Hi J11,J11 wrote:...The phase 2 from leca has been out there for months now and it is only now that it has hit me: the APOE epsilon 4s had a large response to leca on the highest dose. On the 10 mg/kg biweekly dose the epsilon 4s (n=45) had a change from baseline of 0.096 points on ADCOMS versus a 0.180 change for placebo (n=168). A 47% reduction in decline at 18 months for the e4s? That is more than I had expected might be possible for an anti-amyloid.
Table 2 from the article noted that there was a 97.6% probability of superiority against placebo after 12 months for the highest dose arm....
Lecanemab has shown very impressive results with e4 patients and we should prepare now for the celebration...
As of October 2020, Clarity AD had randomized 1,222 participants, with demographic and cognitive scores similar to the Phase 2 study (Nov 2020 conference news). By March 2021, it had exceeded its enrollment goal, at 1,794 patients, the company announced (press release).The trial is set to run until 2024.
In February 2020, the Alzheimer’s Therapeutic Research Institute announced that the Alzheimer's Clinical Trial Consortium (ACTC) would conduct a large BAN2401 study co-funded by the NIH and Eisai (press release). Called AHEAD 3-45, this Phase 3 study started in July 2020. It is a four-year trial that comprises two sub-studies in a combined 1,400 people who are cognitively normal but have elevated brain amyloid. A3 will enroll 400 people with amyloid below the brain-wide threshold for positivity... Their primary outcome is change from baseline on their Preclinical Alzheimer Cognitive Composite 5 (PACC5) Score, also at week 216. Secondary outcomes for A45 include change in brain amyloid PET and cognitive function. Both studies will measure change in tau PET as a secondary outcome. The first person was dosed in this trial in September 2020; as of the July 2021 AAIC, 77 people had been randomized. The trial is expected to run until October 2027.
In June 2021, the FDA designated lecanemab a breakthrough therapy, thus expediting its regulatory review
As for those many relatives who relied on silence and other methods to avoid difficult topics, I suspect we all have families that practiced that to some extent. So in addition to knowing more about genetics, I choose to forgive them what they didn't understand, while I still wish they had shared difficult truths: “Tout comprendre c’est tout pardonner.”The researchers found 8 pathways to Alzheimer's disease (AD) of "perturbed" up-regulated or down-regulated genes that were "uniquely significantly enriched in ApoE4/4 AD". Two other pathways were uniquely significantly enriched in ApoE 3/4 AD and 58 were uniquely significantly enriched in ApoE3/3 AD.
Only seven pathways were shared across all three groups.
According to the article, Bumetanide has been studied for autism, schizophrenia, seizures and depression, "suggesting brain penetration and potential effectiveness in the central nervous system" by "flipping" genes back from an up-regulated or down-regulated state to a more normal state. In the experiments using a mouse model with ApoE4, the Bumetanide "rescued" neuronal plasticity in the hippocampus and spatial learning. Three pathways that appeared to be significantly affected by the drug were the "GABAergic synapse, circadian entrapment and morphine addiction pathways."
J11 wrote:The phase 2 Lecanemab results for the APOE epsilon 4s were stunning. Admittedly this is a delayed headline (almost reading history than your newspaper as this result was published in April), though it is still worthwhile to highlight these results.
The bottom figure from the above post is an attempt to convey the information in Supplementary Table 16 of the article in a more easily understandable graphical format. What we can see is that the APOE epsilon negatives did not appear to have much of a response relative to placebo on ADCOMS for any of the doses. However, the APOE epsilon positives appeared to have a quite large % response versus placebo. At the highest SUVR on the left ~ -0.31, the percentage reduction in decline was ~50%. That is worth repeating:
There was a ~50% reduction in decline on ADCOMS at 18 months for APOE epsilon 4s in the phase 2 clinical trial for the highest treatment arm of 10 mg/kg twice monthly (n=45 treatment; n= 168 placebo).
Slowly Alzheimer's progression in epsilon 4s by ~50% in this population of early mild AD patients constitutes a near functional cure. This represents a substantial treatment advance. Extrapolating this result forward one could imagine that with such a magnitude of slowing of progression the most severe stage of AD would likely not manifest for those somewhat younger than their expected age of cognitive decline onset. It is startling to recognize that for the ~50 million American epsilon 34s, the vast majority could have a clinically proven treatment option that would prevent their manifesting AD.
Nevertheless, this is somewhat speculative as the highest dose that achieved nearly 50% reduction in decline only had 45 APOE + patients. Nonetheless, the next lower dose of 10 mg/kg once monthly with n=218 recorded a 23% reduction in decline. Table 2 from the article further notes that the Bayesian ADCOMS at 12 months for the combined group of APOE epsilon plus and minus had a 32% decline in progression versus placebo. One has reason to assume that much of this benefit would also be driven by the e4+s as they demonstrated almost all of the benefit at 18 months. 1200 of the Phase 3 patients in Clarity now have 12 months data, though perhaps only half would be epsilon 4s.
This is extremely positive news!
The lecanemab results appear to be driven almost entirely by the epsilon 4s. They are not receiving a benefit of ~20% as reported with Aducan, but closer to 50%. Perhaps with some data filtering these numbers would increase. For example, what were the results for the patients with more amyloid clearance? How could the placebo be corrected for the hidden placebo treatment effect? or the rapid progressors or non-progressor placebo? ...
The upper figures in the previous post highlight the superior performance that was also noted in the 302 Aducan trial for e4+s. It is becoming increasingly unclear whether epsilon 4s actually do receive benefit from anti-amyloids. Combining these two subgroups merely obscures the large difference in response. If Clarity had pre-specified e4+s as a top-line result, the trial might have already been halted for success. The e4 results are large. It does seem that some of the e4-s are likely benefiting though it could take some effort to determine exactly the covariates that determine their response.
Also highlighted in the figure for the 302 results is the consistent statistical significance across all measures for the high dose arms for the e4+s, while all of the high dose arms in the e4-s are far wide off such significance. Also the 0.53 CDR-sb gain versus placebo for the high dose for the e4+s is somewhat better than the overall 0.39 gain for the 302 high dose arm. Yet, 0.53 reflects closer to a 30% gain for Aducan versus ~50% gain for the high dose e4+s on Leca in the phase 2. Perhaps this difference relates to the higher SUVR result for Leca and possibly as well as the cleaner trial results due to reduced side-effects etc..
Given the above, It would be very helpful if we could find an early approval mechanism for leca. There is a large dominance of naysayers in the regulatory process. Considering the near perfect 100% failure rate of AD drugs for almost 20 years this is possibly inevitable. However, the results above suggest that we need some more yea sayers. Leca has shown some large positive benefit for epsilon 4s and realistically this would seem to offer substantial benefit. Perhaps let Clarity run to March which would be 12 months of full enrollment of 1800 patients; then begin the up titration for the epsilon 4s who were on placebo while maintaining randomization and then open up Right to Try on a profit neutral basis until full approval were granted. Of course, Depending upon what the regulatory time line is this might not be needed. It is not clear to me whether the plan is to approve leca even while Clarity is ongoing. The rolling submission for leca only mentioned including safety data for Clarity.
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