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 »

Peak excitement!
Tomorrow is the BIG BIG day!

Here are some more of my notes.

- Industrial scale medicine with one size fits all protocols.

What occurred to me was that so much of the FDA approval process is about this industrialization of medicine to scale it to population scale dosing. We want a single dose to treat a generic patient in some mass society.
Surprisingly in this scenario even an e44 patient with additional risk factors is prescribed the same dose as any other patient. Yet, some people simply have lower risk tolerances; some people simply are at much higher risk than others:
Creating bespoke treatment plans to accommodate human differences would seem a reasonable approach. I will look forward to future reports on actual clinical application to see if such individualization actually occurs. Perhaps the registries that are to be created for Lecanemab could have some sort of rival patient flow algorithms-- perhaps the established Clarity protocol would be the baseline and then different protocol flavors could be built from there.


- In the previous post I highlighted once again that the 26% ADAS-cog reported for Clarity in the Backgrounders for the ADCOM was not a good measure. The problem was that the final number at month 18 zagged quite a bit. In the url above we can see towards the bottom in the black dots that the advantage for most of the trial was in the mid-40s percent. The lone black dot at month 18 is the result if we use the linear regression for the full 18 months.


- It occurred to me that this might be a somewhat unusual ADCOM. How many times do they forego an ADCOM for accelerated approval and then have one for full approval? That does seem odd. Lecanemab is currently available, though not funded by CMS. Given the somewhat diminutive size of the FDA backgrounder, one can only infer that the FDA does not seem to have much enthusiasm for this ADCOM, though likely felt it was necessary to at least give it a pro forma performance nonetheless.

- One of my disappointments in the figures is that I would have liked to see all the numbers. The figures for the subgroups only show range bars and no Ns. More numbers please! A Statistical Appendix with all of the numbers from the figures would be much appreciated. Typically there is the too much information argument, though at an ADCOM I think that we are all adults and the TMI argument does not prevail. For grownups, it is more the not enough information argument NEI that is presumably the argument that should prevail. Could we have more information, please? You do not want to be a complainer, though if you don't ask you don't get.

- I mentioned this before, though I think it bears repeating: What happened to the 111 Chinese patients in Clarity?
Clinical trials gov currently lists the patient enrollment for Clarity as 1906? Yet, the Backgrounders talk about 1795?
Where does this 1906 - 1795 = 111 arise? I think this happened because China seemed to be the last to finish enrollment and then for whatever reason these patients never seemed to reach the topline. It is confusing when the clinical trials url has a different number right there. One really starts to wonder whether the statistical plan was followed. They must have the full data set now so it would seem proper to simply provide the results for these patients (as a separate number if necessary).

- So much of our efforts have been devoted to considering the fatalities in the OLE of Clarity. I would be interested in learning about the narratives of patients who developed macrohemorrhages and some broad statistical characterization of those with microhemorrhages. A macrohemorrhage can lead to substantial long term functional impairment. It would be useful to have a better understanding of the risk factors present in the patients thatdeveloped macrohemorrhages.


- This also motivated me to think about AHEAD and how CAA might be present there and how the trial might be managing risk. How much severe CAA exists in the pre-symptomatic stage of AD? The Backgrounder talked of 73% severe CAA in e44s with early AD. That clearly is a lot and was much more than I had believed to be present (I had thought it would be closer to 25%).

This is the quote from the FDA Backgrounder.
Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid in the vascular wall. A
study of the Uniform Data Set of the National Institute on Aging-funded Alzheimer’s Disease Center
system that aimed to identify clinical factors associated with the presence of severe CAA in patients with
pathologically confirmed Alzheimer’s disease found that approximately 73% of ApoE ε4 homozygotes in
the study population had severe CAA compared to approximately 27% that had no CAA, and patients
with CAA were more likely to have intracerebral hemorrhage than patients without CAA (9.3% vs
3.5%).



