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 »

Sorry everyone for slacking back. Too much lake time; not enough serious in office time. However, to a certain extent I feel that I have pre-done my homework. Even lately when I have been thinking of serious office time, I thought maybe I could take this on a remote basis and call it in from the beach. It's not easy when everything seems so lined up for success.

Even any nominal miss will probably be heavily contested. I know that this makes it tails we win and heads we win, though Clarity has been setup with a great deal of hidden APOE e4 clinical benefit that in my mind would simply negate any topline result. As long as all of this is prespecified than I suppose this should be considered to be fair. I will soon post about other prespecifications for the trial so everything is clear before the fact; not afterwards.

It has not been easy to engage with the discussion. It's all here on thread; I am not that sure what has been left unsaid. Even the nominal nays have largely unconditionally surrendered. They do not think that it's even worthwhile to ADCOM this one? There apparently will not be a round 2; I can't even find anyone to get in the ring: they have fled -- ran away. Still, it probably won't hurt to do another ADCOMM, though even the FDA does not see any particular point in chatting anymore and have already apparently rejected this option. This is odd to me given that Clarity has not even read out-- are they really that sure? I would have played it safe and would have deferred on the ADCOM decision. It is possible perhaps that Clarity could read out in such a way that it would be helpful to do a talk through, for whatever reason this was discounted.


One interesting find with anti-amyoids that I have encountered of late is the FAERS (FDA Adverse Events Reporting System) result for Aducanumab and Lecanemab. This is the website

https://fis.fda.gov/sense/app/95239e26- ... e/analysis

that tracks adverse events for medications. Of interest is how minimal the Lecanemab adverse effects have been. The site currently lists 5 patients who were administered Lecanemab and all 5 of these patients had a suspected reaction to plavix or lasix (not Lecanemab). Given that ~half the patients in Clarity are on high dose Lecanemab-- as far as I am aware they were adminstered IV (???) Lecanemab which is now understood to be more risky than equidose equi-efficacious subcu injection-- and almost all of the other half have had the opportunity to roll over into the long term extension and receive IV or subcu treatment. That is just less than 2,000 patients and then there is the phase 2 patients (though this study was depleted of APOE e4s.).

One innovation that I have considered is that perhaps those few patients who would be known to be at particularly high risk could be explicitly designated as off-label patients. The problem when medications have broad label indications is that there will be a subgroup that have extreme comorbidities that could distort any risk involved. By distorting the risk involved many others who likely would be at very minimal risk might not be fully aware how favorable the risk reward ratio would be for them. Perhaps those at high risk of side effects could then be processed in a separate clinical stream. It would not be about denying them coverage, though creating a clinical strategy that was reasonable for their particular circumstances.


Even here as mentioned previously, it does make it difficult to speak clearly about safety when the latest research with sub-cu appears to have greatly moved the risk frontier downwards. Sub-cu just has so many advantages for patients that it is not easy to see why it will not become the standard. With subcu a patient has the inherent autonomy to choose their own level risk profile that is lost in an IV clinic injection model. for example, one could imagine that some patients would choose to uptitrate slower subcu. It is one disappointment that additional ecological style clinical trials have not already been launched. However, I am not completely sure how this would coordinate with the CMS' converge with evidence development policy. I really should polish up on the details of the CMS' final decision as one uncertainty I have is: What will happen if Clarity blows through the topline and there is clear clinical benefit for patients? The accelerated approval process has a somewhat reduced level of rigor concerning efficacy-- as long as you can show a dose response and probably reasonable clinical benefit that's roughly good enough. Sure, Lecanemab could then go full approval, though would patients actually be expected to wait even more months after the accelerated approval considering that the Clarity results are now on the near term horizon?

The other surprise was the number of patients on Aducanumab that are experiencing side effects; many of them quite recently. I am not sure I completely understand this as the commercial roll-out of Aducanumab has largely stopped. Who are all of these patients that are having side effects? Even much of the clinical trial infrastructure for Aducanumab is winding down. The seemingly obvious way to address this would be offer all patients in Aducanumab trials a transfer to Lecanemab upon Clarity readout. Why not reward the patients with the best treatment, once there is no longer any doubt when Clarity reports?
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

I want to pre-specify before the Clarity readout. Lecanemab has such a positive feeling about it; it will allow the benefits from the anti-amyloid perspective to finally reach patients.

