Alzheimer Disease, a Global Problem

Jeffrey Cummings, MD, ScD

With several emerging therapies in the pipeline for treatment of Alzheimer disease and its symptoms making their way through stages of development, the excitement around potential treatments are evident.

For Jeffrey Cummings, MD, ScD, director, Center for Neurodegeneration and Translational Neuroscience and director emeritus, Cleveland Clinic Lou Ruvo Center for Brain Health, he anticipates 2019 to be a remarkable year for Alzheimer disease therapeutics with the first approval since 2003. While the approval will occur in China and will not be available in the United States or Western Europe, Cummings explains that Alzheimer disease needs to be thought of as a global problem.

Cummings explores other potential therapies in the pipeline for Alzheimer disease that excite him and the community such as monoclonal antibodies and drugs targeting neuropsychiatric symptoms in an interview with NeurologyLive.

NeurologyLive: What emerging therapies are you most excited about for Alzheimer disease?

Jeffrey Cummings, MD, ScD: Let me start by saying something about the agents I'm most excited about and then we can talk a little bit more about the whole range of agents that are in play.

I think this is going to be a remarkable year for Alzheimer disease therapeutics. I do expect an approval, the first since 2003, for a new Alzheimer therapy. It will occur in China and the drug will not be available in the United States or Western Europe, but it's likely to be available in China and throughout the Asian countries. The name of the drug is GB971 (Green Valley Pharmaceuticals) and I believe it met the Chinese standard for approval, which is slightly different than the US standard for approval, and I believe it will be approved later this year. This is a real sea change because as I mentioned, we haven't had a drug approval anywhere in the world since 2003 and so this is an important next step in terms of Alzheimer disease therapeutics. I believe they will have to conduct additional trials to have a completely convincing portfolio that this is an effective agent—I know that they are planning a global trial that will include the United States.

I think we have to see the world as global, we have to see Alzheimer disease as a global problem and if a country develops a potential solution, I think we all have to rejoice in that.

There are other drugs in the pipeline that are very promising—I would say the monoclonal antibodies are very promising. These are drugs that are given intravenously and we have several drugs now that have been shown to lower the level of amyloid, or toxic protein in the brain, and to provide a clinical benefit and so those are not approved drugs yet but they are in either phase 2 or phase 3 which means they are fairly along the development pathway and they look better than any drugs we have seen so far—so we're very excited about those.

Another development that I'm really excited about is that we're seeing more innovation in clinical trials and I think part of our problem in developing therapeutics is that our design optimization has not been as good as it should be. We're following the lead of cancer and we're doing things like adaptive clinical trial designs that was used with one of the monoclonals’ and we're also using more sensitive instruments because we're studying more mild patients. If patients have very little wrong with them when we start the therapy, then, of course, we have to have more sensitive instruments that can pick up the drug/placebo difference, and that's finally happening. A new tool called the ADCOMS was used in one of the trials and I think will be used in more of the trials because it did appear to be more sensitive to change in these very mild patients.

We're excited about what's happening both with the immunotherapies and with some of the other non-immunologic therapies, particularly at GB971 molecule.

Finally, I would say that there are several drugs being pursued for the treatment of neuropsychiatric symptoms in Alzheimer disease and I think this really important work because the neuropsychiatric symptoms are so disabling in these moderate and severe patients. There are several trials for agitation, there's a trial for psychosis, and there's increasing interest in sleep disorders in Alzheimer disease, so both on the symptomatic side of controlling the symptoms and the disease-modifying side of drugs that improve cognitive symptoms or slow that the decline, we're seeing reasons for optimism.

What are your thoughts on biomarkers in the space?

I think the biomarkers are really so important because without a biomarker you're essentially just shooting in the dark when you give a patient a drug and hope for a clinical benefit without knowing that you have actually affected the biology of what's causing their symptoms. It's very important that we have biomarkers to inform drug development and eventually to guide the use of these medications.

The biomarkers are coming along very nicely, there's a new approach to Alzheimer diagnosis called the ATN framework, A being amyloid, T being tau, and N being neurodegeneration. This framework is being used more broadly to both diagnose Alzheimer disease, to follow Alzheimer disease over time, and to capture drug/placebo differences in clinical trials. In the original framework, they specified some measures of A, some measures of T, and some measures of N, and even this year, we have seen the progress of more biomarkers that measure one of these features such as a blood measure called neurofilament light (NFL) and also blood measures of amyloid, the amyloid protein in the blood, using new, more sensitive techniques that appear to be very promising.

The biomarkers are progressing, and they are enormously important in terms of being able to advance a therapeutic agenda.

Which pathology do you think plays a bigger role in Alzheimer disease?

I think the answer to that question might be linked to where the patient is in the course of the disease. Very early amyloid is the change in the brain that we can identify, and it is likely that amyloid is a good target in, for example, patients who do not yet have symptoms but who are beginning to accumulate the amyloid in the brain.

On the other hand, later in the disease course tau changes seem to be highly correlated with the changes in cognition, implying that if we could stop the spread of tau in the brain, we could stop the progression of the symptoms. Patients who are symptomatic are going to need cognitive enhancers and those are later in the disease stage in mild, moderate, and severe forms of dementia.

One of the things that we are learning is that this is not going to be a one size fits all or one target is uniformly best throughout the disease, but we have to think about the evolution of the disease, the clinical stage of the disease, and match our therapies to the biology of the patients in these different phases of the illness.

*Jeffrey Cummings, MD, ScD, is a paid consultant for Green Valley Pharmaceuticals.

Transcript edited for clarity.