Okay. Thank you, everyone, for joining us today for our LP-184 Clinical Trial Results Webinar. We'll be talking in depth today with some of our Lantern 's team and also with our collaborator and partner in developing the trial and some of the early science behind LP-184. Dr. Igor Astsaturov from Fox Chase is also on with us as well. I'm going to be talking about, overall, the drug, just to give everyone an overview of the molecule. Then we'll be talking about the scientific background and some of the early development to give people an appreciation for the molecule. Then we'll be digging right into the clinical results from the trial and some of the observations that we've made. We've got a lot of information to present and walk through today, so I appreciate everyone's patience, and we'll take some time for a Q&A toward the end. If you have questions, definitely send them into the chat window, and we'll be selecting questions to go through. With that, I'm going to introduce our panelists today. We've got our Chief Scientific Officer, Dr. Kishor Bhatia. We have our Head of Clinical Development, Dr. Reggie Ewesuedo. As I mentioned, also, we have Dr. Igor Astsaturov from Fox Chase, who's been our collaborator in the development of the molecule. Let's talk a little bit about 184. 184 is being aimed primarily for the treatment of advanced solid tumors, largely focused on tumors that are deficient in DNA damage repair potential. These include tumors such as TNBC, tumors such as GBM, and perhaps even bladder cancer. In fact, in bladder, pancreatic, TNBC, a very large percentage of those tumors have DNA damage repair pathway mutations or deficiencies, which make them exceptionally vulnerable to this drug. Our phase I-A has been completed. We had very good safety and tolerability data coming out of that, and the profile was acceptable. Also, some very encouraging clinical activity across a number of solid tumor types. Most importantly, validation that tumors that have DNA damage repair deficiency tend to have exceptional sensitivity to the drug and is a great tee-up for the future phase I-B, phase II trials that are being planned. We have three orphan designations for the drug. We have two fast-track designations, both of which we'll be pursuing in trials coming into next year. The market potential for this drug is quite exceptional, blockbuster-like potential, because it seems to work in a wide range of cancers, including, as we mentioned, the ones where we have fast-track. About one in four to one in five cancers harbor some type of DNA damage repair deficiency. Those make it particularly sensitive. What we also saw, as Reggie will point out in the trial, is that a very high percentage of patients that had advanced recurrent solid tumors had high levels of PTGR1. As you have seen and heard us talk about that before, PTGR1 is really a smoking gun for potentially transforming the pro-drug into its active cancer-killing molecule. There are about 170,000-plus cases and nearly 400,000 global. It is a very large market. The way it works is that it alkylates or breaks apart the DNA through double-stranded breaks at a very specific location at the three-prime position of adenine. We validated this in early work, and now we are beginning to see it now in the clinical work. This molecule is purely synthetic. Kishor will talk a little bit about what inspired the molecule from a natural substance, but the molecule that we see in the trials is fully synthetic route in manufacturing. It can be combined with checkpoint inhibitors, PARP inhibitors, potentially chemotherapy and radiation therapy, and also a totally novel molecule, Spironolactone. It makes a wonderful combination, which also we believe increases the potential, but also gives us some flexibility in how we design and think about getting to the right kind of efficacy that's going to get us above and beyond the current standards of care. Over 10 patents have been issued or pending for this drug, and we have claims that extend through the early 2040s. With that, I'm going to turn it over to Kishor and Igor to talk a little bit about the backdrop of the molecule and about the early development and insights on LP-184. Let's go to the next slide. I'm going to turn it over, Kishor, to you and Igor. Thank you, Panna. Thank you, everyone, for taking the time to participate in our webinar. As Panna told you, our molecule, LP-184, was actually inspired from a naturally occurring molecule called illudin that occurs in the Jack of Lantern mushrooms. The derivation of LP-184 from illudin is an interesting story, but I think the key message that I'd like to share with you is that the design of the molecule now bestows upon these illudins and bestows upon LP-184 a property of synthetic lethality. I will go through some of the evidence on how we came about it. Panna has already talked about the application of LP-184 into various solid tumors, so I won't spend more time on it. Let's actually go to understand the mechanism of action of LP-184. Our story actually began by looking at correlations between LP-184 sensitivity in a large panel of cell lines. The question we asked is, can we figure out what cell lines are sensitive, what are resistant, and what are the reasons why certain cells are sensitive to LP-184? Two things immediately stood apart. One was that the response of a tumor cell line to LP-184 is