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 »

NF52, thank you for mentioning the question about cognitive outcomes of epsilon 4s versus epsilon non-4s. It had been a frustration for me and it has become even more so now that I have considered it again. I can not understand why the epsilon 4 genotype has not been reported as epsilon 34 and epsilon 44. The different APOE genotypes have different risks and rewards and it would seem appropriate to clearly disclose what is known. However, as the figure above shows, almost all of the trials have neglected to be more specific about these results.

My best guesstimate now is that the e34s have performed quite well in several of the trials. We know that the e34s had a benefit of 0.50 on CDR-sb on Clarity. We also know that there was a 0.53 CDR-sb benefit in the 302 Aducanumab high dose trial for the e4s. If we assume that e34 > e44, then 302 high also had a CDR-sb benefit for e34 of >0.50. Notably this benefit was increasing at the last readout called for futility, so there was probably even more gains that left unreported. The 302 low dose had a 0.40 CDR-sb benefit. This arm outperformed given its amount of SUVR removal, so this would nudge the CDR-sb even higher; it also was increasing at the futility call. The figure above reported that Trailblazer1 had a 0.59 CDR-sb benefit for e4s. We also know the topline Trailblazer2 was 0.696 CDR-sb benefit. The phase 2 Lecanemab arm at the highest dose with the e4s had a 50% cognitive benefit on ADCOMS. The e34s in Clarity and the e4s in the other trials did consistently well. While we do not have the exact results for the e44s and e34s for most of the trials, my guess would be that e34s had a gain of 0.55-0.60 on CDR-sb for the typical trials such as Clarity/ Emerge/etc.. Since e34s have a 55% percent weight in typical trials this helps contain the potential results in reasonable range. If the e44s were to have done particularly well in a trial (say ~1 CDR-sb) the problem is that with only 15% weighting this will not move the needle that much on the overall result (implying that other genotypes would then also need to have also put in a reasonably strong showing).

The big question mark is for the e44s. All we have is the result for Clarity which was a 0.28 relative loss versus placebo on CDR-sb. Given the other trial results this does not seem realistic. Such a score would then force the e34 result much higher to give us the results in the 0.5-0.60 range for the overall e4s.

The e33s are also somewhat of a mystery. We have their results in the various trials and only the Clarity trial gave a strong positive signal. However, given the strong result in TB2, it is difficult to imagine that all of the subgroups did not have at least a moderately strong benefit. If this were not true, then one of the genotypes would need to have had a very strong showing.

Importantly, by dual selecting on tau and amyloid, TB2 introduced the possibility that patients of all genotypes could achieve a strong treatment gain. It might then no longer be proper to compare TB2 results to those of other mab trials.

I greatly wish that we will have more information about the genotype results by the time of the ADCOM. In order to make an informed decision it is important to have the needed information.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by NF52 »

J11 wrote: Wed May 31, 2023 8:50 pm Importantly, by dual selecting on tau and amyloid, TB2 introduced the possibility that patients of all genotypes could achieve a strong treatment gain. It might then no longer be proper to compare TB2 results to those of other mab trials.

I greatly wish that we will have more information about the genotype results by the time of the ADCOM. In order to make an informed decision it is important to have the needed information.
J11, this article from May 3, 2023 may provide a hint as to what the analyses could show, although this one does not differentiate by ApoE status. Since it's a free PMC article, I'm taking the liberty of including most of the abstract:
Could tau-PET imaging contribute to a better understanding of the different patterns of clinical progression in Alzheimer’s disease? A 2-year longitudinal study
Abstract

Background: Monitoring the progression of Tau pathology makes it possible to study the clinical diversity of Alzheimer's disease. In this 2-year longitudinal PET study, we aimed to determine the progression of [18F]-flortaucipir binding [i.e. Tau PET] and of cortical atrophy, and their relationships with cognitive decline.

