Hello, and welcome to the Kymera Therapeutics Q4 2022 Earnings Conference Call. All participants will be in listen only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your telephone keypad. To withdraw from the question queue, please press star then two. Please note this event is being recorded. I would now like to turn the conference over to Bruce Jacobs. Bruce, please go ahead.
Good morning, everyone, and welcome to the Kymera Therapeutics Quarterly Conference Call. I'm Bruce Jacobs, Chief Financial Officer at Kymera, and I'll be joined today by Nello Mainolfi, Founder, President, and CEO, and Jared Gollob, our Chief Medical Officer. After our prepared remarks, we'll open the call to your questions. To ask a question, please press star one on your telephone keypad. If at any time you would like to withdraw from the queue, please press star two. Before we get started, I'd like to remind everyone that some of the comments that management may make on this call include forward-looking statements as outlined in the press release.
Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in Kymera's most recent filings with the SEC and any other future filings that the company may make with the SEC. You're cautioned not to place any undue reliance on those forward-looking statements, and Kymera disclaims any obligation to update such statements except as required by law. With that said, I'll now hand the call to Nello.
Thanks, Bruce, and thank you everyone for joining us today. I thought I would spend a few minutes this morning reflecting briefly on the importance of all the progress we made in 2022, and what we believe it means for our ambitious objective to build a best-in-class, fully integrated global medicines company. 2022 was exceptionally important year for Kymera's evolution. We dosed healthy volunteers, patients with HS and AD, which is the first time for a degrader in immune inflammatory indications, patients with lymphomas, leukemias, and solid tumors with our first three investigational drugs. We've seen now across three programs strong translation of our preclinical PK, PD, and safety into the clinic. This is a substantial accomplishment for a company that is pioneering a new modality.
In addition, we have seen for the first time clinical benefits of a heterobifunctional degrader in immune inflammatory indications and the first proof of concept of clinical differential of a degrader versus a small molecule inhibitor with our KT-474 phase I data. In fact, KT-474 clinical data that we shared late last year from the patient cohort of the phase I study of our IRAK4 degrader exceeded our expectations. We were able to replicate the PK/PD profile of the healthy volunteer portion of the trial in HS and AD patients. The molecule was generally well-tolerated with no serious adverse events, including a resolution of the QT effect.
We demonstrated an encouraging impact on disease-relevant inflammatory biomarkers in blood and skin, and we were able to produce some early but really encouraging signs of clinical activity in HS and AD patients that we think represent strong reasons to believe in the clinical potential of effectively drugging the IRAK4 pathway and in our degrader molecule. Of course, lastly, we reported that our partner, Sanofi, shares their enthusiasm and will initiate phase II studies in 2023. Jared will share a little bit more on this call regarding the next steps for the program, obviously this was an important milestone for KT-474, a molecule that we believe can have a unique and broad role in raising the standard of care in a wide variety of inflammatory conditions.
Assuming the molecule's profile remain consistent as we test it in larger studies and additional patient populations, we believe a small molecule with the emerging efficacy and encouraging safety profile could be a best-in-class medicine across several diseases. This year, we're excited for our partner, Sanofi, to initiate KT-474 studies, initially in HS, followed by AD and potentially other indications. While perhaps somewhat overshadowed by the KT-474 results, we made encouraging progress in our first two clinical stage oncology programs, KT-413, the IRAKIMiD degrader, and KT-333, our STAT3 degrader. Both programs are currently in the dose escalation phases of the phase I clinical studies. In December, we disclosed pharmacodynamic activity in both blood and tumors and knockdown of their targets without any dose-limiting toxicity.
Importantly, we've seen fidelity of translation of PK, PD, and safety from preclinical profiles into these clinical settings, further validating our work and highlighting our ability to replicate our approach to discovering and developing high-value molecules. The promising initial data from these phase I trials position us to share data later this year that we hope will show clinical activity, particularly when we reach the expected active dose levels in our targeted patient populations. Taken together, we believe that these results represent a validation of our R&D approach and strategy. Since we started the company over 6 years ago now, our founding principles have remained unchanged. Harness the transformative potential of targeted protein degradation to address areas of significant therapeutic need and improve patients' lives.
With this goal in mind, we made very intentional choices, which we believe represent a differentiated approach to designs in many key areas, including target selection strategies, disease area focus cutting-edge platform investments and corporate strategy. This strategy and approach, in conjunction with a clear focus on disease target in areas of significant patient need that can't be meaningfully addressed by traditional medicine, has led us to targets and markets where protein degradation is the only or the best way to elucidate the desired biology or clinical outcome.
I hope that as you reflect on the totality of the data we presented in December and our progress in building the company, you share our belief that we have validated the work and investments we've made over the past seven years, almost seven years, resulting in the high quality molecular design and platform capabilities, and a proven ability to translate our understanding of disease biology, PK, PD, and safety from preclinical models into patients, creating high value programs that have the potential to become important new medicines. Before I hand the call over to Jared, I should mention that the three programs I just discussed are just the beginning for Kymera. At the end of last year, we also announced that the FDA had cleared the IND for our MDM2 degrader, KT-253.
MDM2 is a crucial regulator of the most common tumor suppressor, p53, which remains intact in close to 50% of cancers. Jared will share more on our plans for KT-253 shortly. We also hinted at several other programs in our early-stage pipeline in both oncology and immunology indications earlier in the year, further evidence of the productivity of our drug discovery engine. These advances have been fueled in part by innovative computational research tools that have enhanced our understanding of disease biology and allowed us to develop new ways to harness TPD. In addition to leadership in the discovery hub of heterobifunctional degraders, we are also identifying novel molecular glues that expand the therapeutic applicability of our platform, and we hope to share more on this later in the year as well.
