DISCLAIMER: THIS IS NOT INVESTMENT ADVICE. I AM NOT A FINANCIAL ADVISOR. THIS IS FOR EDUCATIONAL PURPOSES ONLY. DO NOT USE THIS INFORMATION FOR INVESTMENTS --MAX HITEK
Be sure to visit Piotr Pietrzkiewicz's Patreon blog "Bio- Scoping", patreon.com, for many interesting articles related to drug development!
A Comparison of the ADAS-Cog Scores for Aducanumab, Blarcamesine, Donanemab and Lecanemab!
2024 07/30 ---Max Hitek
Definitions and Abbreviations
Blarcamesine - - Anavex's drug, also known as A2-73.
AD - - Alzheimer's Disease.
ADAS-Cog - - The Alzheimer's Disease Assessment Scale-Cognitive Subscale. Used to assess the severity of the cognitive impairment. Considered to be the gold standard.
MMRM - - Mixed Model Repeated Measurements.
NCS - - A statistical model/software.
MAB - - Monoclonal Antibody.
Many companies are working on drugs to address the cognitive issues that are seen in Alzheimer's disease (AD). Four companies on the forefront are already able to market their AD drug, or will soon apply to be able to. The major issue with AD is the cognitive decline. The exact cause of the disease is not exactly known, but it seems that the sooner the symptoms can be addressed, the better drugs can perform. There has been very little, if any, success in treating severe impairment, and most drugs are trying to address mild to moderate impairment.
The 'ruler' used to measure AD cognitive impairment is usually the test known as ADAS-Cog. It is generally accepted as a good measure of AD cognitive impairment, and most AD trials use it as one of the endpoints. There has been much discussion for several decades about tau and plaque, etc. as possibly being the cause of AD. But current thinking is that these may be some measure of the disease, and useable as 'biomarkers', but not the cause. In the end, it makes sense to address the real problem -cognitive impairment. That is where the ADAS-Cog test is important. The four drugs being compared here all reported ADAS-Cog results!
Here are the four companies and drugs, which we will look at.
This will be an "apple to apple" comparison, as much as is possible. For example, only High dose data will be analyzed, not low or medium doses. Fortunately, all four companies reported ADAS-Cog scores. There are some notes and caveats to be mentioned. Here they are, in no particular order:
Lilly (Donanemab), in their top line PR1, gives 4 ADAS-Cog scores. They presented their scores two ways, using MMRM and NCS statistical analysis. They only included ADAS-Cog scores for the medium tau patients and the combined medium AND high tau patients. They did not include the low tau patient's ADAS-Cog data(presumably they did worse). Here is the data they gave in the PR1:
INTERMEDIATE tau population
MMRM statistical analysis NCS statistical analysis
Relative % slowing Relative % slowing
35% 32%
COMBINED INTERMEDIATE and HIGH tau population
MMRM statistical analysis NCS statistical analysis
Relative % slowing Relative % slowing
19% 20%
In an attempt to determine what the typical enrolled patient could expect from Lilly's Donanemab, the four values given, were averaged together. This avoids this "data/patient exclusion". The average, 26.5%, is presented in the chart below. Even this excludes low tau patients and patients with no tau.
Biogen (Aducanumab) ran two identical (as far as I can tell) Alz trials, named EMERGE and ENGAGE2. EMERGE showed 27% less decline than the placebo, but ENGAGE showed only 11%. Here again, averaging the two (19%) seems correct. (NOTE:Engage Low dose was 11% and High dose was 11%, showing no dose difference.)
Anavex's Blarcamesine3 ADAS-cog improvement versus placebo, was straightforward at 38.5%. The Blarcamesine trial was only 48 weeks long, whereas the other companies trials were 78 weeks long. The numbers show that Blarcamesine had greater improvment than the others, and in less time.
Esai/Biogen's Lecanemab data4 was also straightforward. The 78 week trial had a placebo decline of 5.58 points and a dosed decline of 4.14 points. This gives a 25.8% reduction in decline versus placebo.
The chart below shows the four drugs, with the averaged scores for Aducanumab and (Donanemab). The bars show the drug's percentage of reduction in decline verus placebo. In other words 0% would be the same as the placebo, no improvement, and 100% would be no cognitive decline at all. Note: This shows the Blarcamesine score, even though the trial was shorter than the others (very conservative display).
Conclusions
Clearly, from this chart Blarcamesine has substantially better performance than the other drugs. The Blarcamesine trial had no inclusions or exclusions based on any tau or plaque or alleles. It is roughly 50% better than the "MABs".
Aducanumab, Donanemab and Lecanemab are monoclonal antibody drugs, frequently referred to as MABs. There were three different MAB drugs, independently developed by different companies, showing similar results. This data seems to raise the question, "Have the MABs reached their limit (approximately 27%) in slowing cognition decline?"
References:
Visit the patreon blog of Piotr Pietrzkiewicz at Bio-Scoping , for other articles. ---Max
1Lilly's PR "Lilly's Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer's Disease" From May3, 2023.
2Biogen's "Evaluation of aducanumab efficacy in early Alzheimer’s disease" As presented at AD/PD 2021.
3 Anavex's presentation "Blarcamesine in Early Alzheimer’s Disease: Phase IIb/III Randomized Clinical Trial" at AAIC 2024.
4"Lecanemab in Early Alzheimer’s Disease" The New England Journal of Medicine, January 5, 2023