Episode Transcript
[00:00:00] Speaker A: Foreign.
[00:00:16] Speaker B: Welcome to the Few and Far between podcast. I'm your host, Chris o'. Brien. Some say the difference between wisdom and intelligence is that intelligence involves knowing, but wisdom involves doing, applying knowledge, experience and empathy to build new ideas such as innovations in clinical research. My guest today has leveraged his experience as a veterinarian and his many years in the medical device industry to create a new treatment for one of the deadliest diseases you've never heard of, as he puts it. Jim Brown, dvm is President and CEO at the Direct Corporation, a late stage biopharma currently focused on the development of epigenetic therapies for alcohol associated hepatitis or aah. In today's episode, Jim takes us along on his journey from the importance of the pet owner relationship to his veterinary practice, to his work at ALZA on on a titanium implant to treat prostate cancer, to his Eureka moment and FDA Breakthrough designation for the treatment of aah.
Along the way, Jim and I explore the mentor mentee relationship, the key differences in running clinical trials in the US versus Europe, and how the most important thing in drug development is people. I hope you enjoy this episode and find some words of wisdom that you can take back to your own company. Okay, let's start the podcast.
Jim, welcome to Few and Far Between.
[00:01:38] Speaker A: Thank you, Chris. It's wonderful to have an opportunity to catch up with you.
[00:01:40] Speaker C: I've been looking forward to this conversation on a couple of levels.
I was talking with someone the other day about wisdom. The difference between wisdom and intelligence. And wisdom comes to us usually through lots of hard won experiences. And I know you have your share of stories there, but let's.
[00:01:56] Speaker A: Unfortunately that's true.
[00:01:58] Speaker C: Well, let's go back in time to the initial spinoff from Alza Corporation. Will you tell us a little bit about how what you were doing kind of there and then what led to a spin off and kind of what happened?
[00:02:09] Speaker A: Yeah, so what I was doing at that time is we had developed a little osmotic pump that is about the size of the tine of a fork. So a very small little pump that we had developed to deliver a drug to treat prostate cancer. And it actually was implanted under the skin and delivered the drug like a slow continuous infusion for a year. So pretty amazing technology.
It was driven by a process of osmosis. So the engine in it was table salt, sodium chloride and it had a little teeny piston. So imagine a system about this long, very thin in diameter that is made out of titanium that just gives you a very slow ejection over a Year's period of time. And in fact, we calculated that that piston moved about the same rate that the San Andreas fault is moving.
[00:02:56] Speaker C: Wow, that's very cool. So the piston is discharging once, is that right? It's kind of very slowly.
[00:03:01] Speaker A: Yes. The system slowly squeezes out the drug and the drug is delivered and then at the end it's removed.
[00:03:07] Speaker C: Yeah, very cool. Okay, so there you are, working on drug delivery and what happens?
[00:03:11] Speaker A: Well, you know, my career. I'd spent the majority of my career in the pharma industry actually on new chemical entity discovery. I'd been at Syntex for more than 14 years and had been involved with a number of teams that had gotten drugs to the marketplace. And so that was really exciting and wonderful opportunity. Then I had a chance after Roche acquired Syntex and move over to Alzen, developed this technology that we call Duros.
[00:03:31] Speaker C: Did you feel at the time. Sorry to interrupt you there, but did you feel at the time, because you'd been part of teams that successfully brought drugs to market, that that was kind of a reasonable expectation, I think. Talk to people in some cases who've spent most or all of their careers to date, even significant careers, without actually getting a drug approved.
[00:03:47] Speaker A: I suppose, yeah, we had wonderful success, really good teams. Been able to be a part of. Yeah. And brought more than half a dozen drugs forward. So, yeah, that seemed like the norm. Right. And in reality, it's. It's a very different. It could because times change and the industry changed and everything else. But yes, that those things did change.
[00:04:04] Speaker C: Okay, so anyway, I interrupted you though, so there you are. And what's the kind of inciting incident that causes you to think of spending this out?
[00:04:11] Speaker A: Yes, we were, but we had a number of opportunities that we wanted to develop for the Duros technology. We had the concept of putting a catheter on there. And you can imagine with a system that small, the catheter is small. The fact the catheter was made out of nitin, all the same material that they make stents, you know, cardiovascular stents, out of highly malleable metal. But the diameter of those catheters was that of a human hair. So very, very fine internal diameter. Really small stuff. Interesting stuff from an engineering standpoint. And so we were looking to deliver those to specific areas, the brain stem and different pieces. And so at the time, though, also was. Was moving more and more to a strong commercial entity and. And eventually ended up selling themselves to JJ and so dollars that were put to R and D. If you look at the multiple of the company, they were probably better spent for the shareholders, keeping those in as profit and advancing the company that way. And so what we did is we worked with the board at Alza and spun direct out of the company and started up.
[00:05:05] Speaker C: Was that a controversial decision or was that sort of obvious? You know, we're trying to maximize.
[00:05:09] Speaker A: No, it was mixed within the senior management team. Certainly that's always going to be the case. Right. Some people want to keep everything together, but others realize that in order to grow. And really what was the most important was both the chairman of the board, Dr. Alejandro Zaffaroni, who started actually Syntex, and Alzen, a number of other companies here in the Bay Area, and Ernie Mario, who was the CEO at the time. They both supported doing this, and so they were able to move it through the board and allow us to spin out and be free.
