Q2 2024 Kymera Therapeutics Inc Earnings Call

Speaker Change: Good day and welcome to the Kymera Therapeutics 2nd Quarter 2024 Results Call.

Unknown Executive: The second quarter, 2024 results 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.

Operator: 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 your questions, please press star, then two. Please note that this event is being recorded. I would now like to turn the conference over to Justine Koenigsberg, Head of Investor Relations. Please go ahead.

Speaker Change: 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.

Unknown Executive: After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star or N1 on your telephone keypad. To withdraw your questions, please press star or N2. Please note, this event is being recorded.

Speaker Change: To ask a question, you may press star then 1 on your telephone keypad.

Speaker Change: To withdraw your questions, please press star then 2.

Justine Koenigsberg: I would now like to turn the conference over to Justine Koenigsberg, Head of Investor Relations. Please go ahead.

Speaker Change: Please note this event is being recorded. I would now like to turn the conference over to Justine Koenigsberg, Head of Investor Relations. Please go ahead.

Justine Koenigsberg: Good morning, and welcome to Kymera's quarterly update call. Joining me this morning are Nello Mainolfi, President and CEO, Jared Gollob, our Chief Medical Officer, and Bruce Jacobs, our Chief Financial Officer.

Nello Mainolfi: Good morning and welcome to Cameras quarterly update call.

Nello Mainolfi: Joining me this morning are Nello Mainolfi, President and CEO, Jared Gollob, our Chief Medical Officer, and Bruce Jacobs, our Chief Financial Officer. Following our prepared remarks, we will open the call to questions. In order to have enough time to address everyone's questions, please limit your questions to one and a relevant follow-up.

Justine Koenigsberg: Good morning and welcome to Kymera's quarterly update call. Joining me this morning are Nello Mainolfi, President and CEO , Jared Gollob, our Chief Medical Officer, and Bruce Jacobs, our Chief Financial Officer.

Justine Koenigsberg: Following our prepared remarks, we will open the call to questions. In order to have enough time to address everyone's questions, please limit your questions to one and a relevant follow-up. Before we begin, I would like to remind you that today's discussion will include forward-looking statements about our future expectations, plans, and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10Q filed with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call. With that, I'll now turn the call over to Nello.

Speaker Change: Following our prepared remarks, we will open the call to questions. In order to have enough time to address everyone's questions, please limit your questions to one and a relevant follow-up.

Nello Mainolfi: Before we begin, I would like to remind you that today's discussion will include forward-looking statements about our future expectations, plans, and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10-Q files with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call.

Speaker Change: Before we begin, I would like to remind you that today's discussion will include forward-looking statements about our future expectations, plans, and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected.

Nello Mainolfi: With that, I'll now turn the call over to Nello. Thank you, Justine, and good morning. Every day, we take important steps towards our goal of building a fully integrated global biotechnology company, demonstrating our ability to consistently deliver first-investing class programs that target validated pathways with the potential to address large underserved disease areas. The progress we've made over the past quarter highlights our novel approach to drug development that emphasizes innovative molecular design. In addition, fidelity of translation from preclinical settings to the clinic, data-driven development strategies, and the commitment to maximize the impact of our science to improve patients' lives.

Nello Mainolfi: Thank you, Justine, and good morning. Every day we take important steps towards our goal of building a fully integrated global biotechnology company, demonstrating our ability to consistently deliver first and best-in-class programs that target validated pathways with the potential to address large, underserved disease areas. The progress we've made over the past quarter highlights our novel approach to drug development that emphasizes innovative molecular design, fidelity of translation from preclinical settings to the clinic, data-driven development strategies, and the commitment to maximize the impact of our science to improve patient safety.

Speaker Change: Thank you, Justine, and good morning.

Nello Mainolfi: Our unique approach has led to the development of a pipeline of exciting, greater medicines with the potential to change treatment paradigms for multiple diseases, as evident in our recent updates and presentations at major medical congresses and publication in peer-review journals over the past months. Our statistics program, for example, was featured at both APS and DDW, MDM-2 at ASCO, and STAT-3 at AACR and EHA. In addition, we published data from our non-interventional trial evaluating a record-expression in patients with H.S. in the journal of investigating dermatology.

Nello Mainolfi: Our unique approach has led to the development of a pipeline of exciting degrader medicines with the potential to change treatment paradigms for multiple diseases, as evident in our recent updates and presentations at major medical congresses and publications in peer-reviewed journals over the past few months. Our Statistics program, for example, was featured at both ATS and DDW.

Speaker Change: Our unique approach has led to the development of a pipeline of exciting degrader medicines with the potential to change treatment paradigms for multiple diseases, as evident in our recent updates and presentations at major medical congresses and publications in peer-reviewed journals over the past few months.

Nello Mainolfi: MDM II at ASCO and Step 3 at AACR and EHA. In addition, we published data from our non-interventional trial evaluating ARAC4 expression in patients with HS in the Journal of Investigated Traumatology. The findings we've shared across these forums highlight the differentiated profiles of our programs. Before handing the call over to Jared for a more detailed overview, I wanted to highlight two important updates in our immunology pipeline. I will start with our IRF4 program.

Nello Mainolfi: The findings we've shared across these forums highlight the differentiated profiles of our programs. Before handing the call over to Jared for a more detailed overview, I wanted to highlight two important updates in our immunology pipeline.

Nello Mainolfi: I will start with our ARAC4 program. As a reminder, KC474, our ARAC4D grader partnered with Sanifis, the first header of bifunctional molecule to have been posed in healthy volunteers and then H.S.D. patients. We have shown in our phase one studies deep degradation of ARAC4 in blood and skin, resulting in impact on biomarkers of inflammation both systemically and in the skin of H.S.D. patients. KT-474 has likely been the most studied degree in the Phase I setting. Last month, we announced after an interim review of safety and efficacy of the ongoing HSNED Phase II trials that some of the intents to expand both of these trials, with a goal to accelerate the path of registration of Phase III studies for both HSNED.

Nello Mainolfi: As a reminder, KT474, our IRF4 degrader, partnered with Sanofi, was the first hetero-bifunctional molecule to have been dosed in healthy volunteers and then HF and AP patients. We have shown in our Phase I studies deep degradation of IRF-4 in blood and skin, resulting in impact on biomarkers of inflammation, both systemically and in the skin, in HS and AD patients. This robust PD profile has resulted in clinical benefits measured by easy and prorated scores in AD and high score and pain in HD.

Speaker Change: I will start with our IRF4 program. As a reminder, KT474, our IRF4 degrader, partnered with Sanofis, the first hetero-bifunctional molecule to have been dosed in healthy volunteers and then HF and AD patients.

Speaker Change: This robust PD profile has resulted in clinical benefits measured by easy and prorated scores in AD and high score and pain in HS.

Nello Mainolfi: KT474 is likely to be the most studied degrader in phase one. Last month, we announced, after an interim review of safety and efficacy of the ongoing HS and AD Phase 2 trials, that Sanofi intends to expand both of these trials with a goal to accelerate the path to registrational Phase 3 studies for both HS and AD. The impact of these expansions effectively allows us to transition seamlessly into more expansive dose range finding phase two studies. As a result, while the modified Phase 2 trials will be larger and extended, the expectation is that this will enable a direct transition into phase 3 more quickly than anticipated.

Nello Mainolfi: The impact of these expansions effectively allows us to transition seamlessly into more expansive dose range-finding Phase II studies. As a result, while the modified Phase II trials will be larger and extended, the expectation is that this will enable a direct transition into Phase III more quickly than anticipated.

Speaker Change: The impact of these expansions effectively allows us to transition seamlessly into more expansive dose range finding phase 2 studies.

Speaker Change: As a result, while the modified Phase II trials will be larger and extended, the expectation is that this will enable a direct transition into Phase III more quickly than anticipated.

Nello Mainolfi: Staying with immunology, we've been talking about the concept of oral degraders with biologics like Actili, a unique body improvisation for Canera's platform in this attractive therapeutic area. Our statistics program best exemplifies this concept. Duploma is the drug that has transformed the lives of almost a million patients with CH2 diseases, and in doing so has become, with sales that are projected to reach 20 billion, a mega blockbuster and one of the largest drugs in this industry. A Canera with developed an oral degrader death by targeting STAT-6, the selective transcription factor of the IL-413 pathway, is able to block the pathway in a similar or superior way.

Nello Mainolfi: Staying with immunology, we've been talking about the concept of oral degraders with biologics-like activity, a unique value proposition for Kynera's platform in this attractive therapeutic. A statics program best exemplifies this concept. Dupilumab is the drug that has transformed the lives of almost a million patients with Th2 diseases. And in doing so, it has become, with sales that are projected to reach 20 billion, a mega blockbuster, and one of the largest drugs in this industry.

Speaker Change: Dupilumab is the drug that has transformed the lives of almost a million patients with Th2 diseases.

Speaker Change: And in doing so has become, with sales that are projected to reach 20 billion, a mega blockbuster and one of the largest drugs in this industry.

Nello Mainolfi: At Chimera, we've developed an oral degrader that, by targeting STAT6, the selective transcription factor of the IL-413 pathway, is able to block the pathway in a similar or superior way. In fact, we've shown in preclinical studies that an orally active picomolar STAT6 degrader, KT621, is more potent than dupilumab at blocking Th2 signaling in cell systems and Overall, the preclinical data generated to date demonstrate the opportunity for KT621, with the best in pathway potential, given its dupilumab-like activity and the convenience of a neural network.

Nello Mainolfi: In fact, we've shown in preclinical studies that are orally active, picomolar, STAT-6D grader, KT-621, is more potent than Duploma that blocking CH2 signaling in cell systems, and equal or superior, blocking CH2 inflammation in preclinical disease models. Overall, the preclinical data generated to date demonstrates the opportunity for KT-621, with testing pathway potential, given its Duploma like Actili and the convenience of an oral pill. We believe that a paradigm-shifting world drug with this profile has the potential to change how CH2 diseases, such as AD, asthma, COPD, and others, can be treated. Our mission is not only to target the patients that are currently on biologics, but the more than 100 million patients, there are not currently on biologics, and by doing so, we have the potential to change millions of lives around the globe.

Speaker Change: is more potent than dupilumab at blocking Th2 signaling in cell systems and equal or superior at blocking Th2 inflammation in preclinical disease models.

Speaker Change: Overall, the preclinical data generated to date demonstrate the opportunity for KT621.

