Hey, good afternoon, everybody. I'm Nicole Leber with Investor Relations at Lantern Pharma, and welcome to our Brain Tumor Awareness Month GBM Key Opinion Leader webinar. May is Brain Tumor Awareness Month, a month dedicated to supporting, empowering, and amplifying the voice of the brain tumor community. According to braintumor.org, an estimated 700,000 Americans are living with a primary brain tumor, and an additional 88,970 people will be diagnosed with a primary brain tumor in 2022. Additionally, the five-year relative survival rate for all malignant brain tumors is only 35.6%. For today's KOL webinar, we'll be focusing heavily on the primary brain tumor glioblastoma, which is the most common malignant brain tumor among adults, with an estimated 13,000 patients diagnosed per year in the United States.
In addition to being one of the most common primary cancers, it is one of the most deadly, with an average median survival of 15-16 months. Several of our panelists today are experts in the treatment and research of cures for glioblastoma. With that, I would like to introduce our esteemed panelists. We have Dr. John Laterra, who is the professor of neurology, oncology, and neuroscience and director of the Department of Neurology, Division of Neuro-oncology at the Johns Hopkins School of Medicine and Kennedy Krieger Institute. We also have Dr. Matthias Holdhoff, Associate Professor of Oncology, Neurology, and Neurosurgery at the Johns Hopkins University School of Medicine. We also have with us Dr. Kishore Bhatia, who is the Chief Scientific Officer at Lantern Pharma. Now I'll turn the call over to our panelists for some more personal introductions, starting with Dr. Laterra.
Hello, it's a pleasure to join you all and be here during Brain Tumor Awareness Month for this session. As I was introduced, I'm a professor and research scientist clinician at Johns Hopkins with my research laboratory at the Kennedy Krieger Institute. I've been exploring mechanisms of brain cancer malignancy and therapeutic target identification for the past 30 years, primarily on the pre-clinical side, with the goal to translate our findings to clinical trials. I'm excited to be here, particularly with regard to what we'll be discussing today, this novel chemotherapeutic agent, LP-184.
I'm Matthias Holdhoff. I am an associate professor of oncology, neurosurgery here at Johns Hopkins and at the Sidney Kimmel Comprehensive Cancer Center. I'm a co-director of our brain cancer program, and as such, I am contributing to the work we are all doing jointly here in our group and in fact, at many centers around the world with the one goal of improving the lives of our patients with primary brain cancers. Of course, glioblastomas are the most common primary brain cancers in adults, and I really welcome this opportunity and appreciate the invitation for this webinar.
I think we are going to talk about a very interesting drug, and this is sort of right up my alley because I'm a clinical investigator working on clinical trials with main focus on new drugs in ideal setting bench to bedside translation for the treatment of malignant gliomas and also CNS lymphomas.
I'm the Chief Scientific Officer for Lantern Pharma. My name is Dr. Kishore Bhatia, and I've spent about 2 decades doing research in oncology, most specifically in epidemiology and translational oncology. Glad to be here to discuss GBM.
Great. Dr. Bhatia, could you provide a background on Lantern and our pipeline and discuss how LP-184, one of Lantern's drug candidates, is being targeted for the potential treatment of glioblastoma?
Yeah. Lantern is a unique biopharmaceutical company. It is one of the few companies that actually leverages the growing amount of data using our proprietary RADR artificial intelligence platform and machine learning. The intent of using data is to transform the cost, pace, and timeline of oncology drug development and make newer, more potent drugs available faster to patients, making the lives of cancer patients better. Lantern, at this time, is currently developing four drug candidates, and these are across eight disclosed tumor targets, including two phase 2 programs. By targeting drugs to patients whose genomic profile identifies them as having the highest probability of benefiting from the drug, Lantern's approach represents the potential to deliver best-in-class outcomes. Lantern Pharma is advancing LP-184 for the treatment of solid tumor indications. That also includes glioblastoma. LP-184 is an acylfulvene-derived prodrug.
When I say prodrug, it requires to be activated in the tumor cells, providing it some kind of preferential specificity by an oxidoreductase enzyme called PTGR1, which is often expressed much higher in tumor cells than in normal cells. The prodrug LP-184, once activated, acts as a synthetic lethal agent in tumors that harbor some specific mutations, particularly those in the DNA damage repair pathways, and appears to be more sensitive based upon our in silico RADR assessment to tumors that have some activated pathways such as the EGFR pathway.
