The promise of donanemab

At the AAIC 2021 conference earlier this month, Eli Lilly presented the results of the phase 2 trial of their donanemab Alzheimer's treatment.  This is the same trial we discussed here back in January.  For me, something interesting came out of their discussion.

Like aducanumab/Aduhelm, donanemab is a monoclonal antibody that removes amyloid plaques from the brain.  It's clear from the phase 1 and 2 trials that it does this quite effectively.  And so it might be a candidate for the same (controversial) approval process that brought aducanumab into the public spotlight.

As we said in Beating the Dementia Monster, amyloid plaques can be silently building in the brain for more than a decade before cognitive problems become evident.  Then there's a tipping point, where defective tau protein associated with tangles propagates through the brain.  This event coincides with the onset of measurable cognitive decline.  So plaque accumulation appears upstream of initiation of obvious tau pathology and decline, and it may be that removal of the plaques slows this process down.

Lilly was able to present some evidence that their treatment may have improved cognition among some test subjects.  But conditional FDA approval would still rest on the hypothesis that removing the plaques stops or slows progress of the disease in a manner that measurably improves cognition.  It's not clear that it does.  

Proving efficacy will require a phase 3 trial with well-managed data.  The FDA's conditional approval process would allow use of the treatment before the phase 3 trial if the phase 2 trial showed, like aducanumab, that amyloid plaques are effectively removed.

So what's special about the donanemab trial so far?  It's that removing the plaques was shown to drive down abnormal tau accumulation, and that it stayed down after donanemab was discontinued.

When a test subject was receiving the treatment, the presence of tau was measured.  When the level fell to that of a normal subject, they switched the treatment from donanemab to a placebo and continued to measure the abnormal tau.  They found that tau levels did not increase after discontinuing the treatment for at least a year, if at all.

But the big question remains:  Does lowering amyloid and tau burdens on the brain improve cognition?  For donanemab, maybe not, although the researchers are applying some analytical techniques to further understand what may have occurred.  But bear in mind that a phase 2 trial uses a relatively small study population.  It may produce inaccurate results due to statistical vagaries -- hence the phase 3 trial with a much larger study population.  

So will Aduhelm find a competitor in donanemab?  We shall see.