乌鸦传媒

Much of the discussion at the American Academy of Neurology annual meeting centered on a from Eli Lilly that announced positive results from the phase III TRAILBLAZER-ALZ 2 study, showing that donanemab significantly slowed cognitive and functional decline in people with early symptomatic Alzheimer's disease.

In this exclusive 乌鸦传媒 video, James Galvin, MD, MPH, of the University of Miami Miller School of Medicine, explains what clinicians and patients need to know about these promising results.

Following is a transcript of his remarks:

This was a phase III clinical trial testing an antibody against the amyloid beta protein, which is the main building block of Alzheimer plaque in the brain. And so what the company released was a press release announcing the positive results of this phase III study that showed significant slowing of the cognitive and functional decline in people with early symptomatic Alzheimer's disease.

They used an endpoint called the , which is a composite score. And this composite score has components of objective cognitive performance, like how people do on a pencil and paper test, and their activities of daily living. So it captures both cognition and function as a composite score. And that showed a significant slowing of the effects between the baseline and 18 months of the trial. That was quite impressive -- a 35% decline in that primary endpoint.

What was also important is that the other secondary endpoints also showed change. So there was a 36% decline in the Clinical Dementia Rating [CDR] Scale, which is sort of the gold-standard clinical trial tool, over 18 months. About 47% of patients actually showed no decline in that CDR sum of boxes. So that's a key measure of the progression of the severity of the disease. So nearly half the patients actually showed no change in their CDR sum of boxes between their baseline and 1 year later.

Fifty-two percent of the patients actually finished medicine, 72% by 18 months finished medicine. So they had cleared so much plaque that they actually stopped taking the medicine, which is really important because all of the other previous clinical trials, there was no stop point of the medicine. You basically are going to continue it forever, but donanemab, at least in the trial, was so effective at removing the plaque, that when they did repeat scans, there was no signal. So they were able to actually stop the medicine, which may have great value that there may be a time-limited period where people are treated.

And that's exciting because right now the best we know about monoclonal antibodies is that once you start, you're pretty much going to continue. There's not a clear stop point. But here, again, more than half, 52%, at 1 year had cleared, 72% by 18 months had cleared. So they no longer had to take the medicines.

There was 40% less decline in their activities of daily living. And this is also really helpful, 39%, so again, almost 40%, lower risk of progressing to the next stage.

So we put that all together, the topline sort of discussion. The medication met its primary outcome and had a significant slowing of cognitive and functional decline by a composite score. It showed a significant decline in a global measure, the Clinical Dementia Rating Scale.

Almost half of the patients actually never changed. And that's important because it's a degenerative disease. Half the people were able to stop the medicine at 1 year, 72% stopped the medicine at 18 months, because they had such complete clearance of the plaque. And then we also showed a specific slowing of functional decline and progression to the next stage. So the medicine met all of its primary and secondary outcomes.

And that's important because if you have to think about not just what's statistically significant, but what is potentially clinically meaningful to a patient. And statistics don't mean anything to people who are living with the disease. To the patient and to the family what's important is, is my disease gonna slow down? Am I going to be able to maintain my abilities for as long as possible? And how effective is the medicine at getting into the brain and doing what it's supposed to do?

And so here we had people who had significant slowing, half the people didn't change at all. They didn't progress to the next stage of disease, and it cleared almost all of the amyloid in the brain. So that's an incredibly successful trial.

And then when you put that in perspective of the other antibodies that have been tested and results have been discussed, what we now kind of know, putting it all together into sort of a bigger picture, is that these antibodies are effective at getting into the brain, whether the trial was successful or not. But it's not just removing the amyloid that's sufficient, you have to remove a lot of amyloid and you have to do it at a fairly quick rate in order to get the most robust clinical effect.

And so donanemab had a greater clearance than lecanemab [Leqembi], that's the ASI [Alzheimer Society of Ireland] product that was recently approved by the FDA for the accelerated approval, which had more clearance than aducanumab [Aduhelm], which was the original Biogen product that got accelerated approval. And all of those had more clearance than gantenerumab, which was a Roche product that . So even though it cleared amyloid, it had no clinical effect.

So you could sort of put them on a continuum that you have to remove a certain amount of amyloid over a certain period of time to see a clinical effect. And so that's been incredibly informative because that helps you think about, well what are the next generation of studies going to look like and what are the best approaches to designing that study?

So that's incredibly helpful. It just shows that you can learn something from successful trials, but you also learn something from all the other trials because now we know it's not just removing the amyloid, it's how much amyloid you remove, how quickly it's removed, how robustly it's removed. And that has a lot to do with the clinical effects that we can see. And again, I think that's a huge step forward in the field.

These things are not cures, they don't reverse the disease, and that may or may not ever happen, but we now have much better tools to aggressively treat the disease. And I think that sets the stage for sort of what's going to be the clinical approach to caring for people who are living with Alzheimer's disease.

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