We appreciate everyone's patience. Good morning, and welcome to Moleculin Biotech's virtual acute myeloid leukemia KOL event. My name is Janine Thomas, and I will be the moderator for today's event. At this time, I would like to remind our audience that remarks made during this webcast may state management's intentions, beliefs, expectations, or future projections. These are forward-looking statements and involve risks and uncertainties. Forward-looking statements on this call are made pursuant to the Safe Harbor Provisions of the Federal Securities Laws and are based on Moleculin's current expectations, and actual results could differ materially. As a result, you should not place undue reliance on any forward-looking statements. Some of the factors that could cause actual results to differ materially from these contemplated by such forward-looking statements are discussed in the periodic reports Moleculin files with the Securities and Exchange Commission.
These documents are available in the Investors section of the company's website and on the Securities and Exchange Commission's website. We encourage you to review these documents carefully. Additionally, certain information contained in this webcast relates to, is or is based on studies, publications, surveys, and other data obtained from third-party sources and the company's own estimates and research. While the company believes these third-party sources to be reliable, as of the date of this presentation, it does not independently verify and makes no representation as to the adequacy, fairness, accuracy, or completeness of, or any independent source or verify any information obtained from a third-party source. Any data discussed regarding clinical trials and progress are considered preliminary and subject to change. So for today's agenda topics, we will start with KOL introduction, then move right to an Annamycin overview.
The discussion will then turn to anthracyclines, powerful treatment tools, then Annamycin's potential to revolutionize the AML treatment landscape, followed by Annamycin, the first non-cardiotoxic anthracycline, and ending with Miracle, the phase III pivotal clinical trial. Joining us on today's call from the team are Walter Klemp, Chief Executive Officer, and Dr. John Paul Waymack, Senior Chief Medical Officer, along with key opinion leaders, Doctors Andreeff, Michael Andreeff, Giovanni Martinelli, and Mohamad Cherry. I'd like to welcome everyone, and we'd like to start with introductions. Dr. Andreeff, we'll start with you.
Yeah, good morning. So I'm a attending physician professor at the University of Texas MD Anderson Cancer Center. I've been involved in leukemia, preclinical research and clinical research for a lifetime. That means very long, and I'm very excited about having finally a new class of agents, an old class of agents with a new agent, that I think has the potential to make inroads into leukemia treatment.
Excellent. Thank you. Dr. Martinelli, we'll go with you.
Yeah, I'm Giovanni Martinelli, University of Bologna. I was for six years also, Scientific Director of Comprehensive Cancer Care Research Network in Romagna, a region of 1.2 million. In my career, I'm constantly involved with in acute myeloid leukemia patients treatment, and, I have my background, roughly 22 clinical trial, in which we started from the dose finding to the registration and reimbursement of the drugs. So most of the drug that are being used in this moment has been passed to my, to, to my hands. So I'm proud to be part also on the developing of these drugs of Moleculin.
Great. And Dr. Cherry?
Thank you for the invitation. I work in Morristown, New Jersey, and I'm the Medical Director of Hematology and Oncology. My main interest is acute leukemia. Actually, I did some of my training at MD Anderson, where Dr. Andreeff is working, and then I came back to University of Oklahoma, where I built the leukemia program close to 14 years ago. Then after seven years, I joined Morristown Medical Center to build the blood cancer program. My main interest, as I mentioned, is acute leukemia, and I'm highly involved in clinical trials, and I'm very interested in the discussions today because the concept of a non-cardiotoxic anthracycline is very, very important in my opinion, and I look forward to this discussion today.
Wonderful. Thank you. So, Wally, you.
Yeah. Thanks, Janine, thank you to our esteemed panelists for joining us today. We view this as a very significant event for analysts and investors. To be sure, those of us that are focused on Moleculin stock are honestly baffled that our market cap is nowhere near what it should be for a phase III asset in a space like AML. It, it's certainly not consistent with our data. Annamycin has delivered some strong efficacy results that we'll ask our panelists to review today, and we've shown in 84 patients treated so far that our drug is completely non-cardiotoxic, something that never previously thought possible with an anthracycline.... We've got an exciting phase III plan that we'll discuss today as well.
And in addition to our strong efficacy and safety data, our drug is patented through 2040 with both Orphan Drug and Fast Track Designation. And all of this has us positioned to deliver important milestones as we finish this year, starting up the MIRACLE trial that we'll talk about today. We expect to announce first patient treated in the first quarter of 2025, and even to provide a peek at the data by the end of 2025. So things are moving quickly, but perhaps most importantly, our key unblinded data readout is expected in mid-2026. And we really believe at that point, that's when development partners will likely be involved to a much greater extent. But all of this begs the question: where is the disconnect in the Annamycin opportunity?
Frankly, this call is really intended to help tease that out. Now, clearly, there are some factors that are common to a lot of small biotechs, including the market in general, which is terrible, and the concern for financing overhang. But there's also a factor that's unique to our technology. And in my view, for the last five years, especially, all investors have been hearing about in the AML space and oncology in general are targeted therapies. And targeted therapies are important, but the fact is that nearly half of all cancers are still treated with an anthracycline. I mean, 32% of all breast cancers, half of AML patients, 70% of all lymphomas, and 60% of all childhood cancers are treated with an anthracycline.
Yet for all their success and importance, anthracyclines haven't fundamentally changed in over fifty years, which means they don't often hit the radar screen when investors are looking for biotech plays. And we think that's really what makes Moleculin such a hidden opportunity. Now, the purpose of today is to give analysts and investors a chance to hear directly from practicing clinicians and thought leaders in AML firsthand. So let me start things off by asking just some positioning questions. First off, notwithstanding the intense focus on targeted therapies in recent times, is it fair to say... I'm asking the panelists now, is it fair to say that there remains a significant unmet need in relapsed refractory AML?
Who starts first? Me?
Yeah. Go ahead. Dive in. Go ahead.
