KT-253 / Kymera Therap - LARVOL DELTA

KT253-AL-101: Safety and Clinical Activity of KT-253 in Adult Patients with High Grade Myeloid Malignancies, Acute Lymphocytic Leukemia, Lymphoma, Solid Tumors (clinicaltrials.gov) - P1 | N=52 | Completed | Sponsor: Kymera Therapeutics, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Nov 2025 ➔ Dec 2024

Trial completion • Trial completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • Solid Tumor

KT-253, a Highly Potent and Selective MDM2 Protein Degrader, Eliminates Malignant Myelofibrosis Stem/Progenitor Cells (ASH 2024) - P1 | "Using UKE-1 cells, a p53 WT JAK2V617F+ cell line, KT-253 treatment was shown to lead to >10-fold increase in the degree of cell growth inhibition and apoptosis as compared to the MDM2 SMI AMG-232 (100nM vs 1000nM). In conclusion, KT-253 is a highly potent and effective MDM2 degrader which upregulates p53 activity in MF CD34+ cells and can selectively reduce the numbers of JAK2V617F+ colonies formed while sparing the reservoir of colonies with WT JAK2. These data provide a compelling rationale for evaluating the therapeutic potential KT 253 in MF patients."

Chronic Eosinophilic Leukemia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Solid Tumor • Targeted Protein Degradation • CD34 • CDKN1A • MDM2

KT-253, A Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy Than MDM2 Small Molecule Inhibitors. (PubMed, Mol Cancer Ther) - "Additionally, a single intravenous dose of KT 253 in combination with standard-of-care (SoC) venetoclax, overcame venetoclax resistance in an AML xenograft model. The data herein define the therapeutic potential of KT-253 and support its clinical development in a range of hematologic and solid p53 wild-type (WT) malignancies, as a monotherapy and in combination with SoC agents."

Journal • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Targeted Protein Degradation

The MDM2 degraders KTX-049 and KT-253 are highly active in wild-type TP53 (WT p53) Merkel cell carcinoma (MCC) (EORTC-NCI-AACR 2024) - "Here, we analyze the in vitro and in vivo efficacy of MDM2 degraders in MCC tumor models and compare their efficacy to an MDM2 small molecule inhibitor, DS-3032.Materials and Established MCCP cell lines with WT or mutant (MUT) p53 and two MCCP patient derived cell lines (PDCLs) with WT p53 were treated with KTX-049, a tool MDM2 degrader, or DS-3032. Selective and potent MDM2 degraders including clinical stage KT-253 show promising efficacy in WT p53 MCC preclinical models. These results support exploration of KT-253 clinical activity in WT p53 MCC where degradation of MDM2 is one of the key mechanisms for impeding tumor growth."

Tumor mutational burden • Endocrine Cancer • Merkel Cell Carcinoma • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • ANXA5 • CASP3 • CASP7 • EP400 • MYCL • TMB • TP53

KT253-AL-101: Safety and Clinical Activity of KT-253 in Adult Patients with High Grade Myeloid Malignancies, Acute Lymphocytic Leukemia, Lymphoma, Solid Tumors (clinicaltrials.gov) - P1 | N=70 | Active, not recruiting | Sponsor: Kymera Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • Solid Tumor

Kymera Therapeutics Announces Third Quarter 2024 Financial Results and Provides a Business Update (GlobeNewswire) - "Dose escalation and enrollment have been completed for both the KT-333 and KT-253 Phase 1 trials. Based on an overall assessment of its clinical oncology programs, and given progress across the immunology pipeline, the Company has made the strategic decision not to continue development of KT-333 (STAT3) and KT-253 (MDM2) beyond Phase 1. Kymera plans to present STAT3 Phase 1 data at a poster presentation at ASH in December. The Company is evaluating partnership opportunities to advance the oncology pipeline beyond its current stage."

