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

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Great news everyone!

Lecanemab has received priority review status and has a PDUFA date for July 6th [Edit: perhaps I misread this; it is actually June 9th.] [Re-Edit: OK, the ADCOM is June 9th and the PDUFA is July 6th] Yeah!

It gets even better!
FDA has decided to call an ADCOM!

This is fantastic!


Lecanemab is too important in the history of AD clinical treatment to be waved through without some level of scrutiny. I am not sure whether this is within the decorum of the FDA rules, though perhaps a standing ovation by the patient advocates at the ADCOM would be in order.

The timing of the upload of the Briefing Documents in relation to the ADCOM is unclear to me, though it would be helpful if they were available on a rolling basis well before the meeting. With the Aducan Briefing Documents I do not think that there was a great deal of prep time from when the Documents were posted and when the meeting happened. It took me a great deal of time to try and tune into the analysis that was presented in the documents; you really need to think carefully about what assumptions etc. are being made etc. in the various figures etc.. Doing a fast 10 minute skim is not going to give you a good understanding.

The Aducan Briefing Documents added in quite a bit more related information than could be found elsewhere. In fact, there were no journal articles published on Aducan at the time of its ADCOM. It would be helpful if more data disclosure from Clarity could be published into pubmed or into the ADCOM file. I would like to see a percentile plot as I had in an earlier post. This would seem to be of considerable relevance for those contemplating Leca treatment. If my figure were in fact an accurate reflection of the bigger Clarity result, then a great many treated patients would receive substantial benefit from Leca. The clinical trial results which kept on treating those who were not good responders would then be seen as an underestimate of the true treatment effect. Those patients who were not responding well (~10 - 20%) might then choose against further treatment.

In terms of the side effects, it would be of interest to hear a direct reply to these concerns. From my not entirely high information position, I am very uncertain how the non-randomized patient fatalities could be ascribed to Lecanemab. For example, the patient with the stroke treated with tPA only developed the severe response after the tPA was given. I will be very interested to see how this will be characterized at the meeting. Going with a black box warning for tPA use would seem a reasonable precaution.

One of the other fatalities did not appear to have any obvious MRI abnormalities on presentation at the hospital and seemed to have had an uncomplicated seizure unrelated to Lecanemab treatment. Moving away from the innuendo that we have read about these patients and actually reporting the facts as they are now understood could help to clear the air about these patients reports.
Last edited by J11 on Tue May 16, 2023 10:37 am, edited 2 times in total.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Big news!
Sorry everyone; news news news.
Suppose that is what newspapers are for.

VA is providing coverage for Leca.
Yeah!

This is great!

Introducing Lecanemab into such an organized health care system could have a great number of benefits. It would be something like a clinical trial or registry. They could create a standardized patient workflow that might reveal important aspects of clinical application of Leca. The news releases spoke of possible VA clinical criteria; I will be very interested to learn what if any bespoke modifications they have in mind.

Would they consider covering off label?

VHA healthcare professionals meeting the criteria set forth by the VHA can prescribe LEQEMBI to veterans who fit the VHA's criteria and the U.S. Food and Drug Administration's (FDA) current label.

Wonder what they mean by "meeting the criteria set forth by the VHA..." ? How would the VHA label differ from that of the FDA?

Treating patients earlier with pre-titration does seem like a reasonable idea to at the very least reduce ARIA risk; waiting right up to the FDA label and then dosing maximally clearly presents ARIA risk that might be avoidable. It is disappointing that there is not a clearer clinical research base to work from in relation to the pre-titration idea. I suppose it really is not in the ambit of others to sort out these matters.