Along with our clinical and scientific progress, we've worked to ensure that we have the people and resources to build our company sustainably. We recently appointed Ellen Chiniara as Chief Legal Officer and Corporate Secretary, where she'll serve as a key member of our leadership team. Ellen joins us from Alexion Pharmaceuticals with extensive experience overseeing legal activities at biopharmaceutical companies, ranging from discovery phase through commercialization. This month, Rebecca Mosher joined us as our Senior Vice President of Translational Medicine from Mersana Therapeutics. She previously held positions of increasing responsibilities in translational medicine, translational research, and molecular pathology at Novartis, Vertex, and Millennium. We also recently appointed Juliet Williams as Kymera's new Head of Research. Juliet was previously our Head of Biology and contributed profoundly to our target selection strategy and drug discovery efforts.
She has more than 20 years of drug development experience, including leadership roles at Novartis, Sanofi, Millennium, and Curis. These important roles will help Kymera navigate our next stage of development as we work to bring revolutionary degraded therapies to patients. Finally, we ended the year in a very solid financial position with approximately $560 million in cash, an expanded runway into the second half of 2025, which will allow us to continue to invest in our clinical programs, discovery pipeline, and platform. Importantly, allow us to read out our IRAK4 phase 2 proof-of-concept study and initial proof of concept for the three oncology clinical programs. Jared will now cover in more details our recent progress for each of our disclosed programs before returning the call over to Bruce for a financial update.
I will finish with some concluding remarks, including covering our key goals for 2023, before handing the call to the operator for a Q&A session in which Jared, Bruce, and myself will be available. Jared?
Thanks, Melo. I'll provide a brief recap of where we stand with our clinical programs and what to expect in 2023. I'll begin with our IRAK4 program. As you all know, in October, we announced the completion of dosing of the patient cohort portion, part C, of the KT-474 phase 1 clinical trial, and we shared the full dataset in December. I won't go over all of the data here today, but if you are interested, you can find the replay of our December meeting on our website. The data are also included in our updated corporate presentation. That said, I did want to share our expectations for the progress of the program in 2023. As you know, Sanofi will be taking KT-474 into phase 2.
Just as they were closely involved in the phase 1 trial that Kymera ran, we jointly discussed the plans for the phase 2 program. As we shared in December, Sanofi is committed to phase 2 trials in at least two initial indications, beginning with HS and followed by AD. As for timing, it is too early to guide to the expected phase 2 start dates. As we have said in the past, at least the first phase 2 is planned to start in 2023. Turning to our oncology pipeline, I want to update everyone on our disclosed programs, which include our STAT3, IRAKIMiD, and MDM2 degraders. Focusing first on our new trial activity, KT-253, our MDM2 degrader, received IND clearance from the FDA in December. MDM2 is the crucial regulator of the most common tumor suppressor, p53, which remains intact in close to 50% of cancers.
Kymera is developing a highly potent MDM2 degrader that, unlike small molecule inhibitors, has been shown pre-clinically to have the ability to overcome the MDM2 feedback loop and rapidly induce apoptosis even with brief exposures. KT253 has the potential to be effective in a wide range of hematological malignancies and solid tumors with functioning or wild-type p53. We plan to initiate dosing patients soon in the phase I trial of KT253. The phase I study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of KT253 in adult patients with relapsed or refractory high-grade myeloid malignancies, acute lymphocytic leukemia, lymphoma, and solid tumors. The open label dose escalation study is intended to identify the recommended phase II dose. It will be comprised of two arms with ascending doses of KT253 in each arm.
The first arm will consist of patients with lymphomas and advanced solid tumors, and the second arm will consist of patients with high-grade myeloid malignancies and ALL. Turning to our two ongoing oncology trials. STAT3 is a transcriptional regulator that has been linked to numerous cancers and other inflammatory and autoimmune diseases. Our phase I clinical trial is evaluating KT-333's potential in hematological malignancies and solid tumors. Specifically, the trial is evaluating the safety, tolerability, PK/PD, and clinical activity of KT-333 in adult patients with relapsed and/or refractory lymphomas and solid tumors. We reported on the first dose level in December, showing initial proof of mechanism for STAT3 degradation in PBMC and no dose-limiting toxicities, with good translation of PK/PD from preclinical models to patients.
Based on the PK/PD we have shown to date, with robust target knockdown for 72 hours followed by recovery, we expect to be at efficacious doses by dose level 3 or dose level 4. This year, we expect to show clinical impact of STAT3 degradation on tumor burden in the target patient populations such as peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and LGL leukemia. The trial's second stage will consist of phase Ib expansion cohorts to further characterize the safety, tolerability, PK/PD, and antitumor activity of KT-333 in relapsed and/or refractory STAT3-dependent T-cell malignancies, as well as in solid tumors. Finally, our IRAKIMiD program, KT-413, is a novel heterobifunctional degrader that targets degradation of both IRAK4 and the IMiD substrates, Ikaros and Aiolos, with a single small molecule.