There are so many dose response plots that I have posted that it is difficult to know which to choose; I have been away from these for awhile so I have grown somewhat rusty with them, yet this is one of the better ones. It separates out by APOE e4 genotype and it shows a fairly large slope for e4s. I posted many of these regressions with slope between 1.25 and 1.40, so I was fairly comfortable with that range on the totality of the patients. However, in this figure the slope moves up to 1.9-2.0 for e4s which is moving towards a moderately large topline in the region of 0.6 on CDR-sb. As noted earlier it would not be unexpected that e44s could do even better. I am hoping that they clarify the SUVR result by genotype as this would help to place the results more accurately into CDR-sb -- SUVR space. Without the genotype specific SUVRs we can only use a single x value for both subgroups even when this would not be a true reading.

APOE + - 2.png
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

isorisk response 2.png
One of the asks in the analysis that I have thought of is to have the modeling that has been done to be put into a user friendly form so that patients would be able to better understand the potential effectiveness in certain risk classes. A great deal of this modeling work was done especially for Aducanumab, though it was not that easy to interpret. By extracting the information from the models that are developed patients could have much better insight into how they would possibly respond. For example, the risk classes could be summed across weights (perhaps obesity BMI, initial cognitive level, age etc.) and then a regression line could be drawn in the figure to represent expected response given different amyloid clearance. There is a fair amount of benefit heterogeneity that has been reported; it would be good to be transparent about this and allow patients to be more fully informed.

One point that has not been stressed enough on thread is that clinical benefit itself might not really be the best measure of success. So many CDR-sb points versus placebo might not be the primary motivator for many patients. Specifically, those in the earlier stages of cognitive impairment often really do not have that much impairment or all that much progression. Of more central importance is preventing future decline.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

A newsy post: The FDA has reversed its stance on Amylyx's ALS treatment and appears set for approval. This could be one of those hidden wins that I spoke of earlier. The treatment also had a phase 2 result in Alzheimer's and now one could expect that once banked up advancing the AD indication would be a reasonable strategy. Given the mechanism of action orthogonal to anti-amyloids, it might not be too optimistic to suggest that this could achieve at least an additive benefit. We could see a range of these amplifers on top of anti-amyloids once we see approval s such as Lecanemab. Some of these amplifications such as Amylyx's product could emerge from obscurity to help us.

World Alzheimer's Day is September 21st. There is so much clinical research on the way that the 21st will be the perfect pre-party celebration.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

World Alzheimer's Day!

There is so much to be excited about now in clinical Alzheimer's.
There are 2 near term beta-amyloid mabs ready to readout and the foundational research in Aducan and others suggest that we should expect good toplines.

Even still, I want to continue to refine my prespecifications before the results of Clarity are announced.

One of the insights from this thread that I am most proud of has been largely rejecting the p-value centric perspective, in favor of the dose-response point of view. It made no sense to me when there was the endless mantra that the low dose arms of Aducanumab in the phase 3s did not hit statistical significance when they were almost exactly on top of their expected regressions given the amount of amyloid clearance attained in low dose. This was also true in the Lecanemab, Gantenerumab (and perhaps other mabs). What is important at the start is confirming the dose-response relationship -- that is the basis of accelerated approval (The actual clinical benefit to patients then merely involves increasing amyloid removal). In the instance of Clarity, if there were lowish amyloid removal of ~0.25 while being on the regression line that could hardly be considered to be a miss. Low amyloid removal is not the expected outcome for Clarity especially given its strong safety profile, though no attempt was made to be more aggressive with dosing to achieve higher amyloid removal.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Sorry everyone for just letting this coast over the finish line, though I am just not sure what hasn't been said that should be said. This is a monumental moment for the global dementia community.

Lecanemab from what I currently understand is a very solid product:

Safety-
By any reasonable standard Lecanemab could be considered to be safe; not merely relative to Aducanumab.
The numbers that will likely be reported for safety from Clarity really will not even be the true clinical numbers as
they have already moved to a subcu dosing approach which is much safer than IV dosing. Patients who prefer greater safety could simply go subcu and not feel pressured in an IV setting to dose more than they would freely chose to.
A range of additional safety enhancements (e.g. with slower uptitration) could make Lecanemab even safer.