predicated by the level of expression of a gene called PTGR1. The graph on the left shows you the very strong correlation between PTGR1 expression and LP-184. The table on the right shows you various genes whose expression made LP-184 exquisitely sensitive, or the pathways in which they were expressed correlated with exclusive sensitivity to LP-184. What the mixture of these two basically told us is that the story is likely that tumors that have high expression of LP-184 but have deficiencies in repair related to one of these pathways where these genes are involved are likely the tumors that are most indicative of response to LP-184. Taking this further from in silico to actually asking questions on the bench, validation of some of these studies, we collaborated with Fox Chase, and Igor's team conducted some excellent studies. One of these studies was to knock out, using CRISPR, PTGR1 in cell lines. As you can see in the graph in the middle, if you knock out PTGR1 in a tumor cell line, and you can look at the green line compared to, for example, the red line, knocking out PTGR1 as in the green line totally obliterates cytotoxicity of LP-184, further proving our in silico-based hypothesis that PTGR1 is very essential to the activity of LP-184. Similar results were obtained when we moved from cell line data to a xenograft data, and that graph is shown on the right-hand side. The basic takeaway message here is that, indeed, even in vivo and in vitro, our in silico prediction confirms that PTGR1 is essential for LP-184 activity. What that means in practical terms is that because PTGR1 is overexpressed in tumor cell lines but not in normal cell lines, this provides LP-184 with a window of selectivity, which is very critical for the therapeutic index of any anti-tumor molecule. Now, moving further along, what this tells us is that it might be important eventually to have an assay where we can measure the level of PTGR1 in tumors. This is precisely what we have done. We developed an RNA RT RQPCR assay to look at the expression of PTGR1 in various tumor settings, allowing us the possibility of providing tumor stratification and moving LP-184 into a precision medicine approach. I will now move to the next slide, which gives the other facet that makes LP-184 particularly exciting. One has to think of combining these two properties that are required for tumors to be sensitive. One we talked about is PTGR1, and I showed you some data. Here, I'm showing you data of cell lines that have mutations in specific genes which are in a pathway called nucleotide excision repair. These are cell lines that have—and you can see this on the graph on the left-hand side—tumors that have mutations in ERCC1, ERCC2, or ERCC6, and therefore are unable to carry out the nucleotide excision repair when exposed to LP-184, are highly sensitive to LP-184. On the right-hand side, the graph tells you about another DNA damage repair pathway, which is the homologous recombination pathway. If you compare the light blue and the dark blue graphs, the dark blue graph is from a tumor that has loss of function for BRCA2, a gene involved in homologous recombination pathway. We'll speak about homologous recombination pathways further. Basically, again, what this message tells us is what we hypothesized using in silico data is indeed true on the bench. That is, tumors that have mutations in DNA damage repair pathways, be it homologous recombination deficient or nucleotide excision repair, are highly sensitive to LP-184. There were a couple of other points that the in silico data provided. What they basically said is that in addition to nucleotide excision repair and homologous recombination repair, there are additional genes, such as those that are involved in replication stress pathways, that are highly correlated with sensitivity to LP-184. This is critical because what this tells you is that we are not just looking at tumors that are deficient in nucleotide excision repair pathway, for example, bladder cancer or homologous recombination pathways, for example, triple-negative breast cancers, but also tumors that have damaged pathways in the replication stress. Why this is important, and I'll show you that in some slides later, is that it means that LP-184 might be able to overcome resistance to PARP inhibitors. It also means that LP-184 might be a very good agent to turn cold tumors to hot tumors for immunotherapy. Although I won't have time to present some of the data, I thought it was worthwhile mentioning some of these properties of LP-184. Here's another piece of data that was very useful in us trying to develop what indications we would focus upon as we move clinically. What this data is doing is it's looking at precise quantitation of double-strand breaks after tumor cells are exposed to LP-184. In addition, what it provides is some of the reasons why homologous recombination deficient tumors might be more sensitive. When we quantitate the amount of double-strand breaks in tumors that have deficiency in homologous recombination, for example, by nonfunctional BRCA2, the total amount of double-strand breaks in those tumors is twofold compared to tumors where BRCA2 is functional. If you put certain things together, PTGR1 overexpression, deficiency of DNA damage repair, these two stars will mostly align where there is a tumor environment. Normal cells express low PTGR1, are