Donanemab and Lecanemab

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
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Re: Donanemab, Lecanemab & Remternetug

Post by NF52 »

Julie G wrote: Thu Dec 14, 2023 2:26 pm Why didn't the MRI suggestive of CAA exclude this candidate from participating in the first place?...I appreciate that we now have more refined "Appropriate Use Recommendations," but they aren't mandates, correct? This makes me very nervous for other patients who aren't as educated as those in our community who wouldn't know to ask for APOE genotyping and to question their MRI results. Given the risks for our population, I wish we had mandated protections in place. Is this something we can push the FDA for?
TheresaB wrote:they urged the FDA to strengthen the language in the drug's prescribing label recommending genetic testing for ApoE4 be mandated. The FDA chose not to be so restrictive advising genetic testing instead
Julie, from what I have read and heard, it is the deep, serious discussion around cases like this that has led to more agreement that people with signs of ischemic blood vessel disease, and above age 75 and with Apoe 4/4 need to be told that the risks greatly outweigh the benefits. This woman was just within the criteria--but that criteria was the best information available in 2018 when the trial was designed.

That is different than telling someone in 2024 with MCI who is 65 and has ApoE 4/4 with slightly "elevated amyloid" and no co-morbid factors that they MAY have a 45% risk of either ARIA-E or ARIA-H, based on 900 study participants who were both 7 years older on average and further along the diagnostic criteria on average. Based on the trial participants, if they have ARIA, they would have a 9% likelihood of having mild symptoms of fatigue, dizziness, headache, nausea, a 3% risk of severe side effects, and approximately 1 in 450 risk of death. They can also be told that the benefits for people in the MCI range were more than twice those in the overall group, with about 70% stable over 18 months, although the benefit is less clear for women with ApoE 4/4 in that age group, based on smaller numbers. That's the basis for careful, considered decisions on risks vs perceived benefits--something that will vary by person. Those risks numbers may change with more people in the OLE and taking the drug, which will help guide patients better.

I agree with the need to do ApoE testing and while I don't have a crystal ball, I think this will be as common as having a blood chemistry panel done before these drugs are prescribed. Every clinician I heard at AAIC and CTAD said these are essential for patient safety. The new PrecivityAD®/Precivity-ApoE™ blood test will make this affordable for patients, and probably approved eventually by CMS for coverage as part of an AD diagnosis. This is from their website:
The PrecivityAD® test is for individuals experiencing memory and thinking issues. The test is only available through a healthcare provider’s order. The test is available in 49 states, the District of Columbia, and Puerto Rico; the exception is New York, which requires an individual state process for CLIA labs. C₂N is working toward obtaining the requisite certifications that will permit the PrecivityAD® test to be available in New York in the near future.
https://precivityad.com/healthcare-providers

An updated version, PrecivityAD2™ was developed through extensive research at Wahington University in St. Louis and tested in Sweden, where referrals to memory clinics are free.
Dr. Sebastian Palmqvist and his colleagues at Lund University in Sweden with the BioFINDER-Primary Care and Memory Care studies..involved over 1,000 patients with cognitive concerns from four independent cohorts. His recent research presented at the 2023 Alzheimer’s Association International Conference outlined that this blood test had very high accuracy (AUC 0.95-0.97) for identifying Alzheimer’s disease pathology, primarily using CSF biomarkers as the reference standard.
The results of the PrecivityAD2™ blood are impressive, and numerous researchers at AAIC and CTAD predicted that within a few years or even sooner, these tests, equal in accuracy to spinal taps of CSF for amyloid and tau, will be used for all diagnoses of Alzheimer's. They are used now in lecanemab trials and are likely to be required as a first step in any center prescribing Leqembii or donanemab. Dr. Palmqvist, who is a practicing neurologist as well as researcher and not an employee of C2N Diagnostics, said that the accuracy of the test is equal or better than CSF biomarkers predicting a positive PET scan and commented "Why would we put people through lumbar punctures when we can give them a blood test and have more information?"

