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 »

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

Post by J11 »

The previous Desmos post was admittedly somewhat obscure even for me; so I'll unpack it.

The basic sentiment is that I am very excited now about the potential move to subq dosing that might occur as we await full approval.

In the Desmos url I show how the subq dosing instead of IV dosing enhances safety (as measured by the rate of ARIA-E) in the total APOE+ sample that was used in a simulation. I then took the 2.3% placebo ARIA as reported for the APOE+ patients in Clarity (see bottom figure above). [I assumed that ARIA-E will continue to occur linearly through time for these placebo.] It will be highly informative when we receive more details about the safety profile of Leca dosing. subq dosing is currently being administered in the Clarity OLE so a considerable amount of experience is being gained with this method. Another trial that further investigated subq Lecanemab dosing more focused on the safety profile than the efficacy would be helpful.

In equation 43 one can pull the slider around and see how the tangents move around through time. The top purple curve is the Lecanemab IV dosing. the purple dotted line is the tangent line and the black dotted line is the placebo rate. As you pull the slider to 16 months the scissors close. From here on out IV dosing has less ARIA-E less placebo. For subq dosing the scissors close at 12.7 months.

The curves below the x-axis show the slopes for the IV and subq curves. Here we can see them crossing the black dotted line which is the placebo rate. At 3 years, the accumulated rate of ARIA-E in placebo equals that of the subq dosing; past 3 years, placebo has a higher projected rate of ARIA-E. Placebo is more dangerous than subq dosing? This is the implication of the simulation curves. Through time ARIA-E declines in the IV and subq populations and after ~13-16 months falls below the marginal rate of the placebo.

It would be extremely positive if Lecanemab could launch under full approval with subq dosing.

The second url above shows that in a small study that there were ZERO infusion reactions with subq dosing.
In the Clarity trial there was a surprising amount of infusion reactions. ~25% of the Lecanemab patients experienced this. For 1% of the patients infusion reactions were considered severe. Subq dosing could potentially eliminate this type of side effect. The Cmax spikes caused by IV as seen in a figure above clearly suggest safety concerns related to ARIA-E; notably these spikes are absent from subq dosing. I will be very interested in reading how such spikes might be potentially be connected to macrohemorrhaging. Without this gunning the engine, subq might achieve largely the same treatment effect with much less patient risk; it is though still unclear how this might translate to ARIA-E macrohemorrhages.

Going subq would seem nearly an uncontested victory. It could greatly enhance the already strong safety profile of Lecanemab, while also removing the treatment barrier of having to go to an infusion center every two weeks for possibly years.

One problem that might arise is that it seems as though they might be intending to have a single standard 720 mg dose format. This might not be ideal. With mg/kg dosing there could be some flexibility for doctors to exercise clinical judgment. With a fixed dose this might not be as easy. One workaround that I have considered is perhaps there could be some internal partitioning feature on the autoinjector that could allow patients to dose as they saw fit. So if you had a 720 mg total dose perhaps you could move a partition in the autoinjector that would release only 1 ml of the dose for 100 mg. In this way the patient would have control over their dosing.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

This is the Clarity ARIA-E by APOE genotype figure.
Notice how this figure once again illustrates the asymptotic risk effect; even in the context of
IV dosing. While still at least somewhat speculative, what we seem to be seeing is that mab treatment
is clearing out CAA and once this is achieved a lower risk of ARIA-E is maintained through the long term.

subq typically reduces ARIA-E by ~3 fold across APOE gentoypes.
The article did not model the APOE e44 genotype for ARIA-E (just included the averaged for APOE+).
yet, reducing by 3 fold from the figure above would reduce ARIA-E in e44s from ~34% to ~11%.
That would clearly be a large reduction. For e34s, ARIA-E would decrease from ~12% to ~4%.

From the epsilon 4 perspective migrating to subq dosing could greatly improve safety.
However, it remains unclear about how this would translate into more serious ARIA reactions.
Considering that ARIA-E is centrally related to ARIA-H, one would guess that a 3 fold reduction in ARIA-E would translate into considerable safety improvement in ARIA-H macrohemorraging.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

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

Post by J11 »

I have been wondering whether some sort of patient revolt might be in order. The idea is that we are currently stuck in between -- no clear funding source over perhaps even for the next several months, and the corporations behind Lecanemab not enthusiastic about pumping more money into the money pit until there is a return on investment.

What I am thinking is that if the government wouldn't fund it and the companies wouldn't fund it ... then why don't we? In the statements online, there are roughly 2,000 per day who transition into MCI dementia status, so 1 million per year. That means there are 10 million people who are within 10 years of reaching official on label use. However, as we have noted the FDA does not have the legal authority to control the off label use of a drug. This decision is left to be decided upon by patients and physicians.

