International Medical Conference Endometriosis 2025:
Endometriosis 2025: Your Mother Should Know, Your Doctor Should Know Better!
Decade Long Multi-omics Initiative Leading to Revolutionary Discovery Guided by JNK Inhibition - Piraye Beim, PhD
Is the founder and CEO of cell matrix pioneering genomics and data science to advance women's reproductive health. And recently it is a recent recipient of AR A PH funding from the White House Initiative, and she leads TIC Therapeutics in developing a novel JK inhibitor targeting pain and inflammation, Dr. Penn.
And as everyone in this room is aware, genomic technology is really ushered in a sea change in the cancer field. And we went from seeing cancer really as a clinically defined disease to more of a molecular molecularly defined disease. And what that sea change has led to is better screening and prevention, more efficiently run clinical trials and many more pioneering therapeutic drugs. And the other thing that we really learned through genomics in the cancer field is that every tumor is a unique snowflake. No two tumors are alike, but even though tumors are distinct from each other, genetically and molecularly, there's some key pillars and pathways that are dysregulated and seem to be the primary drivers of the disease. And also, even though there are thousands of different genetic alterations that have been linked to tumorgenesis and metastasis and those kinds of processes, we also know that there's a pantheon of key molecular targets that really are recurring across this disease.
So when we founded Somatics in 2009, it was really with the vision of trying to catalyze the same sea change from a clinically defined set of diseases to molecularly defined in the women's health field. And so as part of that, one of our primary original goals was really to try to understand for a range of conditions in women's health, what are these key biological factors and what is our pantheon of key molecules and drivers that can be the game changing next generation of molecular targets for therapeutics in this space. So we had the opportunity to invest over $80 million in this work across a decade. And this is one of the things that I often get asked, why did you leave academia? There's your answer. And so we've been able to tap into private capital to be able to progress this groundbreaking work, and I can't possibly share it all with you.
So because I want to get to our drug program, what I'm going to do is I'm going to jump ahead and give you some updates or give you some headlines of what we learned through this work. But what I will say is the work that I'm presenting has been published or presented at meetings over the years. And so as we invested across a decade, what we did was we took both the approach of interrogating existing data sets that were available either through collaborations or through initiatives like the UK Biobank and where we identified data gaps. We collected and analyzed our own unique cohorts that we sourced through our personalized reproductive medicine initiative partners, which spanned collaborators across a dozen academic institutions and medical centers in the us.
We also did studies, for example, this was presented back in 2015, so a decade ago. It's crazy to do the math on that, but early in this work, we also performed a meta-analysis of all of the published transcriptomic data in endometriosis. And one of the biggest signals that emerged early on in our work was really the key role of dysregulated immune system function in this disease. And so I'm just kind of previewing where we're going to end up on the drug front, but this was something that has, even though we're hearing about it today and now it's very front and center for the endometriosis research community, really how important the immune system is for the establishment and progression of this disease. This has been something that's been very high on our radar for over a decade in part due to our ability to really dive across data sets and get that bird's eye view.
The other work that we did that was a big focus at the company was really to try to understand what has already been published. And so we undertook a very ambitious genome genomic annotation project in-house. The things I'm describing to you, by the way, are things that the entire cancer community did and somatics because we work in a field of high unmet need, not only clinically but also from a funding standpoint, we really had to build a lot of these systems. And so really going through and accurately annotating the genome with respect to high quality studies that had been performed in endometriosis was one of the things that we did. So what we were able to do is that we identified over 4,500 publications that as of nearly a decade ago had been published in the endometriosis field. We often hear there's no research. Well, even just 10 years ago, there were nearly 5,000 studies published, specifically looking at the genetics of endometriosis.
Nearly 900 of those publications qualified to be included in our meta-analysis. And what we found is that those publications contain data for the association of 620 unique genes with reproductive conditions, 40 of which showed strong evidence and 12 variants within those genes showed a significantly increased risk of endometriosis. And so when we take a step back, and again, I'm really rushing through a decade of work here. I want to get to the drug program, but I want to walk you through how we got here because many of you have known the company over the years, and we were a diagnostic company. We were a digital health company. Now suddenly we're a drug company. I wanted to feel cohesive for the folks who have known us for many years of how we ended up here as a therapeutics company. But for those of you who don't know us, I want you to understand that there's been a long history of the company that led to the deep conviction that we have in the j and k program that I'm going to share.