Because the test measures both amyloid and p-tau 17 in the blood, it would tell doctors and patients two things that were NOT knowable when CLARITY or the OLE started:
  • Who has high amyloid combined with high tau and therefore is not likely to benefit from anti-amyloid drugs due to more advanced disease, regardless of MMSE score or daily functioning?
  • Who has ApoE 4/4 and is therefore at the highest risk for ARIA-E or ARIA-H, especially if combined with high amyloid (well above the 40 centiloids required for "elevated" amyloid)?
Here's a statement from the company that makes the test about its accuracy and projected use in these drugs:
Dr. Demetrius Maraganore, FAAN, and the Herbert J. Harvey, Jr. Chair of Neurology at the Tulane University School of Medicine, says, “My passion is helping patients to achieve successful brain aging by preventing and reducing the burden of cognitive decline and dementia. In this regard, the PrecivityAD2 blood test makes a significant contribution to the diagnosis of patients with Alzheimer’s disease. It is a convenient and accurate alternative to PET scans and cerebrospinal fluid tests, which are limited in availability. I intend to use PrecivityAD2 in my practice to determine my patients’ eligibility for newly approved Alzheimer’s disease therapies.”
And here's why I think neurologists and memory centers will insist on ApoE 4 testing, from Boston's Brigham and Women's Hospital. I hope it's a model for other centers on transparency with patients and their support partners.
Lecanemab can cause small areas of swelling or bleeding in the brain called amyloid related imaging abnormalities (ARIA). ARIA is usually asymptomatic and detected only by monitoring MRI scans. In the phase III study investigating lecanemab, only 2.8% of subjects receiving lecanemab had symptoms due to ARIA. Most symptoms were mild, involving temporary symptoms including headache, confusion, dizziness, changes in vision, nausea, or difficulty walking, and were temporary. However, ARIA-related swelling occurred in 12.6% of subjects receiving lecanemab, and 8.4% of subjects had both swelling and bleeding, often without producing symptoms. Patients will therefore need to be monitored with serial MRIs (usually monthly) until it resolves (usually within 6 months).
Rarely, ARIA can cause seizures or larger areas of inflammation and/or bleeding in the brain. The risks of ARIA, symptomatic ARIA, and serious symptomatic ARIA leading to hospitalization are highest in people carrying 2 copies of the APOE ε4 gene. In the phase 3 study, the rates of symptomatic ARIA with lecanemab treatment were 9.2% in participants with 2 APOE4 genes, 1.7% in participants with 1 APOE4 gene, and 1.4% in participants who did not carry an APOE4 gene. The rates of serious symptomatic ARIA were 2.1% in participants with 2 APOE4 genes, 0.4% in participants with 1 APOE4 gene, and 0.7% in participants who did not carry an APOE4 gene.
https://www.brighamandwomens.org/neurol ... -lecanemab

This is from the Leqembi website; not the patient info, but what doctors could easily see (as could I): It is from the "Full Prescribing Information". "Study 2" refers to CLARITY. https://www.leqembi.com/-/media/Files/L ... mation.pdf ApoE ε4 Carrier Status and Risk of ARIA
Approximately 15% of Alzheimer’s disease patients are ApoE ε4 homozygotes. In Study 2, 16% (141/898) of
patients in the LEQEMBI arm were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31%
(278/898) were noncarriers. The incidence of ARIA was higher in ApoE ε4 homozygotes (45% on LEQEMBI
vs. 22% on placebo)
[Note that people on placebo also had ARIA, a sign that not taking the drug will not necessarily avoid all risks of brain hemorrhages] than in heterozygotes (19% on LEQEMBI vs 9% on placebo) and noncarriers (13% on LEQEMBI vs 4% on placebo). Among patients treated with LEQEMBI, symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes compared with 2% of heterozygotes and 1% noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, and approximately 1% of heterozygotes and noncarriers. The
recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers [see Dosage
and Administration (2.3)]. [Note: This is because "management" protocol states that dosing should immediately be suspended with even mild symptomatic ARIA-H, and with moderate to severe symptoms, even when ARIA-E imaging is "mild". This is what was not followed before the second and third infusions of the woman who died from edema and microhemorrhages.(not an ischemic macrohemorrhage, which was the 65 yr old with Apoe 3/4 given anti-thrombotics. ] Testing for ApoE ε4 status should be performed prior to initiation of treatment to
inform the risk of developing ARIA
. Prior to testing, prescribers should discuss with patients the risk of ARIA
across genotypes and the implications of genetic testing results. Prescribers should inform patients that if
genotype testing is not performed they can still be treated with LEQEMBI; however, it cannot be determined if
they are ApoE ε4 homozygotes and at higher risk for ARIA
. An FDA-authorized test for the detection of ApoE
ε4 alleles to identify patients at risk of ARIA if treated with LEQEMBI is not currently available. Currently
available tests used to identify ApoE ε4 alleles may vary in accuracy and design
.
As I have said to friends and on this forum: This is not a decision to be taken lightly, and many more people will NOT be eligible than will be. It is, however, a choice that people faced with a life-threatening disease may decide is the right one for them. As we do when people choose whether, or how, to treat cancer, heart disease or other conditions associated with late-life onset, I think patients deserve a high degree of transparency, communication, time and in the end, respect for ownership of their choices.
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Re: Donanemab, Lecanemab & Remternetug