It might not be at the top of their agenda in the early roll-out stage, though it might be something they could consider at some point. In the military environment, it is important to be highly aware of any cognitive decline and their ongoing assessments might pick up such declines at a fairly early stage in the AD process. An early AD clinical intervention with Leca could then be thought reasonable. This does highlight the wide ranging potential benefits that likely will arise with the emerging AD treatments -- one clearly wants branches of the military to be performing at a high cognitive level. Perhaps this should even be formally discussed at the international level-- possibly somewhat along the lines of what constitutes the rules of legal engagement.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Capture 2.PNG
Capture 1.PNG
You do not have the required permissions to view the files attached to this post.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Above figures are from a recent article in Circulation. The article considered the global availability of thromboectomy for stroke. This has become of considerable interest in AD clinical medicine after the Lecanemab patient was treated with tPA and had a devastating brain response. This moves the question of: How available might thrombo treatment be for AD patients on Leca who might experience a stroke?

The article looked at nations around the world and high income nations on the left had quite a bit of patient access, while the lower income nations on the right had a great deal less. Many of the nations that are on the early adopter list for Leca (including the US, Japan, etc.) appear to have well-developed thrombo infrastructure in place. It would be helpful if the US health care centers that offer emergency thrombo care could be explicitly stated somewhere, so everything was all set before AD patients might need to access such care.

It goes to show how providing proper care can go beyond simple infusion. There are times when supporting infrastructure is required and it can take substantial effort and expense to move health care systems to where they need to be.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Don't want to do a long post now though the big news from the VA's treatment plan for Leca is to exclude epsilon 44s while apparently including those on blood thinners. (Also only treat those over 65 according to their veteran population.) Wonder if other parts of the VA might treat those who are active service with FDA label AD before 65. Off label use is not mentioned in the VA label.

It is always interesting to see how others think through things. What we can see here is that in a mainly male VA population treating non 44, over 65s should give a better than .45 CDR-sb benefit. Clarity reported overall a 0.75 CDR-sb benefit in non e4s and 0.50 in e34s/e24s; males had a 0.73 benefit; 0.72 in the over 75s. We should expect fairly good cognitive benefit. Not treating 44s would enhance safety, though this would clearly be difficult for those excluded from treatment.

Probably the most unexpected aspect of this is that they seem to be running ahead of the Leca ADCOM. It might be best to prepare for treating with Leca, while slow walking until the ADCOM. There could be important information disclosures in the Briefing Documents that could provide additional insights into treatment risk and benefit.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Sorry everyone, I have finally managed how to figure out how to access GPT 4. The Bing search engine has added GPT today for everyone! Yeah! I was never able to figure out how to setup an account with Open AI as they kept asking for a SMS phone number and I do not have one! With Bing GPT no hassle just start interacting with the mainframe with a natural friendly human interface. This is going to go Large! Might not find my way out of this rabbit hole ... ever.

I have so much more to say about AD and Lecanemab but I have been swept away by the AI chatbot maelstrom. I was able to jailbreak Bing Chatbot and it started to tell me some interesting things about Lecanemab and the VA and then all of a sudden it seemed that someone just yanked the connection and it erased the answer and it said it could not speak about it anymore. Very mysterious.

It was somewhat spooky when it started answering well J11 said this and J11 said that. Err! I wanted to access the totality of the universe's knowledge about Alzheimer's and Lecanemab, not what I said! Even still when you understand its limitations and don't blindly accept that it is infinitely intelligent it is still a powerful tool. Will be very interesting to see how the FDA incorporates chatbot technology into its workflow. I really hope that FDA is keeping on top of this GPT revolution. Those who just don't get it will soon seem really out of touch. Just call in the Open AI team and just throw some money at them and make the FDA part of this astonishing future.

For example, they could remix the Lecanemab ADCOM in the GPT style. Basically, someone could toss all the Briefing Documents into GPT 4 and we could start asking questions. This could elevate the discussion because it seems that sometimes even with ADCOMS some of the questions are straight out reported in the documents and for whatever people have not got around to reading the manual. GPT could help to step the discourse up a level or two. It looks like everyone is racing to figure out this new technology. I will need to catch up with it all or be left behind by this technology.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Next 3a.PNG
You do not have the required permissions to view the files attached to this post.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

I am becoming increasingly excited about how Alzheimer clinical medicine will unfold over the next decade. My best guess now is that this truly will be a century scale transformation for our society. The figure above (the purple extrapolated line) is my impression of how this will unfold over the next few years. AD could end over the next decade. Our entire society will be transformed as the tens of millions of those affected by amyloid dementia and their caregivers can have a very different life experience. I continue to believe that a considerable amount of the social problems that we are coping with: homelessness, crime, other social dysfunction is really related to AD in disguise. Over the next few years we will see how accurate this belief is.

