Good day, ladies and gentlemen. Thank you for standing by. Welcome to the Tyra Biosciences conference call to discuss the expansion of the development of TYRA-300. As a reminder, this conference call is being recorded. I would like to turn the call over to Amy Conrad from Investor Relations. Please go ahead.
Thank you, Rob. Good morning, everyone, and thank you for joining us. With me today from Tyra are Todd Harris, Chief Executive Officer, Ron Swanson, Chief Scientific Officer, and Hiromi Tada, Chief Medical Officer. Also on today's call are Dr. Michael Bober, Medical Director of the Skeletal Dysplasia Program at Nemours Children's Hospital, Delaware, and Dr. Laurence Legeai-Mallet from the Imagine Institute in Paris, France. Before we begin, I would like to remind you that on today's call, we will be making forward-looking statements concerning Tyra's future expectations, plans, prospects, strategy, and performance, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of risks and uncertainties associated with Tyra's business, including those discussed in our filings with the SEC.
Any forward-looking statements represent our views only as of the date of this webcast, and we should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations to update these statements. I'll turn the call over to Todd.
Thank you, Amy. Welcome, everyone, and thank you for joining us. This is a really exciting time at Tyra. We've demonstrated substantial progress with our pipeline, and I believe we are well-positioned across all our areas of our business. We continue to develop differentiated assets, precision small molecules that target large opportunities in FGFR biology with our accelerated approach to design and our SNÅP chemistry. Our financial profile remains strong with $263 million at the end of Q3 2022 with no debt. We expect to report Q4 and full year 2022 financials later this month. Today, we're pleased to announce that we are expanding the development of TYRA-300, our lead program, an oral FGFR3 selective inhibitor beyond oncology into achondroplasia.
In a moment, Dr. Bober will provide an overview of achondroplasia, the current treatment landscape, and the unmet needs that we believe TYRA-300 can address. Our design goal for TYRA-300 was to develop a competitive FGFR3 inhibitor that overcomes the significant liabilities of approved agents, including tolerability, off-target toxicities, and acquired resistance. The encouraging preclinical results seen with TYRA-300 in oncology and now in skeletal dysplasia models provide us with great confidence to expand our pipeline beyond targeted oncology to pursue genetically defined conditions like achondroplasia. We're excited to have Dr. Michael Bober joining us on the call today. He is a board-certified pediatric geneticist and a world-renowned authority in pediatric skeletal dysplasias. With that, I'll turn the call over to Dr. Bober.
Thank you, Todd. Good morning. I wanted to provide a little background on achondroplasia, which is in fact the most common human skeletal dysplasia, with estimates of approximately 1 in 25,000 children that are born. Achondroplasia is a short limb form of dwarfism where patients have average intelligence. It's an autosomal dominant disorder. Approximately 80% of cases are de novo, and 20% of patients, therefore, are born to parents with achondroplasia.
Achondroplasia is caused by mutations in the FGFR3 gene. FGFR3 receptor functions in a FGF signaling pathway, and this pathway is very important in growth plate function, and it serves as a negative regulator of chondrocyte proliferation and differentiation. Mutations in the FGFR3 gene cause a family of skeletal dysplasias, of which achondroplasia is the most common. The most significant medical problems associated with achondroplasia involve the growth of the skull base and include things like otitis media, obstructive sleep apnea, foramen magnum stenosis, and hydrocephalus. Other medical problems are spinal stenosis as well as bowing of the legs or genu vara.
All right. Thank you for that overview, Dr. Bober. We believe there is tremendous opportunity for a next-generation FGFR3 inhibitor to have a meaningful impact in achondroplasia. Alterations in the FGFR family drive major unmet needs. 7% of patients with cancer have an FGFR alteration, and there are three validated oncology indications with FGFR family alterations. Among these, FGFR3-positive urothelial carcinoma is significantly larger than the others, with an annual incidence of around 40,000 in the U.S. alone. Outside of oncology, FGFR3 germline mutations drive a number of skeletal dysplasias like achondroplasia. With significant clinical sequelae that could potentially be addressed by an FGFR3 selective inhibitor. Approved FGFR inhibitors are all pan FGFR inhibitors, and as a result have significant liabilities, including off-target toxicities. FGFR1 is a key driver of hyperphosphatemia, which requires consistent monitoring and management with diet and phosphate binders.