Post by Julie G »

I think patients deserve a high degree of transparency, communication, time and in the end, respect for ownership of their choices.
Amen and thank you (and others on the site) for sharing your brave journey with Lecanemab! You are pioneers helping us to further the understand its efficacy and effects.
As I have said to friends and on this forum: This is not a decision to be taken lightly, and many more people will NOT be eligible than will be. It is, however, a choice that people faced with a life-threatening disease may decide is the right one for them. As we do when people choose whether, or how, to treat cancer, heart disease or other conditions associated with late-life onset.
I agree that those with Alzheimer's (a life-threatening disease) deserve to chose their treatment, ideally with full-disclosure of risks/benefits. However, because the diagnostic criteria for many of these trials relied heavily on amyloid which hasn't proven to be prognostic, I worry that some taking the drug many not even have the disease and may be unnecessarily exposing themselves to risk.

As an organization, let's think about creating a resource for those considering Lecanemab where we transparently share known benefits and risks for E4 carriers (broken down by age, gender and number of E4 alleles) along with recommendations for safety (imaging, biomarker, and APOE testing) so that members can make a truly informed decision. In a perfect world, this information/testing would be mandated, but as evidenced by the various tragedies that doesn't always appear to be the case. With all of the knowledge on our website, we have an opportunity to help future members struggling with this decision.
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Re: Donanemab, Lecanemab & Remternetug

Post by J11 »

There have been some very important development with amyloid mabs since Lecanemab's approval that need to be included in an update for a current and more accurate view to be discussed. These updates have largely been from CTAD 2023.

Firstly, the perspective that mabs have an average slowing of disease progression of ~35% (e.g., with Donanemab) can now be seen to be mostly inaccurate.
Disease Time CDR-sb.PNG

https://www.desmos.com/calculator/2229w9nw9j

What we see in the figure above is the more accurate description of disease effect with mabs. Amyloid mabs are surprisingly sensitive to even small changes in initial disease stage; until now this observation has not been that obvious to me. Yet, as we see, those who have 2 years ahead of them to reach the clinical trial average disease progression had ~ 90% disease slowing (88% on iADRS and 95% on CDR-sb)!! That is startling! While those who were 2 years more advanced than the average patient had a ~10% disease slowing. That is also startling. In 4 years years patients go from 90% slowing to 10% slowing?! This should make a great many people feel uncomfortable. Amyloid truly is that dangerous and reducing truly is that effective. We have the long term results from Aducanumab that showed that these responses can be long lasting over the span of ~5 years (perhaps the latest updates have extended this out even further).

Considering the anti-amyloid mabs as having 22%, 27% or 36% disease slowing is then very very misleading. I mentioned elsewhere that I do not really think thinking of an average of such heterogeneous results is not that good of a way of applying averages. An average should be more of homogeneous result that is able to statistically characterize some observation-- not largely hide the underlying trend present. From the current knowledge, mabs should be understood more as curative treatments for all of those who are sufficiently early relative to the clinical trial patients. Notably, over even the medium term these will be all of the on label patients. We are rapidly transitioning to a time when all on label mab AD patients could expect to have curative level responses. This is quite surprising even for me when I put this into words, however, from the facts as known it is largely indisputable.