Efficacy-
Leca is largely in the framework of the anti-amyloid mabs that we have considered somewhat relentlessly on thread for years now. Leca is anchored onto the regression line with all the rest and should be expected to produce roughly 25%+ benefit; with the bonus that low side effects allow more patients to be fully dosed. For the APOE e4s the benefits could be somewhat greater; for e44s perhaps even more so.


Without an ADCOM there might be no Briefing Document to argue about (which is a disappointment). Rubber stamping the approval without a thorough think through could leave loose ends untied. I am not even sure whether there will be enough time to have the Clarity results published before the FDA decides.

I have been considering lately how a Lecanemab approval might filter through into the broader social landscape. In this regard one point of interest for me is how Leca and other mabs might be prescribed earlier in the course of cognitive impairment. I am not sure how this might work with the indicated label, though in our experience cognitive impairment was something that was evident decades before a clean diagnosis of AD. The better cognitive tests can pick this up years before the MCI stage. Will those who are silently progressing be able to access Leca before an official MCI diagnosis?

Cognitive impairment has real world consequences for the families and others involved. Growing up in a house environment with this subclinical dementia was difficult. A family member had extreme drug and alcohol behaviors that were never addressed. When mental health workers realized how messed up things were in our family they fleed. The problem seemed to be that with AD cognitive impairment there is simply no sense of awareness that anything is even wrong to those with the mental impairment. Parenting requires top level cognitive skills to navigate through the various challenges that arise which can be largely missing in those with early AD. I certainly wonder to what extent anti-amyloid treatment might be something that the community all but requires from those affected in the future: pretending that the problem does not exist is not a great strategy. This strategy creates an enormous externality the community might be increasingly unwilling to shoulder given that a preventative treatment might be proven effective even within days. When dementia becomes more widely recognized with the upcoming approval, the community's tolerance for low cognitive functioning might be reduced.


One of the perhaps odder things that has occurred to me lately is that the anti-ab mabs might acquire a financial store of value role. The idea is that many financial instruments such as gold etc. really do not have any clear value other than by fiat being declared precious. Central banks have tons of it, though if you're not that into shiny metals it isn't that clear why it should have the value that it does. That's where anti-ab mabs could enter the picture: these mabs clearly do have some intrinsic value; they are probably gram for gram more valuable than gold. For those with a history of dementing illness, ab mabs are on a short list of almost essential commodities for daily living right up there with food, clothing and shelter.

The companies that own the composition of matter patents for them, basically will have the power of a central bank. Whenever they want, they could simply "print" wealth ( by issuing right to purchase warrants for mabs) without it being inflationary because mabs have intrinsic value at almost any scale. This has me wondering whether possibly central banks might find it reasonable at some point to begin maintaining stores of ab mabs as strategic assets. It also has me wondering whether the biotechs themselves might begin thinking in terms of issuing "mab bonds".

They basically could pay whatever "interest rate" they chose by simply linking "payment" to the right to access mabs which have low marginal cost. Given the limited patent protection available, such a debt instrument might be beneficial to all those involved. I suppose this could be one of those -- that is a very very odd idea J11, until it isn't-- and then I guess everyone will talk about how completely self-evident it was.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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J11 wrote: Mon Sep 26, 2022 7:14 pm ...

Lecanemab from what I currently understand is a very solid product:

I am not even sure whether there will be enough time to have the Clarity results published before the FDA decides.

I have been considering lately how a Lecanemab approval might filter through into the broader social landscape. In this regard one point of interest for me is how Leca and other mabs might be prescribed earlier in the course of cognitive impairment....
Hi J11,

Your family has had more experience than most with the variability, severity and difficulty in behaviors, functional and cognitive impairments associated with dementia. Some of those family members might now be able to be diagnosed--perhaps as having frontal temporal dementia or Lewy body dementia, as well as Alzheimer's--and able to have better supports. Having to witness such changes as a child must have been both confusing and scary; especially since in the past most family idiosyncrasies were neither acknowledged nor explained. I hope the upcoming trial results will be the beginning of options for people like your loved ones, even if not yet fully a prevention or cure. And while not getting as much attention as AD drug trials, some promising drugs are in the pipeline for alpha-synuclein pathology (Parkinson's and Lewy Body) and FTD.

