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spk07: Good afternoon, and welcome to our first quarter 2022 earnings conference call. This is Matt Hogan from Direct Corporation. Before beginning, I'd like to remind you of our safe harbor statement. During the course of this call, we may make forward-looking statements regarding Direct's products and development, expected product benefits, our development plans, future clinical trials, or projected financial results. These forward-looking statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Further information regarding these and other risks can be found in our SEC filings, including our 10-K and 10-Qs under the heading Risk Factors. Let me now turn to our financials, which were pretty uneventful in the first quarter. Total revenues in the first quarter of 2022 were $1.9 million compared to $2.2 million in the first quarter of 2021. R&D expense was $8.2 million in Q1 2022, as compared to $8 million in Q1, 2021. The increase was primarily due to higher clinical trial expenses and higher contract manufacturing costs for Larsukosterol. SG&A expenses were $3.7 million in the first quarter of 2022, as compared to $3.5 million in Q1, 2021, primarily due to higher patent expenses and higher consulting and market research expenses. At March 31, 2022, we had cash-in investments of $64.4 million, as compared to $70 million at December 31, 2021. That decrease was only $5.6 million, but we benefited from receiving around $4.6 million from INICOL related to the POSIMIR deal, net of our fee to the investment bank that assisted in the transaction. If you exclude this, our underlying burn rate during the quarter was $10.2 million. With that, let me turn the call over to Jim for an update on certain of our programs.
spk06: Thank you, Matt. Hello, everyone, and thank you for joining us today for our first quarter 2022 update. Our primary focus at Direct is on the affirmed trial of Larsuclosterol for the treatment of alcohol-associated hepatitis, or AH. AH is a lethal and costly disease. that is an unmet medical need with no approved therapy that results in about 137,000 hospitalizations per year in the United States and a 90-day mortality rate of approximately 30%. The average cost of treating a hospitalized AH patient can range from $56,000 to $151,000, with many patients requiring a liver transplant, which can cost upwards of $875,000. The FDA has granted our Lorsuclosterol AH program fast-track designation. A robust 90-day survival benefit in AFIRM could support an NDA filing, and Lorsuclosterol has the potential to be the first FDA-approved treatment for AH. Now let's move to our development program of Lorsuclosterol for the treatment of AH and the AFIRM trial. AFFIRM is a direct Phase IIb study of leucoclosterol in patients with severe AH. It is a placebo-controlled, double-blind, multinational study targeting 300 patients. We are pleased with the progress of enrollment in our AFFIRM trial. We have dosed more patients in the AFFIRM trial during the first quarter of 2022 than in any prior quarter, and if April's enrollment rate continues, the second quarter will be even better. It's our belief that if a firm demonstrates a statistically significant improvement in 90-day survival, it could be the pivotal study for larsuclosterol in the treatment of AH and support an NDA submission. We have now dosed patients in Australia, France, and Belgium. We made excellent progress in opening new clinical sites in the two months since our last earnings call. We are constantly working to improve site performance Since our last call, we've opened nine new sites and closed three non-performing sites for a net of six. We now have 57 sites open and are enrolling at leading hospitals in the United States, Australia, the UK, and the EU. We are nearing the completion of our goal of approximately 70 sites for the trial. We are expanding the number of sites for this trial because a handful of highly respected U.S. clinical sites became available due to the discontinuation of an NIH trial for AH. At the pace of enrollment achieved in the first quarter of 2022, we would complete dosing the last patient in the affirmed trial in the mid of 2023. We expect the pace of enrollment will improve through our clinical site expansion, clinical trial management activities, and the continued lessening of the impact of COVID on the hospitals participating in affirmed. AFIRM is a placebo-controlled trial that has three treatment arms, 30 milligrams and 90 milligrams of leucocosterol and a placebo arm. As with the Phase IIa trial, patients in the AFIRM trial receive an infusion of leucocosterol or placebo on day one, and if they are still in the hospital on day four, they receive a second infusion. The primary endpoint for this trial is 90-day survival. The main focus of the company is to execute this trial to the highest level of quality and in a timely fashion. In 2019, it was reported that there were 137,000 hospitalizations per year in the United States for AH. What physicians have available to them today primarily involves abstinence and supportive care, which includes nutrition and hydration. Corticosteroids are