But basically what I want to do is summarize what we learned across 10 years and nearly a hundred million dollars of research, which is that like cancer endometriosis as well is a complicated disease, but it has some key pathways that are consistently dysregulated. And so you can read them here, but immune response regulation, which I mentioned already, DNA repair and replication, blood circulation. So this is like blood clotting factors, angiogenesis, et cetera, steroidogenesis tissue remodeling and cell proliferation and differentiation. And again, understanding this clinically, these pathways are not surprising, but it was still important from a research rigor standpoint to really establish what are these and what are the key molecules that are disrupted consistently in these.
But it was important to us to not just rest on these insights, but really try to push them forward translationally. And so the next five years after the first 10 years of trying to figure out what is the biology that we need to go after to really cure these diseases, including endo, but the next phase really of the company was, okay, how do we turn these insights into therapeutics? Because while we did launch a groundbreaking diagnostic, which ultimately was not successful for a variety of reasons, primarily because we didn't have the financing to continue the work, but as we tried to push diagnostics out into the field, one of the issues with bringing precision medicine forward in a field like endometriosis is you don't have therapeutic options. And so what we realized is the cancer world, because we were kind of trying to run the entire cancer precision medicine playbook as a small company, the cancer world, the biomarker insights that led to diagnostics grew up together with therapeutics that physicians needed to choose between.
What we found was that the therapeutic development was not pacing with the diagnostic development. And so it ended up being chicken and egg and we had to pick a chicken or an egg, and we picked therapeutics, but then we then had to go through a prioritization because just because it's an awesome biological pathway or a molecule that clearly is disrupted genetically and individuals who have these diseases, that doesn't make it a safe drug target or a druggable drug target. So then we had a big wake up call and a new learning curve to become a drug company. And this is around the time when Dr. Steve Palmer joined the company and he's here in the audience, and you've heard him talk last year about our drug program. But then we went through this process of really trying to find something that was in this sweet spot, and this is how we ended up with j and k.
So you will hear from others you heard from Dr. Palmer last year, and you will hear from Linda Griffith as well, the groundbreaking work she's doing at MIT. The j and k story is an old story as well in the field. But why we ended up prioritizing it is that we were really looking, as we were going through these potential molecular targets, J and K ended up being one where it just checked all the boxes. It was druggable, it's a kinase, it was likely to be safe. And it was clearly central to two mechanisms that are very, very important from a clinical standpoint, which is vital of course for therapeutic because ultimately you need to demonstrate a clinical benefit. And that was pain in immune system regulation, inflammation. And so again, in the interest of time, what I will share is that figure out where we are.
So we know that J and K is a well-known regulator of, one second, I lost track of my notes here, you guys. I'm sorry. I had parent teacher conferences this morning. So I'm trying to switch into scientist mode, but I'm still a little bit mommy brain. So one thing that I didn't mention is that it was really important to us to try to move away from the paradigm of always targeting endocrine function as a way of treating endometriosis. We really wanted to introduce new mechanisms, and we knew that if we could go after J and K, there was longstanding work showing that J and K targets inflammation and oxidative stress. And we felt that this could potentially be groundbreaking in endometriosis treatment because animal work, which I'll show you in a second, had shown in the academic setting that targeting JK through inhibition leads to lesion regression and also pain reduction.
So I want to kind of take a step back and say what we were hearing from investors, and for any of you who want to move your groundbreaking ideas into the private sector, what you're going to hear is all FDA cares about is pain. If you're not targeting pain, you can't get the studies funded. And we didn't want to just target pain, but we knew we had to target pain. And so for us, we were looking really for a pain plus program. And this is where J and K was really groundbreaking for us because there are multiple j and ks and one targets a mechanism that is how peripheral pain gets transmitted to the central nervous system and the other targets immune system function in a way that leads to lesion regression. So that was something that was really important to us. We know that there are competing theories of how endometriosis gets established.
I'm not going to wade into that, but what I'll tell you is it doesn't matter because the important thing is that we know that similar to cancer, endometriosis effectively has a cloaking mechanism, is how I like to describe it to investors. And for a subset of women, they are not able to clear these endometrial like lesions that start to accumulate in their bodies. And so what we wanted to do was really go after the pain mechanisms, but also see if we could disrupt this cloaking mechanism and create an immunotherapy that would allow the body to heal itself, which has really been a game changer in the cancer field. And so again, what was nice about targeting the J and K pathway is that we really had in theory, if we could create a drug that could target these multiple kin kinases in this pathway that would both address CNS sensitization.
