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Walter Klemp

Thank you, operator. Good morning, everyone, and thanks for joining us today. I'd like to kick things off with a brief overview of where we are. The entire Moleculin team has been laser focused on the launch of the MIRACLE Phase 3 pivotal trial for Annamycin. Now, this is a study designed to win approval for Annamycin in combination with Cytarabine for the second line treatment of relapsed and refractory AML patients. This is a global study with sites planned for the US, Europe, and the Middle East. The 25 sites have been selected to date and we've already announced regulatory and ethics approval in our first European country and we expect several more in second quarter. Patient screening has already begun and we still expect our first patient to be treated yet this quarter.
Now, in terms of managing expectations, I should point out that the US will likely be one of the last countries to begin enrolling in this trial. Now, that's not unique to our trial, but rather it's a function of the fact that the approval process between institutional review boards, ethics committees, and hospital contract negotiations just takes longer than in most other countries. We do already have our first IRB approval in the US, but in terms of overall timelines, you should expect the non-EU and Middle Eastern countries like Ukraine, Egypt, and Georgia to start first, followed by the more traditional EU member states, and then finally the US.
One of the most important and exciting aspects of the MIRACLE Trial is the amount and timing of visibility that Moleculin stakeholders will have. Unlike most pivotal Phase 3 trials, we will have multiple unblindings of data so that there is line of sight to exactly how we're tracking. The first of these will be when we reach 45 subjects and we expect to achieve that before the end of this year. Then there will be a second unblinding at the end of Part A of the trial at between 75 and 90 subjects. That should be in the first half of 2026. Part of the reason we expect this to happen so quickly is that the primary endpoint is complete remission after just one cycle, which is approximately one month. So roughly 30 days after the 45th subject is treated, we will be able to see how the drug is performing.
The other really exciting part of this is how much we already know about Annamycin in second-line AML patients. As Paul will discuss in his segment, our Phase 2 data just keep getting better. Overall survival keeps climbing at 11 months and durability has reached nine months and is still climbing. As a reminder, the performance of Annamycin in our latest Phase 2 trial was better than any drug ever approved for second line AML patients. Also, as we discussed -- as disclosed recently, our latest analysis shows that Annamycin overcomes resistance to Venetoclax in AML and is delivering durable complete remission in patients where Venetoclax has failed. And through all of this, we continue to see a complete absence of drug-related cardiotoxicity.
As I mentioned at a recent conference, the latest Annamycin results were frankly so good that a lot of industry players simply didn't believe them. But I can say with confidence that that is beginning to change. A number of key opinion leaders in the US and Europe have now reviewed the data in detail and have even discussed the results with the investigators in the trial, who by the way, spanned seven sites in two different countries. These experts are now recognizing the significance of the data and the potential importance of Annamycin for AML patients. And they are now speaking out about the game-changing implications of what, if approved, will be the first ever non-cardiotoxic anthracycline.
Let me now hand the call over to our Senior Chief Medical Officer, Dr. Paul Waymack, to discuss our clinical activity in more detail. Paul?