Speaker Change: with best in pathway potential, given its dupilumab-like activity and the convenience of an oral pill.

Nello Mainolfi: We believe that a paradigm-shifting oral drug with this profile has the potential to change how Th2 diseases, such as AD, asthma, COPD, and others, can be treated. Our mission is not only to target patients that are currently on biologics but the more than 100 million patients that are not currently on biologics. And by doing so, we have the potential to change millions of lives around the globe.

Speaker Change: We believe that a paradigm-shifting oral drug with this profile has the potential to change how Th2 diseases such as AD, asthma, COPD, and others can be treated.

Speaker Change: Our mission is not only to target the patients that are currently on biologics, but the more than 100 million patients that are not currently on biologics. And by doing so, we have the potential to change millions of lives around the globe.

Nello Mainolfi: We're excited to start our KT-621 Phase 1 trial soon.

Nello Mainolfi: We're excited to start our KT621 phase one trial soon. We usually don't comment on the status of all results of ongoing IND enabling studies, but since one of the most frequently asked questions we've received is the current status of the program, I wanted to provide a brief update. I am very happy to say that we have completed all of the IND-enabling studies with no safety findings of any kind. For example, in our GLP toxicology studies, at all doses tested, we did not see any adverse events of any kind.

Nello Mainolfi: We usually don't comment on the status of all results of ongoing IND-nablic studies, but since one of the most frequently asked questions we've received is the current status of the program, I wanted to provide a brief update. Very happy to say that we have completed all of the IND-nablic studies with no safety findings of any kind. Case in point in our GLP toxicology studies at all those tested with the Nazi and adverse events of any time. This is an important milestone for the program for KMER, and hopefully for millions of patients in the future. With those activities behind us, the next update you should expect will be when we do that first subject.

Speaker Change: We're excited to start our KT621 Phase 1 trial soon. We usually don't comment on the status of all results of ongoing IND-enabling studies, but since one of the most frequently asked questions we receive is the current status of the program, I wanted to provide a brief update.

Speaker Change: Very happy to say that we have completed all of the IND enabling studies with no safety findings of any kind. Case in point, in our GLP toxicology studies, at all doses tested, we did not see any adverse events of any type.

Nello Mainolfi: This is an important milestone for the program, for Kymera, and hopefully for millions of patients in the future. With those activities behind us, the next update you should expect will be when we start the first subject. And, importantly, we look forward to sharing the Phase 1 results in the first half of 2025. I will let Jared share more details on our programs, and then I'll be happy to take questions.

Speaker Change: With those activities behind us, the next update you should expect will be when we dose our first subject. And importantly, we look forward to sharing the Phase I results in the first half of 2025.

Nello Mainolfi: And importantly, we look forward to sharing the Phase 1 results in the first half of 2025.

Jared Gollob: I will let Jared share more details on our programs, and then I'll be happy to ask Jared. Thanks Nello, starting with KT-474. As mentioned, last month we announced Sonofi's decision to expand the ongoing phase two studies in HS&AD following an interim analysis of KT-474 safety and efficacy by an independent data monitoring committee.

Speaker Change: I will let Jared share more details on our programs and then I'll be happy to take questions. Jared?

Jared Gollob: Starting with KT474. As mentioned, last month, we announced Sanofi's decision to expand the ongoing Phase II studies in HS and AD following an interim analysis of KT474 safety and efficacy by an independent data monitoring committee. This exciting development is a great outcome for Kymera and our IRAC-4 program. Importantly, it not only reinforces Sanofi's strong commitment to the program but also provides the potential to inform future registrational trials in a way that should accelerate overall time.

Jared Gollob: Thanks Nello. Starting with KTE 474.

Jared Gollob: As mentioned, last month we announced Sanofi's decision to expand the ongoing Phase 2 studies in HS&AD following an interim analysis of KT474 safety and efficacy by an independent data monitoring committee.

Jared Gollob: This exciting development is a great outcome for Kenara and our Iraq War program. Importantly, it not only reinforces Sonofi's strong commitment to the program, but also to provide the potential to inform future registrational trials in a way that should accelerate overall timelines. The justice step back, the expansion effectively will allow a seamless transition into more expansive dose range finding phase two studies. The goal is really to structure the studies with a necessary regulatory perspective to enable dose selection per phase three. While it will take longer to complete phase two, these two expanded phase two trials in HS&AD will support moving directly to phase three.

Speaker Change: This exciting development is a great outcome for Kymera and our iRac4 program.

Speaker Change: Importantly, it not only reinforces Sanofi's strong commitment to the program, but also provides the potential to inform future registrational trials in a way that should accelerate overall timelines.

Jared Gollob: Just a step back, the expansion effectively will allow a seamless transition into more expansive dose-range-finding phase 2 studies. The goal is really to structure the studies with the necessary regulatory perspective to enable dose selection for phase 3. While it will take longer to complete Phase 2, these two expanded Phase 2 trials in HS and AD will support moving directly to Phase 3. Therefore, the overall timelines for Phase 3, and ultimately for registration, should be meaningfully shorter.

Speaker Change: The goal is really to structure the studies with the necessary regulatory perspective to enable dose selection for phase 3.

Speaker Change: While it will take longer to complete Phase 2, these two expanded Phase 2 trials in HS&AD will support moving directly to Phase 3.

Jared Gollob: Therefore, the overall timelines to phase three and ultimately to registration should be meaningfully shorter. Since the update last month, Sonofi is undertaking activities to update the protocols, and once this work is complete, we expect the new details will be posted on quintrials.gov. Once that happens, we will be able to discuss updated timing related to trial completion and data releases. As a result, we expect the phase two results, which will be shared in their entirety following this expansion, will be beyond our prior guidance of the first half of 2025.

Speaker Change: Therefore, the overall timelines to Phase 3 and ultimately to registration should be meaningfully shorter.

Jared Gollob: Since the update last month, Sanofi is undertaking activities to update the protocols, and once this work is complete, we expect the new details to be posted on ClinTrials.gov. Once that happens, we will be able to discuss updated timing related to trial completion and data releases. As a result, we expect the Phase 2 results, which will be shared in their entirety following this expansion, will be beyond our prior guidance for the first half of 2025.

Speaker Change: Since the update last month, Sanofi is undertaking activities to update the protocols, and once this work is complete, we expect the new details will be posted on clintrials.gov.

Speaker Change: Once that happens, we will be able to discuss updated timing related to trial completion and data releases.

Jared Gollob: As Nella mentioned, KT621, our first in class at 6 to greater, has the potential to be a once daily oral medicine capable of delivering duplomab-legged activity in safety in highly prevalent allergic diseases. We recently presented additional data at the ATS conference that demonstrated activity of KT621 comparable to a saturating dose of the Iowa, Iowa antibody dupilumab in an asthma efficacy model. Including robust inhibition of all the tested cytokines, chemokines, and cell infiltrates involved in TH2 inflammation in asthma. The data also demonstrated reduced disease severity in the lungs after low daily oral doses of KT621 comparable to Duplomab.

Jared Gollob: As Nello mentioned, KTE621, our first-in-class STAT6 degrader, has the potential to be a once-daily oral medicine capable of delivering dupilumab-like activity and safety in highly prevalent allergic diseases. We recently presented additional data at the ATS conference that demonstrated activity of KT621 comparable to a saturating dose of the IL-4 alpha antibody dupilumab in an asthma efficacy model, including robust inhibition of all the tested cytokines, chemokines, and cell infiltrates involved in Th2 inflammation in asthma. The data also demonstrated reduced disease severity in the lungs after low daily oral doses of KT621, comparable to dupilumab.

Speaker Change: We recently presented additional data at the ATS conference that demonstrated activity of KT621 comparable to a saturating dose of the IL-4 alpha antibody dupilumab in an asthma efficacy model.

Speaker Change: The data also demonstrated reduced disease severity in the lungs after low daily oral doses of KT621 comparable to dupilumab.

Jared Gollob: I should also note, as Nella mentioned, that KT621 was well tolerated in our preclinical testing, now in both non-GLP and GLP talk studies, with no adverse events at any doses. We look forward to presenting additional KT621 preclinical data in a poster session next month at EADV, the largest international meeting in Europe for dermatology. We remain on track to commence a phase one single and multiple ascending dose clinical study of KT621 and healthy subjects in the coming months, with data expected in the first half of 2025. We plan to share more details around our development plans for phase one and beyond when we provide additional updates on the program later this year.

Jared Gollob: I should also note, as Nello mentioned, that KT621 was well-tolerated in our preclinical testing, now in both non-GLP and GLP-TOC studies, with no adverse events at any dose. We look forward to presenting additional KT621 preclinical data in a poster session next month at EADV, the largest international meeting in Europe for dermatology. We remain on track to commence a phase one single and multiple ascending dose clinical study of KT621 in healthy subjects in the coming months, with data expected in the first half of 2025. We plan to share more details about our development plans for Phase 1 and beyond when we provide additional updates on the program later this year.

Speaker Change: I should also note, as Nello mentioned, that KT621 was well tolerated in our preclinical testing, now in both non-GLP and GLPTOC studies, with no adverse events at any doses.

Speaker Change: We look forward to presenting additional KT621 preclinical data in a poster session next month at EADV, the largest international meeting in Europe for dermatology.

Speaker Change: We remain on track to commence a Phase I single and multiple ascending dose clinical study of KT621 in healthy subjects in the coming months, with data expected in the first half of 2025.

Speaker Change: We plan to share more details around our development plans for Phase 1 and beyond when we provide additional updates on the program later this year.

Jared Gollob: Founding out our immunology pipeline, we unveiled our first-in-class oral TIC-2 deGrader KT294 at our R&D Day. We have shown that small molecule inhibitors do not block all the scaffolding functions of TIC-2 and therefore are not able to replicate the TIC-2 loss of function profile. In addition, small molecule inhibitors cannot block the catalytic function fully at steady state. The opportunity for this program, with depletion of tick two, is not to just have a drug that is incrementally better than tick two small molecule inhibitors, but to bring to patients an oral, biologic-like pathway blocker, and thereby deliver a best-in-class agent for conditions like IBD, psoriasis, psoriatic arthritis, and lupus, among others.

Jared Gollob: Rounding out our immunology pipeline, we unveiled our first-in-class oral TIC-2 degrader, KT294, at our R&D day. Additionally, we have shown that small molecule inhibitors do not block all the scaffolding functions of TIK2 and therefore are not able to replicate the TIK2 loss of function profile. In addition, small molecule inhibitors cannot block the catalytic function fully at steady state. The opportunity for this program with depletion of TIK2 is not to just have a drug that is incrementally better than TIK2 small molecule inhibitors but to bring to patients an oral, biologic-like pathway blocker and thereby deliver a best-in-class agent for conditions like IBD, psoriasis, ps For this program, we expect to initiate and complete phase one testing in 2025.