- Also in terms of AHEAD what are the stopping criteria for treatment? AHEAD is well before symptom onset so one could see a much lower level of tolerable risk for patients. Specifically, I am wondering what this risk level for patients might be? For example, if a patient in AHEAD were to have a macrohemorrhage would this mean a change in the dosing regimen in order to reduce risk? (Admittedly the problem is that even the placebo patients can have macrohemorrhages, so it would not be clear whether it were Lecanemab or part of the background risk.)


- We know that there are strategies that could reduce risk and could be tried once treatment is available to patients. Titrating is one approach and so too is avoiding IV spiking. The IV spikes have no patient benefit and only crate patient risk. To what extent will risk reducing treatment approaches be used?

Will an innovation cycle begin once treatment gets out into the wild? Just like with software, people could start tweaking the protocol and results could be improved.

- I also found it of note that the e33 fatality was at the day ~120 mark; yet the ARIA side effect chart shows that e33 patients typically have maxed out their ARIA risk in the first 3 months. This makes me wonder how likely it would be for the e33 patient's clinical history to have been influenced by Lecanemab.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Ten minute warning everyone!

Take a bathroom break, grab a coffee etc. now while you still can.


https://www.youtube.com/watch?v=CI9dAd0kaYA
Last edited by J11 on Fri Jun 09, 2023 10:06 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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Here's my doodles from the presenetations.

Stratification was based on ApoE ε4 carrier status (carrier/non-carrier) and not genotype (homozygous/heterozygous)

ADCOMS ( x 100) Placebo 833 39.9 20.9 4.5 (2.2, 6.9) 0.0002
Lecanemab 831 39.7 16.3 --

Headache 73 (8) 101 (11)

Monoclonal antibodies directed against aggregated forms of beta amyloid (Aβ), including lecanemab, can cause ARIA, observed on brain MRI.

It is hypothesized that anti-Aβantibodies accelerate breakdown and clearance of Aβ, which may disrupt vascular integrity and result in leakage into surrounding tissues with parenchymal or sulcal changes observed on MRI:

ARIA-E (edema): vasogenic edema or sulcal effusion.

ARIA-H (hemosiderin deposition): microhemorrhage and superficial siderosis.

ARIA is usually asymptomatic, although rarely serious and life-threatening events can occur. When present, reported symptoms associated with ARIA may include headache, confusion, visual changes, dizziness, nausea, gait difficulty, and focal neurologic deficits.

Cerebral Hemorrhage* 0 (0) 6 (0.7)

Cerebral Hemorrhage 0 1 (0.4) 0 3 (0.6) 0 2 (1)

Deaths Associated With Cerebral Amyloid Angiopathy (CAA) and Inflammatory Vasculitis in Study 301

•A high burden of CAA and findings consistent with an inflammatory vasculitis were identified on autopsy in 2 deaths in ApoEε4 homozygotes on lecanemab, both of whom complained of headaches shortly after exposure to lecanemab. An additional death with possible CAA occurred in an ApoEε3 homozygote with cerebral hemorrhage in the setting of confounding factors including anticoagulant use.

•The inflammatory vasculitis in the 2 cases with a high burden of CAA resembled CAA related inflammation (CAA-ri), a spontaneous inflammatory response to the vascular amyloid deposits which presents with symptoms and imaging findings similar to ARIA-E and ARIA-H. 1,2

•The risk of both severe CAA and CAA-riis highest in ApoEε4homozygotes.1, 3

•Up to 90% of patients with AD are reported to have some degree of underlying CAA, but not all show characteristics MRI findings during life.4, 5

•Risk of lecanemabuse in patients with CAA is not well characterized; the benefit-risk discussion needs to consider the uncertainties with this potential risk.

Safety Summary and Conclusions

•ARIA, cerebral hemorrhage, infusion-related reactions and hypersensitivity are the main safety signals associated with lecanemab.

•Risk of ARIA is higher in ApoE ε4 homozygotes compared to heterozygotes and noncarriers.

•Risk in the presence of CAA, or with antithrombotic use are not well characterized; the benefit-risk discussion needs to consider these uncertainties with the potential risks.

