Hello and welcome to the Moleculin Biotech Key Opinion Leader webcast to discuss the company's positive top-line efficacy results from its MB-107 U.S. phase 1B/2 clinical trial evaluating Annamycin for the treatment of soft tissue sarcoma lung metastases. At this time, I'd 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 those 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 investor 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 has not independently verified and makes no representation as to the adequacy, fairness, accuracy, or completeness of, or that any independent source has verified any information obtained from third-party sources. Any data discussed regarding clinical trials and progress are considered preliminary and subject to change. I would now like to turn the webinar over to today's host, Walter Klemp, Chairman and CEO of Moleculin Biotech. Wally, please proceed.
Thanks, Jenene. Good morning, everyone, and welcome to our Key Opinion Leader discussion group to review the results from our MB-107 clinical trial studying Annamycin for the treatment of advanced soft tissue sarcoma. Dr. Paul Waymack, our Senior Chief Medical Officer, and I will be providing some brief background on the trial and a top-line summary of the results, and then we'd like to engage our KOL panel to discuss these results in more detail and address some natural questions that the analyst community may have. Joining us today as sarcoma experts are Doctors Barend Kasper, Mohammad Cherry, and Sant Challa.
Dr. Barend Kasper specializes in internal medicine and medical hematology-oncology at the University of Heidelberg and is head of the German Interdisciplinary Sarcoma Group and past chair of EORTC for soft tissue and bone sarcoma and current outreach chair for the Connective Tissue Oncology Society. In addition to being a PI in a number of national and international trials on STS, DF, and GIST, Dr. Kasper has authored around 100 scientific publications on the subject. Dr. Mohammad Cherry is the Medical Director of Hematology at Atlantic Health System and an Associate Professor of Hematology-Oncology at the University of Oklahoma Health Sciences Center.
In addition to his role as PI in multiple clinical trials, Dr. Cherry has been focused on groundbreaking research in areas that include the role of epigenetics in chemotherapeutics used for the treatment of sarcomas. Dr. Sant Challa is an Adjunct Professor at MD Anderson Cancer Center and UCLA and has faculty appointments at USC, Cedars-Sinai Cancer Center, and John Wayne Cancer Institute. Dr. Challa has dedicated his career to research and innovation in both bone and soft tissue sarcomas, having conducted over 60 clinical trials, many of which have led to FDA and EMA approvals.
Unfortunately, Dr. Challa had some clinical obligations this morning, and so he may be joining us a little late in the program. To kick things off, let's establish just a little bit of background on STS lung mets. Soft tissue sarcoma is a group of cancers that originate in the body's soft tissues and connective tissues, including muscle, fat, blood vessels, nerves, and tendons. These cancers can occur anywhere in the body but are more common in the arms, legs, chest, and abdomen. Soft tissue sarcomas are relatively rare, affecting about 1% of the population, with an estimated annual incidence of around 13,000 cases per year in the U.S.
As STS advances, it very often will metastasize to the lungs, where treatment becomes quite difficult. Some published research estimates that as many as 80% of STS cases will eventually metastasize to the lungs. Unfortunately, once that happens, the prognosis is very poor, with a median overall survival of around 12-18 months from diagnosis. Surgical resection of the lung-located tumors is the preferred treatment when possible, but often such tumors eventually become too diffuse and pervasive for resection to be practical. At that point, first-line drug therapy is Doxorubicin, often combined with Bisphosphonide, which can be effective with response rates in the 25-50% range.
Second-line therapies are largely focused on histology-driven approaches and, to a lesser degree, immunotherapy. Unfortunately, almost all first-line responders will relapse relatively quickly, at which point options for effective treatment become very limited. Moreover, there are significant toxicities associated with first-line therapy, including the cardiotoxicity of Doxorubicin, plus the renal, neuro, and hematologic toxicities. The second-line approaches to date, focusing on targeted or histology-driven therapies, have had limited positive results, and there remain significant gaps in relevance given the heterogeneity of the disease.
Likewise, immunotherapies have yet to demonstrate a compelling case for their use. As a result, there continues to be a significant unmet need for a better second-line therapy for advanced soft tissue sarcoma. With that as background, let's ask our panelists to weigh in. To start with, it would be helpful if you were able to walk us through the patient journey. Dr. Kasper, how are patients diagnosed, and at what stage do they typically present?
Yeah, thank you very much, first of all, for the kind invitation to participate in this session here, and it's an honor for me, of course. Yes, so we actually see patients in both situations, in the localized and also in the metastatic situation, but we know that more than 50%, maybe even 60-70% of patients with a localized or initially localized soft tissue sarcoma will, during their disease journey, move to a metastatic situation. I can only echo what you have shown in your slides is that the standard is a Doxorubicin-based chemotherapy, and unfortunately, that hasn't changed over the last, we can say, 50 years. We have made a lot of attempts to increase the overall survival of these patients by adding other compounds to Doxorubicin, but to be honest, in the end, we always failed.
