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

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J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

I noticed while I reviewed my posts from yesterday that I included some truly slactivist efforts for the dose response relationships. Most of the plots that I have posted to thread had a slope of ~1.28 when forced through the origin. Yet, when I allowed the origin point to diverge from 0,0 this typically resulted in the shifting upwards and then the line pivoting downwards with a slope ~1.35. Another update from the Biogen research that helped escape the trap of linearity was to use a parabolic curve as seen above with P1 and P2. These different models allow for a tighter fit of the data points to the curves. One problem now though is that we might now largely be beyond those clinical trials that will clarify the response in the mid-range of amyloid clearance between 0.15 and 0.25. So it might not be possible to clearly determine which of the various equations would be the best fit.

One idea that I have thought of is whether it might not have been better to move away from half the patients on placebo and half on treatment. These placebo patients are not providing that much information. More information would be generated if these patients could be more uniformly distributed across the full range of treatment dosing. One could have a good idea of where the placebo would be by simply following the dose response curve backwards tot he origin.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Good idea to have a better understanding of the ARIA from Clarity.

From the press release:
"The incidence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), an adverse event associated with anti-amyloid antibodies, was 12.5% in the lecanemab group and 1.7% in the placebo group. The incidence of symptomatic ARIA-E was 2.8% in the lecanemab group and 0.0% in the placebo group. The ARIA-H (ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis) rate was 17.0% in the lecanemab group and 8.7% in the placebo group. The incidence of symptomatic ARIA-H was 0.7% in the lecanemab group and 0.2% in the placebo group."


From the Leca Phase 2b trial:
"There were 5 cases of symptomatic ARIA-E (lecanemab: 5/46 [11%]), which generally consisted of headache, visual disturbances, or confusion. Radiologic severity for symptomatic cases were one severe at 2.5 mg/kg biweekly; one mild at 10 mg/kg monthly; one moderate at 10 mg/kg biweekly; and two severe at 10 mg/kg biweekly. The 2.5 mg/kg biweekly case was considered a non-serious adverse event; all other symptomatic cases were considered serious adverse events."

What does this look like for Clarity?

Of 1000 treated high dose patients in Clarity:

125 would develop ARIA-E (with IV dosing)
---- 28 of these would be symptomatic
------- 11 of these would be considered severe by radiographic analysis (estimated at 40% from the Phase 2b)
------- {As noted above typically most to all of symptomatic ARIA-E in the phase 2b were considered serious AEs.??}

40 would develop ARIA-E (with subcu dosing estimated)
---- ~9 of these would be symptomatic (estimated)
------- 4 severe radiographic (estimated)

(subcu dosing appears to reduce ARIA-E by ~3 fold)

There is also ARIA-E which would occur in 70 high dose treated IV patients per 1,000

There still is a certain amount of ARIA (E and H) that is occurring, though the currently reported frequency is substantially higher than the state of the art subcu dosing method. Clearly, this makes it difficult to accurately discuss the true level of risk that patients will experience with the newer dosing approach. It is not completely clear to me why in the phase 2b study 80% of all symptomatic ARIA-E patients were considered to have had a severe adverse event. With Aducanumab for some of the infusion doses, ~1% of the patients with ARIA were labeled as having had a severe side effect.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Leca Phase 2b Intermixed.png
Leca tau by dose Edit 20.png
Leca amyloid by dose Edit 10.png
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Time to dust off some of these great figures from previous posts!

The figure on the bottom shows the ordered amyloid clearance for the Leca phase 2b study.
What I did with the desmos urls above is I took the amyloid clearance for each patient for the blue region on the far left (which became the red dots in the url) and the darker purply/bluey region second from the left (shich became the green dots in the url) and I plotted the results with the f2 parabola that was given in the research in the desmos url. This parabola is supposed to show the dose response relationship between SUVR and CDR-sb. It will be extremely interesting to see how well the parabola is able to fit the larger dataset from Clarity. The blue data points on the left
seemed to overstate the benefit by about 0.12 CDR-sb. This is possibly due to the view outlier points that cleared 0.5,0.6 ... SUVR of amyloid. Some of these patients were e3s so perhaps they did not follow the parabola that well on an individual basis.