Paul Waymack

Thank you, Wally. Well, as we have noted during prior updates, there is an incredible unmet need in AML. And especially for those patients who either don't respond to initial therapy, that is their refractory to current therapies, or quickly relapse after first-line induction therapy. And you can see from our Phase 2 data obtained in our MB106 clinical trial, this is where Annamycin excels.
As we have previously reported, we achieved a 50% complete remission rate in these second-line patients. We treated with Annamycin plus high-dose Cytarabine, which is more than double the performance you would expect from existing therapies. And the durability of our responses continues to improve. As Wally mentioned, our median progression free survival has now increased to nine months with our overall survival amongst second line therapy patients at 11 months. And as we previously reported, 78% of them were recorded as negative in terms of measurable residual disease.
So for second-line therapy patients, we believe that our durability is shaping up as truly a game changer. This 50% CR rate in second-line therapy with Annamycin plus high dose Cytarabine compares very favorably to a 17% to 18% CR rate reported in two large recent clinical studies in patients with refractory and relapsed AML. And I should note that in both of these studies, the control arm used high dose Cytarabine, the exact same control arm we intend to use in our Phase 3 study.
Moving on to our new Phase 3 study, the MIRACLE trial. It was designed after an end of Phase 1/2 meeting with FDA. It is to be a randomized study comparing the dosing regimen with which we had great success in our MB106 study, that is, Annamycin plus high dose Cytarabine with the control arm of placebo plus high dose Cytarabine. We chose this design because FDA encouraged it and because two recent large randomized clinical trials in refractory and relapsed AML patients, that is the Mirros and Classic I clinical trials, which are the ones we mentioned in the prior trial, used it, and both achieved approximately a 17.5% CR rate among patients randomized to receive high dose Cytarabine plus placebo. To that end, we can expect we will need for our Annamycin plus high dose Cytarabine treatment arm to beat a 17.5% CR rate to a statistically significant degree for our drug to be approved by FDA for marketing. And again, in our MB106 study, this combination of high dose cytarabine plus Annamycin achieved a 50% CR rate.
For our Phase 3 study, as I noted, we will be comparing Annamycin plus high dose Cytarabine against placebo plus high dose Cytarabine. During Part A of the study, we will have two different Annamycin treatment arms, a 190 milligram per meter square treatment arm and a 230 milligram per meter square treatment arm. There will be unblinding of the data in Part A after the first 45 patients have completed their efficacy analyses and the second unblinding after between 75% and 90% of patients have completed their efficacy analyses. These interim looks at the data are, in part, to determine which of the two Annamycin dosing regimens will be taken to completion of the study. And the primary efficacy endpoint is the rate of complete remission of leukemia at approximately day 35. All patients will be eligible for standard treatments after completion of their experimental therapy.
We have already had one site that has been activated and believe that we may begin treating our first patient before this quarter is over. As I previously noted, Part A of the study will determine which of the two Annamycin dosing regimens take all the way through to completion of Part B. Part B will randomize 222 patients to receive placebo plus high-dose Cytarabine or Annamycin plus high-dose Cytarabine using whichever Annamycin dosing regimen Part A found to be superior.
The next slide documents our timelines. I should note, as shown on this slide, that there is a small possibility that the results from our analyses at the end of Part A could be so definitive so as to confirm the efficacy of Annamycin plus high-dose Cytarabine. If this were to happen, then we might be able, for ethical reasons, to complete Part B as a single-arm study.
Finally, let me note that although we have had no major clinical updates since our MB106 study completed enrollment last year, we have been quite busy clinically designing our Phase 3 study, obtaining regulatory approval for conducting the study on multiple continents, and signing up various hospitals and investigators to participate. As of today, we have approximately 25 sites selected to participate in the study and another approximately 45 who are in the process of completing the selection process. And we still believe that we can begin treating the initial patient in our MB108 study in this order.
Jon, let me pass the baton off to you now.

Jonathan Foster

Thanks, Paul. Well, as we've moved forward with the MIRACLE trial, as Paul just mentioned, so have we with our market cap and our capital raises. With our cash on hand at the end of the year, plus the roughly $9 million that we raised in February of this year, 2025, that combined cash balance of approximately $13 million takes us into the third quarter of 2025. Our focus in 2024 and into 2025 was and remains on the development of Annamycin, while relying on externally funded programs on WP1066 and WP1122. Overall, we reduced our operating expenses in 2024 over 2023 by about $3 million. Our current market cap is $16.2 million with 14 million shares outstanding. This is up from year-end to the issuance of equity in February of 2025. And our trailing one-year trading volume is 1.4 million shares per day.
We remain focused on operational execution and meeting our milestones, it's been very important to us. We've delivered on successfully contracting CROs and sites and early country approvals as we had planned for the MIRACLE trial. And we're looking forward to the next upcoming milestones. In the first quarter through the third quarter of this year, we'll be updating you on MIRACLE trial site selection and approvals by countries.
In the first quarter of this year, as Wally and Paul have discussed, first subject enrolled and treated in our MIRACLE trial, we'll also be doing the data readout and unblinding of efficacy and safety data by the end of this year. And then in the first half of 2026, we'll have the remaining patients given us a total, as Paul mentioned, between 75 and 90 subjects' data. We'll unblind that. We'll share that safety and efficacy data with you, and we'll also set the optimum dose for Part B of the MIRACLE trial. And then the milestones that follow these readouts, and almost just within a year from today, this speed of milestones we believe is exceptional for Phase 3 trial.
Additionally, we expect to publicly release the data readout from MB107, which is our clinical trial of Annamycin and monotherapy treating advanced soft tissue sarcoma metastases to the lungs in April. And we hope to use that data to develop a pivotal investigator-initiated trial in Europe later in 2025. So as one can see, we expect to be extremely busy in 2025.
Wally?