Approved pan- FGFR inhibitors all report over 60% + hyperphosphatemia. These same drugs also inhibit FGFR2, which has been shown to drive stomatitis and nail toxicity. FGFR4 alters bile acid metabolism, leading to liver toxicity and diarrhea. All this data demonstrates that the toxicities of FGFR1, 2, and 4 indeed limit the dosing of these drugs. Here we are showing the discontinuation rates and reduction in dosing reported in the labels of these products, ranging from 23% for pemigatinib to 75% for infigratinib. The dose-limiting toxicities, or DLTs, have primarily been driven by FGFR1 hyperphosphatemia and FGFR4-associated increases in AST and ALT levels. A more FGFR3 selective drug has the potential to hit the target harder and reduce the toxicities associated with FGFR1, 2, and 4 inhibition that have been a challenge with this class of drugs.
FGFR3 inhibition poses no known toxicities in adults, but when an oncology product was used in the pediatric setting, growth velocity improvement was observed, highlighting an opportunity in this population. As Dr. Bober highlighted, FGFR3 is an important mechanism in bone growth. Specifically, overactivation of FGFR3 acts as a brake on bone growth while growth plates are open. FGFR3 inhibition increases proliferation and differentiation of chondrocytes and can enhance growth velocity in children while growth plates are open. The opportunity for an FGFR3 selective inhibitor is clear, but it is a challenge to achieve because the amino acid sequences of the active sites are nearly identical among the FGFR. We leveraged our SNÅP chemistry platform to address this problem. We started by overlaying molecular models for FGFR1 and FGFR3 and identified subtle areas within the active site where we felt we could drive higher FGFR3 inhibition over FGFR1.
This was followed with dozens of candidates co-crystallized in high-resolution structures with the various FGFR family members. The cross-section here on the right of this slide is one such area where we were able to push deeper into the pocket of FGFR3, where FGFR1 is more constrained, leading to greater selectivity for FGFR3 over FGFR1. We are really excited about our opportunity to deliver a next-generation precision therapy to improve the lives of people with achondroplasia. Over the next few slides, Hiroomi and I will walk through our rationale to expand the development of TYRA-300, and Dr. Laurence Legeai-Mallet will review preclinical data with TYRA-300 in achondroplasia. There is a well-defined population in achondroplasia. FGFR3 aberrations drive greater than 90% of pediatric achondroplasia. The lead therapeutic option for this condition is currently VOXZOGO, a CNP analog, which hits the pathway downstream of FGFR3.
VOXZOGO was approved based on growth acceleration from baseline of 1.57 cm per year versus placebo. While VOXZOGO can address growth acceleration, unmet needs remain to be addressed for this population, like disproportionate growth. VOXZOGO has not yet demonstrated improvement of the most serious health conditions associated with achondroplasia, including spinal stenosis and sleep apnea, among others. Importantly, VOXZOGO is a daily injection, which can be very difficult on both parents and children. Recently, infigratinib, an oral pan FGFR inhibitor, demonstrated an annualized height velocity increase of 1.52 cm per year versus baseline in cohort 4 of their phase II trial. Additional data is anticipated from a higher dose cohort. Competitive profiling is critical to our next-generation candidate design process. We have demonstrated that TYRA-300 is more selective for FGFR3 than infigratinib.
Here we are showing data using Ba/F3 cell lines that are driven by FGFR1, 2, 3, or 4. The top table shows the IC50s of infigratinib against each FGFR family member, as well as TYRA-300's high potency for FGFR3 with an IC50 of about 1.8 nanomolar. The bottom table shows full selectivity for other isoforms relative to FGFR3. Importantly, for TYRA-300, we see double-digit separation across all the other family members relative to FGFR3. Let's review the compelling in vivo preclinical data we generated with TYRA-300 in achondroplasia mouse models in collaboration with the Imagine Institute in Paris. It is my pleasure to turn the call over to Dr. Laurence Legeai-Mallet. She has extensive experience running the skeletal dysplasia experiments for all the drugs in this class and is one of the world's leading experts in the field.
Legeai-Mallet.