[00:05:36] Speaker C: Got it. Now, you just mentioned Dr. Alejandro Zeffaroni, and I know you've talked about lessons learned from him. Will you share a couple of those?
[00:05:44] Speaker A: Yes, a couple of them. One was when I was first, you know, talking to him about what we might do, spinning out the company and the like, and he told me one thing. He said the most important thing in drug development, in the biotech and starting a biotech company is the people. He said, just as within real estate, you know, it's the location, location with this, it's the people. He said the technology is going to be available. You'll be able to find some technology. And money markets come and go, but typically money can be. Can be found, but can be found. Having a good team is really what it's all about. And so that's been a core of what it's been a good fortune for me to be able to have as. As we've gone through these more than 25 years here. Direct as well.
[00:06:25] Speaker C: Yeah, I guess people's initial vision for what's going to happen, what kind of assets you're going to develop, can change quite a bit. It feels to me like. That feels to me like a classic young entrepreneur's play to say, like, I've got the magic bullet here. And you're saying, I think it's more complicated than that.
[00:06:39] Speaker A: And yeah, it definitely is. And it's about the team you have, because inevitably, whatever magic bullet you're looking to develop, you're going to run into some snags along the way and may actually have to change direction entirely. And if you've got the right people around you and with you, the right team Then you can make those adjustments and continue to move forward.
[00:06:57] Speaker C: Jim, how important do you think mentorship and being exposed to somebody who's done that kind of work before was for you or is in general when people are looking to start a biotech company?
[00:07:07] Speaker A: I think it was very important for me and Dr. Zaffaroni and Dr. Mario both served in that form. And I think it's extremely important going forward for anyone to be able to have someone who's gone before. As you said, this wisdom is hard earned. Right. And it's getting kicked in the gut and having to start when you think you can't and just go back down to the bottom and crawl your way back up and all those kind of things. And that that's what mentorship can give you, that guidance, that perspective, that there will be a dawn and things will get better and you have a chance to move forward. But also at the good times, it keeps you grounded. I remember when we went public, we were so proud and happy that, you know, we've been able to take the company public. And we called Dr. Zaffroni to tell him, you know, yeah, yeah, hooray, we made it, we did it, we're so happy. And he said, congratulations, boys now. Which was a funny statement to make in general because there were no boys in the room, there were women and men, but it was just his perspective. He was an interesting guy, but he said, congratulations. Now you've taken monies from funds that support widows and orphans. What are you going to do now?
[00:08:05] Speaker C: That's great, that's great. The journey's far from over.
[00:08:08] Speaker A: Right. It's just starting. And now you've taken money from people who are counting on returns on those. And so you've got that responsibility.
[00:08:15] Speaker C: Yeah, I guess that's right. That a good mentor is both counseling you humility on the ups and courage and resilience on the down.
We all need sort of both of those things.
[00:08:24] Speaker B: I'm going to back us up in time a little bit because you have.
[00:08:26] Speaker C: A slightly non traditional background. It's a medical background, but in veterinary medicine. So how did you get started? What did you like about veterinary medicine? Let's talk a little bit about that first. And then I want to talk a little about how that brought you into drug development.
[00:08:37] Speaker A: Sure. I've always had a love of biology and life. Right. And a desire. I was a zoology chemistry undergraduate and went up to UC Davis to go to veterinary medicine and I selected veterinary medicine over human medicine. At the time, it was actually more difficult to get into vet school than it was to get into medical school.
[00:08:52] Speaker C: Interesting.
[00:08:52] Speaker A: It was just the way it was. And. But the reason I selected veterinary medicine was the variety of what one could do in a day. In human medicine, even back when I was younger, it was becoming much, much more truncated and specialized. And now it certainly is that way. You know, people just are specialists in one specific organ system or procedure, even on the surgical side. So it's definitely very highly selective. And you want that when you go in to have a specific surgery, you want someone who has done it many, many times and brings that experience and wisdom to.
But from my perspective, I love the opportunity to be able to do surgery. I could do a cesarean section, I could treat, you know, dermatology cases, see puppies and kittens in the evening, maybe there'd be a trauma hit by car or something, like that dog that would come in and see you have a trauma case as well. So all of those things were fascinating and wonderful and I really enjoyed that a lot. But as I was in practice, and I still have my license and still intend one day to continue to do that on a full time basis again, I began to realize that what I was doing was, you know, you start with treating your patient in front of you, but in reality, you're treating the owners of the patient. Yeah. And that came out really in a strong way for me when I was treating an older cat for a woman who was in a rent controlled apartment that had changed ownership and so her current cat was grandfathered in, but any new pets would not be. And so, and that was very important to her. And this pet was, this cat was extremely important to her because her husband had passed away. She had one child, a son who had been killed in Vietnam at the time. And so she was, you know, she was all on her own. And this cat was everything to her from a family standpoint. And so it became so critical. And I realized, I'm treating the cat, yes, but I'm really helping her. And so I started thinking about how could I go beyond that. And so that led me back into. I had worked for sibo, which was a diagnostics joint venture between Syntex and Marion between my undergraduate and when I went to vet school in my last year or so of undergrad. And I decided to go back and start working on developing medicines and, you know, having an influence beyond what one person could do.
[00:10:53] Speaker C: So that's really an interesting moment, isn't it? Because at that point, you are an expert in your field, you have a practice, you have a business, you have a bunch of expectations, yours and those of other people that you work with. And you decided, I'm going to pivot.