Methods: Twenty-seven AD patients at the mild cognitive impairment/mild dementia stages and twelve amyloid-negative controls underwent a neuropsychological assessment, 3 T brain MRI, and [18F]-flortaucipir PET imaging (Tau 1) and were monitored annually over 2 years with a second brain MRI and tau-PET imaging after 2 years (Tau 2). We analyzed the progression of tau standardized uptake value ratio (SUVr) and grey matter atrophy both at the regional and voxelwise levels. We used mixed effects models to explore the relations between the progression of SUVr values, cortical atrophy, and cognitive decline.

Results: We found an average longitudinal increase in tau SUVr values, except for the lateral temporoparietal cortex where the average SUVr values decreased. Individual analyses revealed distinct profiles of SUVr progression according to temporoparietal Tau1 uptake: high-Tau1 patients demonstrated an increase in SUVr values over time in the frontal lobe, but a decrease in the temporoparietal cortex and a rapid clinical decline, while low-Tau1 patients displayed an increase in SUVr values in all cortical regions and a slower clinical decline. Cognitive decline was strongly associated with the progression of regional cortical atrophy, but only weakly associated with SUVr progression.

Conclusions: Despite a relatively small sample size, our results suggest that tau-PET imaging could identify patients with .a potentially "more aggressive" clinical course characterized by high temporoparietal Tau 1 SUVr values and a rapid clinical progression In these patients, the paradoxical decrease in temporoparietal SUVr values over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. They could particularly benefit from future therapeutic trials, the neuroimaging outcome measures of which deserve to be discussed.
I know from personal experience that the AHEAD trial of lecanemab in people without cognitive impairment is using both an amyloid PET 1 and Tau 1 PET (shortly before baseline) and Amyloid PET 2 and Tau PET 2 (at the 96 week mark; almost 2 years). Having a positive Tau PET is not required for inclusion in lecanemab trials, as you have noted, but having this data, which I assume was available in CLARITY as well as the Trailblazer studies of donanemab, may accelerate the diagnostic value of the Tau PET as a variable for disease stage.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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NF52, thank you for your comment.

My impression is that Clarity does not have tau PET. If they had, I am sure that they would have already highlighted the results as the numbers should greatly amplify when adding in tau selection. Including only amyloid positivity introduces the problem that some will be too tau early and some too tau late. Tau PET helps to select the tau just right. I am sure somewhere on thread I whined ad nauseum on this point during the Clarity randomized trial portion, though I suppose that once everything is locked into a statistical plan, no one wants to change the game plan on the fly.

With Clarity we are talking about 0.45 CDR-sb benefit. Yet, with the Donanemab Trailblazer2 all of sudden the results have magnified to ~0.7! If they disclose the selection within this topline the numbers could amplify more. Also if they report genotype specific data (perhaps at AAIC 2023 in about a month!!!) we could see even bigger numbers. As a rough guess I am assigning e34 as the top performer in TB2. If either of the other genotypes had a noticeable miss it would mean that the e34s would have had to have performed quite well in the trial.


Your initial comment about APOE epsilon response in amyloid mabs has motivated me to think more about it. It is just very disappointing that this has been neglected so much to date. The e44 patients who are considering Lecanemab or other mab treatment really need to have the best assessment of what benefit they might expect. For them there is at least some risk that they will not survive treatment. It is that important to get this right. For the most part the published evidence does not provide that much definitive evidence for the e44s.

Clarity was reported as negative, though even here the other measures ADAS-cog and ADCS MCI-adl reported e44s as having 1/2 and 2/3 relative benefit tot he e34s respectively. However, the one positive is that most of the published studies have shown a benefit of ~0.5 on CDR-sb which suggests to me that e44s have done consistently fairly well and that Clarity might have been an outlier.

The Clarity e33 appears to have been quite the outlier.