The above figure is quite interesting as it highlights some of the problems that Clarity will face when the analysis is reported. Firstly notice that 44% of placebo patients from the Leca phase 2b on the right in red had amyloid clearance! That adds a certain level of confusion; are placebo actually expected to endogenously create their own treatment effect? I think if no one were looking I might just go in there and just "lose" these datapoints. How exactly is a treated placebo truly valid?

Then you look at the patients in blue on the left high dose Leca phase 2b. Notably while all the patients had amyloid clearance, a fair number did not have that much clearance. If I had the chance I would probably also "lose" about a third of the high dose patients. It is once again not that clear to me how you can really test the amyloid removal hypothesis when many of the treated group haven't lost much amyloid.

There is a potential workaround to these problems. For the placebo patients with naturally decreasing amyloid levels, one could simply select patients at any earlier stage. The patients selected in the phase 2b and phase 3 were at a stage in the illness where amyloid levels tend to be decreasing. Earlier in the illness, nearly all of the patients would be in the accumulation stage of amyloid. For the treatment patients, anti-amyloid mab dosage could be increased to nudge amyloid clearance to quicken.

The middle figure is even more interesting. Apparently, there is a sizable subgroup of placebo who have significant amounts of tau clearance. This is somewhat less easily explainable. Perhaps tau PET could help to identify these placebo patients prospectively.

Top figure shows the multiplication of tau and amyloid. We want to see which patients had high tau removal and high amyloid removal etc.. Note that all of the blue labeled patients in the bottom row had amyloid removal (i.e., negative), this means the only way for the product to be positive is for all of these patients to also have had tau removal. The other leca dosing arms also had almost all patients with amyloid removal so they must have also had almost all tau removal to have a positive product. This figure leaves the placebo product somewhat uncertain as to which way the amyloid and tau signs went.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Leca Phase 2b tau 181 vs amyloid.png
Leca Phase 2b tau ordered 1.png
Leca Phase 2b tau by dose ordered 10.png
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

The above figures help to sort out the sign question and to give some idea of how amyloid and tau removal related to one another. Of particular importance to the Clarity trial is the bottom figure above. (Note: this figure is ordered by amyloid I believe). To the far left in blue there is only one fairly negative tau * amyloid product labeled near patient 11. These blue colored patients would be the high dose treated patients in Clarity. It is interesting to note that there is only that one patient 11 who had strong amyloid clearance (~0.40 SUVR the figure a post or two up) and had negative tau*amyloid (also see the middle figure of the above post -- patient 11 had ~ 2 tau accumulation). so this patients was going the wrong way -- strong amyloid removal and tau increase. this was the only clear outlier in the blue marked patients.

For the purply/bluey patients second from the left there are a few who had largish tau amyloid products.

What we see for the placebo is that the patients on the far right who had a great deal of amyloid accumulation also had tau increase which gave a large tau* amyloid product (+ * + = +). The placebo who had a good deal of amyloid clearance (those patients around 171) also had a good deal of tau clearance ( -*- = +). So placebo had two types of tau * amyloid + patients: those with + *+ and those with -*- . The +*+ patients would presumably have had a not as good cognitive response as the -*- patients. There was largely only one type of high dose treated patient with a high absolute product magnitude : -*- = +.

This perspective is likely of considerable importance as it relates amyloid clearance to the presumed direct anti-dementing mechanism of tau removal. For the Clarity study, it suggests that nearly all of the patients who had substantial amyloid clearance would also have had tau clearance. Perhaps only 1 in 25 would go against this trend.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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J11 wrote: Fri Sep 30, 2022 4:22 pm Good idea to have a better understanding of the ARIA from Clarity.

...It is not completely clear to me why in the phase 2b study 80% of all symptomatic ARIA-E patients were considered to have had a severe adverse event.
I know you know this, J11, but others might not know that the results announced this week from the CLARITY study come because it was designed to further test positive Phase 2 results in about 161 people, and to answer some of these questions from the earlier Phase 2b trial (Study 201). In that trial, 161 people were randomly assigned ("blinded") to receive lecanemab and 245 were randomly assigned to placebo for 12months (the CORE group). Then the placebo group was offered the opportunity to continue and receive lecanemebab (i.e. not 'blinded") for 12 months while the earlier group was monitored for amyloid beta levels and cognitive levels for 6 months off-lecdnemab. The second "open-label extension" group was small-only about 12 people.