A Doxorubicin-based chemotherapy is the first-line standard. We often combine it with Ifosfamide. For leiomyosarcomas, we often use Dacarbazine in Europe, and maybe that's one difference between Europe and the U.S. is that where in the U.S. more combination therapies are used, we tend to use our doxorubicin monotherapy for, let's say, elderly patients, depending on the performance status, the comorbidities, and things like that. That's first-line therapy, and I think the options for the second line you nicely presented. We have Trabectedin, Pazopanib, and Eribulin, depending a bit on the histology.
Understood. Speaking of histology, Dr. Cherry, I know you've been focused on epigenetics in sarcoma. Could you comment on how that factors in here?
Yeah, thank you for the invitation, and I'm very excited to participate in this important session. The problem with sarcoma, especially soft tissue sarcoma in general, is they are not considered very chemosensitive regimen cancers compared to lymphomas, for example. The best response rate, depending on what regimen you are giving, is probably between 30-50%. As Dr. Kasper elaborated, anthracycline and mainly Doxorubicin is either used as a single agent or in combination in the majority of patients with soft tissue sarcoma in the advanced stage, especially in the front-line setting. In the United States, we use more, whenever we are able, Doxil, which is a liposomal Doxorubicin, and it's relatively better tolerated.
The main problem that we face is the cumulative toxicities and the dose, and we know that using higher doses of Doxorubicin leads to better responses. If you want me to just highlight about the epigenetics, it's mostly in my studies bone sarcomas like osteosarcomas, and I was trying to figure out how to improve the chemosensitivity and distinguish patients who are responders versus non-responders to chemotherapy. Thank you.
Okay. Great. Maybe, Dr. Kasper, just before we move on to discuss, Paul's going to take us through the actual results, but I'm curious, from your perspective, what do you consider the bar for success, let's say in clinical benefit rate or PFS or OS? What do you see right now is the bar that we need to clear?
Yeah, I mean, as already mentioned, the response rate for Doxorubicin single agent is not very high. I would even say 15%-20% is a quite high estimate. We would, of course, like to see a higher response rate. The progression-free survival of these patients in first line is usually quite short, ranging between two and four months. We were a bit struck, maybe that's something worth mentioning here. We were a bit struck by a trial we currently finalized for patients with liposarcomas where an MDM2 inhibitor was compared to doxorubicin single agent therapy, and there the standard arm was actually very good, and the progression-free survival here was in the range of seven to eight months,
which was very interesting and very surprising. Yes, we would love to have a higher response rate, of course, a progression-free survival in that range, and an overall survival, as you already showed here. The usual overall survival of these patients in the metastatic situation is ranging between 12-15 months, so something beyond that, of course, would be great.
Fantastic. Okay, great. That is really good background. Now let's shift to an understanding of what is different about Annamycin and why we believe it has relevance to treating advanced STS. To start this off, I would like to ask our Senior CMO, Dr. Paul Waymack, to discuss what makes Annamycin so unique. Paul?
Thanks, Molly. Annamycin was designed with the specific intent to eliminate the cardiotoxicity typically associated with anthracyclines. It has several structural changes in chemistry that contribute to this, and its inherent lack of cardiotoxicity is further augmented by its formulation into multilamellar liposomes. The cardiotoxicity of currently prescribed anthracyclines has been well established and, in fact, has resulted in the FDA setting a lifetime maximum limit of 550 milligrams per meter square for anthracycline exposure. Decades of research have shown that even at this limit, there is a 65% chance that treatment will result in some level of cardiotoxicity.
However, because of Annamycin's design and formulation, we have successfully treated patients at up to five times the FDA limit without a single instance of drug-related cardiotoxicity. Now, one of the core questions the inventor of Annamycin has been trying to address relative to soft tissue sarcoma is, why is Doxorubicin fairly effective on the primary tumor but not so effective once the patient has lung metastases? We think the answer may lie in the inherent tissue organ distribution of Doxorubicin. The team at MD Anderson has done extensive animal testing and determined that Annamycin concentrates in the lungs at 30 times the rate of Doxorubicin,
and this increased lung localization results in significantly greater performance in various animal models of lung metastases. While this is really the primary scientific rationale for the MB-107 trial, we should also note that Annamycin's reduced toxicity, especially the lack of apparent cardiotoxicity, and its lack of cross-resistance with doxorubicin give Annamycin an intriguing potential for STS lung mets, either alone or in combination with other therapies. Now, given this scientific rationale for using Annamycin to treat STS lung mets, we have launched into MB-107.
MB-107 was structured as a phase 1B/2 clinical trial where the 1B portion was used to establish a recommended phase 2 dose. We recruited 19 subjects in the phase 1b portion of the study with dose ranging from 210-390 mg per meter squared. We opted for one infusion every 28 days, which is typical of how Doxorubicin is administered in sarcoma patients as first-line therapy. We eventually settled on 330 mg per meter squared as the recommended phase 2 dose and then recruited another 17 subjects in the phase 2 portion of the trial. For intent to treat purposes, the N in this trial was 36; however, four were lost to follow-up for an N of 32 currently available subjects.