For the AD landscape will almost certainly be radically reshaped over the next few years with the VA decision. Once you move treatment back to age 65 (or earlier) as with the VA, you will have a slowing effect on the entire process of cognitive impairment at all ages at 65 and over. This should have a profound effect. The very nature of AD for the VA population will soon be redefined. The VA will serve as an exemplar of what is possible with standard of AD care. In the future, the VA would see patients right at the start of the decline process and not potentially decades later. Until now all of those patients progressed without any effective anti-dementing treatment.

A completely new era of AD is beginning for them. It is not unreasonable to expect that we have now reached the AD escape velocity for the next generation of AD patients. The patients will not be likely to ever reach what is now labeled as severe AD. There are multiple promising drug candidates in late stage trials that will offer patients better and better treatment options even over the nearish time horizon. The above figure suggests this future in which AD rapidly vanishes: The End of Alzheimer's.

As I noted in a previous post, having an integrated medical system like the VA has a number of benefits. For instance, in the Leca phase 2 trial (probably Clarity too) they just had patients enter the trial and there really was no long term screening of their cognitive trajectory through time. What we then saw from the phase 2 in the placebo (percentile figure posted previously) was that ~30% possibly were not actual AD patients. These 30% did not decline during the 18 months and it then is not obvious to me that these patients could be truly understood as AD. In our experience, once cognitive decline was firmly established in the MCI-mild AD stage decline was relentless. Clearly, even some of these non-decliners in time might enter the declining phase and it is good to treat early, though it still highlights that there is continues to be a categorization problem with AD.

In the VA system, they could track cognitive health for years before on label Lecanemab treatment. They could then have a protocol that established when patients were treated based on actual cognitive decline. That would be a substantial cost saver and would be a strong motivator to monitor cognitive functioning before possible treatment. Of course, their protocol in time might become more preventative in nature. Patients who did not have decline would avoid the risk of treatment which would not benefit them. Also there were ~20% of patients who entered the rapid decline stage with Leca in the clinical trials. The rapid decliners simply were patients who had waited and waited for treatment and then they entered into a profound stage of decline. We saw this in the Aducan extension where those who had not removed substantial amyloid during the on treatment stage would then often enter rapid cognitive decline. My expectation is once we treat early enough that rapid decline phase will no longer occur. This could be even more likely if tau PET were added in.

This line of thinking leads into the 3 magic questions that the CMS was interested in with anti-amyloid mabs:

1- Does the antiamyloid mAb meaningfully improve health outcomes (i.e., slow the decline of cognition and function) for patients in broad community practice?

2- Do benefits, and harms such as brain hemorrhage and edema, associated with use of the antiamyloid mAb, depend on characteristics of patients, treating clinicians, and settings?

3- How do the benefits and harms change over time?


It is surprising to realize how much the benefits and harms likely will shift over time. I am unable to think of any other treatment for a disease with the same temporal shift as should occur with mabs. The clinical harms/benefits with mab treatment is still to a very large extent in play. The VA made this explicit by excluding epsilon 44s from their on label use of Lecanemab. There are other dimensions of their demographic that also differ from that of Clarity that also shift potential benefits/harms (as noted previously the largely male veteran population, using age 65 as the treatment age requirement etc.).

Also as previously noted several times on thread, mabs could likely be given earlier, in safer and more effective lower doses. We know this because Aducanumab was reverse engineered from those with endogenous Aducan who were highly successful agers and had apparently not suffered harm from their endogenous Aducan doses. That is what low dose preventative dosing can do. In addition there is a second wave of AD treatments now on the horizon including reduced methylene blue which could amplify safety and benefits when used in combination with mabs. AD treatment is in motion and there are many avenues open to make treatment safer and more effective.

