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 »

Thank you Chicagogirl, yes I was fairly sure that it was not an 8 hour observation, though I remembered how you mentioned that the first visit at least was a full day.

It really is great having someone behind the lines because there are many specifics that you can pick up and probably never make it into the textbook.

I was very surprised when the Florida patient above apparently did not have an observation period after her infusion. That was not consistent with your experience. I would think that a 4 hour or so observation period would be required. Yet, the article noted that she developed a serious headache 1 hour after the infusion. I find it surprising that there is not a next day virtual observation period. Would you find such a virtual visit helpful? Perhaps you could be on your computer and you could have your webcam on and you could go about some activities while being observed. Perhaps some light cognitive tests etc.. I found it unexpected in these mab trials when the patient writeups indicated that there was not much of a followup. A virtual checkin would seem an easy low hassle value added.

I am also unclear about what the meaning of symptomatic ARIA refers to. When you mentioned that you had a headache after the first two infusions, did they in any way indicate that this would qualify as mild ARIA? I am just not sure what is required to have mild/moderate or severe ARIA. The Florida patient could barely get out of bed for a few days, without headaches etc.. I would call that severe ARIA.

Chicagogirl, do you know whether they have given you the GFAP blood test? This is something that I have posted about above and might become the third dimension of screening in AD trials. It is amazing how they continue to refine the patient definition of AD.
Perhaps they could even use this as the first round relatively cheap way of screening patients who will not progress.

Another interesting idea that I have considered is that clinical trials could include a risk stratification estimate in the informed consent process. From what I understand this is now typically not done ?? The idea would be that patients could be provided with the best estimate of what their risk level in the trial might be and then they would be more fully able to consent as an informed patient. So perhaps a APOE epsilon 33 with no microhemorrhages or other observable neuropathology on neuroimaging and without anti-coagulant use could be assigned a 20 percentile risk evaluation; whereas an epsilon 44 with 4 microhemorrhages at baseline, etc.. could be assigned to the 99th risk percentile. The problem that I have noticed to date is that not much of a discussion has emerged to think of risk in these terms of a distribution.

This is a tremendously exciting time for the AD community! As you noted I do try to keep up with the literature, though it feels like a complete flood even when I am trying to stay current with Lecanemab clinical developments. And we are now expecting a data dump on the FDA Leca docket any time! It is so fantastic that there is a APOE4 forum that is open 24/7 for people who can't get enough of Alzheimer's talk. Why, if I were to go to my local area bowling alley I am not sure whether anyone would have much of an idea of what Alzheimer's was. On this forum you always need to be on your toes because there are quite a few that have deep insights into amyloid dementia and are part of an organized study effort to learn about it.

I have to admit that the last walk through on the Florida patient was meant to move the ideas into my contemplation. I am somewhat unclear about the technicals involved with the ARIA patients, though this and a recent article on the tPA patient appear to have shifted the conversation to the idea that the mabs themselves are causing neuropathology. For example, the recent tPA patient article seems to have stated that her stroke was caused by Lecanemab.
I want to have a better understanding of these latest findings before I say more.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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

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The above figure expresses how I have been thinking about mab risk in the last few days. Surprisingly, this type of thinking has been largely absent from the conversation. People talk about patient harms and patient benefits and yet there has been not that much attempt at operationalizing these definitions. While talking generally about patient harms has considerable rhetorical power, it is unable to move us towards some sort of a quantification.

The above figure while hand wavy at least moves us in this direction. Qualitatively I feel that much of the risk in the mab trials have been experienced by those towards the upper ~10% of risk; not so much for those at a lesser percentile of risk. So for the 1,000+ ? patients who were low risk there was one fatality in the randomized portion and the open label extension in Clarity. This one fatality was in the epsilon 33 patient who experienced a great many commorbidities which largely seemed unrelated to Lecanemab. So for a substantial proportion of the patients the rate of fatality on Lecanemab is quite low as experienced in the Clarity trial. The big problem is that it is not easy to have a great feel for the risk involved with only ~1,000 patients treated. It is not obvious what the risk might be when we have 10,000 patients or 100,000 especially out in the wild and not in a highly controlled clinical trial environment. I am not sure whether detailed patients descriptions are provided for the other side effects including microhemorrhages, macrohemorrhages etc.. Yet, the low risk group still seems to have lowish frequencies of these side effects as well.

