Dr Jeffrey CummingsJeffrey Cummings, MD, ScD
Despite significant advances in the community’s understanding of the pathophysiology and clinical presentation of Alzheimer disease, there is still a great need for safe and effective treatments.

Jeffrey Cummings, MD, ScD, director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health and vice chair of the department of brain health at the University of Nevada Las Vegas, spoke with NeurologyLive to discuss several therapies that he’s been following for treatment of Alzheimer disease, including cognitive-enhancing agents and disease-modifying therapies, as well as treatments for neuropsychiatric symptoms.

Cummings highlighted that treatment of agitation and psychosis are very active areas in Alzheimer disease research currently, as this is an urgent unmet need that affects the quality of life of both patients and caregivers.

NeurologyLive: Given recent investigational drug failures, what are some of the ongoing drug targets that you feel are especially promising?

Jeffrey Cummings, MD, ScD: Amyloid plaques are one of the central findings in Alzheimer disease pathology. We know that the plaque is the end product of a process going from a monomer, one molecule of amyloid, to an oligomer which are multiple molecules of amyloid joined together, to the plaque which is the final insoluble form of the amyloid protein.

Different amyloid drugs target the different species of amyloid along this continuum. We have drugs such as base inhibitors that reduce the production of the monomer, and, for example, elenbecestat is one drug that is currently in a clinical trial for the treatment of Alzheimer disease and it acts by reducing the monomer.

There are drugs that address the oligomer, so BAN2401 is a monoclonal antibody that addresses the oligomerized form of Aβ, there's gantenerumab which addresses the insoluble form of amyloid and may address some of the soluble forms as well, some of the oligomers, so there are drugs addressing the amyloid continuum from the monomer to the plaque.

Now we've had many disappointments with anti-amyloid therapy but there is in each case a concern that we were too late in the process, that we underdosed the patients, or that there were aspects of the trial which allowed us to miss seeing the drug/placebo difference. Each trial, although a negative outcome has occurred, has taught us something about how to do better trials, and we still believe that the amyloid target is worthy, that we think there should be an increase in the repertoire of targets that we're testing, and many, many different kinds of mechanisms should be tested to find optimal treatments for Alzheimer disease.

There's a great need for both cognitive enhancing agents on one side and disease-modifying agents on the other. Disease-modifying agents intend to slow the progression of the disease and cognitive enhancing agents intend to improve patients who are already cognitively impaired to a higher level of cognitive function. We are seeing progress in both of these domains.

On the disease-modifying side we have base inhibitors that were testing like elenbecestat, we have monoclonal antibodies like gantenerumab and BAN2401.

On the cognitive enhancing side, one of the agents that we've seen make progress lately is GV-971 a drug that has been developed in China and in a report recently was shown to improve patients cognitive function of the baseline, so we feel that there is progress being made in both modification of the disease course and drugs that potentially could improve cognition.

When I think about the drugs in the pipeline, the monoclonal antibody BAN2401 is particularly interesting, I think, because it used a novel trial design with a Bayesian dose adaptive design, I like that because it's very patient centric, it allows patients to be assigned to the dose that is most likely to succeed—if I were in the clinical trial, that's the dose that I would want—and then there was innovation in terms of the outcome, so the ADCOMS (the Alzheimer's Disease Composite Score) was used to determine whether the drug was successful or not in creating a drug/placebo difference and that's a sensitive measure and I think represents progress in developing tools that are appropriate to the population being included in the trial. There was also a change in several of the spinal fluid biomarkers in that trial as well as a reduction in amyloid and a reduction in a rate of decline on the clinical measures, so I thought that was a good repertoire of innovation and observation that now allows that drug to be progressed into phase 3—so I'm keeping an eye on BAN2401.

GV-971 is a drug that was developed in China, in preliminary studies and in a phase 3 study in China, it improved patients’ cognitive function above baseline. We have seen very few compounds that will do this, so again, that compound is under review in China, it could be available to part of the of the world and if a global trial is pursued and succeeds, then of course it could be a new drug as a cognitive enhancing agent for the treatment of Alzheimer disease. These are 2 compounds that I find of interest, but there are so many interesting drugs in the pipeline that people should have optimism that we're going to find something for our patients.

How is the field addressing the unmet need in treating agitation?

Treatment of agitation is one of the very active areas in Alzheimer disease research now. This is an urgent unmet need that affects the quality of life of patients and the quality of life of caregivers. There's a lot of work in this area using the new IPA definition of agitation, which has been able to define trial populations better and therefore to move clinical trials ahead in an accelerated way.

Drugs that are being tested include brexpiprazole, cannabinoids, AVP-786, which is a combination of deudextromethorphan hydrobromide and quinidine sulfate, AXS-05, a combination of dextromethorphan and bupropion, as well as a study of escitalopram in agitation, and several others, so this field has really opened up in terms of looking at new mechanisms and new ways of treating agitation in Alzheimer disease.

Are there any treatments in development for psychosis that you’ve been following?

Psychosis in Alzheimer disease has been a difficult problem to control and there are no drugs approved for the treatment of psychosis in Alzheimer disease. There's a very interesting trial with pimavanserin for the treatment of dementia-related psychosis and I find this particularly interesting because there are several types of dementia included in the trial including Alzheimer disease, dementia with Lewy bodies, frontal temporal dementia, and vascular dementia, so this is widening the spectrum of dementias included in a single trial that takes the assumptions that a drug is acting on a final common pathway across different disease types and I think that's a very interesting hypothesis. In addition, this trial is interesting to me because it's a randomized withdrawal trial, so patients come in with identified psychosis and everyone gets treatments, that’s so important for caregivers, everyone gets treatment, then the responders are randomly withdrawn from treatment after a 3-month treatment period.

We know that we want to get patients back off of drug as soon as we can, so that's also consistent with best practices, and then we see whether there's more relapse of psychosis in the group that is taken off of the drug compared to the group that continues on the drug. It's a really great design and I think it’s patient friendly and we're looking for more patient centric drug development mechanisms as a field because our patients are our allies in drug development, and we need to make sure that we're putting their interests first.

Transcript edited for clarity.