Lantern Pharma Inc. (LTRN) Earnings Call Transcript & Summary

Good afternoon, everyone. I'm Nicole Leber with Investor Relations at Lantern Pharma, and welcome to Lantern's key opinion leader webinar on synthetic lethality, the unique and powerful mechanism of action behind Lantern's drug candidate LP-184, LP-284 and LP-100. In oncology drug development, synthetic lethality has become a highly desired capability for small molecules as it promotes the selective antitumor toxicity of cancer cells while reducing potential side effects to normal cells. This mechanism of action can exploit vulnerabilities in cancer cells known as DNA damage repair deficiencies, which are common in 25% to 30% of solid tumors. Using synthetic lethality, Lantern's drug candidate LP-184 has demonstrated nanomolar potency across a comprehensive number of in vitro and in vivo preclinical models in solid tumors as well as adult and pediatric central nervous system cancers. Based on its synthetic lethality mechanism of action and strong preclinical results, Lantern is targeting advancing LP-184 to a first-in-human Phase I clinical trial in the first half of 2023. For today's KOL webinar, you'll be listening to Dr. Zoltan Szallasi, who is an expert on synthetic lethality and DNA damage repair deficient tumors. Dr. Szallasi serves as joined appointments as a group leader of the Translational Cancer Genomics department at DCRC and as faculty of the Computational Health Informatics Program, CHIP and Assistant Professor of Pediatrics at Boston Children's Hospital, which are affiliated with Harvard Medical School. In today's webinar, you will hear Dr. Szallasi talk about a wide range of topics surrounding an introduction to synthetic lethality and how drugs with synthetic lethality can be used to treat tumors with DNA damage repair deficiencies. You'll also hear how synthetic lethality can be leveraged to treat cancers with a subtype of DNA damage repair deficiency called nucleotide excision repair. Finally, you will hear him discuss the promising potential of LP-184 synthetic lethality for DNA damage repair deficient tumors, including how LP-184 could be combined with other FDA-approved agents to enhance its efficacy. With that, I'll now turn the webinar over to Dr. Szallasi.

Dr. Szallasi, can you start us off by telling us about your lab and your lab's research focus.

My lab at Boston Children's Hospital is interested in studying DNA repair deficiencies in solid tumors, various solid tumor types. We are particularly interested in developing methods that would use next-generation sequencing to detect and quantify individual DNA repair deficiencies in human tumor biopsies because that would allow us to prioritize patients that have a given DNA repair deficiency present in the tumors, and that would allow those patients -- to identify those patients that would most likely benefit from a treatment that would target that specific DNA repair deficiency. So that's our main focus. So we're mainly using next-generation sequencing mainly somatic DNA, so the tumor DNA, both in the tumor DNA isolated from the tumor cells and also from cell-free DNA. So that's our main research interest and we are also trying to come up with strategies and identify molecular context in which these synthetic lethality-based therapies would be most efficiently used.

Can you tell us about synthetic lethality in DNA damage repair deficient tumors and about some of the drugs that are being developed based upon synthetic lethality concepts.

So synthetic lethality was mainly kind of proposed or created in the context of DNA repair deficiencies. And the basic idea is that for most cancer therapy, the drugs are going to do some sort of a DNA damage that would prevent the replication of DNA. And of course, if DNA cannot be replicated, the cells cannot divide, the cells or the cancer cells will probably or obviously will die. And hopefully, this is the way you can eliminate the tumor. So there are 2 parts of it, mechanistically. One is that if a given DNA repair mechanism is missing, then hopefully, there might be drugs that will be very efficient on that particular tumor type. And the other part or the other arm of this treatment would be interfering with the checkpoints. So in order to repair DNA damage, you need 2 things. You need a DNA repair mechanism and also you need to give some time to the cell to activate those mechanisms. So those are called -- those are the checkpoints. So when DNA damage occurs, the sales sells the DNA damage, it slows down or stop replication, and then the DNA repair mechanisms are activated and the DNA damage is corrected and then DNA replication and cell division can proceed. So basically, that's the idea that if you interfere with either of these arms when those are present in a given tumor type, then that will give you a potentially very efficient synthetic lethality based strategy for treatment. So for the PARP inhibitors were introduced in the context of homologous recombination deficiency. More recently, there have been several drugs in clinical trials that are interfering with the checkpoint. So these are the mechanisms that are going to -- that are needed to give time for the cell to repair all the DNA damage. So the idea is that if you block this checkpoint, then the cell will not have enough time to repair the DNA damage, so in combination with the DNA damaging drug, the cells will basically die. So there are several clinical trials right now in progress. ATR inhibitors is 1 example where [indiscernible] would be a good example of drug, V1 inhibitors are in clinical trials in combination for -- with PARP inhibitors, that would be adavosertib, or CHK1 inhibitor that's another checkpoint a protein, as prexasertib. So basically, these are relatively advanced stages of other synthetic lethality based strategies.