[00:11:06] Speaker B: What ended up being a pretty important.
[00:11:07] Speaker C: Pivot in your life, I guess, right?
[00:11:09] Speaker A: It really was. But it's made for me from my perspective, it's added a lot to my life. It's added dimension and color and experience and, and all the things that make a life what it is. Right. Is an opportunity. You know, we're here, we're all going to live and die. And from my perspective, it's all about wanting to try and leave things a little better than you found them. Right. And so that's really kind of the focus that I've always had.
[00:11:31] Speaker C: I love that.
[00:11:39] Speaker D: Hello there, this is Nicole Raleigh. We'll return to the rest of this episode shortly, but I just wanted to introduce you to the Farmer Forum podcast.
Hosted by me, the Pharma Forum podcast provides a conversational domain for timely on trend insights into the life sciences sector, specifically the pharmaceutical industry.
Each episode invites top thought leaders on the front lines of innovation in their respective fields who share their expertise on subjects ranging from clinical trial transformation and diversification to AI in drug discovery and development, as well as pricing policies and commercialisation and more. The Pharma Forum podcast can be found on Apple Podcasts, Overcast, Spotify, Pocketcasts, Podbean, and pretty much wherever else you download your other podcasts from. Thank you for listening. And now back to the episode.
[00:12:42] Speaker C: Okay, let's now focus on direct and drug delivery first and then we'll talk about how you guys get into drug development after that. So you spin the company out with an initial focus entirely on drug delivery mechanisms, is that right?
[00:12:55] Speaker A: Yes, that was. The focus was on the Dura system and some others. We had designed a technology that could be injected under the skin that would release drugs as well. We brought in different technologies and we also were developing an abuse deterrent version of, of a narcotic that could be taken so it couldn't be crushed and snorted or extracted with alcohol, things like that. And so a little bit safer, you know, from, from that. This was a whole host of different approaches that we were taking. But as time went on, the drug delivery industry became less important to the healthcare system in general. People weren't as interested in. Now I say people, I mean the system. The system was as interested in efficiencies, taking something once a day versus twice a day or a seven day patch versus the three day patch or even the abuse deterrent. The government seemed Very interested in it, but at the end wasn't quite so. And so we ended up going back to where I started in the industry in those 14, 15 years I'd spent at Syntex developing new drugs, new chemical entities, and started to look around for new opportunities. And we had the very good fortune of having an MD, PhD working for us. And she, her job was to be kind of a scout and to look around for opportunities. And she discovered one in Larsugo, Sterile. And that really changed the fortunes of direction.
[00:14:09] Speaker C: So she comes to you and says, hey, I think I've got something interesting here.
[00:14:13] Speaker B: Is that right?
[00:14:13] Speaker C: Like, what does that actually look like?
[00:14:15] Speaker A: Yeah, really, it was, it was interesting. She had looked into this and it was actually a professor of hers from her medical school. She had gone to medical school in Shanghai, which is probably the best medical school in China, and she was the number one student there. And so was interacting, was able to. Her part of her responsibilities was interacting with faculty. And her biochemistry professor was the faculty person who discovered this drug. But this was 20 more than 20 years later. He contacted her and said that he thought he'd made a breakthrough. And so she went out, met with him, came back and discussed it. Her husband was a researcher at Stanford at the time and he said, this is either some of the most impressive science I've ever seen and the most impressive fraud I've ever seen.
[00:14:56] Speaker C: Right, right. If true. Amazing. One of those things. Yeah.
[00:14:59] Speaker A: And so then, you know, she looked at it a little more and then she came and saw me and we talked about it. And I had worked at Syntex for those years and Syntex had started their roots, literally with a root. They had started in the steroid space by extracting steroids from precursor steroids from the barbasto root, which is a large yam that people in Central and South America eat. And they were able to bring progestins and estrogens and make them by extracting from this yam, you know, in kilogram amounts. And so they changed the whole industry and allowed for the birth control pill and allowed for a lot of different things to happen. And so that from there they worked a lot on steroids. So I'd had some experience in that. And this molecule does have this four membered ring steroid backbone. And so I thought, it's a naturally occurring molecule, it's got this structure. And the activity was really interesting. And so I actually got on a plane the next morning and flew out and we met with the professor who had discovered this and he was actually from the University of Virginia Commonwealth University and he'd driven up to Washington D.C. so we met with him there and licensed it as quickly as we could and started down this path.
[00:15:59] Speaker C: And so the initial evidence you saw it was what it was animal trials or what did he have?
[00:16:03] Speaker A: It was, it was a work in mice, it was around feet eating mice, high fat diets and the improvement that that showed in the function of the liver and homa ir, which is insulin resistance, things like that. And it was a fascinating molecule. I thought it could be possibly like a super statin, you know, something without the side effects and have a greater effect on controlling cholesterol and metabolism and the like, because. But then it turned out it was so much more than that and so it's led its path.
[00:16:30] Speaker C: So walk us through that a little bit. So this is one of the interesting stages in the drug development journey is deciding, okay, we've got this thing that looks interesting. What are we going to focus our initial efforts on? So how did you think about the initial disease you were going to focus on and the sort of path to trial and approval and all that stuff?