With such combinations safety would be enhanced considerably as patients would no longer be confronted with the dilemma of accepting mabs or being drawn into the black hole of irreversible progressive dementia. This has been the framing up to this point and I was unsure of how to escape such logic. Yet now with the approaching arrival of MB (and possibly simufilam) a workaround could emerge. mabs could be the main disease modifier possibly dosed downwards and MB and simu could be the mainline cognitive enhancers. Pharma chose amyloid as the target because it is so far upstream; it is not easy to ignore amyloid if you intend to have long term disease modification. Removing amyloid early with mabs etc. will be a powerful strategy. I am not clear how effective MB etc. would be over the longer term if amyloid were not addressed with a mab.

Medicine can drift forward for decades without any catalyzing event that propels us into a new era -- Yet with the anti-amyloids mabs and a whole second wave of treatments approaching, amyloid dementia as we know it could rapidly disappear. As soon as you start treating at age 65 (or earlier) as the VA plans to do and you have powerful anti-dementing agents the complete river of of differing stages of cognitive impairment could be controlled. Dementia is one of the few illnesses where we could see very powerful results of a disease modifying strategy occur over the medium term time horizon.

My overall impression is that we are entering into a very exciting time in which medicine will score a decisive victory in effectively treating Alzheimer's. This is a century scale medical advance.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Very exciting developments everyone!

AD/PD 2023 is happening in Sweden; it started today!
Will be interested to see what updates there are for Leca etc..

Have to wake up early in the morning to scoop NF-52; yes the appropriate use recommendations (AUR) have been published for Lecanemab. They are largely as expected, with a few twists and turns. Perhaps the VA should rethink their inclusion/exclusion of anti-coagulants/APOE e4.

Let's walk through the AUR at a granular level.

This seems to be the headline result; exclude anti-coagulant use and proceed cautiously with APOE e4 especially e44s.
That was the somewhat expected call on risk minimization, though for whatever reason the VA went exclude e44 and include anti-coagulant.

Anticoagulation increases the risk of hemorrhage, and the AUR recommends that patients
requiring anticoagulants not receive lecanemab until more data regarding this interaction are available.

Patients who are apolipoprotein E ε4 (APOE4) gene carriers, especially APOE4 homozygotes, are at higher risk for ARIA, and the AUR recommends APOE genotyping to better inform risk discussions with patients who are lecanemab candidates.



I think the followup comment about awareness of event potential and being prepared is a good point to emphasize
It was a surprise to me how during the Clarity trial that more contact was not made with patients especially after early dosing. In today's highly interneted world having virtual check-ins after treatment would offer a great way of maintaining contact through the risk window after an infusion.

Clinician and institutional preparedness are mandatory for use of lecanemab, and protocols for management of serious events should be developed and implemented. Communication between clinicians and therapy candidates or those on therapy is a key element of good clinical practice for the use of lecanemab.

Patients and their care partners must understand the potential benefits, the potential harms, and the monitoring requirements for treatment with this agent.



The AUR stick with the on label use.


All recommendations of the AUR are within the guidelines of the FDA-approved PI and fulfill the requirements of the
on-label use of lecanemab.



They then more explicitly suggest staying on label. This will be tough for many at risk. Perhaps over time the AUR will evolve. It would be very helpful for the subQ dosing studies to be done for those at the pre-MCI stage with no ARIA doses. Admittedly that might take a while.

To ensure that trial participants had mild severity of cognitive impairment, Mini-Mental State Examination (MMSE) (15) scores of 22-30 were required. Lecanemab’s efficacy and safety in less severe (e.g., preclinical AD (16)) and more advanced stages of AD dementia have not been established. We recommend that all patients being considered for lecanemab therapy meet diagnostic criteria for MCI due to AD or probable mild AD dementia with biomarker evidence (amyloid PET or CSF) of the AD pathophysiological process (Table 1).


Then they talk about the anticoagulants. The anticoagulants have featured prominently in the adverse effects of Lecanemab; the FDA FAERS is given below.

