Good morning. We're back again. This time we have Jon Foster, the CFO of Moleculin. Jon, good morning.
Good morning. Thank you for having me, Jonathan. Thank you to Roth for having us. Glad to be here.
Thank you for being here. I would like you to start by giving a brief overview of what is the key asset at Moleculin: Annamycin.
Oh, great. Super. Well, first of all, before I start, I'm sure you'll be forcing me to make some forward-looking statements. And I encourage everybody to go to our website, look at our SEC filings, and especially look at the Safe Harbor language. So with that, Annamycin. Annamycin is our lead drug. We have three core technologies, but I'm going to focus on Annamycin. Annamycin is designed to be a next-generation anthracycline. By that, I mean it was designed at MD Anderson by the inventor there, Waldemar Priebe, to be resistant to multidrug resistant pumps, the MDR pumps, and also to be non-cardiotoxic. It's been in development for quite a few years. We have put Annamycin into liposomal formulation. It's very unique that the formulation is a multilamellar liposomal formulation. So it's basically like an onion. And that technology is patent pending.
If we get a patent on that, that's another 20 years of exclusivity for a drug that's in a Phase 1b/2, which is very exceptional. We've been in 2 Phase 1b/2 programs, one in AML and one in STS.
Okay. Well, if that's the answer to that question, I want to hear a lot more about the AML side of it.
Oh, but most definitely. Well, let me go, I guess, a little more further as we get into AML. In STS and AML, we've been efficacious to the point where we needed to make a choice: is it AML or STS? STS is such a hard soft tissue sarcoma metastasized to the lung. It's such a hard disease. You're talking placebo progression-free survival is 1.7 months versus what we had in the phase 1B was close to three months. So it's a pretty hard disease. AML is a great space from a standpoint of what we're talking about as complete response is really having an impact on patients' lives. And as I mentioned, the phase 1B in the U.S. is for STS, where the FDA allowed us to go over the maximum lifetime anthracycline dose.
In Europe, they allowed us to go over the maximum lifetime anthracycline dose for AML. Why is that important? It's due to the cardiotoxicity. Currently, current anthracyclines are the key to AML treatment, in my opinion. And also, we were recently over in Europe talking to some KOLs. And one of those KOLs had a great statement. Basically said, "Look, for you to have a durable CR and one that doesn't need maintenance, you need a little bit of an anthracycline." So that's where Annamycin comes in. Due to the lower cardiotoxicity or the lack thereof to date, and avoiding the MDR, it's a natural setting for second-line therapies. So as we move forward into the phase 1b in Europe in AML, we are now in the phase II portion. We reported in January on 15 subjects intent-to-treat population. And that's what I'll be talking about.
We'll update that to probably around 20 when we release our 10-K at the end of this week and early next week. When you start talking about the efficacy, the efficacy we've had, we had 40% CR. That is very important. That's not CRI. That's not CRH. That's complete responses. When you look at that and you compare that to 7+3 traditional anthracycline around about 30% in the 30% range of CRs. For the unfit population of Vidaza, you're talking roughly thereabout as well 30%. You're comparing us in second-line or greater. That's what we reported in 2015. It's just not second-line therapy. It's anywhere from 0- 6 prior therapies. Sorry, it's a little hot in here, but you're used to it. We're excited from that that we're getting 40% in those 15 patients that were all-comers, complete response.
Up to now, between all of our trials, the monotherapy trials that we had prior to we got to combination in MB-106 that I failed to mention, it's Annamycin in combination with cytarabine. It's a 5+3 therapy versus a 7+3 therapy. To date, we've had over 60 subjects reviewed by a cardiologist-oncologist at the Cleveland Clinic. And he's come back and said they've seen no cardiotoxicity. And over 50 of those were treated above the lifetime maximum. Now, look, when you start talking about anthracyclines and cardiotox, when you approach the lifetime maximum, you're going to get roughly 10% of the subjects, the patients, are going to have a cardiac event during therapy. And you're basically, once you get above lifetime maximum, guaranteed to be 100% a cardiac event. So we're looking at LVEF, troponins, I and T, echo strains.
Those echo strains are going to Duke University before they go to the Cleveland Clinic. So we're very pleased to have that lack of cardiotoxicity. But let's keep one thing in mind. We said this last year in the 10K. We'll say it again this year. We're treating very sick patients. So when you're talking about second-line or greater, these patients have either been exposed to Vidaza, 7+3. They've already been exposed to cardiotoxic drugs. At some point, we're going to have a cardiac event that we cannot unrelate to Annamycin. Just a matter of treating sick patients. For us to be where we are today with the efficacy of 40% and the lack of cardiotoxicity, and you combine that with a patent pending on the formulation that would give us another 20 years, traditionally, drugs at this stage are about six years.