In this url I try to gain some sense of where the Donanemab TrailBlazer2 might report out for the APOE genotypes.
I started with the estimate that the APOE e34s have a gain ~0.55 CDR-sb on most trials. I then scaled this up to account for the tau selection added into TB2 and then went with the rough guesstimate of a 0.80 gain for APOE34. That's the solid black line in the url. So the black line and the lines parallel to it are contours. The moving purple dot then shows what the e44s (y-axis) and the e33s (x-axis) need to be for various values for the e33s. I added the red circle to give the most likely range where the reported result might wind up which covers pretty much the entire possibility space.

https://www.desmos.com/calculator/2dhd09xggu
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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This is a report on a patient fatality in the open label that I think has been referred to as the Florida patient who had a stroke like episode. Of the three patient fatalities in t eopen label of Clarity this patient seems to be the most interesting and most perplexing. The article was recently posted to medRxiv.

Another recent report of the tPA fatality was also recently reported. Considering how important this is it would be helpful if the page rights could be bought so that this important research was not paywalled before the big decision.

https://doi.org/10.1101/2023.04.26.23289061


Remarkably given the critical importance of APOE genotype in ARIA risk and its connection to CAA, the article is inconsistent on this question.


pdf page 2 confirmed APOE genotype as e44 by autopsy(?) and CAA etc.(?)
"Autopsy confirmed APOE genotype of E4/E4 and the presence of typical neuropathological features of Alzheimer’s disease along with severe cerebral amyloid angiopathy with inflammatory features, including perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls."


pdf page 4 confirmed e44
"APOE genotyping was not available from her clinical records, so this was obtained as part of her autopsy; she carried two copies of the E4 allele."

On pdf page 11 the patient's genotype is reported as e33.
"Three blocks of tissue were submitted to Vanderbilt’s VANTAGE genomics core for DNA extraction and sequencing to assess APOE genotype. A control panel was simultaneously genotyped to ensure correct allelic discrimination. All three replicates returned identical results, homozygous C/C at rs429358 and homozygous C/C at rs7412, consistent with a homozygous E3 genotype."


I asked CHAT GPT 4.5 what genotype was homozygous at both the APOE AD loci:

"The APOE gene is the most important risk gene for Alzheimer’s disease. The SNPs rs429358 and rs7412 determine the APOE genotype. For both SNPs, either a C or a T can be found on DNA level, leading to either an arginine or a cysteine on protein level, respectively. If the allele is © and the same chromosome also harbors the rs7412© allele, the combination is known as an APOE-ε4 allele1. Therefore, if someone has an APOE epsilon genotype that is homozygous C/C at rs429358 and homozygous C/C at rs7412, it is consistent with a homozygous APOE-ε4 allele"

So the pdf page 11 misstated the e44 genotype as e33.

The description of the evolution while in hospital for this patient appears to have changed. Now there are reported to have been numerous microhemorrhages on neuroimgaing while she was admitted for stroke like behavior.

"A woman between 75 and 80 years old in good general health, with no clinical history of hypertension or neurological disorder except for an approximately four-year history of mild but progressively worsening memory symptoms. Tau and β-amyloid PET scans supported the diagnosis of Alzheimer’s Disease, and she was enrolled in a randomized controlled trial of lecanemab where she was assigned to the placebo group. The patient reported no adverse effects nor perceptible benefits, and at the completion of the trial she was enrolled in the open-label extension which guaranteed treatment with the active drug. She was treated with three infusions of lecanemab, each dose (10 mg/kg) approximately two weeks apart. According to her study partner, approximately an hour after each dose she developed a headache causing her to spend one to two days in bed recovering each time. After the third dose, she began to experience progressively worsening memory impairment which she described as “brain fog.” On the day of hospital admission, she had a seizure which began with left head and gaze version and left sided tonic contraction which evolved into 30 seconds of generalized convulsion. She regained alertness after this event but was never communicative nor purposefully interactive again. Electroencephalography did not suggest ongoing seizures to explain her condition, although she had frontal intermittent rhythmic delta activity. Neuroimaging revealed cerebral edema in the bilateral temporal, parietal and occipital lobes with numerous microhemorrhages. She was treated with 1g daily intravenous solumedrol for three days for suspected amyloid-related imaging abnormality (ARIA) without improvement. She suffered an aspiration event leading to sepsis with multiorgan failure and, consistent with her wishes, aggressive resuscitation measures were not instituted. She expired 5 days after hospital admission. An extended case history is included in the supplementary material."


