Investigating the Miracle Biologic Lecanemab for Alzheimer's Disease - Part 2
Lecanemab’s effectiveness evidence base
Okay, folks, let’s start from…..the start. We two geezers like having our ducks lined up before commenting, as you all know from the Antivirals and Comirnaty series of posts. So the start of the line-up is: how many and what investigations were carried out on the wonder Monoclonal Antibody (MAB) Lecanemab for Early Alzheimer's Disease (AD)?
The Japanese regulator PMDA provides the answer:
As usual (you have to get used to it), we have the nth acronym: OLE, in this case—open Label Extension.
We have phases I, II, and III trials; somehow, the open-label extension is tucked into the last two, 201 and 301.
The sobriquet “core” is strange. Some pharmaceutical companies use the term “pivotal” when they propose the trial, which, according to them, best supports their request for licensing.
Regulators and pharma have long tried to standardise their lexicon, but there may be the odd slip. We assume “core” means “pivotal”. Strange that a phase II trial should be called that, but let’s stop splitting hairs (which Tom no longer has on his head).
Now, let’s focus on study 201.
This is described as “randomized, double-blind, parallel-group study was conducted at 149 study centers in Japan and other countries to investigate the safety, tolerability, and efficacy of lecanemab in patients with early AD (MCI due to AD–intermediate likelihood - NOTE17) and mild AD-D - NOTE 18) (target sample size, 800 subjects - NOTE 19). The duration of the Core study was 21 months at maximum after randomization (up to an 18-month treatment period plus a 3-month follow-up). After the completion of the analyses for the Core study (July 2018), the Core study was followed by an open-label extension (OLE) phase for up to 63 months (up to a 60-month treatment period plus a 3-month follow-up), which was initiated after the gap period (ranging from 9 to 59 months, with a mean of 24 months). In the following sections, in addition to the results for the overall population, the results for the Japanese population are also provided for the Core study, a phase important for the evaluation of efficacy and safety in Japanese patients”.
Translation: MCI = mild cognitive impairment; AD-D = Alzheimer’s disease dementia
The reference to Japanese patients is due to Eisai, the Japanese manufacturer, as is the PMDA regulator. In Japan, the MAB is marketed under the name Leqembi.
OK, all clear? Now, how did they calculate a sample size of 800 (NOTE 19 in the text)? Like this:
If you rapidly scroll back to the first post in this series
and the exchange with our subscriber Vivian Evans, you will see that lecanemab, in whichever formulation you choose, makes no difference when compared to placebo on the Alzheimer’s Disease Composite Score (ADCOMS) outcome. This means that the simulation and the sample size calculation (how many folks did they need to recruit to prove their point) are based on thin air. Remember that Eisai indicated ADCOMS as the “primary efficacy outcome.”
Mark it, please, as we will go back to the choice of primary outcomes.
To finish off, I have a question for you: Do you think that the Telegraph journalist and David Thomas promoting lecanemab were aware of these trivial points?
This is the series' second post on the wonder MAB Lecanemab for Early Alzheimer's Disease (AD). We are desperately trying to make things easy to understand, as 23 SKIDOO likes. However, the regulatory documentation (which is a reflection of the pharma submission supporting the licensing application for Lecanemab) is littered with acronyms, for example, ADCOMS. It would be easy to write a post making fun of all this. Except that we find nothing funny in AD.
We will try to clarify as much as we can—these acronyms do not play a casual role in all this.
Hi Dan, we were discussing writing a piece on amyloid hypothesis this afternoon. In tomorrow’s post we report PMDA’s figures for serious harms on the central nervous system. Let’s pick up the discussion on amyloid at the end of the series. My opinion is that pharma started working on anti amyloid compounds before the whole thing was called into question , so they were stuck with a pipeline which was aimed at something that was not related to AD, or may be partially. As you will see by the amount of money these guys invested in patients’ pressure groups they decided to press on.
It’s a guess, let’s see what you and the other subscribers think.
Best, Tom
Firstly, Mr David Thomas is blessed with utter ignorance regarding the points you raise and have raised so far. For him, it's all about signalling his own virtue by demanding the NHS must use this drug, costs are irrelevant.
Looking at the OLE 201 , they mention that they were giving the drug to patients for 60 months - according to my calculation this would be five (!) years. Assuming that the outcome showed no significant difference to a placebo, as reported on your first article on this drug, we can ask how much a 5-year course of drug application would have cost the NHS ... Clearly, Mr David Thomas cannot possibly have been aware of this cost. Even if we generously assume that the nice drug companies would reduce the cost, the sums are horrendous.
I think this is another attempt by Big Pharma to 'domesticise' a disease or illness by turning it into something which needs constant drug application, 'for life'. This is of course more profitable than researching solutions which would provide actual healing, in a once-and-done scenario.