Just five months ago, an early result from an Alzheimer clinical trial generated a lot of buzz: the anti-amyloid antibody donanemab seemed more promising than previously failed agents. The result of the Phase 2 study was published this week, and sadly did not meet the authors’ own specific expectation (and trial design assumption) of a six point advantage in the test iADRS. The agent did achieve a three point advantage, of unclear significance according to the authors; the editorial calls the trial “encouraging.”
A few details: 257 subjects, about half received donanemab, the rest had placebo. In the treatment group of 131, 40 had an adverse event that led to discontinuation of the med (vs. 9 placebo); 20 had an adverse event that led to the discontinuation of the trial (vs. 6 placebo), but these were not thought to be significant. 35 of the treatment subjects (vs. 1 placebo) had a drug-induced syndrome called ARIA-E (basically brain edema detected on imaging, seen in this class of agents).
The editorial is by Dr. A.I. Levey from Emory: “…Although encouraging, these findings, which amounted to a 3-point difference on a scale ranging from 0 to 144, barely showed significance (P=0.04), and the clinically relevant secondary outcomes of dementia severity, cognition, and functional abilities all failed to show treatment effects….”
The result curves show that both groups of subjects did worse on all test score measures, more so in the placebo group, and neither group stayed stable or improved. PET amyloid scans were dramatically “better” in the donanemab group, but that group also ended up with more MRI brain volume loss (tissue shrinkage).
One might be encouraged by at least four things: that the primary outcome was achieved (with the caveats above); that molecular biologists could design an anti-amyloid monoclonal that is different than others, perhaps more plaque-specfic; that the sponsor and investigations had the fortitude to carry out the trial at all, especially during the pandemic; and then they wrote up their results in a timely fashion for publication. And for nerds, the investigators apparently included a plan for a Bayesian appraisal of the data from the gitgo, even though this time it didn’t come to much, different than the ad hoc appraisal reported for another agent.
The result curves are reminiscent of Kaplan-Meier survival estimate curves in oncology, with an initial hint of difference that nonetheless shows overall decline.
But “encouraging”? For AlzheimerGadfly, who appreciated the science and the effort, it was still disappointing. There’s a bad joke that old oncologists heard a lot: “the clinical trial was a success, too bad the patient died!” One certainly doesn’t want that in AD therapeutics.
Perhaps a change away from the amyloid hypothesis is more encouraging: Dr. J. Cummings reviewed some non-amyloid approaches to AD therapeutics, including “cognitive enhancers.” Maybe they could not only stop the decline in cognitive skills but somehow help restore them. Wishful thinking? One guesses that other anti-amyloid and BACE inhibitor investigators had similar aspirations as they started their trials [The donanemab study actually had a combination arm with a BACE agent, but those subjects were removed from the report.]
As usual, those of us familiar with cognitive decline will need to wait and see.