I find the enlarged text below quite interesting. The patient developed a headache an hour after each dose causing her to spend one to two days in bed recovering each time Was this response even noted under either infusion reactions or ARIA in the Clarity side effects? It is also surprising to me that this was 1 hour after each dose? Aren't the patients required to remain under observation for possibility hours before after an infusion? A virtual Observation room at the patient's home would seem to me to be a great service to offer these patients. i would tend to find a e44 patient treated with an amyloid mab who had the response described quite concerning.
Such a response would suggest that the target (i.e., amyloid) had in fact been engaged. Encouragingly one might then expect that such a patient would be a strong responder, however, it also suggests that there could be considerable risk involved. One might then want to call in experts to help with clinical management which might include titration. down dosing etc..


"She was treated with three infusions of lecanemab, each dose (10 mg/kg) approximately two weeks apart. According to her study partner, approximately an hour after each dose she developed a headache causing her to spend one to two days in bed recovering each time. After the third dose, she began to experience progressively worsening memory impairment which she described as “brain fog.” On the day of hospital admission, she had a seizure which began with left head and gaze version and left sided tonic contraction which evolved into 30 seconds of generalized convulsion."

Of particular interest was this article noted that: "The patient also had severe cerebral amyloid angiopathy.

"The pre-treatment study showed four small cerebral microhemorrhages on gradient echo-T2* (Figure 1c and supplementary Figure 3).
The post-treatment study shows more than 30 microhemorrhages, all in a
It is made available under a CC-BY-NC-ND 4.0 International license .
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

medRxiv preprint doi: https://doi.org/10.1101/2023.04.26.23289061;

cortical or juxtacortical distribution and most within areas of edema (Figure 1d and Supplementary Figure 4). Selected images from the diffusion weighted and apparent diffusion coefficient (ADC) scans associated with her hospital admission are shown in Supplementary Figure 5; there was no major stroke.


Neuropathologically, we found that her condition was associated with marked perivascular inflammation and arteriolar degeneration resembling fibrinoid necrosis, leading to microhemorrhagic changes both in the parenchyma and leptomeninges. The inflammatory features include extensive macrophages and/or activated microglia in the perivascular space, along with occasional multinucleated giant cells. These features were associated with severe cerebral amyloid angiopathy. This constellation It is made available under a CC-BY-NC-ND 4.0 International license .
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
medRxiv preprint doi: https://doi.org/10.1101/2023.04.26.23289061; this version posted April 29, 2023. The copyright holder for this preprint
of findings is similar to the sporadic condition cerebral amyloid angiopathy related inflammation. This case was refractory to treatment. In sporadic CAARI, most cases respond well to corticosteroid treatment, but a minority are refractory and may have poor outcomes.


"This case demonstrates an important gap in our understanding of the molecular mechanisms of ARIA or iCARE. It would be tempting to interpret this inflammatory condition as an antibody-mediated autoimmune attack against β-amyloid in the cerebral microvasculature. However, ARIA and iCARE rates in the clinical trials with aducanumab were also quite high, despite reports that aducanumab preferentially binds parenchymal versus vascular β-amyloid (16). An alternative interpretation is that the induction of β-amyloid clearance mediated by these antibodies traffics much of the β-amyloid through the perivascular spaces, leading to periarteriolar inflammation that can worsen CAA. If this perivascular clearance overwhelms the capacity of the microvasculature, blood brain barrier dysfunction may ensue initiating an inflammatory cascade. This latter interpretation is supported by animal studies (17, 18). Defining and mitigating the molecular mechanism of this side effect may be key to improving the safety of anti-β-amyloid therapies."