In our personal experience with dementia 10 years before diagnosis already meant substantial and frankly obvious cognitive impairment. Close friends and family no longer recognized our loved one. To be honest, if we really thought about the 10 years before the 10 years before we probably could also score it as measurable impairment. In most day to day interaction, people often will not pick up on the subtler slip-ups. It is only when you carefully start paying attention that you can detect some of the earlier changes into preAD. With an FDA approved medication on the shelf now, those 10 million people with self-apparent pre-dementia most clearly seen in even simple memory tests have a potentially Faustian bargain with early treatment.

The patient revolt part would be for these pre-MCI patients to seek treatment ahead of the label with very low predosing. We know from the Clarity study that this would be quite safe. In the phase 2 study, even moving back from 10 mg/kg twice monthly to 5 mg/kg twice monthly greatly reduced ARIA rates. Near homeopathic dosing levels could be tried, though it would in time remove significant amounts of amyloid. Patients who chose to try such pre-dosing could also be selected so as not to include those being treated with anti-coagulants, etc. (i.e., select the low risk patients). [Post Edit: I read through the FDA Summary Memo for Leca where they give more of the background details. Surprisingly, they reported a patient treated with Leca at 1 mg/kg who developed a 10.1 mm macrohemorrhage. Microdosing would need to be supersafe, so dosing would need to be below even 1 mg/kg.]

Of interest as well, such a pre-dosing strategy would then at the same time reduce risk to patients who then followed through with on label use. Waiting until on the official on label diagnosis is reached and then treating with gram scale dosing is not clinically efficient in terms of safety. As a ball figure guess, I would think that the pre-MCI microdosing that I am suggesting would decrease on label risk by an order of magnitude. It already does not seem to demonstrate sound clinical judgment to wait and wait and then treat with the maximal clinically tolerated dose.

The patients would have in essence been pre-titrated possibly for years before the label. Admittedly, the actual efficacy of such pre-treatment has not been established and is still somewhat speculative. However, such a patient initiative could help to generate the needed results to answer the efficacy question. It might be possible with serial MRIs to prove that such early dosing does help preserve the volume of the hippocampi. In my opinion, preserved hippo volume could be taken as near definitive evidence that mabs could meaningfully provide benefit before MCI. All this valuable clinical research could flow back to the patients who helped finance it. The return on patient's investment in relation to the safety/efficacy tradeoff would seem to offer compelling value for patients and others.

How would this be helpful? Well companies at a certain point experience donor fatigue. They have invested so much money into a product and want to see a return. If patients were to provide this return then the additional research could be done with money from revenue and not yet more cash drain to the company.

The patients would likely also have much to gain. Amyloid in the brain as we have seen is quite dangerous in aside from Alzheimer's. Remember that the one fatal macrohemorrhage that occurred in Clarity occurred in a patient on placebo. Ignoring amyloid (as CAA) is clearly not without risk. Indeed, 7.0% of placebo in Clarity experienced an ARIA-E microhemorrhage.

It is in the self-interests of the patients collectively that mab science continues to advance while the CMS funding decision is made. Doing nothing about amyloid (even in the pre-MCI stage) has very substantial health consequences.

In addition to all that mentioned above such a pre-dosing strategy would also send a strong signal that the end of the era of AD is rapidly approaching. If you could now shut off the AD conveyor belt as suggested above starting 10 years before onset, then the countdown to the end of Alzheimer's would begin. The cost savings involved would then become highly conspicuous. The current expense of ~$350 billion dollars per year and exponentially increasing would then be understood as bending downward somewhere off on the horizon. The net present value of the AD would then no longer be realistically ~~ $10 trillion; but perhaps $5 trillion. People want that $5.20? Do they also want that $5 trillion? To collect that mega windfall, we need more treatment ... not less. Once it is recognized how much more cost savings could occur then there could be a rush to move AD treatment forward. The cost of not treating AD would then be seen as being prohibitively expensive.

Someone really needs to launch mabs into mainstream clinical practice. Perhaps it should be the patients? There is so much latent value with Lecanemab that has been on the shelf for years now. It is not clinically efficient to have this mab technology and for it not to be used by those who it could help. It is even less clinically efficient for the now hidden value of Lecanemab in pre-MCI patients to not now be revealed. There are many millions of patients who would likely derive benefit from pre-dosing. Establishing the safety and efficacy of this pre-dosing could then offer the chance for those more risk avoidant types to have solid research science to use to gauge whatever future treatment choices they felt in their best interests. This endless waiting is itself creating considerable harm to the well-being of patients. Time is brain in AD.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by floramaria »

J11 wrote: Mon Jan 09, 2023 7:26 pm Big news that I have only become aware of now is that Cognito has started their phase 3 for gamma entrainment.
https://clinicaltrials.gov/ct2/show/NCT ... w=2&rank=1 Hope trial
Surprisingly they do not appear to have added PET amyloid imaging.

