memory, though from the patient perspective it was a notable victory. The approval has created an entirely new viewpoint for those coping with or anticipating AD dementia. The alternative presented at the time of waiting 5 more years for a readout on another Aducanumab trial would have been unbearable. Here we are now and the lecanemab trial already has the momentum from Aducan built into the common assessment.

One feature that perhaps will be surprising to many in the AD community is that epsilon 3 AD does not appear to derive notable benefit from the anti-amyloids. However, the FDA Briefing Document did not agree with this assessment, though it is not easy to see how the ~0.10 CDR-sb benefit could be called significant. Nevertheless their model did not add a term for APOE genotype. I still think there will probably be some 3s who benefit though this might only be a smallish subgroup. This topic is not completely clear to me, though if 3s largely are non-responders to anti-amyloids, then it would be a big disappointment for many e3 AD patients. The 3s had the least ARIA, though they seemed to have the least gain as well. It is possible that there is a misunderstanding due to confounding variables; it would be very helpful if this issue could be clarified as the approaching clinical trials are reported.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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J11 wrote:What is particularly impressive is that the FDA pretty much has to get it right, most of the time. As a global scale regulator, you need consistently make the right calls in order to maintain moral and intellectual legitimacy. Increasingly Aducanumab can be seen as a difficult call that was called right. Anti-amyloids clearly have a cognitive benefit and there are now a queue of results that likely will confirm this. Ergo, crickets from critics about Lecanemab etc..
You've probably seen this AlzForum arrive today, J11. I was able to hear the detailed and impassioned speech at AAIC by Dr. Yaning Wang, who led the FDA's Division of Pharmocokinetics until 9/21. He responded to critics from the Advisory Group, who said the data didn't show enough benefit and said he directed his group to completely re-study the data comparing ALL the anti-amyloid data from ALL second-generation drugs with a high dose to see if a consistent and significant benefit was observed. ALL performed similarly, with rapid removal of amyloid plaques within 18 months in most cases and a clear trend line of benefit. He clearly stated that the CMS (Medicare) determination of insufficient benefit was incorrect and that many in his and other divisions studying this agreed. It's especially striking because he notes that cognition changes slowly in MCI/mild AD individuals over 18 months.

AlzForum summarizes Dr. Yang nicely:
At AAIC, Yang defended the agency’s decision to grant accelerated approval despite a negative AdComs evaluation. After the FDA advisors had pointed out that there was no way to know whether the positive EMERGE or the negative ENGAGE aducanumab trial was the anomaly, FDA scientists analyzed available clinical trial results from all antibodies in this class. At the time, published data consisted of aducanumab, gantenerumab, lecanemab, crenezumab, bapineuzumab, and solanezumab trials. Wang said that the FDA found a consistent linear relationship between amyloid removal and cognitive benefit across these antibody trials, even for negative ones. ENGAGE was the only trial that did not fall on this line, leaving the FDA to conclude that it was the outlier.

Wang also talked about effect size. He noted that because cognition declines slowly at the prodromal stage of AD, the tiny, measured benefit on the CDR-SB in EMERGE represented a 25 percent slowing. To achieve the [required] minimum clinically relevant difference on CDR-SB in 18 months, the drug would have had to completely halt progression, an unrealistic standard, Wang said.
Dr. Wang also noted that in his 18 years at the FDA, he was in charge of many analyses of drugs for approval and MANY had a trial that showed an outlier effect for undetermined reasons, mentioning a lupus trial in particular. In his view, an outlier negative trial, in the context of almost identical results on multiple trials across a drug class, is simply that-an outlier.

As you've noted, the pre-specified Primary Outcome for clinical benefit on the CLARITY trial should provide some CLARITY on the issue of cognitive benefit over 3-4 years, not just 18 months.:
Extension Phase: Change from Core Study Baseline in CDR-SB [Time Frame: Baseline up to Month 45]
ClinicalTrials.gov/Lecanemab CLARITY
4/4 and still an optimist!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Thank you for your reply NF52.

Yes, I am sure that I would find it very difficult to cope with the CMS rebuff personally as well. I really had not been entirely aware of how murky statistical analysis can be. If you are an accountant, then there are universally recognized procedures that apply and you cannot be faulted for following the manual. With clinical trial statistical analysis there can be a more creative interaction with the data to create an on the spot model for what the numbers are revealing. These trials can have somewhat smallish datasets with outlier points that simply do not really belong with the rest. You have to do the best that you can and give it a great deal of thought because it can often be quite an off road experience. You then feel that your professional integrity is on the line when you make your final call.

The FDA exhaustively analyzed the data set and arrived at a strongly hawkish stance on Aducanumab approval. It wasn't wishywashy. This was my view as well; Aducanumab demonstrated strong anti-dementing effects: more so than many appear to appreciate. As noted many times on this thread ~one third+ of phase 3 Aducan patients in the long term extension achieved long term cognitive stability (i.e. a functional cure). A majority of the FDA analysis team wanted a full approval for Aducanumab. I am not sure whether I would have went full approval, though this is the ball park where the actual high level FDA discussion was considering.