In the bottom we start to see a great many microhemorrhages; article notes ~30. One wonders whether these would have been detected even after the first injection. Simple clinical observation can still be a highly powerful tool to guide treatment choices. Perhaps the registry protocol could specify a post-dose observation period and an immediate MRI if there is a similar headache/stay in bed for 2 days type response occurs.


Florida 1.PNG

These features were associated with severe cerebral amyloid angiopathy. This constellation

of findings is similar to the sporadic condition cerebral amyloid angiopathy related inflammation. This case was refractory to treatment. In sporadic CAARI, most cases respond well to corticosteroid treatment, but a minority are refractory and may have poor outcomes.




"In this case, the patient met diagnostic criteria for CAA. Importantly, the in vivo MRI significantly underestimated the extent of microhemorrhages, confirmed by post-mortem imaging with optimized acquisition settings and on neuropathological inspection. Microhemorrhages on the clinical scan are certainly useful diagnostically but should be viewed as a marker of microvascular disease rather than an indicator of the extent of microvascular disease. The trial exclusion criteria permit enrollment of patients with up to 4 microhemorrhages. These criteria do not consider of the distribution of microhemorrhages and do not standardize the screening MRI protocols, so will likely lead to heterogeneity in the detection of CAA. Detailed MRI-based diagnostic criteria for CAA have been established which are likely to perform better than the coarse criteria employed as exclusion criteria in this and many other clinical trials (14, 15). The difficulty with reliable detection of CAA is likely to be magnified as this treatment moves to the community setting where less sensitive sequences like gradient echo T2* and lower field strength imaging are prevalent, which is likely to permit more patients with co-morbid CAA to meet inclusion criteria. Another important safety consideration is that while patient screening and treatment could be restricted to facilities with adequate and standardized diagnostic capabilities, the treatment of side effects is likely to occur in the community setting in many cases. At present, ARIA or iCARE has rarely been encountered outside of a clinical trial population, so community health care providers would likely benefit from education on the features and risks associated with this side effect."




"The risk of developing iCARE correlates with the presence of CAA and associated risk factors, including APOE4 genotype (10, 13). It seems reasonable to avoid treating patients carrying two copies of the E4 genotype with this medication."

In conclusion, this case should prompt a careful evaluation of the safety of lecanemab treatment and a refinement of the approach to pre-screening potential recipients of lecanemab for cerebral amyloid angiopathy and its risk factors. We advocate that patients should be screened for cerebral amyloid angiopathy using the Boston criteria and should undergo APOE genotyping prior to treatment. The case also highlights an urgent need for neuropathological studies to address the features of ARIA and iCARE.



"An alternative interpretation is that the induction of β-amyloid clearance mediated by these antibodies traffics much of the β-amyloid through the perivascular spaces, leading to periarteriolar inflammation that can worsen CAA. If this perivascular clearance overwhelms the capacity of the microvasculature, blood brain barrier dysfunction may ensue initiating an inflammatory cascade. This latter interpretation is supported by animal studies (17, 18). Defining and mitigating the molecular mechanism of this side effect may be key to improving the safety of anti-β-amyloid therapies"






I have quoted at length above because this patient description introduces a new understanding of the nature of ARIA
in some patients. The other two fatality patients that have been reported to date appeared to have a more easily explainable pathological trajectory. This article has introduced the seemingly new conception of spontaneous multiple microhemorrhaging without anti-coagulant initiators.

This patient report raises the question for me whether there might not be biomarkers that could detect the occurrence of such microhemorrhaging. Could a patient actually experience upwards of 30 microhemorrhages without some obvious change in blood chemistry?
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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"Hospital course: She was started on heparin infusion after atrial fibrillation was identified. Anticoagulation was monitored with factor Xa levels – the highest was 2.5x the upper limit of the reference range. The patient’s clinical trial physician raised a concern for the possibility of amyloid-related imaging abnormality (ARIA) as a side effect from the experimental drug. She was started on Keppra 500 mg BID and 1 g daily of solumedrol which was continued for four doses over three days. To manage agitation, she was sedated using variably fentanyl, propofol, midazolam and dexmedetomidine infusions."