KT-413 was designed to address both the IL-1R/TLR and the type I interferon pathways synergistically to broaden activity against MYD88 mutant B-cell malignancies. KT-413 is on a similar timeline as STAT3 and is currently in the dose escalation stage of the phase I trial, evaluating the safety, tolerability, PK/PD, and clinical activity of KT-413 in patients with relapsed and/or refractory B-cell non-Hodgkin's lymphomas. We reported in December that the first two dose levels have been completed, showing initial proof of mechanism with IRAK4, Ikaros, and Aiolos degradation in PBMC and tumor and no safety signals, with good translation of PK/PD from preclinical models to patients. We are continuing enrollment and expect to be at efficacious doses by dose level three or dose level four. As with KT-333, later this year, we expect to show clinical effect of IRAKIMiD degradation on tumor burden in MYD88 mutant patients.
The trial's second stage will consist of Phase Ib expansion cohorts in DLBCL to further characterize the safety, tolerability, PK/PD, and antitumor activity of KT-413 in relapse refractory MYD88 mutant and MYD88 wild-type DLBCL. We look forward to sharing more progress on these programs throughout the year. I will now hand the call to Bruce, who will share some brief comments on our financial results for the Q4 .
Thanks, Jared. I will quickly cover the financials before turning the call back to Nello for concluding remarks. For the quarter, we recognized $16.1 million of revenue. This total reflects revenue recognized pursuant to our Sanofi and Vertex collaborations. At the end of the quarter, our deferred revenue total on the balance sheet was approximately $63 million. That reflects partnership revenue we expect to recognize over the next several years, excluding the receipt of any potential future milestones. With respect to operating expenses, R&D for the quarter was $43.1 million, of which $4.5 million represented non-cash stock-based compensation. The adjusted cash R&D spend of $38.6 million, excluding stock-based comp, is essentially unchanged from the comparable amount in the September quarter.
Our G&A spending for the quarter was $11.6 million, of which $4.4 million represented non-cash stock-based compensation. The adjusted cash G&A spend of $7.2 million, excluding stock-based compensation, reflects a 13% increase from the comparable amount in the September quarter. On cash, we exited the fourth quarter with a cash and equivalent balance of approximately $560 million. As we shared earlier in the year, we believe that our cash runway extends into the second half of 2025, a projection that now includes milestones related to the phase II start. I'll now turn the call back to Nello.
Thanks, Bruce. With our accomplishments last year, it's clear that Kymera has made considerable progress in its evolution and begun to demonstrate the incredible potential of this modality and our company to make a meaningful difference in patients' lives. We're excited to have the opportunity this year to assess the impact that our four programs may have for patients with cancer and immunological conditions, and to further demonstrate the potential advantages of our technology and platform have over traditional medicines. We feel that we're just getting started and are energized by the opportunity we have in front of us. As I said earlier, 2023 will be a busy year. We have a lot that we expect to achieve, much of which was discussed earlier in the call. Just to quickly state our key 2023 goals, we will collaborate with Sanofi to initiate the first KT-474 phase 2 study.
We're also working to publish the results of the phase I trial in a top-tier journal. We intend to evaluate the effects of our IRAKIMiD and STAT3 programs on tumor burden in patients in our phase I studies. We plan to initiate the KT-253 phase I trial in solid and hematological tumors in order to demonstrate proof of mechanism in patients. With respect to our pipeline, our objective is to deliver at least two new BC-INDs from the preclinical pipeline and also continue our expansions of our novel molecular glue franchise. At this point, I'd like to thank the Kymera team as well as our partners and the patients participating in our clinical trials, and for sharing this journey with us. Thank you all for participating in our call, and I look forward to your questions.
I will now hand the microphone to the operator so that we can take your questions.
Thank you. At this point, we will open the call for questions. As a reminder, to ask a question, please press star one on your telephone keypad. If at any time you would like to withdraw from the queue, please press star two. We will now take a moment to review our queue. Today's first question comes from Eric Joseph with JPMorgan. Please go ahead.
Oh, thanks. Good morning, and thanks for taking the questions. Just a couple questions on the MDM2 program, if we could. I guess first, what is... Maybe can you lay out what proof of mechanism looks like with KT-253 later this year? Does it look similarly in liquid tumors as it does in solid tumors? Secondly, with respect to the anticipated AE profile with the drug, do you anticipate any differences, I guess, relative to competitor MDM2 inhibitors, particularly on the aspect of myelosuppression, any potential to sort of see reduced rates of grade 3 neutropenia with this content? Thank you.
Thanks, Eric. I'll start, and then I'll let Dr. Jared comment more on the proof of mechanism. Maybe I'll take the second question first, just because it actually points to the core thesis for our investment in the MDM2 program, which is creating or allowing us to create a larger therapeutic index that will allow us to finally interrogate this mechanism in the clinic fully. As you heard us say it in the past, the rationale is really based on cancer genetics. If you look at data that's been published over the years and that has fueled all the drug development programs in this pathway, we know that p53 is wild type in more than 50% of cancers.
In those type of cancers, both liquid and solid tumors, if you delete MDM2, if you genetically delete MDM2 with genetic tools that we have, preclinically, you see a high dependency of these tumors, on those pathway or in the presence or absence of MDM2. That basically genetic removal of MDM2 leads to rapid apoptotic response in those tumors that have p53 wild type. If you look on one of those plots that have been generated, it's probably one of the most impressive sensitivity plots that we've seen in cancer genetics.
Now, I think the field has made the assumption, that has been true for many programs in oncology in the past 20 years, since we started to understand, you know, the human genome and the relationship with the human proteome. We made the assumption that inhibiting MDM2 will lead to that kind of response. What we've learned is actually that's not true. We've learned that if you inhibit MDM2 p53 interaction, you are able to actually stabilize p53, but not fully, and mostly because the inhibition of that interaction leads to a upregulation of MDM2. As you're inhibiting the interaction, you see more MDM2 that gets produced, and the small molecule has a hard time fighting that.