•Risks and uncertainties can be described in prescribing information.

•Prescriber and patient education regarding ARIA, and surveillance for any new or worsening neurological symptoms and follow up with unscheduled MRIs, particularly in ApoE ε4homozygotes, may mitigate some risks of ARIA associated with lecanemab.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Here's my notes.

-quorum
Did they establish the question of quorum for the meeting?


-AA comment disqualified member??
Own goal

41:07 on the transcript
Several of the ADCOM were recused because of the comment?

I am not sure about this. Did they say that the Alzheimer's Association comment on the FDA comment page for Lecanemab was a determining factor in making ineligible some of the panel? Isn't that basically disqualifying those on our side? How could the FDA have allowed those who signed the AA declaration to sit on the panel? I am thinking this should be scored an own goal.

-no collaborative report good!

Should have mentioned this before but it is good that there was no FDA - pharma joint reporting.


-no pharma pdf

FDA uploaded their slide deck which was good, though pharma did not. This made it difficult to find the slides when needed. Funny thing was that if they uploaded their deck then the panel members could have pulled up the slides themselves that they wanted to discuss.

- anti-psychotics used in AD management

Just adding in the point that currently other dangerous medications are goto treatments in AD (such as anti-psychotics which can have fatal side effects) for management. This despite FDA lawsuit, though it is not always clear otherwise how to cope with highly impaired AD patients in very resource limited managed care environments.

- tipping point analysis: Err!!!

Actually tipping point analysis was well explained. I was worried about this from the Aducanumab Briefing Document. I was not that sure what the figure in that document meant.


- rapidity depends upon fast dosing

Good point about the balance that needs to be considered between efficacy and safety. However, AHEAD is using titration and for e44s it probably would make sense.
The seizure fatality patient could not get out of bed for 1-2 days after each infusion. Even the ePA e44 patient had a headache after the first dose. Titrating might be a good idea in high risk patients.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Presentation is going great so far.
It will be of interest to see how the FDA interprets the trials.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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More rough notes.
Meeting is going great!
Everyone is really focused and have a good sense of what is important.
Very good questions have been asked.




-Clinically meaningful? FDA agrees
no NPI

I am not sure whether they measured the NPI, though from Emerge/Engage this seemed a highly useful measure. For us neuropsych symptoms was a meaningful clinical outcome.



- Good to stress the difference of 0.5 on CDR-sb

I had not realized how the CDR-sb measure of 0.5 would translate so directly into
clinical meaningfulness. For some of these measures, even a smallish difference does have importance; admittedly, though the difference of 0.45 would spread over the 6 domains.



- Consider genotyping???

That is just difficult to imagine. Not genotyping Lecanemab would not be good clinical management, however apparently this bumps up against insurance eligibility. Perhaps
this is a legislative issue?

-FDA label allows anticoagulants??

I am not sure I understand how the labeling wrt to anticoagulants would change patient access. Would in practice having a contraindication mean doctors would not go off label for those patients?

- CAA to what extent is it about the inflammation: Could there a biomarker???

- Perhaps it would help to move the discussion online

- 3 microhemorrhages for the fatal e33 patient

-anti-coagulant and other high risk patients actually seemed to benefit more

- There has been no mention of the Boston criteria 2.0 ???

This seems odd that what apparently is the state of the art CAA standard has not been mentioned.

- Very good question e4 stratification

I am very unsure how stratifying at the e4 and not the e34 and e44 changes things.
Probably wold have been best to stratify the e34 and e44 separately.

- Could ask pharma about performance of the e44s in the aducan trials.

My guess is that e44s did fairly well on aducanumb

- Good question about anti-amyloid antibodies

Here it is anti-drug antibodies; (Actually this is different than the ADCOM question.
Question at ADCOM was whether anti-amyloid antibodies present before treatment were an exclusion for treatment in relation to CAAri in context of APOE e4.)

[[Re-Edit: Not sure about this.]]