rarely deficient in DNA repair pathways, and LP-184 will basically be ineffective in killing normal cells. Tumor cells that have these defects are going to be highly sensitive. In that sense, LP-184 becomes tumor selective. The story that gets built up is depicted in this schema. Starting with LP-184, in the presence of PTGR1, the cyclopropyl ring of LP-184 gets opened, allowing the cyclopropyl ring to become reactive to a nucleophilic attack on DNA. Therefore, the amount of DNA damage caused by LP-184 is proportional to the levels of PTGR1. In addition, once damaged, this damaged DNA cannot be repaired in tumors that are deficient in DNA damage pathways, and therefore, they die, which is very different than what would happen to normal cells that are exposed to LP-184. We further validated some of the concepts of the nucleotide excision repair pathways. Remember, earlier, I showed you a slide with cells that are mutant in specific nucleotide excision repair pathways. We extended these studies further, again, in collaboration with Igor, looking at ERCC4 knockouts. The panel on the top shows you both the knockout of ERCC4 as well as the data that knocking out ERCC4 reduces the IC50 of LP-184 by twofold. This can also be replicated in an in vivo model of these tumors. Beyond doing genetic engineering to create a depletion of NER, there's a direct application of this principle to define a combinatorial agent for LP-184. This combinatorial agent is Spironolactone. A couple of years ago, there was some very interesting data which showed that Spironolactone can degrade a protein called ERCC3, which is a critical protein for nucleotide excision repair. The panel in the bottom shows that this pharmacological inhibition of ERCC3 by Spironolactone in presence of LP-184 is able to totally regress glioblastoma tumors in mouse models. Now, having some better handle on how NER deficiency affects LP-184, we moved some of our attention to understanding what happens in real-life tumors that have homologous recombination deficiency. In this table, what we are showing you are three different tumor classes. One is non-small cell lung cancer. The middle one is pancreatic cancer, and the bottom is prostate cancer. These are tumors derived from patients where the tumors have specific mutated HR genes shown in the last column. The synthetic lethality of LP-184 in a variety of these tumors is clearly evident. In addition, what you can appreciate is that LP-184 inhibits 77%-90% of cell growth in these tumors compared to 29%-80% in Olaparib. LP-184 is able to perform the same therapeutic levels as a PARP inhibitor in HR tumors. I will show you additional data that will tell you that LP-184 is actually superior to the PARP inhibitors. Now, clearly, when we speak of homologous recombination deficiency, the first tumors that come to mind are triple-negative breast cancer. Breast cancer is a paradigm of BRCA1, BRCA2, and other homologous recombination deficiency. Since the data clearly pointed that the synthetic lethality of LP-184 is unmasked by DNA repair deficiency, we now looked at triple-negative breast cancers. Again, these triple-negative breast cancer tumors that I'm showing you the data for are real-life clinical tumors obtained from patients that are either PARP inhibitor sensitive or PARP inhibitor resistant. Irrespective of what the clinical picture of these tumors were in terms of treatment with PARP, across all the 10 triple-negative breast cancer PDX mouse models, we saw that LP-184 totally regressed all these tumors. This was very, very exciting. It was very exciting that our hypothesis, starting from in silico, going further to in vitro and eventually to xenografts and now to PDX models, appears to stay validated. There is something else that's important here. While there isn't sufficient time to discuss the details of the mechanism of why PARP inhibitor-resistant tumor would be sensitive to LP-184, there are a couple of important aspects that arise from this. One is that LP-184 could be an exemplary partner with PARP inhibitor, not only to overcome resistance, but also to diminish resistance when used in combination. In this graph, what I'm showing you is data both from a PARP-sensitive, PARP inhibitor-sensitive, and a PARP inhibitor-resistant model. If you focus on the graph on the left-hand side, going from left to right, you have the tumor growth with control alone, which is vehicle. You can see that LP-184 has totally wiped out this tumor at 4 milligrams per kg and almost wiped this tumor out at a lower dose of 2 milligrams per kg, clearly showing a dose-response relationship. You can also see the dose-response relationship with olaprib in this. The most exciting part is the last four graph bars on the left-hand side, which show you that a combination of LP-184 at very low levels of 0.75 milligrams per kg and Olaparib at subtherapeutic levels totally wipe out the tumor, be it PARP-sensitive, such as on the left-hand side, or PARP-resistant, such as on the right-hand side. Again, further validation of the fact that LP-184 induces complete tumor regression in HR-deficient triple-negative breast cancer. This applies not just to tumors that are resistant to PARP inhibitors, but also tumors that are resistant to doxorubicin and cyclophosphamide. This is where I was mentioning that LP-184 is similar to PARP, but more superior than PARP. There are