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spk04: Good afternoon, everyone, and welcome to the Direct Corporation third quarter earnings conference call. All participants will be in a listen-only mode. Should you need assistance, please email a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star and one on your touch-tone telephone. To withdraw your questions, you may press star and two. As you also know, today's event is being recorded, and at this time, I'd like to turn the floor over to Tim Papp, Chief Financial Officer. Please go ahead.
spk01: Thank you. Good afternoon, and welcome to Direct Corporation's third quarter 2023 earnings conference call. Before we begin, I would like to remind everyone of our forward-looking statement. During the course of this call, we will make forward-looking statements regarding the results and clinical data from the AFIRM trial, development plans for Larsuco sterol, expected product benefits, market potential, regulatory plans, potential regulatory approval, and the company's financial projections. These forward-looking statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements, including the risk that future trials of Lirsucosterol do not confirm the results from the affirmed trial. Further information regarding these and other risks can be found in our SEC filings including our 10K and 10Qs under the heading risk factors. To begin, I would like to review our third quarter 2023 financial results. Our total revenues in the second quarter or third quarter were 1.7 million compared with 12 million for the third quarter of 2022. This difference was largely due to the recognition of $10 million of milestone revenue related to our licensing deal within a call that we recognized in 2022. R&D expenses were $7.2 million compared with $9.9 million for the prior year. The decrease was primarily due to lower clinical trial and contract manufacturing expenses for Larsuka sterol and the elimination of feasibility programs, offset partially by an increase in spending on other R&D projects. SG&A expenses were $3.8 million compared with $3.9 million for the prior year, so essentially unchanged year over year. As of September 30, 2023, We had cash in investments of $39.1 million compared with cash in investments of $43.6 million at December 31st, 2022. During the third quarter, we completed a registered direct offering raising $13.9 million in net proceeds. Our cash burn in the third quarter was approximately $9.7 million, excluding proceeds from the offering. We believe our cash on hand is sufficient to fund operations through at least the middle of 2024. Now, I would like to turn the call over to our CEO, Dr. Jim Brown, for an update on our programs.
spk06: Thank you, Jim. Hello, everyone. Thank you for joining us today for our third quarter 2023 update. Last week, we announced the unprecedented top-line results from our Affirm Phase 2B clinical trial, which evaluated their sucrosterol and alcohol-associated hepatitis. The affirmed results showed a clinically meaningful reduction in the key secondary endpoint of 90-day mortality for larsucosterol compared with standard of care. To my knowledge, no previously controlled trial has demonstrated an improvement in mortality of this magnitude in this devastating disease. We also saw an encouraging safety profile for larsucosterol with a low number of adverse events for the active arms as compared with the standard of care. We've reviewed the AFFIRM data with many renowned hepatologists and AAH thought leaders. These physicians are excited by the compelling reduction in mortality at 90 days in the Larseco sterile arms. They were especially impressed with the data from the US patients and the safety data from the trial. Our Phase IIb AFFIRM trial was a placebo-controlled, double-blind, multinational study with two active arms dosing 30 milligrams and 90 milligrams of larcicosterol and a standard of care arm of approximately 100 patients each. By comparing against the standard of care, we allowed the physicians to utilize their standard practice for treating AH patients, which allowed for the use of corticosteroids in addition to supportive care such as fluids, nutritional support, and antibiotics for infection. In total, we randomized 307 patients with severe alcohol-associated hepatitis. These were patients with MEL scores ranging from 21 to 30 and moderate discriminant function scores greater than or equal to 32. We enrolled patients in Affirm through a global network of clinical sites, including leading hospitals in the United States, Australia, EU, and the UK. Our sites included renowned liver centers and we had the honor of working with some of the world's preeminent thought leaders in AH. The top-line results in the key secondary endpoint of mortality at 90 days showed a 41% reduction with a 30-milligram dose of larcicosterol and a 35% reduction with a 90-milligram dose of larcicosterol as compared with the standard of care. We also reported a numerical improvement in the primary endpoint, a reduction in mortality or liver transplant at 90 days, though neither the primary or secondary, key secondary endpoint, achieved results that were statistically significant. Impressive results were found in the U.S. population, which comprised three-quarters of the total enrollment in a firm. That was 232 out of 307 patients. In the U.S. patients, we