Tyra Biosciences, Inc. (TYRA) Earnings Call Transcript & Summary

Good day, ladies and gentlemen, and 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. Now 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 Hiroomi 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. In addition, any forward-looking statements represent our views only as of the date of this webcast, and which should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations to update these statements. With that, 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 SNAP chemistry [Technical Difficulty]. 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. And 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. And 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 meaningful impact in achondroplasia. Alterations of the FGFR family drive major unmet need. 7% of patients with cancer have an FGFR alteration, and there are 3 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 dysplasia like achondroplasia, with significant clinical sequela 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% plus hyperphosphatemia. These same drugs also inhibit FGFR2, which has been shown to drive stomatitis and nail toxicity. And FGFR4 alters bile acid metabolism leading to liver toxicity and diarrhea. So 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 label of these products, ranging from 23% for pemigatinib to 75% for infigratinib. And 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, over activation of FGFR3 acts as a break 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 SNAP 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. So 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 is -- which hit the pathway downstream of FGFR3. VOXZOGO was approved based on growth acceleration from baseline of 1.57 centimeters 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. And 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 centimeters per year versus baseline in Cohort 4 of their Phase II trial. Additional data is anticipated from a higher dose cohort. Competitive profile is critical to our next-generation candidate design process, and 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 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 of the other family members relative to FGFR3. Now 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 readying the skeletal dysplasia experiment for all the drugs in this class and is one of the world's leading experts in the field. Dr. Legeai-Mallet.

Okay. Thank you, and good morning or good afternoon. Indeed, in 2009, based on several collaboration between my academic laboratory and pharmaceutical companies, my team has developed the first therapeutic approaches for achondroplasia. Among the various therapeutic approaches, in 2016, I demonstrated the strong effect of low dose of tyrosine kinase inhibitor, [ infigratinib ] on FGFR-3 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 [ worst ] skeleton, in particular, the radial side of the long bone, the vertebra and the [ multi size shape ]. Slide 26. TYRA-300 increased bone growth in this FGFR3 mice mimicking achondroplasia. Using 1.2 milligram per kilo of TYRA-300, we observed a significant increase of 24% of the length of the femur, 38.3% of the tibia and 23.9% of the lumbar vertebrae, thus confirming the benefit effect of the treatment on axial and appendicular skeleton. Comparative analysis with preview data obtained with infigratinib, the other tyrosine kinase inhibitor using exactly the same mouse model show that the effect of TYRA-300 against activated FGFR3 is more important than infigratinib.

Thank you, Dr. Legeai-Mallet. I'm now going to hand it over to Hiroomi Tada, our Chief Medical Officer, to discuss potential patient populations.

Thank you, Todd. So 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. And 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 SNAP chemistry design. Our platform is rich in opportunity, and 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, and 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, and 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. And 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 and target oncology in genetically defined conditions. Tyra is in a very strong position as a company, and 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.

[Operator Instructions] And we have a first question that comes from the line of Tyler Van Buren from Cowen.

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 SURF300 trial to accelerate the achondroplasia development program? And 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?

Yes. Thank you, Tyler. Great question. 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 affected 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 mgs per kg. We don't necessarily see this model as being the predictive model on dose because these are very young day 1 pups and it's a subcutaneous injection. So there is other work that we're doing to make sure that we are effectively thinking about those. But I think we can say with some confidence that 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.

Congrats on this update. I was also going to ask about dosing too. So for infigratinib, I think you mentioned that it's dosing approximately 500x less the recommended dose in oncology. Given your specificity for FGFR3 and from what you've seen preclinically, I guess, would you expect a similar magnitude of reduction in dose going from SURF301 with starting in about 10 mgs per kg as what they're showing within infigratinib or maybe talk a little bit more about that dose reduction.

Yes. 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 lower dose will be feasible. What I would say is a 10x lower dose or an 18-fold lower dose like you see here, we don't think that's necessarily translatable. So I wouldn't want to come across reading that, that magnitude of dose reduction is -- but you might expect to see efficacy. I think it's going to be closer to the doses that you need to approach where you're getting strong FGFR3 inhibition. And of course, that's going to be required for oncology, and it will be required in this indication as well. But I think a lower dose, a more modestly lower dose, not 10x, but simply more modest is probably the right way to think about this.

