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Join Ken Blaker, a health care and technology consultant, and Cuong Do, a health care executive, as they shed light on the latest developments in combating these challenging conditions. From the recent FDA approval of Leqembi to promising anti-neuroinflammation drugs and genetic approaches, we uncover the cutting-edge strategies that could change the future of Alzheimer’s care.

Ken Blaker is a Los Angeles-based health care and technology consultant focused on medical devices and FDA compliance. As an author, Ken has written on a variety of topics, including treatments for neurodegenerative diseases, cancer research, and the opioid epidemic.

Cuong Do is a health care executive.

They discuss the KevinMD article, “Rising longevity and cognitive health: Navigating dementia and treatment.”

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Transcript

Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast and get CME for this episode by clicking on the CME link in the show notes. Today we welcome Ken Blaker and Cuong Do. Ken is a health care and technology consultant. Cuong is a health care executive; he’s the CEO of BioVie. Together we’re going to talk about the KevinMD article “Rising longevity and cognitive health: Navigating dementia and treatment.” Ken and Cuong, welcome to the show.

Cuong Do: Thank you, Kevin, for having us.

Kevin Pho: So I’m going to ask each of you to briefly share your story and journey, and then we’ll talk about the article. Ken, why don’t you go first?

Ken Blaker: Maybe I’ll put them together and start with my own experience of dealing with Alzheimer’s. I had an uncle who was a very prominent orthopedic surgeon in Philadelphia; people may still remember him, Marty Blaker. He was an incredible intellect, and at the end of his life, what I saw was that he descended into dementia. I remember sitting with him and him suddenly grabbing my arm and saying, “How do I know you?” This is somebody who, a few years earlier, could recite passages of books that he’d read 30 years before. At the end, it not only debilitated him; sadly, what affected me most was that it left him prey to some really unscrupulous people who abused his estate. It was a terrible thing to see. It’s a terrible affliction. His specific dementia was Alzheimer’s, and it gave me a great interest in the subject.

I’ve also written a number of things about health care over the years. What generated the article this summer was the full FDA approval of Leqembi, which is certainly a good thing. But it’s a drug that attacks the protein plaques in the brain, and it’s a fairly aggressive action within the brain. There are a lot of side effects, and what struck me is that it’s not by any means a cure, or a reversal, or even a stop of the progress of Alzheimer’s. When I go to the literature, what I see is a distinct relationship between Alzheimer’s and neuroinflammation. That’s been established for over 30 years. So the article was really about the fact that there’s a better way to go than aggressively going into the brain trying to clear up these plaques, when the better method, perhaps and hopefully, will be to clear up the source of those plaques, their cause. That gets into the science, which is why I invited Cuong to join as well, because he can certainly talk to the science of that much better than I can.

Kevin Pho: All right, so before we get into that, Cuong, just briefly share your story and journey.

Cuong Do: Thanks again for having me, Kevin. My background is that I spent 17 years consulting for McKinsey & Company, where I helped build the health care practice. Since then, I’ve been a serial chief strategy officer for large companies, including Merck and Samsung. I’ve been involved with BioVie for a very long time. I’ve been on the board of the company, shepherding it through a program in liver disease. Then, about three years ago, I orchestrated BioVie’s acquisition of an asset that I was convinced could become the first truly effective drug for Alzheimer’s disease. The last condition for the deal, from my own board as well as the seller, was that if I wanted to do this deal, I had to step in as CEO to oversee the development of the portfolio, because I was the one who had the greatest conviction and really understood what was going on. At that point in time I had just retired from Samsung and had a little more time on my hands, so I really had no choice but to step into this role. And I believe in this molecule. I believe in it so much that I took all of my compensation in equity instead of cash.

Kevin Pho: So, Cuong, tell us a little bit about this approach to Alzheimer’s, for those who may not have a medical background. What made you so convinced that this had the biggest promise?

Cuong Do: The medical community has known that Alzheimer’s has an inflammatory component for many decades. Frankly, no one has been able to figure out how to address it, right? Some people tried NSAIDs to see if they would work; they don’t. People tried anti-TNF monoclonals, like Enbrel and so forth, but those have their complications, and they can never cross the blood-brain barrier. So people kind of gave up on inflammation as being undruggable, and that’s why a lot of work has been done on amyloid. Frankly, when I started working in Alzheimer’s back in the late ’80s, it was all focused on amyloid.