several reasons for it. PARP inhibitors are not indicative in tumors that are nucleotide excision repair, but LP-184 is. The spectrum of DNA repair-deficient tumors that LP-184 can affect is far more than PARP inhibitors. It is a great partner for combating resistance to PARP inhibitors and resistance to other standard of care agents. Here are additional data. Now, moving from breast cancer to pancreatic cancer, and the sensitivity of HR-deficient tumors in DNA damage-repair pancreatic models was studied in Dr. Igor 's lab. As you can see, LP-184 is highly sensitive, and tumors with mutations such as in ATR or BRCA1 are highly sensitive to LP-184. When you compare the sensitivity and the potency of LP-184 to other standard of care agents in real-life PDX models, pancreatic PDX models, you find that LP-184 demonstrates 20x-400 x higher potency compared to, for example, gemcitabine. Obviously, all these preclinical data provide us with significant excitement of how to position LP-184 in multiple areas in solid tumors. I will now ask Dr. Reggie to discuss some of the early clinical data. Reggie? Yeah. Thank you, Dr. Kishor. If you might move to the next slide. I think my presentation starts with the clinical review of the program. I thought for this webinar, I should, at a very high level, summarize the message. The first is to announce that we've completed the first in-human phase I-A study. This is, as stated, our very first time of getting into the clinic with LP-184. Obviously, it's not the first time of getting in with a drug that was in the same class, but I will speak to that later on. The second is to let you know our plan, phase I-B, to clinical trials. Panna spoke about some of those. Essentially, there are three areas we're trying to focus on initially with LP-184 advanced monotherapy or combination and triple-negative breast cancer based on the preclinical set of data that we've generated, I think, is on top of that list. There's non-small cell lung cancer. This will be combined with standard of care and dual IO combination in a subset of patients, UAF1, SDK11, PD-L1 lower tumor patients. These patients have a very, very poor prognosis. They don't do well with the current standard of care regimen. We have an investigator-sponsored trial that we're doing with Professor Helle in Denmark. This is in bladder cancer patients that have PTGR1 positive tumors as well as NER-deficient tumors. I will speak to additional clinical development opportunities that we're also exploring and the scientific rationale for that. Could you go on to the next slide, please? There are two things that informed our going into the clinic, the phase I trial. The first one, obviously, is to ask the question, based on the totality of the preclinical data that we have, the toxicity and the PK and what have you, what would be an optimal regimen that we could get into the clinic as a first in-human regimen? We settled on day one, day eight, every 21 days. As is typical, you get into the clinic, you look for signs of whether your regimen is optimal, what safety, other correlative studies that might help you improve on that regimen, or whether you're satisfied with the current regimen. This is the initial regimen. I will speak to some of the thoughts based on the data that we've gathered so far on additional opportunities that we're looking at. The other part is to ask the question around timelines. We all know that phase I studies sometimes take a very long time, sometimes based on just traditional approach and designs. We decided to take an adaptive approach, the Bayesian regimen, I think, the Bayesian strategy design. This allows us really to move fast so that we can answer questions without having any break between those levels. We are able to do that by using the Bayesian design, and that is reflected on the slide. Could you go on to the next slide, please? The objectives are pretty standard for phase I, at least the primary objective. I will emphasize here again, it's first in human. Looking at our safety, but beyond safety. Now, based on the preclinical experience, this is a drug that we believe very strongly is not something that is a typical chemotherapy, cytotoxic, where you reduce the length of the regimen to maybe six cycles and what have you. We believe that this was a drug that we could take for a very long time in the clinic. Patients could stay on it as far as they are benefiting. The tolerability was also key to us to understand that before we declared the recommended Phase II dose. Certainly, the maximum tolerated dose is a given. Secondarily, to inform that primary objective, we wanted to look at the PK of the drug more so. Again, it's a pro drug, nevertheless. We also wanted to look at preliminary activity with a focus on a set of patients for which we had predicted might derive benefit from the drug based on their DNA damage in their repair alterations. Of course, we wanted to understand just going in, do we need a biomarker strategy early on for a subset of patients based on PTGR1, or is our initial hypothesis correct, which is to say patients that are coming into this phase I study, they obviously have advanced disease, and most of them will have aggressive disease, as tends to be the case with this population of patients. Would we observe very, very elevated, a good number of the patients having a very high prevalence of PTGR1 of