You end up having to dose longer, and that creates a very narrow window, if at all, between your antitumor effect and your impact on bone marrow-derived cells, which are one of the most sensitive cell types to MDM2, absence. What we have been able to do with degrading MDM2 is to remove the protein quickly, and we've seen the first two to four hours a rapid commitment to apoptosis. That leads cancer cells that are sensitive to this mechanism to die quickly while healthy cells. While they might have an initial impact, have time to recover between the first and the second dose. That creates in tumors that are highly sensitive, I wanna be sure that's clear, a therapeutic index that no small molecule has seen before in our hands.
What we're talking about, and, you know, I think Jared commented on it before, and this is work that we're still doing. Obviously, I think it's not fair to assume that all p53 wild type tumors will have this wider therapeutic index. I think that's scientifically not true based on our experimentation. We have found subsets of tumor types within the p53 wild type larger set that are highly sensitive, and the ones that are highly sensitive have this increased therapeutic index. Our hypothesis going into the clinic is that we'll have a drug that is well-tolerated while it's being effective in the patient populations that are sensitive to it.
The only indications that we have shared so far where we've seen this high sensitivity are AML, including the patients that are refractory to the existing line therapy. That's an exciting area for us to explore. Lymphomas and some solid tumors that we will be disclosing later in the year or as we go into the expansion cohort. Maybe I'll let Jared comment more on what the proof of mechanism is gonna look like and whether I think your question was also whether it's gonna be different between liquid and solid tumors.
Yeah. Maybe if I can just quickly comment also on the question around myelosuppression. You know, the fact that we have this unique mechanism of action that Nel laid out allows us to dose infrequently, given the drug is an IV infusion once every 3 weeks. That infrequent dosing, we think, is going to give us this unique therapeutic index that will allow us to mitigate myelosuppression by allowing plenty of time for normal cells in the marrow to recover in between doses. You know, coming back to proof of mechanism, you know, our aim for showing proof of mechanism, at least this year, is to focus on impacting the MDM2-p53 pathway in peripheral blood mononuclear cells, which we can do essentially, you know, in all of the patients on the study.
You know, we've done this with our prior programs, 413, 333, looking at impact on the targeted PBMC and where available in tumor as well. You know, here I think in the MDM2 phase 1 trial, the initial focus will be PBMC. Then I think when there is tumor available for biopsy or once we're in RMB, where we're treating high-grade myeloid malignancies, including AML, we may have more opportunities there to also show impact on the pathway in malignant cells, including leukemia.
The next question comes from Eliana Merle with UBS. Please go ahead.
Hi, this is Jasmine on the line for Ellie. Thanks so much for taking our question. You've been mentioning your work in molecular glue, so we just have a couple questions there. First, what's your perspective on the ability of molecular glues to be selective for a single target protein as you think about target selection? Second, non-Cereblon-based glues, is this something you think could be feasible over the next few years, or is this more a longer-term focus for you? Thanks.
Thank you for the question. It's a great question 'cause it allows us to talk about, I think, one of the key differentiator for this company, which has always been to go after hard problems. As you've heard us, and I know your team has paid a lot of attention to what we said in the past on this, on this particular topic. We've said that we are using molecular glues to go after problems that heterobifunctional degraders cannot solve. Maybe just to step back, what are heterobifunctional degraders solving for? They're solving for undrugged or poorly drugged targets where you have inability to bind to that particular disease-causing proteins. We've shown that you can go after transcription factors, scaffolding proteins, et cetera.
Again, there's plenty of targets out there that obviously heterobifunctional degraders can solve meaningful clinical problems. There are also many validated targets in oncology and immunology, in rare disease, in cardiovascular, in CNS, where you don't have an opportunity to find discrete binders to those proteins, mostly because those are, let's say, disordered proteins or difficult to ligand proteins. You either choose not to go after them, or you choose to build capabilities to go after them. We chose, again, the hardest part, which is, you know, developing technologies to go after them. We take an E3 ligase-agnostic approach. Yes, the answer to your second question is yes, there will be molecular glues that aren't new cereblon.
In fact, I think there are already examples out there in the literature pointing to that, those possibilities. We take, as I've always said in the past, a translational medicine approach. We think about what are the clinical problems we're trying to solve for, and what are the molecular mechanism that will enable us to do that. I have to give, again, kudos to our team, you know, led by Juliet and others in our platform team that have uncovered actually a whole new series of proteins that we can go after using a completely new background, motifs that we can engage with an E3 ligase and with some molecular designs that we made.
It turns out that these proteins that we've already identified, there are multiple, are key undrugged, unligandable proteins, many of whom are in immunology and some are in oncology. I think it's unlikely that we will be disclosing the molecular mechanism because we feel this could be, you know, the beginning of a completely new area of molecular glue. I would kind of look back at when the IMiD and Cereblon were discovered and how many targets have then subsequently been drugged by that interaction. I suspect that what we've uncovered here could lead to that type of discoveries. We're just at the beginning. We're very excited. I think we have our first program that is already in lead optimization driving towards a development candidate.
you know, we're, you know, we'll continue to talk about this, and as the program moves into development, we'll talk about what target it is, but probably unlikely that we'll be disclosing the molecular mechanism or even the E3 ligase.
The next question comes from Bradley Canino with Stifel. Please go ahead.