Whereas I truly believe that chronic low-grade inflammation is the root of many bad things that start to go wrong in the body. When you have the presence of TNF-alpha, it triggers insulin resistance. It leads to the production of additional inflammatory cytokines and chemokines, which create additional inflammation. TNF-alpha drives the production of the amyloid precursor protein, so it gives you more amyloid, and it is also responsible for driving the kinases that phosphorylate tau into phospho-tau. So TNF-alpha is, in my mind, the starting point, the crux, the hub of many things involving Alzheimer’s disease.

Kevin Pho: So how far are we from the product? Where are we in the research cycle when it comes to this approach?

Cuong Do: Well, I hope to have much better news for the community later this year. Our drug candidate, NE3107, is a very unique molecule. It’s an oral drug that patients take twice a day. It freely crosses the blood-brain barrier, so it gets into the CNS, where it does its work. We are completing our phase 3 clinical trial right now. The last patient has already come in for his or her last visit, so we are now in the process of cleaning the data and getting everything ready in the database so that we can lock the database, start to analyze the data and unblind, and we hope to unblind and reveal the top-line data sometime after Thanksgiving this year.

If this turns out to be a positive trial, namely if we have an impact on cognition and if we’re able to reduce amyloid beta, well, frankly, that’s how Leqembi was approved, and that’s how Aduhelm was approved. So that may give us an opportunity to have a conversation with the FDA next year about the same accelerated approval while we conduct our confirmatory, second phase 3 trial. Is that likely to happen? I don’t know. I’d probably give it about a 25 percent probability that we can get accelerated approval, because remember, this mechanism is different. It reduces inflammation; it doesn’t attack amyloid directly. So the jury is out on whether we will see a reduction of amyloid beta later this year. Mechanistically, we should expect to see some, but how much, we’ll have to wait and see.

Kevin Pho: So, Ken, when you were telling us that story about your experiences and what you saw with the decline of someone with Alzheimer’s, in general, what kinds of treatment options are currently available to patients in cases like these?

Ken Blaker: What I’m aware of is certainly drugs like Leqembi, which do remove some plaque and slow down the disease. Most of the other treatments I’m aware of, and certainly what was used with my uncle, were cognitive enhancement techniques, or drugs that have an effect on improving memory per se. But of course, none of them actually reverse the disease. What they hopefully do is slow the decline. They’re recommended for anybody with early signs of memory loss. As we age, it’s a common thing, but why is it a common thing? That’s the other question. Why does the body age? As the body ages, one of the effects we certainly see, along with loss of elasticity in other parts of the body, is decline in the brain.

Kevin Pho: And, Ken, as your uncle was going through these more classical, traditional treatments, did he have an appreciable improvement in his symptoms?

Ken Blaker: Not that I saw. No, I didn’t see improvement, and I’m not really in a position to gauge whether it slowed his decline, because the question is how quickly he would have declined if he hadn’t had those treatments or exercises.

Kevin Pho: Now tell us about Cuong’s approach to Alzheimer’s. What specifically resonates with you?

Ken Blaker: I think it’s the fact that it goes early into the cycle of the development of the disease. Rather than treating symptoms, it’s attacking closer to the cause. That resonates with me because I think it’s an inherent problem we have in medicine: We don’t know a patient has a problem until they have it, so medicine has often backfilled by treating symptoms and not always getting to the cause. It’s hard to get to the cause. It’s certainly the goal of everybody in medicine and in medical science, but it’s a very difficult process, and when the patient finally comes in with whatever illness, the symptoms are the initial focus.

Cuong Do: I think part of what happened is that the medical community really got enamored with single-pathway treatments, because around this time, as you may recall, we really started to conquer cardiovascular disease. In cardiovascular disease, you can pinpoint a single pathway. If you want to tackle hypertension, block ACE; it’s very simple. If you want to tackle cholesterol, it’s very simple: Block HMG CoA reductase, which gives us the statins. I think we brought that same mindset over to Alzheimer’s research, thinking that there was a single pathway, a magic bullet that could be used. Alzheimer’s and many CNS diseases are far, far too complicated for that.