Discontinued • Trial status • Acute Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Solid Tumor

Predictive Markers of Response to the MDM2 Degrader KT-253 (EORTC-NCI-AACR 2024) - P1 | "ConclusionsWe identified morphologic and molecular biomarkers of response to KT-253 in adult solid tumors. The responder signature is being further validated and refined using prospectively selected PDX models and emerging clinical data."

Biomarker • Acute Lymphocytic Leukemia • CNS Tumor • Endocrine Cancer • Ewing Sarcoma • Gastrointestinal Cancer • Hematological Malignancies • Hepatoblastoma • Leukemia • Lymphoma • Melanoma • Myelofibrosis • Neuroblastoma • Neuroendocrine Tumor • Oncology • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Wilms Tumor

Kymera Therapeutics Announces Three Scientific Presentations at the EORTC-NCI-AACR 2024 Symposium (GlobeNewswire) - "Kymera Therapeutics, Inc...announced that new preclinical data from its innovative TPD platform will be presented across three poster presentations at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics being held October 23-25, 2024, in Barcelona, Spain. The presentations include new data on its preclinical biomarker-based approach for KT-253, its MDM2 degrader....The Company will also present a poster highlighting its innovative platform capabilities and the case study of the use of targeted protein degradation to provide improved potency and selectivity over traditional small molecule inhibitors for CDK2, a cell cycle regulator and key protein involved in several cancers."

Preclinical • Merkel Cell Carcinoma

Kymera Therapeutics Announces Scientific Presentations at the American Association for Cancer Research 2024 Annual Meeting (GlobeNewswire) - "Kymera Therapeutics, Inc...announced that new preclinical data showing the structural and molecular mechanisms underlying anti-tumor activity of its novel STAT3 degrader, KT-333, were presented in a late-breaking research poster session at the AACR Annual Meeting taking place April 5-10, 2024, in San Diego, California. Additionally, Nello Mainolfi, PhD, Founder, President and CEO, will present in the Major Symposium at the conference highlighting the Company’s unique target selection strategy and strong preclinical to clinical translation observed across the Company’s first-in-class oncology programs, KT-333 and KT-253, a potent and selective degrader of MDM2.... In the STAT3-dependent SUDHL-1 lymphoma xenograft model, reduced expression of canonical STAT3 targets and down-regulation of cytokine-mediated signaling and cell cycle signature genes indicated that cell cycle arrest and subsequent apoptosis were the main drivers of efficacy for KT-333."

Late-breaking abstract • Preclinical • Hematological Malignancies • Lymphoma • Oncology • Von Hippel-Lindau Syndrome

Kymera Therapeutics Announces Second Quarter 2024 Financial Results and Provides a Business Update (GlobeNewswire) - "Dose escalation in the KT-253 Phase 1a clinical trial is ongoing in both Arm A (solid tumors and lymphomas) and Arm B (high grade myeloid malignancies). The Company expects to complete enrollment in the second half of 2024 and subsequently to share the Phase 1a data set as well as guidance on next development steps. Kymera is developing a biomarker-based patient selection strategy for subsequent development beyond Phase 1a and plans to present data later in 2024 at a medical meeting....STAT3 Degrader Program: The Phase 1a clinical trial is ongoing with enrollment focused on Hodgkin’s lymphoma based on encouraging clinical responses. Additionally, the Company is exploring opportunities for future expansion into solid tumors in combination with immune checkpoint inhibitors and other targeted therapies. The Company expects to complete enrollment of the Phase 1a trial and share data in the second half of 2024."

Enrollment status • P1 data • Acute Lymphocytic Leukemia • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Oncology • Solid Tumor

Safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KT-253, a targeted protein degrader of MDM2, in patients with relapsed/refractory (R/R) solid tumors, lymphoma, high grade myeloid malignancies and acute lymphoblastic leukemia (ALL). (ASCO 2024) - P1 | "KT-253 results in potent upregulation of p53-dependent biomarkers and has demonstrated early signs of anti-tumor activity including objective responses in MCC and AML at doses that are well tolerated. Dose escalation is ongoing at DL4 in Arm A and at DL2 in Arm B and analyses from additional pts will be presented at the meeting."