It is when we moved to the high risk patients that we saw more serious side-effects or related patient trajectories. The tPA patient was e44 (no microhemorrhages at baseline), had a stroke, treated with tPA, massive neuropathology occurred, severe CAA discovered and the e44 Florida patient with 4 baseline microhemorrhages, and severe symptomatic response to treatment (also with severe CAA) were clearly at quite high risk.

Actually talking about this risk stratification seems to me to be a useful exercise. It moves us away from the deceptive depiction of their being some uniform risk of 3 fatalities over ~~1500 treated patients. It also seems to offer us a useful way of considering patients who might be too high risk to treat.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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https://www.desmos.com/calculator/fisp4lv6gg

Here the white area in the Venn diagram illustrates a patient subgroup with extreme side effect risk.


FDA ADCOM url
https://www.fda.gov/advisory-committees ... ee-meeting

https://www.regulations.gov/document/FD ... 01/comment
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I found it surprising in one of the comments to the ADCOM that a family doctor overlooked a presentation of presumably stereotypical African Alzheimer's. I suggested earlier on thread that African Alzheimer's might have different features based upon a study that found less hippocampal involvement. From this I thought that there would then be less memory impairment and more logic involvement. This was only conjectural, though the patient report in the comments to the ADCOM confirmed it. The patient had no problem with the memory tests and was then judged non-AD, even while family members were aware of other cognitive deficits.

I am not clear from my personal experience of what dementia without memory impairment would be like, though apparently this is known with African AD patients. I also noted in my earlier comment that there might need to be a psychometric upgrade in order that cognitive testing instruments are able to correctly track cognitive decline in various populations that experience dementia differently. Without such an upgrade it is not entirely clear whether the clinical trials are accurately reporting the results for these patients. High memory scores in these patients would then only reflect a lack of decline along this dimension.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by NF52 »

Chicagogirl" wrote:
Hi J11 (and Chicagogirl),

Your observations would make you a great ADCOMM member or External Data Monitor on clinical trials! I'm going to offer my own experience and understanding of the guidance and practice around risk monitoring, especially during the first 6 months of the AHEAD trial, which I assume was similar to the CLARITY Open Label Extension (OLE) since both trials started around the same time with Lecanamab.

I'll add my comments next to your observations in blue, for ease of comparison.
J11 wrote: Mon Jun 05, 2023 6:39 pm I was very surprised when the Florida patient above apparently did not have an observation period after her infusion... the article noted that she developed a serious headache 1 hour after the infusion. I believe that a 4 hour observation period occurred, which is when that headache was noted in the medical record. It may be that the headache was viewed as an infusion reaction, as long as the participant's mental status, blood pressure and pulse were not alarming. During my first 4-hour period, I was checked on quite frequently and during one visit when my BP was up a bit (after talking about my hoarder sister's needs) they had me wait for another 10 minutes to be sure it went back down. At the center where I go, most people are with spouses or care partners. Doors are always open in the infusion rooms, which have comfortable recliners for both the partipipant and spouse and emergency buttons, and staff frequently pass in the halls and come in to ask how I am doing and often stay to talk for several minutes at least twice per hour. I would have guessed that the staff asked about the pain level and would have called the on-site doctor for something that was an "8 out of 10 pain headache" The Study Site doctor was called in a month ago when I mentioned several days of mild headache, vertigo and lethargy between visits, before they sent the orders to the on-site pharmacist for that day's infusion. He listened carefully, asked questions, looked in my nose and ears, said there was obvious blockage in both indicating sinus blockage and suggested a nasal steroid spray and decongestant during Virginia's pollen season. I had never had sinus problems in NY and didn't recognize that all my symptoms were due to sinus blockage, not edema. (And within days I was feeling great again.) That's the kind of close monitoring and support I have experienced for almost 18 months of infusions.