used in some cases but have shown no survival benefit at 90 days or at one year. There is no approved treatment for AH. A global study published in December of 2021, which included 85 tertiary centers in 11 countries across three continents, prospectively enrolled 2,581 AH patients with a median MELD score of 23.5. This reported mortality rates of 20% at 28 days, and 31% at 90 days. AH has a significant economic cost to the healthcare system. The average hospital stay for an AH patient in the United States is approximately one week, with many staying significantly longer. The average hospitalization cost for an AH patient is approximately $56,000 for patients who survive the first nine days, and approximately $151,000 for those who do not survive. Alcohol-associated liver disease is becoming a leading cause of liver transplants in the United States, with the average cost of a liver transplant exceeding $875,000. With this in mind, Larsuco sterol represents a potential multibillion-dollar opportunity that could save the healthcare system substantial costs. The REC's medical affairs team has substantially increased our AH market outreach and educational efforts to amplify our suprasteril awareness and facilitate affirmed enrollment efforts. We recently hosted the first of multiple regional affirmed study update meetings with our investigators and site study coordinators. It was held in San Francisco and was attended by 14 individuals from eight hospitals. Our upcoming meeting in Chicago is expected to have 25 individuals from 16 hospitals. We recently exhibited at three liver-focused congresses, including well-attended meetings at the Scripps Institute and at Scottsdale, Arizona. We have also retained a medical communications agency to broaden awareness of AH, the affirmed trial, and larsucosterol. Let's review why we are so optimistic about the use of larsucosterol in the treatment of patients with severe AH. AH patients face a 90-day mortality rate of approximately 30%, and there is no approved treatment. In our Phase IIa trial for leucocosterol in AH patients, all 19 patients, including the 12 severe AH patients, survived. Additionally, 14 out of the 19 patients were discharged in less than four days after receiving only one IV infusion of leucocosterol. The prognostic scores from the AH patients in this trial, including LEAL and MELD scores, bilirubin, and other biomarkers were improved compared to baseline. Lorsuclosterol was well-tolerated by all the patients at all the doses evaluated in the Phase IIa trial. There were no serious drug-related adverse events reported in this trial. In addition to the clinical trial results, we also have supporting data from numerous in vivo animal models that demonstrates lorsuclosterol's activity against multi-organ failure, which can occur in AH patients. Lorsuclosterol is an endogenous epigenetic regulator. It binds to and inhibits the activity of DNMT1, 3A, and 3B. DNMTs are epigenetic regulating enzymes that add methyl groups to DNA in a process called DNA methylation. Treatment with our sucrasterol and stressed liver cells can lead to decreased DNA hypermethylation and modulated expression of more than 1,000 genes that are associated with multiple crucial cellular signaling pathways. In July of 2019, Argemi et al. published a study in Nature Communications. In this study, the gene transcription patterns of patients with severe AH demonstrated DNA hypermethylation, altered transcriptomics, and liver cell dysfunction. The expression of DNMT1 and DNMT3A were found to be profoundly increasing in these AH patients, but not in control subjects or patients with other liver diseases that were studied. Larch sucral sterol binds to and inhibits these DNMTs. This adds to the strong rationale for evaluating Larch sucral sterol as a therapeutic agent for patients with AH. In summary, there is a huge unmet need in AH. There is no approved therapy today for AH patients, and the 90-day mortality rate is approximately 30%. AH costs the U.S. healthcare system billions of dollars per year. We are optimistic regarding the potential for success of the affirmed trial due to the results from our Phase IIa study, in vivo animal model results against multi-organ damage, and the association of large sucral sterols mechanism of action with the epigenetic dysregulation seen in patients with severe AH. We have fast-track designation for low sucral sterol in the treatment of AH. Given the high unmet need for hospitalized AH patients, the lack of current treatment options, and the high mortality rates, we believe a robust survival benefit in the affirmed trial would support an NDA filing. Next, an update on potential indications for losucosterol beyond AH. One of the indications we are considering is NASH. We've completed a phase 1A and 1B trial in more than 70 NASH patients that demonstrated reduced liver enzymes, fibrosis markers, and liver fat stiffness and elasticity, reduced circulating fats, including triglycerides, reduced cell death markers, improved insulin resistance, and a good safety profile. Other potential additional indications for leucocosterol that are supported by the preclinical data are acute