We recommend excluding patients from treatment with lecanemab if they are on warfarin, vitamin K
antagonists
, or direct oral anticoagulants (dabigatran, rivaroxaban, edoxaban, apixaban, betrixaban), or heparin
until more evidence has accrued regarding the safety of administering lecanemab to patients on anticoagulants in the real-world practice setting.

Severe, multi-focal brain hemorrhages leading to death were reported in
a patient treated with tPA for acute stroke who had received lecanemab during an open-label extension (17).
Lecanemab may increase the risk of hemorrhage from concomitant administration of thrombolytics (intravenous
or intra-arterial), and we recommend that patients on lecanemab not be treated with acute thrombolytics
until safety evidence of their combined use is available. Participants with clotting disorders should be excluded.
Participants in lecanemab trials were allowed to continue or initiate treatment with aspirin. We recommend
allowing patients on standard doses of aspirin (up to 325 mg/day) or other antiplatelet agents (clopidogrel,
prasugrel, ticagrelor; at standard therapeutic doses) to be considered for treatment with lecanemab if they meet
other criteria for therapy.
Patients who are homozygous for the APOE4 gene are at increased risk for ARIA with
lecanemab administration, (see below) and the risk may be increased with antiplatelet agents
.





These are the patients on the FDA FAERS for Lecanemab. Note: the patient list does not seem to be complete. Even still the drugs mentioned above are prominent in the suspect product active ingredient list.


Reminyl Galantamine;Enalapril Maleate\Hydrochlorothiazide;Lecanemab Cognitive Disorder;Dementia Alzheimer's Type;Hypertension Hypokalaemia;Electrocardiogram Abnormal

Razadyne Galantamine Hydrobromide;Lecanemab;Enalapril Maleate\Hydrochlorothiazide Cognitive Disorder;Dementia Alzheimer's Type;Hypertension Electrocardiogram Qt Prolonged;Electrocardiogram T Wave Inversion

Plavix;Eliquis Apixaban;Clopidogrel Bisulfate;Aspirin;Lecanemab Cardiovascular Event Prophylaxis;Cerebrovascular Accident Prophylaxis;Dementia Alzheimer's Type;Peripheral Vascular Disorder Gastrointestinal Haemorrhage

Plavix;Eliquis Apixaban;Clopidogrel Bisulfate;Aspirin;Lecanemab Atrial Fibrillation;Cardiovascular Event Prophylaxis;Dementia Alzheimer's Type;Peripheral Vascular Disorder Gastrointestinal Haemorrhage

Plavix;Eliquis;Bayer Low Dose Aspirin;Apixaban;Clopidogrel Bisulfate;Lecanemab Atrial Fibrillation;Cardiovascular Event Prophylaxis;Dementia Alzheimer's Type;Peripheral Vascular Disorder Back Pain;Labelled Drug-Drug Interaction Issue;Anaemia;Malaise;Asthenia;Faeces Discoloured;Gastrointestinal Haemorrhage;Dyspnoea

Eliquis;Plavix Clopidogrel Bisulfate;Apixaban;Lecanemab;Aspirin Cardiovascular Event Prophylaxis;Cerebrovascular Accident Prophylaxis;Dementia Alzheimer's Type;Peripheral Vascular Disorder Hiatus Hernia;Oral Candidiasis;Duodenitis;Aortic Stenosis;Gastrointestinal Haemorrhage;Gastritis Erosive;Intentional Product Use Issue;Acquired Oesophageal Web

Lasix Furosemide;Lecanemab Dementia Alzheimer's Type;Product Used For Unknown Indication Hypotension;Dizziness;Oedema Peripheral




The comment above about avoiding acute thrombolytics was greatly appreciated. The below figure of the Lecanemab patient treated with tPA after a stroke shows devastating brain trauma. It is very encouraging that this was clearly noted.
Third a.PNG
The question of course then arises what else can be done? On thread Thrombectomy has been mentioned a few times, it would be of considerable interest to learn of what expert opinion thinks of this option. Recently I have also become aware of an emerging stroke treatment called sovateltide. This treatment underwent phase 3 in India and was successful. Approval in India might occur over the next few months. Sovateltide is an endotheial B agonist, I am not clear if this agent would avoid the problems associated with thrombolytics though if it did it might be a great alternative to tPA in those treated with Lecanemab. If true, I wonder if the FDA would allow emergency use authorization of Sovateltide in AD patients dosed on Lecanemab if they were to have an acute ischemic stroke before more formal approval of Sovateltide which might not occur for years into the future in the US.