[ EISAI Backgrounder p. 11

12.6 Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the
assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies
in the studies described below with the incidence of anti-drug antibodies in other studies, including those of
lecanemab-irmb or of other lecanemab products.
During the 18-month treatment period in Study 1, 63/154 (40.9%) of patients treated with LEQEMBI 10 mg/kg
every two weeks developed anti-lecanemab-irmb antibodies. Of these patients, neutralizing anti-lecanemabirmb
antibodies were detected in 16/63 (25.4%) patients. However, the assays used to measure anti-lecanemabirmb
antibodies and neutralizing antibodies are subject to interference by serum lecanemab concentrations,
possibly resulting in an underestimation of the incidence of antibody formation. Therefore, there is insufficient
information to characterize the effects of anti-lecanemab-irmb antibodies on pharmacokinetics,
pharmacodynamics, safety, or effectiveness of LEQEMBI.]
Last edited by J11 on Fri Jun 09, 2023 4:11 pm, edited 4 times in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Very solid speakers.
Meeting is going great so far; everyone is on message and communicating effectively with good understanding about AD.

really solid speakers probably for me I would be stuttering all over the place.

More notes:


-- Not sure about the idea that MCI fluctuates clinically-- for us cognitive impairment occurred and progressed relentlessly over many many years and nothing seemed to sway its course

-- the subgroups were not powered in the trial so all we have is the topline

-- idea that patients only benefited by 0.45 is not accurate.
Some did better (i.e., improved on treatment).


-- With a treatment then diagnosis has some importance
When there is a treatment there is no reason to delay diagnosis
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Final doodly notes from meeting.

- How was the meeting public? It was all online!!

Not sure what they meant about public meeting statement. Meeting was very well conducted without any screaming or talking over of others which was greatly appreciated.

- Time saving aspect was a real winner

This characterization of disease progression resonated well. It took a while for me to understand of this as thinking along the x-axis and not the y-axis. Most graphical analysis focuses more on the vertical than horizontal.

- Idea that might have been understated is that if patients are not benefiting they will stop treatment. At the clinical practice level, clinicians will actually see patients who are doing quite well -- selection bias

- Reminded that the e33 patient did have a fall; this patient was taken off anti-coagulants and then had an acute myocardial infarction. This raises the potential risk that withholding anti-coagulants could be dangerous for them

- Great that the meeting was so focused on the clinical perspective. Interesting to hear the perspective of the treaters

- No discussion went to the idea of the accumulative risk by risk factors: e.g., APOE4 + anticoagulaants

- Fairly surprised that tPA was mentioned as a possible treatment for stroke after the OLE patient???

The patient's brain melted within minutes of starting tPA treatment. I am very unsure how tPA could be considered for a Lecanemab patient with a stroke.

It would be difficult to seek informed consent from a patient and have to describe what happened to the OLE patient. That was possibly one of the most severe instances of neuropathology ever experienced.

- VA does not allow e44

- e44 has so much CAA it almost completely overlaps (i.e. e44 almost completely overlaps with severe CAA)

-no mention of Boston CAA 2.0.

- Broad agreement on apoe4 genotyping , yet not mentioned at the meeting conclusion




- no transcript is posted to youtube
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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"Not a single patient in this trial [Edit J11: i.e., Clarity] got better."
This is from a comment on the FDA url for Lecanemab full approval.

This statement is categorically incorrect.
For whatever reason this has been repeated on several occasions.

This was posted on thread previously; it is from the phase 2 trial and shows the percentile plot for the patients with provided information. We can see that ~40% of Lecanemab treated patients actually got better or held even in the trial. The recent Trailblazer 2 topline reported that 47% of patients held even or improved. That would constitute hundreds of patients improving on a mab. This is considerably greater than not a single patient suggested above. Probably even more striking in the below figure is that upwards of 80% of treated patients in the phase 2 achieved "near" stability. That is actually quite impressive (caution there is a small sample size here). This will need to be confirmed in the Clarity percentile plot.

Percentiles 1.png
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