Can you both tell us a bit about GBM? What challenges are currently associated with glioblastoma treatment, and how might they be overcome?
Glioblastomas have been very challenging to treat and, as you mentioned before, this is the most common primary brain cancer in adults. We have made less progress than we had hoped for over the last 20 years. Specific challenges for this tumor include presence of the blood-brain barrier and, difficulties with drug delivery. We know that about 98% of the drugs that we give to treat cancer, including many chemotherapy drugs, do not reach therapeutic concentrations in the brain. That armamentarium, the repertoire of drugs we have, we can use, is quite limited. We have so far only one class of drugs, alkylating agents, and namely temozolomide and nitrosoureas, that have been used as chemotherapy drugs and, truly only temozolomide that provided a survival benefit in patients with glioblastomas.
We know that only a subset of these tumors tends to truly benefit from the addition of chemotherapy, and it is not only the drug delivery that's a challenge, it's also the tumor itself. These tumors are somewhat heterogeneous. It's often several pathways that play a role activating these tumors. It's not for lack of trying. There have been numerous clinical trials, including targeted drugs, including immunotherapies that have not provided additional meaningful benefit to our patients. We have a lot to do. Other challenges include that, other than cancers for which immunotherapy has been a promising new tool, and you know, we certainly hear about it all over the literature, all over the media, the response to these treatments has been so far disappointing.
This is in part, we believe, due to a different microenvironment that these tumors are embedded in, an immunosuppressive microenvironment. Also, the fact that these tumors have considerably few abnormal mutations so that the immune system is not as attracted to these cancers as, for example, to some lung cancers or certainly melanomas, bladder cancer, et cetera. There is also the issue that we're dealing with rare cancers. Glioblastomas are the most common cancers in adults in terms of primary brain cancers. However, compared to other diseases, we are dealing with a small number of patients. There is always a challenge for us to advocate for these cancers to be more represented in clinical trials, in earlier phase clinical trials.
There's some I would call it nihilism on the side of investigators and industry and the community saying that, "Well, these cancers are so stubborn, things haven't worked that well." You know, and also if tumors are so difficult to treat, so that has limited the number of clinical trials we have, limited eligibility for trials that otherwise might be really interesting to study new drugs in. It's also limited to clinical trials for cancers other than cancer of the central nervous system.
I thought that was excellent, Matthias, because you sort of covered the landscape, both you know clinically some aspects of the you know cell biological physiologic challenges, and then also the sort of social medical environment challenges of glioblastoma and other common primary brain malignancies. I would just expand on a couple of points you raised, and that is with regard to the temozolomide. That really has been the most major advance in our treatment of glioblastoma. I have to qualify that because that advance really entered the mainstream in 2005. We're talking about 17 years ago. As also as Dr.
Holdhoff pointed out only about 35%-40% or so of patients with glioblastoma are actually found to be sensitive to temozolomide due to a particular molecular feature of glioblastoma. Regardless of whether you're initially sensitive to temozolomide or not, these tumors invariably recur after receiving temozolomide, and those tumors are invariably no longer sensitive to temozolomide or other known chemotherapy agents. At this point in time, we really have no proven therapy that is known to effectively treat recurrent glioblastoma.
Thank you. I'll move on to the next question, which is: What knowledge from genomics have we gained about GBM? Are any pathways amenable to being considered as druggable in GBM?
You know, it's interesting that glioblastoma is one of the most well-characterized malignancies when it comes to the identification of driver mutations and that being mutated oncogenes and mutated tumor suppressor genes. In light of that, one would think that there are targetable mutations and that we've discovered them, and they have been successful clinically. That, unfortunately, has not been the case. In part because of blood-brain barrier issues that Dr. Holdhoff mentioned, that drugs that we know can effectively target mutations in systemic cancers don't adequately enter the brain and the brain tumor. The other aspect is the heterogeneity of these tumors in that tumors can be characterized by being mutated, for instance, in a driver receptor tyrosine kinase, EGFR. The most
A very common mutation is a EGFR deletion, and that gene is referred to as EGFRvIII, variant III. But a subset of tumor cells in EGFRvIII mutated tumors actually express this mutation, and there have been treatment trials targeting this mutation using small molecules using immunotherapy. One can deplete tumors of the cells with this mutation, but the tumor recurs anyway. There are other receptor tyrosine kinases that are mutated or amplified, such as the platelet-derived growth factor receptor, the c-Met receptor tyrosine kinase, in addition to EGFRvIII. There are agents that potentially target all these drivers in GBM.