The above figure adds some additional insight into the evolving understanding. What we can see is that even those with low amyloid levels can still have advanced tau pathology. The problem then is that there are a considerable percentage of patients that need to be treated quite early. Apparently it was reported recently that e4s are even more vulnerable to this effect. sometimes even down to 10 centiloids e4 patients can develop advanced tau pathology. Clearly treating earlier will be an evolving clinical strategy in the years ahead, especially as more clinical experience is gained.



In terms of how to frame the current discussion about the clinical application of mabs, I think it is now completely a non-starter to talk in terms of efficacy. If anything I find that entirely mysterious -- basically, shut down the conversation by making non-falsifiable statements that are not well-grounded near the centroid of issues of legitimate concern. What we can see now is that there are very large treatment effects for early patients. While it is true that there is some murkiness regarding the benefits for e44 patients, it is important to remember that the FDA did extensive modeling with the Aducanumab dataset and in this modeling did not consider e4 to be a valid covariate in treatment response. This is not completely clear to me, though there is the suggestion that e44s seemingly lackluster clinical trial responses as reported in the below the topline outcomes is not reflective of modeling.


The recent article about the Florida e44 fatality patient in the OLE actually helps to move forward aspects of mab treatment that could constructively improve patient experience. For example, the suggestion of moving to the Boston criteria for CAA seems helpful. I am not sure whether this is thought relevant, though I have suggested on the main Aducan thread that perhaps preventative steroid dosing might be useful. The background here is from the Aducanumab FDA briefing documents (second round). It was there reported that many patients treated with Aducanuamb showed rapid and sometimes repeated benefit from steroid treatment after ARIA incidents. What was of interest with the Florida patient was that this patient was amonsgt the minority of patients who are steroid non-responders. This idea was disclosed in the first published report on this patient. What I find surprising is that preventative steroid dosing has not been suggested more strenuously. Why wait until a patient arrives at an ICU to learn that they are steroid non-responsive? Would it not be best to learn of the steroid response early on? Perhaps even in a titration setting? Treat the patient with titrated mabs and steroids and see if ARIA develops. If ARIA develops then the patients is a non-responder and then regroup. This potentially could be one way of identifying those who will not respond to steroids. The irony with the Florida patient is that this patient was a mab superresponder-- this patient removed an enormous amount of amyloid during the first few injections -- to be honest, the patient removed too much amyloid. From what we know this patient would have done very very well on treatment. So, working through this issue of non-response to steroids and hyper response to mabs would then improve the treatment effect for these patients while also improving safety. This does have me wondering whether some type of an amyloid biomarker such as an amyloid blood marker might be a good way of adapting to treatment response. Here the idea would be take blood samples for the first few treatments and try to determine how much amyloid was being removed. If the superresponders could be identified than their treatment could be titrated down -- This would lead to a safer treatment for them as well it would give them the opportunity to capture the potentially large treatment effects.

Best wishes for the holiday season everyone!
2023 has been a spectacular year for clinical Alzheimer treatment!
I am looking forward to an even better 2024!
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Re: Donanemab, Lecanemab & Remternetug

Post by Julie G »