There is a great need of new therapy, a new approach in relapsed refractory acute myeloid leukemia. Most of the companies, I mentioned the big co-pharma companies. I'm in contact with more than 400 pharmaceutical companies in this moment, and you are one, the more relevant one, who decided to work on relapsed refractory acute myeloid leukemia. I presented two years ago a project, a European Commission that was financed for EUR 6-7 million, which is nothing for a pharma, but is a lot of money for university. In order to collect acute myeloid leukemia, relapsed refractory. In Europe, we are expecting to get 22,000 people every year, in this moment, still alive, with a relapsed refractory acute myeloid leukemia.
There is so a big, huge capacity and potential to treat these patients, that in this moment, the survival is less than three months. I personally find very important for a pharma company to stay in the field, to activate and stay in the field with a clinical trial in relapsed refractory acute myeloid leukemia. We are, as we were thirty years ago, in the newly diagnosed patients in relapsed refractory. We don't have drugs, we don't have any possibility. Only one company, which is the Astellas, with gilteritinib, as you mentioned, a targeted therapy, is the only one who has a drug produced in Europe, which is a big market of acute myeloid leukemia in this moment, that are getting a registration of the drug in relapsed refractory.
Also, venetoclax is not registered completely and not completely full plenty in all the European states in relapsed refractory. So there is a totally opportunity for a company to develop their drugs in a relapsed refractory.
Dr. Andreeff, I know you're part of a team that helped develop venetoclax. I'm curious from your perspective. I know in a previous conversation with you, you said to me that you thought that the lack of cross-resistance that Annamycin seems to have might be as important as the lack of cardiotoxicity. Could you expand on that?
Yeah. So let me comment on the venetoclax scenario first. We now have remissions in 70%-90% of patients. Many patients could not even be treated before. However, the vast majority of these patients relapses. And that's where new agents come in, and it will not be highly targeted agents. We need agents that have a broader spectrum of activity and do not target a single mutation. When you really think about last 15 years, there are two mutations that we can target, FLT3 and IDH. And I think that's about it. After 15 years, and venetoclax was so successful because it's not mutation specific. So now we have vast majority of patients who get initially venetoclax and a hypomethylating agents, and then they relapse. And now what?
So now we need agents that are not cross-resistant as venetoclax, and have a different mechanism of action, for sure. And so now we are falling back to our old-fashioned chemotherapy, which hasn't changed in 50 years, as you point out. And now we have a new anthracycline, which may be much better than idarubicin and daunorubicin, and that's the starting point, I think, for this conversation.
Great. Dr. Cherry, any thoughts to add here?
I mean, definitely there is unmet need, and we have to remember that more than 50% of patients are still dying from AML, despite all the recent advances, and the situation is more grim in the relapse refractory setting, where if you don't have a targetable mutation, then your only chance for cure is bone marrow transplant. And as you everybody knows, many of our patients are not candidates for bone marrow transplant, because we're dealing with an older population. So, the exciting idea about a new anthracycline without cardiotoxicity is extremely important, and especially where venetoclax might fail. As Dr. Andreeff has said, that after a hypomethylating agent and venetoclax, if you fail this treatment, then the outcome is extremely dismal. The survival is in the order of two to three months.
I feel that this is the area where there is unmet need, and I'm very excited about this study that you are conducting.
Fantastic. Let me just ask the operator if there are any questions from the audience at this point. We've got other more detailed discussions to go into about the data and the trial design, but in the overall positioning, are there questions from the audience?
Certainly. To remind the audience, if you'd like to ask a question verbally, you can press star one to be placed into question queue, or over the webcast at any time you can type your question to the Ask a Question feature on your screen. Once again, if you'd like to ask a question at this time, you may press star one to verbally ask a question, or you can type your question into the chat box. Our first question is coming from Jonathan Aschoff from Roth Capital Partners. Your line is now live.
Thank you very much. So, Wally, you know, you were talking about the stock, and I certainly get where you're coming from. And so my question is, I think what would help that immensely is if data could happen before, you know, roughly two years from now. So can you maybe help us understand how conservative your timeline estimate is now, and just therefore, how much room there is to show us some cards-
Sure.
sooner than, you know, twenty-four months from now?
Yeah, understood. And by the way, Jonathan, this will... We'll go into this in a bit more detail later in the program, but just, it's a very important question, so, let me give you the short answer, and we can give more detail later. But the short answer is, by mid-'twenty-five, so basically two and a half quarters from now, we expect to have some midpoint data that we think will be indicative of the direction this trial is going. And it's because of the math and the disparity in performance between the control arm and the test arm, but it will start to become obvious that Annamycin is winning this trial. And so you're right in asking that question.
We don't have to wait two years to know that we're winning, okay?
But you know, sooner than two years, like, what you're referring to, that will still be blinded, correct?
Yes.
It will just be performing as a group better than expected if everybody was getting nothing.
Exactly. It will be blinded, but when you do the math, because the HiDAC control arm has a pretty well-known history of a performance level, it will mathematically be obvious. It wouldn't be possible to have as many responses as we will be having if Annamycin weren't performing, so.
Okay, so, you know, just one more follow-on-
Yeah.
And then I'll stop for the moment. Exactly how consistent has your placebo group performed trial to trial, regardless of what trial it's been in? You know, it's still the same placebo group, and only in trials where they're looking at the same types of patients that you're looking at. You know, how consistent has that been over the last decade or so? Because that's gonna be extremely important.
We're gonna show you-
Your placebo group.
Yep, we're gonna show you a chart. Yep, we're gonna show you a chart that shows two very large published, very respected trials where the control arm was HiDAC, which is the same as our control arm, ten years apart. And there's barely a one point difference between the performance in those two different trials. And I know that when we get to that data, I know the docs here will wanna weigh in on. They'll have their own additional thoughts about that consistent data, right?
Okay. Just because, you know, you really have to have as the only variable, the blindness of your data. You know,
Yep
The placebo, it has to be really something you can depend upon, a given-
Yep
Performance when the data you're looking at is still blinded.
Understood.
All right.
I promise you, we're gonna drill down on that a little bit later in this program, okay?
Thank you, Wally.
Okay, you bet. Any other questions, operator?
Not at this time. I'll turn it over to you.
Sounds good.
Sure. We do have a question, actually, Wally, from the audience. Can you talk about how resistance forms to existing anthracyclines, and generally speaking, which tends to come first to, for patients: resistance, relapse, or cardiotoxicity?