saw reductions of mortality at 57% and 58% for the 30 and 90 milligram arms, respectively, compared with the standard of care. Although not a part of the original trial statistical analysis plan, the p-values for these results were both approximately 0.01. Very importantly, larcicosterol exhibited an excellent safety profile with no serious adverse events in either arm and greater than 20% reductions in the number of treatment-emergent adverse events for both active arms of these severely ill patients when compared with the standards of care. Ultimately, these clinically meaningful reductions in mortality coupled with the reduction in adverse events in these severely ill patients reinforce the compelling risk-reward proposition for the continued advancement of Larchicosterol as the first approved treatment for AH. We look forward to meeting with the FDA in the first quarter of 2024 to discuss the affirmed data and the path forward to seek approval of Larchicosterol in AH, including design for a potential registrational Phase III trial using mortality as the primary endpoint. As a reminder, the FDA has granted our lasucosterol AH program fast-track designation. AH is a cause of more than 158,000 hospitalizations each year in the United States, with a 90-day mortality rate of approximately 30%, and is responsible for tens of thousands of deaths each year. There are no effective treatments for AH. If we were able to gain approval for lasucosterol it would likely be the first FDA-approved treatment for this disease. In addition to its high mortality rate, AH represents a significant cost to the U.S. healthcare system. Hospitalizations attributed to AH incur costs of $62,000 to $167,000 each, a total cost to hospitals of approximately $10 billion annually in the United States. As a result, Larcicosterol represents a potential multi-billion dollar opportunity in the U.S. alone and could simultaneously provide overall cost savings to the healthcare system. We look forward to the possibility of bringing this potential life-saving therapeutic to patients with no effective therapies available today. We attended the AASLD conference in Boston, this is the U.S. liver meeting, over the weekend. and had the opportunity to discuss the top-line results with many of our investigators from Affirm and with more than a dozen influential KOLs. The reaction of this physician community has been overwhelmingly positive and enthusiastic about Larsukosterol's prospects. These physicians expressed their frustration with the lack of effective treatment. They recognized that the type of mortality benefit and safety profile suggested by Larsukosterol from our Affirm data would potentially bring a major advancement in the standard of care for these severely ill patients. We now like to take any questions you might have.
spk04: Ladies and gentlemen, at this time, we'll begin the question and answer session. To ask a question, you may press star and then one using a touch-tone telephone. If you are using a speakerphone, we do ask that you please pick up the handset prior to pressing the keys to ensure the best sound quality. To withdraw your questions, you may press star and two. Once again, that is star and then one to ask a question.
spk05: We'll pause momentarily to assemble the roster. Our first question today comes from Francois Bruzois from Oppenheimer.
spk04: Please go ahead with your question.
spk07: All right, thanks for taking the question. Just a couple here. So in terms of the Mortality, can you remind us what it was, the mortality that was seen in the trial? I know there was a fear that maybe the trial would not, or AH patients did not have quite the mortality that people expected. Can you just maybe remind us what you saw in the trial, and was it in line with what you thought?
spk06: Absolutely. Yes, for the overall trial, the global trial, we saw about a 20, we saw a 25% mortality. And we had powered it for about 30% mortality. So it was a little bit lower than we had expected. And that was, in all likelihood, the primary reason why we slightly missed that endpoint. Our biostatisticians told me if we'd had, you know, X number of, you know, 15 plus more patients or something, you know, we would have been able to possibly hit that endpoint. It's interesting when we look at the subset of the data, which is three-quarters of the data from the United States, we see a mortality endpoint rate of 28% in the United States as compared to 12% in the two active arms. So that certainly was almost 60%, so that was highly significant. So in the U.S., it hit right. When we look globally, it didn't. And that's, unfortunately, it's you know, we moved from this small four-patient per group study to 100 patient per group in the 2B. But it gained so much information. And to have a trial that had this kind of signal and when we spent the weekend, you know, as you know, Frank, in Boston with these investigators, they were quite excited about the data we have.
spk07: Okay, great. No, that's great. And then in terms of the, you know, speaking to a lot of physicians over the weekend and whatnot, was there What are the thoughts in terms of their hypothesis, and maybe there were differences in the U.S. versus the ex-U.S. population? Is it too early to see anything you can share there, or should we wait for more information about the potential differences there? Thank you.
