BioTech Nation ... with Dr. Moira Gunn

Dr. Jim Brown from DURECT talks about their clinical trials for Alcohol-Associated Hepatitis, a condition for which there is no approved treatment.

What is BioTech Nation ... with Dr. Moira Gunn?

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Dr. Moira Gunn:

Well over a 100000 people each year check into emergency rooms with alcohol associated hepatitis. It's not surprising that during the pandemic, this number jumped. There is no approved treatment, and frankly, the prognosis is grim. Doctor Jim Brown is the president and CEO of DURECT. When I spoke with him, DURECT's potential treatment for this condition had just entered its phase 2b clinical trial.

Dr. Moira Gunn:

And now, doctor Jim Brown.

Dr. Jim Brown:

It's a big problem. And, unfortunately, during the pandemic, we've seen an increase in the United States of alcohol consumption, that's about 30%. And this has been associated with as well, hospitalizations due to alcohol have increased by about 50%. And the most common reason for this is a a disease called alcohol associated hepatitis.

Dr. Moira Gunn:

Mostly when I think of hepatitis, I think of hepatitis c or hepatitis b. You've got a virus. You've got this is entirely caused by drinking alcohol?

Dr. Jim Brown:

It is. It's an inflammatory process. Actually, it's much more than that. Very involved process. But it's an acute assault on your liver that's brought on most typically by binge drinking.

Dr. Jim Brown:

And, and the patients present with, with fever. They have yellowing of the whites of their eyes known as jaundice. They're tired. They'll often have nausea and vomiting, and they always have a history of recent heavy alcohol consumption or, binge drinking.

Dr. Moira Gunn:

Is there a particular age group that's that's targeted here?

Dr. Jim Brown:

You know, it's it's interesting. There are about a 130,000 hospitalizations per year for, for alcohol associated hepatitis, which we abbreviate as Ah in the United States. And about half those people are between the ages of 40 to 60. Many of them will have cirrhosis, but it's really interesting and this population is on the rise. There are more than 20% are younger people.

Dr. Jim Brown:

There are people in their twenties thirties. They don't have cirrhosis. But there is just more of a culture out there in, in the millennial generation of going out drinking on Wednesdays Thursday nights, and it and can add up to some people in some circumstances.

Dr. Moira Gunn:

Is there a standard of care for this? Is there a way to deal with this once they're in the hospital?

Dr. Jim Brown:

Unfortunately, there really isn't, and and it's a deadly disease. The mortality of patients with Ah is 26% at 1 month and it's about 30% at 3 months and there is no approved therapy today. They will use abstinence, of course. Standard of care will be supportive care. Sometimes they'll use steroids, but they've been shown not to improve survival.

Dr. Jim Brown:

And in fact, unfortunately, the treatment for Ah has not improved, since the 19 seventies. In in the last 50 years, there's been no change in the survival of these patients.

Dr. Moira Gunn:

Now from Durex perspective, what actually goes wrong in the body?

Dr. Jim Brown:

You know, we've all heard about DNA. You know, it's the molecule and the nucleus of all the cells in your body. It's effectively the blueprint of your body. You inherit the DNA from your mother and your father. You have the same blueprint in every cell in your body, but think about all the different cell types tissues that you have.

Dr. Jim Brown:

You know, you've got hair, skin, muscle, bone, and that's because the epigenome allows for this DNA blueprint to be read. But But if you look in the nucleus of a cell, only about 5% of what's in there is the DNA. The other 95% is the epigenome, which is effectively the brains of the operation that allows those genes to be expressed. Back when I was in school, we were taught that the the structures inside the nucleus cells were called histones, and they were there for structural basis. And now we know they're actually way more than that.

Dr. Jim Brown:

They are driving the reading of the blueprint as it were.

Dr. Moira Gunn:

They they're not just holding up the roof.

Dr. Jim Brown:

No. Not at all.

Dr. Moira Gunn:

Not at all.

Dr. Jim Brown:

And in fact, with a disease like Ah and with many other diseases, you get dysregulation of this epigenome. And so you have certain genes turned on and turned off and and then you can move the cell towards unfortunately, disease states can move the cells towards death and, and, you know, the outcomes that you get with the disease like Ah.