Clinical • PK/PD data • Acute Lymphocytic Leukemia • Adenoid Cystic Carcinoma • Eye Cancer • Fatigue • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Hypotension • Leukemia • Lymphoma • Melanoma • Merkel Cell Carcinoma • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Neutropenia • Non-melanoma Skin Cancer • Oncology • Pain • Renal Cell Carcinoma • Sarcoma • Skin Cancer • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • Uveal Melanoma • CDKN1A • GDF15 • MDM2

Kymera Therapeutics to Present New Clinical Data from Ongoing Phase 1 Trial of MDM2 Degrader KT-253 at ASCO Annual Meeting (GlobeNewswire) - P1 | N=70 | NCT05775406 | Sponsor: Kymera Therapeutics, Inc. | "Disease Response Assessments: Arm A: One partial response confirmed in a MCC patient in DL1. Additionally, 3 stable diseases were reported for patients with fibromyxoid sarcoma, ACC, and renal cell cancer in DL1-3, respectively; Arm B: One confirmed complete response in DL2 and one confirmed partial response in DL1, both in patients with post-myeloproliferative neoplasm (MPN) acute myeloid leukemia (AML); Pharmacodynamic (PD) data from Arm A (DL1-4) and Arm B (DL1-2) demonstrated rapid upregulation of plasma GDF-15 protein and upregulation of CDKN1A and PHLDA3 mRNA levels in blood....The Company expects to complete the study and share additional clinical data to inform the program’s next development steps in 2024 at an upcoming medical meeting."

P1 data • Acute Myelogenous Leukemia • Fibrosarcoma • Genito-urinary Cancer • Hematological Malignancies • Merkel Cell Carcinoma • Myeloproliferative Neoplasm • Oncology • Renal Cell Carcinoma • Solid Tumor

Kymera Therapeutics Announces First Quarter 2024 Financial Results and Provides a Business Update (GlobeNewswire) - "KT-253 MDM2 Degrader: The dose escalation portion of the Phase 1a clinical trial in liquid and solid tumors is ongoing. Kymera will present KT-253 clinical data updates in a poster at the upcoming American Society of Clinical Oncology (ASCO) meeting being held May 31 – June 4, 2024, in Chicago, Illinois. The Company expects to complete the MDM2 Phase 1a study and share the full data set later in 2024 at a medical meeting. Kymera is also developing a biomarker-based patient selection strategy for subsequent development beyond Phase 1a and will present data at a medical meeting this year....The dose escalation portion of the Phase 1a clinical trial in liquid and solid tumors is ongoing. Kymera will present KT-333 clinical data updates in a poster at the upcoming European Hematology Association (EHA) meeting being held June 13-16, 2024, in Madrid, Spain. The Company expects to complete the Phase 1a study and share the full data set later in 2024 at a medical meeting."

Clinical • P1 data • Acute Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Prolymphocytic Leukemia • Solid Tumor

Targeting validated but un-drugged oncogenes with small molecule protein degraders (AACR 2024) - "We believe this supports KT-333's potential to address both hematological malignancies as a single agent and solid tumors as a potential novel combination therapy with anti-PD-1 or other targeted therapies.KT-253 is a highly potent heterobifunctional degrader of the murine double minute 2 (MDM2) oncoprotein, a key E3 ligase that modulates the most common tumor suppressor, p53. One patient with a partial response had MCC metastatic to abdominal lymph nodes and skin who had previously been treated with chemotherapy as well as multiple different immune checkpoint inhibitors. Lymph node metastases were responding after the first 2 cycles of treatment, as was the skin metastasis, and after 4 cycles there was an approximately 60% reduction in nodal tumor burden and resolution of the skin metastasis.In summary, these preclinical and early clinical findings support a clear degrader advantage by eliminating oncogenic proteins in key signaling pathways and validate our..."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Cutaneous T-cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • T Cell Non-Hodgkin Lymphoma • GDF15 • MDM2

Kymera Therapeutics Announces Scientific Presentations at the American Association for Cancer Research 2024 Annual Meeting (GlobeNewswire) - "The Phase 1a trials for KT-333 and KT-253 are currently ongoing. The Company expects to complete both studies and share additional clinical data to inform the programs’ next development steps in 2024 at upcoming medical meetings."