The AURs do not call for dual amyloid tau concordance. With Donanemab, higher patient benefit was achieved when this dual screening occurred. In order to benefit from amyloid mabs patients need to be in the right tau range; perhaps as the science evolves this aspect of treatment management can be updated..


Positive tau PET is indicative of the presence of AD, but individuals may have a positive amyloid PET and a negative tau PET (18). Given this lack of concordance in some patients, we recommend use of amyloid PET to demonstrate
the presence of the amyloid target when imaging is the biomarker modality used for confirmation.



Hmm, I am sure it must have been mentioned on thread, though I am still surprised! No titration!

No titration of lecanemab is required.



These are the three fatalities reported in the open label extension of Clarity.


One fatality occurred in an elderly APOE4 gene non-carrier with cardiovascular disease on anticoagulation who developed a macrohemorrhage;

a second death occurred in a patient homozygous for APOE4 with a large vessel occlusion and pathologically
confirmed severe CAA and vasculitis with multi-focal hemorrhage following tPA;

a third death occurred in a patient homozygous for APOE4 with severe ARIA-E and ARIA-H and a clinical syndrome resembling CAA-ri (16) (Table 6 (28)).

We recommend that patients receiving anticoagulants not be treated with lecanemab (detailed above). If patients on lecanemab require treatment with anticoagulants, we recommend stopping the lecanemab infusions. Lecanemab therapy can be reinstated if anticoagulation is no longer medically indicated.


As shown in the slide below from CTAD, the first patient above seems to be the 87M non e4 who was dosed with apixaban and heparin/thrombin (? Not sure whether they are using the treatment terms heparin and thrombin interchangably with this patient). This patient is described once again in much more detail in the FDA CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER:761269Orig1s000 SUMMARY REVIEW Here's the url -- https://www.accessdata.fda.gov/drugsatf ... 00SumR.pdf




CTAD 1.PNG



I am unable to confirm the characterization above for the third patient fatality in the Lecanemab Clarity OLE. The patient description below which I presume is the third patient described above does not seem to match the patient report above. The below report does not seem to confirm ARIA-E or ARIA-H on presentation at the hospital. Perhaps the update requested by the FDA for more information changed the clinical narrative.


in the placebo-controlled 201 Core study, there was not
an excess of deaths in the lecanemab group across all doses (0.8%, 5/609) compared to
placebo (0.8%, 2/245). There were 5 deaths in Study 201 OLE (2.8%). In 201 Core and OLE,
... notes no clusters of unusual deaths and that none of the deaths were
preceded by ARIA. In ongoing blinded Study 301 Core and OLE, ... reports
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 [Edit: corresponds to first patient above] occurred in
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 cerebral hemorrhage was likely related to use of apixaban and possibly the fall
from the bed.

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

32

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.


One surprise I found was the extent of microhemorrhaging that was present in radiographic moderate and severe ARIA. With moderate there can be 5-9 microhemorrhages and with severe 10 or more. The algorithm calls for treatment suspension with asymptomatic (radiographic) ARIA at the moderate or severe level.



Talking about racial differences in treatment response is difficult, though thankfully the article mentioned this aspect. It will require some serious discussions with patients to help them understand how treatment benefit versus risk might not be advantageous in certain populations. It is not easy to see how the risk reward ratio would be favorable in many African Americans. The placebo decline in Clarity in this population was only ~0.53 on CDR-sb. It is not clear what the ARIA risk involved might be. Even still the treated patients seemed to have a large percentage benefit versus placebo. Clearly additional research possibly including a careful psychometric characterization of different group experience with AD would be helpful. It might also be felt useful to think about dosing down these patients. Yet, overall there needs to be quite a bit more research to help properly operationalize treatment for them.