As for lecanemab, CLARITY top-line results will be available any time now.
For some background for others:
The Clarity AD Phase 3 clinical study for lecanemab in early AD is ongoing and Eisai completed enrollment in March 2021 with 1,795 patients. The readout of the primary endpoint data of Clarity AD will occur in the Fall of 2022. The FDA has agreed that the results of Clarity AD, when completed, can serve as the confirmatory study to verify the clinical benefit of lecanemab. Eisai utilized the FDA's Accelerated Approval Pathway in an effort to streamline the submission process for the potential traditional approval of lecanemab in order to expedite patients' access to lecanemab. Dependent upon the results of the Clarity AD clinical trial, Eisai will submit for traditional approval of lecanemab to the FDA during Eisai's fiscal year 2022, which ends on March 31, 2023.

In Japan,... Eisai aims to file for the manufacturing and marketing approval based on the results of Clarity AD during Eisai's fiscal year 2022. Also, in Europe, based on the results of the Clarity AD study, Eisai plans to submit a new drug application in fiscal year 2022...Lecanemab is also being evaluated in the AHEAD 3-45 secondary prevention trial, as well as the DIAN-TU Tau NexGen trial, which tests amyloid and tau therapies given together
THE U.S. FDA ACCEPTS AND GRANTS PRIORITY REVIEW FOR EISAI'S BIOLOGICS LICENSE APPLICATION OF LECANEMAB FOR EARLY ALZHEIMER'S DISEASE UNDER THE ACCELERATED APPROVAL PATHWAY

In summary: This is a second-generation anti-amyloid treatment that is likely to show removal of amyloid plaques, lessening of tau tangles and disruption of amyloid beta oligomers to prevent new plaque formation in people with MCI/mild AD in the space of 18-24 months, with slowing of the rate of expected cognitive decline during the mild AD period of 20-40%. That's not a "cure" for people already diagnosed with both pathology (amyloid beta and tau) and cognitive and functional impairments, but it would represent a first "disease-modifying treatment" (DMT) to presumably have unequivocal results across trials, unlike aducanuamb. Most people diagnosed during the MCI/ mild AD stage appear to have slow progression of impairments across the first 3-4 years, so slowing that by 20-40% could extend that phase, especially if the drug can be given at a lower monthly maintenance dose to prevent re-accumulation of amyloid beta oligomers.

As for that subcutaneous dosing, it's been shown to be comparable to IV infusion, so shouldn't change the validity or reliability of the study. Having that option both reduces the risk of ARIA-E and ARIA-H, but more importantly would make it possible for people in rural or under-served areas far from research centers to receive treatments, potentially even at home. It also would be safer for people with ApoE 4!
Here's some inf on that:
Subcutaneous lecanemab demonstrated similar tolerability and effectiveness to IV lecanemab, as measured by the reduction in beta-amyloid accumulation in the brain, for most patients weighing 57-90 kg. It also showed a good safety profile and was predicted to cause a lower incidence of ARIA-E because its peak concentration in the blood was lower than IV lecanemab.
This lower ARIA-E incidence was observed regardless of ApoE4 status, a known genetic risk factor for late-onset Alzheimer’s.
https://alzheimersnewstoday.com/news/al ... emab-dose/

Accelerated approval may be granted by the FDA if results are as expected in January, which I believe would allow for initial use primarily in medical settings with access to monitoring for side effects and only for people with demonstrated amyloid PET positivity and clinical diagnosis of MCI or mild AD. That would exclude people with more advanced AD and those with vascular dementia, Lewy body, FTD or TBI-related. For now it would also exclude people with evidence of amyloid on blood tests. CSF or PET scans who are cognitively normal, since that is the focus of the "secondary prevention" AHEAD 3- 45 trials. (Secondary because it's after a biomarker for the disease, but before clinical signs of the disease.) Here's the FDA on accelerated approval :
The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.
https://www.fda.gov/drugs/information-h ... al-program

Other second-generation anti-amyloid drugs will be releasing Phase 3 trial results in the next month to few months, including donanemab, gantenerumab and solanezumab.

Might be time to get your chocolate and cashews ready!
4/4 and still an optimist!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

NF52, thank you so much for your response. We go through our whole lives trying to be understood by others and largely we aren't. Finding that just right combination of life perspectives in other people so that meeting of the minds occurs can be so elusive. Without such understanding, we never feel as though we have been heard.

