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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This is the updated figure. On the left I added in the feature that the safe dosing can increase through time as the amyloid clears. On the right I show the daily spiking pattern that happens and I show how the dosing is now below the red line (moderate ARIA), the orange line (mild ARIA) and even the blue line (radiographic ARIA) which increase through time as amyloid is cleared.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Clarity ARIA-E APOE.PNG
ARIA 2.png
Dosing 35.png
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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

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I just wanted to refresh some of these good ones from previous posts.

The figure directly above shows the safety flow through with Clarity. It is good to be reminded that all symptomatic ARIA results in treatment suspension. Only mild asymptomatic radiographic ARIA can be dosed through.

The next figure up shows the responses of different subgroups. This reminds me of how there are known subgroups that have had large responses. What we see in the figure is that those on standard of care AD medications and those with mild AD (also on another slide we see that those >75) have bigger responses as expected as we are enriching with patients with more established AD.

Up another figure we see the infusion reaction numbers. What is of interest here is that it is noted that 6 of 7 severe infusion reactions occurred on the first dose. The Florida patient had 3 severe responses to treatment so this is very very unusual in the Clarity population.

The figures in the first post show the time series for ARIA with the bottom figure showing how subQ compares to IV dosing.
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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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ARIA post cog.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I was wondering whether they measured plasma GFAP (in the context of the Florida patient). Well perhaps at least during the randomized portion, yes, they were measuring GFAP. Interestingly, in the lecanemab patients it fell off quite a bit ( by ~45 pg/ml while rising ~37 pg/ml in placebo). High GFAP was shown to lead to AST+ which was bad; and about 100 pg/ml separated the high and low GFAP groups. So the 85 point change shown above is quite a bit. It would clearly be exciting if they were able to show the results for Clarity by conditioning on GFAP. Using GFAP might be able to select the patients in the trial who would actively decline versus those who would largely remain stable -- i.e., e.g., the 30% of placebo who did not decline. This would tend to increase the separation between treated and placebo.

Also wanted to note that the Clarity results were higher when the post-ARIA results were excluded. This is something I have been uncertain about for a while: Did they really include post-ARIA cognitive tests for patients who were still recovering from ARIA? That would seem to be a distortion of the results. I think this might have been done in Emerge and Engage. You really do not want to give weight to cognitive measures when people are still struggling with brain fog etc. from ARIA. That is a short term distortion that likely should be ignored. The above results from Clarity show that the topline CDR-sb would move up to 0.503 when post-ARIA was ignored.

The figure above that shows the PRIME results once again. What I want to restress is that there are quite a number of patients who have done quite strongly on mab treatment. What we see is that of these Aducanumab treated patients the 10mg/kg group had a 1.26 CDR-sb advantage over placebo; the titration group had 1.19 advantage; the 6 mg/kg had a 0.80 and the 3 mg/kg had a 0.56. That is all told about 100 patients who support the ~1.25 regression result. We also know that many patients in Emerge and Engage also had over 1 CDR-sb advantage over placebo. That is a substantial treatment effect. What I think is happening is that the trials then added in many others who were weaker responders. Nevertheless there is a core group of patients who do quite well on mab treatment. However, without a waterfall figure this is not made obvious.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I also wanted to note how strong the Florida patient's response was. The quote I gave earlier stated that this patient had 24% of her amyloid plaques cleared of amyloid and the other 21% largely devoid of amyloid. That is quite remarkable! After 3 infusions almost half of her amyloid had been removed? This patient was a super responder! You want to find some biomarker such as GFAP that indicates a robust response and then dial back treatment to a safe level.

I am really looking forward to some exciting datasets from the ADCOM upload tomorrow! I suppose strategically it would be best to just tick down the clock and hog the ball, though there is so much great material that could be discussed which could help us to understand more about AD. Make it an early night everyone; Tomorrow is going to be a big day!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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FDA has now uploaded the ADCOM documents!!

https://www.fda.gov/advisory-committees ... s-advisory
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Very exciting everyone!

The ADCOM documents have been uploaded and we are now all busily doing our best to decipher them.

I will give you a quick run-through on the highlights.

The first observation was that the FDA document was somewhat slender at a mere 35 pages.
Admittedly I am slightly disappointed that their Briefing Document was not more voluminous.


In terms of surprises, Table 3 from the Eisai Backgrounder pdf was unexpected with tau PET measured. I have boxed in red that Clarity did in fact have a sample of tau PET and they also measured plasma GFAP. The tau PET had a sample of 122 on placebo and 135 on treatment (257 total). This is of considerable interest as we saw in Trailblazer (phase 2 and 3 studies) that tau selection amplifies study results quite a bit. With dual amyloid and tau selection there is the potential for Clarity's topline to move up from 27% --> ~35% and with strong tau selection --> ~50%. I am very unsure why this top card has of yet not been played. Perhaps ~125 per arm is not quite enough or there would be a problem with it not being randomized.