I find it surprising that there is not a next day virtual observation period. Would you find such a virtual visit helpful? I was given my Study Coordinator's number, which I have used several times during and outside of office hours. The voice mail message includes a number to reach the study doctor if needed and starts with the message to call 911 for severe symptoms . That's also explained in the information before starting.
I am also unclear about what the meaning of symptomatic ARIA refers to. When you mentioned that you had a headache after the first two infusions...would qualify as mild ARIA? I am just not sure what is required to have mild/moderate or severe ARIA. The Florida patient could barely get out of bed for a few days, without headaches etc.. I would call that severe ARIA. If I had called in saying I was in bed for 2 days after the first visit, I would have had an MRI done then. They did an "unscheduled" (i.e. not in the plan) MRI 12 days after the 16th infusion and completely waived Infusion #17 when I had mild, intermittent vertigo and mild headache for about 6 days that did not interfere with my life. The MRI result came back fine, but the study site staff didn't disagree with my conclusion that I was on lecanemab and not a placebo.

"Symptomatic ARIA" refers to confirmed ARIA-E or ARIA-H on MRI concurrent, or in close proximity to symptoms such as dizziness, vertigo, headache, changes in alertness visual disturbances. Some of those symptoms can occur with infusion reactions. The reason for the early and frequent MRIs during the first six months is that most people with ARIA-E or ARIA-H did not have symptoms. My own study doctor, when reassuring me that I had sinus blockage not edema, said he had a patient (possibly on another trial) who needed medical treatment for edema observed on an MRI which was never symptomatic. I agree that the severe symptoms reported by the Study Partner would have warranted an MRI and a pause in infusions to determine if this was ARIA, but suspect that the patient or her care partner decided not to call it in for some reason (why go to a restaurant if she was doing so poorly?)


Chicagogirl, do you know whether they have given you the GFAP blood test? This is something that I have posted about above and might become the third dimension of screening in AD trials. It is amazing how they continue to refine the patient definition of AD. Perhaps they could even use this as the first round relatively cheap way of screening patients who will not progress. They may be using it, but we are not told what blood tests are drawn, only if one shows a level of concern. If they are using GFAP, we'll probably hear after the trial is complete. I suspect it may not be to find who doesn't have tau yet and won't progress, but to determine the earliest period BEFORE tau is significant and cogntive changes may be imminent, when treatment would be MORE effective.

..clinical trials could include a risk stratification estimate in the informed consent process. I don't think a percentile risk stratification is feasible yet, but the consent currently (and re-signed by participants with any change) is that microhemorrhages do increase the risk of ARIA-H. This woman had 4 in the baseline MRI; recent studies of people with AD show that a large percentage do have 1-4....I am somewhat unclear about the technicals involved with the ARIA patients..The protocol for symptoms that are persistent but mild or mild ARIA (< 5 microhemorrhages in total) is to proceed with infusions, and have a second MRI in a month (which I had as follow-up for my "unscheduled MRI"). If a person is sick (as I was with bronchitis once) the infusion may also be paused or rescheduled within 7 days or cancelled. I have had two cancelled, which will be unlikely to affect my results when I finish 4 years! ...For example, the recent tPA patient article seems to have stated that her stroke was caused by Lecanemab. I wonder if the more nuanced finding is that her ischemic stroke in the major cerebral artery which seems like a blockage, not a hemorrhagic stroke, was then exacerbated by her pre-existing CAA and the additional effect of amyloid clearance to fragile blood vessels. In TBI, there's a known "secondary cascade" effect where a patient seems to be doing okay, but the disrupted homeostasis leads to crisis a few days later.
Like you, I wait with bated breath for the ADCOMMs data and--drumroll--am looking forward to being able to post about presentations in the AAIC 2023 conference direct from Amsterdam, thanks to the generosity of the Alzheimer's Association and the Alzheimer's Clinical Trial Consortium Research Participant Advisory Board (a volunteer position; I have no financial interest in Biogen, Eli Lilly or any other Pharma company.) Nancy
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Hi J11 (and Chicagogirl),

Your observations would make you a great ADCOMM member or External Data Monitor on clinical trials! I'm going to offer my own experience and understanding of the guidance and practice around risk monitoring, especially during the first 6 months of the AHEAD trial, which I assume was similar to the CLARITY Open Label Extension (OLE) since both trials started around the same time with Lecanamab.