The subjects recruited into MB-107 were adults with a diagnosis of soft tissue sarcoma with unresectable lung metastases equal to or greater than 10 mm in size. They needed to present with progressive disease following a prior systemic therapy and have an estimated lifespan of greater than three months with an ECOG performance level of two or better. For the entire subject population, median overall survival was 13.5 months. Importantly, these subjects had received a median of six prior therapies. That compares to a historic range of 8-12 months for second-line monotherapies.
We believe that that performance alone would be justification for moving forward with a potential pivotal trial for this indication, but the data get even more compelling when you look at the response from subjects who received the optimal dosing regimen. Here we saw a progression-free survival of around four months and an overall survival of close to 20 months for subjects receiving the optimum dose of 330 mm per meter square or lower as second-line therapy. Now, when we summarize these results, we note a clinical benefit rate of over 59% of a study population of 32 subjects.
We believe Annamycin has the potential to help a wide range of STS patients. Clearly, when you optimize the dose and focus on second-line patients, this is where we think Annamycin's performance really stands out. Has this become a recurring theme for Annamycin? We saw no drug-related cardiotoxicity in any of the subjects, despite most of them being dosed well above FDA's lifetime maximum exposure rate for anthracyclines.
Thanks, Paul. Maybe reflecting on all of this, Dr. Kasper, how do you interpret the OS results here in this trial?
Yeah, it's certainly interesting. I mean, as I mentioned, sorry, as I mentioned before, the overall survival of this patient population in first line is usually something between 12-15, maybe a bit more, months. Looking at this population here with heavily pretreated patients with more than six prior therapy lines, the 13.5 months, of course, is really very interesting and very impressive and outstanding.
Great. I wonder, at the same time, could you also comment on what we're referring to as the clinical benefit rate here? In other words, it looks like we helped close to 60% of the patients. How does that stack up, do you think?
Shall I also comment on that?
Yeah, please. Yeah.
Yeah, okay, okay. No, that's fine. Yeah. I mean, I think the clinical benefit rate is important here because as we, yeah, consider that usually Doxorubicin has a rather low response rate, so the amount of patients who have a stable disease is, of course, very important. Here we can see an overall, even though we do not have many complete responses here, but there is a large proportion of patients with a stabilization of the disease, which is a pretty important goal in this disease.
Great. Maybe, Dr. Cherry, I know you also are looking at Annamycin from the context of hematology oncology as well. I guess with that perspective in mind, what's your take on these results? Maybe if you could expand that into how you would see Annamycin being used by the oncology community at large.
Yeah, I mean, what is interesting in the data you have presented is that the population of patients received multiple lines, and I believe the majority of them have seen Adriamycin. Here you are using another anthracycline as second line to patients who already progressed on Adriamycin. I would suggest to include the percentage of patients who received Doxorubicin or Adriamycin as first line. This makes this data more interesting, and this would apply, in my opinion, to any cancer where anthracyclines are active, and you are showing an impressive survival data with lower toxicity.
Often in our treatment concepts, if someone failed an anthracycline, we do not switch to another anthracycline. We choose regimens that do not contain this regimen. From that perspective, this is very promising, and the survival, which in my opinion, in the second line is an advanced stage, is probably a few months. Now you are demonstrating 13.5 months in the total population, but those who received the proper dose, it's almost 20 months. This is very impressive.
Great, great. Maybe one last thought here to cover, and Dr. Kasper, I'll turn back to you. There's a natural question of how best to proceed with the possible development of Annamycin for advanced soft tissue sarcoma. How would you recommend proceeding to move towards approval? What would you think is a next step?
Yeah, I mean, when looking at the data, of course, the strongest activity seems to be in earlier lines. I mean, we also have good data for these heavily pretreated patients with more than six lines, but of course, if you look at the second line data with the overall survival of 20 months, of course, this is really striking and impressive. I would certainly try to move the compound in earlier lines or maybe even first line because this is the most interesting part. Of course, another aspect is what was already mentioned here, of course, is the complete absence of cardiotoxicity. I mean, we often want to give our patients more than six or seven cycles of Doxorubicin, but we can't, and we are limited by the cardiotoxicity.
With your compound, of course, this is a big advantage, and this would make it very interesting in earlier lines.
Very good. I think that covers it for today, and I really appreciate your participation here and want to thank you for taking time out of your busy days to join us. For now, we'll wrap this up, and we'll look forward to discussing the next steps in developing Annamycin for soft tissue sarcoma. Thank you, gentlemen.
Thank you.
Thank you for the invitation. Thank you.
Okay, take care. Have a great day.
Thank you all for your time and attention today. This concludes the Moleculin Biotech webinar.
Thank you.