Could it have been the heparin that caused the microhemorrhages? Were the microhemorrhages present on admission?
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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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Sorry everyone for being so all over the place but things are so exciting!
alzforum is reporting today that GFAP plasma levels could be a biomarker
that could be used to determine astrocyte reactive positive (+) or negative (-).

The positive (+) astrocyte {AST+} data for cognitively unimpaired people is shown in the
bottom with PET tau as the variable of interest. Yes, there appears to be quite a bit
of tau in those with AST+.

The negative (-) astrocyte reactivity {AST-} patient data is shown in the top. there does
not seem to be that much tau with these people. I would choose to be in the AST- group.

This appears to be a fairly exciting development. Astrocyte reactivity seems to be able to
differentiate patients who will accumulate more tau and then possibly go on to become cognitively
impaired due to AD. Other research I found online said that GFAP can forewarn impending cognitive decline
10 years before a typical MCI clinical diagnosis. The price for a plasma Elisa GFAP test is ~~$500.

This could be extremely important and highly translatable into clinical practice. One might wonder whether
the CMS might even introduce such testing into a sample of those in the Lecanemab registry. Perhaps adding another layer of testing on top of PET amyloid and PET tau could find the mab patients who would not benefit from treatment. The economic incentives coupled with the enhancement of patient safety possibly might make this idea compelling.

On the patient side this could also be of considerable interest. Once Lecanemab is on the market people will want to rationally manage their AD risk. Testing with an FDA approved plasma GFAP ELISA kit would then seem to offer compelling value to the cognitively unimpaired but worried well. I am not a technical expert on the cutting edge AD biomarker tests, though this one does appear to be quite promising. However, I would not be surprised if there were even better ones available.

Importantly, one can now well imagine large pre-symptomatic AD markets arising and as they scaled prices could be reduced substantially. I saw HIV Elisa tests onine for as low as $10!! When given a chance free markets can deliver tremendous customer value.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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The excitement builds!!
This is a once in century medical revolution that we might have to wait decades to see once again.
Everything seems to be in motion.

With CMS greenlighting Lecanemab reimbursement, we might see CMS playing a patient supporting role
in Alzheimer's. Up till now CMS's main motivation has been driven by obstructing AD mab development in order
to "save" money on treatment costs -- notwithstanding the now $350 billion (and exponentially increasing) annual global dementia cost to the government. How might CMS now better align with patient interests? CMS is still motivated by "saving" money but will now be driven to seek cost savings by more clearly defining who the responder class is for mabs. Goal AD patients! We know that even now that the responder class has yet to be precisely established. 30% of Clarity placebo did not decline!

However, as noted above plasma biomarkers such as GFAP could help sort those potential patients who will decline from those who will not. Better identifying the responder class means better efficacy and better safety. Why treat patients with aggressive treatment when they will likely not benefit? A win all around for patients. It is particularly exciting that there is still so much left on the table to improve mab technology through better selection, improved safety, etc..

GFAP and other basic research often linger undeveloped for years if not decades as the academic researchers typically recognize the potential of their innovations but frequently do not have the budget to rapidly advance research knowledge into clinical benefit. Yet, now my guess is that if it were to be assessed that a $1000,000 GFAP (or similar biomarker) study could be conducted in the CMS amyloid mab registry and it were found that GFAP screening could identify Lecanemab non-responders (that might take a year or two) and could reasonably be expected to lead to $1 billion per year of treatment savings, then this idea would not wither for years on the to do list but would move up the priority list more like in weeks-- I am thinking that there is that corner office in someone's future who can connect the dots here. This save money logic would then turbocharge clinical advances in Alzheimer's in a way that has never been possible when the Alzheimer clinical economy was largely non-existent.