Thank you apparently ADCOM is a strictly honorary position (i.e., no compensation), while it would clearly be a tremendous honor, I am sure that I would also find it enormously stressful. I think I will take a miss if nominated.

I'll add my comments next to your observations in blue, for ease of comparison.

I'll add my comments next to your observations in red and quotes from the article (etc.) in green, for ease of comparison.

J11 wrote: ↑Mon Jun 05, 2023 8:39 pm I was very surprised when the Florida patient above apparently did not have an observation period after her infusion... the article noted that she developed a serious headache 1 hour after the infusion. I believe that a 4 hour observation period occurred, which is when that headache was noted in the medical record. It may be that the headache was viewed as an infusion reaction, as long as the participant's mental status, blood pressure and pulse were not alarming. During my first 4-hour period, I was checked on quite frequently and during one visit when my BP was up a bit (after talking about my hoarder sister's needs) they had me wait for another 10 minutes to be sure it went back down. At the center where I go, most people are with spouses or care partners. Doors are always open in the infusion rooms, which have comfortable recliners for both the partipipant and spouse and emergency buttons, and staff frequently pass in the halls and come in to ask how I am doing and often stay to talk for several minutes at least twice per hour. I would have guessed that the staff asked about the pain level and would have called the on-site doctor for something that was an "8 out of 10 pain headache" The Study Site doctor was called in a month ago when I mentioned several days of mild headache, vertigo and lethargy between visits, before they sent the orders to the on-site pharmacist for that day's infusion. He listened carefully, asked questions, looked in my nose and ears, said there was obvious blockage in both indicating sinus blockage and suggested a nasal steroid spray and decongestant during Virginia's pollen season. I had never had sinus problems in NY and didn't recognize that all my symptoms were due to sinus blockage, not edema. (And within days I was feeling great again.) That's the kind of close monitoring and support I have experienced for almost 18 months of infusions.

"She was treated with three infusions of lecanemab, each dose (10 mg/kg) approximately two weeks apart. According to her study partner, approximately an hour after each dose she developed a headache causing her to spend one to two days in bed recovering each time. After the third dose, she began to experience progressively worsening memory impairment which she described as “brain fog.” On the day of hospital admission (When?? How many days since the third injection?), she had a seizure which began with left head and gaze version and left sided tonic contraction which evolved into 30 seconds of generalized convulsion. She regained alertness after this event but was never communicative nor purposefully interactive again. Electroencephalography did not suggest ongoing seizures to explain her condition, although she had frontal intermittent rhythmic delta activity. Neuroimaging revealed cerebral edema in the bilateral temporal, parietal and occipital lobes with numerous microhemorrhages. She was treated with 1g daily intravenous solumedrol for three days for suspected amyloid-related imaging abnormality (ARIA) without improvement. She suffered an aspiration event leading to sepsis with multiorgan failure and, consistent with her wishes, aggressive resuscitation measures were not instituted. She expired 5 days after hospital admission."

On rereading the above, I am struck by how the underlined text highlights exactly when the brain trauma happened. It is startling to realize that at that moment the patient possibly had as many as 30 simultaneous microhemorrhages. That is a lot of spontaneous neuropathology all at once.

It may be that the headache was viewed as an infusion reaction What I found interesting was that there were so few severe repeat infusion reactions in Clarity. I think there was only one patient who had such a reaction. Introducing subQ dosing could be a great help here because infusion reactions seemed to almost disappear with subQ.