P1 data • Acute Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Prolymphocytic Leukemia • Solid Tumor

Kymera Therapeutics Outlines Key 2024 Objectives and Strategy to Progress Leading Portfolio of Immunology and Oncology Programs (GlobeNewswire) - "Kymera’s corporate goals for 2024 include:...Oncology Portfolio...(i) Complete the KT-333 (STAT3) Phase 1a study and deliver additional proof-of-concept data to inform the program’s next development steps in 2024; (ii) Complete the KT-253 (MDM2) Phase 1a study and deliver proof-of-concept data, which will inform a patient stratification strategy for the program in 2024."

P1 data • Trial status • Acute Myelogenous Leukemia • Cutaneous T-cell Lymphoma • Lymphoma • Peripheral T-cell Lymphoma • Solid Tumor

Safety and Clinical Activity of KT-253 in Adult Patients With High Grade Myeloid Malignancies, Acute Lymphocytic Leukemia, Lymphoma, Solid Tumors (clinicaltrials.gov) - P1 | N=70 | Recruiting | Sponsor: Kymera Therapeutics, Inc.

Metastases • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • Solid Tumor

Kymera Therapeutics Announces Third Quarter 2023 Financial Results and Provides a Business Update (GlobeNewswire) - P1 | N=60 | NCT05775406 | Sponsor: Kymera Therapeutics, Inc | "The Company announced that the KT-253 Phase 1 trial has completed enrollment to the first 2 dose levels of Arm A (solid tumors and lymphomas) with enrollment to DL3 ongoing, achieving clinical proof-of-mechanism and initial anti-tumor activity. Enrollment to Arm B (high grade myeloid malignancies, including AML) has recently commenced, and Kymera intends to present data from the KT-253 Phase 1 clinical trial at a medical meeting in 2024...A total of 9 solid tumor patients enrolled across DL1 (n=3), DL2 (n=4) and DL3 (n=2) have received a mean of 2.3 cycles (range 1-6), with initial PD available for both DL1 and DL2 while clinical response data are available only for DL1...A patient in DL1 with relapsed/refractory Merkel cell carcinoma had a confirmed partial response (PR) after 4 cycles with treatment continuing after 6 cycles..."

P1 data • Trial status • Acute Myelogenous Leukemia • Merkel Cell Carcinoma

Kymera Therapeutics Presents Preclinical Data Demonstrating Activity of MDM2 Degraders in Acute Myeloid Leukemia and Merkel Cell Carcinoma (GlobeNewswire) - "Kymera Therapeutics, Inc...reported preclinical data highlighting the therapeutic potential in liquid and solid tumors of potent and selective heterobifunctional degraders of MDM2, including KT-253. The data was presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on October 11-15, 2023, in Boston, Massachusetts and will also be shared at the 10th International MDM2 Workshop taking place October 15-18, 2023, in Tokyo, Japan....These data demonstrate in vitro efficacy of an MDM2 degrader, KTX-049, against p53 wild-type MCC cell lines that was achieved with brief compound exposure. In two MCC PDX models, KT-253 (referred to as KTX-169 in the presentation) demonstrated tumor regressions with weekly as well as every three-week dosing whereas an MDM2 SMI only showed modest tumor growth inhibition."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

Kymera Therapeutics Announces Second Quarter 2023 Financial Results and Provides a Business Update (GlobeNewswire) - "Anticipated Upcoming Milestones...Kymera plans to share updates on its clinical-stage oncology programs later this year, including data evaluating anti-tumor activity in the target patient populations for KT-333 and KT-413 and initial safety and proof-of-mechanism data from the KT-253 Phase 1 clinical trial."