If you look at the neuropathology, we first focused on amyloid beta, because that was the first thing we saw, and then we started looking at tau. But over the decades of working in this area, there has not been a single drug discovered that can reduce the plaques and the tangles and reverse the cognitive decline in Alzheimer’s. Within the last decade or so, I think the community has gotten more accustomed to the notion that plaques and tangles themselves may not be the toxic agent causing the cognitive decline, but that in fact they are inflammatory in nature. They contribute to the inflammation that’s going on, but the reality is that many other things contribute to inflammation, too. That’s why I believe that if you look at the monoclonals that reduce the amyloid buildup, you only see a slowing of the cognitive decline, because in reality all you’ve done is reduce the inflammation caused by the amyloid plaques. You haven’t done anything about the inflammation driven by other factors.

That’s why I believe our drug candidate, NE3107, has the potential to be very different: because we block inflammation at the central node. I say that because all of the inflammatory stimuli out there rely on one common characteristic. They activate something called ERK, the extracellular signal-regulated kinase, which in turn activates NF-kappaB, nuclear factor kappa B, and you need those two to be activated to produce TNF-alpha. That’s where NE3107 works. It blocks the activation of ERK and NF-kappaB and therefore blocks TNF-alpha. So for us, we don’t care where the inflammatory stimulus comes from; we block them all at the central node.

Kevin Pho: So of course we’re talking about NE3107. Over the last few years, there have been several advances when it comes to Alzheimer’s treatment. There’s Leqembi; there’s aducanumab. Cuong, give us your perspective on what we should look for going forward when it comes to Alzheimer’s treatment.

Cuong Do: I think Leqembi really gave the community hope, the first ray of hope in a long time, because up until Leqembi was approved, patients were just continuing to decline. Leqembi is one step forward in slowing the decline, and I’ll let the clinicians figure out which patients can really benefit from it and which ones cannot, but at least it’s a tool out there. And I think that going forward, the community will see that we need to treat Alzheimer’s the same way we treat cancer. No one would ever think of treating a cancer patient with a single drug nowadays; it’s always a combination. Leqembi is the first such drug, and I think additional drugs will come to the market.

I think NE3107 could be the first of a completely new class of molecules that, instead of trying to remove the plaques and tangles that have accumulated in the brain, tries to prevent the inflammation that adds to the plaques and tangles to begin with. As we saw in our phase 2 trial, patients in a very short period of time saw a reversal of their cognitive decline, not a slowing but a reversing of the cognitive decline. We believe the reason is that we reduce the inflammation, and we reduce all the downstream knock-on consequences of that inflammation. By doing so, we allow the body to help restore itself. We allow microglia to help clear the accumulated plaques and tangles, and we essentially restore neuronal health. We improve neuronal health because we increase oxygen availability in the brain and we increase glucose availability in the brain, and that just helps neurons to be healthier.

Kevin Pho: We’re talking to Ken Blaker and Cuong Do. Ken is a health care and technology consultant, and Cuong is the CEO of BioVie. Together we’ve been talking about the KevinMD article “Rising longevity and cognitive health: Navigating dementia and treatment.” I’m going to ask each of you to share some take-home messages with the KevinMD audience. Ken, why don’t you go first?

Ken Blaker: Dr. Alzheimer first published his work on the disease almost 120 years ago, and I think that in the last 30 years we have finally started to understand the mechanisms of inflammation within the brain that have led to Alzheimer’s and other neurodegenerative diseases. I think this is a time of great hope, and Cuong has laid out the science very well. The idea that this is a reversible disease is certainly something possible today, and it wasn’t until very, very recently.

Kevin Pho: Cuong, we’ll end with your take-home messages for the KevinMD audience.

Cuong Do: I think the critical thing to take away from this conversation is that there are alternative mechanisms at play in the treatment of Alzheimer’s. We have all been focused on the amyloid hypothesis, because that’s been the first, the longest and the most researched, and it has now led to a drug like Leqembi, which gives us hope. But we hope to show later this year, when the top-line data for NE3107 read out, that by focusing on what is, in my mind, the ultimate driving factor, inflammation, and by reducing inflammation, we can have an impact on cognition as well. If we’re able to show that, I think we will open up a second front on what is a terrible, terrible disease that affects 6 million Americans and well over 50 million people worldwide.

Kevin Pho: Well, thank you both for sharing your perspective and insight, and thanks for coming on the show.

Cuong Do: Thank you for having us.