What has the clinical experience been with PARP inhibitors? And what are some of the lessons that have been learned?

So in general, the experience with PARP inhibitors has been very positive. So initially, it was start or it was hoped that PARP inhibitors would work out really well in homologous recombination deficient cancer types, especially those that have inactivating or pathological mutations to the BRCA1 and BRCA2 genes. Those tumor types, solid tumor types would be mainly or predominantly ovarian cancer to a lesser extent, breast cancer and, to some extent, prostate cancer. So the clinical trials have been completed on tumor types. And in general, the experience has been very positive. Progression-free survival was very significantly increased with various schedules or various forms of PARP inhibitor therapy. But now the overall survival data are also coming in and those also look very promising. So in general, this whole concept of using synthetic lethality connecting homologous recombination deficiency mainly as determined as BRCA1 and BRCA2 mutations and PARP inhibitors have been a very successful strategy. And in general, patients have benefited a lot from this overall treatment strategy. We have, of course, learned a lot during these clinical trials and the associated research processes or projects. There was a relatively simple idea or mechanism how we thought PARP inhibitors might be working. Obviously, as always in biology, the situation is much more complicated, much more complex. We just started to understand these more complicated interactions between PARP inhibitors and the mechanism by which PARP inhibitors work, we are still working on that. And obviously, we still have a lot to learn about, for example, a combination of various treatment options, for example, PARP inhibitors and immune checkpoint inhibitor therapy may have some very efficient combinations. But understanding the mechanism there is still -- it's a very long process.

What genes are often involved and dysfunctional to make tumors nucleotide excision repair deficient and what are these tumor types?

So nucleotide excision repair is -- well, like everything else in biology is extremely beautiful, extremely complex process with many, many, many players. A few things should be kind of stated for clarity. One is that the DNA damage in nucleotide excision repair can be sensed in 2 different ways. One is that if you have a DNA damage, a [ bulky adduct ], so something that's sitting on the DNA, like a large chemical [ loyalty ], and that's kind of distorting the DNA, the structure that could be detected anywhere in the genome. And that's called global nucleotide excision repair. The other sensing arm, the other sensory arm is related to transcription. So when you're transcribing DNA into RNA, it's a very complicated, very complex process. And obviously, if there is some sort of bulky adduct that's sitting on DNA than the RNA preliminaries, the RNA transcribing machinery cannot proceed and that could be sensed as well. So both of those sensor mechanisms are going to feed into the same common pathway and that will use the same -- treat the same biological process to remove that part of the DNA that has been damaged and just fix it and that kind of correct that part of DNA that was damaged. So there are many important players on that. So usually, those genes are named in something called ERCC gene, so ERCC2, 3, 4, 5, 6 are the key players that play a very important role in this individual part of nucleotide excision repair. The interesting or the important part in these names is that in some cancer types, some of these genes are quite frequently and recurrently mutated. So as I mentioned, in bladder cancer, for example, it is well known that about 10%, 15% of bladder cancer cases have been inactivating mutations in ERCC2. So that sort of suggested that there might be something going on at, for example, in bladder cancer in terms of NER deficiency. So these are the genes that 1 would want to look at in terms of either inactivating mutations or down-regulation or suppression if 1 is looking for nucleotide excision repair deficiency.

Expanding on that last question, could you explain how nucleotide excision repair deficiencies could be leveraged to develop drug strategies to specifically kill tumor cells.