expression in these tumor samples? Those were really the objectives as we got into the study. Could you go to the next slide? I'll take on the first primary objective. This is typical demographics. There was really nothing unusual here for us. Please go on to the next slide. I'll just mention nothing unusual, but from a PK perspective for the clinical pharmacologist in the audience, there was a balance of male and female, and the age obviously was the normal adult, but there was this little bit of spread between young adults and the elderly population. From a PK perspective, we thought it would be interesting to interrogate that data a little bit later on to see whether there was any variability or source of variability based on some of those variables. What did we see as a primary objective? We achieved in full the primary objectives for the study, which was exciting for us. I need not remind you that sometimes we get into the clinic first in human. There are a lot of molecules that are in the graveyard because they couldn't survive based on safety or some unfortunate thing around tolerability and so on. That is why I made the statement that we achieved our primary objective in full. The drugs demonstrated a very, very favorable safety profile. We observed mostly Grade 1, Grade 2 adverse events, and these were manageable. Now, based on the mechanism of action and the class of the drug, we were expecting nausea, vomiting, which happened. This was very manageable. In fact, to the extent that we could have only wanted a single dose of antiemetics was really required when it was needed to control emesis in the patients. The other thing we observed, which is very encouraging for us, was that unlike Irofulven, a predecessor in this class, we did not have any visual or ocular toxicities. That was really an accolade standard for Irofulven. The dose-limiting toxicities, acute onsets, reversible transaminitis in two patients at dose level 12. Thus, we had a 40% DLT rate using the BOIN design. We declared that at dose level 12, we were not going to go any higher than that. We had a lower than 30% DLT rate at dose level 11. Subsequently, that became the maximum tolerated dose. Again, those are the elements of the BOIN design. We observed some Grade 2 toxicities. We declared that dose level 10 actually would be our recommended Phase II dose. Now, in terms of the PK, very, very interesting for us. We really observed good news here that the drug actually demonstrated a very high therapeutic rate of potential. From dose level 7 onwards, we were able to achieve drug concentrations that we believe, if you look at the right-hand side of what we have, looking at the projected therapeutic drug concentrations, you begin to see despite variability, inter-individual variability, from dose level 7 onwards, we're able to achieve that therapeutic above therapeutic concentrations. We think this enhances the opportunities for monotherapy as well as combination treatment regimens. We'll go on to the next slide. Now, let me spend some time on what we're beginning to observe in terms of preliminary anti-tumor activity. This was very, very interesting to us and encouraging. Despite the fact that this was a heterogeneous patient population, we enrolled 63 patients. There were 52 that were available for tumor response. As I speak to you today, we still have four that are still on treatment, and I will detail those very soon. Twenty-eight patients were dosed. Of these, available patients above the therapeutic dose level were available for tumor response. The majority of those patients, obviously, achieved stable disease. Four patients had stable disease that was durable for greater than six months, and they're reflected below: each GBM patient, a patient with GIST, thymic carcinoma, as well as non-small cell lung cancer patient. Now, we decided to also do a deeper dive into dose level 10, which is the recommended phase II dose, the way we see it based on this regimen. There were four patients at that dose that achieved disease control, thus 44%. Twenty-two percent of those patients really maintained control beyond six months, and some of them are still on. Now, we did something else, which was to ask the question, what is happening with patients that have the DDR alterations of interest? Those are reflected here, ATM, CHEK2, BRCA, like Kishor talked about, KEAP1, STK11. We were fortunate, as we looked at this, that eight of those patients, 57%, really had stable disease. More importantly, 21% of them maintained that for much longer time. Some, in fact, most of them are still on for more than a year. Could you go on to the next slide? I thought I should highlight for you why we're excited and experienced with some of these patients. We take the first patient. It's a 50-year-old patient who came into the study with obviously advanced thymic carcinoma. Thymic carcinoma, obviously, is a very rare carcinoma, but nevertheless, this patient was diagnosed in December, about 13 years ago, had completed four lines of therapy, including our standard of care regimen and some investigational product. Lastly, a protein degrader before coming into our study. At study entry, we decided to look at what would be the expected PFS for patients like this. Now, it's ranged in the literature depending on how many lines of therapy, but you end up with 3.8-14.7 months. Luckily for us, there was