Speaker Change: In addition, small molecule inhibitors cannot block the catalytic function fully at steady state.

Jared Gollob: For this program, we expect to initiate and complete phase one testing in 2025.

Speaker Change: For this program, we expect to initiate and complete Phase 1 testing in 2025.

Jared Gollob: In summary, these timelines put us in a position to share phase one data for our two new immunology programs, Stat Six and Tick Two in 2025, which is shaping up to be a very busy and exciting year for Chimera.

Jared Gollob: In summary, these timelines put us in a position to share Phase I data for our two new immunology programs, STAT6 and TIK2, in 2025, which is shaping up to be a very busy and exciting year for Kymera. Due to its differentiated mechanism, KT253 has shown the ability to overcome the MDF2 feedback loop and rapidly induce apoptosis with brief exposures in preclinical studies. This provides an opportunity for an improved efficacy and safety process, including responses in one of two valuable patients with Merkel cell carcinoma and two of two patients with post myeloproliferative neoplasm acute myeloid leukemia at doses that were well tolerated without the traditional hematological toxicity seen with small molecule inhibitors.

Speaker Change: In summary, these timelines put us in a position to share Phase I data for our two new immunology programs, STAT6 and TIK2, in 2025, which is shaping up to be a very busy and exciting year for Kymera.

Jared Gollob: Moving to oncology, this also has been a busy stretch for our two clinical programs, KT253 and KT333, targeting MDM2 and STAT3 respectively. We've recently shared updates demonstrating the disease-modifying impact of these degraders at ASCO and IHA, highlighted by major responses in liquid and solid tumors. In addition to the clinical activity that has been demonstrated, we have been particularly encouraged by tolerability, which has exceeded our expectations in both cases. That has resulted in our ability to escalate to higher dose levels than expected. As a reminder, MDM2 is an oncogenic protein that modulates the most common tumor suppressor, P53.

Speaker Change: We've recently shared updates demonstrating the disease-modifying impact of these degraders at ASCO and EHA, highlighted by major responses in liquid and solid tumors.

Speaker Change: In addition to the clinical activity that has been demonstrated, we have been particularly encouraged by tolerability, which has exceeded our expectations in both cases.

Speaker Change: That has resulted in our ability to escalate to higher dose levels than expected.

Speaker Change: As a reminder, MDM2 is an oncogenic protein that modulates the most common tumor suppressor P53.

Jared Gollob: While small molecule inhibitors have been developed to stabilize and upregulate p53 expression, they have been unable to show meaningful clinical benefits of p53 stabilization with acceptable safety margins. We believe this is likely due to their inability to overcome a feedback loop that increases MDM2 protein levels when p53 is upregulated. Due to its differentiated mechanism, KT253 has shown the ability to overcome the MDM2 feedback loop and rapidly induce apoptosis with brief exposures in preclinical studies. This provides an opportunity for improved efficacy and safety profile. We're encouraged by the data emerging from the KT253 Phase 1 dose escalation trial.

Speaker Change: While small molecule inhibitors have been developed to stabilize and upregulate p53 expression, they have been unable to show meaningful clinical benefits of p53 stabilization with acceptable safety margins.

Speaker Change: Due to its differentiated mechanism, KT253 has shown the ability to overcome the MDF2 feedback loop and rapidly induce apoptosis with brief exposures in preclinical studies.

Speaker Change: This provides an opportunity for an improved efficacy and safety profile.

Jared Gollob: In our ASCO poster in June, we provided a clinical update from 24 patients as of April 9. That update included 16 patients in arm A with solid tumors of lymphomas up to dose level 5, and 8 patients in arm B with high-grade myeloid malignancies up to dose level 3. We demonstrated potent upregulation of P53 pathway biomarkers in signs of anti-tumor activity and multiple tumor types shown to be sensitive from preclinical models. Including responses in one or two valuable patients with Merkel cell carcinoma and two of two patients with post myeloid proliferative neoplasm acute myeloid leukemia.

Speaker Change: In our ASCO poster in June , we provided a clinical update from 24 patients as of April 9th.

Speaker Change: That update included 16 patients in arm A with solid tumors and lymphomas up to dose level 5 and 8 patients in arm B with high-grade myeloid malignancies up to dose level 3.

Speaker Change: including responses in one of two valuable patients with Merkel cell carcinoma and two of two patients with post myeloproliferative neoplasm acute myeloid leukemia at doses that were well tolerated without the traditional hematological toxicity seen with small molecule inhibitors.

Jared Gollob: At doses that were well tolerated without the traditional hematological toxicity seen with small molecule inhibitors. Those escalations in the phase 1 A clinical trial are ongoing, and we expect complete enrollment in the second half of 2024 and subsequently to share the phase 1 A data set in guidance on next steps.

Jared Gollob: Separately, we expect to present our biomarker-based patient selection strategy for the next phase of KT253 development at a medical meeting later this year. In June, we provided a clinical update on our Stat 3 program at the European Hematology Association Annual Meeting. KT333 is a potent, highly selected to greater stat 3 and the first heterobi functional to greater against a historically undrug transcription factor to enter the clinic. Nick. The poster provided a clinical update as of June 3rd from 47 patients enrolled through seven dose levels with a mean of 9.1 doses. We are encouraged by the data generated to date, showing strong target knockdown and blood and tumor, induction of interferon gamma response in blood and tumor, and signs of preliminary clinical efficacy in lymphomas at tolerated doses.

Speaker Change: Separately, we expect to present our biomarker-based patient selection strategy for the next phase of KT253 development at a medical meeting later this year.

Jared Gollob: In June, we provided a clinical update on our STAT III program at the European Hematology Association Annual Meeting. We believe the emerging data in Hodgkin's lymphoma patients are particularly intriguing, with complete responses in two of three heavily pretreated patients who had progressed after prior checkpoint inhibitor therapy and anti-CD30 ADC, enabling subsequent potentially curative stem cell transplants. However, we have seen activity in syngeneic mouse solitumor models in combination with anti-TD1 drugs. This is likely driven by STAT3's immunomodulatory mechanism, which we believe provides an opportunity for combination with anti-PD-1 in both Sabo tumor and Hodgkin's lymphoma patients.

Speaker Change: KT333 is a potent, highly selective degrader of STAT3 and the first heterobifunctional degrader against a historically undrugged transcription factor to enter the clinic.

Speaker Change: The poster provided a clinical update as of June 3rd from 47 patients enrolled through 7 dose levels with a mean of 9.1 doses.

Speaker Change: We are encouraged by the data generated to date, showing strong target knockdown in blood and tumor, induction of interfering gamma response in blood and tumor, and signs of preliminary clinical efficacy in lymphomas at tolerated doses.

Jared Gollob: Preclinically, we've seen robust single-agent activity in T and NK cell lymphomas, as well as a strong genetic rationale for why staff retargeting should be active in Hodgkin's lymphoma. This has translated well in the clinic in terms of the anti-tumor responses we have seen in Hodgkin's lymphoma, CT, CL, and NK cell lymphoma. We believe the emerging data in Hodgkin's lymphoma patients is particularly intriguing, with complete responses in two of three heavily pre-treated patients who had progressed after prior checkpoint inhibitor therapy and anti-CD30 ADC, enabling subsequent potentially curative stem cell transplants. Because we did not see strong signals of pre-clinical activity as a single agent in solatumors, it's not been surprising that we have observed only stable disease and a handful of solatumor patients enrolled into the trial.

Speaker Change: This is translated well in the clinic in terms of the anti-tumor responses we have seen in Hodgkin's lymphoma, CT, CL, and NK cell lymphoma.

Jared Gollob: However, we have seen activity in syngenic mouse solatumor models in combination with anti-TD1 drugs. This is likely driven by statuaries immunomodulatory mechanism, which we believe provides an opportunity for combination with anti-PD1 in both solatumor and Hodgkin's lymphoma patients. Given the activity we've observed in Hodgkin's lymphoma, which includes the two aforementioned complete responses, we are focused on enrollment of additional Hodgkin's lymphoma patients to further explore the very encouraging activity we've seen there. We believe there is also an opportunity for future expansion into solatumors in combination with anti-PD1 and other targeted therapies. We expect to complete enrollment of the study and share data in the second half of 2024.

Speaker Change: This is likely driven by STAT3's immunomodulatory mechanism, which we believe provides an opportunity for combination with anti-PD-1 in both salvo tumor and Hodgkin's lymphoma patients.

Speaker Change: We believe there is also an opportunity for future expansion into solid tumors in combination with anti-PD-1 and other targeted therapies.

Bruce Jacobs: We look forward to keeping you updated on all our pre-clinical and clinical programs. Before we take questions, I'll hand the discussion to Bruce to review our second quarter of financial results. Thank you, Jared. As our review, our second quarter 2024 financial highlights, please reference the tables found in today's press release. Revenue in the second quarter of 2024 was 25.7 million. All of that was attributable to our synopeic collaboration.

Speaker Change: Before we take questions, I'll hand the discussion to Bruce to review our second quarter financial results.

Bruce Jacobs: Thank you, Jared. As I review our second quarter 2024 financial highlights, please reference the tables found in today's press release.

Bruce Jacobs: Revenue in the second quarter of 2024 was $25.7 million. All of that was attributable to our Sanofi collaboration.

Bruce Jacobs: With respect to operating expenses, our need for the quarter was 59.2 million. Of that, approximately 7.3 million represented non-cash stock-based compensation. The adjusted cash our need spent of 51.9 million, which excludes that stock-based comp, reflects a 22% increase from the capital amount in the first quarter of 2024.

Bruce Jacobs: On the GNA side, our spending for the quarter was 17.4 million, of which 7.1 million was non-cash stock-based comp. The adjusted cash GNA spent of 10.3 million, again, excluding stock-based comp, reflects a 21% increase from the copper bull amount in the prior sequential quarter.

Speaker Change: On the G&A side, our spending for the quarter was $17.4 million, of which $7.1 million was non-cash stock-based comps.

Bruce Jacobs: Fishing up with our cash balance at the end of the quarter was 702 million. Our cash balance is expected to provide a runway into the first half of 2027, and will enable us to execute on multiple data readouts, including oncology proof-of-concept results in 2024, KKE474 Phase II data, and several clinical inflection points for our Stat6 and Tick-2 programs expected in 2025.