So nucleotide excision repair efficiency has a very interesting history. So we have known about nucleotide excision repair in general for many, many decades. So those guys that received the Nobel Prize a couple of years ago showing or kind of discovering and describing the various DNA repair mechanisms described nucleotide excision repair several decades ago. And implicitly, we knew or we thought that nucleotide excision repair should be damaged in cancer types as well in various solid tumors as well. But we didn't really have much evidence for that. It's not that trivial to detect a, given DNA repair deficiency in a real human cancer biopsy in a real human patient. So since platinum treatment has been around for many decades from -- since the '80s. So that means close to 40 years now. And we -- since we knew how platinum works, introducing various forms of DNA damage, either cross-linking between DNA [ strength ] but more frequently within the same DNA strength, so we knew that platinum based on its mechanism should be very effective against a tumor or any sort of cell that has damaged nucleotide excision repair. And since platinum is a very efficient drug. So if you just think about Lance Armstrong, right, he was treated with platinum and he has a very advanced cancer, but 1 can find many other examples. So in some cases, Platinum is an extremely efficient drug to treat or to eliminate cancer cells. So we sort of expected that nucleotide excision repair deficiency should be present in cancer, but we didn't really have hardcore evidence that it is actually present in the real human tumor cases. Recently, a couple of years ago, [indiscernible] laboratory showed that this is actually, this is in fact, the case. It basically looked at a [indiscernible] gene, it's called ERCC2, which is very often mutated in bladder cancer, and this is 1 of the key enzymes of nucleotide excision repair. And he just simply showed that if you take these mutations that are frequently present in bladder cancer and you take cell lines and if you introduce those mutations into the cell lines, then you are actually making those cancer cases nucleotide excision repair deficient. So basically, this was the first evidence that nucleotide excision repair deficiency is, in fact, present in human tumor cases. Therefore, it should be exploitable therapeutically if by nothing else then by the administration of platinum, which should be a very efficient drug to treat nucleotide excision repair deficient cells.

Shifting now to Lantern's drug candidate LP-184, could you tell us how LP-184 works in tumors with nucleotide excision repair deficiencies.

LP-184 or it's like earlier incarnation, which is [ acylfulvene ] has been -- acylfulvene has been around for now almost 30 years or so or even more. So it will bind to DNA. It's an alkylating agent. It will form bulky adduct. So it's a bit a relatively -- it's not a huge molecule but it's a relatively large molecule. It's going to bind DNA and it shouldn't be there. So if, for example, or [ RNA preliminaries ] in transcription wants to proceed along DNA, if we kind of hit it. And all of it's removed, it just cannot proceed. So transcription is going to be blocked. So there have been a couple of very nice papers in the early 2000s when a Dutch Institute [indiscernible] Americas Group showed very clearly that transcription coupled repair very efficiently remove this drug. This is kind of interesting. We are not quite sure we understand why it is so efficiently removed by transcription coupled repair, but that's kind of the advantage of this drug as well because if -- in normal cells, noncancer cells, transcription coupled repair works really well. So that means that most normal cells in our body that are not cancerous that do have transcription coupled repair, we'll be able to remove this drug very efficiently, or this bulky adduct the DNA damages very efficiently. So that's what LP-184 or acylfulvene does it just bind the DNA. It is removed by transcription coupled repair, and if DNA repair -- if nucleotide excision repair Is damaged, so in either the transcription coupled repair sensing arm or the common pathway, which that is the effect of that actually fixes the DNA damage then that's going to be leased for the cell because it cannot remove this DNA damage and DNA replication or transcription is completely blocked and the cell will die. And that's what these experiments show, so these very early experiments showed very clearly and just to give some impressive numbers here if -- and just kind of going back very briefly to PARP inhibitors and homologous recombination deficiency, if you remove BRCA1 or BRCA2 from a cell, so you have a normal cell and you have a cancer -- you have a normal cell or you have a cell with BRCA1 activity and you remove the key homologous recombination gene BRCA1, then that cell will become 100 to 1,000 for more sensitive to PARP inhibitors. So that's extremely -- there is a huge therapeutic window there. So the -- there is a very similar therapeutic window for LP-184 in the context of nucleotide excision repair deficiency. So if you have a control cell and normal cell and then other cell with the only difference is that you remove 1 of the key nucleotide excision repair enzymes, that's the ERCC2, then that cell will become several orders of more sensitive to acylfulvene relative to the normal cell. So that's a huge difference that gives a very convenient therapeutic window when the doctor or when we'll know that the drug will not kill at a given concentration. We'll not kill the normal cells because those are very efficiently dealing with the DNA damage as opposed to the cancer cells that do not have the mechanism to remove the drug. So that's basically the concept of synthetic lethality and that's basically the concept of LP-184 efficacy. There is 1 other important factor here that 1 needs to remember, which makes the use of LP-184 a bit more complicated than a general other targeted agent, is that LP-184 in its form that it's in the vial is an inactive drug. It needs to be activated. And the enzyme that's activating is called prostaglandin reductase, PTGR. PTGR1, are different isoforms of that as well. And that enzyme needs to be present in order to activate the drug, it has its advantages and disadvantages, 1 advantage is that white blood cells do not express PTGR1. So in general, LP-184 acylfulvene are not toxic for white blood cells, which is a very important consideration in determining side effects or toxicity. The downside is that if PTGR1 for some reason, is not expressed in that cancer, then the drug will not work. So for LP-184 to work, you need to consider 2 factors or 2 issues. One, the cell needs to be NER deficient, nucleotide excision repair deficient. The second one, the cell will also need to express this activating enzyme PTGR1.

