Okay, we are ready to get started. Welcome, everyone, to Moleculin Biotech's AML Clinical Day. My name is Jenene 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 event are made pursuant to the safe harbor provisions for the federal securities laws and 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 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 resources 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 that any independent source of verifying any other information obtained from third-party sources. Any data discussed regarding clinical trials and progress are considered preliminary and subject to change. So with that, we are going to talk about today's agenda. So we are going to start with opening and introductions, and then Mr.
Klemp will introduce Annamycin. Then we'll go into the AML, the unmet need, Annamycin for the treatment of AML, a data review. Then we'll go to the Annamycin opportunity in AML, and then driving towards the pivotal study for the company, and we will end with a Q&A session. Okay, so joining us from the Moleculin management team, we have Walter Klemp, the Chairman and CEO, we have Dr. John Paul Waymack, who's Senior Chief Medical Officer, and we have Jonathan Foster, Chief Financial Officer. Okay, and we are pleased to have with us a key opinion leader, Dr. Martin Tallman, who will be joining us. Could we start with an introduction with you, Dr. Tallman?
Yes, thank you. Most recently, I've served as a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. I've also recently served as chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Cornell Medical College. I was a professor of medicine at Northwestern. I had the privilege in 2001 of serving as the president of the American Society of Hematology, and I've served as the chair of the Leukemia Committee of the Eastern Cooperative Oncology Group, and I was immediate past chair of the National Comprehensive Cancer Network AML panel, and I'm very pleased to be a member of the Moleculin Scientific Advisory Board.
Well, it certainly is a privilege to have you join us today. Okay. So, we also have a Dr. Michael Andreeff. He likely will be joining us. He is attending to some patient needs at the moment, so we're hoping that he will be able to join us throughout today's discussion. And at that time, we'll have him provide his background as well. Okay. Okay, so I will now turn it over to Mr. Klemp to provide the corporate overview. Wally?
Thanks, Jenene. One of our core beliefs is that anthracyclines continue to be among the most important treatments for AML patients, not to mention numerous other indications. The fact is that despite all the advances in targeted and immunology-based therapies, the majority of successful cancer treatments still rely on chemotherapy. And Annamycin, we believe, is, for the first time, going to make critical anthracycline therapy safer and more accessible to a majority of patients, and many more lives will be saved because of it. Now, this is perhaps one of the most important opportunities in the history of Moleculin.
I mean, the data we will discuss today are significant, and I would argue vastly more significant than the investing public understands, and that's why we, we have invited the world's foremost experts on AML on the call with us, so, so that our listeners can finally begin to grasp just how significant this is. Annamycin is now phase 3 ready. The data we are discussing today are stronger than any asset ever approved for use in AML, and this is a space where we believe lesser assets have delivered billions in value to shareholders. Now, the press release we just put out this morning added two more patients to our results, increasing the overall N in this study to 20 and improving on an already fantastic performance from Annamycin. Now, we'll hear more about these data from Dr. Paul Waymack, our Senior Chief Medical Officer, in a bit.
But the bottom line here is that Annamycin's performance to date is truly remarkable, and it's beginning to turn heads in the AML community. For those of you who are new to the Moleculin story, it's important to understand that we aren't just pushing some incremental tweak in a me-too effort for a highly specific niche. Annamycin is about shifting the entire paradigm for how anthracyclines are used, and as one of the first indications of that shift, we believe we're on the verge of creating a new standard of care in second-line AML. Now, this has been a long, hard struggle. Since we licensed this discovery in 2016, we've invested close to $150 million in proving to people that what was believed to be impossible is now happening.
Four clinical trials and more than 80 patients later, we're only weeks away from presenting history-making data to the FDA in order to finally launch a pivotal approval clinical trial by the end of this year. Now, Annamycin is truly a next-generation drug. It features major structural changes from existing anthracyclines and then enables radically improved uptake with a patented lipid-based delivery system. That results in something that no one thought possible, and that is a truly non-cardiotoxic anthracycline. And it turns out that it's not just non-cardiotoxic; it is generally less toxic than currently prescribed anthracyclines, while it avoids cross-resistance with other anthracyclines, and it's more potent than doxorubicin in most tumor models. But the absence of cardiotoxicity, we believe, will be a true game changer. The currently used anthracyclines are so cardiotoxic that the FDA stipulates lifetime maximum exposure levels.
In fact, if a patient is dosed beyond the 550 mg per square meter limit, there's a 65% chance of a cardiac event, and if that patient goes beyond 850 mg, this risk is 100%, and there's an 8% chance of outright heart failure. We believe those risks can now be eliminated with the use of Annamycin. In fact, in the gold standard animal test for chemotherapy cardiotoxicity, where doxorubicin has shown 100% cardiotoxicity, Annamycin is 0% cardiotoxic. But Annamycin gives up nothing in terms of efficacy compared with the most commonly used anthracycline, doxorubicin.
Annamycin outperforms dox head-to-head in a highly aggressive AML mouse model, and when you combine with Cytarabine in this same model, we see significant synergies, with the combination outperforming Cytarabine alone by over 240%. It's this combination, and we call this AnnAraC, that has been the focus of our latest AML clinical trial, MB-106, and as we are discussing today, that trial has produced some impressive results, especially in second-line patients. Now, we think this is particularly important given the magnitude of the unmet need for second-line therapies in AML. And here to talk a bit more about that unmet need and the opportunity in AML is Professor Martin Tallman. Dr. Tallman, would you mind kicking things off with a brief overview of AML and the significant unmet need?