I find it surprising that there is not a next day virtual observation period. Would you find such a virtual visit helpful? I was given my Study Coordinator's number, which I have used several times during and outside of office hours. The voice mail message includes a number to reach the study doctor if needed and starts with the message to call 911 for severe symptoms . That's also explained in the information before starting.

Some patients will never call – even if they are in bed for a few days. Virtual observation room would seem a great innovation here. It would have picked up on this patient. Making it a virtual visit means that it would not have to be a burden on patients. they could simply go about typical daily activities on the computer etc. while perhaps interacting in some way with a virtual agent.

I am also unclear about what the meaning of symptomatic ARIA refers to. When you mentioned that you had a headache after the first two infusions...would qualify as mild ARIA? I am just not sure what is required to have mild/moderate or severe ARIA. The Florida patient could barely get out of bed for a few days, without headaches etc.. I would call that severe ARIA. If I had called in saying I was in bed for 2 days after the first visit, I would have had an MRI done then. They did an "unscheduled" (i.e. not in the plan) MRI 12 days after the 16th infusion and completely waived Infusion #17 when I had mild, intermittent vertigo and mild headache for about 6 days that did not interfere with my life. The MRI result came back fine, but the study site staff didn't disagree with my conclusion that I was on lecanemab and not a placebo.

"Symptomatic ARIA" refers to confirmed ARIA-E or ARIA-H on MRI concurrent, or in close proximity to symptoms such as dizziness, vertigo, headache, changes in alertness visual disturbances. Some of those symptoms can occur with infusion reactions. The reason for the early and frequent MRIs during the first six months is that most people with ARIA-E or ARIA-H did not have symptoms. My own study doctor, when reassuring me that I had sinus blockage not edema, said he had a patient (possibly on another trial) who needed medical treatment for edema observed on an MRI which was never symptomatic. I agree that the severe symptoms reported by the Study Partner would have warranted an MRI and a pause in infusions to determine if this was ARIA, but suspect that the patient or her care partner decided not to call it in for some reason (why go to a restaurant if she was doing so poorly?)



I think the problem is that without a virtual observation visit the patients cannot be risk stratified and standardization of treatment protocol can be done. For example, I read somewhere that there was another Clarity patient who couldn’t get out of bed for a day or two and then the trial staff told the patient that it would be best to terminate treatment because next time they might not be able to bring the patient back. So the safety protocol varied from site to site. With an observation visit the trial could be more standardized. Without reading all of the patient level online discussion this variance would be missed.

Yes, one thing that I found encouraging was that the Clarity trial protocol stopped treatment for any symptomatic ARIA; also moderate and severe radiographic ARIA. It was only mild radiographic ARIA that they dosed through.



Chicagogirl, do you know whether they have given you the GFAP blood test? This is something that I have posted about above and might become the third dimension of screening in AD trials. It is amazing how they continue to refine the patient definition of AD. Perhaps they could even use this as the first round relatively cheap way of screening patients who will not progress. They may be using it, but we are not told what blood tests are drawn, only if one shows a level of concern. If they are using GFAP, we'll probably hear after the trial is complete. I suspect it may not be to find who doesn't have tau yet and won't progress, but to determine the earliest period BEFORE tau is significant and cogntive changes may be imminent, when treatment would be MORE effective.

"While most of the plaques looked entirely typical, 21% appeared to have been “cleared” – which is to say, a distinctive rosette of dystrophic neurites was present without the typical amyloid staining at its center. A further 24% of the plaques had minimal staining of amyloid deposits (Supplementary Figure 8). These features were associated in some cases with intense immunoreactivity for IBA1/microglia (Figure 2d).

Numerous areas of microhemorrhage were visualized histologically along with arterioles with varying degrees of fibrinoid necrosis and perivascular inflammation. The bulk of the perivascular inflammation was composed of macrophages with occasional multinucleated giant cells; some T-cells were also present in the perivascular inflammatory milieu (Figure 2e-I and Supplementary Figure 9). The patient also had severe cerebral amyloid angiopathy."