kidney injury, pancreatitis, stroke, sepsis, and others. We are currently carefully planning our next indication for Larsuco sterile. Next to Posimer. Posimer is a novel, non-opioid, sustainably leased local anesthetic that is approved to produce post-surgical analgesia for up to 72 hours following arthroscopic subacromial decompression. We license the development and commercialization rights for Posimer in the United States to Intercall Pharmaceuticals. We selected Inacol as our commercial partner because of their strong commercial team and because they are focused on the post-surgical pain market. Inacol remains on track to launch POSMRI in the United States during the second quarter of this year. The direct will receive a $2 million payment upon first commercial sale with a potential of up to $130 million in additional commercial, regulatory, and intellectual property milestone payments, as well as a tiered low- to mid-double-digit royalties on net product sales in the United States. In summary, we continue to make great strides with Affirm. We have 57 clinical sites up and running. In the last two months, we've added a net of six sites. We now have clinical sites open in the United States, Australia, the UK, and the EU. At the pace of enrollment achieved in the first quarter of 2022, we would complete dosing the last patient in the Affirm trial in the middle of 2023. We expect the patient enrollment will improve through our clinical site expansion, clinical trial engagement activities, and with the continued lessening of the impact of COVID on the hospitals participating in AFFIRM. Our confidence that the AFFIRM trial will be successful is driven by our compelling Phase IIa study, the mechanism of action of larcicosterol which ties directly into AH, and our multiple preclinical animal studies where we saw a profound survival benefit in relevant acute organ injury models. We have fast-track designation by the FDA for our AH program. We expect that if we achieve a robust survival benefit, this study would support an NDA filing. Beyond AH, the mechanism of action for losucosterol provides further scientific rationale for developing treatments for other acute organ injury and chronic diseases. We would now like to take any questions that you might have.
spk01: Okay, ladies and gentlemen, if you would like to ask a question, please press star 1 on your telephone keypad. Again, to ask a question, press star 1 on your telephone keypad. And I'll just give it a few moments for the queue to build. Okay, our first question is coming from Kristin Kluska with Cantor Fitzgerald. Kristin, your line is open.
spk00: Hello, everyone. This is Rick on for Kristin. Thank you for taking our questions. We've got two for you today. A recent global study in the American Journal of Gastroenterology concluded that MELD score was better at predicting mortality in AH versus MDF. With findings like this in mind, how are you thinking about how the field might assess the totality of data in the AFIRM trial, including endpoints such as MELD for Lorsuka sterol?
spk06: I think that's a great question, Rick. Thank you. And I would note that in our Phase 2A trial, the MELD scores, the average score MELD score, median MELD score was 24.5. But I think the best person from our team to answer that would be Norman.
spk03: Thanks. It is a great question. They made that, you know, that had a very specific meaning. It was the score at enrollment. And you'll recall that the study we're doing, the endpoint is no longer a soft endpoint like LIL score or MELD score. It is actually survivable. So it's designed as a pivotal trial with a hard endpoint. That said, most trials still include MDS, that's moderate discriminant function, as an enrollment criterion because it is a pure liver measure, whereas MELD score includes creatinine and a number of other scores include other factors. So they all contribute to the ability of the score to predict survival from an acute episode, but really what we're interested in is the actual survival at the end of 90 days.
spk06: Yeah, I think it's also interesting from the literature that's been published more recently, one can get further affirmation of the relationship between a given male and survival at 90 days as well, which is also, I think, a good point to take in.
spk00: Excellent. Maybe just one more. You mentioned the activities ongoing with the medical communications agency that you've contracted. Could you talk about the specific goals you're looking at when it comes to education in this space? Do you view talking to physicians about sort of the lack of efficacy from steroids and AH as a main goal? Do you plan on kind of talking about the clinical results for larsucosterol to date, or are you kind of looking at an all-of-the-above approach?
spk06: I think we're definitely looking at all of the above to help kind of enhance awareness of this therapy as it approaches. Although I would, from most of the thought leaders we've spoken to, people are already, there's an awareness of it. But Norman, having in the not too distant past, a couple of years ago, being one of those thought leaders out in practice, what would you say to that?