Good morning, and thanks for the updates. Two questions from me. First, Nello, I guess with the recent announcement for the departure of the global head of R&D at Sanofi, John Reed, and the company searching for a new successor, I'd just like to hear your optimism that KT-474 has enough, I guess, advocates or champions, so to speak, at Sanofi, so that the program will continue to be prioritized even with any future shakeup of portfolio strategies and initiatives from a new R&D head. For Jared, on KT-413, can you remind us the type of DLBCL patients that are being recruited in terms of likely prior therapies? Are these patients post-Polivy, CAR T, bispecifics, et cetera?
If so, what is your confidence in the ability to recapitulate the preclinical model results in such a heavily appreciated population, particularly with the MYD88 mutation? Thank you.
Great. Brad, that was a perfect question for our colleagues at Sanofi. I will try and answer it, obviously understanding that I cannot speak for them. First, you give me the opportunity to thank John that has been an amazing partner along the way from the beginning, which was when we started to talk about a partnership on KT-474, all the way through his last day. I will say that we've had the fortune to connect with several leaders in the company, without naming names, at the executive level that have continued along the way to be excited, to be helpful, to be supportive of the partnership and understanding and appreciating the value of 474.
Again, speaking for Kymera, I have no doubt that the molecule is in the right hands and there is the excitement, commitment and appreciation of what this molecule can do for, to be honest, millions of patients out there. I expect that there will be no change of priorities or commitments going forward. Regarding the second question, again, I'll leave it to Jared to answer.
Yeah. Thanks, Brad. You know, on the KT-413 study, you know, we are recruiting B-cell malignancies, including DLBCL, and including, you know, patients with MYD88 mutations. You know, as you noted, you know, many of the patients will have had prior therapies. We anticipate that many of these patients, you know, will have had, and especially if they had DLBCL, you know, perhaps prior CAR T, if they were eligible, maybe prior Polivy or even Tafasitamab. I think what's important here to note is our unique mechanism of action. You know, the fact that with KT-413, we're drugging IRAK4, and we're also drugging the IRF4 pathway with the IMiD activity, it makes this a unique mechanism of action.
We don't expect there to be cross resistance, you know, to these other therapeutics, like cellular therapies or like bispecifics. I think we're confident that with the right patient population, especially those with the MYD88 mutation, sort of regardless of prior therapies or how many prior therapies, we still expect that the mechanism of action here should yield, you know, significant anti-tumor responses with four one three.
The next question comes from Vikram Purohit with Morgan Stanley. Please go ahead.
Hi, good morning. Thanks for taking our questions. We had two, one on KT-474, one on your STAT3 program. Going back to your relationship with Sanofi, just wondering if you could provide some more color on what are some of the considerations that you're thinking through with Sanofi when you explore indications beyond HS and AD for phase 2 development for this molecule? For STAT3, I was just curious to get an update on where efforts stand with evaluating a STAT3 degrader in autoimmune and fibrotic conditions, and when we could expect to hear an update on that effort. Thanks.
Thanks, Vikram. First question is, if you actually look historically at how we developed the molecule and this program, you know, there is a slide that actually we haven't changed in a couple of years in our deck, which are clinical opportunities that could be realized by targeting the IL-1R/TLR pathway. We've, you know, usually shared these kind of TH1, TH17 driven diseases like HS, like RA, like lupus, IBD, and others. We've shown the TH2 type diseases, you know, like AD, asthma, COPD and others. We said that, you know, with validation of this mechanism in some of those diseases representing kind of these two slightly kind of differentiated ways to thinking about immunology, then you can think about expanding further.
I believe that high level, both, you know, Sanofi and Kymera are looking at the opportunity in that way. Now, practically, what we have prioritized, as you know, is HS and AD, and we've been fortunate, I have to say, that even with small patient numbers in a study design land and even study design generally that was not set up to look for clinical activity, we've been fortunate to have seen really early validation of this mechanism in both HS, again, TH1, TH17, AD, TH2 type inflammation. You know, obviously we look for further validation in a placebo-controlled randomized phase 2 study. We do the study with high degree of confidence and expectations based on the data we've seen so far.
I, the conversations that obviously are happening and will continue to happen is, you know, what are the next type of indications that we will go after? What I will say that I can't, again, speak for the collaboration in terms of particular indication. What I will say from our perspective, and even from my perspective, there is such a high unmet need in many of those indications where there are really no small molecules with a activity and safety profile that we can match with our IRF4 degrader. Obviously, I'll start with AD. I don't think there is one. Going to HS, I don't think there is one. I go to IBD, large unmet need. I don't believe there is a good molecule now that can really help patients go through a horrible experience.
I look at RA, which is commercially quite crowded, but again, I think there is an opportunity for a well-tolerated active drug. I look at lupus, which is an unsolved disease. I look on the other side on the TH2 type inflammation. Again, there are really no good small molecules in those indications that I mentioned earlier, like asthma, COPD, pruritus and others. I think we have a large opportunity. I think we have to be rational with how we select the opportunities, and we have to be data-driven. I suspect we will be updating, you know, you all on as we make those determinations.
Clearly, initial proof of concept in a randomized study in phase two will be the drivers of further selection downstream of these initial two diseases. You know, I think we have a unique opportunity here in the landscape to help millions of patients, as I said earlier. Let's not forget, and I don't wanna spend a whole, you know, 20 minutes on this, let's not forget that the unique value proposition of KT474 is that this is a systemic anti-inflammatory molecule with broad anti-inflammatory effect, with local anti-inflammatory also effect. The molecule has demonstrated systemic anti-inflammatory efficacy, as measured by also biomarkers across a wide variety of downstream cytokines and chemokines.
