Authors: Jeffrey Cummings (Cleveland Clinic Lou Ruvo Center for Brain Health, NV, USA)
Jeffrey Cummings is a neurologist/clinical trialist and is the Vice Chair for Research in the Department of Brain Health at the University of Nevada, Las Vegas (NV, USA). He is also the Director of the Center for Neurodegeneration and Translational Neuroscience at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. Dr Cummings is extremely interested in drug development for treatments into neurodegenerative disorders, particularly surrounding treatments for symptomatic aspects of the disease, including cognition and behavioral disturbances, as well as disease-modifying approaches to the treatment of neurodegenerative diseases.
In this interview, Dr Cummings speaks to us about the current landscape around antibody therapeutics for Alzheimer’s disease, including clinical trial outcomes for various monoclonal antibodies and whether we should be shifting our focus away from the amyloid hypothesis.
1.What are the major challenges in developing antibody therapeutics for Alzheimer’s disease?
There are several different types of challenges. One is, what is the appropriate target for the antibody? For example, solanezumab was mainly focused on the monomeric form of amyloid-β (Aβ). We believe that bapineuzumab was focused primarily on the fibrillar or insoluble form of Aβ and that BAN2401 is focused primarily on the protofibril form. Thus, there is still uncertainty about what species of Aβ is the best target for a monoclonal antibody.
Another problem is the very low entry of antibodies into the brain – approximately 1% of all the antibody administered actually crosses the blood–brain barrier. We’re not exactly sure of how the peripheral dosing should be guided in order to achieve the central exposures necessary for therapeutic response.
There is also difficultly with target engagement. That is, how can we tell that the antibody is doing what we want it to do? Currently, we have good measures for the fibrillar, or plaque form of Aβ, and we do see molecules such as BAN2401 and aducanumab reducing the plaque burden in Alzheimer’s disease. However, we’re not sure that this is the best target. We have measures but we are not sure if these are assessing the aspects that are most critical to the disease process. Our ability to demonstrate the engagement of the target is limited by our currently available tools. I would say those three problems comprise major challenges to the development of monoclonal antibodies.
2.Thus far, results from Phase III trials with monoclonal antibodies for Alzheimer’s disease have brought rather disappointing results recently. In your opinion, what explanations might there be for these results?
I would say that they reflect the challenges that we have reviewed above. Solanezumab was focused on the monomer and we now think that the monomer may not be critical, particularly in patients who are already symptomatic. These patients have a fully developed burden of the oligomer species and insoluble plaques. Thus, reducing the number of monomers available may not be a good therapeutic intervention.
The most mysterious of all the failures is aducanumab and we have very little information – almost none – about why that molecule failed. We only know that Biogen (MA, USA) announced that it was futile to continue the trial. At present, we do not know whether this means it didn’t lower the plaque burden, or whether there was no improvement in the clinical sphere, or whether there was too much measurement variability because they had so many countries involved.
There are many possible explanations for why that study was declared to be futile and we don’t know that it was the biology of the antibody, or that of the disease, that determined the futility decision. So yes, we’ve had disappointments, but we’ve also had what looked like successes in the BAN2401 study. I think the BAN2401 trial was a very well-structured study in terms of being a large Phase II trial going through very robust dose-binding and using more sensitive outcomes than we’ve seen in other trials.
I believe we are seeing progress in trial methodology and I think that it is showing up as an improved ability to demonstrate a drug–placebo difference with these interventions.
3.Given these clinical trial outcomes, should we be shifting our focus away from the amyloid hypothesis?
My own view is that we have not yet exhausted the amyloid hypothesis or disproven it. Again, I would cite the BAN2401 data as a monoclonal antibody with an epitope on the protofibril that appears to be succeeding in reducing the fibrillar form of Aβ. We assume, though we have not proven, that it’s also reducing the oligomeric form of Aβ. It appears to be having a clinical benefit in terms of reducing the rate of progression compared with placebo.
I do believe that we should be expanding our repertoire of targets for both small molecules and for monoclonal antibodies. There are a group of monoclonal antibodies that are now being developed that are targeting tau, particularly extracellular tau, as we know the tau molecule spends time in the extracellular space as it goes in a prion-like manner from one neuron to the next. We believe that tau is vulnerable during that period, and of course, the antibody does not have to enter the cell, which is another attractive aspect about this target.
I am very much supportive of the idea that we are looking at anti-tau antibodies as well as anti-Aβ monoclonal antibodies.
4.In your opinion, where might the biggest use of antibody therapeutics lie for Alzheimer’s disease? For example, could it be more beneficial for people who are in symptomatic or pre-symptomatic stages?
I think this will depend on the target of the monoclonal antibody. For example, those that are directed at Aβ may well have their greatest utility very early in the disease – maybe even in the very early preclinical phase before a full load of fibrillar amyloid has been deposited in the brain.
Tau molecules on the other hand may well be used much later in the disease course because tau appears to be driving much of the cognitive change. Therefore, giving patients who are in the prodromal phase the tau antibodies, we might be able to prolong that phase and delay the onset of the dementia phase. I believe it’s possible that the tau monoclonal antibodies would have one stage of optimal utilization and the Aβ monoclonal antibodies would have another stage where they are optimally used.
5.What lessons can be learned from previous clinical trials going forwards?
In my opinion, learning from Phase II has been overlooked in some of the development programs. Stronger Phase II trials to understand better the biological activity of the monoclonal antibody, as well as the clinical directional changes, would help decision-making and might reduce the kind of resource catastrophes that we have observed in these failed Phase III trials. I would say one lesson is to understand the molecule and the biological effects of the molecule better before a Phase III trial is launched.
6.Where do you anticipate the field will be in 5–10 years’ time?
I believe we will succeed at this. I am encouraged by the BAN2401 results and by some of the early findings in the tau monoclonal antibodies. I would say we will have defined populations where monoclonal antibodies will be used and that they’re very likely to be used in conjunction with small molecules. For example, there has been a lot of thought into possibly reducing plaque burden with a monoclonal antibody and then following that with a BACE inhibitor, or a γ-secretase modulator, that would reduce the re-accumulation of the plaque. Thus, we would have an induction phase and a maintenance phase, much like they do in cancer therapeutics.
Clever combinations of antibodies and small molecules will be where we are in the next 5- to 10-year window that you have enquired about.
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.
Jeffrey Cummings has provided consultation to all the companies affiliated with the antibodies listed in this interview.
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