Okay. Thank you. Good morning or good afternoon. Indeed, in 2009, based on several collaboration between my academic laboratory and a pharmaceutical company, my team has developed the first therapeutic approaches for achondroplasia. Among the various therapeutic approaches, in 2016 I demonstrated the strong effect on low dose of tyrosine kinase inhibitor, infigratinib on FGFR3 mouse model recapitulating the achondroplasia phenotype. In 2022, in collaboration with Tyra, using the same protocol, we treated this FGFR3 mice with subcutaneous injection of TYRA-300. Here you can see on the X-ray the impressive effect of the TYRA-300 treatment on FGFR3 treated mice compared to control. The treatment has improved the whole skeleton, in particular the radius size of the long bone, the vertebra, and the modified skull shape. Slide 26.
TYRA-300 increased bone growth in these FGFR3 mice limiting achondroplasia. Using 1.2 mg per kilo of TYRA-300, we observe a significant increase of 24% of the length of the femur, 38.3% of the tibia, and 23.9% of the lumbar vertebra, thus confirming the benefit effect of the treatment on axial and appendicular skeleton. Comparative analysis with previous data obtained with infigratinib, the other 1,000 kinase inhibitor, using exactly the same mouse model, show that the effect of TYRA-300 against the activated FGFR3 is more important than infigratinib.
Thank you, Dr. Legeai-Mallet. I'm now gonna hand it over to Hiroomi Tada, our Chief Medical Officer, to discuss potential patient populations.
Thank you, Todd. We believe the promising preclinical data we have with TYRA-300 in achondroplasia provides a solid data package to support advancing the program into the clinic. We plan to submit an IND that allows us to initiate a phase II clinical study of TYRA-300 in pediatric achondroplasia in 2024. We believe that with a selective FGFR3 inhibitor, we also have a significant opportunity in conditions beyond achondroplasia, including a family of skeletal dysplasias driven by the FGFR3 pathway. We are working on our development plans and look forward to sharing more details on this program in the future. With that, I'll turn it back to Todd for closing remarks.
Thanks, Hiroomi. Before we take your questions, I want to summarize the recent progress across our precision medicine pipeline. We continue to make steady progress with our differentiated assets, all of which have come from our in-house SNÅP chemistry design. Our platform is rich in opportunity. Each one of our assets was designed to be best in class within their respective indications. We're really pleased with TYRA-300's results to date. We continue to enroll patients in our SURF301 clinical study in oncology. We look forward to expanding into achondroplasia with plans to submit an IND to allow us to initiate a phase II clinical study in 2024.
We also announced today that our investigational new drug application for TYRA-200, our FGFR1, 2, 3 inhibitor, has been cleared by the U.S. Food and Drug Administration, we expect to dose our first patient in a phase I study focused on FGFR-resistant patients with FGFR2-positive intrahepatic cholangiocarcinoma in the second half of 2023. The remainder of the pipeline is progressing well. We expect to nominate lead candidates from our FGF19, FGFR4, and RET programs, giving us a robust pipeline of precision medicine programs that target oncology in genetically defined conditions. Tyra is in a very strong position as a company, we will continue to innovate and push the boundaries of what's possible in drug development. With that operator, we're ready to take questions.
At this time, I would like to remind everyone, in order to ask a question, please press star then the number one on your telephone keypad. We have a first question that comes from the line of Tyler Van Buren from Cowen. Your line is open.
Hey, guys. Good morning. Thanks very much for sharing the exciting preclinical data. I have a couple for you. I guess the first one is: How do you expect to leverage the early PK/PD and safety learnings from the ongoing SURF301 trial to accelerate the achondroplasia development program? The second one is, based upon the preclinical data, what will the minimum active dose in humans be, and how does that relate to the dose you're using in oncology?
Thank you, Tyler. Great questions. Of course, because we are in a phase I in oncology and are able to look at PK/PD, there's quite a bit that we'll be able to leverage from that study to help us move effectively into phase II. I think an important thing to highlight here is that we do expect a different dose to potentially be effective here in this space. You can see from the model that we have here that we've done with Laurence, it's a much lower dose than our oncology models that we've shared previously, which were 18 mg per kilo.
We don't necessarily see this model as being, you know, the predictive model on dose because these are very young day one pups, and it's a subcutaneous injection. There is other work that we're doing to make sure that we are effectively thinking about dose. I think we can say with some confidence that, you know, it is likely going to be a lower dose that will be effective from what we've seen to date in these models.
Your next question comes from the line of Maury Raycroft from Jefferies. Your line is open.