Speaker Change: KTE 474 Phase 2 data and several clinical inflection points for our STAT-6 and TIC-2 programs expected in 2025. This concludes our prepared remarks and we would be happy to now address any questions you may have. Operator?

Unknown Executive: This concludes our prepared remarks, and we would be happy to now address any questions you may have.

Unknown Executive: Operator? We will now begin the question and answer session. To ask a question, you may press Star of N1 on your telephone keypad. If you were using a speaker phone, please pick up your hands up before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press Star or N2. At this time, we will pause momentarily to assemble our roster.

Operator: We will now begin the question and answer session. To ask a question, you may press the star of N1 on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been answered and you would like to withdraw your question, please press the star of N2. At this time, we will pause momentarily to assemble our roster.

Speaker Change: We will now begin the question and answer session. To ask a question, you may press star then 1 on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys.

Eric Joseph: Our first question comes from Eric Joseph with J.P. Morgan. Please go ahead.

Speaker Change: and many more. Thank you. Thank you.

Speaker Change: Our first question comes from Eric Joseph with J.P. Morgan. Please go ahead.

Eric Joseph: Oh, hi, good morning. Thanks for taking the question. I'm just wondering if you could elaborate a little bit further on the type of data you and Sonofi were able to review as part of their decisions to expand the Phase 2 program. I'm wondering whether safety, whether it was just based on safety, or whether there was an advocacy component, or some surrogate thereof. And I know that there's some moving parts to work through here, but I guess you have a little bit of a little bit further on the type of data you and Sonofi were able to review as part of their decisions to expand the Phase 2 program.

unknown: Just wondering if you could elaborate a little bit further on the type of data you and Sanofi were able to review as part of their decision to expand the Phase II program. I'm wondering whether safety was just based on safety or whether there was an efficacy component or some surrogate thereof.

Eric Joseph: I'm wondering whether safety, whether it was just based on safety, or whether there was an advocacy component, or some surrogate thereof. And I know that there's some moving parts to work through here.

unknown: And I know that there are some moving parts to work through here, but I guess you have a loose sense of when it will be expanded and whether there might be interim readouts within. Thanks.

Eric Joseph: But I guess you have a little loose sense of when there could be moving might see data from the Phase 2 trial after it's expanded, and whether there might be interim readouts within. Thanks.

Nello Mainolfi: Yes, thanks for the question, Eric. So, the, so there was an entry analysis of both safety and advocacy, as we said. And as we said, the companies, both Sonofi and Camero, had access to the blinded data; there was IDNC that had access to both blinded and unblinded data. I can't speak to, again, the content of the review or the questions that were asked, but obviously what we should conclude from this update that we provided a few weeks ago, and now we're obviously highlighting again, is that the review of the data was supportive of further investment into the program.

Speaker Change: Yes, thanks for the question, Eric. So, there was an interim analysis of both safety and efficacy, as we said.

Speaker Change: And as we said, the companies, both Sanofi and Camaro, had access to the blinded data. There was IDMC that had access to both blinded and unblinded data. I can't speak to, again, the content of the review or the questions that were asked, but obviously what we should conclude...

Speaker Change: from these updates that, you know, we provided a few weeks ago and now we're...

Speaker Change: The review of the data was supportive of further investment into the program. Don't forget that this is...

Nello Mainolfi: You know, don't forget that this is one of the few programs in the pipeline where, you know, where Sonofi is running multiple phases studies in parallel without having previously run a proof of concept study in a possible control manner. So, it speaks again, I think to the level of enthusiasm that we both have for this program. With regards to timelines, we hopefully will be able to see an update on a clinical trial.gov in the next in the upcoming months. And that will include also expected completion dates. And at that time, we should be able; we will be able to comment on the timelines.

Speaker Change: And that will include also expected completion dates, and at that time we should be able, we will be able to comment.

Eric Joseph: As we said, Jared said earlier, it's going to be beyond the first half of '25 that was initially guided to. But at this point, we're not able to provide more accurate guidance. Okay, great.

Speaker Change: on the timelines. As we said, Jared said earlier, it's going to be beyond the first half of 25 that was initially guided to, but at this point, we're not able to provide more accurate guidance.

Eric Joseph: Thanks for taking a question, and I'll hop back and keep. Thanks.

Speaker Change: Okay, great. Thanks for taking the question and I'll hop back in queue.

Operator: Our next question comes from Geoff Jones with Oppenheimer. Please go ahead.

Jeff Jones: Our next question comes from Jeff Jones with Oppenheimer. Please go ahead.

Jeff Jones: Good morning, guys. And thanks for taking the question. Just a quick one on the R&D and GNA trends. Obviously, picked up significantly from the prior quarter. With the extensive work you have going on, just how should we think about the trends there? And then in fall, as well on the jump in collaboration revenues from Sonofi, how should we think about that?

Speaker Change: Morning guys and thanks for taking the question. Just a quick one on the R&D and G&A trends obviously picked up significantly from the prior quarter.

Bruce Jacobs: Thank you. Yeah, sure, this is Bruce, Jeff. Thanks for the call. So, in terms of the trends, there's, there's, you know, nothing unusual there in terms of the growth order of a quarter versus what we had expected. As the year progresses, as obviously we get closer to the start of the studies for Stat Six, you know, you'll see that come through in the R and D line. GTA is just, you know, modest growth, the organization. You know, we have and guided towards annual burn typically don't, but, you know, I've last looked at the street, they're generally in the right ballpark, but definitely for this year, a little more back and loaded than front and loaded.

Bruce Jacobs: Yeah, sure. This is Bruce. Jeff, thanks for the call. So in terms of the trends, there's

Speaker Change: We haven't guided towards...

Bruce Jacobs: And that's typically how our carriers have gone and represented what you'll see this year in terms of the revenue. There was just a catch up in revenue related to the Sanity Alliance. All the revenue is, is a result of that. So that resulted in a higher level, this, this quarter, but I think it will be a little unusually high be to be the rest of the year and you can, you can do some calculations based on the deferred revenue. So I hope that helps a little bit. Happy to take more offline as well. I appreciate that person.

Kelly: I'll jump back in here. Our next question comes from Kelly; she was Jeffries. Please go ahead.

Speaker Change: I appreciate that, Bruce, and I'll jump back in queue.

Operator: Our next question comes from Kelly Shee with Jeffreys. Please go ahead.

Speaker Change: Our next question comes from Kelly Shee with Jeffreys. Please go ahead.

Kelly: Congrats on the progress, and thank you for taking my questions.

Kelly: Maybe I'll start a sixth program. Based on the multiple preclinical studies you have presented findings with, could you comment on more specific plans for the phase one? Would it be like a single indication or multiple indications, or the desire has been made on the discoveries from preclinical studies? Which one to prioritize?

Kelly Shee: Congrats on the progress and thank you for taking my questions. Maybe I'll start a sixth program. Based on the multiple preclinical studies you have presented findings with,

Kelly Shee: Could you comment on more specific plans for the Phase 1? Would it be like a single indication or multiple indications, although this area has been made on the discoveries from preclinical studies, which one to prioritize? Thank you.

Kelly: Thank you.

Jared Gollob: Yeah, thanks.

Bruce Jacobs: Yeah, thanks. Maybe I'll let Jared comment on the Phase I plans. We haven't described the details of our plans before the Healthy Volunteers, but I think maybe just to remind you what we're – the update that we're giving today on the program is really about the fact that we were able, actually, to accelerate our path to Phase I, and we're able to conclude and complete our IND-enabling studies, and so we are on track, if not earlier, compared to what we had said, Maybe, Jared, you can provide some high-level description of our Healthy Volunteers study. Yeah, so the Phase I Healthy Volunteers study –

Jared Gollob: Maybe I'll let Jared comment on the Phase One plans. We haven't described the details of our plans before the health volunteers. I think maybe just to remind what we're the update that we're giving today on the program is really on the fact that we were able actually to accelerate our path to phase one and we're able to conclude and complete our ending. So we are on track, if not earlier, compared to what we had said to start the phase one study.

Jared Gollob: Maybe Jared, you can provide some high level of description of our active volunteer studies. Yes, so the Phase One health volunteer study being in healthy volunteers, we expect to be able to move through it quickly. It will be a traditional single sending dose and multiple sending dose phase one study. The MAD portion will consist of 14 daily doses. You know, within that study, you know, as we did for the Iraq for phase one, we'll have a number of different pharmaceutical dynamic measures, which will be critical to that study in addition to looking at safety. And those measures will include looking at stat six, for example, in blood and skin.

Jared Gollob: Yeah, so the Phase 1 Healthy Volunteers Study, being in Healthy Volunteers, we expect to be able to move through it quickly. It will be a traditional single ascending dose and multiple ascending dose Phase 1 study. The MAD portion will consist of 14 daily doses. Within that study, as we did for IRAC-IV Phase 1, we'll have a number of different pharmacodynamic measures, which will be critical to that study, in addition to looking at safety.

Speaker Change: It will be a traditional single ascending dose and multiple ascending dose.

Speaker Change: Phase 1 study, the MAD portion will consist of 14 daily doses.

Jared Gollob: And those measures will include looking at STAT6, for example, in blood and skin. And also, importantly, we'll have an opportunity to look at several different Th2 biomarkers in the circulation, in particular, to be able to look at IgE and TARC, giving us an opportunity to show impact on the biology of the IL-4, IL-13 pathway, even in healthy volunteers.

Jared Gollob: And also importantly, we'll have an opportunity to look at several different TH2 biomarkers in the circulation, in particular to be able to look at IgE and TARC. You know, giving us an opportunity to show impact on the biology of the IL-13 pathway even. and Healthy Volunteers.

Jared Gollob: Thank you.

Vikram Purohit: Our next question comes from Vikram Purohit with Morgan Stanley.

Speaker Change: Thank you.

Vikram Purohit: Please go ahead. Hi, good morning. Thank you for taking our questions. We had two on the INI pipeline.

Vikram Purohit: First on 474, just wanted to get your latest thoughts on when we could learn more from your self-insanity on indication expansion beyond HS&AD and what might be flowing into those decisions. And then secondly, for the TIC-2 program, just wanted to see how you're thinking about indication selection, rather. How broad do you think the development program could be, and what will you be looking for in the initial phase one data to help make those decisions? Thanks. Thanks, Vikram. So I'm fortunate for us. We said in the past that we believe this pathway has relevance in a broad variety of diseases.