liquid biopsy done, and this patient showed a CHEK2 alteration. We started on treatment, LP-184, in November of 2024, and is currently on cycle 17 of treatment and have continued to have benefit beyond 12 months. What was notable to us was, obviously, the patient has several lesions. It was just mixed response, but it was a maximum target lesion reduction of 26%. Gradually, we're beginning to see this reduction in individual tumors, but 26% is the most we've observed till date. The second patient is a 62-year-old female, stage 4 GIST, diagnosed in 1994, and had the natural history of this disease that patients stay on for a long time. Nevertheless, the patient has been on several lines of therapy, including, again, investigational agents and those that are in the standard of care. At study entry, the median PFS was 4.8 months-6.3 months. Again, the patient had an ATM alterations, and we're very interested to see how the patient does. This patient is now on cycle 19, beyond one year on study. We've had this very stable disease, and the target lesion that was in the maximum reduction is about 9%. The last patient I want to tell you about is a 62-year-old male, again, stage 4 squamous non-small cell lung cancer that was diagnosed about three years ago. He completed two lines of therapy, including standard of care and IO monotherapy prior to study entry. He progressed very rapidly through the IO agent. At study entry, again, the median PFS was expected to be 2.5-7.6 months. This patient has a BRCA1 alteration. Started treatment about two years ago and currently is on cycle 34 of treatment and continues to have clinical benefit, very notable target lesion reduction of 22%, approaching a partial response. Now, the reason I mentioned the number of cycles of treatment is just to correlate or validate what I said, looking at LP-184, the mechanism of action, and obviously our preclinical data, you could see this is not your traditional cytotoxic chemotherapy. Patients are staying on for a very long time. I will mention these patients that I've mentioned to you, none of them have had DLTs. There's been no discontinuation. We've had very low rates of discontinuation interruptions in our phase I study, including these patients. In fact, two of them had to go on to a higher dose level. In patient dose escalation above even our recommended phase II dose, we wanted to understand that tolerability of the regimen as we prepare for that development in other indications. We talked about the PTGR1. We are fortunate to have a lot of samples from some of these patients. What we found out was that 87.5%, about 90% of our patients for which we were able to get samples had PTGR1 expression levels that were above what is required for bioactivation of LP-184. We also tried to look at the patients, their prior therapy, whether they had alkylating agents or prior DNA damaging agents and what was really happening. Again, we found out the majority of those patients, regardless, had this very high level of expression of PTGR1, which is good news for us in terms of LP-184 and this stage of disease that we're going after for patients. Could you go on to the next slide? Let me spend some few minutes on our planned phase I, phase II clinical trials. Next slide, please. This is just another slide showing at a very high level. I think I will explain it in the next subsequent slide, telling you about the market potential, the trial sizes that we're going after in this on the end of the trial highlights as well. I think the subsequent slide will take each of these in some detail. The first one is the monotherapy in relapse, in advanced, pretty much metastatic triple negative breast cancer patients with HR deficiency. If you're familiar with what the FDA has been talking about recently with Project Optimus, we talked with the FDA. They encouraged us to do this. We have single agent two-dose levels. We'll be looking at our recommended phase II dose and perhaps another dose that we'll agree with the agency and then move on from there. The next study is, okay, I'm looking at this. Somebody went to, sorry, somebody went to be too fast for me. The phase II obviously is the Simon two- stage. Again, we are trying to be very pragmatic and ask questions very early. Is this drug really doing what we expected it to do based on all our preclinical data and what we've seen in the clinic? If the answer is no, we want to be able to pivot very quickly. The Simon two- stage is an approach and a design that we are taking across our programs. The primary objective, again, in this case, is to look for the right dose with Project Optimus and then preliminary activity. Secondarily, we'll look at the longevity of those activities and also try to validate PK in a particular indication of interest as well. The next slide. There is the combination. I do not want to dwell too much on this. I think Dr. Kishor talked about it, the scientific rationale. The only thing is, remember, when we looked at that preclinical data, there was synergy, not additive action. We're taking a very, trying to take two things. Try to see for a lower dose of LP-184 in this study, but also the dosing regimen to make it a little bit more frequently and ask the question whether that will really be the optimal dose for us to use in combination with the lab rate. The good news is I told you about the safety profile of LP-184 