Hi, good morning. Congrats on this update and thanks for taking my questions. I was also gonna ask about dosing too. For infigratinib, I think you mentioned that it's dosing approximately 500 times less than the recommended dose in oncology. Given your specificity for FGFR3 and from what you've seen pre-clinically, I guess would you expect a similar magnitude of reduction in dose going from SURF301 with starting at about 10 mg per kg as what they're showing with infigratinib? Or maybe talk a little bit more about that dose reduction.
Thanks, Maury . I think we'll stay away from commenting too much on infigratinib study and dose relationships. I think they've put out quite a bit of information there. I do think that a, you know, a lower dose will be feasible. What I would say is, you know, a 10x lower dose or an 18-fold lower dose like you see here, we don't think that's necessarily translatable. I wouldn't, I wouldn't wanna come across reading that that magnitude of dose reduction is what you might expect to see efficacy. I think it's gonna be closer to the doses, you know, that you need to approach where you, where you're getting, you know, strong FGFR3 inhibition.
Of course, that's gonna be required, you know, for oncology and it will be required in this indication as well. You know, I think, a lower dose, a more modestly lower dose, not 10x, but something more modest, you know, is probably the right way to think about this.
Got it. That's helpful and makes sense. Also wanted to ask about vosoritide, which is currently a once daily injection. I guess, thinking further down the line strategically, given the presumed convenience of having a daily oral, do you think a path forward could ultimately entail non-inferiority or how do you think about that?
That's a great question. I'm not sure I'm ready to comment on that just yet in terms of study design. I do think that it might be worthwhile to hear from Dr. Bober on this point on what the experience on, you know, daily injectables would be and what the opportunity I think to innovate beyond it would be. Maybe, if I could hand it over to Dr. Bober to comment on that, for your question, I'll do that.
Hello. Yes, I think you're correct in thinking that the oral medication would have some better uptake and patients would prefer to be on that than a subcutaneous injection.
Got it. makes sense. I think those are most of my questions. Maybe one other question just on, just any additional thoughts on trade-offs to hitting FGFR 3 more exclusively, or is that primarily allowing you to dose higher? I guess how do you think about potential for some toxic amount?
Yeah. I think it's really important, from our experience, in looking at the toxicities and tolerability challenges with all of the pan- FGFR inhibitors that have been approved to date, you know, it's clear that, you know, that a challenging profile comes along with hitting FGFR1, FGFR2, and FGFR4. We showed some of that data with the adverse event profile and the labels of those agents as well as the discontinuation and reductions. It's gonna be really important in this patient population to be ultra-safe. I think, you know, on the one hand, you know, you're gonna wanna dose quite a bit under any activity from the other isoforms. A selective agent allows you to still meaningfully hit FGFR3 hard enough, you know, while sparing those isoforms. You can really maximize the benefit and efficacy, while avoiding the toxicity.
Got it. Makes sense. Thanks for taking my questions.
Your next question comes from the line of Matthew Biegler from Oppenheimer. Your line is open.
Hey, guys. Thanks for sharing this exciting update in preclinical data. I wanted to ask Dr. Bober maybe dovetailing on a prior question or something maybe, Todd, that you just said about the risk to benefit for these patients. Just how safe does a chronic drug, like this need to be? I'd imagine the profile in oncology is obviously different than in a pediatric rare disease. Dr. Bober, can you just kinda speak to that? Like how safe does it need to be versus, you know, the trade-off to the benefit?
Well, I mean, as a clinician you want it to be as safe as possible and have as minimal side effects and maximal on target effects. I think it's kinda speculative for me to guess what's tolerable and what's not. I think we need to do the trial. I'm excited to hopefully get to a point in a trial where we can figure out in the real world.
Okay. That's fair. I'm just wondering also, Todd, if there's any theoretical risk to long-term inhibition of FGFR3. Obviously, the oncology setting will be more acute and short duration in nature than this, which is more of a long-term, type of dosing strategy. Is there anything that we should be aware of that, you know, we'll be watching out for as it relates to the safety profile? Thanks.
Yeah. Not that we are anticipating from FGFR3 inhibition. It's a. I don't know if Dr. Bober or Dr. Laurence have any other comments on that question. Feel free to speak to it. All right, Matt. Yeah. Not that we're aware of.
All right. Fair enough.
Yeah.
Thanks, guys.
Your next question comes from the line of Geoff Meacham from Bank of America. Your line is open.