And I 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 daily injectables will be and what the opportunity, I think, to innovate beyond it would be. So 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 be -- would have some better uptake and patients would prefer to be on that than a subcutaneous injection.

And I think those are most of my questions. Maybe one other question, just on just any additional thoughts on trade-offs to hitting FGFR3 more exclusively? Or is that primarily allowing you to dose higher? I guess, how do you think about potential for some [ tox ] to come up?

Yes. 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, it's clear that a challenging profile comes along with hitting FGFR1, 2 and 4. And we showed some of that data with the adverse event profile and the labels of those agents as well as the discontinuation of reductions. It's going to be really important in this patient population to be ultrasafe. And I think on the one hand, you're going to want to dose quite a bit under any activity from the other isoforms. And a selective agent allows you to still meaningfully hit FGFR3 hard enough, while sparing those isoforms. So you can really maximize the benefit and efficacy while avoiding the toxicity.

Your next question comes from the line of Matt Biegler from Oppenheimer.

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, but Dr. Bober, can you just kind of speak to that, like how safe does it need to be versus 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 kind of speculative to -- 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 tried it out in the real world.

I'm just wondering also, Todd, if there is 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. So is there anything that we should be aware of that we'll be watching out for as it relates to the safety profile?

Yes, not that we are anticipating from FGFR3 inhibition, but I don't know if Dr. Bober or Dr. Laurence have any other comments on that question, feel free to speak to it.

Your next question comes from the line of Geoff Meacham from Bank of America.

This is Hao calling in for Geoff Meacham. I think first one is really still on the clinical development plan part. I just wanted to confirm 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 ACH patients? And then second question is really, I think, the TYRA-300 in preclinical study showed some antitumor activity in FGFR3 listed model. So I'm just curious if any preclinical study has been done in ACH sort of in terms of particularly FGFR resistant specific mutation sort of models?

Well, this is Hiroomi. I'll take the first question. So I think it's important to understand that the oncology division and the endocrine division are very different at FDA. So in order for us to do a study with people with achondroplasia that we have to go through the endocrine division, and so that's a separate IND and requires a separate study. So we would not be able to do a study with both oncology patients and people with achondroplasia. 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 ahead of the Phase II study, where we might look at additional biomarkers perhaps in a healthy volunteer study or something like that. So it's a matter of us engaging with FDA. We think that we have compelling data to start doing that. And as we move toward IND, we'll certainly continue to talk to FDA about what the best path forward will be for us.

And 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 a very different biology from the cancer setting. So there is no ACH resistance model.

Your next question comes from the line of Mitchell Kapoor from H.C. Wainwright.

The first question I wanted to ask was just on other isoforms of FGFR. So I know that targeting those could be potentially problematic from a safety standpoint. But could you talk about how those other isoforms could potentially contribute to efficacy benefit in achondroplasia?

Yes. So thank you for the question, Mitchell. I think this was a really important question to highlight that achondroplasia is -- it is a condition driven by the genetic mutation in FGFR3 with -- and FGFR3 has a primary role in chondrocytes in the growth plate. So really, we don't expect any efficacy to be driven from the other FGFR isoforms in this condition. And as a result, they really are the important off targets to avoid, given their known activity in biology that can drive toxicities and tolerability challenges when they're inhibited.

And then just on moving into pediatric patients with this new lower dose potentially. Obviously, the FDA is typically sensitive on pediatric patients on safety profiles. Are you aligned with the FDA on this strategy? Or is there any reason to believe that they may want to see a little bit more before going into pediatric patients?

I think we're very much aligned with ensuring that we bring a very safe dose to these patients that we carefully monitor dose in a Phase II to ensure that we can select the dose that's given to give the most appropriate benefit and be safe for long-term use. So from that perspective, I think high alignment, but there's a lot of work to do to get there, of course.

And I'll also add that, to go into children, we do need to do additional toxicity studies preclinically, which are not required in the oncology setting. So we will be kicking those off this year as part of our IND package that we'll be submitting next year.

And maybe the last one for Dr. Bober. I just wanted to ask about what would be clinically meaningful from a bar for success standpoint in these patients.

So 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, and I want my patients to be healthier. Having said that, I think in a 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.

And 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 want to 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 want to 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 options 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. So thank you again. And with that, I'll hand back to the operator, Rob.

Ladies and gentlemen, that concludes today's conference call. Thank you for your participation. You may now disconnect.