Dr. Moira Gunn:

So when you say dysregulation, you mean, normally, the the 95%, the the epigenome there is operating on the 5% DNA. Everything's working out great. But when there's a problem, it starts going awry. It's either not working or it's doing things it shouldn't do, and that's called dysregulation.

Dr. Jim Brown:

That's absolutely right. And we, until now, have known very little about it. We do use, medicine that changes the epigenome in the field of oncology to kill cancer cells. What you do there is you go in and you disrupt the epigenome and the cells will die. But with, what we're doing at Direct, we have an opportunity to actually repair the epigenome to bring it back more towards normal, and that has allowed for a a greater understanding of, of this component of biology and medicine.

Dr. Jim Brown:

It's fascinating.

Dr. Moira Gunn:

I'm assuming with alcoholic hepatitis that your liver isn't working anymore. So we're talking about this dysregulation inside liver cells. So, when this goes awry, we're talking about liver cells that aren't functioning anymore. And then, I guess, your liver isn't functioning anymore?

Dr. Jim Brown:

That's absolutely true. And it starts with the liver and then, unfortunately, goes to other organs. But just, you know, to focus on the liver cells themselves right now, the literature has, told us that what happens in these Ah patients is the epigenome becomes dysregulated and, through a process called hypermethylation. It's very specific. We don't have to get into that.

Dr. Jim Brown:

But the reality of it is these major pathways in these cells are shut down. And so a lot of genes are turned off that shouldn't be and genes are turned on that shouldn't be. And you end up going down the process of cell death and dysregulation, which not only damages the liver, but eventually extends to the kidneys and the lungs as well and get multi organ damage.

Dr. Moira Gunn:

Now I know at Direct, you're working and have been working for some time with a molecule called DUR 928. What is that? What does it do? How does it relate to Ah?

Dr. Jim Brown:

Yes. DUR 928, it's a naturally occurring regulatory molecule that's found in all of us, actually. In fact, we've looked at it in in many different species of mammals from, things as small as mice in Hampshire's all the way up to monkeys, dogs, pigs, and humans, and we all have the same concentration in our body. It's fascinating in that it is made in association with the mitochondria. It travels to the nucleus, and it helps maintain homeostasis as it were of the epigenome and cellular function, not of the liver not only of the liver but of many many other cells.

Dr. Jim Brown:

So what we've been able to do with the U R 928 is show in a number of cell culture models and a number of, of other models that it's able to restore function of the cells. And we've also now been able to use it in Ah patients and show that it improves the function of, these patients as well.

Dr. Moira Gunn:

Now you've gone through phase 1. We know it's safe for humans, and you did a 2 a, that initial study. And according to my notes, 19 patients just to try to see what happened. What what was that study about? What did you do with those 19 patients?

Dr. Jim Brown:

Well, first off, as, you know, we've been talking about, Ah is a horrible disease. 26% of Ah patients die within a month and 30% die within 3 months. In our first study, as you talked about, we had 19 patients and they all lived over that 28 day study. And I think what's equally as impressive as that is 14 of these 19 patients left the hospital within 3 days of their first dose and their only dose of 928. So that speaks to some of the epigenomic component of this.

Dr. Jim Brown:

We're restoring the function of the epigenome of the nucleus of these cells, just a single intervention in 14 to 19 patients. And if you think about it, most of the time, those patients would be in the hospital for weeks and, unfortunately, a third of them would never go home. And in this case, 14 to 19 walked home before day 4.

Dr. Moira Gunn:

So what's your next your phase 2 b, I guess, would be the next one. What are you doing there?

Dr. Jim Brown:

It's a trial in 300 patients, with severe Ah. We're testing 2 different doses of 928, and we're also testing against, the standard of care, which is, you know, supportive care of these patients, a 100 patients per group. And the endpoint of this trial will be survival at 90 days.

Dr. Moira Gunn:

Now no one signs up for this trial in advance. No one. No one says I'm gonna go on a binge, but I wanna get all the paperwork out of the way. And yet these are extremely sick patients. How do they how do you find them, and how do they how are they able to give their consent to this, entry?

