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 »

alzforum posted an article about another ??? amyloid that apparently is involved in CAA -- AD namely medin. medin appears to assist in the formation of amyloid plaque. When I read this article I wondered whether the GWAS for ARIA in the aducanumab trials might have helped uncover medin. The alzforum article did note that there was a medin gene (MFGE8) variant that truncates the protein and abolishes its activity which lead to lower medin protein and this protected against coronary artery disease and dementia.

What did not seem to be noted was that reducing medin and thereby reducing CAA pathology one might reduce ARIA risk during mab treatment. Those with certain mutations might be at higher (or lower) ARIA risk and could be prospectively identified. Once mabs are out in the clinic such research might help to further enhance mab safety.

Of additional interest, the article noted that medin levels appear to contribute to cognitive decline beyond amyloid and tau. Perhaps medin PET scanning could be used to prespecify CAA risk and help to explain more of the variance in cognitive benefits for those on mab therapy.

https://www.alzforum.org/news/research- ... omotes-caa
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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That is interesting! From the Eisai's current press report: Clarity has an additional 111 subjects
with ongoing treatment in China? I had wondered about that as the enrollment in China appeared
to continue past the date to meet the primary endpoint ~ September 15th. I am not sure how they
will account for these other patients as the topline has already been posted. Perhaps the 1795 patients
will be understood to be the main patient sample and others will be included in a supplementary sample.

"1,795 participants of mild cognitive impairment (MCI) due to AD and mild AD
(collectively known as early AD) with confirmed presence of amyloid pathology
in the brain in the global study, and an additional 111 subjects ongoing in China"
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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We haven't spoken to date much about the opening horizon of combination treatment. The combination of Lecanemab and leucoMB possibly could be especially powerful. In the well-worn fire analogy: Lecanemab puts out the fire and leucoMB takes care of the smoke. I have recognized for quite some time that leucoMB has demonstrated very strong clinical effects. Yet, at the same time mabs are further upstream and can address the underlying cause of the illness- amyloid. The endless focus on the exact cognitive benefit of Lecanemab might potentially be somewhat misplaced. In a fire it is not some great intellectual paradox that you want to both put out the fire and control the smoke at the same time. It's not that tough to see that. In medicine for whatever reason often it is not easy to see the forest for the trees.

In a fire it is the smoke that is typically the most hazardous part, yet it is also important to put out the fire so that the smoke can be then subdued. Stopping the actual upstream driver of Alzheimer's is step 1. Step 2 is then addressing the downstream effects that cause cognitive decline. The discussion has concentrated too much on an overly reductionist understanding of neurodegenerative illness.

Perhaps a Leca & Leuco combo trial could start as early as next year! That would be great!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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CDR-sb Clarity.PNG
Slope 1.PNG
ADCS-ADL.PNG
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Last edited by J11 on Wed Nov 30, 2022 11:01 pm, edited 2 times in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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When I looked at the above figure I admittedly felt disappointed. The green and the black line for all appearances are essentially parallel at 18 months. If this were true, then continued treatment with Lecanemab would create no additional cognitive benefit. Treatment might then be thought of as being somewhat pointless; a small cognitive benefit that never accumulates through time.

This interpretation however is not consistent with previous posts to thread on other mabs. In fact it is also not true for the Clarity result.

https://www.desmos.com/calculator/vn048weyl4

As seen in the above url, the gain does grow through time. with simple linear regression for Clarity placebo, Lecanemab treatment and the difference it can clearly be seen that the benefit does grow through time. The accumulation of benefit is 0.02626 CDR-sb points per month. The linear regression has very high R^2 for all of three of the lines.

This difference approach replicates the middle slide above from the Clarity presentation.


What is even more exciting is that the ADCS figure (bottom slide above) suggests that on a functional measure this enlarging effect through time is even more prominent.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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The big obsession with this thread has been to try to relate CDR-sb with SUVR. Over the now over thousand posts this relationship has been explored and I think satisfactorily confirmed. The FDA approved Aducanumab under accelerated approval based upon this concept.

Lecanemab is awaiting the FDA's decision under this same accelerated approval mechanism. It was therefore somewhat disappointing that the latest Clarity results were not reported in the common SUVR units (instead they went with centiloids) so that a comparison could be made with the previous trials in CDR-sb vs SUVR space. I have looked around a bit and I have the formula to convert centiloids (reported for Clarity) and SUVR (reported for all of the other mabs.). When I used the formula I calculated a difference of 0.323 SUVR for amyloid removal on the treatment arm versus placebo for Clarity. The big question is how does this correspond to the regression equation and CDR-sb? As mentioned this is the relationship that the FDA is nominally using for its approval decision.

Below url shows this. SUVR is set at 0.323 and this corresponds to 0.505 CDR-sb; Clarity reported out at 0.45. Not bad. I had originally speculated that Clarity's SUVR 0.306 (as reported in the phase 2b) which would have been exactly equal to 0.45. So, yes, the CDR-sb vs SUVR relationship established on thread held.