Speaker Change: The TIC-2 program, just wanted to see how you're thinking about indication expansion, or indication selection rather. How broad do you think the development program could be and what will you be looking for in the initial phase 1 data to help make those decisions? Thanks.

Speaker Change: Yeah, thanks Vikram. So on 474, as we said in the past,

Vikram Purohit: Our initial foray is in a skin and a germ. So with HS&AD, you know, again, based on pathway agents with existing proof of concept, you know, we expect this started to be relevant in respiratory, in both asthma and COPD, in GI inflammation, IBD, as well as traditional, let's say rheumatology, both array and lupus. So the opportunities are vast. As we communicated in the past, there is a process that has been ongoing within the collaboration to prioritize a series of indications that the team has done. And I, you know, again, I cannot speak for, for Santa Fe. I will have the final decision making on this.

Speaker Change: We believe this pathway has relevance in a broad variety of diseases. Our initial foray is in skin and derms, so with HS and AD. You know, again, based on pathway agents with existing proof of concept.

Speaker Change: We expect this pathway and this target to be relevant in respiratory, in both asthma and COPD, in GI inflammation, IBD, as well as traditional, let's say, rheumatology, both RA and lupus, so the opportunities are vast.

Speaker Change: As we've communicated in the past, there is a...

Speaker Change: a process that has been ongoing within the collaboration to prioritize a series of indications that the team has

Speaker Change: The team has done. And I, you know, again, I cannot speak for Sanofi, who will be the final decision making on this, but all I can say is that, you know, the recent update and what we have seen, I think, continues to support the enthusiasm around the program and the potential eventual expansion. I leave it to Sanofi to speak to the timing of that. But I will say that at least we're getting, you know, closer to, to hopefully that decision.

Nello Mainolfi: But all I can say is that, you know, the recent update and what we have seen, I think continues to support the enthusiasm around the program and the potential eventual expansion.

Nello Mainolfi: I'll leave it to Santa Fe to speak to the timing of that, but I will say that at least we're getting, you know, closer to hopefully that decision. And with regard to TIC2, you know, again, as Jared said earlier, this program is really for us an opportunity to provide an oral molecule with a biologics-like profile. And actually unique biologics like profile. You know, if you think about, you know, this pathway is involved in I-23 out 12 and type 1 interferon. And being able to block the three pathways fully with a single oral small molecule should provide a highly differentiated profile.

Nello Mainolfi: With regard to TIK2, you know, again, as Jared said earlier, this program is really, for us, an opportunity to provide an oral molecule with a biologics-like profile and actually a unique biologics-like profile. So, you know, if you think about this pathway is involved in I23, I12, and type 1 interferon, and being able to block those three pathways fully with a single oral small molecule should So, there are lots of potential diseases that one could go after, you know, others have gone after psoriasis, psoriatic arthritis, IBD, lupus, obviously are up there. But there are potentially others that could be interesting. I think our goal will be in phase one study to demonstrate that our mechanism of action is able to show

Speaker Change: With regard to TIC-2, you know, again, as Jared said earlier, this program is really, for us, an opportunity to provide a neural molecule with biologics-like profile, and actually unique biologics-like profile.

Jared Gollob: You know, this pathway is involved in I23, I12, and type 1 interferon, and being able to block those three pathways fully with a single or a small molecule should provide a highly differentiated profile.

Nello Mainolfi: So there's lots of potential diseases that one could go after, the ones that, you know, others have gone after: psoriasis, psoriasis, arthritis, IBD, lupus, obviously are up there. There are potentially others that could be interesting. I think our goal will be in phase one study to demonstrate that our mechanism of action is able to show a full blockade of these pathways, unlike any other agents that has been tested so far. And then a plan would be to do a proof of concept in an indication that will actually demonstrate that differentiated profile.

Speaker Change: So, there's lots of potential diseases that one could go after, the ones that...

Speaker Change: You know, others have gone after the RISIS.

Speaker Change: A full blockade of these pathways, unlike any other agents that have been tested so far. And then our plan would be to do a proof of concept in an indication that will actually demonstrate that differentiated profile. But we'll speak with more details about that once we're closer to our Phase I study.

Nello Mainolfi: But we'll speak with more details about that once we're closer to our Phase One study.

Nello Mainolfi: Thanks for the contact.

Brad Canino: Our next question comes from Brad Canino with Steeple.

Speaker Change: Understood. Thanks for the contact.

Brad Canino: Please go ahead. Thank you. Two for me.

Brad Canino: First, and Nelly, just talk about this a little bit, but given the recent external news, can you discuss the confidence of Tick-2 as a tractable target for IBD? And then second, maybe a bit of a strategy question, but years ago before this named pipeline really evolved to the shape it is today. I mean, you naturally highlighted a lot of the discovery efforts at Kymera. And I just want to pull back and ask, how would you characterize the degree of discovery efforts now? What are some of the areas of focus? And how do you maintain that while also asking a lot of questions individually and collectively across the clinical pipeline today?

Speaker Change: And then second, maybe a bit of a strategy question, but years ago before this named pipeline really evolved to the shape it is today, I mean, you naturally highlighted a lot of the discovery efforts at Kymera, and I just want to pull back and ask, how would you characterize the degree of discovery efforts now?

Speaker Change: What are some of the areas of focus and how do you maintain that while also asking a lot of questions individually and collectively across the clinical pipeline today? Thank you.

Jared Gollob: Thank you. Thank you, Jared. Do you want to take the first question?

Jared Gollob: I'll take the second one. Sure. Yeah, in terms of your question around our approach to targeting Tick-2 and our expectations for activity in IBD, you know, there have been some challenges with the Tick-2 small molecule inhibitors to show activity in IBD. You know, with Ducra, for example, part of that might be due to the fact that while it's hitting, say, IL-12, IL-23, because it's also not selective just for Tick-2. It's also hitting Jack. It's also probably affecting IL-10, which can be a real problem in IBD because if you block IL-10, you're going to interfere with new coastal healing, which is going to be an important component of any sort of therapeutic where you don't interfere with that.

Jared Gollob: Thank you. Jared, why don't you want to take the first question and I'll take the second one? Sure. Yeah, in terms of your question around, you know, our approach to targeting TIC-2 and our expectations for activity in IBD,

Speaker Change: With DUCRA, for example, part of that might be due to the fact that while it's hitting, say, IL-12, IL-23, because it's also not selective just for TIK2, it's also hitting JAK, it's also probably affecting IL-10, which can be a real problem in IBD, because if you block IL-10, you're going to interfere with mucosal healing, which is going to be an important component of any sort of therapeutic where you don't interfere with that. So we think one of the real advantages of our TIK2 degrader is that we can maximally block...

Jared Gollob: So we think one of the real advantages of our tick-tube degrader is that we can maximally block the key inflammatory pathways, IL-12, IL-23, and type 1 interferon, while at the same time completely sparing IL-10 signaling, and we think that that will be a distinct advantage for our approach in this disease, and that's why we anticipate being able to show activity in IBD as well as in the other indication

Jared Gollob: So, we think one of the real advantages of our Tick-2 degree is that we can maximally block the key inflammatory pathways IL-12, IL-23, anti-bony interferon, while at the same time completely sparing IL-10 signaling. And we think that that would be a distinctive vantage for our approach in this disease. And that's why we anticipate being able to show activity in IBD, as well as in the other indications that Nello was discussing earlier, including the derm indications like psoriasis and lumen indications like lupus. Yeah, and just maybe to add a small statement on the recent data. I think it's important to look at the profile of the molecule tested and their activity of blocking the relevant pathways.

Speaker Change: The Key Inflammatory Pathways, IL-12, IL-23, and Type 1 Interferon, while at the same time completely sparing IL-10 signaling, and we think that that will be a distinct advantage

Speaker Change: For our approach in this disease, and that's why we anticipate being able to show activity in IBD, as well as in the other indications that Nello was discussing earlier, including the dermal indications like psoriasis and wound indications like lupus.

Nello Mainolfi: Yeah, and just maybe to add a small statement on...

Nello Mainolfi: I think it's important to look at the profile of the molecules tested and their activity at blocking the relevant pathways. And so it's difficult, as you know well, Brad, to...

Nello Mainolfi: And so, it's difficult, as well, Brad, to compare or to use the other trials as a testament to the value of that biology in that particular disease, without taking into the context of the actual molecule profile.

Nello Mainolfi: With regards to the discovery efforts, I think one thing that we've been consistent with that Canara has been the focus on pathways that have high degree of validation. And within those pathways, going after targets that have not been drugged or drugged well. And I think if you look at the type of targets that we've gone after, what really rises to the top are two main classes, transcription factors. And we have, you know, Stat 3 and Stat 6. As an example, or scaffold in protein, Iraq 4, TIC 2. And I believe that general philosophy will continue to be the same.

Brad: The context of the actual molecule profile.

Speaker Change: With regards to the discovery efforts, I think one thing that we've been consistent with at Kymera has been the focus on

Speaker Change: As an example, or scaffolding protein, IRECT4, TIK2, and I believe that the general philosophy will continue to be the same. As we mentioned earlier in the year, we have increased substantially our effort in immunology. Again, we've talked about STAT6.

Nello Mainolfi: As we mentioned earlier in the year, we have increased substantially our effort in immunology. Again, we've talked about stat 6 with an amazing profile so far. We've talked about TIC 2 with great potential. We've talked about Iraq 4, 3 years now.

Speaker Change: with an amazing profile so far. We've talked about TIC-2 with great potential. We've talked about IREC-IV for years now. You'll hear about new programs, hopefully as early as next year, again, in the context of difficult-to-drug or impossible-to-drug targets.

Nello Mainolfi: You'll hear about new programs, hopefully as early as next year. Again, in the context of, you know, difficult to drug or impossible to drug targets with other modalities within, you know, the same in immunology landscape. I think I might argue all and our vision. And I have the highest degree of confidence where I said today is that we will have the best in industry or in immunology pipeline. And if we don't already have that. And I think that's what you know, the world should expect for us in the next few months of year.

Mark: Next question. Our next question comes from Mark from with TD Cohen.

Mark: Please go ahead. Thanks for taking my questions.

Mark: It's a library we're going to talk about, maybe one quick one on ecology, just the 253 update. Can you clarify if the data presentation this year, just the bio-marker approach, or should we also expect the full clinical update this year to happen this year, or is that going to be a next year event?