P1 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Cutaneous T-cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Marginal Zone Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma

Kymera Therapeutics Receives FDA Orphan Drug Designation for KT-253, a Novel, Highly Potent and Selective MDM2 Degrader for the Treatment of Acute Myeloid Leukemia (GlobeNewswire) - "Kymera Therapeutics...announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to KT-253 for the treatment of Acute Myeloid Leukemia (AML). KT-253 is a highly potent and selective degrader that targets MDM2, the crucial regulator of the most common tumor suppressor, p53."

Orphan drug • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

PULSE DOSING OF POTENT AND SELECTIVE HETEROBIFUNCTIONAL MDM2 DEGRADER KT-253 DRIVES TUMOR REGRESSION AND DEMONSTRATES DIFFERENTIATED PHARMACOLOGY COMPARED TO P53/MDM2 SMALL MOLECULE INHIBITORS. (EHA 2023) - "MDM2 SMI DS-3032 was dosed at its clinically equivalent dose and regimen of 3 days on/11 days off. In summary, our data suggest that pulsatile, higher doses of the MDM2 degrader KT-253 are superior to more frequent lower doses by inducing rapid apoptosis in MDM2-dependent cancer cells. The acute pulse dosing regimen of KT-253 has the potential to demonstrate an improved efficacy and safety profile compared to the more frequent dosing of MDM2/p53 SMIs in the clinic."

Hematological Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • MDM2

Kymera Therapeutics Presents Data Demonstrating Superior Efficacy of KT-253, a Potent and Selective Heterobifunctional MDM2 Degrader, Compared to Small Molecule Inhibitor in Preclinical Leukemia Models at the European Hematology Association Congress (GlobeNewswire) - "Kymera Therapeutics, Inc...will present preclinical data on KT-253, a potent and selective heterobifunctional MDM2 degrader. The data will be presented at the European Hematology Association (EHA) Congress, taking place from June 8-15, 2023, in Frankfurt, Germany....New results show that a single, high dose of KT-253 administered intravenously (IV) in preclinical models of acute lymphoblastic leukemia (RS4;11 ALL) and acute myeloid leukemia (MV4;11 AML) led to >90% MDM2 degradation in tumors within one hour of dosing, strong p53 upregulation and induction of apoptosis within the first 8-24 hours, and sustained tumor regressions."

Preclinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Solid Tumor

Kymera Therapeutics Doses First Patient in Phase 1 Oncology Trial of MDM2 Degrader KT-253 (GlobeNewswire) - "Kymera Therapeutics, Inc...has recently dosed the first patient in the Phase 1 multicenter, open-label, dose-escalation clinical trial evaluating its investigational MDM2 degrader KT-253. The Phase 1 study will evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and clinical activity of ascending doses of KT-253 in adult patients with relapsed or refractory high grade myeloid malignancies, acute lymphocytic leukemia (ALL), lymphomas, and solid tumors."

Trial status • Acute Lymphocytic Leukemia • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Kymera Therapeutics Announces First Quarter 2023 Financial Results and Provides a Business Update (GlobeNewswire) - "Anticipated Upcoming Milestones: Kymera will present preclinical data highlighting KT-253’s pharmacological profile at the European Hematology Association (EHA) Congress in June and plans to share initial safety and proof-of-mechanism data from the Phase 1 clinical trial later in 2023; The Company will provide clinical trial updates focused on PK/PD and safety on its KT-333 and KT-413 programs at the International Conference on Malignant Lymphoma (ICML) in June. Kymera, as previously announced, intends to present data evaluating anti-tumor activity in the target patient populations for KT-333 and KT-413 later this year."

P1 data • Preclinical • Trial status • Hematological Malignancies • Lymphoma • Oncology