Above reminds me of the recent alzforum article about reactive astrocytes. One would then wonder whether there might be a marker for what the Florida patient was experiencing. It is surprising to me that there is not more an individualized protocol for patients especially those who might be at high risk. The Florida patient clearly seemed to be at extreme risk prospectively and yet the safety protocol used for her was the same as that for all other treated patients.

..clinical trials could include a risk stratification estimate in the informed consent process. I don't think a percentile risk stratification is feasible yet, but the consent currently (and re-signed by participants with any change) is that microhemorrhages do increase the risk of ARIA-H. This woman had 4 in the baseline MRI; recent studies of people with AD show that a large percentage do have 1-4.

One thing that I clued into was the idea that the logic they used was more an OR logic: the patient has APOE e44 OR 4 microhemorrhages OR anticoagulant use OR comorbidities (exclusions were considered separately). I found using ORs surprising -- patients with every possible risk factor is then considered to be just as any other patient. It is only when you start thinking in terms of AND logic that all of a sudden you realize that the Florida patient is not a typical risk patient but a patient with near astronomical risk.

Baseline MRIs were from Phase 2 and 3 studies (MCI or Mild AD, MMSE ≥22), acquired from 1.5T or 3T scanners and centrally evaluated. We report the type and number of ARIA-E/H lesions as of August 2022.
Results
Baseline demographics of the two studies were similar (~50% female, age 69 years, MMSE 25-26). In 242 homozygotes (211 from Phase 3) there were no subjects with ARIA-E, 72 with any MH, 23 with >4 MHs, of whom 15 had >10 MHs, 2 had macrohemorrhages >1 cm, and 20 had superficial siderosis lesions.
quoted from Alzheon website

Yes, I snagged the above from the Alzheon site. I wanted some idea of what sort of typical CAA type neuropathology was present in the e44s at baselines …. quite a bit. 72 of 242 had a microhemorrhage …. at baseline ? 23 of 242 had more than 4 microhemorrhages and 15 of these 23 had more than 10?? there is clearly quite a bit going on. Also interested that they used 1.5 T and 3T scanners for the MRIs. The Florida patients article used a 7T scanner on post-mortem.



...I am somewhat unclear about the technicals involved with the ARIA patients..The protocol for symptoms that are persistent but mild or mild ARIA (< 5 microhemorrhages in total) is to proceed with infusions, and have a second MRI in a month (which I had as follow-up for my "unscheduled MRI"). If a person is sick (as I was with bronchitis once) the infusion may also be paused or rescheduled within 7 days or cancelled. I have had two cancelled, which will be unlikely to affect my results when I finish 4 years!

I was unclear about that. By technicals I am thinking of the technical descriptions that the two recent patient fatality reports described. This one https://www.medrxiv.org/content/10.1101 ... 23289061v1
and the recent Journal of Alzheimer's article had especially technical comments that I wanted to think about more; also https://pubmed.ncbi.nlm.nih.gov/36599061/

These reports are using expert level medical concepts and I did not want to breeze over what the articles were saying without developing a better understanding. I suppose the problem is however, that some of the questions that they are asking about the ARIA biochemistry are simply unanswerable at this time.


...For example, the recent tPA patient article seems to have stated that her stroke was caused by Lecanemab. I wonder if the more nuanced finding is that her ischemic stroke in the major cerebral artery which seems like a blockage, not a hemorrhagic stroke, was then exacerbated by her pre-existing CAA and the additional effect of amyloid clearance to fragile blood vessels. In TBI, there's a known "secondary cascade" effect where a patient seems to be doing okay, but the disrupted homeostasis leads to crisis a few days later.

Yes, I am quite uncertain about this claim that the stroke was caused by Lecanemab. That is a big claim that cnneds big evidence. I would be extremely interested in knowing what the chemical composition of the thrombus was. I guess typically with a stroke it might be largely cholesterol etc.. What if with the tPA patient it were more amyloidal?