I'll invite one of the clinicians to weigh in on that.
This question could be for me, probably.
Please, yeah.
Until now, we get a great, great confidence with this drug. We were a bit at the beginning; we get some potentially difficulties on preparing the drugs with pharma and. But on the clinical level, we find the drugs absolutely, absolutely sure and safe. All the patients treated were very, very well tolerating the infusion, and all the patients getting particularly no sign of difficulty to get the - and we don't get any management of the difficulty to deliver the drugs, and no cardiotoxicity at all until now. So it was true. Let me say, when you started experimental drugs, you, the company say is safe, but it's true that the drugs is safe in this moment. It's very safe.
I think too, if maybe I thought I heard something else in that question, which was, when you treat a patient first line, is it more common that they are refractory to first-line treatments? Is it more common that they relapse? And/or how common is it that you can't treat a patient first with seven plus three because of cardiac issues?
Is that for me, this question?
Any of the three. Any of the three is for you.
I find that when we move to a relapsed refractory population, so particularly the patient fit for previously three plus seven program or fludarabine-based intensive chemotherapy, or Mylotarg plus chemotherapy, three plus seven plus Mylotarg, and other patients has been treated this way. The patient comes out from this one or two cycle of initial chemotherapy, very fragile. Usually, the patients has lose a lot of weight. They are potentially previously infection, particularly lung infection, fungal infection. The quality of the patients, let me say, even if checked and controlled by the inclusion criteria, is a poor population. A population that is more fragile from the induction phase and the previously exposed to the chemotherapy.
So that population is a population that sometimes also has a prolonged exposure to neutropenia, and is a population that at the end of the day becomes an additional fragile population, even if they were fragile from the beginning. So it's very difficult to treat the patients in this situation. A lot of people believe that they have not to be submitted again to another course of this kind of drug, but the drugs we used was successful for at least safety profiling.
Hmm. Okay. Great, thank you. Other questions before we move to the next section?
That's it, Wally, we can move on.
Sounds good. Okay, so, let's we'll dive deeper now into a discussion of the data, and to do that, I'm gonna invite our Senior Chief Medical Officer, Dr. John Paul Waymack, to start us off. Paul?
Thanks, Wally. Annamycin has now accumulated a solid set of data, starting with single-agent clinical trials in AML patients in both the U.S. and in Europe, and culminating in our most recent combination trial, where Annamycin was combined with high-dose Ara-C or HiDAC, which generated some significant efficacy numbers and formed the basis for our meeting with FDA to establish a phase III approval trial plan. And when you look at the results from our last phase I, II trial, you can see why we are so excited about these numbers, especially in second-line patients.... where we saw a 50% CR rate, which we believe is significantly better than any drug currently approved for this class of patients.
These were not only durable responses, but we saw responses in fit patients coming off seven plus three therapy, and unfit patients coming off Venetoclax therapy, as well as other first-line therapy regimens. Now, we recognize the N is relatively small when we focused on just second-line patients in our study. But when you look at all the patients treated around the recommended phase IIF dosing regimen, in the last three trials combined, we're talking about 35 relapsed or refractory patients, showing a CR rate that would likely win approval if repeated in a pivotal trial, especially when you compare these results with the results that have won FDA approval thus far for second-line AML therapies. As you see here, of the five drugs approved by FDA for use in second-line AML patients, the average CR rate is about 21%.
And of course, since all these are targeted therapies, they are only relevant to a small subset of AML patients, which contributes to the significant unmet need for a broadly effective second-line therapy treatment. Molly?
Sorry to unmute. Sorry. Thanks, Paul. With this as a brief review of the data, let me ask our panelists to weigh in. Maybe to start with, given that targeted therapies have been approved on an average of a 21% CR rate, do you find the durable 50% CR rate for Annamycin compelling for second-line patients? I mean, I know you do, but I think our audience would like to hear it.
Okay, so the answer is unqualified yes, if we can sustain this.
Right.
You know, it's a small number, so I'm sure we are all cautious about this. But, if we get close to that, if we have 40%, that would still be. So in my own thinking, if a drug is one-third better than the standard of care, it should be approved. That means a one-third higher response rate or a one-third prolongation of survival. That's for me. P-values, for me, personally, do not matter. I don't care about the p-value if the survival benefit is one week or one month. So but that's my own personal standards. And when you look at the data, we are more than doubling the response rate here from 20% or less to 50%. If it's 40%, it's still a 100% more than what we have. So to me, this is highly significant.
So we need a phase III trial to show if this is real or not. And when you look at the individual patients that were treated, these are really bad patients. So I don't think there was a patient selection, which is always a suspicion when you have wonderful data. So these are bad patients, 50% responses. If you can replicate that in a phase III, this should lead to approval. That's my opinion.
Great. Any other thoughts, Dr. Cherry?
Yeah. I mean, what is interesting that even in patients with targetable mutations, you are getting higher response rate. And remember that 50% of patients don't have any targetable mutations. But as Dr. Andreeff mentioned, if this results are translated to the phase III clinical trials, and even if it is a little bit lower than 50%, this is, you know, a huge news for the community. Yes, definitely, you know, the preliminary results are exciting.
Great. Hey, Dr. Martinelli, one question we get often is, would you imagine that once approved and a safety track record is established, could you imagine Annamycin being used in a first-line setting? Oh, well, I think you're muted. You may be muted.
Okay, sorry. Apologize.
There we go.
Absolutely is a great drugs to be tested. I think is the best drug to be tested in this moment, in the first line, because it's a drug that there is no resistance mechanism. Until now, we know.
... against the use of these drugs. Of course, we are working on a general mechanism, which looks like to be not general, but is peculiar for acute myeloid leukemia. All the types of acute myeloid leukemia we know has a difficulty to be targeted in the self-renewal mechanism. So depending from the level of the leukemia stem cells, all the patient with an acute myeloid leukemia has a similar sensitivity to anthracycline. So this is a potential drugs that has to be introduced together with some target therapy. That's my opinion. Either or later, either or not, but it has to be integrated with the target therapy.