Biomarkers 2.png



There were more details provided about the OLE fatalities.

This is the tPA patient in the FDA Backgrounder.

Acute multifocal intracerebral hemorrhage was reported in a 65 year-old female, homozygous for ApoE ε4, with no microhemorrhages or superficial siderosis at screening MRI. Her relevant past medical history was patent foramen ovale. The subject completed 301 Core on placebo. Based on

26

the adverse event dataset, she started complaining about headaches after the first dose of lecanemab in the open-label extension phase. Four days after the 3rd dose of lecanemab, she experienced garbled speech and left gaze preference. A CT scan showed hypodensities in the left temporal, and parietal and right occipital region, and an occlusion of the M3 branch of the left middle cerebral artery. An occlusive left sided ischemic stroke due to an LM3 occlusion was diagnosed. After administration of the thrombolytic medication tissue plasminogen activator (tPA) the subject experienced a headache and agitation and imaging showed bilateral intracerebral hemorrhage with subarachnoid hemorrhage and EEG showed nonconvulsive seizures.



What this description provoked for me was the observation of how this patient just as with the Florida patient developed a severe response after the third dose while experiencing noticeable symptoms on the first dose. What I then considered as in the figure below is how when one starts out on dosing there is a natural titration that occurs even when one is not titrating. So, you give the first dose and it might reach a Cmax of 100 micrgr/ml Leca and there is a half life of 5 days. This means that on the 14th day you will have ~ 12 microgram/ml in your system and you add in another 100 microgram/ml and your Cmax is now 112 and so on. Even without titration you are still titrating!

Why is that relevant? 2 of the 3 fatalities in the OLE were with patients on the third dose as this uptitration was occurring. We saw this also with Aducanumab. This makes it all the more important to be highly observant of symptoms on the early doses. A virtual observation visit would standardize the coding of the symptoms so it would be better known what was and what was not especially unusual.
UpDosing.png

More details were given of the Florida patient in the FDA backgrounder. Interestingly, it seems that at screening the patient did not have microhemorrhages but the OLE MRI found 4 microhemorrhges. One might then wonder whether it is not so much the baseline number of microhemorrhages but the temporal change. 4 microhemorrhages over 18 months might then be thought too many. The recent article on this patient also noted that the Boston criteria which was not used in this study (specifically Boston Criteria 2.0) considers the position of the microhemorrhages in addition to their number and apparently is the state of the art CAA detector. I wonder whether this CAA staging approach might be discussed at the ADCOM?

"According to the narrative provided by Eisai, the screening MRI prior to enrollment in 301 Core only showed a left parietal meningioma < 1cm, and no microhemorrhages. According to the pre-print manuscript but not confirmed by Eisai, the pre-treatment MRI before the open label extension showed 4 small cerebral microhemorrhages."


"Relevant past medical history included chronic kidney disease, aortic atherosclerosis, hyperlipidemia. She had the third dose of lecanemab on Extension Day 31. Based on the pre-print manuscript the subject had been complaining of headaches occurring about an hour after each infusion. After the third dose of lecanemab, she began to experience progressively worsening memory impairment described as “brain fog.” One week after the third dose of lecanemab, the subject experienced a sudden onset of difficulty speaking, left head and gaze deviation, and left side weakness, reported in the original CIOMS report as a possible cerebrovascular accident and possible seizure. The manuscript described the event as a seizure, after which she regained alertness but was not communicative or with purposeful interactions."

The big surprise for me in this description of the patient history was that the "seizure event" occurred one week after the third injection. It simply illustrates for me how some patients simply will not seek medical attention even when they desperately need it. By carefully considering these patient reports we could think of risk management strategies that could help the hundreds of thousands of others who might be treated with Lecanemab. Not seeking needed medical care is not an uncommon behavior. This patient demonstrated it to what seems to be an extreme degree, though many others would probably behave similarly. Considering the patient's e44 genotype, on an anti-amyoid mab and was having these symptoms an objective observer would reasonably have called this a medical emergency well before the hospitalization. These headaches are a detectable sensation by the patient of amyloid being actively clearly from their brain's blood vessels. This is something that patients need to learn is potentially quite dangerous. Virtual observation visits would help.

The FDA ADCOM url has provided the lineup for Friday. I wonder whether they will upload any presenter slide decks before the meeting? It would make everything so much easier to follow along with.

I am also interested to see whether all the documents will be thrown into a Large Language Model like ChatGPT. I have been able to get an instance of a LLM functioning on my computer, so creating a Leca ADCOM chatbot should be highly doable. Will be very interested to see if this will be done.

I had not been aware that severe infusion reactions resulted in treatment discontinuation.

"Of the 898 patients treated with lecanemab, 7 (0.8%) patients experienced severe infusion-related
reactions and almost all resolved between Days 1 and 4 post reaction, and all were discharged
without further incident. All were discontinued from study drug per protocol. No placebo
patients experienced severe infusion-related reactions.
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