It would be very helpful if there were specific training of mental health professionals informing them of the nuances of the dementia life experience so that they were prepared to hear the stereotypical features when they were voiced. I am not clear about how aware many of them are aware how dementia filters through the generations. One would expect that if such a perspective were fully recognized, then many of the social challenges that AD causes would not be as problematic. It is just largely that there has never been a true effort in embracing the dementia village concept in modern society.

Yes, that was spot on about behaviors not being explained or acknowledged. It is quite startling when I think about how the family simply sat back and relabeled it as a "bad children" problem when there was almost certainly measurable cognitive impairment at play in the parental generation even fairly early on. Clear dementia is easy to demarcate; with the more nebulous term "cognitive impairment" it is not as easy to pin down. It is probably much easier to describe more in term so how our lives unfolded. The impairment became intertwined with our early development.

What I find of particular interest was how well life started off for us for quite a while and then all of sudden childhood was declared over and substantial problems emerged. If I had better insight into the possible lurking cognitive deficits involved, then it would have been so much better for my own well-being to have simply dropped out of physical school at a fairly early age and went remote. A large part of the problems that arose were a direct consequence of making normalizing assumptions about my life trajectory that did not turn out to be valid. There was too much pretending and willfully ignoring that AD was going to somehow not be a centrally important feature of my life experience.

In our particular instance the family history of dementia was even more deliberately obscured as one of my parents took a flight out of the dementia heartland and did not look back. My suspicion is that the dementia backwoods developed in response to governments constantly defaulting on promises to care for those with dementia. It is so easy to make such promises and then default on them. There was very little leverage that those with dementia would typically have when such moral bankruptcies occurred.

The backwoods strategy basically would allow for social and political power to accumulate in the dementia heartland outside of the typical cynical urban power centers that find it all too convenient to simply renege on implicit promises. The problem was that my relative did not seem to understand the logic involved in this, and only saw the probably fairly disturbing reality of numerous extended relatives with dementing illness which could be seen as a near endless burden. Jumping on a plane and arriving in an anonymous city without such connections probably felt like a pretty good deal. The problem is that it isn't that easy to escape genetics. You can't outrun what is encoded in DNA (at least until now). Of course, with current embryo selection even the DNA part is no longer as fixed in stone for future generations.

I have found this new full genome DNA technology to be profoundly powerful in offering insights into personal psychological truths that have until recently been deeply obscured. How can one even start with a valid psychotherapeutic exploration of the self without having a firm understanding of what that self might actually be (especially in relation to others)? My polygenic scores provided deep insights; most of these I would have never been able to figure out by myself. The big shocker was the near 100th percentile score in reactive behavior related to post traumatic stress disorder. That was a stunning find! Combining unrecognized PTSD type behavior with an unacknowledged AD dementing family context is pretty much hitting the jackpot for mental health problems. I would be surprised if those with such a combo did not develop severe behavioral problems. This is a combination for very high risk personal disaster. If one were to simply ignore the risks involved, then things would not go well. Funnily , enough if this genotype were recognized early enough, then fairly effective workarounds (such as online education etc.) could be applied. One of the problems that I often encountered in our own family circumstance was that such ideas were ignored. Surprisingly we were big fans of embracing the mainstream conception of normal, even when it was not that aligned with our life circumstances.

I am going to be so happy when the dementia risk in the community unwinds and the kids who would have developed within the context of dementing illness don't. I know how difficult it can be when the development path you are on is simply not congruent with that of those around you. Most people get on the main highway of development from an early age and then keep on motoring through life. For me, as soon as I was able to get on the dementia detour bypass, life worked out so much better. You really want to stay with the tour group and everything, though it helps a great deal when you finally realize that it's all been a big mistake and that your tour group really wasn't your tour group at all. I had a fair number of such confusions in my life. What do you mean you don't want to be a 24/7 AD caregiver for the next few ... several .... years? For me life was much more about saying unexpected good byes than spending the expected lifetime of friendship together.

My understanding of exactly what constitutes my family flavor of neurodegeneration continues to evolve; it would of course be more than slightly embarrassing if what I have been referring to for years as "dominant AD" was not exactly "dominant AD". I leave open the possibility that whatever it is, it might not be AD, though it sure seems like AD and has been referred to and treated by experts as such. Even still, I am aware that other features of neurodegenerative illness were reported in my full genome. It would clearly be more than frustrating if AD were to be cured, though we still had problems with some unknown dementing syndrome. I suppose that a fair proportion in the wider dementia community should brace themselves for such a shock with the upcoming approval of Alzheimer's disease treatments.




