Following on from our previous two posts 

We look further into the “Core” Phase II study 201, which enrolled 856 people with early Alzheimer’s Disease (AD). Of these, 180 went on to participate in the OLE (Open-Label Extension) phase, which lasted up to 6 months plus three months for follow-up.

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We have seen that Lecanemab (even in high doses for up to 18 plus 3 months) made no difference compared to placebo to the primary efficacy outcome of the study: the Alzheimer’s Disease Composite Score (ADCOMS). Again, apologies about the pandemic of acronyms, but it’s ain’t us guv; it’s the pharma!

And one more thing: ADCOMS was chosen as a primary outcome by the manufacturer, not by us or the regulator. You may be interested to know that the many funders of the group who created ADCOMS includes Eisai Ltd and nine of the thirteen authors are or were employees of Esai. 

Here again, the tabular view of the evidence development programme from the Japanese regulator PMDA review of the Monoclonal Antibody (MAB) evidence development plan:

We have also discussed the study 201 basis of power calculation: a simulation of the efficacy of Lecanemab based on “assumptions” of efficacy which would make even Covid modellers proud (sorry, Bird F word, now oh no sorry again, Dengue+monkeypox modellers)

So it doesn’t work for ADCOMS compared to placebo.

As in all trials and decisions to use an intervention, the trick is to have reliable information on the trade-off between benefits and harms. Since the 201 results do not appear miraculous, let’s look at the harms.

We would have liked more detailed definitions, but we have to rely on the Japanese PMDA report.

Here’s a summing up of the Serious Harms from the trial:

Because of the randomisation scheme, the denominators in each arm are still small. 

The events are so bad that these poor people drop out with nasty stuff like brain swelling, infusion reaction (a general term that can range from mild malaise to anaphylaxis), cerebral microhemorrhages and atrial fibrillation (which had already been picked up in the phase I study 104). 

In the OLE phase, up to 20.6% of participants, including placebo recipients, had an infusion reaction, but only 42 out of 180 participants were from the placebo arm. There may be more of this stuff, but it's impossible to tell without looking at individual case notes.

Taken together the data appear to show a dose response relationship. Let’s leave one of the founding fathers of modern trials to explain what that means:

From this, you can see a dose-response in adverse events: the more MAB, the worse it gets.

Based on this Phase II trial so far, would you like your 80-year-old dad to have 60 months’ worth of Lecanemab at the knockdown price of 21,000 GBP per annum?

This is the series' third post on the wonder MAB Lecanemab for Early Alzheimer's Disease (AD). We are trying to make things easy to understand, as 23 SKIDOO likes. However, the regulatory documentation (which reflects the pharma submission supporting the licensing application for Lecanemab) is littered with acronyms, such as 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 possible—these acronyms do not play a casual role in all this. 

The phase 3 trial will be the next topic.

Readings

Hill, Austin Bradford (1965). "The Environment and Disease: Association or Causation?". Proceedings of the Royal Society of Medicine. 58 (5): 295–300. doi:10.1177/003591576505800503. PMC 1898525. PMID 14283879.

Wang J, Logovinsky V, Hendrix SB, et al. ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trialsJournal of Neurology, Neurosurgery & Psychiatry 2016;87:993-999.