It's also shown, as you know, a preferred distribution in tissues, especially as you've seen in skin, as well as we know, an anti-TLR activation, in anti-inflammatory effect. Has this really unique combination of both molecular properties as well as pathway engagement properties that makes a very unique molecule in the landscape. We're excited to continue to develop the molecule to explore further, you know, how many other diseases we can potentially develop it in. The other question.
STAT3?
Yeah, the STAT3, yes. STAT3, as I said, you know, relatively recently that that is an area that we are continuing to do work. you know, we plan to be able to update further later in the year. I can't maybe share more than what we said recently.
The next question comes from Michael Schmidt with Guggenheim. Please go ahead.
Good morning. This is Paul on for Michael. Thanks for taking our question. We just have two on the MDM2 program. I guess first on the dosing strategy, is there potential in the study to evaluate alternative dosing intervals that could potentially optimize the clinical profile in 253 between solid versus liquid tumors, given possible differences in PK/PD in those settings? Or are you fairly comfortable with the every three week dosing across all tumor types? Secondly, obviously, you're just starting monotherapy dose escalation, but how are you currently thinking about the strategy for 253 in combinations? It seems like, you know, coming out of ASH, a bit of a class combination might be on the table for AML. Just wanted to get your thoughts there. Thank you.
Thanks. That's a great question. Maybe, Jared, do you wanna take them?
Sure. Maybe starting with the dosing schedule. You know, as you stated up front, you know, we are going in with a once every 3 week IV infusion, which we think, you know, has the potential to be highly active based on our preclinical models, but also has the ability to mitigate myelosuppression. We do have flexibility based on our preclinical tox studies to dose less frequently, even every 2 weeks, if we thought that was necessary. Your question is an interesting one, you know, could we ever envision a situation where you might have 1 schedule for liquid tumors and 1 for solid tumors? That's always a possibility. I think we do have that flexibility.
Our plan, though, right now is our expectation rather, is that every 3-week dosing will be, you know, active at both liquid and solid tumors. At least we do have that flexibility to dose less frequently if we think it's, you know, necessary, you know, from a pharmacodynamic standpoint and if we think that it would be tolerated from a safety standpoint. In terms of combinations, you know, that's obviously a very good question as well. You mentioned Venetoclax.
You know, we've been doing some, I think, very interesting preclinical work, looking at our drug, you know, in both Venetoclax resistant and sensitive AML models, and we can see activity of our MDM2 degrader as a monotherapy, even in Venetoclax-resistant models, which is very encouraging for the possibility of our seeing activity with our drug in AML patients who have previously seen Venetoclax. More and more patients are getting Venetoclax either in the upfront setting or in the relapse refractory setting. We've also seen some very encouraging data with our drug combined with Venetoclax, either in Venetoclax-resistant or Venetoclax-sensitive AML. You know, we will have the opportunity to look at that combination.
I think that will be probably one of the combinations that we do prioritize once we're, you know, through with monotherapy dose escalation, have a good sense for the safety profile, and then start to look at combinations that we can use for development in the future. I think I wanna be clear that I think we do feel that the activity we're seeing preclinically is such that we believe that there's a substantial opportunity for MDM2 degrader as a monotherapy, you know, in both liquid tumors and solid tumors. I think these combination approaches always give us even additional development opportunities that we wanna take advantage of.
The next question comes from Marc Frahm with Cowen. Please go ahead.
Hi. Thanks for taking my question. Maybe just following up on MDM2, some of the dosing questions. Just what is the kind of target degradation profile you're aiming for in terms of kind of % reduction? I think of, you know, given all you're saying about kind of this therapeutic window, just as at least as important is, you know, the duration of that degradation.
Mar, thanks for the great question. What we've seen preclinically is that the degradation above 80%, 80%, 90% for really a short period of time, even 2 to 4 hours, is enough to lead to this really profound apoptotic response. That's why actually we designed this type of drug with this type of dosing paradigm where we dose it IV, where we are able to reach this really high, quick, high Cmax initially that leads to quick downregulation and then clearance of the drug relatively quickly so that we can optimize on degradation of the target in tissues that are, you know, highly sensitive so that we can capture maximal antitumor effect, and then we can kind of take the time for healthy cells to recover before we dose again.
Actually monitoring the MDM2 degradation and pathway engagement is a large piece of work that the team here has done, given actually the complexity of the pathway and also how to measure MDM2 levels, which are initially already relatively low. It's actually also some really innovative science that we've done here at Kymera to monitor and to understand both target engagement in terms of MDM2 degradation, but also downstream biomarker readout, which for us are just as critical, right? Seeing the right biomarker either increase or decrease downstream is what really drives that kind of antitumor effect. I think as a part of that proof of mechanism data that Jared was mentioning, that we'll share hopefully this year, at least obviously that's the goal and plan, we'll obviously have that type of information.
You know, depth and of target engagement, time of target engagement, and also safety that will go with that.
The next question is from Mike Kratky with SVB Securities. Please go ahead.
Hi, everyone. Thanks for taking our questions. For KT-413, can you talk a little bit about the potential next steps from a clinical development standpoint and how you could aim to pursue a potential accelerated regular path forward here? Just beyond that, I mean, how should investors think about the potential sequencing of indications you're going to be pursuing? Thanks.
Thanks, Mike. Jared, do you wanna take that one?
