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.

Post by J11 »

Looking at the ARIA-H slide at the top of this set of posts, we can get a better feel for this type of AIRA in the context of Lecanemab. We see the three types of ARIA-H: microhemorrhage, superficial siderosis and cerebral macrohemorrhage. Clearly it is somewhat surprising to see how common microhemorrhages are. Fully 7.0% of the placebo had a microhemorrhage (isolated without ARIA-E), while this occurred in 6.7% on lecanemab. This point needs to be constantly repeated: it is surprising, though is likely highly underappreciated-- 7% of the typical AD population will experience a microhemorrhage during 18 months even without undergoing treatment? One would certainly like to know what the percentage would be in a non-AD population.

I am becoming increasingly unclear where the line between stroke/macrohemorrhage etc and AD should be drawn. They are more intertwinned than I had been aware. I am very interested in learning what the rate of stroke/macrohemorrhage will be once patients have been treated with Lecanemab for a year or two. We are only seeing the risk events that occurred within the reported trial timeframe. However, there is no reason to expect that those on placebo would miraculously have less ARIA risk after the trial ended; if anything their risk probably would escalate. Yet, with Lecanemab treatment such risk realistically would decline. Removing the amyloid from the cerebral vasculature over time would be expected to help reduce risk of macrohemorrhage etc..

It would have been better if we had been given more detailed descriptions of the patients affected by severe side effects during Clarity. What we can see from the slides is that there were 7 severe ARIA-E events and 5 severe ARIA-H events. (I am not sure whether or not these events overlap or not). The ARIA-H severe events would typically refer to macrohemorrhages. Such an adverse response is obviously of great concern. No obvious treatment could help with such a side effect. These macrohemorrhages were defined as being 1 cm or larger which is substantial. As noted above, though, 60 patients experienced a microhemorrhage.

The bottom slide also caught my attention. To the top right in the table it is reported that those on anticoagulants during the phase 2 CORE and OLE did not actually experience macrohemorrhages. 0 out of 11 -- 0 out of 18. This probably could help explain the confusion that we have gotten into with Clarity. Those on anti-coagulants were thought to be at low risk and then on Clarity with the OLE those on anti-coagulants were actually found to have a 3.6% risk (5 of 140) of macrohemorrhage and for 2 of these patients they had a fatal response. These 2 on anti-coagulants were all of the 2 noted fatalities on lecanemab (Core or OLE) at that time, though we are now aware of a third fatality.

To be clear about the risk: for those not on anti-coagulants the risk of macrohemorrhage and on Lecanemab (during core and OLE) is 5/1468 = .341%. The risk of severe ARIA-E presumably would then be added onto that.
Last edited by J11 on Fri Jan 06, 2023 8:54 am, edited 1 time in total.
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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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The above post shows the clinical information for the 65F e44 (second reported fatality) in the Lecanemab OLE from yesterday's NEJM article. It clearly indicates that this patient was negative for anticoagulants. In the slides above, this patient was clearly included in the anti-coagulant use group.
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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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Obviously this is a very disturbing response to treatment within the environment of Lecanemab. The article characterized the response as "with necrotizing vasculopathy involving amyloid deposition". I had wondered how this response could best be described-- necrotizing vasculopathy is probably even more dramatic than I had thought of. My description would have been more along the lines of dissolving the cerebral vasculature which in effect is what "necrotizing vasculopathy" seems to imply.

Of great importance, the NEJM article notes that:

" ...computed tomography (CT) performed just before t-PA administration showed hypodensities in the
left temporal–parietal regions and a distal left middle cerebral artery branch occlusion but no
hemorrhage
."

I had not been entirely clear about the time sequence involved. I had though perhaps Lecanemab might have had at least some more direct role in the side effects before tPA administration. Apparently not. There was an absence of hemorrhage before they treated with tPA and then the figures above with profound neuropathology occurred.
As a first round approximation it is not self-evident that Lecanemab was of direct causal importance in this particular patient. The top most question for me is how this would have turned out if they had treated with thromboectomy. It would seem to be a research priority to investigate how patients on ab mabs with ischemic stroke will react to thromboectomy.