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

My guess is that the 0.323 SUVR that I calculated is actually on the high side. There might be some trick involved that I am unaware that is inflating the number. ~0.30 feels closer to the true value. Part of the TLR part is that Clarity actually used three different beta-amyloid imaging agents -- florbetapir, florbetaben and flutemetamol. florbetapir gave me 0.323; I did the conversions for the other 2 agents and the numbers were way off. I think it might be that florbetapir is largely the standard agent used. For example, in the phase 2b for Lecanemab they only used florbetapir. It is possible that when they went for more of a global phase 3 with Clarity that different nations used others agents.


Below is an edited figure to keep everything clear. The black dot at (-0.3061, -0.451) is where we expected Clarity
CDR-sb to wind up. Using the walk over formula to convert the centiloids reported for Clarity to SUVR we wind up with -0.323 SUVR and -0.5046 (That's the purple dot). The regression was fairly accurate in predicting the result. Even still I suspect that using the "true" number for SUVR, the regression result would be even more accurate.
CDR-sb vs SUVR Edit.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Patient Flow a.png
Demographics a.png
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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These figures are for Clarity.

In the bottom figure I was surprised how many screening failures there were. 70% of those who believed that they had AD did not meet inclusion or met exclusion criteria? That might be one of the more disappointing ideas that will emerge once Lecanemab is available many people will be told that they do not have Alzheimer's -- the disappointment here would mean that there was some other neurodegenerative illness involved that likely has no treatment options. AD might soon go from perhaps the most dreaded of modern diagnoses to one of lesser concern.

In the top figure above what I found of interest was how the patients at baseline in Clarity had experienced cognitive symptoms for on average 4 years and had been diagnosed for 1.5 years. The patients were described at the earliest stages of AD and yet still had had symptoms for 4 years? I am not sure whether this would apply to those with MMSE =30, though one certainly does begin to wonder what this will imply for clinical management. Will patients who have clear subjective memory complaint perhaps e44 etc. really be expected to wait until their brain neurodegenerates enough to officially qualify for on label treatment?
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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J11 wrote: Mon Nov 21, 2022 7:16 pm That is interesting! From the Eisai's current press report: Clarity has an additional 111 subjects
with ongoing treatment in China? I had wondered about that as the enrollment in China appeared
to continue past the date to meet the primary endpoint ~ September 15th. I am not sure how they
will account for these other patients as the topline has already been posted. Perhaps the 1795 patients
will be understood to be the main patient sample and others will be included in a supplementary sample.

"1,795 participants of mild cognitive impairment (MCI) due to AD and mild AD
(collectively known as early AD) with confirmed presence of amyloid pathology
in the brain in the global study, and an additional 111 subjects ongoing in China"
The accelerated approval is based solely on the Phase 2 data, which was submitted before the latest CLARITY results. CLARITY serves as the confirmatory trial for full approval. I assume the data from China may be used to support approval in Japan as broadly an Asian sub-group.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by NF52 »

J11 wrote: Sat Dec 03, 2022 7:25 pm These figures are for Clarity.

In the bottom figure I was surprised how many screening failures there were. 70% of those who believed that they had AD did not meet inclusion or met exclusion criteria? That might be one of the more disappointing ideas that will emerge once Lecanemab is available many people will be told that they do not have Alzheimer's -- the disappointment here would mean that there was some other neurodegenerative illness involved that likely has no treatment options. AD might soon go from perhaps the most dreaded of modern diagnoses to one of lesser concern.

In the top figure above what I found of interest was how the patients at baseline in Clarity had experienced cognitive symptoms for on average 4 years and had been diagnosed for 1.5 years. The patients were described at the earliest stages of AD and yet still had had symptoms for 4 years? I am not sure whether this would apply to those with MMSE =30, though one certainly does begin to wonder what this will imply for clinical management. Will patients who have clear subjective memory complaint perhaps e44 etc. really be expected to wait until their brain neurodegenerates enough to officially qualify for on label treatment?
It seems reasonable to me that people might have both subjective cognitive impairment and some mild cognitive changes for a few years before they or their loved ones agree to a referral for an assessment by their family doctor--and even longer before they would be ready to enroll in a clinical trial. CLARITY enrolled and completed the trial during the pandemic, which they noted required working very closely with families to gain their trust.

The 70% "failure" rate in screening is quite common, from what I've heard, and one of the reasons many groups including the Alzheimer's Prevention Registry and APT Web Study are encouraging people who might be interested in an array of trials (short and long-term; drug and non-drug) to enroll. My understanding is also that many people "screen fail" because they might have co-morbid conditions that would be exclusionary, are unable or unwilling to be in an MRI machine several times, do not have a study partner available, fall above or below the cognitive cut-offs or were unwilling to come in for infusions during COVID before vaccines were available.

In previous trials run before PET scans were available, post-hoc analysis showed that about 30% of people didn't have amyloid beta even though they had a diagnosis od dementia. I heard people at the conference acknowledging clearly that "dementia" and "Alzheimer's" are multi-factorial diagnoses, with vascular disease and inflammation being key factors.

It seems very unlikely that AD will become a disease of lesser concern, but more likely that it will be recognized as a disease with many causes, and that the earlier those causes are recognized and, if necessary, ameliorated, the better.
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