Dr. Jim Brown:

That's a really good point. You know, we have explored the potential of duronite28 in a number of acute diseases, things like sepsis or acute kidney disease, and we can talk more about these later. But the reason we selected Ah for our first indication is because unlike a a stroke, for example, where if, I had a stroke and I had a twin brother who had a stroke and there was a 12 hour delay between myself getting in there and my brother getting in there 12 hours earlier, he's gonna have a better outcome just because of supportive care. So you had a lot you have a lot of patient variability in in stroke trials and sepsis trials and kidney trials, and you see these with with, you know, very difficult, paths to approval for drugs in these areas. With Ah, the disease is a very insidious disease and and the people die over a month or 2 months or 3 months, but it's a very slow process.

Dr. Jim Brown:

So that's, the circumstance that is different with Ah. It's a slow insidious process that if one can intervene, potentially one can make a difference and save someone's life.

Dr. Moira Gunn:

Now what other diseases or conditions are caused by these kind of problems with the epigenome that might be helped with DUR 928?

Dr. Jim Brown:

Yes. The diseases we're looking at and where we have tested this in various models and shown that it helps is in in diseases like acute kidney injury or in diseases like sepsis where you have endotoxin, super high amounts of endotoxin, or things like overdose of of Tylenol or acute pancreatitis. These are all cases where 928 has been shown to work. In some of these cases, we don't know yet whether there's hypermethylation. So this is a case where the drug is maybe leading the the the way forward in the in the path for under better understanding of the disease.

Dr. Jim Brown:

It's it's kind of a hand in glove thing. We we understand in some cases there's hypermethylation. We can move in with DUR 928 and help treat the epigenome. In other cases, we know DUR 928 helps in this, at least in this animal model, should be able to help in humans. And then we'll go in there and then find out whether or not there is hypermethylation.

Dr. Moira Gunn:

I think this is fascinating. Usually, we think there's a condition. Let's give the person the drug. Let's see if it cures what it is you're saying. Sometimes just giving the drug gives us information about how this is whole system works.

Dr. Jim Brown:

Absolutely. Yeah. This is a this is a very different way of thinking about medicine. You know, I was raised and and and and went through school during a time when when drugs were much simpler. You would simply have a drug like a like a statin, for example, that that inhibits one of the enzymes in making cholesterol.

Dr. Jim Brown:

So if you have high cholesterol, you give this drug, it reduces the production of, you know, of cholesterol at that one point, but you get buildup of of, you know, predecessor molecules and you get side effects and all the rest of these kind of things. With DUR 928, we're changing the whole set point of a cell. And, because of that, which is another fascinating thing about this, we've really not seen much at all in the way of side effects with this drug in the most seriously ill patients one can think of, And, and that's been fascinating. It's been a very safe drug to use.

Dr. Moira Gunn:

Now very interesting for me is that you're a doctor of veterinary medicine, not an MD, not a PhD in microbiology or all the normal folks that walk through my door here. Why is a background in veterinary medicine a good thing here?

Dr. Jim Brown:

I think it's for me, it's worked out really well, obviously. I've I've I've it's been a great career and I've really enjoyed it. I I still have my license to practice veterinary medicine here in California and I enjoy doing that. But the reality of it is it gives me, I think, really good insight because I can look at animal models of certain disease states and, and look and see how it might apply to human medicine. And, and we're all you know, we like to think of ourselves in such a different way as as humans, but we're all animals.

Dr. Jim Brown:

Right? Humans are are, you know, 5 to 6 foot primates typically walking around. You know, and with veterinary medicine, they get the great opportunity to be able to understand the the physiology and and disease circumstances, of primates, but also of, you know, horses and ruminants and, dolphins and all the different kind of species that are out there. So it's a it's a it's a great multiple, you know, approach to, to disease. But yeah.

Dr. Moira Gunn:

Well, I really appreciate you coming in, Tim. I hope you'll come back and see us again.

Dr. Jim Brown:

Oh, thank you so much, Moira. I really appreciate the opportunity, and I look forward to it, anytime.

Dr. Moira Gunn:

DURECT's phase 2b clinical trial is now complete with what doctor Brown describes as compelling results. They anticipate having their end of phase 2 meeting with the FDA shortly and to begin discussions on the design for the phase three trial. Doctor Jim Brown is the president and CEO of DURECT. More information is available at durect dotcom. That's durectdirect.com.