[00:16:46] Speaker A: Yes, well, we ended up, you know, we did about a dozen different animal models where we looked at activity of the molecule and found fascinating stuff. We found that it improved things like acute kidney injury improved there, it improved in sepsis, it improved a circumstance with acute pancreatitis, which in a stroke model. In fact, there was a European clinical research organization, or excuse me, non clinical research organization that the director of the lab there offered to do the next study for free because he was so impressed with if he could be on the publication, he said he would do the next study for free. So which in all my career I've never had them offer anything for me. So I figured we were honest.
[00:17:25] Speaker C: I will confirm that is unusual.
[00:17:28] Speaker A: And then we did some work over in Japan in a model for NASH or MASH and, and showed some remarkable data there. So we had a host of different things and we ended up selecting alcohol associated hepatitis as the lead disease to pursue. And the reason we did that is chronic metabolic diseases, Those take just 120 or million or more per trial. They're very expensive in five years plus very long, very drawn out circumstance. And it does influence a lot of people. There are in the, you know, four or five thousand people maybe a year in the United States that die from that disease. And so it's a very influence in the circumstance.
[00:18:01] Speaker C: I think you told me there was no standard of care for this, right? No Treatment, basically there isn't.
[00:18:06] Speaker A: And for alcohol associated hepatitis, yeah, there's. There's no treatment at all. And in fact, that influences a lot more people than even as far as deaths go on an annual basis than the metabolic conditions, there are 160,000 hospitalizations every year for alcohol associated hepatitis. And 30% of those people die. So that's more than 100 people dying every day. That's close to 40,000 people dying every year. That's as many people as die from breast cancer, as many people as die from automobile accidents, and there's no therapy.
[00:18:34] Speaker C: Shocking. It's a shocking number.
[00:18:35] Speaker A: Yeah, it is. And the average age is 44 years old in the trial that we did. Yeah, 20% of these people are young women in their 20s and 30s that don't have cirrhosis. But there's more binge drinking in this generation. There's a little bit more fatty liver. And those two things go together and help create the circumstance for this drug. And so that's why we ended up picking alcohol associated hepatitis as our lead condition. Because unlike stroke and sepsis and acute kidney injury and things like that, where time is very important, it's always important to treat. But, you know, in a stroke, I could have a twin brother who could have a stroke. We could have the exact same lesion. And if he gets to the hospital 12 hours before me and just gets standard of care, supportive care, he'll do better than I will. And so if you try to run a clinical trial, then the time to treatment has a huge impact on it.
[00:19:21] Speaker C: I want to slow down on that. And so the first thing you said was cost. Right. This is a less expensive path to approval, to develop. Yeah. Through the development process. And then because time was less of a factor here, less variability, higher probability of getting consistent results, maybe. Is that a fair way to say it?
[00:19:38] Speaker A: That's a fair way to say it, yeah.
[00:19:40] Speaker C: Yep. And then, as you said, massive societal impact. This is a terrible condition that we don't have a treatment for at present.
[00:19:46] Speaker A: Yeah, it is. As our Tim Papp, our CFO says, it's the most deadly disease you've never heard of. Yeah, yeah.
[00:19:51] Speaker C: That's a great way to describe it. Is that the rubric that folks should keep in mind when they're thinking about? You know, if you're at that stage in the process, you've got an interesting looking asset of some kind. It could be applicable in several different ways. So I think what we just said was cost, complexity of trial, maybe that is, you know, the ability to Kind of get consistent data and path to approval and unmet need or utility.
[00:20:13] Speaker A: Yeah, those are the things certainly that we look at. And I think those should be your drivers. I think you want a strong pharmacoeconomic argument and that that's easy in this case because this disease costs 10 massive billion dollars every year. All these hospitalizations and 40,000 or so lives. So there's a huge need for it. There's no effective therapy out there. That's very important because if you got a competitive therapy out there, then you're going to have to beat the competitive therapy. And that can be a much difficult thing to do. And not a lot of competition in the space. A lot of companies have tried but they've all failed in this area. So we don't have any competition in this space right now to speak of. And so that's an important piece as well. And then certainly the time of the clinical trials, the cost of the clinical trials are very important. And if you have an opportunity to save lives, whether it's in the space of oncology or in this case with acute hepatitis, that's always very important because the agency definitely pays more attention. And that witness that we received breakthrough therapy designation with this drug, even though in our phase IIB we missed on our primary endpoint, we were close enough and the data were significant enough that they allowed for. The FDA, allowed for a breakthrough therapy designation.
[00:21:17] Speaker C: Yeah. That's extraordinary. Do you think that startups, startup biotech companies, early stage biotech companies think through the things you just said often enough. I think specifically about the pharmacoeconomics of it and understanding unmet need.
[00:21:30] Speaker A: I don't know. I mean, this certainly was drilled into me. This is going back to the experience days of life. You know, early on in my career we couldn't develop any drug unless it had a good pharmacoeconomic argument. As we laid out all those strategic things that I spoke of. I think if a team primarily comes out of academics, academia, then more likely than not, they may not. They may think, oh, I've got a good thing for this and I'm going to pursue it. And so you may not get that. And then that has enabled unfortunately some false starts that we have seen where companies are well funded, they go off and three years later they're having to start again in another direction because their initial project didn't work right.
[00:22:06] Speaker C: Yeah, Sometimes I'll hear folks on the academic side of the world refer to the pharma and biotech world as the dark side. You know, kind of leaving Academia to go to the dark side. And it's so funny to me because the people that I meet in this world are almost exclusively mission driven people in the sort of biotech and pharma world. And I think about clients and colleagues and all the folks that I know, there are surer paths to making a lot of money than drug development, that's for sure.