... then somehow the CMS talked it back from the full approval consensus to accelerated approval and then to more of a conditional accelerated approval; as if somehow the efficacy had not truly been established. What was perhaps the most surprising background context to emerge was that apparently CMS never actually consulted with the FDA about the quant analysis. Doing a zoom call or something would have been my guess for the minimum slacktivist effort: No zoom call.


I will quote my esteemed colleague J11's post from Sat Feb 05, 2022 12:33 am:

"Possibly not the most reported story was from meeting on Thursday of The House Committee on Energy and Commerce Subcommittee on Health, though it provided some important insights into how the CMS analyzed the Aducanumab data set. The FDA was asked if they consulted with the CMS to help the CMS understand the extensive analysis done by the FDA. Surprisingly, the answer was NO? Anyone, zoom call? Don't even have to go on a plane and get COVID or anything. Um, the FDA supercomputer famously maxed out and the analysis team had to go with only 10 million simulations -- they found that "it was essentially impossible that Aducan was the same as placebo" that wasn't worth a conversation?

CMS was not interested in talking to the FDA people who dimmed the lights in a whole city because they just needed to know the truth about Aducan? The truth that they found was that there was virtually no chance that Aducan was not better than placebo? Admittedly, I would have liked it if the FDA had been more transparent (or at least simplified their results) so that the lay public could make sense of their models presented in some of the FDA Aducan documents. It is very difficult to understand why the CMS decided it was not worthwhile to talk to the FDA who had all of this largely unpublished research that they spent many person years acquiring. CMS decided to read the results from pubmed instead? They decided to take a literary and not quantitative approach to what is largely a quantitative question?"

I found that very surprising (and still do). The CMS decided to merely do a literature search when realistically they would have access to the FDA quant team who had comprehensive insight into the Aducan dataset which they had analyzed for years? How can the CMS analysis be considered to have fulfilled its due diligence requirement when they neglected to speak with those most able to provide an interpretation of the anti-dementing benefits of Aducanumab?

My long-held suspicion is that the phase 1 result for Aducanumab was so strong that the phase 3s were not primarily intended to replicate the initial result. Instead of weighting the patients in the mild AD demographic, the phase 3s chose to weight 80% with MCI: The phase 3s were intended more as the next step in anti-amyloid development of early treatment/prevention. In this MCI cohort it would not be easy to show a strong CDR-sb benefit.

In terms of the supporting points on the regression, yes there were many. High dose -- low dose -- medium dose; across multiple anti-amyloid agents. Funnily enough I am not sure whether they even found all the anti-amyloidal agents that showed cognitive benefit. I do not remember ever seeing 40 Hz noted even though its MOA is through amyloid. There were many of them. I seem to recall that I found another early phase result back ~20 years ago.


Yes, I am still unclear about the Engage high dose result. However, it is of interest that even in this high dose group that there were those who received near maximal high doses and demonstrated large cognitive benefit. It would probably be helpful in the future that spreadsheets with individual level data read outs were made available. With the regression approach dosage is not actually that important all you want to see whether the relationship between dose and response is as expected. By examining individual level data perhaps it could be decomposed so that the patients could be placed in more homogeneous subgroups.

The other comment about the Engage high dose as an outlier is that the result was rapidly evolving towards expectation. Moving clinical trial decision making more towards computer algorithms would probably be very wise and away of human meddling clearly could have benefits. A trial result that was moving as quickly as that of the Engage high dose would be allowed to continue to evolve, even through a nominal futility signal.

I will be interested to see whether the upcoming data release will also have an early peek at the long term extension.
They could give us another data point to plot in CDR-sb vs SUVR space and as well we could have a unique glimpse into intra-patient decline on treatment versus control. This would offer the potential added bonus of being able to curate those patients who did not appear to be true AD patients after 18 months. The placebo period could then act as a filtering mechanism.

Hopefully, they will report the results in SUVR as well as centiloids. clinical trials.gov reports that Lecanemab will report PET amyloid as centiloids; I want to be able to plot the result and the rest are on the SUVR scale. Some of the other trials strangely never seem to provide the conversion to SUVR.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Dosing 1.PNG
Dosing 3.PNG
Dosing 2.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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hayato-et-al-subcutaneius-dose-selection-aaic-2022-poster.pdf
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Very exciting!

The first post above shows some figures from the pdf above that was presented at AAIC 2022. Problem with AAIC is that most of the presentations never seem to make it to the web; with CTAD they post all the abstracts as a pdf. For this year hopefully they will do even more because it really feels like we have now reached essentially the era of AD disease modification. One hopes that this will be recognized as a moment to embrace open science so that everyone has good access to the latest science.