Yeah, sure. Yeah, yeah, thanks for that question. I mean, clearly for us with KT-413, you know, the MYD88-mutated B-cell malignancies are front and center in terms of development. There, I think we see, you know, at least three potential opportunities. DLBCL, of course, where the mutation is seen in about 25%-30% of patients, which represents a substantial opportunity. We're talking about, you know, prevalence numbers that are in the thousands.
We think also, you know, Waldenstrom's macroglobulinemia is another very interesting opportunity since about 90%-95% of those patients have this mutation and is their high unmet need, you know, both in the relapsed refractory setting after BTK inhibitors, but even upfront, you know, to find novel therapies that can achieve complete responses rather than just partial responses. Finally, you know, primary CNS lymphoma, where this mutation is seen in about 80% of patients, also a very, very high unmet need for that population, albeit a smaller population than DLBCL. I think when we think about this drug, we have to think about the unique positioning here, especially within DLBCL. You know, in DLBCL, there really is no therapeutic that is aimed at a genetically defined subset of DLBCL.
As one knows, you know, in this, in this disease, you know, the genetics of the disease now is really more important than the histology. More and more the trend is really defining, you know, genetic populations based on their outcome, their survival to frontline R-CHOP or other frontline therapies, and really trying to hone in on genetic subtypes, what the prognosis is of those subtypes, and then finding new drugs, you know, that can take advantage of vulnerabilities in patients with those different genetic abnormalities. I think 413 has the potential to be the first drug, you know, for MYD88 mutated lymphoma. This mutation confers actually a worse survival outcome after frontline R-CHOP. There really is a high unmet need for these patients.
Having a drug that really for the first time would be going after a genetically defined subset of DLBCL, we think positions this uniquely, not just therapeutically, but also from a regulatory standpoint. We know there are precedents, you know, from FDA for granting accelerated approval for drugs that are active, especially in genetically defined subsets within oncology. We do think that there is a real accelerated approval opportunity here in relapse refractory MYD88 mutated DLBCL, with a potential rapid development path, you know, following phase 1B that could even just consist of an open label phase 2 study that could lead to accelerated approval. That is a possibility, we think, for DLBCL. That I think is really the first near-term opportunity for developing this drug in MYD88 mutated malignancies.
With that being said, we think there could be also rapid accelerated approval opportunities in second line Waldenstrom's if we have, you know, transformative activity, you know, in patients who have progressed after prior BTK inhibitors. That could also lead to a rapid development path. Certainly in primary CNS lymphoma, where there's a very high unmet need and very few drugs at all being developed in that space, I think there too, we see another potential rapid development opportunity.
The next question comes from Derek Archila with Wells Fargo. Please go ahead.
Hi, this is Yvonne for Derek. Thanks for taking our questions. Two quick ones from us. First, on the STAT3 program, what kind of data update can we expect this year? The second question, from a TPD perspective, given you are developing glues, heterobifunctional degrader, and tissue-specific ligases, is there any plan to look at extracellular proteins?
Great. Thanks. Great question. Maybe I'll start with the second one. You know, we always look at what is the unmet need and the problem that we're trying to solve. I personally feel that, you know, 80% of the proteome, roughly, hopefully, I don't have the number wrong, is intracellular. We have really great tools today to drug extracellular proteins. The real opportunity for extracellular proteins is if you have, if you're able to compete with biologics by, you know, developing molecules that you can be kind of as infrequently dosing as the antibodies do, or more, or if you have an oral degrader or extracellular protein. I think there are clearly opportunities there.
At this stage of the company, I don't think that's an area where there is the highest opportunity and risk reward scenario at this stage. You know, as we continue to grow the company, there might be opportunities also to go into that space. We actually looked at that a couple of years ago and decided not to go into that particular space. With regards to your first question on STAT3, as we said, you know, in the press release and also in the remarks that we made earlier, you know, the goal this year is to dose patients at exposures and degradation profiles that we expect to be therapeutically relevant. We also hope and expect and are driving towards recruiting patients at those doses where we expect to see clinical activity.
Meaning these are tumor types that we've seen frequently pre-clinically to be sensitive to STAT3 degradation. What we expect to hopefully share this year is, are we seeing an anti-tumor response in patients that are, again, theoretically sensitive to STAT3 degradation, at the right dose and at the right again, length of dosing. It will be what we call an initial proof of concept. It will be, is that STAT3 degradation in the right patients elicit an anti-tumor response.
As a reminder, please limit yourself to one question in the interest of time. The next question comes from Kalpit Patel with B. Riley. Please go ahead.
Good morning, this is Andy on for Kalpit. Thank you for taking questions. Some from us on KT-413. I understand that you're looking for meaningful clinical activity in dose levels 3 and 4, but have you observed any evidence of anti-tumor activity so far, even if it's just stable disease?
Second, you noted needing to maintain target knockdown for 72 hours, and we're seeing robust target knockdown in plasma of the target proteins, Ikaros and Aiolos, but they're rebounding, to or above the baseline levels near the end of the dosing interval. Do you anticipate tweaking the dosing frequency, perhaps from every 3 weeks to every 2 weeks to ensure adequate depletion of target proteins at all times? Is sustained depletion actually needed based on your preclinical models for meaningful antitumor activity?
Great. I think these were three questions, but okay, the first one was, I forgot already.
Antitumor activity, that's fine.
Yeah. Obviously, what we said, we expect to share data at a scientific meeting or in an event in which we decide to share data, and we decided not to give the kind of updates along the way. I guess I'm not gonna answer that question. On the second one, which is second and third, are good questions. First, I wanna remind everybody that, and there are slides on our website, that actually the degradation profile that we believe, at least we know preclinically, and we believe will translate clinically into antitumor effect and good safety, is the one where we degrade these proteins for about 72 hours, and then we need to see full rebound of those proteins before we dose again.