Happy holiday's to you, J11! Can you share the CTAD link(s) that have provided the data points for the graph you've created? I don't see anyone else making this claim. If Lecanemab offers 90% slowing of disease progression in the early stages, that is impressive indeed, even if it doesn't apply to E4 carriers.
In terms of how to frame the current discussion about the clinical application of mabs, I think it is now completely a non-starter to talk in terms of efficacy. If anything I find that entirely mysterious -- basically, shut down the conversation by making non-falsifiable statements that are not well-grounded near the centroid of issues of legitimate concern. What we can see now is that there are very large treatment effects for early patients. While it is true that there is some murkiness regarding the benefits for e44 patients, it is important to remember that the FDA did extensive modeling with the Aducanumab dataset and in this modeling did not consider e4 to be a valid covariate in treatment response. This is not completely clear to me, though there is the suggestion that e44s seemingly lackluster clinical trial responses as reported in the below the topline outcomes is not reflective of modeling.
I think we've had an important and necessary conversation about the efficacy of Lecanemab for E4 carriers, given the focus of our non-profit. I'm deeply grateful for those who've shared important warnings to keep our community safe and especially to all who are participating in the trials and sharing their experiences. This is how we are furthering understanding.
What was of interest with the Florida patient was that this patient was amonsgt the minority of patients who are steroid non-responders. This idea was disclosed in the first published report on this patient. What I find surprising is that preventative steroid dosing has not been suggested more strenuously. Why wait until a patient arrives at an ICU to learn that they are steroid non-responsive? Would it not be best to learn of the steroid response early on? Perhaps even in a titration setting? Treat the patient with titrated mabs and steroids and see if ARIA develops. If ARIA develops then the patients is a non-responder and then regroup. This potentially could be one way of identifying those who will not respond to steroids.
Interesting idea, especially if it would have helped to disqualify this patient from participating. However, it's important to keep in mind that steroids do come with negative side effects especially for older patients including an increased risk of diabetes, heart attacks, and osteoporosis along with a down regulation of the immune system. Read more here.
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Re: Donanemab, Lecanemab & Remternetug

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J11 wrote:
Julie G wrote: Tue Dec 19, 2023 7:45 am If Lecanemab offers 90% slowing of disease progression in the early stages, that is impressive indeed, even if it doesn't apply to E4 carriers.
Julie, I haven't seen the 90% figure, but did see several discussions about impressive results in the "low tau" group.

P-tau 181, which can now be measured in blood plasma, is part of the new PrecivityAD2™ blood test and so can differentiate individuals into three groups, all of whom previously were viewed as simply "amyloid positive":
  • high-tau, in which anti-amyloid drugs are likely to be significantly less effective
  • medium tau, in which the risk/benefits of anti-amyloid treatment should be carefully discussed
  • low-tau, those who showed the highest benefit in trials and who may have the least risk of CAA-related severe ARIA-E or ARIA-H
All of these abstracts are from CTAD2023 in the Journal of Alzheimer’s Prevention: https://link.springer.com/article/10.14 ... d.2022.129

