Alzheimer Disease, A Rapidly Changing Field

Marwan Sabbagh, MD, Director Lou Ruvo Center for Brain Health, Cleveland Clinic

Marwan Sabbagh, MD

The past few decades have been quite difficult for clinicians treating Alzheimer disease, however, the field is rapidly changing and there has been substantial progress in understanding molecular and cellular changes associated with the disease’s pathology.

With an urgent need to develop new treatments, the industry has been moving forward in the monoclonal antibody space where there are currently 3 compounds continuing in phase III clinical trials, and the fourth, BAN2401, just announced results from its phase II clinical trial.

Marwan Sabbagh, MD, director, Cleveland Clinic Lou Ruvo Center for Brain Health, spoke with NeurologyLive in an interview about the current therapeutic landscape noting that many drugs and devices are in the phase III, a chance of hope and excitement for patients and clinicians.

Sabbagh also shared his thoughts on the amyloid hypothesis, adding that while many believe the amyloid theory is dead, he thinks it’s more nuanced because amyloid is important to the whole overall conversation, potentially affording the opportunity to see drugs approved through this pathway.

NeurologyLive: Can you discuss the current therapeutic landscape of Alzheimer disease?

Marwan Sabbagh, MD: It’s changing very rapidly and we in the last, say, 2 years had a big push for the monoclonal solanezumab, which was a monoclonal targeting monomeric Aβ with the idea that by clearing out amyloids, you would slow down the progression. It did not meet its prespecified endpoint and for the most part, for symptomatic dementia solanezumab has not moved forward. The reason for that is because the prevention trial that uses solanezumab A4 is moving forward and continues to move forward. In the monoclonal antibody space there are 4 compounds that are still moving forward, and again, the idea is they target amyloid and clear amyloid. Those are aducanumab, that’s the Biogen drug, crenezumab, which is a Genentech drug, and gantenerumab, a Roche drug—all continue to move forward in phase III clinical trials. New to the scene is BAN2401, which just announced their data about 2 months ago in the AAIC showing, a commensurate change in direction with amyloid clearance and clinical stabilization going in the same predicted direction.

Monoclonal antibodies for Alzheimer are still moving forward, monoclonal antibodies that are targeting tau are starting to pick up steam, and there are 2 that are now in phase II trials, AbbVie and Biogen.

Base inhibitors, which are oral anti-amyloid production oral medications, have not shown as much success as we would like. The Merck drug verubecestat did not meet its prespecified endpoints and I think for the most part has ended. The others in the class have had significant emphatic toxicity, and therefore I don’t see the base inhibitors making a lot of progress moving forward. The early study, which was a version of the A4 study, which was a prevention trial using a base inhibitor was stopped because of liver toxicity, and so, again, the class of base inhibitors are not moving forward.

In the last 18 months, we were also hot about a class of drugs called 5-HT₆ antagonists, there were 2 lead compounds: idalopirdine and intepirdine. One was the Lundbeck compound and one was the Axovant compound, but both failed to meet the prespecified endpoint of efficacy in their phase III programs, and for the most part that class of drug has been abandoned.

Another drug that has been looked at is the RAGE compound, this is Azeliragon. That drug didn’t meet some of the prespecified endpoints in their phase III study, but there is some efficacy of signal still, so I think the company is moving forward with more studies, and so that class hasn’t concluded its direction.

All these data I’m talking about are in the last 18 months, everything I’m discussing was not 10 years ago, this is very current. The point here is that there are many, many drugs and devices, for that matter, actually in the phase III space, and there’s still a cause for excitement and hope.

What are the value of biomarkers in this space, and which are specifically needed?

MS: That’s a very important question, very germane to the timing. Ten years ago, we would’ve said detection of plasma amyloid is unreliable, and we would have said you are dreaming if you are even trying to work on detection of plasma tau.

In the last year, there’s been huge traction around the concept of reliable detection of plasma amyloid that the ratio of Aβ40 and Aβ42 turned out to be a very good predictor of the disease process. There are now several companies working on reliable assays for plasma tau, and the reason there is a real hard push to peripheral diagnostics is that CSF testing is expensive, invasive and hasn’t picked up as much traction as we liked. Athena has owned that space for a long time, Roche and Fujirebio are developing CSF detection assay platforms and probably within the year we’ll see alternatives to the Athena platform for CSF detection assay. Ideas showed that there was at least in the preliminary data, some evidence of clinical utility for amyloid imaging in the clinic, however, it is still not reimbursed. Amyloid imaging has not become a common practice in clinical medicine.

The point is that there’s a huge area of unmet need on the diagnostic side, and peripheral diagnostics are moving forward because they can be far cheaper and far more efficient, so it’s getting a real hard look right now. At the AAIC there were many discussions about development of peripheral biomarkers.

Physicians need to know this shouldn’t be long-term, I suspect we could see peripheral blood type tests within 5 years, certainly, even maybe sooner than that. Additionally, physicians need to know what they’re all going to look like from a medical standpoint, they would kind of be like a prostate-specific antigen for a man or hemoglobin A1c, not inherently diagnostic, but detection of signal that would warrant further investigation.

What are your thoughts on the amyloid hypothesis?

MS: I like speaking to my peers and I’ve done a lot of web work, WebExs, video seminars and conference calls, and the reason I say this is because my field is changing so rapidly, but to most physicians they think everything is staying the same, and are just giving Aricept and assuming nothing’s changing, but that is absolutely not true.

Many people believe amyloid is early disease process, it is an early seminal event, overproduction or under cleansing of amyloid leads to a cascade of events, that leads to tau, neurofibrillary tangles, inflammation, excitotoxicity, so that the antecedent event to all the events that occurred later on is the overproduction or under cleansing of amyloid. There are species of amyloid that are toxic and accumulation of amyloid tend to be negative or deleterious.

People say the amyloid theory is dead, I think the amyloid theory is more nuanced. We can’t be reductionists and say we’re amyloid, we’re baptists and tauists, it’s not that simple. We know that in symptomatic dementia amyloid does not correlate well to clinical progression, tangles, tau, and synapse loss correlate better to symptomatic dementia.

We’ve been using drugs to target amyloid in symptomatic dementia and a lot of them have failed. The question is, is it because it’s the wrong target, or is it because we’re treating the disease too late, meaning the brain’s full of amyloid, there’s no point in trying to cut it out once your brain’s full of amyloid. I think a lot of focus is on using drugs that target amyloid in a more dynamic state earlier on.

We were really down on production or clearance, production meaning the base inhibitors that I talked about, or clearance meaning monoclonal antibodies that I talked about, as not working. The early generational drugs of bapineuzumab or solanezumab showed a discordance between signal efficacy and target engagement. Bapineuzumab showed very reliably you could reduce the amount of amyloid in your brain on PET scan but didn’t show a lot of clinical signal, probably because we kept reducing the dose. Solanezumab showed a clinical signal in the early studies but showed no evidence of cutting amyloid on PET.

The new generations of the drugs, particularly aducanumab and BAN2401 show directional concordance of reduction of amyloid correlating well with clinical stabilization. Amyloid is still important, still germane to the conversation, still a reliable target, still important to the whole overall conversation, and we still could see drugs approved through that pathway.

Transcript edited for clarity.