spk06: Yeah, certainly. There certainly were some things that they focused on, and we are investigating more thoroughly. And the first thing that they focused on was the differences in age. we saw the age of the U.S. population at 43. And to a person they were saying, yeah, these are the patients we're seeing. They're younger. I had a number of them quote back the kind of numbers we've been talking about, you know, 20 some odd percent of their patients are young women in their 20s and 30s without cirrhosis. And we certainly saw that in our trials. You know, we saw younger people, 43 percent, excuse me, 43 was the mean age in the United States. And ex-U.S., it was 50. Even higher in Europe, I think it was 52. So, and there was a physician from Southern California, from USC, who we spoke to, who talked about some papers that he had written showing that if you were over the age of 44, you had a much greater chance of dying from this disease. So we know in a lot of diseases, the older you are, the more susceptible you are to dying. And certainly in this population, that's the case. And so that was one component that we learned. The other thing that they focused on was the amount of cirrhosis. The U.S. population had 76% cirrhosis, which means, you know, it fits with being younger, you would have less cirrhosis. But the ex-U.S. population was, especially for the EU, with biopsy confirmed, 90% cirrhosis, which means much, basically means much less liver available to respond to the drug, fortunately. But we're still teasing out the differences because the other differences, there were, you know, a much smaller population of patients and they were, you know, divided and randomized across Australia, the UK, and the EU. And so you can also get into mismatching of a balancing of that as well, which can lead to greater variability.
spk05: Thank you. Sure.
spk04: And our next question comes from Carl Burns from Northland Capital Markets. Please go ahead with your question.
spk03: Great. Thanks for the question. I'm wondering if there's any rationale for the FDA to not allow mortality as a primary endpoint in a Phase III trial, considering the limited number of liver organs available for transplantation, the mortality benefit that you saw, particularly in the U.S. population, and then the safety profile, which was clearly better than the standard of care, which is something we simply don't see. Thanks.
spk06: Yeah, I think, first of all, the FDA is happy to, from the correspondence that I've been associated with them, they would prefer mortality over anything else, quite frankly. And that will be, if another trial is required for approval, we will do a trial looking at survival. So if you look at the secondary endpoint, if you look at the U.S. population, those would be good surrogate populations and analyses that we would do if we were required to do another phase three, or a phase three trial for this drug, because you're right, the mortality is horrific. And, you know, transplant, there's only, there's less than 2% of these patients are going to be transplanted in the U.S. There are a quarter of liver transplants, but that's about 2,000 livers, and there are 158,000 of these hospitalizations as of a couple years ago, probably growing at about 4% or 5% a year. So, you know, they always lag behind their actual data with what we can get from the government literature. There are probably 98% of these patients in the United States never have a chance at a liver. And their only option then is what is out there today. So their only option is to potentially die at a rate of what we saw in this trial in the US, 28% or 30%, depending on how you look historically. So it's a horrible circumstance. And these physicians were so excited about the data we have. And the ones who were involved with the trial were telling us stories about patients that they just really, Really, after, you know, having the week, you know, where we had to talk about the data that we had, it was really heartening and really lifted up the spirits of everyone who was there. It really did.
spk03: Great. So, on that thought thread, then, I'm wondering, is there any possibility or do you think there's any possibility that Lucica Cero could be used on a compassionate basis given the safety profile in the meantime?
spk06: You know, I don't – compassionate use is a possibility. But what we'll do is we'll go have a conversation with them. We'll talk about the potential for an accelerated review as a possibility as well. So we're just going to have a conversation with the FDA about what we have. This is certainly a highly lethal condition with no therapy. As you said, it's got a very clean profile. I would just say it at that, leave it at that, from just a very nice profile from an adverse event standpoint. So we'll have that conversation with the FDA in the first quarter and find out what the next steps will be.
spk03: Got it. Thanks. And then just one last question. There's been some concern about not seeing a dose response. But if we look at the U.S.-only population, again, you explained some of the nuances with respect to mismatching. But clearly, you did see a dose response. I think it was like 58% of the 90-meg dose versus 57.1% in the 30-meg dose. So is that correct? And what's your thought on that? you know, some of the comments are out there in terms of not seeing dose response. And that's my final question. Thank you. Yeah, thank you. Thank you, Carl.