in our single phase I study. We do not anticipate any overlapping toxicities that would make the regimen difficult. After the initial phase, we'll go on to, again, the Simon two- stage for the phase II. The next slide, please. The same is true for the non-small cell lung cancer with the KEAP1 STK11 mutation. These are patients, obviously, that have a low PDL1 expression. They do very poorly with standard of care. We're trying to figure out the right regimen initially before we go on to the phase II portion of the study, again, using the Simon two- stage. The next slide, please. Lastly, the IST, the investigator-sponsored trial that we're doing with Dr. Helle Pappot in Denmark. This is quite an interesting study. It's a biomarker-driven study. We know this is a very difficult population. The one thing we know about this set of patients is that even when you have the dose from patients that don't have advanced bladder cancer, they tend not to still tolerate such doses too well. The approach here from the investigator was to learn from what we have done and use a dose level 10, which is really a very soft spot. It's not the maximum tolerated dose. Dose level 11 is. Go below that and ask the question whether that will be okay for this patient population before we then go on into a Simon II stage design again and ask the question of activity of this regimen in this patient population. All right, the next slide. Let me conclude by spending a few minutes on the additional clinical development opportunities that we see. Of course, there is more than just what I will highlight here in terms of combinations and what have you. The first thing to highlight is a post-radiation treatment opportunity for patients with pancreatic adenocarcinoma. What we do know, and Dr. Igor is on the call as well, is of interest to him. This strategy is that if you expose these tumors to radiation, you upregulate PTGR1, so they overexpress that. The second thing we want to do, obviously, is to optimize tumoral exposure based on our phase I via alternative therapeutic dosing schedules. I will stop there. I think that's my last slide. Thank you, Reggie. Perhaps this is a good segue to also request some comments from Dr. Igor, particularly trying to understand how, as a clinician, you see these two set of results. The preclinical results, you have been a part of several of those studies. You know them quite well. And you've been aware of some of these upcoming clinical results. How would you tie these together in terms of where do you see the drug? How do you see it? Thank you, Kishor and Reggie and Panna for first inviting me and also for pulling this off. This was when I started collaborating with you, it was a remote, lofty goal to develop this compound that was abandoned by the drug industry decades ago. Now we're at the point where when we're discussing how to move forward for specific indications, the fact that you have completed phase I is remarkable, that you see in these heavily pretreated patients months and months, beyond 12 months activity and stable diseases. Clearly, speaking to the fact that this is a mechanism-based therapeutic. I firmly believe that drugs that succeed in the clinic are the ones that are mechanistically based. The rationale for PTGR1 testing is very solid. I think it's clearly a way to convert the prodrug to a fully effective, fully functional alkylating agent. I think it's very interesting, the sort of idea of combination with other DNA damaging agents since the way it works on ERCC family-mediated DNA repair mechanisms is entirely different from double-stranded DNA damage repair that is dismantled by a PARP inhibitor, so platinum. In heavily pretreated breast cancer patients or any cancer patient that has BRCA or homologous recombination deficiency, that will be really a niche where you can develop this drug for clinical use. This also encompasses a significant subset of pancreatic cancer patients, about 10%-15%. I do also think that the opportunity is with bladder cancer where the prevalence of ERCC3, ERCC4 mutations is pretty high. I think this is something to look forward to, to see the results of bladder cancer trial from your collaborators in Copenhagen. Thank you, Igor. If I understand correctly, most of the patients we had in phase I were those who had experienced at least three or four previous lines of therapy. There were none that had lower than that, correct? Very small numbers, especially we had just a few numbers of patients with GBM, for example. Yeah, in GBM, yes, of course. I mean, that was a very different. Yeah, what about GBM? The other ones that came with typical phase Is, certainly if you have one or two that have two lines of therapy, that is the exception. Yeah, that's the thing. How patients who have become refractory to multiple lines of therapy still being stabilized with LP-184 monotherapy is pretty remarkable, I think. I mean, one would expect that tumors that have not been subjected to additional lines are likely going to be more sensitive. That should be the case. Again, that's why we're trying to, if you go in combination therapy like we're trying to do with non-small cell lung cancer, that obviously is first-line treatment. We expect to see better results. Nevertheless, it's almost like the flip side of the coin when it comes to safety, right? Despite the fact that these patients were heavily