World news – The physician-scholar continues to play a key role in major Alzheimer’s research

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Clinical studies show encouraging results for a second investigational Alzheimer’s drug – and Brown University, Butler Hospital, and Rhode Island Hospital were again heavily involved.

Dr. Stephen P. Salloway is Martin M. Zucker Professor of Psychiatry and Human Behavior at Brown University and Professor of Neurology at Warren Alpert Medical School. (Photo: Nick Dentamaro / Brown University)

PROVIDENCE, RI [Brown University] – Two major advances in Alzheimer’s research were made possible by the work of Rhode Island researchers – including Dr. Stephen Salloway, Professor of Neurology and Psychiatry at Brown University, who is also responsible for neurology and memory aging program at Butler Hospital in Providence.

Salloway will be celebrating 30 years at Brown this coming summer and has been on throughout his tenure focused on Alzheimer’s disease. Four years ago, he led recruiting and imaging for a clinical trial of a promising biogenic drug called aducanumab, which is currently under review by the U.S. Food and Drug Administration for approval as a potential therapeutic for Alzheimer’s patients. </ This month, Salloway is co-authoring a New England Journal of Medicine study of an Alzheimer's drug by Eli Lily and Company called donanemab. The study, which was conducted at 56 research sites in North America, including two in Rhode Island, found that the use of donanemab in patients with early-stage Alzheimer's disease resulted in improved cognition and ability to perform routine activities.

Salloway , who works at Warren Alpert Medical School in Brown and is affiliated with the Carney Institute for Brain Science, shared what the test results mean, how the drugs are related, and what role Rhode Island is playing in Alzheimer’s research.

This Study is a Phase II trial of a new antibody called donanemab that targets and helps remove amyloid plaques in the brain. This treatment is for people with early-stage Alzheimer’s disease who have either mild cognitive impairment or mild dementia. Fortunately, the drug showed substantial reductions in amyloid plaque and also slowed memory loss on tests of memory and daily function. It is very encouraging to see that the drug may have the intended effects.

Tau-PET imaging was used to determine eligibility for the Donanemab study, the results of which were recently published in the New England Journal of Medicine were. Brown researchers helped develop amyloid and tau tracers. Only people with moderate dew uptake (like the picture above left and a milder version of the middle picture) were included. (Pontecorvo, Brain 2019)

One innovation is the use of new imaging technologies. Positron emission tomography (PET) tracers, some of which we co-developed at the Butler and Rhode Island hospitals, have been used to more accurately classify the disease in terms of changes in the brain. All study participants had to be amyloid-positive above a cutoff and then also have a moderate tau level for the first time, which is another marker for the disease. The thought was that in the earlier stages of the disease it would be better to lower the amyloid as it is then that it builds up. And if a patient has advanced levels of tau, they may be less responsive to treatment.

Another new thing about this study: After the PET scan showed that the amyloid levels were lowered to a more normal range treatment was discontinued while patients continued to be monitored. Previously, once we have tested such antibodies, we will continue treatment each month until the end of the study.

There are some biochemical differences in that they target different components of the amyloid plaque molecules. But they have the same effect: in low concentrations, they cross the blood-brain barrier into the brain and bind to amyloid plaque. They stimulate the immune system to break up the plaque, and then the plaque is removed by the vascular system.

We looked at the same stage of the disease in both studies. Only people who were amyloid positive participated with aducanumab; We did not use tau as an inclusion criterion as in the Donanemab study. The participants in the Donanemab study may therefore be more inclined to have a milder level of pathology. There will be a wider range in the aducanumab study. There may be people with advanced tau pathology.

The results of the two studies look pretty consistent: both drugs lowered amyloid and had some advantage in slowing memory loss. It is encouraging that this treatment mechanism has the clinical benefit that really was our primary goal, namely to show that we can target a key component of Alzheimer’s disease that is associated with clinical improvement or stabilization.

Donanemab is located is currently in a phase III study in which a larger number of participants will participate. It’s a crucial study to hopefully replicate and expand on the results we saw in Phase II. And if the results are positive, this drug will be submitted to the FDA for approval.

The development process has had its ups and downs, but we’ll hear in June whether or not aducanumab will be approved. I personally have had 65 people on this drug, some of them for more than five years. There is a sizeable group that does better than expected. Hopefully in the future we can be more specific about who is most likely to respond to treatment: this is one of the advances in the Donanemab study, and using tau-PET as a marker of tau formation could be a useful predictor of that Response to this type of amyloid-targeted treatment. I am encouraged by these results from the Donanemab study and have a good feeling about aducanumab.

If aducanumab is approved, it would be the first disease-modifying type of treatment for Alzheimer’s to target a core pathology. We hope to be able to offer patients a new treatment this year. It will open a door for us to provide some biological foothold in the battle against Alzheimer’s that we can build on and improve upon in our research here at Brown and elsewhere. I’m very excited about this and look forward to the opportunity.

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