First post above! I am not sure if this is really new news, though it is very impressive nonetheless. Going equidose subcutaneous versus IV dose has large benefits in reducing ARIA. the top figure shows how there is this massive spike with IV dosing. Apparently this IV dosing pattern of PK offers no actual benefits; only risk. By simply changing up the route of administration to subq from IV there is a multi-fold reduction in ARIA risk. It is quite startling. Are we now really talking about ARIA risk in the 2-4% range? At some point it was pushing 70% ... then with the straight IV leca it was ~12% ... and now we are at ~4% for APOE+ and 2% for APOE- ??? That is remarkable. Could 34s have an ARIA risk possibly less than 3%? The bottom figure in the first post then shows that these super low ARIA rates can be achieved with the same SUVR reduction (and presumably the same CDR-sb benefit). Notably the remaining risk with subq dosing is still somewhat strongly front-end loaded. The figure does not show this well, as it looks much flatter than the red line (IV dosing); nevertheless about 2/3 of the ARIA risk still occurs in the first third of the treatment interval.

{Might be interesting to see whether adding a month or two to the uptitration duration with subq Leca could result in even lower ARIA.} Once they can give firm indications that Leca for pre-symptomatic patients can be thought of more as a lifestyle treatment (i.e., with minimal risk of ARIA), then an entire newly and vast market opens up. More importantly, pre-patients would then have a plausible treatment that might be highly attractive in terms of price and potential benefit. For someone in the workforce, spending ~$1,000sish per year would offer a compelling economic value for treatment.

I certainly hope that they do a datalock for ~September 1st on Clarity for the extension patients on subq especially. The great part here is that the ~1,000 placebo patients who were eligible for the LTE were dosed with either IV or subq. So, we should already have a fairly large dataset to see what happens in the real world with subq dosing. Patients would likely have a great deal of interest in essentially getting this "free benefit" of much lower ARIA. If patients are likely going to want to dose subq (if possible), then this clinical trial information should be clarified as part of the regulatory process. The models developed in the above figures should be clinically confirmed with the Clarity dataset.

Overall this is massive news. The ARIA risk now appears to have been reduced by two thirds from the already highly impressive results from the phase 2 leca trial. For e34s ARIA might be approaching ~2%!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Everyone this could be a big one.
Put down your coffee/milk/ etc..
Be seated comfortably, this could be important.

This is a J11 Level 3 Brainwave Announcement.

The background over the last few months is that I have been taking it easy; practicing my golf swing. Really have not seen much to do but watch as the countdown clock moves us ever closer to a world with viable treatment for amyloid dementia. ... and then I came across this:

https://stemcellres.biomedcentral.com/a ... 22-02933-w

Doggie dementia? Apparently all dogs are APOE e44. Who knew?
In the study they injected the dogs with a quarter million hippocampal cells and this resulted in rapid reversal of dementia. Two (of 6) of the dogs treated were considered to have reverted to normal dog behavior; others were no longer categorized as demented. The injections increased the dogs' new hippocampal cell counts by 9 SD versus control. As a reminder, statistical charts do not actually go that high-- maybe more like 5 SD.

Hmm, interesting where's the brain wave?

So, what's it all about J11, some might ask? How does this make it to Level 3 on the J11 Brainwave scale?

Well, what I found interesting is that apparently this general procedure has already been done in humans for Parkinson's with some success. Yes, soooo...

Hippocampal surgery is doable in people, though it is somewhat invasive; they need to drill through your skull. Yet, once this is done apparently even while the hippocampus is deep inside the brain, one can access the hippocampii by separating the temporal and frontal lobes without incision (basically just need a fancy shoehorn). One might then simply inject the new neurons into the hippocampii.

OK, but where's the Level 3 here?

What I thought would be interesting that while one injected these hippocampal cells (with likely a largish effect on AD dementia memory impairment) one might also consider CRISPRing the new neurons to have cognitive enhancement.

Hmm, interesting.

Current GWAS has found ~300 IQ points of human intelligence. What if there were a GWAS that could determine the optimal genotype of the human hippocampal neurons to implant? The cells are first harvested from an autologous skin sample and then grown in vitro to avoid immune rejection. What if you could add 500 IQ points of intelligence by having optimized these harvested and bioreactored hippocampal cells injected after CRISPRing while treating AD?

That is probably up there as a Level 3 if this were doable... I mean it would take down human civilization as we know it, wouldn't it?

Yes, I would think so. I had thought that perhaps Cognitive Singularity might be 30 years away. One would need the GWAS studies and then ... one would need the right gamete selection technology and then ... one would need 20 years for the kids to grow up. The transformation of human civilization by uplifting human intelligence by 100s of IQ points until this had been decades away.

Why wait?

What if we could avoid all of the delay and simply inject optimized CRISPRed cells into those with AD? Perhaps like tomorrow? No, great technological breakthrough would be needed for this.

We could instantly create 500 IQ humans! That is the Cognitive Singularity part; of course, it would be very unclear how humanity could cope with such a massive intellectual uplift.

There are quite a few people still trying to recover from the blinking VCR light problem. How might they cope with a planet of humanoids with 500 IQ? Probably be a good time to prep up and take a trip to the wilderness; very unsure how we will be able to manage superintelligence.
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