Adding on to that, what tumors could be targeted using LP-184.

So as I already mentioned, the -- for a long time, we didn't really know whether nucleotide excision repair deficiency exists in solid tumor types. So the first tumor type in which we -- I mean the research community obtained hard evidence, hardcore evidence that actually is present in solid tumor types is bladder cancer. And the reason for that was that 1 of the key nucleotide excision repair enzymes ERCC1, ERCC2 has inactivating mutations in 10%, 15% of the cases. So by definition, one would think that bladder cancer would be a good target for LP-184 or acylfulvene therapy, which is, in fact, the case as we have shown and others shown in preclinical studies. So -- but in general, 1 would think that any tumor types that have and an inactivation of any of the key players of NER, nucleotide excision repair should be sensitive to the drug provided PTGR1 expression is also present. So this kind of takes us back to the agnostic concept that I mentioned in context of immune checkpoint inhibitors and microsatellite instable tumors, so we kind of hope that in any solid tumor types, where we can have evidence that nucleotide excision repair is deficient or damaged, are probably good candidates for LP-184 therapy. Now the tumor types for which we have at least some preclinical evidence that there might be good candidates are in addition to bladder cancer, which is probably our strongest candidate right now. We do have evidence that breast cancer, subset of breast cancer -- we do not know exactly what percentage. We are not talking about the overwhelming majority. We are talking about 5% to 10%. But we have evidence that the subset of breast cancer is nucleotide excision repair deficient, the reason [indiscernible] we know that probably these are the cases that are very sensitive to platinum treatment, platinum therapy. We also have evidence based on preclinical models that gastric adenocarcinoma cases are nucleotide excision repair deficient. Again, these are tumor types. That's probably a good indicator always that if I a given tumor type occasionally gives you very good response to platinum, then probably that's a good indicator that NER nucleotide excision repair deficiency might be present. And a very interesting recent set of results we have recently produced suggest that kidney cancer, a subset of kidney cancer cases are somehow nucleotide excision repair deficient. So how or why we are still working on it, there seems to be some sort of hypoxia normoxia regulation, but it's very clear that the subset of kidney cancer cases are also LP-184 sensitive. Now [indiscernible] lab, it was a lab working in parallel with us about a couple of years ago on acylfulvene sensitivity and NER deficiency, produced some sort of an overall estimate, just looking at all of the tumor types they characterize at [ Sloan Kettering ] with the impact and all when we characterized when they look at the mutational profile or the inactivating mutations in about 500 genes, and based on that, he found that for most solid tumor types, the number or the possible proportion of NER deficiency will vary between a few percent up to 15% to 20%, depending on the solid tumor type. So what I hope will be the case because I think this is a promising drug, is that we will be able to establish some sort of a tumor agnostic -- diagnostic for NER deficiency. And those patients that have strong indications of NER deficiency and PTGR expression, independent of the tumor type or the histology will benefit from this treatment.

Would you expect drugs like LP-184 to be used in combination with other synthetic lethal agents?

