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.

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Yes, waiting for CTAD will seem like forever. 2 Months??!!
I think this year they put the CTAD main presentations more towards the afternoon and not sunrise, so there's always that.

The Lecanemab news appears to have broken about 7PM last night so that would be 8AM Tokyo time; earlish their time.

The iADRS composite seems to have consistently been the better cognitive instrument across Aducanuamb and other AD trials. It is the most comprehensive of the tests and has shown larger cognitive benefit and lower p-values. iADRS might report an heroically low p-value, given we already have 0.00005 for CDR-sb. Nevertheless, sometimes you get locked into a certain test because -- as with CDR-sb -- all the numbers fall into place with it and you want to stick with the test that has accumulated the most evidence of showing the dose response relationship. Perhaps other tests would also strongly confirm dose response.

The Lecanemab results are right where they were expected; the primary, all the secondaries hit their p-values and even more importantly it appears that the numbers will be right near the regression line. There's nothing like a suborbital High Dose Engage to explain away in Clarity. I was worried that I might have to do some elaborate mesmerizing handwaving to explain the results -- though, no , no hand waving was necessary.

I had prespecified that it was more being true to the regression line that I was following. The 0.45 result seems to be right where it should be in terms of the regression. Then as a bonus I rotated to the p-value (which I had prespecified was less of a focus than the regression) and the p-value was very strong. Everything fit into the pre-existing knowledge base quite well.

Aducanumab largely was the dress rehearsal; Lecanemab is about winning style points and making this look effortless. Yet, behind all of that is decades of grinding science and near endless frustration.

This has me wondering about the Nobel Prize for Medicine for 2022 announcement that is approaching for October 3rd. Lecanemab is the news of the century. True medical breakthroughs such as this do not happen every day. I wonder whether the Nobel committee would react to this news over the next few days.

I also will be interested to see what signals might be sent from others in the Lecanemab ecosystem. It will be very interesting to see how the CMS might respond over the next few weeks. The concerns that CMS raised about safety and efficacy have now largely been resolved. Sending out preliminary signals that national coverage is now within the range of discussion would clearly be quite helpful.

I've already had the talk with a family member. Lecanemab is now something on the mediumish term radar for us. Probably will first want to APOE genotype this family member; maybe then do one of the newly approved diagnostic tests ... and then perhaps lifestyle preventative dosing. So far so good. I am just unsure whether this will need to all be pushed into a black market underground type drug market. We are highly aware of how devastating pre-clinical type AD cognitive impairment can be; it does not seem to be a realistic option to say "well, we'll just wait until their is self-evident cognitive impairment and widespread neurodegeneration to do anything."

Low dose, safe, preventative, reasonable cost anti-amyloid treatment seems a reasonable option for us now.
Last edited by J11 on Wed Sep 28, 2022 10:07 pm, edited 2 times in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Really big day everyone!

Alzheimer Liberation Day (Part 2)!!

Looks like they are already on subcutaneous dosing.
These mini type clinical trials have moved through the system quite rapidly in the past.
Obviously, will be anxiously awaiting multi-dose subcu dosing in healthy subjects.
https://clinicaltrials.gov/ct2/show/NCT ... w=2&rank=1

I am also now wondering how the FDA might respond to the latest development.
Lecanemab's PDUFA is January 6th. Given the results, I wonder whether perhaps the actual decision date might now be moved forward into 2022. The as reported topline is an essentially conclusive result. There is not a great deal of room left for productive debate or obvious reason to delay the launch.

With Aducanumab, I will be interested to see whether the product will now be officially abandoned. As previously suggested perhaps those on Aducanumab trials could now be migrated to Lecanemab dosing. In a slightly more than a year we have now entered the era of second generation anti-amyloid mabs.



alzforum is reporting the result and is expressing sober but unambiguous optimism.
https://www.alzforum.org/news/research- ... ne-results
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Hmm, there are other large mabs now on the short term reporting horizon.

https://clinicaltrials.gov/ct2/show/NCT ... w=2&rank=3
September 21, 2022 Gantenerumab Phase 3 962 116 weeks

I think there is another in the Graduate series though it is not easy to find.

This is the list of large Gante phase 3s.
NCT03444870 June 6, 2018 (start) 1016 Graduate 1
NCT03443973 September 21, 2022 (primary completion) 982 Graduate 2
NCT05256134 April 19, 2022 1200
NCT04374253 February 1, 2021 2032

The 973 trial should read out any day.
The 870 trial probably could read out any day too, it appears though that this trial has not been updated
on clinical trials gov to reflect its current status.

With Gante, I am somewhat less sure about what to expect for the read out.
They are using a longer treatment interval, etc. Nonetheless, one could reasonably expect strongish results.

Gantenerumab could report out in days??
It took Lecanemab ~12 days from last patient last visit to topline report.
Gante might report out starting next Monday? Prepare!

Another strong mab result with Gantenerumab could truly toss cold water on any attempt to have a productive argument about mabs.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Dosing 1.PNG
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Dosing 30.png
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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The top figure is a great one to repost. It shows how subcu dosing compares to IV dosing in terms of Cmax etc.
All those with IV dosing (in black) create no patient benefit related to cognitive scores; all it does is create risk of ARIA. The subcu (in blue) avoids those spikes and it also avoids much of the ARIA risk.