So I'm fascinated by that. But I think you're right. I think that's a really important point. I want to highlight or emphasize that if you don't have a pharmacoeconomic strategy early, you're probably putting your whole project.
[00:22:44] Speaker B: At risk because you can say, well.
[00:22:45] Speaker C: Gee, I shouldn't have to think about such things. But that's not the world we live in. You're not need to raise a lot of money, you need to satisfy investors that there's a path to a return on that money or you won't be able to actually put drugs into bodies. You know, you won't be able to.
[00:22:58] Speaker B: You know, help people.
[00:22:59] Speaker A: That's exactly right. And that really was the. What happened in the drug delivery space is there weren't strong enough pharmacoeconomic arguments. One could come up with once a week therapy versus, you know, twice a day. But the healthcare industry didn't want to pay for the difference. They thought, you know what, people can take a pill twice a day and they're fine and it only costs this, I'm not going to pay 10x that, you know, for the convenience of a once a week thing.
[00:23:23] Speaker C: Yeah, I think that makes a lot of, makes a lot of sense. All right, let's talk a little bit about the science. So will you tell us a little bit about the mechanism of action here? Explain what we're talking about.
[00:23:31] Speaker A: I'm happy to. For me, it's amazing.
It's an epigenetic regulator. And you know, the epigenome is something that is, you know, we hear about it now, but we're just starting to really, at least I am just starting to really appreciate it. And the best way that I have found to think about the epigenome is to think about your own self and your own body. You have the same DNA in every cell in your body given to you, your mother and father. And yet think about all the different tissue types that make you up as a person. You've got hair, skin, muscle, ligaments, you know, nerve tissue, all of these different tissue types, tremendously different if you look at them. Bone and yet same DNA. How is that possible? And the reason for that is the epigenome. If you look into the nucleus of a cell, more than 95% of what is in that nucleus is not DN DNA. DNA is 2 to 4%. It's a very small percentage of that. The rest of it is the epigenome, which when I was in school we thought of it as, it was the chromatin, it was more structural, that kind of thing. It opened up during cell division, but no one really understood what it was all about. Well, it turns out the epigenome is actually the brains of the operation. It's equivalent to, you know, these computers that we're using right now. If one considers the DNA to be the hardware, then the epigenome would be the software, it'd be the apps of it all.
[00:24:45] Speaker C: That's a really helpful analogy.
[00:24:46] Speaker A: And so you have during embryogenesis when you're being formed in your mother's womb, during development you get certain genes are turned off and turned on. That allows for different tissue types to develop and those things occur. It's permanent methylation. Typically methyl groups are put on to prevent a gene from being read. Genes are read with, you know, messenger RNA kind of traveling. The DNA opens up and then you get this gene cassette is read and that's stopped by methylation. And turns out what our drug does, lukosterol, is it modifies back more towards normal hypermethylation. There are three enzymes called DNA methyltransferases that mammals have that put methyl groups onto DNA. And what this molecule does is it changes the expression and the activity of those enzymes and turns on and turns off more than a thousand genes in doses. And very frightening to think about it, but it's a naturally occurring molecule and it has been shown unbelievably safe in all of the non clinical, all of the tox studies we've done, we dosed. Unbelievable. As much as you could give the animal and have enough room for nutrition, it still had to be safe. Just fascinating molecule from the safety standpoint. And that proved out in our alcohol associated hepatitis trial. We did a trial in about 300 patients who were severely ill with this disease. And in fact in whole group 28% died within 90 days. And yet we saw 20 to 24% fewer treatment emergent adverse events than the standard of care. So we actually had effectively a safer path for those patients by virtue of giving the drug. And we saw globally for the whole trial 30 to 40% fewer people dying. And in the US 57 and 58%, so almost 60% fewer deaths. So we had really Wonderful efficacy and safety.
[00:26:30] Speaker C: So two things there. I want to talk about the difference between the global arm and the domestic arm in a second. But what was the primary endpoint there? Was it reduction in mortality?
[00:26:38] Speaker A: Yeah, the primary endpoint that we put in there was reduction in mortality or transplant. And that was the two things that we had in there. And we showed what I described there in those. And if one looks very complicated to kind of unpack a trial, as it were, but if one looks at the US data and if one looks at patients treated within 10 days, we win on all of those fronts. And that ends up being three quarters of the patients, 270, some odd, 76 patients, I think out of the 300.
[00:27:05] Speaker C: Was that the difference with the international arms, that speed of treatment?
[00:27:08] Speaker A: Yeah. So we conducted this trial called Affirm. It was a trial done to try and treat patients with alcohol associated hepatitis. These are these patients who are severely. They have severe alcohol associated hepatitis. So 30% die within 90 days. And we looked at mortality in 90 days. And because it's an epigenetic regulator, we only dosed it once or twice because you don't, you know, if you have your computer has a problem, you don't have to have somebody from the out to your house every 12 hours or hopefully. Right, right, right, right, yeah, hopefully they come out, they fix it, you're good. And so they were dosed on day one, and if they were still in the hospital, they received a second dose three days later and that was it. Then we just followed them for 90 days. The unfortunate thing for us is that we conducted the trial, we started and then the pandemic hit. And so that changed the circumstances of enrollment and the like. And so that makes sense. People who were not considered essential workers, which were the study coordinators, were not allowed to go into the hospital.