Presentation 2: Biomarker Assessments from Clarity AD: Downstream Implications of Targeting Protofibrils and Tau as a Predictive Biomarker
In the low tau subgroup, 60% of lecanemab treated patients had improvement on CDR-SB (vs 28% on placebo) and 76% had no decline on CDR-SB (vs 55% on placebo) at 18 months. Lecanemab slowed tau pathology in temporal lobe (early Braak regions). In addition, lecanemab impacts different brain regions in low tau PET group vs intermediate tau PET group consistent with stage of disease. In those with low tau, lecanemab impacts medial temporal (which is the earliest tau region) tau progression, while in intermediate tau (which on average has tau already in temporal and parietal regions), lecanemab impacts tau progression on PET more broadly. Conclusions: Biomarker assessment results from Clarity AD show that lecanemab treatment has an overall effect on tau PET for all patients, arresting tau progression/spread in low tau patients and changing the tau accumulation trajectory in patients with higher tau levels. Results from Clarity AD in low tau subgroup supports earlier treatment with lecanemab.
Presentation 3: Lecanemab for the Treatment of Early Alzheimer’s Disease: The Extension of Efficacy Results from Clarity AD,
In the ongoing open-label extension (OLE) study, we evaluated whether the treatment benefits were maintained at 24 months and assessed the impact of baseline tau PET levels on the long-term treatment response... Assessments included the Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), AD Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL) and amyloid PET. Of the 1486 subjects that completed 18 months of the double-blind core study, 1385 participants enrolled in the OLE... Across efficacy assessments, participants with low tau at core baseline, initially assigned to lecanemab, continued to show benefit of lecanemab treatment beyond 18 months, and participants initially assigned to the placebo arm began to demonstrate evidence of benefit subsequent to lecanemab being started in the OLE.
EFFICACY OF DONANEMAB BY APOE4 CARRIER STATUS IN TRAILBLAZER-ALZ 2, A PHASE 3 RANDOMIZED CLINICAL TRIAL IN EARLY SYMPTOMATIC ALZHEIMER’S DISEASE
Apolipoprotein E ε4 (APOE4) carrier status was identified as a risk factor for incidence of amyloid-related imaging abnormalities1 which could negatively impact treatment response and benefit-risk; therefore, an expanded view of the clinical efficacy benefit for APOE4 carriers is warranted... Results: In the low-medium tau population, APOE4 carriers (n=848, including homozygous n=190, heterozygous n=658) were younger with minimally higher baseline clinical assessments than non-carriers (n=330). Change in iADRS [Integrated Alzheimer's Disease (AD) Rating Scale] [for APOE4 carriers[ score at 76 weeks was...a 36% slowing of disease progression... versus...a 35% slowing of disease progression [in Apoe4 non-carriers.]. Change in CDR-SB score at 76weeks was... a 37% slowing of disease progression versus... a 38% slowing of disease progression [in non-carriers]. The corresponding percent slowing for the ADAS-Cog13 and ADCS-iADL was 35% and 39% in APOE4 carriers and 28% and 41% in APOE4 non-carriers. Homozygous APOE4 carriers had numerically lower treatment effects than heterozygous or non-carriers on both the iADRS (% slowing for: homozygous: 30%; heterozygous: 37%; non-carrier: 35%) and CDR-SB (% slowing for: homozygous: 12%; heterozygous: 43%; non-carrier: 38%), but still favored treatment with donanemab. Finally, amyloid clearance was robust amongst all donanemab-treated participants although numerically smallest in homozygous carriers likely due to ARIA-related dose pauses/discontinuation. Conclusions: Similar clinical efficacy of donanemab treatment is observed in both APOE4 carriers and non-carriers.
The following abstract is about safety, and compares the binding of lecanemab vs donanemab to amyloid in cerebral amyloid angiopathy (CAA). The Apoe 4 status of these brain donors is not specified.
BINDING PROFILES OF LECANEMAB AND DONANEMAB TO DIFFERENT AMYLOID-BETA SPECIES
Lecanemab is mainly targeting soluble aggregated Aβ species, while donanemab is reported to target pyroglutamate Aβ (AβpE3) in plaques. There is strong evidence that soluble Aβ aggregates are more toxic than monomers or insoluble fibrils.... The incidence of ARIA-E [edema] might correlate with antibody binding to Aβ fibrils in the cerebral vasculature, cerebral amyloid angiopathy (CAA). An ARIA-E rate of 24% was reported for donanemab, and a rate of 12.6% was reported for lecanemab... Conclusions: The binding profiles of lecanemab and donanemab to distinctive Aβ species were investigated with three different methods. Lecanemab showed strong binding to Aβ protofibrils in different severity stages and exhibited low binding to all CAA samples analyzed, independent of AβpE3 content. Donanemab had stronger binding than lecanemab to Aβ fibrils isolated from meningeal CAA from AD brains.... This could have an impact on clinical efficacy and safety of lecanemab and donanemab when treating patients early in the disease.
Below is a screenshot from CTAD2023 showing the analysis of full CLARITY results, with an association between number of baseline microhemorrhages, Apoe4 status and risk of ARIA-E. This information that was not available before the death of the woman with 4 baseline microhemorrhages at the age of 79, who had an 82% chance of ARIA-E with lecanemab. [Even so, the symptoms of the woman who died after her third infusion should have resulted in an immediate cessation of the drug after the first, and definitely the second infusion.]

This new information and tau levels will allow doctors to have more personalized discussions with potential patients, since Apoe4 and amyloid status alone are insufficient to identify the highest risk or the highest likely benefit.
Image 12-3-23 at 1.15 AM.jpeg
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Re: Donanemab, Lecanemab & Remternetug

Post by J11 »

I call this a cure for Alzheimer's!!!
95% slowing of progression on CDR-sb?


Considering that it is not that easy to do that much better than 100% in AD, this implies that
e34s and e44s likely did quite well. They would had to have done quite well because perhaps the
e33s might have hit 120% yet this means that the e4s could not pull down the average that much and still
be at 95%.


This is not a highly selected group of patients either.
They are only considering the disease stage in years and there is this dramatic
difference that can be seen that occurs over only 2 years either side of the average patient in TB-2.

With additional selection based upon age etc. and the results can only get better.