And you'll hear about that at the conference this year, and we heard about it last year as well, but also really go after inflammation in a way that causes disease regression. And so we've made some, I think, very exciting progress on that front. So this figure is showing that the work that was done by our collaborators at Baylor College of Medicine, so when Steve Palmer came to somatics as CSO, he had been working for many years at Baylor College of Medicine on using the DNA encoded chemical library technologies that he established there to go after kinase inhibitors for this pathway. So one of the challenges in developing kinase inhibitor drugs and why they're often primarily used for cancer is that it's very hard to get specificity. And so you often have off-target effects and those side effects can be tolerated in something like cancer treatment.
But we knew for women's health that it would have to have a very clean safety profile. And what that means is a very, very strong specificity for the kinases. The other thing that we knew from previous work looking at J and ks for endometriosis or similar conditions is that the prior J and K pathway targeting drugs preferentially targeted J and K two. And that led to some issues that would create a problem from a safety standpoint for a woman chronically being on these drugs. So one of the challenges that Steve really had to tackle when he was at Baylor working on this is how do we get really exquisite specificity for closely related kinases, but preferentially for one and three because those are the mechanisms we care about the most in endometriosis. And this is why he turned to the DNA encoded libraries method because you can really get very high specificity that way.
So achieved success with that. And so the next was really to demonstrate whether these unique new J and K inhibitors that preferentially targeted one and three would achieve the cellular responses that would potentially translate into a clinical response in endometriosis. And so he progressed through the work at Baylor, and this was NIH funded work, a number of the inhibitors to look at four genes that are related to the process of inflammation that are relevant for endometriosis. So he looked at IL six, ptg, S two IL eight, and MMP three. And so these are related to inflammation, neutrophil recruitment and cell migration. And so the results in this work showed that immortalized I primary human endometrial stromal cells show similar suppression of these markers as endometrioid cells. And he was able to show the biological effect that we were seeking in these drugs in this model.
So the next was to move into an animal model. And so again, had a good signal from the in vitro models that this would translate. But then we wanted to see in the context of an in vivo system that these molecules also had the ability to reduce endometriotic like lesions the size and volume in a mouse model. And so this was the next phase, and we showed that that indeed did happen. And so in the next phase, again, the big question for investors is, okay, but does it actually impact pain? And so this is work that, so at that phase, cellmatics, again, we had the long history of the company in our development of interest in immune regulation for targeting endometriosis. Through our relationship with Steve and the longstanding work that he and others did, including at Baylor, we knew that there was this jnk inhibitor program and we had seen the early data.
And so we were fortunate to have the ability to in-license those first compounds, those compounds again, were academic compounds. They weren't really game ready to be drugs. And so the primary work we've been doing at Somatics is improving the drug-like quality of those molecules. And we've made significant progress in that. We haven't published it or announced it, but we will do that later this year. But the other really big thing that is really table stakes for us, and this is new data that we haven't presented before. So we're really excited about this really ultimately does this impact pain? And so there's a really elegant system to look at pain that is relevant for j and k targeting and endometriosis. So it's a lipopolysaccharide trigger of inflammation and pain through toll receptors. And the reason that this is a really elegant model is that we know that there's VRE and other pain assays that again, we aren't a hundred percent sure we're going to translate into the clinic, but they're the best we've got.
But those are very expensive. They're very time consuming. And so it doesn't really help for drug screening because those end up being prohibitive from a time and a cost standpoint. And while we are working on partnerships that would allow us to test our drugs kind of last mile in those models for us, we needed something that was more tractable for drug screening. And so we implemented the LPS trigger model. And what we showed is through this rapid pain screening model, is that we also see a significant effect on pain. If anybody wants to ask me, I'm happy to describe how this works, but basically the mouse will arrive in pain and will grimace. And so the investigator records those grimace scores and things. And what we see is that treatment with RJK inhibitors does actually address pain in this model.
So basically that's the last data slide that I'm going to show. But what I'll say is that this is now a orally bioavailable, relatively safe. So this means it would be a pill that somebody would take, it's non endocrine disrupting. It directly targets pain. It also causes lesion regression in animal models. And really, so the next big question is, is this going to translate into humans? And I won't share that data because Linda Griffith, our collaborator, MIT will tell that story. But we are working with Linda and we're very lucky to work with the extremely sophisticated system she has set up to give us a sense of whether this is going to translate into humans. And I will save that punchline for her. But we're really excited about Jane k inhibitors and if you'd like to learn more, you can find me tonight at dinner or later. Okay. Thank you.