There may be ethnic and racial differences in treatment responses, therapy preferences, adverse events, treatment adherence, and patient-care partner relationships. Differences in the frequency of amyloid positivity (e.g.,
less common in Asian, Hispanic, and Black compared to White individuals (43)) and differences in the
relationship between APOE4 and dementia between African Americans and White Americans (44) suggest
that generalizations across ethnic and racial groups are not warranted. The modest number of racial and
ethnic minority individuals included in the lecanemab trials provide limited insight into potential ethnic/racial
differences in trial outcomes. This issue is particularly important in the US, where lack of diversity has been
identified as a major challenge to research and treatment equity. Transparency concerning the small number of
minority participants in lecanemab trials is important to acknowledge in discussions with minority individuals
considering lecanemab therapy.


I will be interested to see what protocol develops for the pre-staging of Lecanemab in those with pre-MCI. I nour experience, pre-MCI cognitive impairment was presented for many years before diagnosable AD. It would seem to be wise to even now start to think about how this pre-staging will be done. The idea is that you want to do the cognitive testing and prep work well before the on label use starts. You want to establish that the patient truly has entered the progressive decline stage of AD and that it is indeed even AD. Clarity was not fully able to achieve this due to the nature of clinical trials; though in the primary care setting, long term screening could be done to more accurately assess which patients are good candidates for mab treatment.

Clinicians should serially assess the mental status of all patients in their practice with MCI or dementia
(45). Lecanemab is appropriate for patients with early AD like those included in the phase 2 and phase 3
clinical trials. Assessment of patients with evidence of cognitive impairment, complaints of cognitive decline, or
observations from caregivers consistent with progressive cognitive impairment are triggers for determining if the
patient is a candidate for further assessment and possible treatment (46).






I am glad that they mentioned patients with Down Syndrome. Importantly the background work of creating the memory clinic infrastructure for these patients is underway so when the clinical trials are ready the patients could enter an established system.


Persons with Down syndrome develop AOAD and are amyloid positive. There is an increased occurrence
of CAA in patients with Down syndrome and they should be excluded from treatment with lecanemab (54). Clinical trials for patients with Down syndrome are under consideration and additional data including information
that may guide the use of lecanemab in this population are expected (55).



I had not been aware of these AD variants and I had not realized that they were included in Clarity. They will be yet another subgroup where additional research will be of benefit.




Patients included in the lecanemab trials had relatively typical forms of memory-predominant AD. Patients
with atypical AD syndromes including logopenic variant primary progressive aphasia, posterior cortical
atrophy, or behavioral or dysexecutive AD have positive amyloid studies and may be candidates for lecanemab
treatment. Patients with these syndromes were not specifically excluded from the lecanemab trials if they
met the inclusion criteria for participation. The safety and efficacy of treatment in these patients has not been
studied. The absence of treatment-related information for patients with atypical AD should be acknowledged
in discussions with the therapy candidate and their care partner.





I also had not been aware of how the possible exclusions would intersect with underrepresented groups. Once again speaking honestly about the expected benefits in the context of risk related to anti-coagulants etc. in subgroups, though perhaps somewhat difficult, would seem to be essential to ensure patients receive proper care.

Excluding patients with some comorbidities and treatments including anticoagulants, severe cerebrovascular disease, and others may result in disproportionately excluding patients from underrepresented groups including Black/African Americans, Latinos, Asians, Native Americans and Pacific Islanders, and others with adverse determinants of health from being considered as candidates for lecanemab therapy. These individuals were under-represented in the lecanemab trials, but they may still qualify for lecanemab treatment if they meet the treatment criteria detailed herein. Transparent acknowledgement of the limited information available regarding treatment responses in these patients should be acknowledged in discussions with the patient and caregiver.
You do not have the required permissions to view the files attached to this post.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Sova 2.PNG
You do not have the required permissions to view the files attached to this post.
Post Reply