As I mentioned by Dr. Andreeff before, until now, there is a lot of emphasis on targeted therapy, but there is only the IDH1, and potentially also some cases of FLT3, but not all of them. ATRA, which is a general mechanism, ATRA and ATO, in promyelocytic leukemia, that are really able to eradicate the leukemia stem cells. So we need to get a backbone of drugs that works. I cannot say all the cases, but in the majority of the cases with acute myeloid leukemia. Probably the ABL1 positive leukemia is the only one who was and could be also resistant to acute myeloid leukemia treatment with anthracycline. It's the only type of 4% or 6% of the entire population of acute myeloid leukemia.
Another potential category that will be difficult to be touched by an anthracycline is probably the P53 double mutated. But the other types of leukemia could be on an, and are until now, extremely sensitive to the anthracycline, in particular these drugs.
Great. Great. Let me just ask anything from the audience as it relates to this question about the positioning of Annamycin and the data that Paul just went through?
Wally, we don't have anything at this time.
Sounds good. So, Paul, I think it's worth drilling down just a bit on the unique attributes of Annamycin, as this tends to get lost in the wider clinical discussions.
Yes, Wally. Indeed, the construct of Annamycin is at the core of what makes it so different. The inventor took key aspects from three different currently prescribed anthracyclines, then combined that with the addition of an iodine atom that significantly changed the PK and PD characteristics. The result is a complete lack of cardiotoxicity that initially the FDA was not buying into. In fact, in our first U.S. trial, FDA would not allow us to dose any patients over their current lifetime anthracycline limit. But I am happy to report that in our last meeting with FDA, we requested that the Cardio-Renal Division weigh in on this issue.
After being provided with the data from 84 Annamycin-treated patients, most of whom received well over the limit, and some of whom we took to over five times the lifetime anthracycline limit, the Cardio-Renal Division concurred with us that they saw no evidence of cardiotoxicity. And so they are now allowing us to treat patients over the lifetime anthracycline dosing limit in our phase III trial. Beyond the elimination of cardiotoxicity, though, we also see in preclinical models that Annamycin avoids the cross-resistance seen with a number of existing AML drugs. This not only includes currently prescribed anthracyclines, but also cytarabine and venetoclax. Wally?
Yep. Here again, it would be great to gain some perspective from the panel. You know, now that even the FDA is beginning to acknowledge Annamycin's lack of cardiotoxicity, can you folks comment on the utility of a truly non-cardiotoxic anthracycline?
I can mention that in the acute leukemia arena is extremely important fact, because the majority of patients diagnosed with acute leukemia, they would receive anthracycline and their induction chemotherapy. And over multiple lines of treatment, you reach, you know, the maximum amount, and for each anthracycline, you have, like, certain number.
... and often in the relapse setting, you face this dilemma, you might, like, exceed the limit because of the risk of cardiotoxicity. So, being able to give anthracycline despite this fact, and for example, many of my patients have secondary AML. They were treated for their breast cancer with an anthracycline years before this diagnosis, and even during induction, you cannot give anthracycline, which is very inconvenient and will affect the outcome. Now, we have studies that have shown that if you double the dose of anthracycline, especially for daunorubicin, from 45 milligrams per meter square to 90 milligrams per meter square in frontline AML, you are improving the response rate and overall survival.
In AML is extremely important, and this, in my mind, translate to other cancers where anthracycline is useful.
Dr. Andreas, it looks like you had a question.
Yeah. Yeah, I'd like to add a different twist. On the slide, you could see that this drug is MDR1 independent, so that's the P-glycoprotein that pumps out anthracyclines and many other agents. To me, that would indicate that perhaps Annamycin is just a better drug, so regardless of the lack of cardiotoxicity, which I think I was present at this FDA meeting, and I think it's pretty clear there is no cardiotoxicity. Beyond that, we need better drugs. Annamycin has the potential because of the independence of MDR1. To follow up with what Giovanni was saying, AML stem cells have very high levels of MDR1 P-glycoprotein, and a drug to eliminate these cells has to be independent.
Venetoclax does that to a degree, but Annamycin, I think, has the potential of doing that as well. So it's not just the lack of cardiotoxicity, I think it's the potential of having a much better anthracycline that makes it interesting.
Yeah, definitely.
If I can add something regarding this. We strongly need an MCL-1 inhibitor for treating and promoting apoptosis in acute myeloid leukemia stem cells. And we know the anthracycline, whatever is the types, Annamycin is probably the best one, promote a strong MCL-1 inhibition without any endothelial activity. So the endothelia are still remain protected, because they express several times more MCL-1, and so the endothelia are protected. In the meantime, the blood cells, particularly the stem cell blood cells, are targeted. So this is another issue that we need to get an anthracycline. We are talking about leukemia, we can talk regarding all the types of cancer.
If we get a strong MCL-1 inhibitor, we induce a strong irreversible pro-apoptotic activity, which means that whatever is the DNA damage level, whatever is the background molecular or cytogenetic alterations, we strongly promote the apoptosis. This is unable to repair the activity that MCL-1 inhibition will promote at a pro-apoptotic level. So it's a drug with a greater vast majority of activity on leukemia stem cells, whatever is the background genomic or molecular.
Thank you. Thank you. We're about to move on to the discussion of the phase III trial, but before we do, are there any questions from the audience on what we've covered so far?
We received a question from the webcast. The question is: Can you talk about the difference in dosing for Annamycin versus the three other anthracyclines you showed on the previous slide? Are patients able to get a higher dose or a similar dose, but perhaps for longer duration, or both?
Great. And let me just, for positioning, because not all the panelists are focused on the specific aspects of the trial history here. But most of the patients treated, where we've seen responses, have been in the 190-230 milligrams per square meter of Annamycin. That, of course, is in combination with HiDAC. So that's your reference point versus, let's say, traditional seven plus three therapy.
Can I make a comment for our person who are listening? I don't believe we have to increase the dosage to match the doses of an anthracycline. A lot of company make the mistake to consider the initial stage of leukemia as the only one to be cured. So when we start to treat leukemia, we get thousands and thousands of billions of cancer cells, and so we need more drugs. But moving to the reduction, the cytotoxicity activity, we need daily less drugs. And particularly in the elderly population with an acute leukemia, we make experience that also in Venetoclax patient, we start at the beginning with 800 in a B-cell leukemia, then we reduce it to 400, then we reduce to 200.