One of the more noticeable changes of consciousness that I have been experiencing of late is the feeling of increasing personal power. With our dominant style AD, we have largely been a permanent underclass. It has been fairly hopeless. APOE e4 really isn't a permanent genetic feature in the same way that dominant AD is. Hitting e44 generation after generation is likely fairly rare, though with dominant AD there will be that one branch of the family that keeps hitting the dementia jackpot generation after generation--- that was us.

e34 has largely not even been a binding dementing genotype in our family. It is more the unknown e33 dominant dementia that has been trouble for many centuries. With such a life disadvantage, it has largely been impossible to truly escape from it. The anti-amyloid mabs offer the first viable means of getting on life's up escalator. This has been a big boost for me lately. Once you get on the up escalator good things start happening and it isn't as if this requires some enormous effort: Everything can fall into place naturally.

Given the substantial life challenges that we have faced the treatment financing problem does not seem that tough. If you have a life time to save, then it is amazing how much wealth you can accumulate. It becomes all the easier when you realize that the mabs will actually go off patent in about 10 years. It is possible that we will not truly need this treatment even in 10 years. However, from my current perspective I do not think that it is wise to think in terms of delaying treatment; my current thinking is that the earliest low dose approach would probably be the best.


I really hope that there will be some path to Leca access over the near term for those who would benefit. The entire conversation to date has been framed purely in terms of dementia. Yet, dementia ~MCI defined in terms of ~30 or less MMSE completely ignores the cognitive deficit that is present for years before. The more sensitive tests can pick up on these more subtle thinking problems many years in advance. In my experience, these subtle deficits were much more difficult to cope with. In day to day life, such behaviors can often be overlooked by casual observers. However, if you are a parent or other in a position of responsibility it is important to have more than minimal competence. Daily life typically requires cognitive ability above 85 IQ to navigate effectively.

Leca could help people avoid the descent into the more subtle aspects of pre-MCI. I suppose if the FDA does not provide a broad label then a black market for Leca will develop. It is simply too important for too many people not have treatment options for cognitive impairment. The FDA might have been thinking exactly along these lines when it had a nearly completely unrestricted label for Aducanumab treating "Alzheimer's disease" ??? Clearly it would be problematic to take such a route with Leca with Ahead in progress, though there is the certain reality that many millions of people who are in the pre-label population will soon have an approved treatment that they can see on the shelf, that is likely very safe for them and probably would be quite helpful for them therapeutically.


In terms of the clinical aspects of Leca, yes I am seeing just a whole line of green lights. There are not that many points that need clarification. One of the only complications that I have thought of is: What if the Clarity results are so strong that the FDA simply opts for full approval over accelerated approval on the first round?

I will be very interested to see how they might be able to further optimize Leca. Subcu was a very good idea: moving away from those extreme dosing oscillations that occurred with IV dosing made a great deal of sense. These oscillations strangely only added risk without any actual patient benefit. Subcu is a pure win for the patient. This would be an especially good product feature to firm up in the short term with additional clinical evidence. Such a clinical trial could actually be done quite rapidly. One might only have to dose patients for 6 months to gather more dosing results; perhaps they could also addin an arm for slower uptitration. Possibly in an ecological type study they could just leave it up to the patients to set an uptitration schedule that they felt most comfortable with.

I am somewhat surprised though that there has not been more clinical activity with Lecanemab. It is a notable feature of the split between the biotech versus big pharma standard operating procedure to sweat it out over the line with whatever is on the table in the clinical trials and then add in fresh resources once an approval is in hand. Anti-amyloid mabs will be such a massive drug class that deepening out the clinical research knowledge base would seem a highly reasonable strategy to already have in motion. Clearly, this could happen even within days after the Clarity results are announced. As soon as the mabs are money in the bank, then the AD research infrastructure can into high gear. It has been so difficult for all of these decades to be draining billions of billions of dollars from pharma's bank accounts without ever any revenue generation. Once a revenue maker is established, it will be so much easier to create the positive feedback needed to move this further and further downfield.


