Kymera Therapeutics Shares Phase 1 Trial Data on MDM2 Degrader KT-253 at ASCO

Kymera Therapeutics, Inc., a clinical-stage biopharmaceutical company pioneering the development of targeted protein degradation (TPD) therapies, announced promising new data from its ongoing Phase 1 clinical trial of KT-253. This investigational drug, designed as a selective heterobifunctional small molecule degrader of MDM2, has shown initial efficacy in a variety of tumor types. The announcement was made during the American Society of Clinical Oncology (ASCO) Annual Meeting held from May 31 to June 4, 2024.

Encouraging Early Results

KT-253 has demonstrated preliminary signs of effectiveness in treating tumors, including Merkel cell carcinoma (MCC) and acute myeloid leukemia (AML), at well-tolerated doses. Notably, the drug has shown significant upregulation of p53 pathway biomarkers even at the lowest dose levels, indicating effective target engagement. Kymera's Chief Medical Officer, Dr. Jared Gollob, expressed optimism about these findings, which suggest that KT-253 could offer a better therapeutic index compared to traditional MDM2 small molecule inhibitors.

Patient Responses and Safety Profile

The clinical trial data, collected from 24 patients as of April 9, 2024, revealed encouraging responses. In Arm A, which included 16 patients with solid tumors or lymphomas, one patient with MCC achieved a partial response. Additionally, stable disease was observed in patients with fibromyxoid sarcoma, adenoid cystic carcinoma (ACC), and renal cell cancer. In Arm B, consisting of 8 patients with high-grade myeloid malignancies, including AML, one patient achieved a complete response, and another a partial response.

Dr. Naval Daver from The University of Texas MD Anderson Cancer Center, a clinical investigator for the study, highlighted the promising results in AML patients who had previously failed multiple therapies. Importantly, no severe hematologic side effects such as neutropenia or thrombocytopenia, commonly associated with traditional treatments, were observed in either arm of the study. The most frequent adverse events included nausea, fatigue, and decreased appetite.

Next Steps for KT-253

The ongoing Phase 1 trial aims to further evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of KT-253. Kymera plans to share more comprehensive data and insights into its biomarker strategy later this year, which will guide the next phase of the drug's development. The company expects to provide additional updates at a medical meeting in the second half of 2024.

The Mechanism of Action and Future Potential

KT-253 targets MDM2, a critical regulator of the tumor suppressor protein p53, which remains functional in nearly half of all cancers. Unlike traditional small molecule inhibitors that have struggled to stabilize p53 effectively due to a feedback loop increasing MDM2 levels, KT-253 has shown the ability to overcome this loop and induce cancer cell death with brief exposures in preclinical studies.

The Phase 1 trial is designed to assess the potential of KT-253 in patients with relapsed or refractory high-grade myeloid malignancies and various solid tumors. Early evidence supports its mechanism of action and potential efficacy, laying the groundwork for further clinical development.

Conclusion

Kymera Therapeutics' KT-253 represents a promising advancement in the field of oncology, offering a novel approach to targeting the MDM2-p53 pathway. The early clinical data are encouraging, suggesting that KT-253 could become an important new treatment option for patients with difficult-to-treat cancers. The company's ongoing commitment to targeted protein degradation underscores its potential to bring innovative therapies to the clinic, aiming to significantly improve patient outcomes.

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