Now, we know that for elderly, very elderly, fragile population, we can use only 50 milligrams of venetoclax. And this is the same for all the drugs from ponatinib in acute lymphoblastic leukemia with tyrosine kinase inhibitor. All the drugs we are using, we start with a lot of drugs because we get a great amount of cancer stem cells at the beginning. But after a few days, a few hours, these great amounts of cells come down. So I'm not afraid to reach the higher level of infusion of these drugs, since probably we don't need to reach so high level. Also, this will be important for the development, the price, and so on.
But, it's important to understand how we can treat the patient with the low level of the drugs, which low level can be reached in the majority of the patients with without any significant toxicity, particularly in the combination that we need to have in order to avoid any mechanism of resistance.
Yes, yes, Michael?
Can I add to this? Dr. Martinelli talked about the inhibition of MCL-1. So MCL-1 is the most important resistance factor to Venetoclax, and the MCL-1 inhibitors have failed and discontinued, that's a different topic. But if Annamycin inhibits MCL-1, the combination of Venetoclax and Annamycin would be the next step, not just Ara-C Annamycin, but Venetoclax Annamycin. There's a huge unmet need for that, because, as I mentioned before, the vast majority of patients relapse after Venetoclax. And we have published several papers showing that MCL-1 is the main resistance factor. So require some pre-clinical work. This could be done in four weeks or two months to show that Annamycin should be highly synergistic with Venetoclax.
Of course, that's not for today's discussion, but to give the audience an idea where this could go, not just with ARC, but certainly with venetoclax, which would open up a huge number of patients, of course. Thank you.
Fantastic. Well, Paul, I think we should keep plugging forward and dive into the phase III clinical trial.
Indeed. As Wally alluded to earlier, we had a very productive meeting with FDA, where they were impressed by the strength of our phase II data, and FDA agreed that a phase III trial could be constructed around using CR rates, that is complete remission rates, measured approximately one month after initiation of therapy, as the primary efficacy endpoint for a new drug application approval. We are calling this the Miracle Trial, which stands for Moleculin Relapsed Refractory AML, Annamycin, Clinical Evaluation, and hence, the acronym. And part of the reason why we are so excited about this trial is that it allows some early looks at the data. Part of this stems from the fact that the FDA asked us to evaluate more than one dosing regimen of Annamycin using an adaptive trial design.
We have structured this as an adaptive trial design with a part A and a part B. In part A, we are comparing Annamycin using two different dosing regimens in combination with HiDAC to a third treatment arm using HiDAC plus a placebo. This three-arm comparison design will allow us to break the blind after the initial 90 patients, thereby allowing us to select the optimum Annamycin dose to be used to complete part B of the trial. Of course, this also enables us to see how the trial is progressing with unblinded data. With as many as 90 patients, we think this will end up being a fairly definitive read on whether or not the trial is destined for success. It is worth noting that we believe approval has been significantly de-risked, in that the historical CR rates for HiDAC are very well established.
Two large, major published studies generated highly consistent HiDAC CR rates in refractory or relapsed AML patients at around 17%-18%. Now, if you compare those numbers with Annamycin's results in all refractory relapsed AML patients, we're seeing about double that performance. But the Miracle trial will not be conducted in all refractory relapsed AML patients. It will only be in second-line AML patients, where our performance is almost three times better than HiDAC alone. Given that history here, we feel confident that the Miracle trial will lead to a new drug application approval. Wally?
Thanks, Paul. Given the question that we got from Jonathan Aschoff earlier, I wanted to kind of circle back to the panel and ask your opinion about how consistent you think the response rates should be from HiDAC as a control arm. I mean, how reliable do you think that 17%-18% performance number is? You're on mute, Dr. Martinelli.
It takes time sometimes to move around on mute, to mute. Sorry, I apologize. The question is correct, and we are conducting now a pragmatic clinical trial that I'm spreading all the Europe. We get in this moment 18 countries that participate to the so-called impact acute myeloid leukemia program. And the question was in this pragmatic after relapsed/refractory acute myeloid leukemia, if a patient is sufficiently fit, what's the best procedures, what the best treatment could be? An intensive one or a non-intensive one. Which means an intense one, which is whatever is currently present in relapsed/refractory AML patient, Fludara, FLAG-Ida, MEC, HiDAC, and so on, which is the current European program for relapsed/refractory population fit for chemotherapy again.
Let me say, the patients are not too much excited to pass through another high-intensity chemotherapy program. Secondly, in the low intensity, there is only Ven-Aza. That we know that Venetoclax, Ven-Aza, has a roughly less than 47% potential capacity, and most of the patients had a pulmonary infection, and some of them died. We get at least 5% of deaths during the treatment. So the possibility of intensive chemotherapy, personally, I'm not so excited to make a difference in harm between 119 and 230, if I understood correctly, the dosage. Because what's the difference will be just 30 milligrams more of anthracycline, if this anthracycline is active in the majority of the patients.
So personally, I don't find this an exciting part of the project, even if necessary, probably because it has been discussed with probably FDA and so on. What I'm thinking is, is this a program only for fit patient relapsed, or we would like, the company would like to also to catch all the intermediate fit for chemotherapy? The patient that the clinical European clinician has adopted to treat the patient with intensive chemotherapy again, versus some less intensity approaches since the patients. I'm thinking about the sixty-five, sixty-eight, seventy-two years old population that, but probably also sixty-one, who has failed the first intensive chemotherapy and then has to be treated again.
Is this approach that can catch the majority of relapsed refractory population in order to get a clear indication that Annamycin could be or will be the best drug to treat any relapsed refractory population? That is my refuted question to the panel.
So, Paul, you might weigh in relative to inclusion, exclusion criteria here, because I think that speaks to Dr. Martinelli's question.