We're at a very unique reflection point.
You said at some point you might get some cardiotox. Are you at your dose? Are you certain you're at the dose you need to be using?
Yes. Great question. We got to 230 g per meter squared in the phase 1b portion in the combination study with cytarabine. The reason we chose cytarabine was because we started our trial in Poland. The trial is being conducted in Poland and Italy right now. For AML, STS is U.S. But the doctors in Poland really wanted us to do in combination with cytarabine. If we had the cash runway, we'd have done what AbbVie did with venetoclax and combined it with three different other drugs like decitabine or I've got the other one, but also azacitidine. We would have done that as well. We chose one, cytarabine, which is also used a lot in monotherapy as maintenance in Poland.
So we're very pleased that when we got to 230 mg per meter squared, we had a CR at 190, 190 mg per meter squared, and then a CR at 230. And these were one out of three. And these were very, very sick patients. One had had up to six prior therapies. We went into phase II. We limited it to three prior therapies where we were the third therapy. And we're focusing on second-line therapy. As you look at well, let me get back to your question. So I'm meandering a little bit. But at 230 mg, we saw enough efficacy for us to say, "Let's open up the phase II portion." When we open up the phase II portion, we're looking at first-line and second-line and third-line therapies. Second-line, we believe, is the true nugget from a standpoint of the unmet need.
When you start looking at the waterfall for AML, you have 50% unfit, 50% fit. And then you waterfall that into potentially targeted therapies. And they may have a 20% CR rate. You end up with about 50% of the AML population still needing a second-line therapy. And we think that's very key. And that's where we're targeting Annamycin.
A lot of the companies I cover are going after AML. What do you say when you're asked to differentiate Annamycin among what's in the clinic now and not approved?
Well, when you look at Vidaza, it's not an anthracycline? It's a great drug. It's had a lot of good responses. The first patient we treated, for example, in MB-106, which was the trial in Italy and Poland for AML, we've recruited very quickly in that trial. We actually, last year, dosed the first patient in February. And now we're getting close to concluding that trial. So where are we different? Vidaza is not an anthracycline? As I said earlier, some doctors believe you need a little bit of an anthracycline to get to a lasting, durable CR. We're not a 7+3; we're not a traditional anthracycline with the MDR issues or the cardiotoxic issues. With regard to targeted therapies, right now, there are five approved targeted therapies in the U.S. There's one for IDH2, a couple for IDH1, FLT3, and CD33.
All five of those have been approved in the U.S. Four were done on single-line therapies, single-line trials. One was a dual-arm trial. But they did that, I believe, to also get approved in Europe. So those targeted therapies had a CR rate somewhere between 17%, and there was one just above 30%. Most are in the 20% range. But when you start looking at their efficacy versus their prevalence, you get to only about 20% of the AML patients get to a CR by them. We're treating all-comers, whether we're agnostic to prior treatments or mutations. And we are measuring we're keeping up with mutations. But with the sample size that we have, we really can't make any correlation to any mutations. But when you compare that from a standpoint, we're treating all-comers.
So if you look at the potential base of second-line therapy, you're seeing that we're getting 40% to CR versus all five of those targeted therapies, at best, are getting 21% of the AML population to a CR. So when you filter through the waterfall, you get to about 58%-60% of patients need second-line therapy. So again, I can't harp enough that with that huge of an unmet need, you have an anthracycline that's been proven to lack cardiotoxicity, have efficacy at 40%. It really fits a really good niche in there at the second-line therapy.
Yeah. And so with a bona fide chemotherapy that's demonstrably safer, you keep saying second and further lines. First-line, aren't you going to?
Well, we hope that to be somebody else's problem. We would prefer we think going for second-line therapy, there's such a huge unmet need that trying to prove to the regulatory bodies, whether in Europe or the FDA, the sample size that you would need to say that you were first-line therapy for beating Vidaza or 7+3 would just be too great of a financial burden. We think going after roughly 60% of the population in second-line therapy is a much, much smarter financial play.
Okay. So it's going first and foremost in AML much more than STS. Is that a financially driven decision? Because it seems to me that AML did kind of jump out ahead of STS more than it originally was.
Well, I guess there are two factors. One is that in AML, those five targeted therapies got approved on CR alone, not overall survival. If you start looking at STS, you're going to have to look at overall survival. So it's going to be a longer trial. From a standpoint of patients, there are roughly 20,000 AML cases versus 13,500 STS patients. And most of those are going to go on to advanced STS, which is essentially metastasized to the lung. So there's a greater population in AML.