Could you comment on targeted therapy and precision medicine approaches impacting clinical outcomes in GBM?
Right. This question does overlap some of what we've been discussing. I think precision medicine has been effectively applied in certain circumstances to the care of our patients. I think in glioblastoma the most common use of molecular diagnostics that drives precision medicine is in the interpretation of MGMT gene methylation. MGMT, O6-methylguanine-DNA methyltransferase, is routinely evaluated for whether it's expressed in glioblastoma. That is determined by an assay that looks at its gene promoter methylation, and if the promoter is methylated, the gene is silenced, and the enzyme is not expressed. That enzyme reverses the effects of our best chemotherapy, temozolomide.
Finding that the gene is methylated predicts that patient's tumors will be sensitive to temozolomide, and that clearly translates to improved tumor response and improved patient survival. That assay is very, very important, and it's also being used in clinical trial designs that are intended to test other agents in substitution to temozolomide. More specifically, if the MGMT gene is not methylated, the gene is expressed. It predicts that patients' tumors will not be sensitive to temozolomide. It justifies the elimination of temozolomide to from the clinical treatment regimen and substituting temozolomide with an agent that's under investigation.
I would like to add a couple of points that all sort of support what you just said. I think a lot of therapies we have so far were not very precise. The treatment that builds the backbone for our current approach to glioblastomas consists of best possible surgery, followed by radiation. Radiation given to the area of the brain that's involved by tumor, not very specific therapy. You could argue that temozolomide, an alkylating drug, is also not very specific. We're not as precise as we want to be. These biomarkers, MGMT being one example, and in context of the L might be the PTGR1, helps us really select patients that might benefit or have a higher likelihood to benefit from a given therapy.
First of all, how does it work and why is it so unique? How does LP-184 fit into areas of precision medicine for GBM?
Firstly, as I mentioned some time earlier, LP-184 is a prodrug. It needs to be activated by an oxidoreductase called PTGR1. PTGR1 is often expressed preferentially higher in many tumor cells. Thus, one property that LP-184 has is that requirement for activation provides it with a window of tumor specificity. Once activated, the active metabolite of LP-184 goes on to damage DNA. It causes certain lesions in DNA that cannot be repaired by global genomic repair pathways and are dependent upon repair by transcription-coupled nucleotide excision repair. What this means is that if the damage is not repaired, tumor cells will die. Often, tumor cells differ from normal cells because of certain mutations, and therefore, these tumor cells have vulnerabilities that are not present in normal cells.
One aspect of this vulnerability is that they are inefficient in repairing the damage caused by LP-184. Thus, while normal cells will recover from this damage, tumor cells do not, and therefore LP-184 can preferentially kill tumor cells.
That sort of covered some of that. In addition to the oncogenic mutational predictors of sensitivity, there is bioinformatic gene expression data that predicts that LP-184 will be particularly active against tumor cells that are deficient in the transcription-coupled nucleotide excision repair mechanism. About 30% or so of glioblastoma have low expression of genes required for nucleotide excision repair. The basis of this is strongly supported by the evidence that cells repair the DNA damage caused by LP-184 through nucleotide excision repair mechanisms. I would add even, you know, in terms of very basic clinical translational aspect of LP-184, it is an alkylating agent.
In that broadest class, it falls within, you know, the alkylating agents which are temozolomide and the nitrosoureas. However, LP-184 modifies DNA at a different site than those other alkylating agents. It primarily alkylates at N3 of adenine, and that DNA modification is insensitive to the expression of MGMT. As we discussed earlier, MGMT expression is one of the major limitations of temozolomide efficacy. Tumors that are predicted to be insensitive to temozolomide due to MGMT expression, and that is approximately 60%-70% of glioblastomas, may be sensitive to LP-184 therapy.
Okay. Next question is, can you elaborate a little bit on the results from preclinical studies with LP-184 performed to date and their implications on clinical translation, clinical trial design, et cetera?