spk03: Yeah. So the At the moment, our focus is actually on getting patients enrolled. So this is not an unknown. This is a very well-recognized entity among hepatologists. So among liver doctors and transplant physicians, this is very well known. What we're trying to do is educate people who refer to transplant centers and hepatologists so that they send the patients with these. A lot of times these people are seen as patients with a poor prognosis, nothing to be done. The old data on not being transplant candidates is still lingering. So a lot of people that are out of the field just view these patients as being hopeless and may not consider transferring them. So we're trying to reach out and say there is something that can be done. This trial is ongoing. So if you have a patient like this, please refer to one of the centers. And as Jim mentioned, we have centers essentially across the country. And so I think in nearly every major city we have a center. So that's the focus of our education. In terms of our outreach to our investigators, they are very sophisticated, but our meetings with them are really focused on what are the best practices, what are the techniques that are helping them get patients enrolled in the study. The enrollment in a study is always somewhat different from the actual number seen because the entry criteria are quite strict and we're maintaining those for the clinical trial.
spk01: Okay, our next question is going to come from Francois Brisbois with Oppenheimer. Francois, your line is open.
spk05: Hi, thanks for taking the question. Just in terms of enrollment here, is it fair to say that this might be a little ahead of expectations based on, you know, the prior discussion about completing enrollment in mid-23 and now maybe having last patient dosed in mid-23? And if you do have last patient dosed in mid-23, can you just remind us what that means for a potential timeline to read out?
spk06: Yeah, first off, I'll start with the latter part first. Yeah, if we roll that last patient in the middle of the year, From that last patient being dosed, there's a clock of 90 days. And so post that, it'll be last patient, last visit, and then we'll be cleaning up the data, which we are doing real time right now, but there'll be a finalization of cleaning up of the database before locking and then an analysis, which will take some amount of time. I don't want to project it at this point in time, but I do know that Norman and the team are working in real time to ensure that the time from that last visit to when we can break code analyze the data, it's going to be as short as possible. And I don't want to come out and project anything other than the middle of next year at this point in time, but just to have you know that we are certainly optimistic and hoping that we can do better than that, and the team is striving towards that every day. And, you know, so far it looks like the winds might be blowing in that direction, but we'll have to wait and see. Norman, would you add something to that?
spk03: No, I think that's exactly right. The clinical team is working very hard. We have a phenomenal completion rate in terms of paperwork for the patients. We're trying to make sure that when we get to the end, there is a minimum delay between the data wrap, data lock, and the final analysis.
spk05: Okay, great. So just to be clear, so changing the language from complete enrollment in mid-23 to last patient dose in mid-23 is pretty similar. It's not necessarily too much ahead of – it's kind of in line, if anything, maybe a little incremental, but nothing major here.
spk06: Right now, yeah, we're holding to our original timeline, but with the potential of doing better, yes.
spk01: Our next question is going to come from Edward Ark with HC Wainwright. Edward, your line is open.
spk02: Hi, everyone. This is Thomas Yip asking a couple questions for Ed. Perhaps first, for a firm study in Roman, as you outlined, last patient dosing expected mid-23, as I previously discussed, Based on pace of enrollment in first quarter 2022, it sounds quite positive pace. I wonder if you could provide specific, more quantifiable number of patients enrolled in a quarter, and perhaps what is the rough percentage progress of the affirmed study enrollment so far?
spk06: You know, we gave an update last time saying we had hit 100 patients because it was one-third of the way through. We don't want to be giving it, you know, at such frequent levels because you're going to have changes in a weekly or monthly rate. But that's why we tried to give as much color as we could within the bounds of what seemed reasonable. So we, you know, stated that that first quarter was our best quarter yet. And the second quarter is starting off to be even better. So that is what we can say at this point in time. when we hit what we consider our next major milestone in enrollment, then I think we'll make that announcement at that time. I think that's the best we can do for clarity right now.
spk02: Got it. We understand that. Perhaps another question for enrollment. As you pointed out, the first patients have been enrolled in Australia. I just wonder, based on or your experience with the oldest site so far. Do you observe any seasonality trend in new cases, of course, as it flows into patient enrollment, given Australia's approaching winter months?
spk06: Yeah, that's a good question. I don't know. Norman, you're closer to it than I am. Are you seeing some seasonality or some things associated around holidays, that kind of thing?
