A Promising Drug for Alzheimer’s Disease with William Klein, PhD, and Richard Silverman, PhD

[00:00:00] Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. An experimental drug called NU-9 discovered here at Northwestern University and approved for clinical trials for the treatment of ALS also improves neuron health and animal models of Alzheimer's disease according to a new Northwestern study published in PNAS. This discovery is giving scientists hope that the drug could be effective in multiple neurodegenerative diseases by addressing the underlying mechanisms of disease. Today I welcome the study's co corresponding authors, Richard Silverman and William Klein to talk about this discovery. Richard Silverman is the Patrick G. Ryan Aon professor of Chemistry and professor of Pharmacology, and invented NU9. Dr. Silverman previously invented the blockbuster drug Lyrica to treat nerve pain and epilepsy. William Klein is a professor of neurobiology and neurology at Northwestern and an expert in Alzheimer's disease and leads a pharmaceutical company that has a therapeutic monoclonal antibody to treat Alzheimer's disease currently and clinical trials. Welcome to the show. 

[00:01:24] William Klein, PhD: Thank you. 

[00:01:25] Richard Silverman, PhD: Thank you. 

[00:01:25] Erin Spain, MS: It is so nice to have you both here to talk about some really exciting developments in this drug in NU-9, the Dr. Silverman you invented here at Northwestern University. Can you take me back to the discovery of this molecule and the path to developing it and how it works? 

[00:01:42] Richard Silverman, PhD: We're talking, oh, 15 years ago actually, and another professor here at Northwestern, Rick Morimoto came by and said he was interested in protein folding. He was starting a collaboration with somebody in a small company who was interested in his assay, for protein aggregation, and wondered if I would be interested in doing medicinal chemistry for this project to try and find some molecule that would be important to inhibit proteins that aggregate and cause neurodegenerative diseases. And, the assay that he had specifically worked on was related to the disease, ALS, myotrophic Lateral Sclerosis. and so that's what we started on. And we had, what's called a high throughput screen. This is many compounds. It was 50,000 compounds that were screened in the Muramoto assay that had been converted to this high throughput format. and they looked for molecules that inhibited protein aggregation from a mutation that's known to cause And we got quite a number of molecules that did that. and in fact, too many. Uh, and so it was part of my job and another computational chemist to sort of hone down these. Numbers of compounds into something that was more manageable to modify structures and, and make something useful. And so between the two of us, then we're able to hone it down to three separate classes of structures that had multiple molecules in those classes that were active. And so we knew it wasn't just, you know, a one shot pony. It, it really was something that was reproducible. so that was my job. I had these three classes and I was then assigned, make them more potent, make them better. 

[00:03:48] Erin Spain, MS: If you're enjoying this episode of Breakthroughs, please share it with a friend. Now back to the show.  

[00:03:54] Richard Silverman, PhD: And so over a period of eight years, something like that, I had students and postdocs in my group m odify the structure. We couldn't do it by classical medicinal chemistry approaches where, you know, what the molecule's binding to that's causing this effect. We didn't know. What the target protein was because we discovered this through what this is called a phenotypic screen, where we're not looking for something to block a particular protein, but we're looking for molecules that prevent proteins from aggregating, and we didn't know why. We just wanted to inhibit the proteins from aggregating so that we could prevent the ALS. And so typically when you know what the target is, you can then get crystal structures. You can design molecules that have the right shape, the right structure and build from that. We were going blind, basically. I knew the structures were active and now we just had to do random modifications at first to see where on the molecule can you change it,, and make it better. And so then once we saw what parts of the molecule we could change, and we then started to put other groups on, and that's why it took so long to do that. And so then we ended up with three molecules that we felt were optimized and would be ready to move forward. And that's when we started to do pharmacokinetic studies to see are they metabolized rapidly? I. Are they not soluble? Can they cross the blood brain barrier? Because this is a disease in the brain. The molecule has to get into the brain, and so that was many. More years to hone the structures to something that then had the properties that will allow you to take a pill and then get it to where it needs to get, which is the neurons in the brain. And so we optimized those three classes and of the three classes, one seemed to be superior to the other two. And that molecule then is this molecule, NU-9, that uh, is the basis for that PNS paper you talked about. 

[00:06:25] Erin Spain, MS: NU-9. Just tell me about the name. 

[00:06:27] Richard Silverman, PhD: coming from Northwestern, I thought I've been here now 49 years, so I bleed purple. But the nine, strangely enough, in the paper that we published that had that molecule in it, it was the ninth molecule in the list. And so I figured, all right, let's go with that. 