Yeah. We've worked with Lantern to evaluate LP-184 in what we consider to be state-of-the-art preclinical models, cell models in vitro and tumors grown in or in brain, in animals, in mice, in vivo. We were excited about doing this based on data initially obtained by Lantern using the NCI-60 cell lines, showing that the small number of traditional glioblastoma cell lines that exist in the NCI-60 panel were sensitive to LP-184 and in particular, cells that are known to express MGMT and be insensitive to temozolomide.
We've evaluated LP-184 in a number of additional traditional human glioblastoma cell lines and in more modern models such as patient-derived GBM neurosphere lines and patient-derived xenograft lines. We're finding that many of these majority of the 10-15 or so models that have been looked at have IC50s, inhibitory concentrations of LP-184 in the range of certainly in the nanomolar range, which is quite low. Cells that were clearly insensitive to temozolomide, not achieving IC50s with temozolomide at concentrations of hundreds of micromolar, have been sensitive to LP-184 in the 100-200 nanomolar range. That was exciting in vitro.
We've evaluated LP-184 in tumors grown in mice subcutaneously and in brain, and found the drug to be extremely active in causing tumor regression in subcutaneous glioblastoma models, including tumors derived from neurospheres and also traditional cell lines. That LP-184 also prolonged animal survival in mice bearing pre-established tumors in brain. The confluence of this, I think, is quite promising in the potential for this drug to, you know, be effective in patients or certainly supports, in my view, the need to proceed with clinical testing of this drug.
Okay, we'll move on to the next question, which is: How can LP-184 be leveraged to fill current treatment option voids as a targeted therapy option in select patient groups? Can you define those patient groups and the methods being considered to select them?
Yes. A drug such as this, which meets basic criteria, in terms of preclinical efficacy, a good rationale for drug delivery, and matched with a great need for new drugs, is something we take very seriously. Wearing my hat as a clinical trialist, working in glioblastoma, I think this is quite an interesting drug to pursue. The place a new potentially efficacious compound might have in treatment of glioblastomas is certainly wide open. We do not have a lot of drugs that provide a true benefit. If this was a drug that showed, after showing tolerability, if it showed an efficacy signal in recurrent glioblastoma, it would be very tempting to try.
It would be very reasonable to try testing this drug as an example in newly diagnosed glioblastoma in combination with radiation in MGMT methylated or unmethylated tumors. Certainly when early phase studies are done and the first phase I trials in recurrent disease such as within a phase 2 prospective study. That would also be important to find out if there are correlative biomarkers that might predict a response to treatment. What could be the role of MGMT methylation for this cancer when we use it as an antitumor agent in recurrent disease? What about PTGR1, which is required to activate LP-184, which is a prodrug into its active form. There are a lot of interesting important questions to answer.
I would just add to that, we commented earlier on the role for transcription-coupled nucleotide excision repair as a mechanism for relative LP-184 resistance. Conversely, tumors that are deficient in expression of the genes that are required for transcription-coupled nucleotide excision repair would be predicted to be sensitive to LP-184. In addition to PTGR1 expression as a possible predictive biomarker of LP-184 sensitivity, component expression of transcription-coupled nucleotide excision repair genes might also be a predictor as well.
There are also agents, and as we think about how one might ultimately develop LP-184 clinically, there are well-tolerated drugs currently used for other indications that can deplete tumor cells of transcription-coupled nucleotide excision repair gene products and theoretically sensitize tumors to LP-184. One could imagine once you know either incorporated into early clinical trials or later stage clinical testing to consider combinatorial agents that sensitize tumors to LP-184 through these mechanisms.
Okay, I'll move on to the next question, which is: What are the clinically relevant molecular or genetic subsets of GBM patients, and how can we balance trial enrollment timelines with optimal representation from shrinking subsets of molecular subtypes?
The challenge in clinical trial development is to balance the potential benefits of focusing on molecular subsets with practical aspects of successful enrollment over a reasonable period of time, and also with the uncertainty, particularly in terms of a drug like this, with regard to the ability of molecular subsets to predict drug sensitivity or resistance.
Yeah.