About those tasty cashews ... yes that is something of a problem. We are currently involved in house repairs and we are not in state to receive our party favors. I know it is probably not that appropriate to ask, though might they put off the news for say a week or two until we are all stocked up for the big party? This is a once in century moment for medicine, it would be somewhat of a disappointment if we had to wait a century for the next big news/party.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Um, did Biogen really just go up $78 per share? I am guessing there's good news!! Yeah!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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https://investors.biogen.com/news-relea ... et-primary

LECANEMAB CONFIRMATORY PHASE 3 CLARITY AD STUDY MET PRIMARY ENDPOINT, SHOWING HIGHLY STATISTICALLY SIGNIFICANT REDUCTION OF CLINICAL DECLINE IN LARGE GLOBAL CLINICAL STUDY OF 1,795 PARTICIPANTS WITH EARLY ALZHEIMER’S DISEASE
September 27, 2022 • Investor Relations

ALL KEY SECONDARY ENDPOINTS ALSO MET, DEMONSTRATING HIGHLY STATISTICALLY SIGNIFICANT RESULTS
PROFILE OF AMYLOID-RELATED IMAGING ABNORMALITIES (ARIA) INCIDENCE WAS WITHIN EXPECTATIONS
EISAI AIMS TO FILE FOR TRADITIONAL APPROVAL IN THE U.S., AND TO SUBMIT MARKETING AUTHORIZATION APPLICATIONS IN JAPAN AND EUROPE BY THE END OF EISAI FY2022, WHICH ENDS ON MARCH 31, 2023

TOKYO and CAMBRIDGE, Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") and Biogen Inc. (Nasdaq: BIIB, Corporate headquarters: Cambridge, Massachusetts, CEO: Michel Vounatsos, "Biogen") announced positive topline results from Eisai’s large global Phase 3 confirmatory Clarity AD clinical trial of lecanemab (development code: BAN2401), an investigational anti-amyloid beta (Aβ) protofibril antibody for the treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and mild AD (collectively known as early AD) with confirmed presence of amyloid pathology in the brain. Lecanemab met the primary endpoint (CDR-SB: Clinical Dementia Rating-Sum of Boxes*) and all key secondary endpoints with highly statistically significant results. Eisai will discuss this data with regulatory authorities in the U.S., Japan and Europe with the aim to file for traditional approval in the US and for marketing authorization applications in Japan and Europe by the end of Eisai’s FY2022, which ends March 31, 2023. Additionally, Eisai will present the Clarity AD study results on November 29, 2022, at the Clinical Trials on Alzheimer’s Congress (CTAD), and publish the findings in a peer-reviewed medical journal.

* CDR-SB is a numeric scale used to quantify the various severity of symptoms of dementia. Based on interviews of people living with AD and family/caregivers, qualified healthcare professionals assess cognitive and functional performance in six areas: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The total score of the six areas is the score of CDR-SB, and CDR-SB is also used as an appropriate item for evaluating the effectiveness of therapeutic drugs targeting the early stages of AD.

Lecanemab treatment met the primary endpoint and reduced clinical decline on the global cognitive and functional scale, CDR-SB, compared with placebo at 18 months by 27%, which represents a treatment difference in the score change of -0.45 (p=0.00005) in the analysis of Intent-to-treat (ITT) population. Starting as early as six months, across all time points, the treatment showed highly statistically significant changes in CDR-SB from baseline compared to placebo (all p-values are less than 0.01). All key secondary endpoints were also met with highly statistically significant results compared with placebo (p<0.01). Key secondary endpoints were the change from baseline at 18 months compared with placebo of treatment in amyloid levels in the brain measured by amyloid positron emission tomography (PET), the AD Assessment Scale-cognitive subscale14 (ADAS-cog14), AD Composite Score (ADCOMS) and the AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL).

The incidence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), an adverse event associated with anti-amyloid antibodies, was 12.5% in the lecanemab group and 1.7% in the placebo group. The incidence of symptomatic ARIA-E was 2.8% in the lecanemab group and 0.0% in the placebo group. The ARIA-H (ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis) rate was 17.0% in the lecanemab group and 8.7% in the placebo group. The incidence of symptomatic ARIA-H was 0.7% in the lecanemab group and 0.2% in the placebo group. There was no imbalance in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) between lecanemab (8.8%) and placebo (7.6%). The total incidence of ARIA (ARIA-E and/or ARIA-H) was 21.3% in the lecanemab group and 9.3% in the placebo group. Overall, lecanemab’s ARIA incidence profile was within expectations.