Speaker Change: Thanks for taking my questions. Maybe one quick one on ecology, just the 253 update, can you clarify, is the

Nello Mainolfi: And then maybe a broader question on the eye and eye portfolio and just kind of kind of mirrors approach. Do you view the oral convenience of your molecules is so important that it's acceptable to develop molecules that end up having clinical profiles or maybe not quite as good as the leading injectables? Or is the idea here that you really have to show every bit as much efficacy, if not more, than anything that's out there? So on the first question, what we've said is we've been talking for a while about our commitment to share a biomarker-based strategy for forward-looking recruitment strategy for 253 and MDM2 based on sensitive biomarker.

Speaker Change: Do you guys view the oral convenience of your molecules as...

Nello Mainolfi: So on your first question, what we said is, you know, we've been talking for a while about our commitment to share a biomarker-based strategy for forward-looking recruitment strategies for 253 and MDM2 based on sensitivity biomarkers. And so we will hopefully be able to share that this year at a medical meeting. What we said about our, you know, clinical data is that our plan, and our expectations are that we should be able to complete those escalations this year.

Speaker Change: So on your first question, what we said is, you know, we we've been talking for a while about our

Speaker Change: Thank you so much for joining us today, and I'm delighted to be here to talk to you about our commitment to share a biomarker-based strategy for forward-looking recruitment strategy for 253 and MDM2 based on sensitivity biomarker, and so we will hopefully be able to share that this year at a medical meeting.

Nello Mainolfi: And so we will hopefully be able to share that this year at a medical meeting. What we've said about our clinical data is our plan, and our expectations are that we should be able to complete those escalations this year. As you know, that doesn't depend only on us, but it depends on also the safety profile of our drug and how many doses would be required to reach MPD. As you've seen for stat 3, we actually ended up escalating probably more than we had anticipated because the safety profile was better than we had anticipated based on our pre-clinical data.

Speaker Change: You know, our plan, our expectations are that we should be able to complete.

Nello Mainolfi: As you know, that doesn't depend only on us, but it depends also on the safety profile of our drug and how many doses would be required to reach MTD. As you've seen for STAT3, we actually ended up escalating probably more than we had anticipated because the safety profile was better than we had anticipated based on our preclinical data. And so for MDM2, again, our desire to share the totality of the escalation data, and so the reason why we're saying we'll share the data after we complete the escalation. It all depends on when we complete the escalation.

Speaker Change: As you know, that doesn't depend only on us, but it depends on also the safety profile of our drug and how many doses would be required to reach MTD. As you've seen for stat 3, we actually ended up escalating probably more than we had anticipated because the safety profile was better than we had anticipated based on our preclinical data.

Nello Mainolfi: And so for MDM2, again, our desire to share the totality of the escalation data, and so the reason why we're saying we'll share the data after we complete the escalation, it all depends on when we complete the escalation. We expect that we should be able to do that by the end of the year, but it will depend again on the safety profile and the timing to reach MPD. The trial is recruiting extremely fast, and so that recruitment of patients is definitely not on the critical path; it's really the profile of the drug.

Speaker Change: And so for MDM-II, again, our desire to share the totality of de-escalation data, and so the reason why we're saying we'll share the data after we complete de-escalation, it all depends on when we complete de-escalation. We expect that we should be able to do that by the end of the year, but it will depend, again, on the safety profile and the timing to reach MTD. The trial is recruiting extremely fast.

Nello Mainolfi: We expect that we should be able to do that by the end of the year, but it will depend, again, on the safety profile and the timing to reach MTD. The trial is recruiting extremely fast, so recruitment of patients is definitely not on the critical path. It's really the profile of the drug. With regard to the immunology pipeline, I mean, I think we said it early in the year, we have selected targets that

Nello Mainolfi: With regards to the immunology pipeline, I mean, I think we've said it early in the year, we have selected targets that are able to be superior to equal, actually, I should say, or superior at blocking those pathways than upstream biologics. That is actually true for IRF4, which should be superior to individual upstream I1 biologics. Even that you should be able to block the pathway fully. And so I have a clinical activity of the combined I1 family, cytokine blockers. It is true for statics and duploma, but we've shown that we can block the pathway the same way.

Speaker Change: are able to be superior to, equal, actually I should say, or superior at blocking those pathways.

Speaker Change: which should be superior to individual upstream I1 biologics given that it should be able to block the pathway fully and so have a clinical activity of the combined I1 family cytokine blockers.

Speaker Change: It is true for STAT6 and Dupilumab. We've shown that we can block the pathway the same way. Hopefully, also, we'll be able to show that in the clinic for TIK2, for the TIK2 program. So, I think what we are trying to do, which is unprecedented,

Nello Mainolfi: We'll hopefully also be able to show that in the clinic for TIC-2, for the TIC-2 program. So I think what we are trying to do, which is unprecedented in the history of immunology development, is to have an oral drug that does not compromise on efficacy. There is our goal. Again, compared to On Pathway Biologics. And so again, I think statics is the easiest example to outline. We believe, based on the biology that we have experimented and have shown so far, that we can block the pathway just as well as the duploma, which is the IRF4 receptor of blocker.

Nello Mainolfi: And so we expect the clinical profile in terms of pathway blockade that resolved in clinical activity to be at least as good as the Piloma. So I think we historically had to compromise on efficacy with an oral drug. We are trying to say here for the past few months that our ambition is that that will not be the case anymore.

Nello Mainolfi: And that's really the, when we say paradigm shift, which is a concept that has been praised also by the broader community with our programs, it's just about that. It's the ability to actually change how we think about what should patients take as a drug that suffered from these diseases. And I think that our programs can change that part.

Speaker Change: which is a concept that has been praised also by the broader community with our programs is just about that. It's the ability to actually change how we think about what should patients take as a drug that suffers from these diseases.

Speaker Change: And I think that our programs can change that paradigm.

Kalpit Patel: Thank you. Our next question comes from Kalpit Patel with B.

Kalpit Patel: Riley. Please go ahead.

Speaker Change: Our next question comes from Kalpit Patel with Be Riley. Please go ahead.

Kalpit Patel: Yeah, hey, good morning. Thanks for taking the questions. You mentioned the expansion of the IREC4 trials also includes testing of additional doses. Maybe help us understand the decision making for that specifically and why more doses need to be tested now. And as a follow-up, if you can share, can you give us any additional color, if the new doses are outside of the 50 to 200 milligram daily dose range. Thank you. Yeah, great question, Kalpit. So, as you know, in order to initiate a phase registration, a phase three study, it is expected from a sponsor to have a degree of dose ranging to establish the relationship between efficacy and safety.

Kalpit Patel: Hey, good morning. Thanks for taking the questions. You mentioned the expansion of the IREC-IV trials also includes testing of additional doses.

Kalpit Patel: Maybe help us understand the decision making for that specifically and why more doses need to be tested now.

Speaker Change: Great question, Kalpit. So, as you know, in order to initiate a phase 3, a registration of phase 3 study, it is expected from a sponsor to have a degree of dose ranging.

Kalpit Patel: And so if you looked at the existing, let's use H.S. a phase two study that we, there it's actually still now on clinical trials. That actually had one dose and one placebo. It would have been extremely difficult, if not impossible, to go from that type of study into a phase three registration study without exploring multiple doses. So that's what's driving the addition of other doses is the acceleration of getting into, after this study, into a phase three study. With regards to the type of doses, again, we're not in liberty to actually comment. I would also point to that actually, in Europe, actually the doses are revealed much sooner than in the US.

Speaker Change: Again, we're not in liberty to actually comment. I would also point you that, actually, in Europe, actually the doses are revealed much sooner than in the U.S. So, you know, if you do some investigative work, you...

Kalpit Patel: So if you do some investigative work, it's not that hard to figure out what the existing dose versus the new doses will be, but maybe I'll stop here. What I will say is that those will be within the range that you say; unfortunately, I can't comment more on where there will be. Okay, great, thank you.

Speaker Change: It's not that hard to figure out what the existing dose versus the new doses will be, but maybe I'll stop here. What I will say is that the doses will be within the range that you said. Unfortunately, I can't comment more on where they will be.

Michael Schmidt: Our next question comes from Michael Schmidt with Guggenheim. Please go ahead.

Operator: Our next question comes from Michael Schmidt with Guggenheim. Please go ahead.

Michael Schmidt: All right, thanks for taking our question. This is Paul on for Michael.

unknown: All right, thanks for taking our question. This is Paul.

Paul: Just following up on a prior question on stat six, can you talk about how we should interpret that early biomarker data coming out of the healthy volunteers next year? For instance, is there a certain threshold of CERMAGE or TARC reduction that you're hoping to see, or is any directional and just dependent reduction sufficient to give you confidence in that program?

Paul: And then just as a follow-up, is the goal here just to establish a proof of concept, or could the PDD data actually guide your thinking on target indication prioritization? Thank you.

Paul: Yeah, no, great, great question, Paul. So, let me start with, so, you know, obviously, we built a really robust pre-cleanable package, right? We've shown in vitro, first that we degrade this target fully with picomole or concentrations in old relevant cell types. When I say relevant, I mean cell types; human cell types are relevant to all these TH2 diseases, whether it's respiratory, DRMGI. We've shown that if you look at pathway inhibition, so I have 413 biology downstream of the receptor, we're able to block that pathway actually more positively than the Pilimab. If we go in vivo, we've shown either in a topic third model or more translationally in the asthma model, that's a 30-day HDM model.

Speaker Change: Yeah, no, great question, Paul. So, let me start with...

Speaker Change: So, you know, obviously we've built a really robust preclinical package, right? We've shown...

Jared Gollob: We've shown that with 90% degradation of Stat6, we have an ability to block a placer of TH2 biomarker as well as disease endpoints, either equally or better than the pixel. So, we've shown pre-clinically, in terms of pharmacology, that this drug behaves like a very, very robust, probably best in class pathway inhibitor. We've also shown the safety profiles to be so far absolutely pristine, with what we talked about earlier in the year. In January about that we hadn't seen any adverse events in non-GLP talks. Today were saying as an update that even going through GLP talks we haven't seen any adverse events and any of those that we tested.

Speaker Change: with 90% degradation of STAT6.

Speaker Change: We have an ability to block a plethora of CH2 biomarkers, as well as disease endpoints, either equally or better than the PXENT. So we've shown pre-clinically, in terms of pharmacology, that this drug behaves...