[00:27:56] Speaker C: I remember this period.
[00:27:57] Speaker A: Yeah, people drank more. So there was, yeah, there was more of this disease happening because people were drinking more, but they were wa.
Afraid to go to the hospital until they were much sicker. Yeah.
[00:28:05] Speaker C: Okay.
[00:28:06] Speaker A: And so beyond the scope of our trial, we went up to a meld score of 30. A meld is a model of end stage liver disease. It's a mark, it's a. Uses a number of different things to look at the probability that you're going to live and put you on a ranking for a liver transplant. And if you get to a meld of 30, you've got about a 60% chance of dying. It's a slope, a steep slope. In the next 90 days, in the next 90 days. And so we took patients from a 20 to a 30, which means kind of a 20% up to a 60.
Anyway, we were conducting this trial and the pandemic was there. And so we decided to go outside the United States in order to occasionally have hospitals where Covid wouldn't be so brightly burning and we might be able to enroll some patients and keep the timeline, keep as close to the timeline as we could. And so we expanded it into Australia, into Europe and the UK and we found that this disease, alcohol associated hepatitis, the patient journey is different outside, in different kinds of healthcare systems than it is here. Generally speaking, especially in Europe, where we had just by randomness put more of the ex US active patients. It was because we randomized centrally. But basically the active drugs we had three arms, we had one placebo arm and two active arms. More of the placebo patients went to Australia where patients generally did very well and just was random. Lot and more of the dosed patients went into the Franco Belgian region. In Europe, where patients weren't dosed for a very long time, in fact, the average time to dosing there was about two weeks. Weeks. So from hospital presentation, the hospital to dosing was 13 to 14 days. In the US it was three or four days. And in the United States their average age was 44. So these were younger people who had a probably greater probability of living because the younger you are, the greater chance you have surviving. And in Europe in particular, they were in their late 50s. So and all these people have alcohol use disorder. So if you add, you know, 14, 15 years onto someone who has alcohol use disorder, then you're in a much more delicate circumstance as well. So you add the age and the delicacy of the circumstance, plus being in the hospital for 14 days and not getting treated, not getting dosed, that also basically your probability of living now is not as much on the drug and it's more on your own body's ability to survive. So you know, we've done various analyses where we've taken it just separated out, just the US alone. And the data look amazing. They look highly statistically significant, very remarkable data. And if we look at just time to dose dosing, within 10 days case, the same thing looks very positive.
[00:30:27] Speaker C: So this was part of the argument I'm sure you guys made when how you got breakthrough, right?
[00:30:31] Speaker A: And that's why the FDA granted us the breakthrough therapy designation. That's why the the study was published in New England Journal of Medicine evidence, you know, even though, you know, the results were what they were because there's been Nothing new in 40 years to help these patients. And these data were pretty remarkable.
[00:30:45] Speaker C: So I want to double click there on another point that you made thinking about and understanding the patient journey under different medical systems. So I think, think, you know, folks who are thinking about a global trial, international arms to their trials tend to think about what's the quality of medical education and medical data, are there good sites, is this condition diagnosed regularly in this market, that kind of stuff. But understanding patient journey and, you know, time to treatment and some of the stuff that you just went through, another really important factor in sort of structuring your trial.
[00:31:13] Speaker A: It is, and it's something that, you know, you may, you know, you should consider for sure. It seems obvious, right?
[00:31:19] Speaker C: But most wisdom is in hindsight, I find.
[00:31:21] Speaker A: Yes, it is. And of course during the pandemic things changed even more too. They were there, conditions were just different in general. So things were delayed and everything else. So it kind of exacerbated, I think, that whole circumstance.
[00:31:33] Speaker C: So Jim, what comes next for the company? What's your primary area of focus? What are you guys doing now?
[00:31:37] Speaker A: So, Chris, what we're focused on is bringing Larsucal Seril to the market. You know, with this huge unmet need that's out there with so many people dying and with the cost being as high as they are for this disease, we really want to make sure that we do everything we can to try and bring that drug forward. So we're all about starting a phase three. We've met with the FDA, we've planned out what that phase three would look like. It'll be a 200 patient trial. We think it'll take about two years to complete. And if we look at that trial, the three lessons that were critical that we learned from our phase 2b trial were first off, we're going to conduct the trial in the US because then we can avoid some of the patient journey circumstances that we talked about earlier. And the healthcare provision is more uniform.
And the next one is we are going to randomize centrally so we eliminate variability that can happen from within a certain hospital. If they were to receive all placebo and they only enroll patients who weren't as sick or whatever the case might be. So if you're working at a given hospital, we will send you four packet of four, two will be active and then two will be placebo. When you use those up, you'll get another package of four. And so if you've enrolled 12 patients in the trial, we'll have an even split of six and six. And then lastly, we're going to treat within 10 days because we learned that time to dose is very important. Makes sense. Logically, we dose within the US Typically within three or four days, but we're going to make sure that everyone's dose within nine days or less, otherwise they won't be enrolled in the trial. So those are our three key lessons.
[00:33:00] Speaker C: That's really exciting. And obviously behind this you have a bunch of other potential uses for the drug.
[00:33:06] Speaker A: Right.
[00:33:06] Speaker C: I assume is. But wait, there's more coming in the future.