It is best to leave this up to CAA experts, though the topline quote for this incident could plausibly be that
this was a treatment related fatality. If this patient had not received tPA, then she would be alive and healthy today.
Attributing the consequences of tPA treatment to Lecanemab does not plainly follow.

I greatly wish that each of these tragedies can serve as a learning moment. It is not the best way to learn. It would have shown a great deal more intelligence if these events had been anticipated and then avoided. However, it is even worse when events happen -- nothing is learned -- and then more events happen.

Lesson 1:
We have had the fatal event with the Canadian patient on Aducanumab who was dosed through even when the MRI indicated that treatment should be suspended. Lesson learned: Allow patients to email their imaging to an expert specialty radiology centre for high level analysis.

Lesson 2:
We have had the fatal event with the 65F e44 with the MCA stroke treated with tPA. Lesson learned: Avoid tPA treatment and when possible treat alternatively with for example thromboectomy.

There are probably a few more learnable moments here though the patient details have not always been described with precision. Lesson learned: Be more open so that lessons can be learned and everyone can benefit.

One other surprising feature that I found in some of the commentary was that apparently with the 65F MCA patient the doctors went to the internet and read up on tPA and then felt they had the knowledge they needed to treat. This seemed surprising to me. Did they really only rely on their clinical judgment to make this decision? I found that quite surprising. They then treated with an 8mg bolus dose of tPa and then dosed with 76 mg dose. 50 minutes in and after 65.7 mg of the dose had been delivered the patient went into medical crisis.

That is very unexpected. Perhaps doctors should be more about following expert guidance from artificial intelligence programs or a global human 911 expert center. Doctors would then be doers and not top end thinkers. After they put in a 48 hour shift it is difficult to reasonably expect them able to have even minimal cognitive ability. A global 911 type system would seem to be an obvious and potentially invaluable resource for patients on a planet wide scale. Great part of this is that it could happen with or without approval of establishment medicine. Basically, if you are on Lecanemab and your wife is e44 with an MCA stroke you could call this 911 number and ask them what they thought of treating with tPA. Clearly, the experts would need to think about that (and it is always so much easier to be right afterwards and not before), though this would give you a fighting chance to have a better outcome than a worse one.
Last edited by J11 on Thu Jan 05, 2023 8:45 pm, edited 3 times in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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J11 wrote: Thu Jan 05, 2023 5:06 pm
Hi J11,
Hope you don't mind if for the sake of clarity (pun intended) I insert some comments and resources into your post.
Clearly it is somewhat surprising to see how common microhemorrhages are. Fully 7.0% of the placebo had a microhemorrhage (isolated without ARIA-E), while this occurred in 6.7% on lecanemab. These percentages are actually for concurrent ARIA-E and ARIA-H, the middle section is for isolated ARIA-H, which tended to occur late in the trial and sporadically, as expected in a population with AD pathology and some CAA.This point needs to be constantly repeated: it is surprising, though is likely highly underappreciated-- 7% of the typical AD population will experience a microhemorrhage during 18 months even without undergoing treatment? One would certainly like to know what the percentage would be in a non-AD population. You may want to delve into this source I found: [url=phttps://ad.biogenpro.ca/content/dam/intl/europe/canada/ad/biogenpro/en_CA/pdfs/ADvance_Program_ARIA_Module_EN.pdf] ADVANCE ™ Biogen Alzheimer's Education: Detection and management of ARIA[/url]
Image 1-5-23 at 7.59 PM.jpeg
...

It would have been better if we had been given more detailed descriptions of the patients affected by severe side effects during Clarity. What we can see from the slides is that there were 7 severe ARIA-E events and 5 severe ARIA-H events. (I am not sure whether or not these events overlap or not)..... I think that ARIA-E and ARIA-H severity are assessed separately for severity, even if both occur at the same time or within the first 6 months.