The gamma phase 3 is set to complete in 2025! Things are moving.
Gamma entrainment could remove amyloid without side effects.
Hi J11~ Happy 2023! Thanks for including this news about Cognito. I hadn’t heard much about them recently. It is an exciting area of research.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Happy New Year Flora!

Yes, there is so much exciting AD research.
2023 really could be THE breakthrough year for AD clinical results.
There is such a long lineup ... it's not easy keeping up with it all.

It is beginning to feel like we are moving directly from one all time high to the next.
There is a certain near manic quality to this excitement.
J11 officially declares the start of THE AD Celebration!
2023: A year of AD celebrations!

We have Solanezumab's phase 3 A4 trial perhaps in weeks;
another potential accelerated approval with Donanemab also in weeks (this one has been very quiet, I have not even been able to determine what the PDUFA date is! );
perhaps approval for LMTM in 2023 and also full approval for Lecanemab this year.

I am so grateful that I have been released from the dementia prison that my family has been stuck in for centuries.
Dementing illness has been the central driving feature of my life to date; now I can explore other aspects of my existence. I suppose this is a fairly rare occurrence; mostly people become locked into a particular life and then inertia takes over from there. The important point to keep in mind is that we never get to see the Ghost of Christmas Future. We can now gradually diverge from our dementia destiny and never fully appreciate what that other path would have been like. However, I am very aware of how the path to relentless dementia progression unfolds; ergo the gratitude.

What we are currently witnessing is a once in a century scale medical breakthrough. The interlinked clinical syndrome of AD/stroke/CAA is within a group of the Big 3 illnesses (Cardiovascular, Cancer and AD ...) that at the center of 21st century population scale pathology. It is especially exciting that the "Alzheimer's in General" framing of the illness in the mab trials has held together quite well. In particular, Clarity suggested benefits across all demographics. Interestingly, the Hispanic and African misses, if anything, hint at the possibility that they actually benefited more not less.

One can only guess that there is likely a fair amount of Pavlovian salivating happening out there in other disease research such as cancer (and possibly even cardiovascular illness) because they have become so fragmented into micropatient populations with specific genetic mutations. The current framing of cancer is that it is hundreds of distinct illnesses.

Yet, in AD, a strong narrative emerged that AD is AD. APOE epsilon 4 genotype played an important role in helping to conceptualize AD as a cohesive disease entity. Without such cohesion, it is possible that there are other similar neuroproteinopathies that potentially could have a similar clinical development program as that of AD, though these diseases are still too murky/protean/indistinct.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

The FDA published a summary pdf of Lecanemab the day before the accelerated approval day.
https://www.accessdata.fda.gov/drugsatf ... dacted.pdf

The 3 OLE Clarity fatalities that have been widely reported in the media were described in this pdf. Of interest, none of these patients on first reading would seem to have been directly related to Lecanemab treatment: None of these patients appeared to demonstrate ARIA on presentation to the hospital before treatment was started.

I was not clear what to make of these three fatalities reported for Lecanemab in the OLE.
It seemed that perhaps some newly emerging pattern related to Lecanemab treatment was unfolding. However from the below patient descriptions below this does not appear to be true.

The background for patient [1]'s trajectory does not clearly indicate a connection to Lecanemab treatment.
There are so many other comorbidities that arose that it would be very difficult to ascribe a cause to the fatality.

Patient [2] which has been discussed on forum is also not obviously caused by treatment. The imaging before tPA did not find the macrohemorrhages that occurred after tPA was administered.

The big surprise for me was the write-up for patient [3]. On arrival to the hospital : "an MRI with and without contrast was reported as showing “no mass, no definite bleeding or edema or stroke”. This patient did not have
ARIA either?

None of these patients presented to the hospital with evidence of ARIA consistent with a side effect from Lecanemab?

pdf p. 32

301 Core and OLE ...
"12/1899 deaths (0.6%), none of which was preceded by documented ARIA, although 1 was an
intracranial hemorrhage (subject ) confirmed to be a patient receiving placebo in a
December 14, 2022, response to an information request. There were no deaths reported in
studies 101, 104, 004, or ongoing study 303. One additional death in ongoing 301 OLE was
reported to the Agency on December 20, 2022 and reported in the journal, Science, on
December 21, 2022, and is described below.