Good morning. This is Hal calling in for Geoff Meacham, and thank you for the question. I think first one is really on the clinical development plan part. Just want to confirm, you know, for the first one phase I study, will there be any change, for example, including some patients of ACH? And then for the phase II, do we think it could be like maybe a basket trial with like multiple cohorts in both tumors and the, you know, ACH patients? And then second question is really, I think the TYRA-300 in preclinical study show some antitumor activity in FGFR3-resistant models. I'm just curious if you have, if any preclinical study has been done in ACH, sort of, in terms particularly in FGFR-resistant, specific mutation sort of models.
Well, this is Hiroomi. I'll take the first question. You know, I think it's important to understand that the oncology division and the endocrine division are very different at FDA. In order for us to do a study with people with achondroplasia that, you know, we have to go through the endocrine division. You know, that's a separate IND and requires a separate study. We would not be able to do a study with both oncology patients and people with achondroplasia.
You know, that said, we'll certainly be able to use the information we get from our phase I around PK and pharmacodynamic effects, in addition to potential studies to ahead of the phase II study, where we might look at the additional biomarkers perhaps in a healthy volunteer study or something like that. you know, it's a matter of us engaging with FDA. We think that we have compelling data to start doing that. as we move toward our IND, we'll certainly continue to talk to FDA about what the best path forward will be for us.
To answer your second question, the resistance isn't really relevant in the ACH setting, because it's a germline mutation, all the cells have it, and it's very different biology from the cancer setting. There's no ACH resistance model.
Okay. Thank you so much, and congrats on the progress.
Thank you.
Your next question comes from the line of Mitchell Kapoor from H.C. Wainwright. Your line is open.
Hey, everyone. Thank you for taking the questions today. The first question I wanted to ask was just on other isoforms of FGFR. I know that targeting those could be potentially problematic from a safety standpoint. Could you talk about, you know, how those other isoforms could potentially contribute to efficacy benefit in achondroplasia?
Yeah. Thank you for the question, Mitchell. I think this is a really important question to highlight that achondroplasia is, you know, it is a condition driven by a genetic mutation in FGFR3. FGFR3 has a primary role in chondrocytes in the growth plate. Really, we don't expect any efficacy to be driven from the other FGFR isoforms in this condition. As a result, they really are the important off targets to avoid, given their known, you know, activity and biology that can drive toxicities and tolerability challenges when they're inhibited.
Okay, great. Thank you. Then just on, you know, moving into pediatric patients with this, with this new lower dose potentially, obviously, the FDA is typically sensitive on, you know, pediatric patients and safety profiles. Are you aligned with the FDA on this strategy, or is there any reason to believe that, you know, they may want to see a little bit more, before going into pediatric patients?
I think we're very much aligned with ensuring that, you know, that we bring a very safe dose, you know, to these patients, that we carefully monitor dose in a phase II to ensure that we can select the dose that's gonna give the most appropriate benefit and be safe for long-term use. From that perspective, I think high alignment, but there's a lot of work to do to get there, of course.
Yep. I also add that, you know, to go into children, we do need to do additional toxicity studies pre-clinically, which are not required in the oncology setting. We will be kicking those off this year, as part of our IND package that we'll be submitting next year.
Okay, great. Thank you. Maybe the last one for Dr. Bober. I just wanted to ask about, you know, what would be clinically meaningful from a bar for success standpoint in these patients?
Excuse me. That's a very good question. In my mind, clinically meaningful means the improvement of associated medical problems. I think the way that I look at it almost is we'll take height as a side effect. I want my patients to be healthier. Having said that, I think in the real world perspective, if the average growth velocity and height increases were the same or better with the daily dosing, then we have a preferred. I think the families would prefer to take the oral medication.
Okay, great. Thank you all so very much.
Thank you, Mitchell.
There are no further questions at this time. Mr. Todd Harris, I turn the call back over to you for some final closing remarks.
All right. Well, I just wanna close by thanking, first and foremost, Dr. Bober, Dr. Laurence Legeai-Mallet for joining us on the call today, for the work that you do in this population and for the work that you've done to help us and support us in moving TYRA-300 forward as an option. I do wanna thank all of the folks on the call today and the thoughtful questions. We're really excited for the progress of our pipeline, the potential opportunities to improve the outcomes of patients with cancer and people and children with achondroplasia and other genetically defined conditions. An exciting day for us as we start to move forward in a variety of new directions here as well. Thank you again. With that, I'll pass it back to the operator, Rob.
Ladies and gentlemen, that concludes today's conference call. Thank you for your participation. You may now disconnect.