Yes. In our phase I, II study, we enrolled all patients, be they fit or unfit, including we have one 80-year-old who is now a year and a half post-treatment, still in complete remission, traveling the world. So we are not limiting it to just fit patient or unfit. They both seem to do very well. Even the unfit, they do not have cardiac deterioration, they tolerated generally well. So for our pivotal trial, we are allowing any patient to enroll, be they fit or unfit, within reason. As long as they don't have liver failure or kidney failure, they can be enrolled because they all did well in our phase I, II study. That also helps speed recruitment, I would point out.
Yeah. Yeah, that will be very important. The speed recruitment will be an important issue. So the proposal is very exciting, and it can be fitting a lot of interest at European level, at least. And a lot of country doesn't have nothing, because they get nothing to be proposed a relapsed/refractory AML population. So even if I prefer to simplify the program that has been discussed with the FDA, so is probably the good program to be done. I personally believe that if you get a good data with the 190 milligrams, why not to use this, which is probably the most safer?
Because you have not only cardiotoxicity, you have to take in account also the fungal infection, the lung infection, the fever, the general infection that anthracycline could integrate in the activity. So it's not a fragility related only to cardiotoxicity, but it is related to the patient that we are treating with a failure before, and a long, prolonged high exposure to intensive chemotherapy. So-
I would point out, that is why the FDA requested this design, where we do 90 patients with the 230 milligrams, the 190 milligrams in placebo, so that if there is no difference, we will go forward with the 190. I would also point out, as Wally has stated in the past, we know what to expect from HiDAC. Those two trials each had over a hund- well over 100 patients getting HiDAC plus placebo, so this 17%-18% is pretty well established. So although we will not be unblinding the data, if we the data as a whole, when it is still blinded, Annamycin versus placebo, if we are getting CR rates of 30% or better, we got a pretty good idea from where it is going, or at least I think we can guess.
Dr. Cherry, Dr. Andreeff, would you agree with that, that kind of mental gymnastics there, that the HiDAC performance is well enough known in history that we can probably make that kind of conclusion?
There's nothing better known than HiDAC, right? After fifty years, after fifty years, you should have some idea what the efficacy is.
Okay.
Yeah, yeah. This is another point. Sorry, Cherry. Mohamad, sorry. This is another point that the control arm is not so attractive either for researcher or for the patients.
Yeah.
Personally, I believe that we know what we are expecting with HiDAC. And this is something that arises the question, who the patients who will receive HiDAC without getting suspicious that the rate of CR could be so low in this arm? So personally, I believe that venetoclax/azacitidine in relapsed/refractory population could be a control arm. I don't know what the NDA, also what the FDA is asking for a company in the intensive chemotherapy. But probably the intensive chemotherapy could be a potential control arm also in this program.
Dr. Cherry, looked like you had a comment.
I mean, it's an acceptable, you know, comparative arm, and I imagine many of the patients that will get enrolled have already received Venetoclax and hypomethylating agent, and this is in the second line setting, but for HiDAC as a single agent, I think what is proposed and the percentage of CR are consistent with the historical value.
Mm-hmm. And it's worth pointing out, Paul, I think, mentioned this in his section, but to your point, Dr. Martinelli, we were very sensitive here. In fact, Dr. Andreeff was on the phone with the FDA, explaining to them. Because originally, the FDA wanted this to be a longer duration of treatment, and Dr. Andreeff just said: "Look, you know, that's borderline unethical to treat someone who's not responding, to continue to treat them with HiDAC." And as soon as the word unethical came out, the FDA backpedaled quickly and said: "No, no, no, no. We don't want anything that might be considered unethical." And what was suggested was that after thirty days, if the patient's not responding, they can move to, essentially, investigator's choice. And so to your point, Dr.
Martinelli, we think it, this at least helped to make the trial maybe a little more attractive. Even if a patient's going to get the control arm, it's only thirty days, and then immediately moved to, you know, whatever their clinician recommends.
As a former FDA medical officer, let me also point out that this design they wanted, where the HiDAC can be expected to get a 17%-18% CR rate, the drugs the FDA has approved for second-line therapy, their average is 21%. It's not a big difference between 18% and 21%, and as Wally said, after 30 days, you can go into anything you want, and we are not having difficulty finding sites that wanna be part of this study and consider this study an ethical study.
Yeah. Let me just pause for a moment and make sure there aren't any questions from the audience that we can wrap this up with.
As a reminder, if you'd like to ask a question verbally, please press star one, or you can type your question into the Ask a Question field on your screen. Janine, over to you at this time.
Thank you, Kevin. So Wally, we do have quite a few from the web, and I will start asking them now. So the first one is: Can you talk about the difference in dosing for Annamycin versus the three other anthracyclines you showed on the previous-- I think we just asked that. I'm sorry.
Yeah.
I apologize, Wally.
Yep.
Yeah, sorry. So is the strategy to seek FDA approval for Annamycin-Ara-C combination or Annamycin standalone? And if the latter, will the trial tease out the benefit of Annamycin versus Ara-C to support the approval?
I guess that's for me.
Sure.
The indication for the initial approval would be the combination for treating refractory relapsed AML, and it would be based on our having a higher CR rate with Annamycin plus HiDAC, compared to HiDAC alone. That would be our initial indication. Obviously, as has been discussed, we would move on to other leukemias, or we would move on to first line, we would move on to third line, we would move on to other leukemias, other cancers in general. But we're going down this road first because it's the quickest path to an NDA.
Okay. Our next question: What is the cost of the phase III A, approximately?
That estimate is around $60 million.
Okay, Kevin, can you take Chad, please?
Certainly. We do have a question from Chad Young from Maxim Group. Your line is now live.
Hi, yeah. We were just wondering if you could remind us on potential timelines to data and what would be considered a clinically meaningful outcome?
Sure. So, the trial, we're right now in the site selection mode, and we expect to have our first patient treated in January of 2025. We're bringing on a lot of sites. There's a tremendous amount of interest here, and we'll be on multiple continents. So it should move quickly. We expect to reach the midpoint of part A of the trial by, let's say, around the fourth quarter of 2025, third or fourth quarter of 2025. And at that point, as we've been discussing, we would be able to share the data broadly, the overall data with the public.