Considering this updated understanding it would not be unreasonable for European regulators to
consider the on label treatment group as those with earlier disease. Doing this means that instead of treating a patient 2 years past the average with an expected response of ~8% slowing on CDR-sb one could treat a patient 2 years before the average and have an expected 95% slowing and essentially a functional cure. Waiting until
the patient is past the average simply means they have entered into the accelerating decline phase where mabs will not help much even in the short term.

Stage Benefits.PNG
Page 35 of the Additional Insights from Trailblazer-ALZ- 2 pdf from CTAD 2023.

https://assets.ctfassets.net/mpejy6umgt ... ersion.pdf

Disease Time CDR-sb.PNG

https://www.desmos.com/calculator/2229w9nw9j
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Re: Donanemab, Lecanemab & Remternetug

Post by NF52 »

Julie G wrote: Tue Dec 19, 2023 7:45 am If Lecanemab offers 90% slowing of disease progression in the early stages, that is impressive indeed, even if it doesn't apply to E4 carriers.
J11 wrote: Tue Dec 19, 2023 12:35 pm 95% slowing of progression on CDR-sb? ...With additional selection based upon age etc. and the results can only get better. ...
Doing this means that instead of treating a patient 2 years past the average with an expected response of ~8% slowing on CDR-sb one could treat a patient 2 years before the average and have an expected 95% slowing...Waiting until
the patient is past the average simply means they have entered into the accelerating decline phase where mabs will not help much even in the short term.
J11, thanks for sharing the slides from the Donanemab presentation at CTAD. They helpfully provided a QR code with all of their data slides.

Julie, here is the slide (shown in J11's post also) for the basis of 95% slowing of decline prediction.
Estimating stage-dependent treatment effects.png
It represents a model, but one drawn from the actual results of each patient in the TRAILBLAZER ALZ-2 trial. If I understand the model, statisticians started with the assumption that every patient has an individual "latent disease time parameter." Some patients declined quickly, even on the drug; others not at all, even on placebo. Using their baseline CDR-SB and the iADRS composite scores, they plotted where the average participant was at baseline, which they termed "disease stage 0 years". This doesn't mean they had no Alzheimer's; it's simply a way of anchoring a range for better or worse scores at baseline, to determine where someone likely was on the AD disease trajectory (from MCI to severe). They then charted each person's scores over time and worked backwards to determine how many years before or after the average baseline disease stage each person would have been when starting the trial.

Someone who scored a 0 on the CDR-SB (no cognitive impairment) or a 144 on the iADRS (a perfect score) would be predicted to be 6 years before the average disease stage of those in the trial (and obviously not eligible for this trial of people with MCI/mild AD). But some who scored in the MCI range, with a 0.5 on the CDR-SB and a high score on the iADRS might have been 4 years "behind" the average participant in disease stage and 6 or more years behind those close to the "moderate AD" stage. The model predicts that those who were about 2 years earlier than average in disease stage, based on their baseline cognitive scores when they started treatment would show a 95% slowing of decline over 18 months.

The model prediction of 95% slowing disease progression is supported by the 60% of those with low-tau who showed actual improvement on the CDR-SB scores with lecanemab, and the overall 78% with low tau who with no progression on the CDR-SB. While this data for the slide above for donanemab, it seems in both drugs that maybe around 80% of people in this early stage of disease might be able to have 95% slowing of progresion--or no decline at all--- over 18 months. While that may not hold true for everyone with Apoe 4, it suggests that moving even further back--before the MCI stage, as the AHEAD and TRAILBLAZER ALZ 3 trials do, might be the most beneficial. Time will tell on that prediction.

People who moved from placebo to treatment in the OLE were, by definition, around 2 years further in their own disease timeline, regardless of their initial disease stage. That may be one factor in why three deaths were seen in the OLE of lecanemab related to treatment, but none related to the drug in the main trial of about 800 people. Both lecanemab and donanemab researchers now link earlier disease stages to Tau PET levels and the areas of the brain in which tau is seen, and believe that removing amyloid slows the progression of tau and reduces it in areas like the medial temporal lobe which are affected early.
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4/4 and still an optimist!
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Re: Donanemab, Lecanemab & Remternetug

Post by J11 »

The desmos url is showing how the genotypes fit the 95% slowing constraint.
On the purple line the y-axis represents the percentage slowing that could occur for the e33s.
Given this level of y, then the x-axis value (i.e., the total percent slowing for e4s) is then determined.
Then for this same level of slowing for the e33s, we can construct the line constraining the result for
the e34s and e44s.