Walter Klemp

Thanks, Jon. Again, we want to thank everyone for your support throughout 2024. Now, it all comes down to this truly pivotal year in 2025. Look, Annamycin isn't just disruptive, it has the opportunity to change history, becoming the first ever non-cardiotoxic anthracycline. And its unique patented structure is designed to be not just safer and more tolerable, but its lack of cross resistance with traditional cancer therapies means it truly has the opportunity to fill a huge unmet need, not only in AML, but in a wide range of cancers.
The clinical advancement of Annamycin is now in extremely rare territory. You just don't find small biotechs that go into a pivotal Phase 3 trial with data better than any drug ever approved in the space and then have the opportunity for an early look at approval data. And in our case, the approval bar is extremely low, and we expect everyone will have a chance to confirm that before this year is out. Moleculin has a diverse, exciting pipeline and is guided by one of the most experienced development teams in biotech. 2025 is our year to bring this all together. You won't want to miss what's about to unfold.
So thanks again everyone and have a great day. Now, open for questions.

Question and Answer Session

Operator

(Operator Instructions) Jonathan Aschoff, Roth Capital Partners.

Jonathan Aschoff

Thank you. Good morning, guys. I was curious, what efficacy is required to pick one Annamycin dose at 45 patients rather than waiting until 90 if it doesn't happen at 45?

Walter Klemp

Well, that's a multivariable equation that we would be ill-advised to speculate in too much detail. But generally speaking, let me start by saying this, and I'm going to invite Paul to maybe give some additional thoughts. If we do as well in Part A, if Annamycin does as well as it did in the Phase 2 clinical trial, and HiDAC simply performs as prior clinical trials have indicated, then we probably hit that number, that statistical significance that's required to frankly shorten the trial and accelerate approval even faster. That said, I mean, one, we don't have to be that good to win approval, but I know you're asking what could excel, what would it take to accelerate. But there's another possibility here, and we would argue a probability, and that is that the HiDAC numbers are not -- are likely not to be as good as the historical numbers.
And the reason is because those historical numbers were allowed multiple cycles of the drug to get their 17% to 18% CR rate. Whereas our CR rate of 50% came with just one cycle, and that's all that HiDAC is allowed in this trial as well. So we expect HiDAC will probably underperform published statistics because they're going to be limited. It's going to be limited to one cycle. So there are multiple ways to get to the point you're looking for, Jonathan. And obviously, we can't speculate too much about which of those outcomes. That's why we got to run the trial. But, Paul, do you have additional thoughts there?

Paul Waymack

Yes. As Wally said, this is a multivariable equation with not only what is the efficacy, what is the safety, what is the pharmacokinetic data, there will be also the secondary endpoints. It is very difficult to predict. As I said, I think the odds are against us ending early, but it is a possibility. It is a definite possibility.

Jonathan Aschoff

All right. Thanks for that. Towards the end of the trial, what was the thinking that went into cutting off about 10% of patients from Part D? Was there much thinking behind that or not really that much?

Walter Klemp

Well, that really came as a result of FDA, when they review protocols, will often comment and make suggestions. In this particular case, they specifically requested or suggested that we follow a slightly different biostatistical scheme than originally planned. And that recommendation essentially allowed us to reduce the number of patients.

Jonathan Aschoff

Okay. That's straightforward enough. On the other program, what is the STS lung met efficacy bogey you need to hit to proceed to, even if it's just a investigator-sponsored pivotal trial?

Walter Klemp

Well, I mean, we've frankly already hit that. In really broad strokes, the STS patients we've treated turned out to be much more, if you will, challenged than we originally expected. The early part of the trial was focused on third and fourth line patients, but as the trial progressed and we got through the Phase 2 part of the trial, that got even worse. So now we haven't published, officially published the results yet, but we're about to. But what you'll see is we were really treating the bottom of the barrel.
And we were getting -- we're seeing OS numbers that are what you would normally expect in first-line patients who were treated with Dox, for example. Well, to get that kind of performance in third, fourth, and beyond line, it has already gotten the attention of sarcoma experts. One of the most prestigious sarcoma institutes in Europe has looked at the data and said, we'd really like to, we think this thing is ready for a pivotal approval trial and we'd like to be leading that if possible. So we still need to get the clinical study report done and published. Like I said, that's coming, but the data are very strong.