[00:06:46] Erin Spain, MS: Lucky number nine. And this really ended up being more than potential, you were able to. Actually tests in animal models, and now it's been approved for FDA clinical trials for the treatment of ALS. Tell me where all this stands right now with that project. 

[00:07:02] Richard Silverman, PhD: Yeah, so, it's very expensive to do studies that the FDA wants to approve for clinical trials and then even more expensive to do the clinical trials. And so I started a company and licensed NU-9 from Northwestern into my company called AKAVA Therapeutics and so the compound then changed names when it went into the company. It's called in the company Akv nine. I kept the nine in that one too. And so we raised funds to do all the studies, the FDA wants to decide if it can go into humans and that took a couple of years to do that. And then we filed, uh, all the paperwork, with the FDA and, we had done lots of studies in animals for efficacy, how it, whether it works or not, and also whether it has the right pharmacokinetics, whether it can get to where it needs to be, and also toxicology. Because it has to be a safe drug, and we found that you can use really large doses of this in the animals, and it doesn't hurt them. That whole document was sent in and then approved. 

[00:08:21] Erin Spain, MS: So we haven't started the clinical trials yet, but this is all your ducks are in a row at this point. 

[00:08:27] Richard Silverman, PhD: Yes. All we need is the money to do that because now it's in my company and it's up to my company to raise the funds for the clinical 

[00:08:37] Erin Spain, MS: Well, there has been a lot of excitement about the potential of this drug. And Dr. Klein, I wanna bring you in because you're an Alzheimer's disease expert and ALS and Alzheimer's disease do share some important cellular and molecular mechanisms. Can you tell me about those similarities and what made you think that NU-9 might work for Alzheimer's disease too? 

[00:08:57] William Klein, PhD: Well, Rick made me think that ordinarily scientists are terribly skeptical and, you know, we're taught don't believe anything that you're not forced to believe. and Rick alluded to the fact that Nu 9 non can affect several different protein compounds that give rise to ALS and to me that was the real clue for going with his suggestion, let's try it for Alzheimer's too. So we had discovered, uh, quite some time ago, a novel toxin that now most people think is responsible for the onset and progression of Alzheimer's disease. It's a normal metabolite that, uh, to itself and is kind of like a hormone from the dark side. It's different from amyloid plaques that everybody knows about, but uh, it's evolving into the actual nasty culprit that's involved. so Rick suggested, why don't we. Test NU-9 to see if it blocks the formation of this compound. Uh, call it an amyloid beta ligament. It's about the size of a normal protein. 

[00:10:04] Richard Silverman, PhD: And that's an aggregate also, which made the connection. 

[00:10:08] William Klein, PhD: exactly. So, there's a PhD student in chemistry that worked between our two labs to collaborate in doing the cell biology and toxicology in my lab on Alzheimer's with the compound that Rick and his team had developed. And lo and behold, it was very exciting . If you subject these nerve cells, these, uh, which we can grow in a dish, to. The precursor, the stuff that does aggregate. Normally the neurons will take it out of the medium and inside their cells they will, uh, make the toxins because that's the tendency of this protein to self aggregate. And we have an assay to measure it. Interestingly, the uh, the way we measure it is with an antibody that also is named NU. So 

[00:10:58] Richard Silverman, PhD: That's really confusing. 

[00:10:59] William Klein, PhD: We came from different directions and ended up with, uh, the same names. We have NU-1 through NU-20. It turned out to be remarkably successful in these initial experiments, and we found that the mechanism which we're still chasing down for its absolutely precise molecular target was not exactly what we might have expected. It didn't block the formation of these aggregates but it accelerated the removal of them. So, uh, there's this process that's going on within the neurons that gets rid of garbage in essence. And, these. Toxins, these pre toxin precursors when they self associate, really slow down that process and that's why they tend to accumulate. But nNU-9, accelerates the basis for clearing it out. the garbage truck coming by three times a week instead of just one. and, the trash just never builds up in the cell. And, you've got some rescue going on. Then we go from there to animal models. And naturally you start in a test tube, then you work with cells, then you go to animal models. And we have animal models that developed pathology very much like Alzheimer's disease. And lo and behold, the NU-9 was terrific at blocking the accumulation of a beta, aggregates or these oligomers, in the brain. And they block the form of Alzheimer's pathology that is induced. So making the toxin not accumulate the effects of the toxin are no longer there. So it's a successful compound in our trials. 

[00:12:39] Erin Spain, MS: This was the PNAS paper. This was a small proof of concept study as you just described, but have you ever seen anything like this before in your work with Alzheimer's disease? 