[00:33:09] Speaker A: Yeah, that's true, we do. This drug itself has great potential. We've shown amazing potential in acute kidney injury, which is responsible. Kidney damage is responsible for about 20% of hospital beds in the US and a number of other potential diseases that could be treated with this drug. And then as we've learned, gained a little bit more insight into the epigenome. We also have an opportunity here to expand our pipeline beyond that into the treatment potentially of cancer, where we have shown some really interesting early data. It's only in early days, but it looks to be maybe safer than other drugs which change methylation and can be used more broadly. Currently the drugs out there, dicitabine and azacytidine, which are oncology drugs, are used to treat blood cancers like leukemias or if it cancers that need to be treated. And they do very well there. We believe that our new molecules could potentially be used for those diseases, but also for other solid tumors. And unlike those molecules that change methylation, that need the DNA to open up during a cell cycle, here, this we're able to change methylation regardless of when the cell is where it is in its cycle. And so they can be dosed anytime. You don't have to dose for six weeks. You can dose without those kind of long intermittent circumstances there.
[00:34:22] Speaker C: That's obviously pretty exciting.
[00:34:24] Speaker A: Yeah. Potentially fewer side effects.
[00:34:25] Speaker C: Wow. Okay, so lots still coming. All right, in closing, you've been a CEO for a long time. You've shared a bunch of practical ideas already. But some thoughts, some closing advice for people who are, are maybe for somebody who's considering or is a first time CEO now, or even for folks who are considering leaving academia to come into a career in biopharma. But I'm particularly interested in what you'd say to a young CEO who's getting going.
[00:34:50] Speaker A: Yeah, I would say to him or her. I think it's very important to consider who your team is. What I learned from Dr. Zaffroni still holds today. It's really all about the people. So get the best people around you. And then when you look at your board, consider what is your end game for the company. If you're looking to develop a therapy to a certain point and then merge or sell the company, then you'd have one construct of your board. It would be more regulatory, more science focused. If you're looking to commercialize, if you're looking to bring it all the way through, then I think one needs to be aware that we're in a highly regulated environment and the political components of it all need to be taken into consideration. And so in that regard, I remember a company that they brought for their state, an ex governor of their state onto the.
And this person was also very active in the federal government. And so that I think that serves them very well going forward.
[00:35:40] Speaker C: Right. That person might not be a scientist, but might have the ability to help you in places where you're otherwise weak. Exactly. That's a great insight. And I want to triple underline your point about pharmacoeconomics and having a strategy there. I think so important for early stage companies that are excited about the initial science.
[00:35:56] Speaker A: Yes. You've got to make sure that your drug makes sense, sense, economic sense. You've got to be able to show, in my opinion, you've got to be able to show you can save the healthcare system money or it's probably not have the path that you would think going forward.
[00:36:09] Speaker C: Jim, that's incredibly helpful. Really exciting what you guys are doing. Thanks so much for joining us on Few and Far between today.
[00:36:15] Speaker A: Well, thank you so much, Chris. I really appreciate it. It was always so fun to be able to speak with you. So thank you for your time. Likewise.
[00:36:21] Speaker C: Likewise.
[00:36:26] Speaker B: Welcome producer Adam.
[00:36:27] Speaker E: Hi Chris. Great episode. It was so great to hear some of these things from someone who's been in the industry a long time and all the experience they've got. I want to start with his great analogy about DNA being the hardware and the epigenome being the software. It's just a brilliant analogy and I wanted to know what you thought about it in terms of how it's going to affect future innovations in theory.
[00:36:52] Speaker B: Yeah, I thought so too. Really, really helpful way to parse that. And you know, if we sort of then lean into that metaphor a little bit, what is he saying? Well, it's a lot easier to make modifications to software than it is to make modifications to hardware. I think that's really where he's going. And you know, the epigenome presents enormous opportunity as we go Forward. It'll be really fun to watch what Jim and his team continue to do here, along with lots of other folks that are exploring this aspect of biology.
[00:37:18] Speaker E: I completely agree with you. And moving on from that into the clinical trial that he conducted, he went into a lot of detail about the dosing timelines and schedules in the US versus the trials that were run in Europe and Australia. I mean, could this deter companies from running trials in these countries, or is it just something where you have to do your due diligence and your research?
[00:37:40] Speaker B: Yeah, good question, Adam. I don't think it should deter anyone. I think what it says is you can't, you can't assume that things are going to be conducted in the same way in different countries. You know, whatever the standard of care is, standard practice is in the country that, you know, in this case the United States, you can't assume that even in other countries with highly sophisticated medical systems, Australia, Europe, et cetera, that things will be done in exactly the same way. And delay in diagnosis caused him some challenges for his European participants. It sounds like the results were so impressive with the US that they were able to still secure a good result when they talked to the fda. I think the key thing there is to make sure you're talking to people who are experts in that local geography and incorporating their feedback into protocol design and study execution plans.
[00:38:26] Speaker E: Very good. I wanted to say, I'm sure you realize this, but in our past episode when we were talking to Michael Tolentino, he had a eureka moment.
[00:38:35] Speaker C: Yeah.
[00:38:35] Speaker E: And it seems like Jim also had a eureka moment. Something that was really too good to be true, tested it looked at it and it turns out it was true. What's your take on this trust but verify thing? It really seems to work for a lot of these up and coming companies.