Here's a description from a December 2022 article Comparing ARIA‐E severity scales and effects of treatment management thresholds using Gantenerumab studies. It seems to be using a framework meant to be applied across studies.
Image 1-5-23 at 8.06 PM.jpeg
This is a February 202 article describing rating severity for aducanumab; again it seems likely it would have been similar for CLARITY:
In the aducanumab phase 3 studies, treatment-emergent events of ARIA-H microhemorrhage and ARIA-H superficial siderosis events were independently assessed. The severities of ARIA-H microhemorrhage and ARIA-H superficial siderosis were categorized based on the number of treatment-emergent microhemorrhages or foci of superficial siderosis: mild (≤4 new incident microhemorrhages / 1 focal area of superficial siderosis), moderate (5–9 new incident microhemorrhages / 2 focal areas of superficial siderosis), or severe (≥10 new incident microhemorrhages / >2 focal areas of superficial siderosis) (21).
Detection and Management of Amyloid-Related Imaging Abnormalities in Patients with Alzheimer’s Disease Treated with Anti-Amyloid Beta Therapy
Always fun to burrow into the data!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Thank you NF52 for posting this information.

Yes, the first figure was from my post of Fri Dec 23, 2022 12:20 am when I was trying to get up to speed on ARIA.
ARIA-H with macrohemorrhage clearly seems to be a focal point of concern for safety. Patients with a macrohemorrhage would seem to be in a very very high risk subgroup for extreme negative response.

I am not as clear about those with severe ARIA-E without ARIA-H. It will be very much appreciated when more information is presented for these patients.
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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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The top two figures are the MRIs for the third Lecanemab fatality.

It really would have been so helpful to have ADCOMMed this and then we could all at least agree on facts.
The possible learnable lesson here could be to stay with the exclusions. There is question as to whether this patient was even eligible per the core inclusion/exclusion rules. The purple boxes in the middle MRI are the microhemorrhages identified by radiology experts. The orange boxes are J11 non-expert question boxes. Are these also microhemorrhages?

The core Clarity study read out very clean on safety. The placebo had a higher mortality rate than treatment on the core. One of the placebo patients in the core had a fatal intracranial hemorrhage as a result of a macrohemorrhage, while none of the treated patients had a fatal macrohemorrhage.

It is only when we move to the unblinded OLE that safety problems seemed to emerge. Yet, even here there are now a great many questions about these patients. Treating a MCA stroke with tPA in the context of Lecanemab seems highly problematic. Other issues might also be present in other of these patients and it would be good to discuss them.

The bottom figure above includes on the left what seems to be a pure ARIA-E event. It does not appear that an ARIA-H occurred concurrently for this patient. What I found notable here is that even an isolated ARIA-E can cause lasting impairment-- for this patient MMSE went from 25 to 16 year later. For an ARIA-E you might guess that fluid in the brain could simply resolve through time without lasting harm-- this was not true for this patient.

On the right we see what happens when we have the combined force of ARIA-E and also ARIA-H. Here the ARIA-E on the left part of the right surrounds a large brain region and then this causes a massive ARIA-H legion of 7 cm with MMSE falling from 25 to 13.

I really want to see full descriptions for these patients and some perspective on where they are on a prespecified risk scale.

It was such a great feature of Clarity that they stopped dosing all patients with symptomatic ARIA. The patients who developed severe ARIA were those whose first side effect was severe. Big question would become: How to prospectively identify such patients? The highlight from that for me was also that it is truly the symptomatic ARIA that would seem to be of the most clinical relevance. These are the patients who had outward symptoms from ARIA. The radiographic ARIA is more about detecting the patients who are experiencing brain ARIA often without outward symptoms and preventing these patients from progressing to a symptomatic ARIA.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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There was a miscommunication problem with the ARIA-H slide. I want to go back to it.
It is startling and bears repeating.

63 placebo patients ( N= 897 7.0%) experienced a Microhemorrhage while in the 18 month Clarity trial.

Sometimes you read something like that and it just rolls over you, you yawn and then continue with your life.

63 microhemorrhages on placebo.

J11 can only do so much to capture the thread readers attention.
Basically, 7.0% of AD patients will typically experience a silent stroke over 18 months.
It is quite startling when you think about that.

At some point the AD stroke nexus will need to be explored more fully.
Of interest is that Lecanemab could play an important part in potentially resolving the problem.
The especially high risk of stroke in AD would seem to be related to the pervasive CAA that is present
in AD patients.
Last edited by J11 on Thu Jan 05, 2023 10:07 pm, edited 1 time in total.
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