I don't think the symptoms were severe in most of these people; most in fact were asymptomatic. I think the determination was to go with the MRI reading of size of edema in determining severity. But the section before your quote references fairly good safety profiles:
Study 201 Core and OLE Pooled ARIA-E Rates
In the Core and the OLE, ARIA-E was observed in allele groups administered 10 mg/kg biweekly at the following rates: ApoE4 carriers [combining ApoE 3/4 and 4/4] 13.8% (11/80), ApoE4 carriers homozygous 42.9% (6/14), ApoE4 carriers heterozygous 7.6% (5/66) and ApoE non-carriers 7.1% (9/126). The overall ARIA-E rate was 9.7% (20/206) of patients treated with lecanemab 10 mg/kg biweekly.

ARIA-E Rates Frequency and Severity
In the Core study and OLE, the majority of ARIA-E events occurred within the first 3 months of treatment (75% [12/16]) and resolved within 4 months of onset. For the majority of patients, the radiographic severity was mild or moderate; severe radiographic severity was reported in 1.2% (2/161) of patients. The majority of ARIA-E was asymptomatic; with symptomatic ARIA-E reported in 1.9% (3/161) of patients. Symptoms reported in association with ARIA-E included headache, visual disturbance, confusion, aphasia. There has been a single case of ARIA-E associated with seizure in the Core study and OLE to date.
The CLARITY trial (a Phase 3 trial) did several things differently:
They recruited a much larger and more diverse participant group.
They titrated the dose gradually, to "ramp up" over a period of about 6-8 weeks to a full dose.
They paused dosing for anyone with significant symptoms, and got additional MRIs at those times to see what was going on. It appears that pausing the dose during symptomatic periods allows the brain time to handle the 'waste management" and be able to re-start safely. To my knowledge--and I have talked with people involved in this, NO One has died from the drug!
The same changes are being used on the AHEAD study being documented by "Chicago Girl" on the forum.

This seems important to me:
Clarity AD Phase 3:...the Clarity AD clinical trial ensured greater inclusion of ethnic and racial populations in the U.S., resulting in approximately 25% of the total U.S. enrollment including Hispanic (22.5%) and African American (4.5%) persons living with early AD, which mirrors the U.S. Medicare population...

Clarity AD Subcutaneous Substudy: Eisai is developing a subcutaneous formulation of lecanemab with the potential to be administered at home by the patient or caregiver via an auto-injector with a more rapid administration than the IV formulation (<15 second SC injection versus ~1h infusion)....the SC [subcutaneous] dose...is hypothesized to have similar amyloid reduction with potentially.. less than half the ARIA-E rate as IV. Eisai is evaluating the SC formulation in the Clarity AD OLE.
LATEST FINDINGS ON LECANEMAB – CLINICAL EFFICACY, ARIA RATES, BIOMARKERS RELATIONSHIP TO CLINICAL OUTCOMES AND DOSING REGIMENS – PRESENTED AT AD/PD™ 2022 ANNUAL MEETING

A drug that could be injected once a week under the skin could be combined with ALL of the other great lifestyle interventions available to people with MCI/Mild AD. It won't be the only treatment; we don't have just one antibiotic or one chemotherapy regimen or even one brain food--but it may be welcomed by those who are at most imminent risk of further cognitive decline.
4/4 and still an optimist!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Thank you for correcting me, NF52. Yes, I was very unsure how the numbers were supposed to line up.

"There were 5 cases of symptomatic ARIA-E (lecanemab: 5/46 [11%]), which generally consisted of headache, visual disturbances, or confusion. Radiologic severity for symptomatic cases were one severe at 2.5 mg/kg biweekly; one mild at 10 mg/kg monthly; one moderate at 10 mg/kg biweekly; and two severe at 10 mg/kg biweekly. The 2.5 mg/kg biweekly case was considered a non-serious adverse event; all other symptomatic cases were considered serious adverse events." It seemed surprising to me that 4 of 5 symptomatic ARIA-E were categorized as serious?