... the Agency became aware of two additional deaths due to
intracerebral hemorrhage greater than 1 cm in the 301 OLE.

One event occurred in an 87-year-old male with a past medical history including atrial fibrillation, hyperlipidemia,
coronary artery disease, lacunar stroke, and cerebral microhemorrhage, with current
medications of donepezil, apixaban, and atorvastatin, as well as tamsulosin. The patient
sustained a fall on Day 77 after 6 doses of study drug, followed by pneumonia, COVID, and an
ulnar pseudoaneurysm treated with thrombin, and another fall from bed. A subsequent MRI
on Day 116 showed a left occipital intracerebral hemorrhage (> 1 cm). Apixaban was
stopped. This was followed by a myocardial infarction on Day 122 and TIA-like events on Day
126. The patient died on Day 144 due to the cardiopulmonary causes. ...

The second event occurred in a 65-year-old woman with MCI, homozygous for ApoE ε4, who
completed 301 Core on placebo and enrolled in 301 OLE. This case has been recently
published.23 Four days after the third dose of lecanemab, the participant was noted to have
garbled speech, and was taken to an emergency room. A CT of the head diagnosed a leftsided
ischemic stroke due to an LM3 occlusion. Tissue plasminogen activator (tPA) was
administered. Within 8 minutes after tPA she experienced a headache, and within 40 minutes
she became agitated. Repeat imaging showed bilateral intracerebral hemorrhage with
subarachnoid hemorrhage. The tPA was stopped and cryoprecipitate and tranexamic acid
were given for reversal of tPA. She was treated with Haldol for agitation and lorazepam and
Keppra for seizures. Her blood pressure was greater than 200 mmHg, for which she was
started on nicardipine infusion. Her encephalopathy worsened and she was intubated. MRI
performed 3 days after the CT scan showed extensive multicompartmental ICHs, innumerable
hematomas, SAH and right intraventricular hemorrhage with 5 mm leftward midline shift and

bilateral uncal herniation. At the patient’s directive, she was extubated and died eight days
after the last dose of study drug. A subsequent autopsy was reported to show extensive,
multi-focal intraparenchymal hemorrhage by gross pathology examination with microscopic
examination demonstrating AD neuropathologic change and widespread necrotizing
vasculitis involving blood vessels with cerebral amyloid angiopathy. Dr. Erten-Lyons notes
that a large vessel stroke, thrombolysis and cerebral amyloid angiopathy are all associated
with an increased risk of intracerebral hemorrhage which confound the ability to draw any
conclusions on causality.

An additional notable report of death in the 301 OLE (Mfr. Control No. :EC-2022-123944(0),
subject ), was submitted to FDA on December 20, 2022, and reported in the
journal, Science, on December 21, 2022.4 This was a 79 year old female with early
Alzheimer’s disease who completed 301 Core on placebo and was enrolled in the OLE in
. The patient was homozygous for ApoE ε4. The patient received 3 doses of
lecanemab 10 mg/kg every two weeks in the OLE. The last dose of study drug was
administered on . According to the CIOMS report, 1 week after the last
dose the subject experienced a sudden onset of difficulty speaking, staring into space, and
left side weakness, reported as a “possible CVA (cerebrovascular accident)” and “possible
seizure”. The subject was taken to an emergency department and was intubated and
hospitalized. An MRI with and without contrast was reported as showing “no mass, no
definite bleeding or edema or stroke”. A prior MRI from , was notable only for a
“a previously noted left parietal < 1 cm meningioma”. A seizure was suspected but no
definite seizure activity was noted. It was reported that the subject had never been on
anticoagulation during the study or in the hospital. The subject was extubated and 5 days
after the original event, developed respiratory distress and passed away. According to the
CIOMS report, the subject had risk factors for seizures, including underlying Alzheimer’s
disease, and for cerebrovascular disease, including advanced age, hyperlipidemia, aortic
atherosclerosis, chronic kidney disease, and prediabetes. According to the CIOMS form, an
autopsy was performed but results had not been reported to the investigator site.
Descriptions of brain bleeding and swelling, treatment of the event with steroids, and
multiorgan failure noted in the Science description, are not noted in the CIOMS form and
have not been submitted to the Agency for review. The Agency has requested that the
applicant provide additional information on the case, including MRI images and the autopsy
report. The applicant has not been able to obtain additional information as of January 3,
2023. The confirmation of the events reported in the Science article and their relationship to
study drug cannot be determined at this time; however, the available information does not
change the risk-benefit assessment for this review."
Last edited by J11 on Tue Jan 17, 2023 7:02 pm, edited 1 time in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by NF52 »

J11 wrote: Mon Jan 16, 2023 5:38 pm The FDA published a summary pdf of Lecanemab the day before the accelerated approval day.
https://www.accessdata.fda.gov/drugsatf ... dacted.pdf
Hi J11,

Thanks for finding and posting these comments from the FDA's accelerated approval of lecanemab (Leqembi). They will likely be discussed again in the decision on full approval expected in March or so.