spk06: I think what we can glean first from the fact that both doses showed very well is, first of all, both doses showed very well, right? So that means you grab the population of 100 people, dose them with a drug, phenomenal result, almost 60%. Grab another 100 people, check them, get standard of care. Once again, another phenomenal response, almost 60%. You can't really tease out the difference between you know, 57 and 58, nor can you really between 35 and 41. These are, what they're showing is the drug is having an effect and that, you know, and so most likely biologically we're probably, if you think about a curve, you know, we're probably at the asymptotic component of the curve where we're just near the top of, so one dose versus another dose is not going to make an appreciable difference there. And so that'll be a conversation with the FDA. We certainly know a lot more about how the drug works in various animal models, and other studies we've done. We know it's an inhibitor of DNMTs, DNA methyltransferases. We know it reduces hypermethylation. We know these patients have elevated levels of these enzymes. And so all that is well understood from a scientific standpoint. And the finer points of which dose to be selected will be a conversation we have with the agency at the end of the day.
spk05: And we're prepared to use either dose going forward. Great. Thanks again. You're welcome. Thank you.
spk04: Once again, if you would like to ask a question, please press star and then one. If you remove yourself from the question queue, you may press star and two. Our next question comes from Ed Arts from HC Wainwright. Please go ahead with your question.
spk02: Hi, everyone. This is Thomas Yip asking a couple of questions for Ed. Thank you for taking our questions. First question, based on what you've learned from Affirm so far, Can you discuss what are some inherent variability of the liver transplant endpoint in the study?
spk05: Well, there's, when you look at transplant, it's just inherently variable.
spk06: And, you know, that's the reality of it. It's available, as I said earlier, to less than 2% of the patients who have this disease. And the Administration of the transplant is very variable as well. It depends on which center you're at. It depends on what is your level of insurance coverage, whether or not you have a match, how aggressive your surgical team is. And it also depends on how sick you are. There are a number of patients who are too sick when they first come in to get a transplant. So we think about the use of large suco sterile in this setting. Certainly in a survival trial, a trial where you're looking at mortality, there are a certain number of patients who would be in the standard of care group who would get a transplant and survive. And that's true. But witness the fact that we had a safety, or not safety, it was fine, but we had a mortality signal even considering those. And I believe from talking to some of the people and understanding the path for some of the patients in this trial, that what we're also seeing is, for lack of a better term, a bridge to transplant. Where some of these patients are severely ill at the beginning may not be alive long enough to get a transplant, but because they were dosed with Arsuclosterol, they were then potentially able to get a transplant six or eight, ten weeks later. So that's another component of it all. And rather than try and separate that out and tease it out, it would be very difficult to do. We're simply just going to look at mortality and let transplants fall where they may. And so that's how we're going to deal with that, because there are so many factors that influence transplant that the drugs can't influence. The only thing the drug really can do towards transplant is keep you alive and make you a little healthier so that you might be still around if the liver by chance came up, as rare as it is.
spk02: Understood. That makes sense. And then perhaps just one more question from us. So you discussed a little bit earlier how the U.S. populations with lower mean age and also a low percentage with cirrhosis. So I wonder, how do you look at potential of ex-U.S. markets, perhaps discussions of the EMA? Is that on the table?
spk06: No, I mean, we will be talking with the EMA as we go forward. You know, we're just now starting to take the additional cuts of the data and look at that. And we will look at the data for a number of different reasons, you know, for all these different characteristics and try to understand how it responds because I'm certain that both the FDA and the EMA will want to understand that. My sense is that we'll be able to help patients, you know, we've dosed this in CHOP-QC patients who are dying or their livers are failing and for other indications orally and saw some nice improvements in these patients just, you know, single dose safety studies, but saw some interesting biomarker changes and the like. So I do think there's the potential to help these patients. That being said, you know, we're going to drive forward for approval in the U.S. based on the U.S. data, and then we'll take on the rest of the world in these more severely ill patients as time goes on. And that's where we've got a long ways to go in its early days in analysis.
spk05: Okay.
spk02: Yeah. Thank you, guys, for taking our questions. Definitely look forward to that day meeting in the first quarter.
spk05: As do we. Thank you.
spk04: Ladies and gentlemen, with that, we will conclude today's question and answer session. I'd like to turn the floor back over to Jim Brown for any closing remarks.
spk06: I just would like to thank you all for your time today and for your support. And as always, if you have any Further questions, please reach out to him and myself or others on the team that you know, and we're happy to get on the phone and talk to you. Thanks a lot, and take care.
spk04: Ladies and gentlemen, with that, we'll conclude today's conference call and presentation. We thank you for joining. You may now disconnect your lines.
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