Like you, I wait with bated breath for the ADCOMMs data and--drumroll--am looking forward to being able to post about presentations in the AAIC 2023 conference direct from Amsterdam, thanks to the generosity of the Alzheimer's Association and the Alzheimer's Clinical Trial Consortium Research Participant Advisory Board (a volunteer position; I have no financial interest in Biogen, Eli Lilly or any other Pharma company.) Nancy

Amsterdam should be epic. It will be a week after the FDA Lecanemab PDUFA. The timing worked out perfectly. The only way it could have been better is if the conference were in the Eastern Standard Time zone. This is now super super exciting! The FDA is expected to release the ADCOM Briefing files imminently.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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

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Very very exciting everyone! Only days away now! Probably should make one of those countdown clocks. This is history everyone-- we all need to be on our best behavior. History like this does not happen every day.


I think I might have found something. In the above figure we see the result that I have posted a few times to the thread showing how the subQ dosing is quite a bit better than IV. The IV dosing has this spiking behavior that is not really all that helpful. The IV spikes represent all risk and no return; the subQ dosing is more about slow and steady and lower risk.

The idea that I thought of is: Why not have the benefits of subQ NOW! using IV dosing?? If patients were all setup with a port, then they could easily do daily dosing that would look much more like the blue curve than the black spikey ECG. So, basically one could then have the benefits of subQ today without having to wait possibly years while they do the confirmatory studies.

J11, tell us like we were 3 months old. Don't jive us. Err, OK. Look at the black spikey curve on the left of the figure. They injected 10 mg/kg Q2W and the Leca serum concentration went from 0 --> ~225 microgram/ml. It tops out at the red horizontal line shown. This is what an injection at an infusion center would give you .... pharmacodynimacally the concentration has went straight up vertically. .... and then as we can see the concentration then goes down almost vertically and settles in at ~50 microgm/ml after 2 weeks at which time another dose would start the roller coaster ride once again.

This is the basic setup that the Florida patient went through. The red dot that is shown on the left and two to the right is an estimate of where the patient's ARIA side effect might have eased. Using the PK model perhaps we could even estimate what this dosage might be. Yet, the point is that the patient continued to receive this bolus dosing and had 3 instances of severe side effects. Each dose blew right past the concentration at which her symptoms emerged.

What happens instead if they used subQ dosing? We see the blue curve in the figure that shows a more sedate journey that lacks all the highs and lows. The blue curve never reaches the concentration level shown by the red dots so the subQ would not activate the ARIA response. The figure also shows that with subQ it becomes possible to titrate up and find where symptoms might emerge with more precision. Here we see at the orange dot and line to the left that once symptoms occurred at this level then we could wait it out until hitting the top of that dosing and then allow the dosing to be set such that a maximum of the green line would be achieved and therefore precisely preventing unwanted ARIA. Also note to the right that if we ever wanted to break out of the tight dosing range all we would need to do is stop dosing and the concentration would fall as occurs with IV dosing. However, subQ might be somewhat slower to fall off as the subQ dosing would have a reservoir that would need to be exhausted. The Florida patient would then have had very minimal side effects. The side effects if they were to have occurred would have been mild and would have resolved quickly.

The subQ dosing has considerable advantages. There is much more control over side-effects. With IV dosing it can take days for ARIA to subside as with the Florida patient. Basically, the patients might have to go to ICU and just wait it out as the concentration of Lecanemab gradually declined. With the tighter amplitude of subQ, one might only need to wait hours for symptoms to reside. Also the concentration would never spike in the same way so when titrating one would always be close to more moderate ARIA side effects.

What I thought of today was why not substitute the subQ with daily IV dosing? This would then largely mimic the benefits of the subQ dosing without having to wait years while this is all formalized. Even better, when using daily IV dosing there seems to be more of a spikey pattern so side effects could resolve even faster if they were to occur.

This method of administration would seem to be considerably safer than the bolus IV approach that we have talked about on thread. One could simply remove all the no return spiking behavior and replace it with the slow and steady base dosing which is the driver of the treatment benefit.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

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