[00:38:51] Speaker B: Yeah, I mean, I think there are a few lessons from that. First, don't rule out the possibility of getting lucky. So I think, you know, one of the points that Mike made in particular was if you see something that seems too good to be true, be cautious, make sure you validate, you confirm, etc. But don't assume it can't be true, because if it is, it might open fantastic door. And that's, I think, what we heard in the conversation with Jim as well. So open yourself up to that. The other thing that's important, I love the expression that you want to increase the surface area that is exposed to luck. And you do that by opening yourself up to what's happening in your field pretty broadly. So in Both of these cases, these guys were reaching out to people who were experts in the field. They were maybe reading obviously the traditional journals, but also looking a little further afield. In one case case to Northern Ireland, in this case with Jim, a researcher who was now in California, but who had been working internationally. And so looking for those folks reading broadly, being open to possibility expands the surface area that you exposed to luck and gives luck a chance to work in your direction.
[00:39:53] Speaker E: That's a very good point and kind of following up on that, one of the things that I have noticed in our podcast episodes is you kind of bring out the confidence, common sense ideas when we talk about things. And you said in this episode that if you don't have a pharmacoeconomic strategy early on, you're putting your whole project at risk. And to me that sounds like something that's just common sense, but it can really be a problem for some of these biotechs.
[00:40:18] Speaker B: Yeah, I mean, I think you're right. I think it's essential that people have a theory of how this thing that they're working on is going to save money for the medical systems that are the ultimate targets, whether that is insurers in the U.S. or governmental systems in Europe, et cetera. If you don't have at least a thesis of how your thing is going to save the system money, the likelihood of you getting broad adoption is probably pretty low. There are some exceptions there which are cases where we have no cure horrible diseases where there's no cure today. Even then you're making an argument of societal value because you're potentially saving a life that otherwise would not be saved. So, yes, essential. And then you asked, you know, how do people get far down the road sometimes without that? And I think some of that comes from, I'd say, the downside of what is really a good thing in our industry. Most of the people who work in pharma, broadly in life sciences, are mission driven people. They're doing this work because they think it's good for humanity, for the planet, and they are motivated by that. Sometimes those motivations can cause people to maybe not to pay attention to practical concerns, and that's a problem. I think you've got to sort of have your investors and ultimately your customers in mind. When you're thinking about the treatments that you're trying to develop. That doesn't mean that you don't care about the patient, of course, but we all live in the world, so you have to come up with something that patients are going to be excited about and will benefit them. But that also has an economic argument for it, so that it can get reimbursed, it can get approved across a bunch of different geographies. Geographies around the world.
[00:41:46] Speaker E: And that sounds very similar to things we've discussed previously about people in academia versus people who are more focused on the. On the industry itself.
[00:41:55] Speaker B: That's right. I mean, I think academia does not necessarily reward a practical answer. There's much more reward given to asking a set of interesting questions. There are plenty of exceptions to this, of course. So if you're reading this and raising your eyebrow or listening to this and raising your eyebrow, we're not trying to make a blanket statement, but I think that can be a challenge. And we've heard several of our guests talk about the transition from an academic research environment into biotech. And biotech has to pharma has to focus on where the rubber meets the road stuff, which is, you know, the kinds of things we're talking about here.
[00:42:25] Speaker E: Good point. Finally, I'm going to go back to the mentorship relationship. I think you've mentioned that you've been in the position of mentor and mentee. I have as well. And I wanted to get your thoughts on the investors, investment of energy and synergy on both sides of the mentor mentee relationship. You spoke last time about the effort that people put into it, and I wanted to kind of zoom in on that a little bit.
[00:42:48] Speaker B: Yeah, great point. So I think as a mentee or a putative mentee, somebody who wants to be a mentee, it's incumbent on you to feel like you're putting more effort into that process. You should not expect your mentor to be chasing you down, seeking you out, all that kind of stuff. Stuff you should be viewing it as. I'm going to do more of the work, not all of the work, however, because the mentor has to be willing to spend their time, their effort, and sometimes to put a little bit of reputational oomph behind something that you're doing. So if a mentor endorses you or endorses a project that you're working on, that comes with some reputational risk for them. So you want to make sure that you make that worth the time of the mentor who's getting involved. But yeah, like any relationship requires work on both sides. And your job, I think, as the mentee, is to make it as easy as possible. It's not always completely easy, but as easy as possible and as attractive as possible for the mentor. And you do that by doing a bunch of the work around scheduling and prep and stuff like that when you're going to meet with your mentor. Also, by sharing feedback about stuff that was helpful to them. I got a note recently from somebody that I mentor who just said, hey, that last conversation that we had was really helpful and, you know, kind of made my day. So there's reward that flows in both directions.
[00:43:56] Speaker E: Yes, I agree. That was a good answer. I like that. Okay, thanks, Chris.
[00:44:00] Speaker B: All right, Adam. Always fun.
[00:44:01] Speaker C: Thank you.
[00:44:07] Speaker B: Thank you for listening to the latest episode of Few and Far between conversations from the front lines of drug development. Our podcast is now available on Apple Podcasts and other streaming services. Please take a moment and leave us a user review and rating today. It really helps people discover the podcast and we read all the comments. Those comments help us make Few and Far between better and better. Also, be sure to subscribe to Few and Far between so you don't miss a single episode. Got an idea for a future episode? Email us at fewandfarbetweenioro.com or contact us on our website at biorossi.com I'm your host, Chris O'. Brien. See you next time.