[00:12:50] William Klein, PhD: What I think is that this is a very exciting molecule and as we study more about the mechanism, we can begin to see that it makes sense. There aren't compounds like it. But there's thoughts about the basic mechanisms that make sense in terms of what people had already established 

[00:13:10] Erin Spain, MS: So what happens next? You're already on this road to clinical trials with ALS, so now for Alzheimer's disease, what's the path forward here? 

[00:13:19] Richard Silverman, PhD: The first phase of clinical trials is with healthy subjects. And so you just wanna find out at what dose do you start seeing some side effects. And so you do a study with healthy subjects where you. Keep increasing the dose until they start complaining about something. And then, you know, that's, that's as high as you you ever wanna go. So that doesn't matter what the disease is because the safety is safety and that's what it is. So then it splits off to phase two with. Patients and you would have to then do two separate clinical trials, one with ALS patients and one with Alzheimer's patients. And then see what dose you need for each of those diseases. And then. You'd have the trial go for as long as you can and something like ALS Unfortunately, the these patients die very quickly. I think it's 90% are I. Dead within 10 years, 50% within five years. And so you can't have a, a normal long clinical trial. Your clinical trial is typically about six months because many of these patients will be dead in a year or two. And so you have to have a drug that's effective enough that you could see a difference between the placebo and the treated in a six month. Period. And so those are short trials. There also are not that many people with ALS, although you hear about it all the time. It's what's known as an orphan disease. There are less than 200,000 people at any given time in the US with. That disease, partly because they die so quickly so they don't accumulate a disease like Alzheimer's. However. There are millions of people that have that, and so you can run trials with many more people. And of course, the FDA then wants you to run trials with many people, and you can run it longer because you may not really see an effect in six months. You may need to dose for a couple years before you really start seeing. Differences. and so that's a much more expensive clinical trial, more people and longer time. And so you you have to separate those two. 

[00:15:47] William Klein, PhD: everything that Rick said is spot on. And with, respect to the Alzheimer's trials, we're still in some serious preclinical phase research and, uh, that's not in the cost, of hundreds of millions of dollars to do that. But, you know, given the current situation in federal funding, even something that's as promising and as NU-9 for preclinical research for Alzheimer's disease, is kind of stuck in the weeds. in, uh, in Washington DC. 

[00:16:17] Erin Spain, MS: What do you want the public to know about the potential of this drug? Why should people maybe be invested in seeing this move forward? 

[00:16:26] Richard Silverman, PhD: Yeah. I think as we've seen, in ALS, it's effective against mutations that are completely separate from one another. They're not related to each other. I. They work separately and now they work in Alzheimer's models. We wanna then try it on other neurodegenerative diseases. One of the things it does is improve the health of mitochondria. And so there are a lot of mitochondrial dysfunction diseases and so this could spread out into a lot of different neurodegenerative problems. And so this should be exciting, I think to more than just the relatively few ALS patients. This is something that I think could be useful for many different diseases. 

[00:17:15] William Klein, PhD: And the compound itself is close to. The bullseye is the common mechanism that unifies so many of these degenerative diseases. So the fact that ALS proteins, they're good proteins, but they've gone bad in Alzheimer's disease, you have good proteins that go bad this is a drug that can, affect, both can clear them both out when they go bad. 

[00:17:42] Richard Silverman, PhD: Well, I would say that this could be a game changer. Usually it's, you know, one drug per disease, and you change diseases and you have to change drugs because the scientists are focused on a single. Target that is important for that one disease. And then when you go to another one, that target may not be so relevant, so you have to find another molecule for a different disease, whereas this one is hitting. Whatever the target is, it's hitting pathways and mechanisms that are common to all of these diseases. And so, this really could affect multiple diseases, the same treatment. So from my view, the more we learn about NU-9 here, the more excited I get about it. And I think that kind of excitement is legitimate. 

[00:18:32] Erin Spain, MS: Well thank you so much Dr. Silverman and Dr. Klein for being on the podcast sharing this remarkable story. We can't wait to see what happens next with NU9 

[00:18:41] Richard Silverman, PhD: Thank you. 

[00:18:42] William Klein, PhD: Thank you for the invitation. 

[00:18:43] Erin Spain, MS: You can listen to shows from the Northwestern Medicine Podcast Network to hear more about the latest developments in medical research, health care, and medical education. Leaders from across specialties speak to topics ranging from basic science to global health to simulation education. Learn more at Feinberg. northwestern. edu slash podcasts. 

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Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

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The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

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The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

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Disclosure Statement

Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.