pretreated, I go back to the primary objective. We still saw this drug did so well in terms of the safety. One expects to be very good in combination with Olaparib, which those patients would probably be second line, most of the first line. Yeah. Yeah, they could be second or third. One of the couple of observations, and we'll take some more questions. We do have fast-track designation in triple negative breast cancer. That's one of the things that we're particularly excited about because if we see some, based on the design of the phase I-B, phase II, the BOIN design, if we start seeing some really good indications, there's a lot of opportunity to go from there to a pivotal kind of approval. We comment on that. What we're also seeing, and I think we touched upon it slightly, is that PARP inhibitors and LP-184 are really, as predicted, of course, in silico, but they're really almost perfectly synergistic agents. PARP inhibits the repair of the DNA of the cancer cells. When you have this PARP inhibition, even if you break apart, what our drug does works on the other side of the barbell. It destroys and creates the double-stranded breaks that then PARP works, the PARP inhibitors work to delay or destroy the ability to repair it. One is completely destroying. The other side is avoiding it from repair. It is a very synergistic agent. We hope to see some really good data. Very importantly, because of the synergy we have seen preclinically, we hope to see some of that. Again, we have seen evidence in the BRCA patients. If you look at the BRCA patients, the BRCA patients had much lower dose levels, which then points to the fact that we were getting sufficient damage at a lower dose level because, again, the preclinical data suggested that there was synergy at lower doses of BRCA with lower doses. Now, the dose that we used preclinically that we saw, again, complete tumor inhibition was at 0.75, which translates into almost a suboptimal dose in the humans. It is kind of an interesting observation. Again, BRCA over time, as you take these BRCA inhibitors, PARP inhibitors, you start creating tolerability issues. We have seen already in some of the ovarian cancers, you have already seen backing off of some of the approvals because of the tolerability issues that we have seen clinically. There is a real opportunity. We like to think of 184 as almost like a pipeline in this molecule. We have seen a number of cancers. We have seen a number of different ways to combine this drug with other drugs by combining mechanistically the ways that they would work together. A lot of this is all data-driven. Yeah. Yeah. If I may, there's another point that's, I think, particularly important, at least for me, it's been a very exciting aspect of LP-184 with respect to TNBCs. A large proportion of triple negative breast cancers, and there are two clinicians here, so correct me if I'm wrong, actually often present with brain mets. Now, LP-184 also has a property that it crosses the blood-brain barrier. In fact, some of the studies we did, which I didn't discuss, were asking, would LP-184 prevent brain mets? We used animal models and were basically able to show that, yes, it does. Therefore, as we move further along in TNBC, that's another aspect of LP-184 that most of the other drugs don't have. Yeah, there is a good penetration to the brain. Most of the metastases are settled as micrometastases until they become clinically apparent. If you come in with this agent that can reduce the burden of these micrometastases, then sure, the answer is yes. Yeah. Kishor, Igor, Reggie, any closing comments about 184? I personally, I will just quickly close by saying that given my experience, I wouldn't get into that. It's not about my background. The reality is that when I look at a drug like this and the experience of the fact that you're able to dose this long in patients and not find any kind of cumulative toxicity, I think to me, that's very, very encouraging because that's the problem with most drugs. One other thing that I am pleasantly encouraged, PTGR1 is expressed in hepatocytes and actually a pretty significant level. I was worried about potential hepatotoxicity. It's remarkable that you don't see much of it. It's a really credit to you, first of all, pulling off this amazing phase I trial to demonstrate the tolerability of the agent. It kind of paves the path forward to its full clinical exploration. Yeah. That lack of hepatic toxicity is a particular strong evidence of the dual aspects that require PTGR, that require LP-184 to be cytotoxic, which is not just PTGR1, not just DNA repair deficiency, having both these together. That's why I think it becomes such a great molecule for precision therapy where you can understand, does the tumor have high PTGR1? Does the tumor have HRD, NER, replication stress? Then yes, in that tumor, this molecule is going to kill it. Right. Great. Kishor, Dr. Igor, Dr. Reggie, thank you guys all for your time. I want to thank our audience for participating. We're able to get this done exactly in one hour. That's pretty good. Very good rehearsal. Thank you all for joining us. Please send us your questions, and we look forward to future trials. More importantly, we look forward to answering more questions about ideas and where to take this molecule in other interesting combinations as well. Thank you, everybody. All right. Thank you. Thanks.