Speaker Change: Like it, very, very robust, probably best-in-class pathway inhibitor. We've also shown the safety profile to be, so far, absolutely pristine, which we talked about early in the year.

Speaker Change: In January about that we hadn't seen any adverse events in our non-GLP talks. Today we're seeing as an update that even going through

Jared Gollob: So also, the safety profile is quite compelling. So the goal of the phase one study is to demonstrate that everything that we've done so far in preclinical species, or really most of the things that we've done preclinical species, replicated human. And importantly, the pKa that leads to a dose-dependent and robust degradation in blood and skin, and then we're using the biomarker that depicts it as modulated to just confirm, to be honest, it's totally expected but confirm in humans that blocking Stat 6 will lead to downstream biomarker changes, which again we've shown extensively in all sorts of preclinical models.

Speaker Change: GLP Talks. We haven't seen any adverse events in any of those that we've tested, so also the safety profile is quite compelling.

Speaker Change: So the goal of the Phase I study is to demonstrate that everything that we've done so far in preclinical species, or at least most of the things that we've done in preclinical species, replicated humans. And importantly, the PKA that leads to a dose-dependent and robust degradation in blood and skin. And then we're using the biomarker that depicts it as modulated to just confirm, to be honest, it's totally expected, but confirming humans that...

Jared Gollob: If you look at the data that the pigs that are shown, and I encourage everybody to kind of study that, so there were a line on expectation. You've seen that with Dupy you can reduce the torque and also IG in 28 days, and so if you look at that data, somewhere between 20 and 40% depending on the biomarker that you use. Again, it shows that there is a pathway in addition, even in healthy volunteers that don't have ongoing inflammation, and so it's a confirmation of target engagement.

Speaker Change: If you look at the data that Dupik has shown, and I encourage everybody to kind of study that, so that we're aligned on expectations, you've seen that with DUPI you can reduce TARC and also IgE in 28 days, and so if you look at that data, somewhere between 20 and 40%, depending on

Jared Gollob: I don't believe we will use that data for any decision making with regards to indication given that those are again qualitative biomarkers in a healthy volunteer population. Our goal would be to go in patients soon thereafter to establish a more robust both proof of mechanism and to respond.

Speaker Change: decision-making with regards to indication, given that those are, again, qualitative biomarker in a healthy volunteer population. Our goal will be to go in patients, soon thereafter, to establish a more robust, both proof of mechanism and proof of concept.

Jasmine: Our next question comes from Ellie Merle with UBS.

Jasmine: Please go ahead. Hi, this is Jasmine for Ellie. Thanks so much for taking our question. We have two on oncology. So for stat 3, could you give a little more color and talk about your view on the potential opportunity in touch with lymphoma? And then secondly on your MDM2 strategy specifically in solid tumors, are we going to hear an update on this when you give your biomarker patient selection update this year? And just based on the vectors of action, what can you say about what you see is the most applicable set of solid tumors? Thank you.

Speaker Change: We have a 2-1 oncology. So for stat 3, could you give a little more color and talk about your view on the potential opportunity in Hodgkin's lymphoma?

Speaker Change: And then secondly, on your MDM2 strategy, specifically in solid tumors, are we going to hear an update on this when you give your biomarker patient selection update this year? And just based on the mechanism of action, what can you say about what you see as the most applicable set of solid tumors?

Jared Gollob: Yeah, maybe starting with your question on Stat 3 and Hoshkin. We reported that we've seen complete responses in Hodgkin's lymphoma, you know, in patients who have been gone on to hopefully curative transplant. So that, you know, very encouraging data in Hoshkin is consistent with what is known about the genetics of Hoshkin's disease where there's amplification of PDL1 as well as Jack amplification, both of which, you know, would render those tumors potentially responsive to Stat 3 targeting. So, as we've guided previously, you know, with the Phase I study, we've now completed those escalations and enrollment now is really focused on enrolling additional Hodgkin's patients.

Speaker Change: Thank you.

Speaker Change: Maybe starting with your question on STAT3 and Hodgkin's, we've reported that we've seen complete responses in Hodgkin's lymphoma in patients who have then gone on to hopefully curative transplant.

Speaker Change: Amplification of PD-L1 as well as JAK amplification, both of which would render those tumors potentially responsive to STAT3 targeting.

Jared Gollob: We see there being several different development opportunities for the drug, and we continue to see the sort of activity that we've seen today. Those include opportunities for the drug as a model therapy in third line and beyond for patients who have had prior anti-PD1 drugs or prior, you know, anti-CD30 ADCs, and also a potential opportunity up line and second line in combination with anti-PD1.

Speaker Change: on enrolling additional Hodgkin's patients. We see there being several different development opportunities for the drug and we continue to see the sort of activity that we've seen to date.

Speaker Change: Those include opportunities for the drug as a monotherapy, in third line and beyond, so for patients who have had prior

Speaker Change: Pd1 drugs or prior, you know, anti-CD30 ADCs.

Speaker Change: And also a potential opportunity, upline and second line in combination with anti-TD1.

Jared Gollob: So I think it would be very interesting in terms of what we see for the remainder of the study this year, what we plan on reporting data later this year once we've completed enrollment of those additional Hoshkin's patients that can provide both efficacy and safety update at that time.

Speaker Change: So, I think it will be very interesting in terms of what we see for the remainder of the study. This year, we plan on reporting data later this year once we've completed enrollment.

Jared Gollob: With regard to MDM 2 and patient selection, I think Nell will refer to this earlier. You know, we have had an ongoing extensive effort frequently to identify different solid tumor types that are specifically sensitive to the greater mechanism of action. And we've been in the process of developing a biomarker signature of sensitivity using various solid tumor models. And our plan, you know, is to present later this year at a medical meeting and update so that people can see sort of what those preclinical data are showing and how those are potentially guiding how we plan to further enrich for a certain solid tumor types for the MDM2 degree program.

Speaker Change: to identify different solid tumor types that are specifically sensitive.

Speaker Change: to the Degrader Mechanism of Action and we've been in the process of developing a biomarker signature of sensitivity using various, you know, solid tumor models.

Jared Gollob: So stay tuned for that presentation, hopefully later this year, where we can provide more details on what that biomarker strategy is going to look for.

Jared Gollob: Blake.

Brandon: Great, thank you.

Brandon: Our next question comes from Andy Chen with Wolf Research.

Operator: Our next question comes from Andy Chen with Wolf Research. Please go ahead.

Speaker Change: All right, thank you.

Brandon: Please go ahead. All right, this is Brandon for Andy.

Speaker Change: Our next question comes from Andy Chen with Wolf Research. Please go ahead.

unknown: Hey, this is Brendon for Andy. Um, congrats on the progress.

Brandon: Congrats on the progress this far.

Nello Mainolfi: Would you mind, can you please discuss some of the challenges in creating the 6th to greater, where the hurdles you were first developing it? And if another to greater company puts their mind to it, how quickly could they discover, I'll go from the discovery stage to IND and how difficult would that process be? Great question. So first I would say that 6th has been a target that it's been on the priority list of the biopharm industry that I can at least remember for the past 10 years. Since the early proof of concept of to Pilumab and this part we're relevance to TH2 inflammation and I believe that in most most pharmaceutical companies that have had an effort in this space, we've spent years working on this program.

Andy Chen: And if another degrader company puts their mind to it, how quickly could they discover, go from discovery stage to IND and how difficult would that process be?

Andy Chen: to Pilumab and this pathway relevant to Th2 inflammation and I believe that

Speaker Change: You know, most, most pharma companies have had an effort in this space.

Nello Mainolfi: We're not going to talk about details. At some point, we will. And the death and breath of work that we've done in 6th and our ambition to own this target completely from all points of view of pharmacological blockade of 6th, I think it was fundamentally driving all the effort that we've had so far. This is one of the best molecules we've made at Camera in the past 8 years, and I think it's going to be difficult to compete both timing and quality with Camera, given everything that we've shown so far. But I can't speak to what it will take others.

Speaker Change: from all points of view of pharmacological blockade of Z6.

Speaker Change: at Kymera in the past eight years, and...

Speaker Change: I think it's going to be difficult.

Speaker Change: to compete both timing and quality with Kymera, given everything that we've shown so far. But I can't speak to what it will take others. I don't know the capabilities that other companies have.

Nello Mainolfi: I don't know the capabilities that other companies have. I know that there is nobody.

Nello Mainolfi: There is no company that is, you know, a clinical stage or almost clinical stage as we are, and I haven't seen any data from any other company, so it's hard for me to comment on the competition.

Speaker Change: I know that there is nobody, there is no company that is, you know, in a clinical stage, almost clinical stage as we are, and I haven't seen any data from any other company, so it's hard for me to comment on the competition.

Srikripa Devarakonda: Our next question comes from Crippa DeVraconda with Truist. Please go ahead.

Speaker Change: Our next question comes from Srikripa Devarakonda with Truist. Please go ahead.

Srikripa Devarakonda: Hey guys, thank you so much for taking that question. It's all in up on the previous question regarding statics de-grader. One of your peers is developing; it's not like you said, Nello, it's not in the anywhere close to the clinic, but they're developing a statics de-grader in collaboration with sanities.

Speaker Change: One of your peers is developing, it's not like you said Nello, it's not anywhere close to the clinic, but they're developing a statistically greater, in collaboration with Sanofi. So from a big point of perspective, obviously they're trying to cost a wide net.

Srikripa Devarakonda: So from a big point of perspective, obviously they're trying to cost a wide net, but can you help understand how sanities collaboration can develop potentially develop a statics de-grader might or might not impact your collaboration for Iraq for de-grader. Do you think there could be any overlap.

Nello Mainolfi: And then just the clarification on the KT-474 dose expansion that you announced. You're adding more patients; you know, expanding the doses. It seems like you know you've talked about there being an acceleration towards the study. Can you just clarify whether this has been discussed with the FDA already? Thank you. Yeah, so thanks for the question. So on the first one, you know, we came here and sanities have obviously different goals and different strategies to accomplish their goals. And we come together around Iraq for, but we know there's everything else that we do as independent companies is obviously independent of each other.

Speaker Change: You're adding more patients, you know, expanding the doses. It seems like, you know, you've talked about there being an acceleration towards phase 3 study. Can you just clarify whether this has been discussed with the FDA already?

Speaker Change: Thank you. Yeah, so thanks for the question. So on the first one,

Speaker Change: Different goals and different strategies to accomplish their goals, and we come together around ARAC4.