When I have thought of the Florida ARIA fatality from Clarity, I wondered whether this patient was actually in compliance with the safety monitoring. This patient had a can't get out of bed for 3 days response an hour after each of her Lecanemab transfusions and this was somehow overlooked? I have been unable to find the working definition of severe symptomatic ARIA, though I think that can't get out of bed for three days would qualify. As we see in the figure below only 1 of the e4 homozygotes was considered to have had severe symptomatic ARIA. Was this the Florida patient?

From what I can make out the Florida patient was at truly extreme risk:

The patient was epsilon 44. (~ top 15% of risk)
The patient had 4 microhemorrhages at baseline. (This greatly amplifies ARIA risk)
The patient had severe symptomatic ARIA like responses to all of three of her infusions including before her fatality.

Subsequently it was determined that the patient also had severe CAA.

This patient seemed to have had most of the major risk factors and must have had very high risk (prospective to her hospitalization). As a rough guess I would estimate this patient was easily in the top 1% of risk of the Clarity patients.
I believe that I have read of another patient (possibly in Clarity) who had similar symptoms after infusion who was advised to stop permanently treatment and did so.

This marginal patient percentile risk perspective is a very powerful way to conceptualize the clinical management of high risk patients. When framed as above it is not easy to see how this patient would be thought a good treatment risk.

The article that discussed this patient above suggested that epsilon 44s should not be treated with Lecaneamb.
What seems obvious to me is that a patient with such extremely high total risk should not be treated with Lecanemab without expert guidance (if at all). For this patient it is not so much that there was one particular risk factor on board but several of them multiplicatively amplifying risk. Some simple weighted (sum or product) heuristic would seem an appropriate clinical practice upgrade. I am not sure to what extent clinical medicine is intended to intersect with clinical trial medicine. Perhaps when clinical medicine devolves to the point of thinking well let's see how this innovation goes for this high risk patient that it might be thought better to leave that for the clinical trial process. Clearly the challenging part involved with this is knowing where the boundary level to extreme risk should be drawn.

Ironically, as noted previously this patient likely would have had a strong response to Lecanemab treatment as the assumption is that Lecanemab was inducing a near flood of amyloid from her brain on each infusion. Remarkably, the symptomatic ARIA like events after infusion began within ~1 hour? I am still very unclear how this is possible as Chicagogirl notes that in AHEAD 345 there was an 8 hour ??? observation interval after the first infusion and they only used half doses for the first few treatments.

In a real world setting one could imagine a range of strategies that might be considered to improve clinical care of Lecanemab patients particularly those at high risk. While titration was not felt necessary for Clarity, there appears to be patients who probably would benefit from such a procedure. It would be very helpful in the registry or in other clinical trial settings to explore what choices for risk reduction patients might make if given a free choice.

We are past the time in which proving efficacy for mabs is of central importance. Clarity and Trailblazer2 have ended that conversation. Now in this post-trial context in which patients have more flexibility in their treatment, there could be a range of innovations introduced that will improve safety.


Safety 2.png
ARIA Symptomatic.png
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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J11.........Chicagogirl notes that in AHEAD 345 there was an 8 hour ??? observation interval after the first infusion and they only used half doses for the first few treatments.

Small correction........

Visit 6 (1st infusion). After the paperwork etc. the infusion took 1-1/2 hours and then had a 4 HOUR observation period.

Visit 7 there was a 2 hour observation period after infusion.

Visit 8 was a 2 hour observation period. These were all at half dose as is the upcoming Visit 9.

Visit 10 will be at full dose.

I did have a headache at the study site the first 2 infusion Visits. I have only had time to get one cup of coffee before having to leave for the site. Last time I had my 1st cup at home and 2nd cup in a travel mug during my hour drive into the city. No headache that Visit, so it will be 2 cups by the time I get to the center going forward. Plus the extra cup of coffee benefits my veins by plumping them up.

J11.... Wanted to thank you for deep dive you do into the details. I especially like when you summarize it into easy to read sections. I read quite a bit, but not as many medical articles that you do. Thanks

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