From your quote "The majority of ARIA-E was asymptomatic; with symptomatic ARIA-E reported in 1.9% (3/161) of patients. Symptoms reported in association with ARIA-E included headache, visual disturbance, confusion, aphasia."
They seemed to take these same ~3 patients and first describe them as symptomatic and largely benign and then in the next paragraph with my quote relabel nearly all symptomatic ARIA-E as "considered serious adverse events."

The Clarity press release referred to 12.5% ARIA-E in the Lecanemab treated group with 2.8% symptomatic. I am interested to know what percentage of the symptomatic patients in Clarity were considered serious and what operational definition they use for "serious". It would be helpful if they had a clinically defined standard for severity of ARIA so that these side effects will be comparable between studies.


Thank you NF52, yes I have been wondering also about perhaps a microneedle dosing format for anti-amyloid mabs. Micronedles --> no injection and perhaps enhanced safety? Possibly a patch like product could be a delivery method.

Yes, my overall understanding is that Lecanemab has moved the safety standard quite a ways forward versus Aducanumab. My earlier post showed how much reduced the ARIA-E percentage is with Lecanemab versus Aducanumab. That is only with the straight dosing. As you noted we are now migrating to the era of a subcutaneous dosing approach which the simulation suggests should be even safer. The write-up from the phase 2b study did introduce some complications. For example the e4 high dose arm was closed by the regulators, so it is not that easy to know what the "true" ARIA-E risk was for these patients. It is also confusing how they seemed to imply that nearly all symptomatic ARIA patients were somehow "serious". That does not seem to be true. With Aducanumab some infusion dose levels had up to 83 ARIA events with only 1 of these patients considered to have a severe side effect. Many patients can have ARIA like symptoms without it being considered a severe response. I was reading comments online and one of the commentators reported that their loved one had been in the Clarity study and had had symptomatic ARIA and this was not considered serious it was more like a headache; and was even welcomed as it was an indication of drug response. I am very unsure what they meant when they equated symptomatic ARIA with serious side effect: Often this is not true.

With Aducanumab, the serious ARIA side effects were reported as .3% of patients. My impression is that Lecanemab might initially report closer to ~0.1% and then subcu dosing could move it quite a bit downwards from there. I think it is important to get ahead of this discussion though and not leave it unsaid. What seemed to happen with Aducanumab was that the medical community largely abstained from commenting about the ARIA concerns through the FDA consultation and then went passive aggressive in the clinical roll-out. It is best to talk openly about this now in order to avoid a repeat.

From what I can see there are numerous potential approaches to reduce ARIA risk. Subcu would be a good one to ramp up even now over the short term. We only need a few months at the start to see how the risk would decline. Another potential reducer would be pretitration dosing. I would be very interested to see what might happen if AD patients who were a year or two from onset were first pretitrated with mab and then went through the typical treatment plan. One could guess that this would help lower ARIA risk quite a bit. ARIA risk is clearly a moving target and it is in such flux that it is not that easy to predict how much more risk will be removed for those soon to receive clinical dosing.

Perhaps also they could try something as simple as an APP to keep track of patients. It almost seems as though some of these patients would have symptomatic ARIA like headaches and then continue to their next dose without this information reaching their clinician. Some sort of computer monitoring app might be able to pick up on such side effects.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

NF52 was so right to emphasize how completely Clarity nailed its topline. The readout was an Olympian moment. No other such moment leaps to mind in the whole history of Alzheimer's in the same way of fulfilling expectations so exactly. Not really that sure whether I can recall that many other such singular events ever occurring in any field.

They got to plate and just schmunched it.

Are there any questions?
No, no, please if there are any questions please ask them now.
Oh, I see no questions.
Very good.
OK, then I am heading to the cashew buffet table.

It feels so great to witness such excellence.
There was no obvious weakness to find fault in.
In terms of the state of technological development in anti-amyloid mabs, the Clarity result represented perfection.

Of course, even now they are running up field with the yard sticks as the science is now in rapid evolution.
Perhaps at CTAD they will disclose the subcu dosing ARIA-E results for the long-term extension for those who on trial were on placebo. The modelling suggest that ARIA-E risk will be reduced by multiple times (~3-4) with subcu over IV dosing. Additional safety enhancements also seem doable.
Last edited by J11 on Tue Oct 04, 2022 2:33 pm, edited 2 times in total.
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