Like everything in biology, everything is connected. Always there are very deep interaction between different mechanisms. And obviously, because nature keeps reusing the same mechanism, the same tricks and it just ensures robustness for the living cell. The different DNA repair pathways are also very intimately interconnected. So ERC function, homologous recombination, the Fanconi pathway and nucleotide excision repair has very profound mechanistic interaction. So this is just been this is kind of pretty well mapped out. So it wouldn't be very surprising that there is some evidence experimental evidence only preclinically that probably PARP inhibitors and drugs targeting NER deficiency would be a good combination. So this has been raised before. It wasn't investigated in sufficient depth. But since platinum is a very good drug to target nucleotide excision repair-deficient cells, it will suggest that PARP inhibitors should be combined with platinum. The problem was that it wasn't truly clear, it was very well defined, which tumor cases or what sort of molecular background would make a cell very sensitive to this combination. So we do not really have strong clinical evidence or directions how we should be applying it. But the same applies in the case of LP-184 as well that combination of PARP inhibitors with LP-184 should be explored, preferably in a mechanistically justified and mechanistically informed manner, that would tell you that this is the molecular mechanism would very profoundly impact both NER, nucleotide excision repair and homologous recombination. Those links or those mechanisms probably exist. We know that they exist. We need to see how often they are present in tumors and those cases are probably good candidates for these combination therapy. We, in fact, have some very preliminary preclinical model-based evidence that this is my [indiscernible] strategy . So the nice thing about this thing is that while I do not want to understate or underestimate side effects or secondary malignancies and in general the side effects or toxicity of PARP inhibitors and LP-184, but these drugs are probably relatively less toxic, definitely less toxic than, for example, an intensive platinum therapy. So it might be actually a viable strategy to target those specific tumors with this combination, especially in advanced setting in stage 3 or stage 4 setting -- highly metastatic in more cases. One thing I forgot to mention about PARP inhibitors at the beginning when we were just talking about success about PARP inhibitors that it is very impressive how well PARP inhibitors perform in advanced cancer cases as well. So that's -- I really want to emphasize here that the synthetic lethality based therapies may really provide a significant benefit in those cases with very advanced highly metastatic Stage III, Stage IV cases as well.

What about LP-184 in combination with spironolactone.

That's a good question. So the idea with spironolactone is that suppressing -- so 1 needs -- so we know for a fact that without suppressing nucleotide excision repair activity, these drugs will not work. That's very clear from all the preclinical models and even for PDX models. So spironolactone is -- that was a kind of [indiscernible] observation. It is actually very interesting, but it was [ short ], it was seen that spironolactone, which is a quite commonly used drug in cardiovascular diseases, suppresses ERCC3, which is 1 of the key enzymes of NER, ERCC2 and ERCC3 are heavy cases, and they are actually unwinding the DNA that allows kind of cutting out the damage part and then kind of filling in the -- that the part that was removed. So ERCC3 is a key [ NER enzyme spironolactone ] definitely, suppresses expression, and in preclinical models, it's certainly the case that suppressing ERCC3, using spirolactone, we'll make a cell LP-184 sensitive that's very clear. In a human being, we do know that spirolactone doesn't cause too much problem in the therapy concentrations because people take these drugs and they benefit a lot in cardiovascular diseases, and they do not have toxicities at least related to suppression of protein production. One needs to see -- and that needs to be done experimentally or in a human clinical trial setting that if you use the therapeutically justified concentration of spironolactone to what extent is that going to change the expression of protein level of ERCC3 in normal and in cancer cells. So if you say that I could just simply target cancer cells with very high doses of spironolactone on the [ end ] that will make cells NER deficient and LP-184-sensitive. How is it going -- how will that play out in a clinical setting -- that's a question that's certainly worth asking. That's a very interesting and worthy endeavor. We should probably get the answers for that as soon as possible, that may make NER proficiency or the NER deficient, so that may be helping the treatment. But let's not forget that PTGR expression also needs to be present. So -- but it would certainly increase the number of potentially sensitive tumor cases to LP-184, -- but then again, we need more detail on that.

Thank you for joining us today, Dr. Szallasi and for your fascinating insights on synthetic lethality and Lantern's drug candidate LP-184 I'd also like to thank the audience today for tuning in. And if you enjoyed this webinar, please visit Lantern's website to download this or any of our past key opinion leader webinars. Thank you.