And so talk about fit versus unfit AML patients and where Annamycin should have an advantage.
Well, I've touched upon that a little bit already. But to go a little deeper, you got to understand that, as I mentioned earlier, we're agnostic to prior treatments. We've seen, from a standpoint of Vidaza, failures and relapses where they had a CR. For example, the 78-year-old had a CR for 17 cycles of Vidaza. And we got that patient to a CR last February. And that patient, as we reported in January, is still at a CR. From a standpoint of the targeted therapies, that is something left to be explored, I think, for the future. Targeted therapies are sometimes added in as a triplet therapy to a Vidaza or a 7+3. We believe that that is a possibility for down the road, that Annamycin could potentially fit into a triplet therapy as we're a 5+3 therapy.
So we believe we fit nicely underneath the fit or unfit. We're not going to compete with Vidaza or 7+3. But from a standpoint of combinations, we think there is more to be explored out there.
And so talk about the next steps. Let's at least start in AML for that. Because we see a couple of patients more, a couple of patients more. How many patients are we going to see before we're going to enter a trial that you can file with?
Well, first, let me hit upon value. When you start talking, and this kind of relates to the last question you asked. When you start talking about value, which will then lead into answering the question you just asked, Venetoclax represents a half of $2 billion a year in revenue, $500 million a quarter. That's for AML and CLL. If you look also from a standpoint of what did Vyxeos sell for? It was purchased by Jazz. Basically, a 7+3 reformulation is $1.5 billion. And Servier just acquired two of the targeted therapies we just talked about for $1.8 billion + another $200 million in future outlays. So $2 billion. So you're talking about especially the targeted therapies are very small populations being impacted by it. So that leads into what are the next steps?
Well, one is we'll be shortly announcing our second-line therapy results out of this MB-106 trial. So while you mentioned the.
Which will be 20 patients, you said?
Yeah. So.
Roughly.
We've roughly that we would figure by the time we announce our year-end earnings, we'd be roughly at 20 patients. Well, we think giving that all-comers complete response rate plus stratifying it for second-line therapy, which will help us power the next pivotal trial, we can approach the FDA and the EMA for a pivotal trial. We call it MB108. We think that somewhere based on the prior therapies that were the targeted therapies in their trials, four was single-arm, one was double-arm. We think that's somewhere between 100-150 patients. We're going to approach the FDA in the second quarter. We should have feedback midsummer this year. Once we get that trial allowed by the FDA or the EMA, we believe that we could get that trial up and running in Europe.
We'd like to also be running it in the U.S. by the end of the year. The hospitals, the clinics that are already running the current trial, the combination trial, they're eager to get into a pivotal trial.
Right. Because you're giving me a trial size. Because it sounds to me like you have a CR rate that you don't have to beat to make the go-forward decision and to know how big to make a pivotal trial.
Well, you're exactly right. At a 40% CR rate, you can power a pretty good small pivotal trial if you're just trying to beat or match the current second-line therapies.
What do you need to see in soft tissue sarcoma with lung mets to care to go forward?
Well, as you know, a lot of our trials I haven't talked about for WP1066 or STAT3 inhibitor or WP1122, the WP1066 portfolio has really benefited from investigator-led trials. And there's one potentially going to happen on WP1066. Just like that, we believe that in STS, our discussions in Europe could potentially lead to an investigator-led trial and funded trial in Europe on STS. But investigator-led trials go slow. But we believe that a trial head-to-head versus doxorubicin in first-line therapy would be very, very key. And when you have a key opinion leader telling you that's what they want to run, that really, really bodes well for, we think, Annamycin and STS.
So then talk about, especially as the CFO, it should be easy for you, the spend that you intend on making outside of Annamycin. Is that spigot really turned off, or?
It's very tight. We really rely on WP1122 is an inhibitor of glycolysis. And cancers and viruses are highly glycolytic. That drug, we're looking at running on preclinical work at universities. And then 1066, we're looking for that next trial to be that STAT3 inhibitor to be in combination with radiation, most likely at Northwestern. And that would be funded by a grant at Northwestern via a grant there.
Right. And those earlier Biosika and such, I mean, that's just going to.
Yes.
Stay quiet for a while.
Exactly.
I think that's a good use of resources.
Well, it will stay quiet. But from a standpoint, we believe that we can get some preclinical work done at universities on their time, not our time.
Yeah. Well, I mean, it certainly sounds like you have quite a differentiated product that comes from a long line of efficacy.
Yes. We're very excited about Annamycin and what it holds forward in the future.
Thank you very much, Jon.
Great. Thank you.
Yeah.