It will be blinded, but because there's such a huge differential in expected performance between the control group and the test group, it will be mathematically obvious whether or not the trial is succeeding. That's why Jonathan was kind of trying to drill down on how reliable the HiDAC numbers are, and Dr. Andreeff kind of put that one to bed for us. And then the next milestone of data would be the completion of part A, and that's expected in around second quarter, let's call it mid-2026.
Great.
Great. Okay, our next question from the web is: Are you expecting much of a difference in response rate between the two Annamycin doses? And given these patients are earlier stage than your previous study, do you think that there's potential to push the dose even higher?
Paul, do you want to start us off there?
Yes. We could have pushed the dose higher. At 230, we did not reach MTD. We could have gone higher. However, at that point, we elected to stop dose escalation because we were getting a 50% CR rate. Go find in an FDA-sanctioned clinical trial, anybody in that ballpark, you can't find them. So at that point, we said, "It's an old Virginia saying, when you're riding Secretariat, don't get off." We are at 50%. It was time to stop and just further enlarge that to further validate the 50% rate, and that's what we got. The FDA thinks this is a really impressive rate, so that's why they're saying: "We don't want you going higher. We want you going lower." That was conveyed to us at the meeting.
Go lower because this is impressive at two thirty, but can one ninety get you the same results?" They didn't want us to go higher. The numbers we got at two thirty was more than enough. They want to see if one ninety is as good. If it is, then for part B, we'll do one ninety. If it's not, we'll do two thirty. But FDA, we agreed when we said at two thirty, we're stopping, we're going to the FDA, and FDA concerned, don't go higher, go lower.
Okay. Our next question is: Thinking about the data that will be reported at the part A mid-point in twenty twenty-five, what would you consider to be a good indicator to show that Annamycin is working or at least trending in the right direction?
... Yeah, Paul, you answered that once before, but would you mind repeating that?
No, but first, the midpoint in Part A, we're not gonna unblind. We're just looking at the data actually in real time, and saying: Is this above the 17-18% you would expect with justHi DAC? The higher it is, the more convinced we are. When we do the unblinding, which would be in mid-2026, we will take the numbers, and if, as expected, Hi DAC is between 15% and 20%, it would be a little broader range because it'd just be 30 patients. We would expect the 230 milligrams of Annamycin to be well above 30% CR, maybe about 40%. 190, probably almost as good, if not as good.
We're not expecting statistical significance, but if the P value comes in at point one or so, we will be quite pleased and be going forward.
But I would just add at that point, at that midpoint, the blinded data review, if you will, at forty-five patients. Practically speaking, that it means approximately fifteen patients in the HiDAC arm, the control arm, fifteen patients in the one ninety arm, and fifteen patients in the two thirty arm. Mathematically speaking, we don't expect a statistical difference between the one ninety and the two thirty arm, based on history. And we've done one ninety as a single agent, as well as two thirty as a, well, two forty as a single agent, and then we've done both of those dose levels in combination with ara-C, historically.
We have enough data to suggest we don't expect a big difference, and if there isn't, then you've got a 40%-50% CR performer against a 17% or 18% CR performer at a 2-to-1 ratio. Mathematically, that says the outcome is gonna be somewhere north of 27%, and probably somewhere south of 40%. And if it's in that range, we're golden, right?
May I make a comment?
Please.
I personally believe that you have to randomize two to one or three to one, as we have done in Gilteritinib registration phase III clinical trial, that we published in New England Journal of Medicine in 2019. The randomization to two to one or to three to one could be potentially protect the project, enrolling speedily the majority of the patient in the experimental arm, in protecting the benefit of the population that has in the control arm, that we know they are in some way not potentially be able to obtain a greater amounts of CR. Secondly, it has to be also defined better, how you can use. I totally agree with you in the potentiating the protocol, downloading the drugs during the protocol.
So potentially also downloading the drugs during the first phases of the treatment, but this is another issue. You have to define better in the unfit population for transplant procedures, because if you get a CR in 50% of your population, you have to transplant the patients in a salvage transplant, at least in Europe. And this salvage transplant has to be very careful because you save the patients from the CR with a higher CR, and you lose the patient in the transplant. So at the end of the day, the overall survival, which is not the end point, I don't know if it is the end point, or event-free survival, has to be very carefully indicated.
Because if you get in CR and you move immediately to the transplant, and they're getting that in a salvage transplant, you lose the patients, not for your drugs, but for the transplantation procedures. So he has to cut off immediately the CR rate that has been obtained from the overall and event-free survival, which is a secondary endpoint, and has to be cleaned from the toxicity of the transplantation.
Yep. Yeah.
I'd like to extend a little bit on the CR. Not all CRs are created equal. We have MRD assessment. Paul, could you go back to the slide? I think you flashed MRD negativity somewhere.
So, Justin, I don't know if... Are you able to navigate back to that, the swim lane chart that has the CRs going horizontal?
Yeah. Yeah, yeah.
Yeah, so-
Okay. So the FDA is getting very interested, finally, in MRD, and the problem is that there are no standardized assays. However, 78% MRD negativity, that's a different story than just 50% of poor CRs, where the patients relapse after four weeks. So I think I find this very impressive here. This is really spectacular. This is by flow, I suppose. In most cases, not the most sensitive, but one in a thousand, one in ten thousand cells. So-
This means that these remissions should be durable, and the transplant outcome depends on MRD negativity. And so these patients should also benefit significantly from an allo transplant. And we know this is a predictor for outcome in allo transplant. So that's another aspect we didn't discuss, but these CRs are deep CRs, and... Okay, so that's my MRD point.
Very important point. Very important point. Janine, anything else on your list?
I do have a question from Jonathan Aschoff from Roth Capital Partners. Your line is now live.
Thank you. When you guys were talking about dose, I'm very curious about the doctors who actually administered this drug. Where is their head when it comes to the willingness, with complete comfort, to go, you know, pretty far beyond two thirty to, you know, eke out more efficacy? Or is there something that they see that would keep them in that, you know, one ninety to two thirty?