spk03: That's an interesting question. We haven't actually seen seasonality. There is quite a lot of variation week to week and month to month, but I haven't noticed that it's particularly seasonal. So you're thinking people may drink more on certain holidays that certain times are either lower stress or more time. We haven't really seen that. We have seen a major effect of a COVID that seems to be easing up a little. And so there was a tremendous block in getting patients to hospitals that seems to be easing. So I think that will have more of an effect than the seasonal effects.
spk06: I think that's a very good point. Yeah, we know some of our investigators, in fact, almost all of them have described circumstances where the hospitals were challenged during COVID. Maybe Norman, you can give a little more light as to what it was like and how it's changing.
spk03: So we had, with COVID, there were, especially early last year, a lot of hospitals wouldn't allow non-essential staff in. So the coordinators weren't allowed to come in. Then when they came back, what we noticed is that patients were delaying coming to the hospital. So If someone is drinking and saying, I'm not feeling very good, maybe I should go to the hospital, but they're afraid, they may stay home and drink longer. And then by the time they come in, they're much more ill and outside of criteria for this study. So we had a lot of that. We had some hospitals that just blocked transfers for a while. And so one of our really excellent sites is for a while just couldn't accept any patients. And a lot of this trial is driven, and a lot of hepatology for that matter, is driven by referrals from peripheral hospitals to these major centers.
spk01: Okay. It looks like we have another question from Francois . Francois, your line is open.
spk05: Okay. Sorry. Thank you. Just an extra one here. You talked about the goal. Maybe I think it was over 60, and now it's around 70. based on the NIH trial that stopped for 8H, anything that was publicly disclosed there as to why it might have stopped? Is it anything to do with enrollment difficulties or any of that?
spk06: No. Yeah, I didn't want to give any additional information other than it was unfortunately stopped for not being effective.
spk05: Okay, perfect. Thank you.
spk06: Yeah, yeah, sure. Okay.
spk01: Our next question is going to come from Jeffrey DeCyber with KB Advisors. Jeffrey, your line is open.
spk04: Thank you, and gentlemen, thank you for taking my calls. I have two questions. Jim, you told us that you might give us an update when the next major benchmark or hurdle might be reached on the trial. You shared with us that the 100, the one-third marker, What's that next hurdle going to be? Is it the halfway mark? I think that's a reasonable question.
spk06: That's an excellent question, but I think I just wait and see, you know, when we get there. But, yeah, you're not too far off of thinking in those kind of terms. You know, if you look at a, you know, you're filling up your tank with gas or whatever, you know, you look at various increments. So that's not unreasonable. But, yeah.
spk04: All right. Something like that. Thank you. Second question, a little more of an administrative one, but one that impacts shareholders. It's been a while since the direct share price has been under a dollar. Can you remind us what your timelines are in terms of having to take some action, either to get the share price above a dollar through reverse split or through market action before there would be any delisting issues?
spk06: Yes. We're, you know, unfortunately that, you know, we, we saw a, you know, a reasonable market cap, but just the unfortunate thing is, you know, we have, you know, have because of the long, um, history of the company, a great number of shares out there. And so our price is, you know, where it is in this current market. Um, but we feel very comfortable where we are from a financial standpoint at this point in time with regard to the, um, So there's a point at six months, which I think comes in the mid of this year, a little bit past the mid of the year, and then you have another 180-day grace period. I don't know, Matt, do you want to speak to that?
spk07: Yeah, just briefly. I think if the stock price goes over $1 for 10 consecutive days before August 8th, then we're kind of out of the penalty box. If not, as Jim mentioned, we have another six months to get there. And one other way of getting there would be to seek shareholder approval to do a reverse stock split. The NASDAQ would accept that if you have to go that route.
spk06: I can tell you we are working on initiatives and things to hopefully not allow that to happen, but one never knows.
spk04: Right. So August 8th, I think you said, is kind of the first penalty box date. So we've got quite a bit of time between now and then.
spk07: Yes, and even then there's solutions.
spk04: Okay, thank you.
spk01: Okay, and as we're saying, we are out of time for questions.
spk06: Okay, well, thank you, Lisa, and thank you for everyone listening. And as always, if you have additional questions, please feel free to reach out, and we look forward to talking to you all soon. Take care. Bye-bye.
spk01: Okay, this concludes your call. You may now disconnect.
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