Donanemab slows cognitive decline in early Alzheimer’s disease

Much of the discussion in American Neurological Association Annual Meeting centered on press release Eli Lilly and Company announced positive results from the Phase 3 TRAILBLAZER-ALZ 2 trial showing that donanemab significantly slows cognitive decline in patients with early symptomatic Alzheimer’s disease.

in this exclusive Today’s Medpage James Galvin, M.D., MPH, of the University of Miami Miller School of Medicine, explains in a video what clinicians and patients need to know about these promising results.

Below is a transcript of his remarks:

This was a Phase III clinical trial testing antibodies to the amyloid beta protein, a major component of Alzheimer’s plaques in the brain. So the company issued a press release announcing positive results from this Phase III study showing a significant slowdown in cognitive function and functional decline in patients with early symptomatic Alzheimer’s disease.

They used an endpoint called Integrated Alzheimer’s Disease Rating Scale, which is the composite score. This composite score then includes components of objective cognitive performance, such as performance on pencil-and-paper tests and activities of daily living. Therefore, we obtain both cognition and function as a composite score. And it showed a significant blunting of effect between baseline and 18 months of the study. This was very impressive, with his 35% reduction in the primary endpoint.

Also important was the change in other secondary endpoints. Therefore, the clinical dementia rating decreased by 36%. [CDR] An 18-month scale is a gold standard clinical trial tool of sorts. In fact, about 47% of patients showed no reduction in her CDR total on the box. Thus, it is an important measure of the progression of disease severity. That is, nearly half of the patients had no change in her CDR total on the box between baseline and his 1-year follow-up.

In fact, 52% of patients finished the drug, and 72% finished the drug by 18 months. So they removed so much plaque that they actually stopped taking the meds. This is very important because all clinical trials to date have had no point at which the drug should be stopped. It’s basically going on forever, but donanemab was so effective at clearing plaque, at least in trials, that repeat scans yielded no signal. So they were able to actually stop the drug. This is considered to be of great value in that people have limited time to receive treatment.

This is interesting because what we know so far about monoclonal antibodies is that once started, they are almost always sustainable. There is no clear stopping point. But even here, more than half of his 52% had cleared after a year, and 72% had cleared by 18 months. So they no longer need to take medicine.

Decline in activities of daily living decreased by 40%. This is also very helpful. At 39%, almost 40% less risk of moving on to the next stage.

So we put it all together and had a topline kind of discussion. Medication met the primary outcome, significantly slowing cognitive decline on the composite score. It showed a significant decline in a global scale, the Clinical Dementia Rating Scale.

In fact, almost half of the patients did not change at all. This is important because it is a degenerative disease. Half of the people were able to discontinue the drug at 1 year and 72% were able to discontinue the drug at 18 months because the plaque was completely removed. It also showed that functional decline and progression to the next stage were specifically slowed. That is, this drug met all primary and secondary outcomes.

And this is important because we need to consider not just what is statistically significant, but what is potentially clinically meaningful to patients. And statistics mean nothing to people living with the disease. The important thing for patients and families is whether my disease progresses slowly. Will I be able to maintain my ability for as long as possible? And how effective is the drug in getting into the brain and doing what it’s supposed to do?

And here are the people who slowed down significantly, and half the people didn’t change at all. They did not progress to the next stage of the disease, and nearly all the amyloid in their brains was cleared. So this is an incredibly successful endeavor.

And if you think about this in terms of other antibodies that have been tested and their results are being discussed, what we now know is, putting it all together in kind of a big picture, these antibodies are: Brain, whether the trial was successful or not. However, just removing amyloid is not enough, and to have the most potent clinical effect, a large amount of amyloid must be removed, and it needs to be removed at a fairly rapid rate.

Therefore, donanemab showed better clearance than lecanemab [Leqembi]that’s ASI [Alzheimer Society of Ireland] product that was Recently Approved by FDA For early approval with approval prior to aducanumab [Aduhelm]which is a Biogen original product, fast approval. And they all had more clearance than Roche’s product, gantenerumab. failed a clinical trial. Therefore, even if amyloid was removed, it had no clinical effect.

So we can put them on a continuum that a certain amount of amyloid must be removed over a period of time to see clinical efficacy. This is very informative. Because it helps us think about what the next generation of research will look like and what the best approach is for designing that research.

It’s very helpful. This just shows that you can learn something from a successful exam, but you can also learn something from every other exam. This is because it is known that not only the removal of amyloid but also the amount of amyloid removed, the speed of removal, and the strength of removal are important. And that has a lot to do with the clinical effects we can see. Again, I think this is a big step forward in this area.

These are not cures and do not reverse the disease. It may or may not actually happen. But we now have much better tools to actively treat this disease. And it will prepare us for what will be a clinical approach to caring for people living with Alzheimer’s disease.