Since this agent has the potential to be broadly effective, though albeit perhaps more effective in some subsets than others. How do you walk that line when designing a clinical trial? As was commented on earlier, there's bioinformatics data that predicts increased GBM sensitivity in tumors that have EGFR activating mutations and that have PTEN AKT mutations. Those mutations are relatively common in glioblastoma. Certainly one strategy, at least initially, would be in a phase two trial to power the trial with sufficient numbers of patients to retrospectively determine if one of these molecular biomarkers actually associates with response or not, as opposed to pre-selecting patients with these mutations as part of clinical enrollment criteria.
You know, personally, based on this drug, I feel that a better approach would be to not be selective at time of enrollment. Ideally, try to power the study high enough to perform a retrospective analysis, and then if there's a suggestion of a signal, then, you know, work with that in future trial design.
I would agree with you, John, and this is that the drug we have a lot to learn about. The hope is that this drug will serve a broad population of patients, that it will not just serve a niche of a certain, you know, molecular signature, but that it's a considerably non-specific or limited specific kind of drug along the lines of other treatments that have worked in the past. Studying the efficacy first, looking at subgroups, the second step might be the approach that would be the most fruitful for this drug. If there's a succinct molecular marker that's associated with response, certainly then one would also try to design more focused, more targeted clinical trials based on the biomarker.
We are hopeful that this drug, which does fulfill minimal criteria to make it to a clinical trial in brain cancer, and only a few drugs do it. We're hopeful that this drug gets the best possible chance to show its true colors and show us whether it can actually be of potential impact for our patients.
Okay. How can LP-184 be used in combination with other agents in GBM? For which GBM setting would it be most valuable to test a combination therapy approach?
Yeah, this is an excellent question. The way we study new compounds in the setting of glioblastoma is either looking for a response signal in recurrent disease, and once we're getting into combinatorial questions, the question is, are we thinking about combining with radiation or are we combining with other drugs? An attractive way to study a possible added benefit to radiation is the population of MGMT promoter unmethylated tumors that overall do not benefit, at least for the vast majority, to the addition of temozolomide, where you could study safety of combining the drug with patients receiving radiation alone. That has been an increasingly accepted way to study combination of radiation and drugs in the newly diagnosed setting.
Once that safety is established, you could consider adding, broadening that approach and consider adding temozolomide. Certainly there are other combinatory options, but that would be a relatively standard way to go about this, a systematic way to introduce this drug into current standard of care, into the standard of care treatment framework in glioblastoma.
I would agree with that, Matthias. That was a great general discussion of chemotherapy drug development approaches. I would add that one potentially exciting aspect of LP-184 is the finding that deficiency in transcription-coupled nucleotide excision repair sensitizes cells to LP-184. We have preclinical laboratory data that if we pharmacologically deplete tumor cells and tumors in vivo of one key component of the transcription-coupled nucleotide excision repair mechanism, then we sensitize cells and tumors to LP-184. We can do that with an FDA-approved drug that crosses the blood-brain barrier called spironolactone. Spironolactone is a drug that's been used for decades as a diuretic for patients.
It's very well tolerated, and importantly, it does cross the blood-brain barrier. Separate from its diuretic mechanisms, spironolactone was found to deplete cells of a transcription-coupled nucleotide excision repair component, ERCC3, through protein degradation. We have found that spironolactone can decrease the IC50, the LP-184 IC50 by 4- to 5-fold in glioblastoma cells in vitro. Treating animals that have glioblastoma tumor xenografts, combining LP-184 with spironolactone appears to substantially improve the anti-tumor response. One, I think, interesting and good challenge in, you know, how we think about clinical trial design for LP-184 is how and/or when we consider a combination strategy using an agent like spironolactone in the clinical trial.
Okay, last question here. How has Lantern Pharma established a collaboration with neuro-oncology at Johns Hopkins, and what are the next steps in this effort?
When we are looking at collaborators to further develop the potential of LP-184 in glioblastoma, Dr. Laterra's lab and Johns Hopkins were a natural alignment. Dr. Laterra's lab has previously developed several studies in glioblastomas, and therefore the lab has expertise in areas that would be very useful in this collaboration. This includes the development of neurospheres, intracranial xenografts, so on and so forth. As importantly, Dr. Laterra's lab has also conducted studies in various areas of glioblastoma that are essential for the understanding of how LP-184 could be developed further, including the studies on EGFR hyperactivation, the studies on MGMT, so on and so forth. Therefore, the natural alignment allowed us to approach Dr.