Clarity AD was a global confirmatory Phase 3 placebo-controlled, double-blind, parallel-group, randomized study in 1,795 people with early AD. The treatment group was administered a dosage of 10 mg/kg bi-weekly of lecanemab, with participants allocated in a 1:1 ratio to receive either placebo or lecanemab. The baseline characteristics of both placebo and lecanemab groups are similar and well balanced. Eligibility criteria allowed patients with a broad range of comorbidities/comedications: hypertension, diabetes, heart disease, obesity, renal disease and anti-coagulants, etc. Eisai’s recruitment strategy for the Clarity AD clinical trial ensured greater inclusion of ethnic and racial populations in the U.S., resulting in approximately 25% of the total U.S. enrollment including Hispanic and African American persons living with early AD. Due to the inclusive eligibility criteria and the successful recruitment of diverse ethnic and racial populations in the U.S., Clarity AD’s population is generally comparable to the country’s Medicare population.

“Since Eisai launched Aricept in the U.S. and Japan in the late 1990s and obtained its approval in over 100 countries, Eisai has provided the drug to people living with dementia while building empathy for them and their families through disease education efforts and community involvement. The positive result of the lecanemab, an anti-Aβ protofibril antibody, pivotal study after almost 25 years since Aricept’s launch is an important milestone for Eisai in fulfilling our mission to meet the expectations of the Alzheimer’s disease community. Alzheimer’s disease not only presents a great challenge for patients and their families, but it also negatively impacts society, including decreased productivity, increased social costs and disease-related anxiety. We believe that helping to alleviate these burdens will positively impact society as a whole,” said Haruo Naito, Chief Executive Officer at Eisai. “Additionally, the lecanemab Clarity AD study results prove the amyloid hypothesis, in which the abnormal accumulation of Aβ in the brain is one of the main causes of Alzheimer’s disease, when targeted with a protofibril-binding therapy. Eisai believes these findings will create new horizons in the diagnosis and treatment of Alzheimer’s disease as well as further activate innovation for new treatment options. The successful results of the Clarity AD clinical trial would not be possible without the truly inspiring dedication of the study’s participants, their families and caregivers and the clinical investigators around the world. We thank all the people involved in the study for their invaluable contributions.”

“Today’s announcement gives patients and their families hope that lecanemab, if approved, can potentially slow the progression of Alzheimer’s disease, and provide a clinically meaningful impact on cognition and function,” said Michel Vounatsos, Chief Executive Officer at Biogen. “Importantly, the study shows that removal of aggregated amyloid beta in the brain is associated with a slowing of disease in patients at the early stage of the disease. We want to thank the many patients who participated in this groundbreaking global study and want to acknowledge the clinical investigators who worked tirelessly to increase the enrollment of traditionally underrepresented populations. As pioneers in neuroscience, we believe defeating this disease will require multiple approaches and treatment options, and we look forward to continuing the discussion about the significance of these findings with the patient, scientific, and medical communities.”

In July 2022, the U.S. Food and Drug Administration (FDA) accepted Eisai’s Biologics License Application (BLA) for lecanemab under the accelerated approval pathway and granted Priority Review. The Prescription Drugs User Fee Act action date (PDUFA) is set for January 6, 2023. The FDA has agreed that the results of Clarity AD can serve as the confirmatory study to verify the clinical benefit of lecanemab. In an effort to secure traditional FDA approval for lecanemab as soon as possible, Eisai submitted the BLA through the FDA’s Accelerated Approval Pathway so that the agency could complete its review of all lecanemab data with the exception of the data from the confirmatory Clarity AD study.

In March 2022, Eisai began submitting application data, with the exception of Clarity AD data, to Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) under the prior assessment consultation system with the aim of obtaining early approval for lecanemab so that people living with early AD may have access to the therapy as soon as possible.

Eisai serves as the lead of lecanemab development and regulatory submissions globally with both Eisai and Biogen co-commercializing and co-promoting the product and Eisai having final decision-making authority.
Last edited by J11 on Wed Sep 28, 2022 3:26 pm, edited 1 time in total.
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