The middle figure shows how ARIA risk evolves through time, extended past the simulation of the figure. What I found of interest when thinking about this was how the placebo ARIA risk was more of a flow variable while the treatment groups as shown in these middle figures would be more of a stock variable. Here the placebo group has a risk of ARIA-E of ~2% every 18 months and yet this would be an ongoing risk that they would experience because no treatment was applied to these patients to reduce their risk. What we see for the treated patients is that slope of the risk curves through time approaches an asymptote. The interpretation is that the mab treatment is gradually resolving
the risk of the amyloid risk through its removal and after 18 months of treatment there is close to zero newly occurring ARIA-E. With this interpretation one would that through time the difference of risk for ARIA-E between the placebo and treated would become larger and larger-- with the mab treated patients having lower risk. Basically, the mab patients dealt with their ARIA-E risk and then moved on, while the placebo never addressed their ARIA-E risk and would continue to experience consequences from this risk. It is not completely clear though what level of severity would be typically involved with placebo ARIA-E risk.

This line of thinking returns us to the topic of cerebral amyloid angiopathy and how ignoring it has its own level of risk. This possibly includes outcomes such as strokes etc.. Clearly it would be worthwhile if this were to be given more attention. There would be probably be a considerable number of people who would be more than happy to recognize this (ARIA-E, ARIA-H micro-hemorrhage, macro-hemorrhage, etc) as a risk and proactively manage the risk instead of ignore it. This would be true even outside of the narrowly defined boundaries of strictly AD.

The bottom figure shows how ARIA-E risk has changed starting from the Aducan phase 3s, to Lecanemab Clarity IV and then to the simulation using subcu dosing by APEO genotype. It is remarkable how large the risk reduction has been; the figure almost needs to be on a log scale to accommodate the very large decline in risk. The decline for the e44s has been especially large: from 64% with Aducan, ~~15% in Clarity, to ~~8% with subcu dosing.

What is particularly noteworthy is that with Lecanemab subcu dosing for the e33s and e34s they are approaching a similar ARIA-E risk as placebo. It is possible that they might even below placebo risk. This could happen as explained above because the ARIA-E is actively being reduced with mab treatment. Once the amyloid has been removed then presumably the treated groups would no longer have ARIA risk, while the risk for placebo would continue
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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

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In one of the posts yesterday I suggested that Aducanumab perhaps should now be abandoned as a product. My thinking was motivated by the large ARIA risk that was highlighted in the post above. What this table highlights for me is how the risk of Aducanumab is highly dependent upon the treatment context. After the first 10 mg/kg dose is given there are only 3 additional serious ARIA events that occurred and these 3 events were in the context of 143 (81+8+54) events during these infusion rounds.

What this suggested to me is that perhaps Aducanumab after the 8th dose might have similar ARIA risk to that of Lecanemab. This could be a question to explore further as it is possible that there might be advantages for some patients to be treated with Adu over Leca due to their somewhat different biological targets.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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ARIA 25.PNG
Minimal 1.PNG
revue neurologique

High-clearance anti-amyloid immunotherapies in Alzheimer’s disease. Part 1: Meta-analysis and
review of efficacy and safety data, and medicoeconomical aspects
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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An article in press from revue neurologique reviews efficacy and safety for anti-amyloid mabs.

The bottom figure shows the CDR-sb results for various mab trials. To the bottom in red is the minimally clinically relevant difference. What is somewhat problematic in using minimally clinically relevant difference is that it is a stock variable. Someone has an MMSE of 20 and this is clearly different for this someone when they had an MMSE of 25: there is clinically relevant difference in the two scores. Perhaps for MMSE the minimally clinically relevant difference would be ~3 points. (Answer to this skill testing question is revealed later on in the figure and is suggested to be 1.25 and 2.3 MMSE points.) Problem is that this is a stock variable.

It is then compared to the results of clinical trials which are flow variables. Best not to compare stock and flow variables; it's like comparing 100 bushels of corn and a production capacity of 10 bushels of corn per day. It is not that easy to sensibly make this comparison. Analogy applies to AD decline (flow) and minimal comparable difference (stock): apples and oranges.

The above figure reports 2 serious instances of side effects in Lecanemab treated patients. These reports have as of yet not been included in the FDA's FAERs database of side effects. It would have been helpful if they had included a label or indication in the figure in each of Part A and B; one can assume that the left figure is before and the right figure is after. From the viewpoint of a completely inexperienced MRI observer, these images clearly would seem of concern.

It would have been helpful if the full APOE e4 genotype had been provided for each of the patients. It would also be useful to have the wider context of these patients in relation to the overall Clarity trial population. It should be noted that safety of Lecanemab treated patients is very much a moving target. For example, the reported 12.5% ARIA-E risk for Leca treated patients in Clarity from yesterday no longer is reflective of the risk patients will experience as subcu dosing rolls out. The figure ~2 above indicates that subcu dosing is predicted to be multiple times safer than IV dosing. This does make it more challenging to have a valid discussion of treatment risk; it is no longer obvious whether discussing legacy IV dosing is relevant. It is also possible that additional risk reducers will emerge with more clinical experience; considering how rapidly mab safety has recently been evolving such additional risk reduction does not seem that unlikely.

One could well imagine that with subcu dosing, patients could exercise much more caution especially on the uptitration phase and hold back on another dose if they had a head ache etc. in a way that perhaps they wouldn't if they felt under pressure to receive treatment in an IV infusion setting. This feature of human behavior might not have been realistically modeled in official clinical trials to date. In the figures of ARIA above both the patients develop ARIA reactions towards the early end of their dosing: 4 and 2 months. I am very interested to see whether a sloower uptitration is tried with Lecanemab for those who would feel more comfortable with such a dosing schedule.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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