Laterra, and we had wonderful early discussions, and now we have had this active collaboration that has been very fruitful for the last two years. We are now on the path to defining a clinical protocol for a first in human trial in glioblastomas in collaboration with Johns Hopkins and with Dr. John Laterra.
My laboratory at Johns Hopkins in the Kennedy Krieger Institute has been collaborating with the team at Lantern Pharma for a year and a half now. Again, focused on really asking the question, does LP-184 fulfill the preclinical requirements that make it exciting enough to really invest the substantial resources to bring it to clinical trial, exciting enough that raises the promise of potentially improving the quality of life and survival of our patients with glioblastoma. This collaboration, sort of a standard laboratory pharma collaboration where Lantern Pharma and I had discussions about the key questions and I proposed some research studies to answer those questions.
Lantern Pharma has funded those experiments. We've now been in discussion with the clinical team with regard to clinical trial opportunities and clinical trial design. That's been done primarily through my clinical colleagues here at Johns Hopkins.
I think this is a really exciting example of how a collaboration can become fruitful. Of course, a lot of drugs sort of strand early on, don't fulfill the minimum criteria to be developed. This drug makes the initial checkboxes for clinical trial involvement. It's kind of a beautiful story. If there's a drug that has been tested within, you know, our team member's laboratory, and then there's a discussion about this drug, there's some excitement that is developing, and then there are people on the clinical side that want to bring this to the bedside. In many ways, a reason we all go into oncology is to bring new drugs, new compounds from the laboratory into clinic. This might be one of these examples.
It happens to be a drug that was developed, or co-developed in one of our laboratories. Sometimes it's different. This is a, I think a collaboration that we're all very excited about. There are many of us that will want to play a role one way or the other. We have identified a principal investigator within our group, who will be the chef, and a lot of us will be sous chefs. We'll try to make the best out of this, really, outstanding opportunity.
Okay. With that, we'll start with some live Q&A here. We have Dr. Kishor e Bhatia with us today to answer your questions. If you have a question, be sure to type it in using the Q&A tool down below. I will ask your question. We have some that have already come in here. Kishore, can LP-184 be of use in other brain cancers besides glioblastoma?
Yeah. One advantage with LP-184 is that it has very good activity in several other solid tumors as well. If you couple that efficiency of tumoricidal activity, 184, it has the potential to be efficient also other brain tumors.
Kishor, we're having a little bit of trouble hearing your audio at the moment.
Can you hear me now?
Yes, much better.
LP-184 has activity against a variety of other solid tumors. That includes lung, brain, breast, colon cancer. If you couple this with the ability of LP-184 to cross the blood-brain barrier, clearly it has potential in the treatment of brain metastases, other brain metastases.
Okay, great. We have a few more coming in here. What challenges exist in applying LP-184 to the newly diagnosed glioblastoma setting?
The standard of care for newly diagnosed glioblastoma is going to be temozolomide. One aspect of using temozolomide, as we all heard, is that it won't work in tumors that express MGMT. Over a period of time, temozolomide treatment will result in resistance due to MGMT expressing clones. One area to consider which we are discussing further on is to understand if a combination of LP-184 and temozolomide in early tumors might solve this problem.
Okay. We have one additional question that I see coming through here, and some of this may have been answered already, but how does LP-184 compare with temozolomide in glioblastoma?
Both work in a similar fashion. Temozolomide, however, does not have a correlation with certain genomic features. LP-184 is far more sensitive in tumors that either underexpress DNA repair genes or have activation of certain pathways. These are features that are commonly found in many glioblastomas. In that sense, LP-184 has ability to be more targeted to specific tumors and can be personalized in that sense. The other major difference is that the DNA lesion caused by temozolomide and LP-184 differ considerably. The N3 adenine lesion caused by LP-184 is not a substrate for MGMT, and therefore LP-184 is agnostic to MGMT expression.
Okay. I just saw another one coming through here. Is there any opportunity for immunotherapies to be used with LP-184 in combination work?
Those are studies that are ongoing, and we don't have the answer as yet, but those are ongoing studies.
Okay, great. Those are all of the questions we have today. Thank you, everybody, for joining, and have a great rest of your day.
Thank you.
Thank you.