Yes, thank you, Wally. For those of you that aren't familiar with the disease, AML is a type of cancer, specifically a hematologic malignancy, that starts in the blood-forming cells in the bone marrow, leading to the rapid growth of abnormal, generally immature white blood cells, and this occurs to the detriment of normal blood formation. And if you can't form normal red blood cells, white blood cells, and platelets, this manifests as symptoms including profound fatigue, frequent infections, and easy bruising and bleeding. There are about 160,000 cases worldwide and about 20,000 newly diagnosed patients each year in the United States. And unfortunately, the five-year survival overall remains at less than 30%. So AML represents a significant unmet need for more effective and tolerable therapies, particularly in older adults and also in the relapse and refractory setting. Next slide.
Now, this is a slide which we call the AML patient journey. It's a very, very simplified slide, and we start with patients, newly diagnosed patients. For many years, for about 40 years, from 1973, when 7 and 3 or conventional induction chemotherapy was described, until 2017, when the first targeted therapy, midostaurin, was approved by the FDA. That 44-year period, we had no new drugs approved in AML, and our major decision was: Is the patient fit or not? If they were fit for intensive chemotherapy, they got 7 and 3, 7 days of Cytarabine and 3 days of an anthracycline. We tend to use daunorubicin. And if they were not fit, we really didn't have anything to offer them.
Now, today, we still ask as an early question, "Is the patient fit for intensive chemotherapy?" But now we can say are they fit for intensive chemotherapy or lower intensity therapy with either a targeted agent or a Cytarabine-Venetoclax? And we ask a second question, which is important, and that is: Do they have a molecular target for which we have a drug that will be effective? Patients who achieve remission, many of whom undergo bone marrow transplant, and those who don't, undergo consolidation chemotherapy. But despite this progress, a favorable outcome is in about 40% or less of patients, so that leaves about 60% of patients who still succumb to this disease, and that indicates that it remains a significant unmet need. Next slide, please. Now, the unmet need in AML is manifested in several ways.
First of all, second-line patients that don't respond to first-line therapies represent a significant proportion of patients, and side effects limit the ability to use intensive treatments in older patients or those with other health issues, comorbidities. Many patients don't have the genetics for targeted therapy, and some don't respond even if they do have the target. Next slide. In this slide, we show you the targeted therapies that have had limited benefit. They hold a great promise, and there's been a lot of excitement about them, but when you really look at the data, they have limited benefit to date. This shows you that the bar for approval for five of the recent approved targeted agents has been relatively low, at about 20%.
In the right-hand side of the slide, you can see that in the pie graph, if you exclude patients who have the targets of IDH 1 or 2 or FLT3 mutation, that leaves about 53% of patients who are ineligible for targeted therapy, for approved targeted therapy. Next slide. I think I'll turn it over to-
Yeah
... Wally.
So if you don't, if you don't mind, before we get into Dr. Waymack's portion, we are very pleased to see that Dr. Andreeff has joined us. So welcome, Dr. Andreeff. Okay, it's-
I think you may be on mute.
Yeah.
Okay. Can you hear me now?
Now we can hear you. Perfect.
Okay.
So-
So I'm very happy to help, and I think you heard a fantastic introduction on where we are with leukemia therapy. My own involvement with the drug goes back over 20 years, and we can talk about it later, I guess, but it's a very exciting compound. And there's no competition and no equal to it. So to introduce myself, I'm a physician at MD Anderson Cancer Center. I run a large research group, and we have developed a number of new treatments for AML in particular, including Venetoclax and FLT3 inhibitors. Dr. Tallman gave you a very nice introduction and background where we are today.
The so-called targeted therapies are, in a way, too targeted because we are sometimes eliminating one single clone of leukemic cells, but other clones grow out. So, I'm in favor of more generic approaches. For instance, the BCL-2 inhibitors, Venetoclax, are active, to a degree, and we know the limitations by now, but they're not super selective, like the IDH inhibitors that you just heard about. Okay, with that background, I'm very happy to be a part of this discussion.
Well, we certainly appreciate it, and we know that you have a hectic schedule, so we're going to keep things moving, right on. Now we're gonna turn it to Dr. Waymack. Thank you.
Thank you, Martin. And I would like to say that I am very pleased to be able to present our latest data to you. These data will show efficacy for Annamycin when used in second-line therapy in AML patients that greatly exceeds that seen with all FDA-approved medications. As can be seen in this slide, when used in combination with Cytarabine, Annamycin achieved a 50% CR rate, a 60% CRc rate, and as Wally and Martin previously showed, these rates are double that seen with all the currently approved drugs. And this was accomplished without a single patient in a single clinical trial showing any evidence of cardiotoxicity.
It is also important to note that unlike the clinical trials that got the five currently approved drugs on the market for refractory and relapsed AML, trials in which enrollment was only in patients with certain genetic mutations. Our study non-selectively enrolled all patients with refractory and relapsed AML. Thus, our data indicate that 60% of the entire refractory and relapsed AML population could benefit from Annamycin. On the next slide, I would like to review the chronology of our clinical trials. Our first clinical trial, MB-104, was a study conducted in the U.S. in patients with refractory and relapsed AML. The patients in this study received either 100 or 120 mg/m² of Annamycin as monotherapy. This limitation in dosing was due to FDA concerns about potential cardiotoxicity.
Our second clinical trial was conducted in Europe in patients with refractory and relapsed AML, using a dose escalation design. In this study, the dosing cohorts reached 240 mg per square meter of Annamycin. Our third and ongoing clinical study, MB-106, treats patients with AML with a combination of Annamycin plus Cytarabine. We anticipate our fourth and pivotal phase 3 clinical trial will commence sometime early in this coming year. The next slide, please. In MB-104, seven patients were treated with either 100 or 120 mg per square meter of Annamycin as monotherapy. The Annamycin was found to be very well-tolerated and to exhibit no evidence of cardiotoxicity. One patient in the 120 mg per square meter dosing cohort achieved a morphologic leukemic free state, despite the extremely low dose of Annamycin.
The next slide will review our MB-105 study, which was conducted in Europe since they did not share FDA's cardiotoxicity concerns. This trial also tested Annamycin in refractory and relapsed AML patients as monotherapy, in doses ranging from 120 to 240 mg/m². Once more, this study found no evidence of cardiotoxicity. Regarding efficacy, the highest dosing cohort, that is the 240 mg/m² cohort, demonstrated an 80% overall response rate. In light of the efficacy seen in this study, moving on to the next trial, as well as the preclinical data Wally previously showed, we moved on to our third clinical trial in AML patients, MB-106.
In this study, in an attempt to improve durability of responses, Annamycin was combined with 2 g of Cytarabine, and patients were allowed up to 3 cycles of this combination. This slide shows the top-line efficacy data. The second column from the left shows all patients enrolled in the study, that is 20 patients, and you will see that we have a 40% CR rate, a 45% CRc rate, and when you add in the PR patients, a 55% overall survival rate. The column that is second from the right is probably the most important of the columns. This is in second-line therapy patients, and as you can see, there are 10 patients who received Annamycin as second-line therapy. These patients achieved a 50% CR rate, a 60% CRc rate, and a 70% overall response rate.
You will notice that there are two other columns, the per protocol columns, which exclude 2 patients who dropped out because they could not even complete their first dose of study drugs. One was due to an allergic reaction to Annamycin, and one due to an allergic reaction to the Cytarabine. I would again like to point out that these efficacy data document response rates that are more than twice those reported for the other drugs approved for treating refractory and relapsed AML. If we can move on to the next slide. This slide details the 9 patients who achieved a CR or a CRi in MB-106. To the far right, you will see that among the 7 patients who were treated as third line and beyond, we had a single patient who developed a CR.
That patient has now undergone a bone marrow transplant, is alive, and is doing well. The next two columns to the left are in our first-line therapy patients who achieved a CR. Two of the three patients achieved the CR, which is, of course, a 67% CR rate, but admittedly, currently, the number of patients is limited. However, we continue to recruit patients, and these two CRs are alive and doing well. The final six columns to the left are the second-line therapy patients who achieved a CR or a CRi....
You will note that 4 of the 6 are alive and doing well, and in fact, the one to the far left, that 78-year-old patient who is rapidly approaching 80, is not only alive and doing well, he lives in Italy, and two weeks ago, he went on vacation outside of Italy because he was doing so well. You will also notice that we have a couple of patients who did not do as well. One developed pneumonia and died, and one relapsed because they were unable to continue receiving therapy because of an ongoing infection. We noted that both of these patients were treated a ntimicrobial prophylaxis and treatment guidelines. This situation has now been corrected through counseling.
My final slide plots out the durability of responses in the 9 patients who achieved the CR. You will note that the current median duration of response is 4.9 months. However, since 7 of the 9 patients are alive and doing well, this number will continue to grow over time. To summarize these data, in patients with relapsed and refractory AML, who require a second-line therapy, we are achieving a 60% CRc rate. This is double the efficacy rate with drugs currently approved for treating refractory relapsed AML. We have achieved these results while failing to identify any cardiotoxicity in any patient in any clinical trial.
In light of these facts, we intend to proceed to the initiation of a pivotal phase III study by early next year, with the goal of generating clinical data that will support the submission of an NDA for the initial indication of treating second-line AML patients. Thank you, and I will return the microphone back to Martin.
Thanks, Dr. Waymack. I wanna talk a little bit about the opportunity that we see for Annamycin. Next slide. Dr. Waymack went over some of these data, but I'd like to emphasize, make a few points. In the 104 trial, the monotherapy trial at a lower dose, there still was a 17% CRi rate, and the drug was well tolerated. In the 105 trial, the second monotherapy study at the higher doses, there was an 80% overall response rate in the 240 mg/m² cohort, and there was a, apparently a positive correlation between response rate and dose, and the drug was, again, as you heard, safe.
Finally, in the WP1066 combination study of Annamycin and Cytarabine, when one looks at all, all patients, 45% CR, composite CR rate, and in second line, 60% composite CR rate, with a durability up to 12 months, and that should only increase. So the addition of Cytarabine in this study, we think supported, is supported by compelling preclinical data, showing improvement over monotherapy, Annamycin monotherapy. Next slide. Now, this shows you the results of Annamycin versus current therapies, and there are five of the targeted therapies listed here, with the black bar showing complete remission rate and the purple bar showing the prevalence weighted benefit, that is the CR rate times the eligibility. And despite the excitement and promise of these targeted agents, you can see that the remission rates are still quite reasonably low, and the impact is also quite low.
5.8% benefit overall in gilteritinib-treated patients, 2.3% in enasidenib-treated patients, ivosidenib patients, 1.7%, olutasidenib, the other IDH1 inhibitor, 2.4%, and gemtuzumab ozogamicin or Mylotarg, only 1.3%. And that compares to 50% CR rate and the prevalence weighted benefit of 50% for the combination of Annamycin and Ara-C. Next slide. And this shows you Annamycin versus current and upcoming therapies. And you can see in first line for VYXEOS CPX-351, and then AZA, the CR rates are in first line, this is 38% for VYXEOS and 37% for Venetoclax azacitidine. Then in the blue, you see second-line therapies.
You can see, second line, you can see the CR rates vary, where IDHIFA and TIBSOVO, 19% and 25% respectively, for the three menin inhibitors, respectively, 35%, 18%, and 24%, and that's compared to 50% in second-line complete remission rate for Annamycin. Next slide, please.
... We talked, we discussed this slide before. Shows you the current AML treatment paradigm. And again, we wanna make the point that despite the development of Venetoclax and cytidine-targeted therapy, there's still a large potential candidate population of about 60% that we think may benefit greatly from Annamycin. Next slide.
So, that's Marty, thank you so much for that overview. Because Michael had to join us late here, I just wanted to offer up... Michael, is there anything about the results that Paul discussed or the overview that Marty gave that you'd like to add to?
Yeah, so this is very striking data. And what's interesting is it holds up for patients who had Venetoclax-based treatments, but also patients who had chemotherapy, I guess. Now, we are involved in a large number of new agents, and the data as shown here is always inferior to these really incredibly high response rates to Annamycin. I could maybe add some mechanistic thoughts about it. One reason why Annamycin is so effective is that it is independent of efflux pumps. So cells have pumps that pump out xenobiotics, so drugs. One famous pump is MDR1 P-gp. Another one is MRP.
We have shown in the past, together with other investigators, that Annamycin is independent of these pumps, so the drug stays in the cells and does its job killing the cells, and is not subject to these efflux pumps. It's just one thought that may in part explain why Annamycin is so effective.
Great. Perfect, thank you. I'll just sort of kind of wind up the prepared part of this presentation, because I know we're probably eager to get to answering some questions from the analyst community. The all of today's discussion is really a prelude to the eventual approval of Annamycin, and of course, for that to happen, we're driving toward a pivotal clinical trial in second-line AML patients, as Paul mentioned. We also think from an investor perspective, what is about to unfold has potentially massive value inflection potential. And the reason for this is that we believe the next major events, the FDA feedback, the triggers of pivotal clinical trial, the output from the pivotal trial, and the potential for an NDA submission, they all represent the opening of an exit window for our shareholders.
Since I know it may be of interest to the analysts on the call today, I did wanna quickly outline what we are targeting for in the upcoming pivotal trial that Paul mentioned. We're gonna be meeting with the FDA soon, and we expect that meeting will provide clarity on our pathway for new drug approval. Specifically, we're looking to conduct a pivotal registration trial in second-line AML patients. Our goal is to have this trial structured similarly to the current MB-106 trial. The main difference will be to focus only on second line, to the exclusion of first line and third line and beyond, and the primary endpoint will be durable composite complete remission. Now, ideally, this would be another open label, single-arm trial, and that would allow us to report results on an interim basis.
In general, this proposed trial design is consistent with several recent new drug approvals, so we think there's good precedent for the design. So, Jenene, back to you, and maybe time to open up for some questions.
Absolutely. Okay, so we are ready for the Q&A, and we're going to start first with those that have raised their hands. So we have Jonathan Aschoff of ROTH Capital. So, I believe we will be able to open up Jonathan's mic, and he might have... Jonathan, you may have to take yourself off mute.
I just did. Can you hear me?
We can.
Gotcha.
Wonderful.
Hey, Jonathan. How are you?
Thank you for joining.
Hi, guys. Thank you very much for convening this KO call. So I'm curious, you know, what do you intend to have to hit with enrolling 100-150 regarding CRc durability in that trial? You know, there's no comparator group, so there's no differential, so what is it-
Right
... you have to hit?
So, Paul, I think you’re probably the most qualified, given that you designed the protocol with the help of a lot of input. So, do you mind taking that question?
Yes, and I guess the final answer is we will hit what the FDA demands. What we're proposing to them is, as Wally says, similar to 106, second-line therapy. As Wally and Martin have shown, the drugs that have been approved recently for second-line therapy, the five of them, have CR rates of between 15%-30%. So what we would propose to the FDA is that-
... we will show that the lower limit of the 95% confidence interval for our durable CR rates is above 30%, or somewhere 25%-30%, we're above that. Not the mean, but the lower limit of the confidence interval, which is readily doable if we are anywhere close to the 60% we're seeing now. If we're at 45%, it is readily doable when you do the statistical calculations. So that would be our initial proposal. As Wally mentioned, the last 5 drugs to be approved, they've all been approved based solely or mostly on single-arm studies. We hope FDA will continue that acceptance rate, but we will learn more when we meet with them.
Okay, thank you. That was helpful. You know, you guys have been recently, you know, management that is, recently strongly emphasizing not yet receiving the valuation you deserve. So maybe to understand that, you know, can you help us out with what are the equipotent doses of, let's say, Annamycin versus dox? And outside of the obviously absent cardiotox, does that equipotent Annamycin dose give you any higher rate of any other toxicities? Or, you know, is it simply that investors wanna see more second-line patients treated with AnnAraC at the 230 mg per meter squared dose?
Well, let me, let me start by responding to some of the questions about the comparative toxicity and relative dosing levels, but then I'm gonna invite, doctors Tallman and Andreeff to weigh in with their thoughts on this too. It's an important question, Jonathan. As it relates to equipotent comparisons, typically speaking, if you look back in history, the conclusion was it takes about 1.7x Annamycin in most models to be the equipotent equivalent, if you will. But, once you extend that to hard-to-treat tumor models, like the one that we showed the preclinical data for... I mean, Dr.
Andreeff may wanna comment on that model because he knows it well, but that's one of the most difficult to treat animal models for AML there is. Antamycin substantially outperforms doxorubicin, and we see that in model after model. There are a few solid tumor models where doxorubicin appears to be superior, but it's the exception, not the rule. What I will say is, in every instance, even at massive dosing of Annamycin, we don't see the toxicity in animal models that is seen from doxorubicin, not just cardiotoxicity, but other toxicities as well. There doesn't seem to be any offsetting or overweighted toxicity related to Annamycin. We haven't seen that in humans.
What we have seen in our clinical trials is not only the absence of cardiotoxicity when we would expect to see it, especially if we've taken some patients up to 3,000 mg per square meter of cumulative dosing without any instance of cardiotoxicity. But also, it doesn't have vascular activity like doxorubicin does. Interestingly, we see a dramatic reduction in alopecia in patients. Just across the board, Annamycin seems to be better tolerated by patients. Now, let's be clear, we haven't done a head-to-head comparison in humans between doxorubicin and Annamycin. So I'm—this is all anecdotal comparison, not a rigorous scientific comparison in a head-to-head trial. But I think that the data are somewhat overwhelming here. But, Doctors Andreeff and Tallman, what are your thoughts relative to Jonathan's question?
So if I may, respond. When you look at the side effects in the table, the clinical trial, the patients have neutropenia and fever, and other cytopenias. That is all expected in a trial with acute leukemias. So I did not see any, toxicity, let's say, neurotoxicity, and of course, not cardiotoxicity or anything else that would raise a flag. So I think the toxicities are mostly related to the disease and not to the drug treatment. Maybe Dr. Tallman has some thoughts about it.
Oh, I agree with you, Michael.
So I was just curious, in slide 33, when you showed five other drugs and response rates around, you know, 15%, 20%, 30%, 30% or so, what are the ends, you know, the, the average sort of end or the range of patients that treated that contributed to that data, you know, to compare your MB-106 data to?
So Paul, I know you've perused all of these trials in detail. Do you mind filling in on Jonathan's question there?
The numbers for the pivotal trials that got those drugs approved range from about 75 to a couple hundred who got the drug.
Right.
So when we are proposing to go in and say 100-150, we're in the ballpark. And again, we're not going in and saying mean, median, we're saying the lower limit, the 95% confidence interval, which so that if you went there, the numbers don't matter. That's been factored into the confidence intervals.
Okay, my next question is, you know, it seems like you have enough data to end phase II, you know, especially with your timeline and the press release stating it's a 1H 2024 end of phase II meeting. So are you done enrolling? It sounds like you are.
... Paul, do you wanna talk about the enrollment strategy here? 'Cause I know it's somewhat confusing.
Yes.
We're going to a meeting with the FDA, and yet this trial is continuing. So do you mind explaining that for folks?
If you go and see the approvals for these drugs that were approved based on a single-arm study, they had generally, in some way, shape, or form, a confirmatory randomized trial. We are therefore expecting that if they grant approval of the design of a single-arm study, it will be accelerated approval with a randomized trial being required to follow. We don't wanna do that in second-line therapy. We wanna get something out of it, so we would therefore propose to FDA that the confirmatory trial be randomized first-line therapy. Now, in order to design such a trial, we're gonna need to be able to do power factor calculations. As I mentioned, we've enrolled 3 patients. 2 of them were CRs, which is 67%, but if you do the confidence intervals, they are above 100%, literally. It's... The numbers are kind of weird.
We're gonna have to get more patients in first-line therapy. We intend to continue enrolling first-line therapy patients because even if the FDA were to say, "You don't need to do a confirmatory trial," we still wanna do first-line therapy. That's the ultimate market. We think we work there. We have so far. We're gonna need adequate numbers to define power factor calculations for a subsequent pivotal first-line therapy study. We will continue to enroll patients in first-line therapy until we have adequate data from 106 to design such a study. In contrast, for second-line therapy, the 10 patients we have, that gives us more than enough power to design our pivotal second-line therapy study, and so we have ceased enrollment in second-line therapy.
We don't need any more, and we're telling the sites, "Enroll first-line therapy patients," which we will continue to do until we have sufficient numbers to power a first-line therapy study.
Okay, thank you, for that. And lastly, may we assume that the new CRs, you know, that we've seen since the Q4 2023 conference call, they're all from the newly evaluable patients rather than improvements in patients previously evaluable?
Paul,
That is, that is correct.
I think that's correct.
That is correct.
I will note that your question is important, or it's meaningful, I think, to the audience for them to understand, 'cause John has pointed this out in previous conference calls, that we've had some patients along the line that started out as CRis. So they had, you know, below 5% bone marrow blasts, but an incomplete recovery of blood counts. But then they turned into CRs, with a subsequent, just either with the passage of time or a subsequent dose of Annamycin and Ara-C. So we do have a history of CRIs improving to CRs, but in this case, the data you saw from the previous announcement, everything that's been changed is just the addition of new patients.
Very helpful. Thank you for the call.
Okay. Thanks, Jonathan.
Wonderful. Thank you, Jonathan. Okay, so now we have, Vernon Bernardino from H.C. Wainwright. We are going to open your line. I believe you'll have to unmute yourself.
Great. Thanks, Jenene, and thanks, Paul, and Jenene for having this virtual seminar. And thanks, Dr. Andreeff, Tom, and Waymack for participating. Lots of my questions were asked, but one question I had is regarding the pivotal study. Given the activity of this drug and the results that could be really, really promising, would a pivotal study need to have, let's say, an early stopping point? And how many patients would you really need to see that the results are really promising so that you could stop that?
What do you think the FDA point of view regarding an early stopping point would be, considering obviously, if you let some patients continue on therapy without stopping, it could be, I guess, unethical because, you know, others could benefit if the drug could get approved sooner rather than later? Thank you.
Understood. Understood. Paul, that's definitely your wheelhouse. Do you wanna take that?
Yes, and the answer is: it depends. If we are allowed to do a single-arm study, then it is very risky scientifically to stop it early. There have been instances in the past, in other diseases, where it was a single-arm study, they stopped early, or they were recommended, but when they refused and went on to the end, the difference disappeared. So it's, when you know the results, because everybody's getting the drug, it might be a temporary blip, and you say, "Stop it now." However, if we're allowed to do a single-arm study, again, based on the results from 106 and power factor calculations, 100 patients is more than enough to have the lower limit of the confidence interval way above what we're setting. So, I don't think that would be too onerous.
If we're doing a randomized trial, then obviously we'll be having an independent committee look at unblinded data from time to time and make recommendations about whether or not it is ethical to continue the study, not only because of failure reasons, which we don't think there's futility with this drug from what we're seeing. But also because the results are so good, it would be unethical to continue denying the therapy to the control arm. And this will all be discussed at the meeting with the FDA.
If I could commit to memory, when do you anticipate on having an end of phase 2 meeting?
So we've signaled to the market that we intend to have feedback from the FDA in the first half of this year. So, the first half-
Mm
... of this year is rapidly approaching, so you can interpret from that confidence and that guidance that, proper communications and the sequencing of, notice periods, you know, is taking place. So, John, do you wanna embellish?
No, no, I would just say that, we're sticking to the end of the year, and for that to happen, you know, as Wally stated, the communications and the letters all have been going back and forth, if we're gonna stay on that timeline, and we're very, very confident of that timeline.
Yeah, when you say the end of the year, we're sticking to the end of the year-
Correct
... as a starting point for the pivotal trial.
I mean, well, I meant end of the first half.
Yes, right.
Sorry, for the FDA meeting. Thank you for that.
There we go. Yeah.
Great. Thanks for taking my question. I'm excited for you guys.
Thank you.
Thanks, Vernon.
Vernon, we appreciate your questions, for sure. Okay, we do have another analyst, Kemp Dolliver from Brookline Capital Markets. So Kemp, we are going to unmute you, if you can unmute yourself as well, and we'd be happy to hear your questions.
Great. Thank you. So a couple of questions. First, you know, with regard to FDA, you know, FDA guidance, your guidance and the endpoint, and, you know, this may be just a matter of semantics, but I wanna be sure that the data look apples to apples with the way FDA looks at it. And, you know, there's the new term they're using of CRH, which relates to hematological recovery or remission. So how should we think about the data you've generated so far relative to that measurement? Assuming they're gonna slice the data that way.
Paul, I think you're best qualified to comment on the definitions in the clinical trial design.
Well, let me say first that CRH is sort of equivalent to CRi. There's been a change in the nomenclature, but it's where the cancer has gone from the marrow, but the blood has not returned to what it should be, but it's heading that way. FDA's position has been that CR is better than CRi or CRH, and that's established in the literature. You, CRi or CRH, whichever you wanna call it, is better than a non-response. It's not as good as a pure CR. So, FDA generally puts more value in a CR, which is fine with us, 'cause if you go back and look at the data, we are 50% CR, 60% CRI. The other drugs, they're more split half and half, even, for CR, CRH. So, if the FDA wants to say, "Just do CR," I'm fine.
We can live with that. If we have to do a randomized trial, we would especially like to do that because we are even more ahead of the crowd with that than the combined CR, CRi.
Great. How might the inclusion/exclusion criteria in the phase III differ from the phase II?
Again, back to you, Paul.
As I said, in our study, we're taking everybody. We're taking whatever your mutation, we'll take you. Whatever your age, we took 'em, we took them all. In fact, as I mentioned, I think our first patient in the 106 trial about to turn 80, doing great. We've had them down in their early 20s. We don't discriminate. The other 5 drugs approved, they are very selective in whom they take. Now, with good reason. Their drugs are designed to hit one particular mutation. We take 'em all, and we're doing better with them all. So we don't plan to exclude patients.
We will be monitoring all of these mutations, so that if we find a particular group that does really well or badly, that can go in the labeling for our drug, but we don't plan to select out any particular group. Anybody needing second-line therapy, we propose to enroll them. Now, for a few reasons, there's this exclusion: you can't be pregnant, and a few other things, which is true of all studies. But the selectivity used by the companies getting their selective drugs approved will not apply to us. We'll take everybody.
Great, thank you. And, you know, the last question relates to sites, because you referenced a, you know, pretty important problem at one site. And you will be running in the U.S., you know, trial sites in the U.S. in the phase III. So when you think of Europe, how will that, I guess, complexion of your European sites differ from the 2 sites you're using now?
Yeah, Paul, I think you're still-
Yeah
... you're, you're on deck.
Well, obviously, we would've loved to have done 106 and 105 in the U.S., but the FDA had concerns about cardiotoxicity, and I'm not gonna object. I mean, scientists can look at data in good faith and come to different decisions. They said, "We're worried-
... European sites that were not, so we went to Europe. We had 9 sites, we have utilized in Poland and Italy. All of them worked well except one site did not follow what has been published as accepted normal. It's very unfortunate because those 2 patients who we've lost, they might still be durable if they'd followed the guidelines. They did not realize those guidelines were in place. We were suspicious why both failures were infections in that one site, so we sent a team out that monitored, identified the problem. The site apologized, said, "We will follow these guidelines from now on." And other than that, they were a great site. So we intend to use the sites in Europe we're using now. We have met with investigators in Germany who would like to participate in the pivotal trial.
We will enroll sites in the U.S. also. If we're gonna have to enroll 100-150 patients, we wanna speed this process as much as possible, which means more sites. So we would anticipate doing this throughout Europe and throughout the U.S.
Do you have a range for the number of sites?
I think we're right now. We're assuming it's gonna be in on the order of magnitude of probably 25 sites, but possibly many more. I will say, Kemp, that predicting the willingness of sites is somewhat dangerous at this point, until we know for sure what the trial design the FDA you know what trial design the FDA will accept. For example, if they insist on this being a randomized trial, the interesting question is, what's the comparator? Because there's technically other than the targeted therapies, there's technically no other drug approved for use in second-line patients. Historically, we've seen other companies default to Cytarabine as the control arm.
Even though it's technically not approved as a second-line therapy for AML, it's commonly used. So I think that's how they got there. But I can tell you, I've run into a lot of clinicians that they just shake their head and say, "I don't like that trial design. I don't... I'm not sure it's ethical, and you know, I'm not sure we would participate in it." So we're cautious about predicting how many sites we're going to have until we know what the trial design is that will be accepted by the FDA.
Understood. Thank you.
Mm-hmm.
Wonderful. Okay, so we have our next question, comes from Jason McCarthy of Maxim Group. Jason, we're gonna open up your line, and you'll have to unmute yourself.
Okay, great. Thanks for taking the question. I have more of a, kind of an abstract question, if you would. Because if you think about, using something like Annamycin, or we can call it a next-gen anthracycline, even up towards first-line, can you talk a little bit about how chemotherapy historically has been administered with a week on, week off, and a week, for seeing how the patient did, and then you kinda cycle back around? And how something like Annamycin may be able to change that narrative, and how, a chemotherapy could potentially be used by pushing the dose and, and changing how often it's used?
You know, certainly, Moleculin has a response to that, Jason, but I, I'd love to invite the independent clinicians on the call to comment on that. So, Dr. Andreeff, have you... Do you have any thoughts there about how to position Annamycin in that way?
Yeah. So the standard treatment, as Dr. Tallman explained, is 7 plus 3. So, we have three days of anthracycline, seven days of Ara-C, and it all depends on PK, and I think the PK studies are still ongoing. This is not a week on, week off treatment. This is a one-time treatment over a week, followed by a three-week observation period that allows count recovery and assessment of response. So, I'm not familiar with the latest PK data, but this- I don't see a major change in this established regimen for 50 years, the combination of Ara-C and anthracycline. And the Ara-C dose used here is 2 g per square meter. That's on the high side. I think we can get the same or even better responses with 1.5 g per square meter.
That's what we are using. Dr. Tallman, any thoughts?
No, I agree. Having said that, it may not change the logistics of delivery and administration of chemotherapy. I can tell you that we are very excited about the possibility of Annamycin substituting and even replacing the current anthracyclines because of its increased efficacy, its ability to avoid some resistance mechanisms. So we're very enthusiastic. As enthusiastic as we are about seeing what this drug will do in a larger trial in second line, I think we're very excited about its potential first-line therapy.