Nello Mainolfi: We know, obviously, we're aware that sanities are highly interested in statics. In fact, sanities are only competitive in statics in the statics world. You know, they have the license to all the statics agents that are available out there, even the hours isn't. And so that I think, you know, from one point of view, if we needed, personally, I didn't think we do, but validate how important this target is and how valuable this target is for any company. Again, given the sanities that two collaborations with two modalities for the same target, right, a small molecule in either any degree.

Speaker Change: In the StatSix world, they have licensed all the StatSix agents that are available out there, even if ours isn't. And so I think, from one point of view, if we need it, personally I don't think we do, but it validates how important this target is.

Speaker Change: And how valuable this target is for any company, again, given that Sanofi has had two collaborations with two modalities for the same target, right? A small molecule inhibitor and a degrader. But we are, we have a very strong relationship.

Nello Mainolfi: But we are; we have a very strong relationship. We, we have an amazing team that works on 474 on both ends. And we don't believe, don't expect that, you know, our, let's say, statics competition will have any impact on 474, with regards to the doses that you've asked about. So the goal for the expansion, as we said, is in order to accelerate the entry into a registration study.

Nello Mainolfi: We have an amazing team that works on 474 on both ends, and we don't believe, don't expect that, you know, our, let's say, our STAT-6 competition will have any impact on 474. With regards to the doses that you've asked about, so the goal for the expansion, as we said, is in order to accelerate entry into a registrational study, and I think the

Nello Mainolfi: And I think the, the, I don't know if there was a specific question. Oh, yeah, so with regards to the FDA, I can comment on that. Obviously, whenever there is a protocol amendment, there is a process, but given that Santa Fe is the official sponsor, they're in charge of that particular path. Thank you.

Speaker Change: Thank you, Jared. With regards to the FDA, I can't comment on that. Obviously, whenever there is...

Chris Shibutani: Our next question comes from Chris Shibutani with Goldman Sachs. Please go ahead. Great, thank you very much.

Speaker Change: Thank you.

Chris Shibutani: Many questions have been asked. Perhaps two on the bigger picture side. One, thinking about additional immunology indications from your R&D date, it started the year you had a slide. That included the end market opportunities being very vast in some of the traditional indications like MS and rheumatoid arthritis. It would seem that there's a lot of existing therapies; combinations tend to be the playbook. The industry is also looking to figure out how to better identify patients, patient selection strategies. My questions are two-fold.

Speaker Change: Great, thank you very much. Many questions have been asked, perhaps two on the bigger picture side.

Speaker Change: One, thinking about additional immunology indications from your R&D day at the start of the year. You had a slide that included, you know, the end market opportunities being very vast in some of the traditional indications like MS.

Speaker Change: and rheumatoid arthritis. It would seem that there's a lot of existing therapies, combinations tend to be the playbook and the industry is also looking to figure out how to better identify patients' patient selection strategies. And my questions are two-fold. One...

Chris Shibutani: One, how are you feeling about the potential to expand into CNS type indications, noting that degraders are small molecules, but larger. And number two, how are you starting to thread in patient selection strategies in terms of thinking about how you can enhance probability success? I know that, Santa, facing control of the advanced clinical development. But is there any scientific work, biomarker data, that is helping inform what you think might be a way to allow a better sort of patient population to study to enhance your success there? Thanks. Yeah, no, thanks, Chris. So, I mean, this is fronted center of what we do here at Caymeer.

Nello Mainolfi: Yeah, no, thanks, Chris. So, I mean, this is the front and center of what we do here at Kymera. I think our work with STAT6 and the ability to select patients with Th2 inflammation is, in a way, although it's obviously something that comes with the mechanism, it's one of the few examples of targeted therapy in immunology. As you know, the example we showed in neosinophilic asthma and COPD is just an example of how you can actually now prospectively select patients for these populations.

Nello Mainolfi: I think our work with Stat6 and the ability to select patients with TH2 inflammation, that in a way, although it's obviously something that comes with the mechanism, it's one of the few examples of targeted therapy in immunology. As you know, the example with DuPixen in using a Phelic asthma and COPD are just an example of how you can actually now prospectively select patients for these populations.

Speaker Change: Patients with Th2 inflammation, that in a way, although it's obviously something that comes with the mechanism, it's one of the few examples of targeted therapy in immunology. As you know, the example with Duprexen in eosinophilic.

Nello Mainolfi: I'll address one more, and then I'll let Jared come, and also what we do in terms of patient selection. But on the brain, on the CNS angle, I think we and others, I will say, have demonstrated extensively that degraders can access the CNS compartment. We have internal examples, several internal examples that we've shown that pre-clinically. So, I don't, the choice of going into CNS indications will be driven by the mechanism, the opportunity, the, again, the immediate need, and less by, you know, the capability of the, or the ability of the technology.

Nello Mainolfi: I'll address one more and then I'll let Jared comment also on what we do in terms of patient selection. But on the brain, on the CNS angle, I think we and others, I will say, have demonstrated extensively that degraders can access the CNS compartment. We have internal examples, several internal examples that we've shown preclinically.

Speaker Change: I think we and others, I will say, have demonstrated extensively that degraders can access the CNS compartment. We have internal examples, several internal examples that we've shown that preclinically.

Jared Gollob: So, I don't, we, the choice of going into CNS indications would be driven by the mechanism, the opportunity, the, again, the unmet need, and less by, you know, the capability or the ability of the technology. Jared, do you want to comment a bit generally on target selection? Maybe in terms of the patient selection sort of question, I mean, this applies, you know, to IRAC4 and to STAT6 and, I think, to TIC2 as well.

Jared Gollob: Jared, do you want to come and be them generally on target select? Yeah, maybe in terms of the patient selection sort of question. I mean, it's applied, you know, to Iraq four and the stat six, and I think it ticked to as well. I think it's a very important question, but I think it's also important to emphasize that our expectations regarding the activity of these world degraders is that we should not have to narrow the patient population up front in order to be competitive. If we are as active as upstream biologics, we believe that these drugs could be approved and used up front, you know, for very broad populations of patients across these very large indications for stat six and Iraq four and tick two.

Speaker Change: Jared, do you want to comment a bit on generally on patient selection? Yeah, maybe in terms of on the patient selection sort of question, I mean, this applies, you know, to IRAC-IV and to STAT-VI and I think to TIC-2 as well. I think...

Jared Gollob: I think it's a very important question, but I think it's also important to emphasize that our expectations regarding the activity of these oral degraders are that we should not have to narrow the patient population up front in order to be competitive. If we are as active as upstream biologics, we believe that these drugs could be approved and used up front for very broad populations of patients across these very large indications for STAT6 and IRAC4 and TIC2.

Jared Gollob: It's a very important question, but I think it's also important to emphasize that our expectations regarding the activity of these oral degraders is that we should not have to narrow the patient population up front in order to be competitive. If we are as active as upstream biologics, we believe that these drugs could be approved and used up front, you know, for very broad populations of patients across these very large indications for STAT6 and IRAC4 and TIK2.

Jared Gollob: With that being said, you know, we are building in, you know, to our studies. We did this with IRAC4 and certainly we're doing this with STAT6 and TIC2, you know, extensive pharmacodynamic assays in phase one and phase two that include proteomics and transcriptomics on blood and also, for example, on skin lesions, you know, for patients with, you know, skin diseases when they come onto our study, whether it be AD for STAT6 or psoriasis potentially for TIC2, that will allow us to retrospectively look at these various proteomic and transcriptomic profiles to then help us understand whether there are, you know, patient subsets that might be benefiting even to a greater extent than the broader population, and that might be important in helping us differentiate from other things.

With that being said, you know, we are building in, you know, to our studies. We did this with Iraq four, and certainly we're doing this with stat six and tick two. You know, extensive pharmacodynamic assays and phase one and phase two that include proteomics and transcriptomics on blood, and also, for example, on skin lesions, you know, for patients with skin diseases when they come on to our study, whether it be 80 for stat six or psoriasis potentially for tick two, that will allow us to retrospectively look at these various proteomic and transcriptomic profiles to then help us understand whether there are, you know, patient subsets that might be benefiting even to a greater extent than the broader population, and that might be important in helping us differentiate from others.

Jared Gollob: With that being said, we are building in to our studies, we did this with IRAC-4 and certainly we're doing this with STAT6 and TIK2, extensive pharmacodynamic assays in Phase 1 and Phase 2 that include proteomics and transcriptomics.

Jared Gollob: On blood and also, for example, on skin lesions, you know, for patients with skin diseases when they come onto our study, whether it be AD for STAT6 or psoriasis, potentially for TIC2 that will allow us to retrospectively look at these various proteomic and trans-platonic profiles to then help us understand whether there are, you know, patient subsets that might be benefiting even to a greater extent than the broader population. And that might be important in helping us differentiate from other therapeutics.

This concludes our question and answer session.

I would like to turn the comments back over to Nello Manifoli for any closing remarks. Thank you. So I just want to thank everybody. Actually, we made it almost to 9:30. So maybe just to highlight the key news of today, one which we had shared, you know, a few weeks ago on the expansion of the 474 phase two programs in Poet HSNED. We are very excited and thankful to Sanofi for their increased investment and confidence in the program. And then more recently, the news of today was they, you know, were really, really close to initiating our phase one study with KT61 and especially showing that we've completed all the ending studies with, you know, a great safety profile.

unknown: So, I just want to thank everybody. Actually, we made it almost to 9.30.

Nello Mainolfi: So, maybe just to highlight the key news of today, one which we had shared a few weeks ago about the expansion of the 474 Phase II programs in both HS and AD. We're very excited and thankful to Sanofi for their increased investment and confidence in the program. And then, more recently, the news of today was that we're really, really close to initiating our Phase I study with KT621 and especially showing that we've completed all the IND-enabled studies with, you know, a great safety profile. And so, we're really excited about updating you all next time on our progress towards our first in-human dose, which should happen soon. So, thanks again. We're available with any follow-ups today.

Jared Gollob: Thank you so much to Sanofi for their increased investment and confidence in the program. And then more recently, the news of today was that, you know, we're really, really close to initiating our phase one study with KT621, and especially showing that we've completed all the IND-enabled studies with, you know, great safety profile, and so we're really excited about updating you all next time on our progress towards our first in-human dose that should happen soon. So thanks again. We're available with any follow-ups today.

And so we're really excited about updating you all next time on our progress towards our first inhuman. Those that should happen soon. So thanks again. We're available with any follow-ups today.

The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.

Speaker Change: The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.

Goodbye.