Jonathan Aschoff

A full investigator-sponsored idea for a pivotal trial. That was pretty much entirely inbound interest.

Walter Klemp

Yes.

Jonathan Aschoff

Thank you very much, guys.

Walter Klemp

Thanks, Jonathan.

Operator

Jason McCarthy, Maxim Group.

Walter Klemp

Hey, Jason.

Jason McCarthy

Hi, guys. Thanks for taking the questions. So first question, just in terms of the overall cost of the trial, what are you guys thinking there?

Walter Klemp

Jon, you want to handle that one?

Jonathan Foster

Yeah, I mean it's a Phase 3 trial, So if you go out to the full patient load, you're talking upwards of $60 million, $70 million. But our cash burn for the next -- rest of 2025 is $5 million a quarter. We've been very public about that. And then that goes up probably to $7 million or $8 million a quarter in 2026 as we begin filling out some of the CMC requirements for an NDA. And -- but what's very important to us is getting this data out so we can get back to conversations with bid and big pharma that are very, very interested in these midterm data readouts.

Jason McCarthy

Okay, great. And then just a more broad question here. I mean, we're seeing this theme emerging more in AML development of moving to frontline, once showing activity in the relapse refractory setting. You guys, just general thoughts there.

Walter Klemp

Yeah, I'm going to suggest that Paul tackle this question, but in general, we get that question a lot. Once we get approval in second line, is it logical for this drug to be used in first line? But, Paul, you want to expand on that?

Paul Waymack

Yes. Once we document that this drug works and have filed our NDA, we're going to be in multiple different areas. Now, one of which we have to be doing a pediatric study to comply with the pediatric requirements that are in place, we're going to be doing a third-line therapy study, which FDA requires.
But I agree with you. Ultimately, it's first-line therapy, which is the biggest market, because you don't get the second or third line unless you were initially a first-line therapy patient. And we have clearly shown, I believe, that unlike all other anthracyclines, we are not cardio toxic. Unlike other anthracyclines, we don't have a problem with the multi-drug resistance. And we do agree, however, that first line therapy patients should get 7+3, where the three is an anthracycline. So we should have that market plus half of all first-line therapy patients should get 7+3, where the 3 is an anthracycline.
So we should have that market plus half of all first-line therapy patients should get 7+3, but they don't because they're unfit, meaning they're over 65 or they have a heart problem. Well, that doesn't apply to us. We've treated people who are unfit in our 106 trial and we had no problems. So we agree eventually, first-line is our ultimate objective in AML and we will proceed there once we have shown that we're approvable for an NDA for second-line therapy.

Jason McCarthy

Okay, great. That's all for me. Thank you.

Operator

Vernon Bernardino, H.C. Wainwright.

Walter Klemp

Hey, Vernon.

Vernon Bernardino

Hey, Wally. Thanks for taking my question. And hey, Jonathan and John. Just wanted to follow up on the questions about the MIRACLE doses. Just wondering if you could walk us through the rationale for choosing the 190 dose discussions at the FDA, and then also what dose do you anticipate using for the soft tissue sarcoma trial?

Walter Klemp

This all relates to the now infamous Project Optimus that FDA has embarked on. But I think Paul's probably in the best position to maybe comment on the rationale and what we expect going forward. Paul?