Well, what I can tell you is they had no problems with 230. They understand why we stopped escalating, but the 230, that's one dose, one dose in a day. They get three of these, so they are actually getting about 700 milligrams per square meter in a cycle, which is more than the lifetime acceptable level for FDA. So just one cycle, we're above the lifetime maximum rate, which got the FDA's attention. And we did this in Europe. We were not doing something illegally in the US. We did it in Europe. We went to 230, cycle of three doses, and then we did a second cycle and a third. So we are in patients, in some of these patients, we're around 2,000 milligrams per square meter in this trial.
In our sarcoma, we're over 3000 milligrams per square meter. All of these patients have serial EKGs, serial echocardiograms, none have shown any cardiac impairment. So as far as Annamycin, we have yet to find an MTD in our AML studies and our sarcoma studies, despite repeatedly dosing patients many times above the lifetime maximum level as recommended by FDA.
Yeah, I mean, I asked because you said there wasn't a toxicity problem. You know, 50% efficacy is something you are happy to stop at. You know, 50 is not 100. There's a lot of room to go above 50, and therefore, I'm looking for, you know, I was asking about the doctor's comfort in going higher than that. You start showing, you know, some ridiculously high efficacy, let's say, you know, if this drug is approved in AML with higher doses, and I just think each time you can do that, you make it really clear AML is not the only place to use it.
That sounds like another of the many excellent phase IV studies we hope to conduct in a few years.
Thank you.
You know, Jonathan, as Dr. Martinelli pointed out, these are not without adverse events, right? There is the potential for infection, and logically speaking, that potential for infection goes up as we continue to weaken the patient with higher and higher doses. It's not. We don't want to leave listeners with the impression that this is a benign drug. It, you know, it's chemotherapy, so there are limits, practical limits. I think the conclusion was really once. Again, I think it came out in some of the discussions that our clinicians offered up here today.
Once you reach a threshold level, then there, you can hit diminishing returns as you try to go higher and higher. And so that's all of that kind of factored into how we established this recommended phase II dose.
I want to add something. In other areas like sarcomas, for example, where you use anthracycline as single agent, whereas actually it's the most active single agent in certain sarcomas. And I think this is where a higher dose seems more reasonable because you are using it as single agent. But of course, this will be in later phases. But this is the area where I think, you know, to evaluate how much you can push with other non-cardiotoxicity is the area that I would recommend exploring, of course, later on.
Great.
May I make another comment, please?
Yeah.
Yeah. It is absolutely important not to lose any patients in CR. I saw your MRD picture slides, and if you lose a patient for infection in CR after obtaining a second CR because they are relapsed refractory, is something that is not acceptable, because you have to take as much as possible, alive, the patient, relapse refractory, that they obtain in CR. This is a fantastic data, in my opinion. Very, very promising, very, very interesting. So it will be very crucial not to lose any patients obtaining CR... even if this CR is deeper or not deeper, it depends, but we have to design a program that has permitted that if the patient obtain a CR, we get for sure a prolongation of survival.
So we the aim of our project is to catch. And so we have to design a protocol in which we get the majority of patients rolled in the program, in the experimental arm, without I personally believe not two cohorts of dose, which is something that make at least for me a bit of confusion. But yeah, it could be decided. And not lose any patient obtaining CR. So all the patient obtaining CR has to be alive as much as possible.
Yeah.
So whatever is the program after the first cycle has to be very careful, taking into account.
Yep. Yep. Janine, any other questions out there?
Yes, we have another question from the web, Wally. The question is: What specific outcomes from the Miracle Trial would you find most compelling when considering the use of Annamycin in your clinical practice?
Aha! Well, from the company's perspective, we're very focused on approval, and, of course, approval will be based on CR at 30 days. You know, essentially the immediate response. But I think Dr. Martinelli, I think you were just commenting on that, which is, it's not just getting to a CR, it's getting them to a bone marrow transplant or getting them an increased overall survival. So, are there other thoughts along those lines? I actually think Dr. Martinelli really did answer that question. It -- and we couldn't agree with him more that it's not just... I think, actually, Dr. Andreeff's question about how deep the CR relates to this as well.
It's not just a game where we get to that magic CR number, and we can check the box and move and walk away. That's the start of hopefully extending this patient's life. But if you're not prepared, if you're not prophylaxing for infection and prepared with an allo transplant, if one's available and all of those things, if you're not prepared for success, you can lose everything you hope to gain there. So that I would say overall survival, frankly, is probably the most important endpoint in the study, even though it's a secondary endpoint. We're not going to be approved on the basis of overall survival, but tell me if you guys disagree, but I feel like overall survival is the ultimate litmus test.
Can I say another point that arising from several programs. It's not necessary, the induction consolidation, second consolidation and transplant, which is the sequential use of intensive chemotherapy in a young leukemia patient fit for chemotherapy, has to be immediately translated in a relapsed or refractory population. It, it's not. It comes from a history of this sequential use of the drugs, but it's not necessary. In relapsed refractory population, we can do just one shot, a good one shot, and then take the advantage from this one shot to move to the salvage transplantation or maintenance therapy, which has to be defined.
Yeah.
So the sequential use, induction consolidation one, consolidation two, transplantation is a heritage, is something that comes from the back, from the previous, from the older part of the history of the treatment of acute leukemia. Venetoclax, Venetoclax and azacitidine has demonstrated that you can obtain a CR in just one shot in the majority of the patients, and then second or third is just adding a bit of CR in the population, the entire population. So personally, I believe that we have also to take the one-month CR is a fantastic ideas, if it works, to move on later in a consolidation with less intensity, more or less intensity than the previously approaches we have done in acute myeloid leukemia in a relapsed or refractory population. I don't know if it is clear.
Okay. One last check, Janine. Did we clear the board here?
We cleared the board, Wally.
Okay. Well, gentlemen, you've been incredibly generous with your time, and this has been remarkable. So, really, really appreciate it. I have a suspicion this is gonna be viewed by a lot of folks, even after the fact, because of the importance of what was said here today. So thank you very much. We look forward to the Miracle Trial moving forward and to getting your thoughts on the data as it starts to roll out.
Thanks to you. We will see in next meeting.
We'll see you soon. Okay. Take care, guys. Bye-bye.
Bye.
Bye-bye.
Thank you. That does conclude today's webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation.