In their third quarter 2023 earnings call, Moleculin Biotech (NASDAQ:MBRX) shared encouraging preliminary Phase 2 data for their lead program, Annamycin, showing potential in treating both acute myeloid leukemia (AML) and advanced soft tissue sarcoma (STS). The company expressed optimism about their cash runway extending to Q3 2024, and the interest shown by investors and investigators for funding and conducting trials for its other products.
Key points from the call include:
- Promising results were reported for Annamycin in AML, with a 38% response rate among heavily pre-treated patients, comparable to the approval rate of Veneza. Some patients who were treated with doses exceeding the maximum allowable anthracycline dose exhibited durable responses.
- In STS, Annamycin achieved a 78% response rate and promising overall survival data.
- Moleculin Biotech plans to initiate pivotal approval trials for both AML and STS next year.
- The company is considering an "all-comers" trial for first-line patients.
- The estimated cost for a Phase 2, 3 pivotal study for AML is around $18 million, and external funding is expected for the STS trial. The estimated cost for a Phase 2B study for SDS would be less than $5 million.
- The company also discussed potential indications for their products, including triple negative breast cancer, renal cell carcinoma, and pancreatic cancer with liver metastasis.
Moleculin Biotech (NASDAQ:MBRX) is confident that these results support a marketing approval pathway for Annamycin. The company also discussed their plans for clinical trials and potential funding for their treatments. The executives highlighted the potential for their anthracycline drug to accumulate in the liver without causing significant toxicity, a crucial factor in treating pancreatic cancer.
The company's executives also highlighted the potential of their anthracycline drug to accumulate in the liver without causing significant toxicity. The progression-free survival (PFS) data presented for their product in STS showed a median of 3.4 months in a specific subgroup, which they believe is clinically meaningful when compared to other similar treatments. The company aims to include both PFS and overall survival (OS) as endpoints in their clinical trials, with the hope of showing improved OS compared to existing treatments.
The executives mentioned that the number of patients needed for pivotal trials in AML and STS-LM is still uncertain but estimated to be in the few hundreds. They expressed excitement about the positive data and their plans for establishing a pivotal pathway for their drug, Annamycin.
InvestingPro Insights
In light of the optimistic news from Moleculin Biotech's Q3 earnings call, it's important to consider some financial indicators and insights from InvestingPro. The company, with a market cap of $17.17M USD, is currently navigating a challenging financial landscape. InvestingPro data indicates that Moleculin Biotech's P/E Ratio is at -0.57, suggesting that the company is not profitable at this time. The 1 Month Price Total Return is at a strong 20.0%, indicating a positive market reaction over the last month.
Two InvestingPro Tips relevant to this context are that the company holds more cash than debt on its balance sheet, and it has liquid assets that exceed short-term obligations. This is a positive sign as it could help the company fund its clinical trials and extend its cash runway. However, it's worth noting that the company has been quickly burning through cash, which is a common scenario for biotech firms in their developmental stages.
InvestingPro offers many more tips for those interested in gaining a deeper understanding of Moleculin Biotech's financial health and potential. These insights can provide valuable context for interpreting the company's promising clinical trial results and future plans.
Full transcript - MBRX Q3 2023:
Operator: Greetings, and welcome to the Moleculin Biotech Third Quarter 2023 Conference Call and Webcast. [Operator Instructions] As a reminder, this conference is being recorded. At this time, I’d like to turn the call over to Jenene Thomas, Investor Relations. Thank you. You may begin.
Jenene Thomas: Thank you, Gerald. Good morning, and welcome everyone. At this time, I would like to remind our listeners 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 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 that any independent source of verified any information obtained from third party source. Any data discussed regarding clinical trials and progress are considered preliminary and subject to change. So joining us on the call today from the Moleculin’s management team are Walter Klemp, Chairman and Chief Executive Officer; Dr. John Paul Waymack, Senior Chief Medical Officer; and Jonathan Foster, the Executive Vice President and Chief Financial Officer. I would now like to turn the call over to Walter Klemp, Chairman and CEO. Wally, please proceed.
Walter Klemp: Thanks, Jenene. Hello, everyone. I'm Wally Klemp, Founder, CEO, and Chairman of Moleculin Biotech. We are really excited to welcome you to this Q3 earnings call. We've been saying for some time now that this would be our year of data, and we are finally able to deliver on the Phase 2 data we've been hoping for. To be clear, this is preliminary and subject to change, and there's a lot more data to come in the next few quarters. But we have a start, and it's a good one. We're going to share it with you on this call. As we walk through the data today, I'd ask you to keep in mind one of our core beliefs. That is that the most important therapeutic tool for both AML and advanced STS has been and continues to be an anthracycline. Despite the fact that there have been more than a dozen new drug approvals in these indications over the last five or so years, the first line therapy for both indications and the best hope for a positive outcome remains with the use of anthracyclines. Unfortunately, today's anthracyclines have major limitations that prevent most patients from sharing in this benefit. But those days are about to be over. Moleculin intends on making this indispensable tool available to those patients who have until now been excluded from their use. And of course, the drug we intend to do this with is Annamycin, our lead program in a pipeline that is both deep and broad with a long list of potential additional high-value targeted indications. As many of you know, we're doing this with a highly efficient capital structure by exploiting a global network of preeminent collaborators. Now, our pipeline is robust and too complicated to capture in just one slide. After all, between the trials that we've completed, are currently running, and are approved to begin, we're talking about 11 clinical trials for our technologies. Today, we'll focus on just two of them. Our European trial in acute myeloid leukemia and our U.S. trial in advanced soft tissue sarcoma. As a reminder, we have orphan drug designation and fast-track status in both indications, and we have a strong patent position for Annamycin and a range of potential indications. For those of you who are new to the story, it's critical to understand why the use of anthracyclines has been limited for so long. Far and away, the greatest limitation to current anthracyclines is cardiotoxicity. This is the primary reason patients either can't receive anthracyclines or have to terminate treatment before receiving the desired benefit. As well, there are also limitations resulting from tissue organ distribution and multi-drug resistance mechanisms. As a result, there are many patients who simply don't get to benefit from today's anthracyclines. Now, when it comes to cardiotoxicity, the data are quite surprising. Anthracyclines are so cardiotoxic, in fact, that the FDA has established a lifetime maximum allowable dose of 550 milligrams per square meter. As you can see from the chart on the left, if you only accumulate 100 milligrams per square meter, your risk of cardiac impairment is negligible. But if you go up to that maximum, there's a 65% chance you will experience some form of cardiac impairment. And if you go up to 850 milligrams, it's 100% certain you will have some kind of impairment. Now to make this even more graphic, the chart on the right shows that 600 milligrams per square meter, there's an 8% chance you'll have full-on heart failure during treatment. When you translate this reality to our lead indications, you see that more than half of all patients diagnosed with AML cannot receive currently prescribed anthracyclines because they're deemed unfit due to age or poor health. Likewise, in advanced soft tissue sarcoma, even though the standard-of-care therapy is always anchored around an anthracycline, usually doxorubicin, only about 30% of patients will respond and all of those will relapse. And once they're at the lifetime maximum allowable dose, they're relegated to a range of drug cocktails that do little or nothing to extend their lives. The best answers currently available are simply not enough. In AML, that is a drug called venetoclax, most often used in combination with azacitidine. This VEN-AZA combination is capable of generating a complete response in 37% of patients, which is good for that 37%. And this drug generates a half a billion dollars a year in revenue for AbbVie (NYSE:ABBV). But there's a strong consensus among clinicians that VEN-AZA is just too hard on patients. It's very difficult for patients to tolerate and its clear there needs to be a better answer. In advanced STS, the best fall back treatments appear to be dacarbazine and trabectadine. But the best they can offer is about a three month PFS to around half the patients with no appreciable improvement in overall survival. There simply must be a better answer. And now there is. Annamycin is what we call a next generation anthracycline that's designed to be non-cardiotoxic and appears to be improving outcomes in both AML and STS. In AML, we've completed Phase 1 testing and are now in Phase 2. And in STS, we've not only completed Phase 1, we've also completed enrollment in our Phase 2 study and are preparing for a pivotal approval trial. Annamycin does have orphan drug and fast track status in both indications and importantly, strong patent protection through 2040. So when we say Annamycin is non-cardiotoxic, we mean 100% non-cardiotoxic. It's important to stress this as there are other players out there with anthracycline technologies that they claim are less cardiotoxic than doxorubicin. But to our knowledge, no one is capable of making the claim we make because we're the only ones testing every aspect of cardiotoxicity and then submitting our data to an independent cardiology expert at the Cleveland Clinic. And in addition to being completely non-cardiotoxic, we appear to be easier on patients than currently approved anthracycline. As a small example, 65% or more patients treated with doxorubicin will lose their hair. We're seeing less than 10% of patients having any hair loss with Annamycin. But despite the fact that Annamycin is easier on patients, it is actually more potent than doxorubicin in most tumor models. And it's able to avoid the multidrug resistance mechanisms that limit the efficacy of doxorubicin in many patients. And that means even though we're concentrating on AML and STS, Annamycin should be relevant to 10 times as many patients once expanded to additional indications. As it relates to expanding our pipeline, by the way, we are very effectively utilizing non-dilutive institutional funding for clinical development. In addition to our sponsored research at both MD Anderson and UTMB, we've benefited from clinical development funding from MD Anderson, Emory University, and the Madame Curie Institute in Poland. And we're expecting several clinical trials to benefit from outside funding this coming year. And our sponsored research has paid some big dividends thus far. In addition to demonstrating the synergy between Annamycin and Cytarabine that's now playing out in our Phase II AML trial, this ongoing research also eliminated the fact that Annamycin is 30 times better at accumulating in the lungs than doxorubicin, making it an ideal candidate for advanced STS, which is most commonly what is the point of metastasis is to the lungs. So with that as background, I'd like to invite our Senior Chief Medical Officer, Paul Waymack, to give you the specifics on the new data.
Paul Waymack: Thanks, Wally. It has taken a long time to get to the point of generating Phase 2 clinical data for AML, but we are finally there. Part of the challenge from a regulatory standpoint was needing to demonstrate the safety and the efficacy of Annamycin as a single agent before combining it with Cytarabine for AML patients. Given that we also had to demonstrate that patients could be safely dosed at well above the FDA's maximum allowable anthracycline dose, this also meant we had to work with patients who were receiving third, fourth, fifth line, or worse therapies, which are the most difficult patients to treat and expect any impact. Now notwithstanding all these challenges, we are now finally treating AML patients in a Phase 2 study with Annamycin in combination with Cytarabine, a combination our preclinical testing suggested would be even more effective for AML patients. And this appears to be the case. We now have data from the first eight patients who incidentally entered our trial with a median of four prior therapies. We are very pleased to report that among patients who have completed their Annamycin dosing, we have three complete responses. This represents a 38% response rate, something that would not be expected in such heavily pre-treated patients. For comparison, you may recall that Wally mentioned the approval of Veneza [Ph] was based on a 37% complete response rate. So we are already performing at a level that we believe will support marketing approval of Annamycin. And what's more, we are doing this in heavily pre-treated patients, whereas the Veneza trial for approval was in first line therapy patients. When you look at the specifics relating to our complete responders, there are some valuable insights that are now apparent. First, one of them responded to Veneza but then relapsed. One was refractory to Veneza and the other had no prior exposure to Veneza. The first two responders are now confirmed as durable with one at eight months of remission and climbing and the other having just received a bone marrow transplant three months after treatment with Annamycin. We can't yet declare durability for the third patient simply because not enough time has passed since their treatment and remission. It's also worth pointing out that all three of these patients were treated well above the lifetime maximum allowable anthracycline dose of 550 milligrams per meter square. Again, this is what we were hoping to see in AML and if we continue to see this level of activity, we think we'll be in a very good position to establishing a marketing approval pathway. Turning to our soft tissue sarcoma, we now have complete enrolment of the Phase 2 arm of our U.S. clinical trial and are able to present some preliminary data from the trial as a whole. There's a lot to process here but in total, we believe this trial's data bodes well for an ultimate approval in advanced soft tissue sarcoma. The unmet need here is so great that most of the recent approvals have been based on the very modest improvements in progression-free survival or PFS. It took us a while in this trial to zero in on the optimal dosing regimen and it turns out that the most productive dosing regimen is not the highest dose we tested. When isolate for this optimum dose, which turned out to be around 330 milligrams per meter squared, the column on the far right shows that we had a 78% response rate with 56% of the patients reaching three months or higher progression-free survival among patients who had received one or two prior therapies. That compares favorably with other approvals for the indication, but it's only half the story. One of the shortfalls of second-line therapies is delivering extended overall survival. Although we haven't had enough elapsed time in the Phase 2 group to reach the medium overall survival, since 12 of the 17 patients receiving Annamycin are still alive, and the median overall survival won't be reached until the number still alive falls all the way down to eight, we can look to the Phase 1 cohort's data where we see overall survival at 11 months and climbing. Considering that the median number of months from diagnosis for patients entering the Phase 2 portion of our trial was 20, the overall survival that we appear to be headed for could be an even stronger basis for a marketing approval. We had the pleasure of sharing these data with a group of soft tissue sarcoma key opinion leaders at the recent CTOS, that's Connected Tissue Oncology Society Conference in Dublin, and the enthusiasm was high. As a result, we now have two different groups proposing to run their own versions of a pivotal approval trial, which we expect to be kicking off next year. I'll now hand it off to our Executive Vice President and Chief Financial Officer, Jon Foster, to wrap up the call. Jon?
Jonathan Foster: Thanks, Paul. We ended the quarter with roughly $25 million in cash on hand, and our balance sheet remained clean with no debt and little overhang with warrants. With our current burn rate, this cash will get us into the third quarter of 2024, a runway that we've been consistent in our discussion since our last major equity raise in 2021. We have just short of 30 million shares outstanding. This runway allows us, we believe, to deliver these milestones into 2023, early 2024, and set the table for delivering the milestones later in 2024. Regarding Annamycin for the treatment of AML, with MB-106 being an open-label trial, we will continue our quarterly clinical trial updates and also concurrently with other events, such as scientific conferences or other public presentations. With us delivering the efficacy discussed, recruitment has picked up, and we expect recruitment to be fulfilled in early 2024, if not sooner, and engaging with the FDA and the EMA with the end of Phase 2 meetings. From that, we expect to identify the next steps for the next pivotal clinical trial and begin that at the earliest in the second half of 2024. Regarding treatment of advanced soft tissue sarcoma, we will continue to monitor subjects for OS and PFS, and we expect to report in the second quarter of 2024 that final readout. That's not stopping us in moving forward with discussions with investigators for a possible investigator-funded trial, either partly or fully in first-line treatment of advanced STS, just as Paul discussed. The response to our meetings with investigators at CTOS leads us to believe that the next program could be identified in either the U.S. or the EU in the first half of 2024 and initiated in the second half. All of these milestones are building upon the efficacy data that we just discussed. Wally?
Walter Klemp: Thanks, Jon. For quite some time now, we've been touting the non-cardiotoxic nature of Annamycin, but there is just no substitute for data. We've now treated 66 patients, most of whom were taken well above the lifetime maximum allowable dose, and not a single one has exhibited any signs of cardiotoxicity. But the absence of cardiotoxicity is meaningless without efficacy. And up until now, that's been the big unanswered question. Could Annamycin actually deliver enough activity in a phase 2 setting to be worthy of marketing approval? Well, that question is now being answered. Yes, the data are preliminary, and we need to substantiate what we've shown you with a few more patients. But with those caveats in mind, Annamycin is delivering, and it has everything it needs in order to become what we believe will be a multi-billion dollar drug. And it all comes back to our core belief. The most important tool for AML and advanced STS, as well as a host of other hard-to-treat cancers, is an anthracycline. Those anthracyclines haven't been improved in decades. Annamycin finally represents a real improvement in anthracyclines, and we're going to make this tool available to those patients who, until now, have been denied this opportunity. So that wraps up our prepared presentation for the quarter, Jenene. We'd be happy to handle any questions folks have.
Operator: Thank you. We will now be conducting a question and answer session. [Operator Instructions] Our first questions come from the line of Jonathan Aschoff with ROTH MKM. Please proceed with your questions.
Jonathan Aschoff: Thanks. Good morning. Congrats on the data, but what I wanted to ask about it, can you really exclude from the percent CR rate analysis in AML, the Cytarabine, SAA, SAE, as well as the stroke patient? Shouldn't that denominator be 10?
Walter Klemp: Paul, I think you're probably best to address the statistical basis for establishing CR rates. You want to tackle this one?
Paul Waymack: Yes. Certainly, in a pivotal trial with the intent to treat analysis, you would include them all. As a Phase 2 study, we do things differently. In a pivotal trial, because the person had an allergic reaction to Cytarabine, we would have just continued treating with Annamycin alone since in the 105 monotherapy trial, we were getting similar results of a CR rate around 40%. We just wanted to present here patients who had finished. I would point out we've got another patient in this trial who finished their therapy. We have verbal confirmation from the site that they had a CR, but we don't put that in the slide deck until we have the written documentation. So we are trying to be very specific in a Phase 2 study with patients who have documented data and who exactly followed the protocol, whereas in the pivotal Phase 3 trial, it would be more broadly in the intent to treat analysis.
Jonathan Aschoff: Okay. Is it fair to say that for the STS LM data set in today's press release that it is no new data compared to the update a week ago?
Walter Klemp: Yes. John, you're most familiar with what's been publicly shared. Do you want to dial that in?
Paul Waymack: No. I would disagree, Jonathan. If you look at the chart that we presented on slide 19 and also in the queue and also believe the press release, when you start, remember we took all comers into this trial. We took up to people with up to 11 prior therapies. If you look at the right-hand side of that chart, you get down to where you're looking at second and third line therapies. Add a dose that we zeroed in on, and we're getting substantially better data. I'd look at that waterfall. I'd look at that waterfall data.
Jonathan Aschoff: But it's the same N of patients that was prior reported on. It's just greater duration data, correct?
Paul Waymack: No. We reported the 67% was Phase 1B, and then we moved on, and now we're presenting the Phase 2 data. And so what we did was we added 17 patients, and you can see the waterfall data, how it goes across that chart. And so we end up, once we start looking at the 330 milligrams and below patients, we found out that 360 and 390 was just too much, and people with less prior therapies. We got better results. We got results, comparative to dacarbazine and trabectadine. And worse ones.
Jonathan Aschoff: To be fair to me, though, I mean, I've written up notes in the past of three Phase 1B patients at the recommended Phase 2 dose and 14 Phase 2 patients, all of whom must be taking the recommended Phase 2 dose, and that adds up to 17.
Walter Klemp: Yes, I think the point here, Jonathan, is since that last report, we now have updated PFS, updated OS, as well as segment data that just hadn't been elucidated. So I take your point, but I think there's important new information that we're sharing for the first time in this release.
Jonathan Aschoff: All right. Now, lastly, how many patients do you expect to have to enroll in a pivotal trial for both AML and STS-LM?
Walter Klemp: So, Paul, you spent more time than anybody focusing on the proposed pivotal trial protocols, and I know you've had lengthy discussions both with investigators and statisticians, so you want to tackle that one?
Paul Waymack: The ultimate answer is whatever the FDA demands. For soft tissue sarcoma, we have not finalized the plans for the pivotal trial yet because, as I mentioned, patients are still going on, and we have not reached median overall survival and the like. We would anticipate it will be in the few hundreds, but we can't give you an exact number yet because that trial, the efficacy data are still coming in. For the AML, as we have mentioned before, we would like to go for first-line therapy. The 106-trial we're doing now, we are now enrolling first-line therapy patients to get data to make sure that the results are similar, if not better, than what we have seen to date. Based on FDA guidance documents, we would propose going to the FDA and getting approval based on a single trial. There is a pathway for a single trial with single-arm therapy through accelerated approval with subsequent confirmatory trial through the accelerated approval process. We would propose that. A single-arm trial would take about 100 patients. If we're required to do a randomized trial, it would be about 300.
Walter Klemp: Paul, let me add on to that. You mean elderly and unfit first-line, correct?
Paul Waymack: Yes, for our first-line therapy in elderly and unfit patients, we would do a single-arm study, which is not that far off from what Venexa [Ph] was doing, and get approval on a single-arm study, accelerated approval. And then, again, if you do accelerated approval, you need a confirmatory trial, more of a traditional randomized trial where we would go broader indication, randomized versus an active control arm.
Jonathan Aschoff: Okay. Just to make it clear that it's somewhere in the lower triple digits of patients per trial is helpful. Thanks. Can you lastly answer, what kind of progress have you made in finding funding or getting an investigative sponsored trial going with the other two products, 1066 and 1112?
Walter Klemp: So, let me start there, but, John, you may have some nuance that you want to add to this. One of the – probably one of the most prolific areas of outside funding has been with our STAT-3 inhibitor, 1066. And just a quick recap, MD Anderson sponsored a trial there, then Emory University in pediatric brain tumors, and then the investigator that was at MD Anderson moved to Northwestern (NASDAQ:NWE) University. And we've been in ongoing discussions with that investigator. It's very likely that that investigator will come through with another externally funded trial for brain tumors in 1066. And we know that the folks at Emory are awaiting some additional data to come from the adult progress before they kick off. They've already indicated they want to kick off another pediatric brain tumor trial. So they're symbiotic there. They're comparing information. There's essentially a consortium of folks across the U.S. that have now recognized there's clearly some potential for activity of 1066 in brain tumors, and especially when it comes to pediatrics. And then finally, we continue to grind away on an IV formulation for 1066. And on the investigators I've just described have all made it clear the instant that we have an IV formulation, they intend to switch to that because we all recognize that the PK characteristics are probably going to be better with an IV delivery of that drug. On the 1122 side, we continue to right now just be moving at what I call grant speed on the basis of U.S. government grant funding of virology research as it relates to 1122. So that's our primary focus there. But let's face it, that stuff is highly speculative and it's slow moving. So I would say that the slowest program we have in the portfolio right now is 1122.
Paul Waymack: All right. Thanks. And then I would add to that. I would add that the Northwestern trial is already listed on clinicaltrials.gov. It's 1066 in combination with radiation against GBM.
Jonathan Aschoff: Okay. Thank you. And the queue [Ph] will come out later today?
Paul Waymack: The queue should have already been filed.
Jonathan Aschoff: Okay. Thank you, guys.
Paul Waymack: Thanks, Jonathan.
Operator: Thank you. Our next questions come from the line of Jason McCarthy with Maxim Group. Please proceed with your questions.
Jason McCarthy: Hi, guys. Thanks for taking the questions. In the STS data, with the median PFS, it looks like its 3.4 months for patients who are less than 330 mg per meter squared. You mentioned that the overall survival median so far has reached 11 months in 15 patients from Phase 1B. What was the trabectadine OS before it was approved? I know it didn't move the needle much on OS, but it did. It must have had an OS. That's the first. Yes. Okay.
Walter Klemp: I'll jump in there because I looked at the paper they're referencing. They really don't go into PFS, I mean, OS data. They really focus on PFS data. That's why we're so excited about the median OS that we're receiving.
Jason McCarthy: Okay. And mechanistically, for Annamycin, what do you think the differences are where you're having to go 330 mg per meter squared or less in the STS trial, but you're going higher in the AML trial?
Walter Klemp: Let me start that off and, Paul, fill in wherever you think I maybe haven't covered it adequately. I think there are two dynamics here at work. One of them is the specter of thrombocytopenia in patients. So we know that even though we can technically cross the hurdle of not reaching a DLT and keep, in fact, we never did establish an MTD in that trial, but as we bumped up against 390, the handwriting was on the wall that the thrombocytopenia issue with patients was going to become a barrier to ongoing treatment. And so we felt like, okay, we're seeing similar activity at lower dose levels, so let's not push the envelope here. Let's work in the center of the therapeutic window, if you will. More specifically to your, because I understand your question, why do we think that we might not get any more benefit out of higher dosing because classically speaking, higher is better with an anthracycline? You go to the maximum. There's a scientific analysis that the inventor has gone through whereby there are some mechanistic reasons when you get to a certain level, as you know, is a topoisomerase to poison, there appears to be the potential for a point of diminishing returns where you simply can't get any more cell kill benefit out of increasing the dosage, but you can actually start to have some sort of counter-effective results. And we don't have the specific mechanism data to support that argument, but it's a theory. But there is a theory out there that says there's a point where you can go too far with TopII poison and not get any additional benefit out of it. Paul, do you want to add anything to that?
Paul Waymack: Let me just add just the indications. You are correct, and that's a good point. The 330 we're doing for soft tissue sarcoma is actually lower than the 230 we're doing for AML because the 230 is for three straight days, which becomes 690. If you look at the soft tissue sarcoma, our number one by far adverse event is low blood counts, especially platelets. That forces us at times to stop. We could go up to 390. We didn't have a DLT, but we had to delay therapy because of the low platelet counts, because it was hitting the bone marrow. Well, with AML, that's where you've got to hit. That's where the cancer is. It is the blood cells in the bone marrow. You've got to blast the hell out of them, essentially, and wipe them out for a while. So the toxicity that is forcing us to hold and delay dosing in soft tissue sarcoma if we go too high, that's not an issue with AML because in AML, here, the safety location is also the efficacy location. So it's just with an adverse event for one indication for the other, that's efficacy. So I think that's the primary reason for the difference in why we're keeping it a little lower than soft tissue sarcoma than in AML. If that makes sense to you.
Jason McCarthy: Got it. Last question. You had mentioned potentially selecting another indication next year. Can you provide a little bit more detail as to what you may be thinking, perhaps, along the lines of where an anthracycline may be a key therapy or a go-to therapy, kind of what the PFSOS might look like in whatever said indication?
Paul Waymack: Yes. I mean, we can't speak to speculating on what the human PFSOS implications of this would be, but we've got very compelling data in a number of indications. For example, triple negative breast cancer metastatal lungs. Also, renal cell carcinoma metastatal lungs. But the one that probably gets the most excitement out there is pancreatic cancer and specifically pancreatic cancer met for the liver. And as I'm sure, Jason, most pancreatic cancer patients present with liver mets. And so it's the most common site of metastasis. And we've talked for now a long time about the fact that we can hyperaccumulate in the lungs. It turns out we also hyperaccumulate in the liver as compared to doxorubicin. I think the ratio is like six to nine times more than doxorubicin. So it might be the first opportunity to actually bring an anthracycline to the table in pancreatic cancer. So if we were to kind of pick and choose and say, what investigator funded study would we be most enthusiastic about? It's probably that one.
Jason McCarthy: Okay. Just to follow up to that then, because you're accumulating in the liver, does that reduce the potential for healthy tissue talks in the liver? Because a lot of chemotherapies are just not used in the liver because the liver is already weak. Because it has either liver mets or primary tumors there.
Walter Klemp: Well, I mean, what we know from the animal data is that we don't see any disproportionate increase in liver toxicity in animals vis-a-vis doxorubicin, even though we appear to accumulate it nine times the level. Paul, you've been monitoring liver toxicities in human patients. What's your perspective there?
Paul Waymack: To date, we have seen no indication of liver toxicity. You look for liver toxicity based on what's called High's criteria. That's [Indiscernible]. He's a famous physician in liver disease. We've seen that. We have not seen Billy Rubin go up. We have seen liver enzymes fluctuate a little, but they never go up to a clinically significant degree. As of now, I guess we're approaching 70 patients being treated in all of our studies. We don't have evidence of liver toxicity.
Jason McCarthy: Great. Thank you, guys.
Paul Waymack: Thanks, Jason.
Operator: Thank you. Our next questions come from the line of Jeff Jones with Oppenheimer. Please proceed with your question.
Jeff Jones: Thanks for taking the question, guys. Congrats on the quarter and the updated data. A couple of questions. Following on from what's been discussed already, my understanding of your path forward in STS lung mets is that you're looking at, similar to Trabectedin, a PFS endpoint for approval. Is that correct?
Walter Klemp: Well, I think we would modify that to say we really think that we've got a shot at moving the needle materially on OS. So, correct me if I'm wrong, Paul, but I think of our window of opportunity here to be the combination of both PFS and, for the first time ever, PFS that actually translated into increased OS.
Paul Waymack: Again, from a regulatory standpoint, we would, in any clinical trial, would be measuring both variables, PFS and OS. We would prefer to have PFS since it would be quicker approval, obviously, but as Wally said, the data are becoming very impressive for OS. So, we would probably, at an end of Phase 2 meeting, propose to the FDA initial approval on PFS and then add OS into the product labeling just for better marketing opportunities.
Jeff Jones: Okay. That makes sense. And then, I guess, as I look at the PFS data across the subgroups that you've provided, while it's 3.4 in the 330 mg per meter squared with less than two prior lines of therapy, it's in the two to two and a half range when you look at the more intent-to-treat populations for both the Phase 1b and 2. And, Trabectedin, the PFS, was somewhere on the order of two and a half months. So, even taking the 3.4 months, you're adding a month, a month and a half to PFS. And so, it goes to the question of clinical meaningfulness. And, as you probably know, there was a company that just dropped a trial or dropped a program with the PFS of 3.6 months. So, they just abandoned the product with the 3.6 month PFS. So, that overall…
Walter Klemp: So, Jeff, one thing I would point out that I think is a point of difference is, first of all, it's not greater than a first-line therapy. It's two or fewer prior therapies in that right-hand column. But, it's important to note that we chose the most difficult subset of patients in our inclusion-exclusion criteria here. So, we're not taking all advanced. This was not an all-comers trial. This is not all advanced soft tissue sarcoma. This was only lung mets. And, in every trial we've ever seen published, while no one actually gives specific data for the subgroup of lung mets, most of those trials will somewhere in their text acknowledge that the lung mets subgroup underperformed vis-a-vis the overall population. So, because we accumulated in the lungs the way we do, we deliberately chose this worst possible selection criteria. Now, having said that, we think the more likely approval trial design will be an all-comers trial, and it's very likely to be first-line patients. So, we realize that the data we're talking about today is not precisely the target that we're setting for a likely approval trial, but everything gets easier for us, we think, as we design this approval trial structure.
Jeff Jones: Okay. That's helpful. Thank you. On the AML side, you're in sort of your timelines. You're talking about an end of Phase 2, the first half of 24, and a potential pivotal start second half of the year. And as you were talking about, that is depending on single arm or otherwise in a randomized study, 100 to 300 patients, what did the costs look like for pivotal study, both, frankly, in AML and SDS at lung meds, or SDS as you were just implying?
Walter Klemp: John, that's clearly in your ballpark. You want to handle that one?
Paul Waymack: Oh, sure. So, you're talking about a Phase 2, 3 study, pivotal study? You're talking roughly $18 million, drug included.
Jeff Jones: In which indication?
Paul Waymack: AML.
Walter Klemp: And, Jeff, we might not have been that articulate about it, but it looks like there's enough in Paul's segment, he mentioned this, there's enough enthusiasm on the SDS side among institutions that are specializing in this. It looks very likely that we're going to have external funding for a pivotal trial on SDS.
Jeff Jones: Okay. What would the total funding be required for the SDS pivotal study?
Walter Klemp: Well, I would say, from a, well, it really depends how much we get from the externally funded trial. I get.
Jeff Jones: And you're talking about? Exclusive of external funding. So, all in, and then external funding would obviously reduce your investment requirement.
Paul Waymack: Yes. Phase 2B, not a pivotal, would probably, just to get it off the ground, would be fairly cheap. We'd estimate less than $5 million. That does not include the pivotal population.
Walter Klemp: Well, I think practically speaking, it's, frankly, it's not a lot different than the pivotal AML trial in terms of cost.
Jeff Jones: Okay. That's helpful. Thanks, guys.
Walter Klemp: Thanks, Jeff.
Operator: Thank you. We have reached the end of our question-and-answer session. I would now like to turn the floor back over to Mr. Klemp for closing remarks.
Walter Klemp: Thanks, Gerald. Look, we're clearly excited about this data, having it for the first time. Something real to talk about. I think we're finally at that point where we're able to stop talking about what might happen in the future and start talking about what is happening right now. Look, our loyal supporters have been patient for a very long time. So, we couldn't be happier to be finally delivering this kind of data. And for those of you who are new to the story, frankly, your timing couldn't be better. You should expect more positive updates in the next few quarters because this data is building. And so, we're going to establish a pivotal pathway for Annamycin, and we'll communicate that as quickly as we can to the marketplace. This is what we've all been waiting for. So, thank you a lot and have a great week.
Operator: Thank you. This does conclude today's teleconference. We appreciate your participation. You may disconnect your lines at this time. Enjoy the rest of your day.
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