I also put some rough guesstimates of where the upper and lower bounds for the different groups could be.
For the e44, I chose low of 50% slowing and a high of 150%; for the e34s I chose a low of 100% and a high of 175%; and for the e33s a low of 75% and a high of 130%.

https://www.desmos.com/calculator/w4kbtrbcfd

This is not meant to be overly exact, though it does show that the basic genotype constraints along with some basic assumptions of the range of the different gentoypes, implies that all of the genotypes would need to do fairly well for the numbers to work out as reported. It is true that the e44s can then surprisingly underperform (as in Clarity0, though with the 95% constraint here a noticeable underperform would then force the e34s to do unreasonably well (perhaps 200%). My current impression is that overperformance potential (i.e. better than 100% reduction in decline-- at the group level will be bounded more to about 140%). This largely forces the genotypes to all do well.
Baseline Demo Donaneamb 1.PNG
Donanemab Addendum 1.PNG
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Re: Donanemab, Lecanemab & Remternetug

Post by J11 »

What is extremely exciting is that TB-2 had this Addendum sample with n=1053! They seem to be exactly the patients that could more fully answer these questions about the early patients with no/very low tau. I am not clear what how much of this group has been reported on to date. Also the above talks of safety and biomarker assessments -- one can only hope that there will be cognitive readouts.

Perhaps the registry studies with Lecanemab might give us some insight into the slowing of decline in the early patients as well.
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Re: Donanemab, Lecanemab & Remternetug

Post by J11 »

Capture 19a - Copy.PNG
Intermediate-High tau vs. amyloid centiloid 2.png
This is also an important update from CTAD 2023.
This is from the Lecanemab presentation.

The first result that I found to be quite startling was the 95% slowing in those 2 years before the average patient
in TB-2. That was shocking! 2 year delay in treatment can really make that much of a difference in a patient's cognitive trajectory? I would not have guessed that that would be true.

In the above what we see is that the equally surprising result that even fairly modest amyloid levels can signal advanced Alzheimer's. I also would not have guessed this to be true. The top figure from CTAD 2023 largely hides the result. However, when you consider the percentage of patients with low tau as a function of their centiloid amyloid score you see the figure shown above. The totality of the numbers provide a strongly logistic result. As we can see patients even with the seemingly low amyloid level of 60 centiloids amyloid already are 40% intermediate/high tau. Even 40% of those with fairly low amyloid levels already have advanced AD in terms of their neuropathology? With current mabs, these patients are almost untreatable. At the very least these patients will not receive 95% benefit but perhaps closer to 8%.

It is difficult not to wonder whether some rethinking of who should be the on label patients might be in order. Perhaps the FDA should consider special ADCOMS to occasionally discuss these issues in Alzheimer clinical medicine and perhaps in other therapeutic categories. It seems increasingly necessary that a safety study should be done to pursue microdosing as I have often mentioned on the main Aducan thread. If not then they might consider ADCOMS for further mabs; it seems like a missed opportunity that Donaneamb did not have an ADCOM. An ADCOM seems like not a bad venue to ask the sort of questions that have been raised by the CTAD presentations and contemplate the answers. Nonetheless, from what we can see with the 95% slowing of disease progression in early patients, it not difficult to predict that mab treatment patient benefit will simply only increase in the years ahead.


As mentioned above in one of my posts, an alzforum article noted that e4s appeared to have higher percentage of intermediate/ high tau even at low amyloid centiloids.

With respect to steroids yes they can pose a health risk. Strangely, there is something called steroid dementia syndrome. Steroids can cause irreversible dementia and have even caused irreversible cognitive impairment in children. However, as a short term screen to determine whether mab patients will respond to steroids if they develop ARIA it might be a worthwhile tradeoff. Otherwise, you have patients such as the Florida patient who then wind up at the ICU and there is no available treatment to offer them.
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