... and just lastly, what level of durability of response do you think you need to see, in addition to what we've seen already, including the data this morning, to be clinically meaningful? And, you know, how do you look at that across the number of lines of therapy that patients may have gone through, whether it's second or now looking towards third line or possibly later than that? Can you kind of break down what would be meaningful in each of those lines?
Let me just remind for anybody that tuned in late, the data we've shown today, which is new data, so we haven't disclosed durability up until now, 'cause we just hadn't had the passage of enough time. But in today's presentation, we're basically at 5 months, 4.9 months, durability of response, and that's that number's growing, so we're probably gonna be better than that. But the... Having said that, it's just a telling time where we are now. Let me defer to the two independent clinicians to get their thoughts on durability.
So my take would be that this is not the most important endpoint. What we want is a complete remission, hopefully MRD negative, followed by transplant. So if you relapse and you have the good fortune of achieving a second CR, the next step will be an allo transplant. And again, there is almost no age limit anymore for allo transplants. So the goal from my perspective would be to get the patient to transplant in the best possible shape, and that means, MRD negativity, at least by flow cytometry. Martin?
I agree, and it's... You made a couple of important points. The best endpoint may not be overall survival for second-line patients, because most, if not all, will go to a transplant. Not only is the age not a, well, not a limit anymore, but the identification of a suitable donor is also not a limitation. So most patients will get an allogeneic transplant, so complete remission emerges as the most important endpoint, I think.
Okay, let's just... Sorry, one last quick one, 'cause you just mentioned something about transplant, and we saw this in the Actinium trial. It was antibody radiotherapy. It's very different, but it was for in place of chemotherapy regimens to get relapsed refractory patients with AML to a bone transplant. They were very successful. But if you have something like Annamycin that is in these later lines of therapy and you are getting these CRs, does that open up the discussion as this is potentially a new standard of care to get people bridged to a transplant?
Yeah, let me, I mean, again, invite our independent clinicians to comment on that. We'd love to hear your thoughts.
Yeah, I think if Annamycin really replaces, and I can certainly see that happening, has the potential to replace the current anthracyclines, more patients should get to a transplant. And in fact, more patients will get a, will hopefully achieve a complete remission. And we say most patients will get to transplant, but it even raises the possibility that you may not need transplant as often if a durable MRD negative CR is achieved at a higher rate with, with Annamycin.
In patients with core-binding factor leukemias, they today are being treated not with transplant, but they get, Ara-C-based, Ara-C anthracycline combinations. In these patients, I could see, you know, cures, increased cure rates with the Ara-C Annamycin combination, and that would be one group that would not need a transplant.
Got it. Thank you, guys, for taking the questions. Great call today.
Thanks, Jason.
Thank you, Jason. Okay, this does conclude the Q&A. I think before we close the event, we'd like to do a quick around the table, so to speak, of parting comments. So, you know, we'd love to speak, have... You know, Dr. Tallman, maybe you go first. Do you have any closing remarks?
Just that I've appreciated the opportunity to participate today, and I was very excited to join the scientific advisory board. I think this is a very exciting agent. I think it has great potential, not only for second line, as we've mentioned several times, but in first line.
Thank you. It was an honor having you with us. Dr. Andreeff, how about you? Any closing remarks?
No, I think Dr. Tallman really summed it up. The response rates are unprecedented in relapsed patients. Very exciting, and the duration is also unusual, so I'm very optimistic about this agent.
Well, it's a true privilege having you with us. Dr. Waymack?
I would also like to thank everybody for calling in, and we at Moleculin look forward to another such call next year as we give you an update on our hopefully ongoing phase 3 pivotal trial.
Wonderful. Okay, Wally, we will end with you. Any closing remarks?
Well, I'm gonna sound like the typical business guy. But first, I really do want to extend a very hearty thanks to Doctors Tallman and Andreeff for joining us today. Your time is valuable, and this was really important for Annamycin and then for AML patients. Look, as I have in other recent discussions, you know, I wanna emphasize that our current stock trading value is frankly nonsensical in light of this recent data. Look, we're now Phase 3 ready. We have dramatically better data than any drug approved for second-line use in AML, and some of those other assets have recently been valued in the $ billions. I'm a recent buyer of our own stock. I'm putting my money where my mouth is, as are my senior management colleagues, Paul and John, on this call.
It's our belief that once enough of the right investors finally pay attention to what's been happening here, Moleculin stock could run up, and quickly. I believe when that happens for us, a lot of people are gonna be asking themselves, "How did I miss this?" Now is the time for investors to filter out all the noise and look at the hard data, and hopefully this discussion helps convince more investors to do just that, Jenene. Thank you.
Great. Thank you. John, I just realized I don't wanna leave you out. You weren't on my screen, and I see you, I see you there, and I would love to hear your parting remarks. Thank you.
Well, first of all, I wanna thank Dr. Tallman and Dr. Andreeff for joining us. It's such a great privilege to have you guys join the Science Advisory Board. I would just like to echo what Wally and Paul have both said. We have really set out a timeline roughly six months ago, and we've stuck to that, and I hope that not only investors take stock in what Wally and Paul have said, but also that we've been able to deliver what we've said we were going to deliver. So stick with us, and thanks for your time today.
Great. This does conclude the Moleculin AML Clinical Day. Wanna thank everyone for joining. We will have a replay on the company's website at moleculinbio.com. Thank you.
Thanks.