It's confusing that some documents and presentations refer to the 201 and 301 study and extensions. The 301 study is the CLARITY study, as you note, and the deaths all occurred only after that trial concluded and moved in the Open-Label Extension.

I think the question now is not whether ARIA-E or ARIA-H directly causes macrohemorrhages, since the data clearly shows that the two do not appear linked. This 2022 article on The relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer’s disease explains how amyloid beta (Aβ) itself causes damage to the endothelial lining of the blood brain barrier, which may explain why 5 or so people on the placebo arm of CLARITY had macrohemorrhages, whether or not they had CAA.
Brain capillary endothelial cells are the key components of Aβ clearance mediated by BBB... Excessive Aβ exerts potent detrimental cerebrovascular effects by promoting oxidative stress, inducing chronic inflammation, and impairing endothelial structure and functions. All of these are main causes for the reduction in Aβ clearance across the BBB and the accumulation of Aβ in the brain parenchyma.
It also suggests that earlier clearance of Aβ may be safer and important for those with ApoE4 prior to the neuroinflammation and vascular damage seen by the time MCI and AD are diagnosed.

The report you quoted on the death of a 65 year old woman with ApoE 4/4's notes: "Four days after the third dose of lecanemab, the participant was noted to have garbled speech, and was taken to an emergency room. A CT of the head diagnosed a leftsided ischemic stroke due to an LM3 occlusion." LM3 refers to the a specific segment of left side of the middle cerebral artery. I found this drawing of how large and extensive it is:
https://www.meddean.luc.edu/lumen/meded ... mcacor.htm
And this July 2022 description of the major causes of ischemic stroke's suggests a cardiac cause:
The middle cerebral artery is the most common, pathologically affected blood vessel overall....
Embolism of the MCA
An embolism is a detached mass...which is transported through the blood vessels until it is lodged in the MCA. As a general rule, a proximal occlusion will cause damage to a large surface area and be devastating. ...Thrombus formation commonly is associated with sites proximal to the MCA, such as internal carotid plaques, common carotid plaques, and atrial fibrillation, resulting in thrombus formation and embolism. .....Wernicke’s or conduction aphasia may be seen if the inferior division of the MCA is affected.

WebMD notes that
People who have Wernicke’s aphasia can’t understand words. They speak with regular rhythm and grammar. But the words don’t make sense. They don’t realize that what they’re saying is nonsense

That sounds like the "garbled speech" that sent her to the ER. https://www.webmd.com/brain/what-is-wernickes-aphasia A devastating injury led to her death, but if that clot or thrombus came from her carotid artery, it's hard to see how lecanemab caused it.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Thank you for your reply NF52.

It would be better if one could do a full search of the FDA website and see all their materials on a subject such as Lecanemab. I needed to have a direct link to actually find the pdf. All I could find on a search of the FDA site was the accelerated approval press release. It would be even better if they could have all the information in a folder.

The Summary report had quite a bit of interesting information that helped to give an idea of how the FDA interpreted various features of the Leca accelerated approval.

Could Leca be given full approval by March?
I thought that this could take months and months.
If this could be approved by March then they would need to have the ADCOMM (if they decide to have one) in the next month or two.

Yes, for those who are not paying attention it could be confusing. All the patients fatalities in the Clarity OLE will now be with patients treated with Lecanemab because all the patients on the OLE are now being treated with Lecanemab. The impressive result at CTAD during the Clarity presentation was that none of the Lecanemab treated patients in the core randomized portion of the trial had a fatal response to treatment. The fatality rate in placebo was actually nominally higher that treatment. One of the placebo patients actually had a fatal macrohemorrhage, though according to the Summary pdf this patient did not experience ARIA (which is somewhat confusing because in the writeups macorrhage is considered ARIA-H).

I had been uncertain about the Lecanemab treated patient in Clarity with a fatal stroke which was deemed non-ARIA.
I wasn't sure if a stroke uncomplicated by the Lecanemab conditioned brain environment would be possible. However, the FDA Summary Memo, describes the three fatalities in the OLE and the two stroke (or stroke like) patients apparently entered hospital without any obvious ARIA (especially macrohemorrhage) on MRI.
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