Actually, the fact that by week 3, we see full recovery of these proteins not only is good, but it's necessary, at least based on preclinical data, to avoid seeing neutropenia and other safety events that come with IMiD. We do have flexibility to change dosing paradigm if we need to. Right now we're really asking the biological question of, is the degradation profile that we've seen preclinically to be the most active in MYD88 mutant tumors out of all the other agents that we've tested, does that translate in similar levels of antitumor activities in the clinic? I think only after we kind of answer this question, we can start talking about, is there an opportunity to tweak the dosing one way or the other.
The next question is from Zhiyuan Xu with Berenberg. Please go ahead.
Good morning. Thanks, Rick, for taking the question. I have a quick one. On your updated corporate deck, you disclosed some of the discovery programs will be around IL-4, IL-13 pathway. I thought that's interesting. Can you talk about the sort of the potential advantage for using a protein degradation approach versus a biologic approach, also talk about the unmet medical need in associated in those diseases?
Yeah. Thanks, Zhi. That's a great question. We only have a couple of minutes. I could spend a couple of hours on this, but just very quickly. We built the company with working in pathways where there is high validation, where we believe protein degradation can unlock the biology better, fully or for sure with a better technology. You know, I think I'm not gonna reveal anything new that, you know, an antibody for that particular pathway is probably going to be the largest drug in the market in the next few years. It's been approved in AD and in other, I believe, 4 other indications.
We believe that there is both an opportunity to develop an oral drug in that pathway, and actually, we believe there is an opportunity to develop a better drug in that pathway, meaning a drug with a better efficacy profile. You know, I don't have to do the math on the opportunities, but obviously, if you look at Dupixent in AD and the penetration, and how much money that drug makes a year, you can imagine an oral small molecule that can serve that patient population in a better way, what are the opportunities there? That's really what we're trying to solve for, help patients be treated with the best drug, which we believe is what we're working on.
The next question comes from Tymour Ivannikov with Raymond James. Please go ahead.
Yeah, thank you for the question. Just for your KT-474, just trying to understand the strategy for the studies a little better. I think HS study is starting first. Do you think there will be an overlap in time, you know, between those two studies? Just want to make sure that, you know, there is no gatekeeping factors in HS study like safety or efficacy data that Sanofi may want to see before starting the AD study.
That's a great question. I mean, I'll answer short because we're kind of out of time. From our understanding, there's high likelihood that there will be an overlap between the studies. I don't believe there are data expectations that will inform necessarily, you know, when and how the second study will start. Again, this is, we will talk more about the specifics as the studies initiate. That's, you know, those are questions that Sanofi will have a better answer for.
The next question comes from Geoff Meacham with Bank of America. Please go ahead.
Hi. Thanks for taking the question. This is Joe on for Geoff. We've talked a bit about the collaboration with Sanofi so far. I was wondering, how are you thinking about additional partnerships and collaborations in the near term? You called them out in your press release as a strategic objective for the year. Can you provide, like, a little bit of color on, like, what types of partnerships you may be pursuing?
Yeah, it's a great question. Again, I'll try to be brief. There is two ways to think about strategic partnerships. One is what are technologies, even assets, or early tools that will enable Kymera to grow better, faster? Are there instead companies that we can partner some of our programs or our technology to create more value together versus independently, developing or commercialized drugs? I will say that those both areas are areas that we always think about, and I don't have any specifics to update right now, but obviously a company like Kymera with the expertise that we build, there is way more that we could do than what we're doing. The question is how do you get that, how do you solve that right?
I think at this point, I don't have any specific update on it.
The last question today comes from Kelly Shi with Jefferies. Please go ahead.
Okay. Congrats. This is John Tan on for Kelly. Thanks for taking our questions. I have a question on K four. Can you provide more color on how you will work with Sanofi going forward? Do you anticipate continuing to engage with them over the course of phase two initiation and maybe expanding the collaboration to other of your immunology programs that's coming up? Thank you.
I mean, we had the fortune to have a really good partner with Sanofi along the way. I will continue to say that because it's true. We've worked very closely with them when we were running our program, the program, and we already are working very closely as now they're operationally and financially responsible for the program. I would also remind everybody, we have an opt-in mechanism before phase 3, so we're fully vested in the success of the program. Not only we have committees in place to obviously follow progress, but we actually have, you know, almost, you know, weekly or biweekly interactions with them to make sure that we both give our best for the success of this drug. I have no doubt that that will continue to be the case.
I think there was a second question about other collaborations maybe. I can't really comment on that. For now, the rest of our pipeline, that we've talked about is our own. That's for now what we're doing and continuing to generate value. We're well financed, as you see, to continue to advance these programs and create values. That's our goal at this point.
This concludes the question and answer session. I would like to turn the conference back over to Nello for any closing remarks.
Yeah. First, I would like to thank everybody for listening to our call, for the engaging Q&A. You all had great questions. Hopefully we did our best to answer them in the most comprehensive way possible. You know, we're excited about what we've done, but, you know, we've always had aspire to do better year by year. We hope and expect that 2023 will be even more exciting than 2022. Encourage everybody to follow us and reach out to us if you have further questions. You know, we always wait for amazing data to speak for us. We're excited to see how all these programs unfold and help patients in a wide variety of indications. Thanks again for the time. Apologies for being a bit late, and have a good rest of the day.
The conference has now concluded. Thank You for attending today's presentation. You may now disconnect.