Paul Waymack

Yeah. Obviously we chose 230 for this study because 230 got the great results we were seeing in our 106 study. For Optimus, FDA wanted us to go to a lower dose. We went to 190 because we had used that also in our 106 study and saw efficacy. And the FDA has not required us to go any lower. As far as which one I think will work, I actually think both of them will work to a reasonably similar degree. And so I think it's going to be a very close call.
It's not an easy pick. If I did 230 versus 110, I'd pick 230. But 230 versus 190, I can't make you a prediction right now as far as which one we'll use. We'll see what all the data show, because it's going to be a lot of data. It's going to be efficacy, short-term, long-term. It's going to be safety. It's going to be PK. It's going to be a wealth of data, which we're going to have to go through very quickly.
As far as the sarcoma question, it's an entirely different dosing regimen. We have used monotherapy to get our results, but we've used a much higher dose. We've used just one -- each cycle is just one dose. We're around 300 milligrams per meter square. We're getting good efficacy, reasonable safety. So I think we will be around there, but before we were to finalize a dosing regimen for a pivotal sarcoma study, we would request an end of Phase 1/2 meeting with FDA to get their blessing on their entire plan.

Vernon Bernardino

Okay. Thanks for that. Just one follow-up. Regarding the 190 dose, I guess we could expect if it was 230, you're going to hit and be better than HiDAC CR rates for what was observed in Mirros and Classic I. But in the 190 dose, do you have to be superior to the 17%, 18% that was observed to continue to perhaps apply for early or you still need to go to 230 if --

Paul Waymack

Yeah. When we look at the interim results, if one dose is clearly superior to the other, let's say 230 has a much better complete response rate and similar safety, then the comparison would be the 230 dose versus placebo. We're going to have to be better than whatever we get with the placebo plus high dose Cytarabine in order for FDA to approve it. If we go through all the way, randomized part B, if our data from 106 are anywhere close to resembling what we're going to get in 108, it's going to be an easy win.
As far as if we document statistical significance just after part A, it's a little complicated because of the fact that biostatisticians will tell you the alpha of [0.05] is for the entire trial. And so you save most of it for the end. So 0.05 would not get you approval after Part A. It would have to be a very statistically significant number. The P would have to be less than 0.01. How much less? That, again, it depends on the totality of the data, on the safety data, the PK data, and the efficacy data. So it's difficult to predict.
It's easier to predict for, we go through to Part B, because there, unless something really bad happens, as long as your improvement with Annamycin plus Cytarabine is significant compared to placebo plus Cytarabine, and the P is less than it's going to be about something like 0.048, we lose a little of that because of the interim look. It's an easy call that we will win. After Part A, it's a very complicated process. It's difficult to do --

Walter Klemp

Let me add one insight here, Vernon, that might also kind of tie this together for you. Let's just say that we get to the 45-subject level, and it's just obvious that 230 is a better choice than 190. And we could shorten that by saying more effective, but it does have to be -- have to meet all the safety requirements too. So safety and tolerability and have a decent PK profile.
So let's just assume that all those boxes are checked and 230 is clearly a better choice than 190. At that point, we probably would just drop continuation of treatment at 190. Now, there's a timing problem here. It's a good problem, but it's still an issue. And that is that once you get 25 sites up and running, the rate of recruitment picks up dramatically. And so by the time we get the 45-patient data, scrub it, and lock the database and disclose it, we could well be all the way to 90 patients anyway.
But in a perfect world, if we saw the results at 45 and let's just assume that 230 was the winner, then we would stop recruiting the 190 arm because we don't need any more data. And that's why when you look at our Part A in the timelines and the disclosures that we say somewhere between 75 and 90 patients. And that's because we're anticipating the possibility that we may have a clear winner at 45 and therefore no need to keep recruiting at the other dosage. Does that make sense?

Vernon Bernardino

Yes. Will that be able to preserve the 190 though? Such that, should any safety signals appear?

Walter Klemp

Of course, that's always a possibility. And we don't want to sound overly confident here, but we've got enough experience with this drug, not just in MB106, but in MB105 and MB104 that were, the single agent trials in AML, as well as the STS trials, we've got a pretty clear picture of the safety profile of this drug even above 230. So we're, I think that's a very unlikely event, but of course if we got down the road and it looked like 230 was all of a sudden surprisingly a problem, then we could revert to 190. But I believe we will have enough data certainly by the end of Part A, that everyone will have a lot of confidence in that choice.

Vernon Bernardino

Thank you. This is very helpful and insightful. Thanks for taking my questions.

Walter Klemp

You bet, Vernon.
So operator, I think we're done. Appreciate everybody's time and attention. And again, thanks for joining us.

Operator

Thank you. That does conclude today's teleconference and webcast. You may disconnect your lines at this time and have a wonderful day. We thank you for your participation today.