BTX-9341 / BioTheryX - LARVOL DELTA

First-in-human Phase 1 study of BTX-9341, a CDK4/6 bifunctional degrader, as monotherapy and in combination with fulvestrant in patients with advanced and/or metastatic HR+/HER2- breast cancer - first emerging data (SABCS 2025) - P1 | "BTX-9341 monotherapy shows a favorable safety profile, with the most common AEs being decreased neutrophil and white blood cell counts, at doses that show encouraging preliminary PK/PD and efficacy, enabling further evaluation of monotherapy and in combination with fulvestrant. The trial is actively enrolling with anticipated completion of dose escalation enrollment by the end of 2025 (Clinical trial: NCT06515470)."

Clinical • Combination therapy • First-in-human • Metastases • Monotherapy • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK2 • CDK4 • HER-2 • RB1

Characterization of BTX-9341, a bifunctional degrader of CDK4 and CDK6 for HR+/HER2- breast cancer. (SABCS 2024) - "CDK4/6 inhibitors (CDK4/6i) such as palbociclib, abemaciclib and ribociclib are used to treat HR+/HER2- breast cancer, but patients can develop resistance via many mechanisms, several of which converge on upregulation of the cyclin D-CDK4/6 signaling node...BTX-9341 mediated downregulation of CDK2 and cyclin E1, which are known to drive resistance to CDK4/6i, was more pronounced and more sustained than that mediated by CDK4/6 inhibitors including approved inhibitors such as palbociclib and inhibitors under clinical development such as PF-07220060...These results indicate that utilizing a degrader such as BTX-9341 may be more effective in a post CDK4/6i setting than switching to a new CDK4/6 inhibitor. Based on this data, we have initiated a Phase 1 clinical trial with BTX-9341 as a monotherapy and in combination with fulvestrant, for HR+/HER2- breast cancer patients who have progressed on CDK4/6i therapy."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCNE1 • CDK2 • CDK4 • CDK6 • CRBN • ER • HER-2

First-in-human Phase 1 study of BTX-9341, a first-in-class, CDK4/6 bifunctional degrader, as a monotherapy and in combination with fulvestrant in patients with advanced and/or metastatic HR+/HER2- breast cancer. (SABCS 2024) - "Rachel M. Layman and Dr. Matthew Goetz have contributed equally to this abstract."

Clinical • Combination therapy • Metastases • Monotherapy • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • HER-2

Biotheryx Announces First Patient Dosed in Phase 1 Clinical Trial of BTX-9341, a First-in-Class, Dual Bifunctional Degrader of CDK4/6, as a Monotherapy and in Combination with Fulvestrant for HR+/HER2- Breast Cancer (PRNewswire) - "Biotheryx, Inc...announced that the first patient has been dosed in its Phase 1 clinical trial evaluating BTX-9341, an investigational oral and bifunctional degrader of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6), as a monotherapy and in combination with fulvestrant for patients with advanced and/or metastatic hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer who have previously received CDK4/6 inhibitor therapy either in the adjuvant or metastatic setting."

Trial status • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of BTX-9341 in Advanced and/or Metastatic Breast Cancer (clinicaltrials.gov) - P1 | N=82 | Recruiting | Sponsor: Biotheryx, Inc.

Metastases • New P1 trial • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor

Characterization of BTX-9341, a bifunctional degrader of CDK4 and CDK6 for HR+/HER2- breast cancer and glioblastoma multiforme. (ASCO 2024) - "These downstream effects including inhibition of CDK2 and Cyclin E transcription were sustained up to 72 hours with BTX-9341 treatment but recovered at 24 hours with palbociclib treatment...In HR+ breast cancer cells, BTX-9341 in combination with fulvestrant had a synergistic anti-proliferation effect... BTX-9341, a degrader of CDK4 and CDK6 and inhibitor of CDK2 and Cyclin E transcription, displayed enhanced activity compared to CDK4/6i in breast cancer and GBM in vitro and in vivo. This indicates that a degrader approach to targeting this pathway in breast cancer may be more effective than current therapies, and that BTX-9341 may also be a promising candidate for brain metastases and GBM."

Brain Cancer • Breast Cancer • CNS Tumor • Eye Cancer • Glioblastoma • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor • CDK4 • CDK6 • CDKN2A • CRBN • HER-2

Biotheryx Announces U.S. FDA Clearance of Investigational New Drug Application for BTX-9341, a First-In-Class, Dual Bifunctional Degrader of CDK4/6 (PRNewswire) - "Biotheryx, Inc...today announced that the U.S. Food and Drug Administration (FDA) has cleared the Company's Investigational New Drug (IND) application for BTX-9341, a novel cyclin-dependent kinase 4/6 (CDK4/6) bifunctional degrader. The Company plans to initiate the Phase 1 clinical trial in the second half of 2024 and intends to enroll patients with HR+/HER2- breast cancer resistant to CDK4/6 inhibitor therapies."

IND • New P1 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology

Discovery of BTX-9341, a bifunctional degrader of CDK4 and CDK6 for HR+/HER2- breast cancer (AACR 2024) - "CDK4/6 inhibitors (CDK4/6i) such as palbociclib, abemaciclib and ribociclib are used to treat HR+/HER2- breast cancer, but patients can develop resistance via many mechanisms, several of which converge on the upregulation of the cyclin D-CDK4/6 signaling node. 14 Nov. 2021, doi:10.3390/ijms222212292"

Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • CDK6 • CRBN • ER • HER-2

BTX-9341, a bifunctional degrader of CDK4 and CDK6 for glioblastoma multiforme (AACR 2024) - "This indicates that BTX-9341 may be effective in patient populations for which temozolomide is ineffective...BTX-9341 treated mice also had much better survival than abemaciclib treated mice, the only CDK4/6i which has BBB penetration...The xenograft data indicates that BTX-9341 can inhibit growth of MGMT methylated and unmethylated GBM cell lines, and that BTX-9341 can inhibit tumor growth in the brain more effectively than BBB penetrant CDK4/6i. Together this data shows that BTX-9341 may be a promising candidate for treating GBM."

Brain Cancer • Breast Cancer • CNS Tumor • Glioblastoma • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • CDK4 • CDK6 • CDKN2A • CRBN • HER-2 • MGMT

Discovery of BTX-9341, a bifunctional degrader of CDK4 and CDK6 for HR+/HER2- breast cancer. (SABCS 2023) - "CDK4/6 inhibitors (CDK4/6i) such as palbociclib, abemaciclib and ribociclib are used to treat HR+/HER2- breast cancer, but patients can develop resistance via many mechanisms, several of which converge on the upregulation of cyclin D-CDK4/6 signaling node. These results show that BTX-9341 displays excellent single agent activity in vitro and in vivo particularly in comparison to clinically approved CDK4/6i and that this activity is maintained in CDK4/6i resistant models. This indicates that a degrader approach to targeting this pathway may be more effective than current therapies, and that using this modality in a post CDK4/6i setting may be more effective than switching CDK4/6 inhibitors."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDK4 • CDK6 • CRBN • HER-2

Biotheryx to Present New Preclinical Data on Bifunctional Degraders for CDK4/6 and SOS1 at 2023 ASCO Annual Meeting (PRNewswire) - "Biotheryx...announced two poster presentations at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting....BTX-9341 demonstrated in vitro CDK4 and CDK6 degradation in multiple breast cancer cell lines and potent inhibition of cell proliferation....Biotheryx's SOS1 bifunctional degraders demonstrated antiproliferative effects across a range of KRAS-mutant cell lines. Treatment with SOS1 degraders in KRAS-mutant xenograft models resulted in greater than 90% degradation of SOS1 in tumors and subsequently led to significant tumor growth inhibition as a single agent."

Preclinical • Breast Cancer • Oncology • Solid Tumor

Biotheryx Presents Preclinical CDK4/6 and SOS1 Protein Degrader Data at AACR 2023 Annual Meeting (PRNewswire) - "The presentations highlight preclinical data for bifunctional degraders of cyclin-dependent kinase (CDK) 4/6 for the treatment of solid tumors, and bifunctional degraders of son of sevenless homolog 1 (SOS1) for the treatment of KRAS mutant cancers. Additionally, the Company has nominated BTX-9341 as a development candidate for the CDK4/6 degrader program and has commenced IND-enabling studies....Biotheryx's CDK4/6 bifunctional degraders demonstrated in vitro CDK4 and CDK6 degradation in multiple breast cancer cell lines and potent inhibition of cell proliferation. This potency was shown to be superior to CDK4/6 inhibitors and due to Cereblon-mediated target degradation."

Preclinical • Breast Cancer • Oncology • Solid Tumor