sovilnesib (AMG 650) / Amgen, BeiGene, Volastra Therap - LARVOL DELTA

A novel KIF18A inhibitor for targeting chromosomal instability in cancer (AACR 2025) - "IAM-K1 has robust anti-proliferation activity in a number of cell lines, representing different cancer indications, and is approximately 2-3 fold more potent than a reference compound AMG650...The anti-tumor activity is correlated with an increase in pHH3 in xenograft tumors, consistent with the on-target mechanism of mitotic arrest. Together with a predictive biomarker approach, targeting KIF18A with IAM-K1 and other compounds in this series is expected to provide a novel anti-cancer treatment to patients with a wide therapeutic window."

Oncology • KIF18A

Design, Biological Characterization, and Discovery of Novel Cyclohexenyl Derivatives as Kinesin KIF18A Inhibitors for the Treatment of Ovarian Cancer. (PubMed, ACS Med Chem Lett) - "A novel class of kinesin KIF18A inhibitors were discovered through modification of the clinical compound AMG650...Oral administration of 16 can induce a dose-dependent antitumor efficacy in the OVCAR-3 model without significant reduction in body weight. Compound 16 showed potential as a candidate for the clinical treatment of ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor • KIF18A

A Study of Sovilnesib in Subjects With Ovarian Cancer (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: Volastra Therapeutics, Inc. | Not yet recruiting ➔ Recruiting | Phase classification: P1b ➔ P1

Enrollment open • Metastases • Phase classification • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Solid Tumor

Volastra Therapeutics Announces First Patient Dosed in Phase Ib Clinical Trial of Sovilnesib (Businesswire) - "Volastra Therapeutics...announced it has dosed the first patient in its Phase Ib clinical trial evaluating sovilnesib in patients with platinum-resistant or refractory high-grade serous ovarian cancer (HGSOC). This trial (NCT06084416) is a randomized dose optimization study of once-daily oral sovilnesib at different dose levels to establish the recommended Phase 2 dose....Sovilnesib was granted Fast Track designation in this indication by the U.S. Food and Drug Administration (FDA) based on its initial clinical data as well as the high unmet need in this population."

Fast track designation • Trial status • Ovarian Cancer

GSC000190, a highly potent inhibitor of KIF18A, for tumors with chromosome instability (AACR 2024) - "In vivo, GSC000190, at approximately one tenth of systematic exposure comparing to that of AMG650, the leading clinical KIF18A inhibitor, causes tumor shrinkage in multiple CDX models including ovarian, colon and lung cancers. In an HGSOC PDX model which is resistant to platinum and olaparib, GSC000190 induced strong tumor regression both as single agent and through combination without significant body weight reduction...GSC000190 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GSC000190 is now under IND-enabling study and P1 study is planned in the second quarter of 2024.Legal entity responsible for the study: The authors.Disclosure: All authors have declared no conflicts of interest."

Colon Cancer • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • KIF18A

PRECLINICAL EVALUATION AMG 650, A SMALL MOLECULE INHIBITOR OF KIF18A, IN PEDIATRIC SOLID TUMORS BY THE PEDIATRIC PRECLINICAL IN VIVO TESTING (PIVOT) PROGRAM (CTOS 2023) - "In osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma models, antitumor activity of AMG 650 was variable, ranging from no objective responses to one model with a complete response. Identification of specific determinants of sensitivity and the evaluation of activity in combination will aid in potential use of AMG 650 in these pediatric tumor settings."

Preclinical • Ewing Sarcoma • Oncology • Osteosarcoma • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Wilms Tumor • KIF18A • TP53

Volastra Therapeutics Announces First Patient Dosed in Phase I/II Clinical Trial of VLS-1488, One in a Portfolio of Novel and Differentiated KIF18A Inhibitors (Businesswire) - "Volastra Therapeutics...announced the dosing of the first patient in a Phase I/II clinical trial evaluating VLS-1488. VLS-1488 and sovilnesib (formally AMG650) make up Volastra’s innovative clinical portfolio of differentiated KIF18A inhibitors specifically designed for the treatment of solid tumors characterized by high levels of chromosomal instability (CIN). The Phase I/II trial (NCT05902988) evaluates safety, tolerability and preliminary efficacy of VLS-1488 in patients with advanced tumors....Phase Ib trial for sovilnesib, Volastra’s second KIF18A inhibitor, is anticipated to open in Q1 2024."

Trial status • Ovarian Cancer

A Study of Sovilnesib in Subjects With Ovarian Cancer (clinicaltrials.gov) - P1b | N=120 | Not yet recruiting | Sponsor: Volastra Therapeutics, Inc.

Metastases • New P1 trial • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Solid Tumor

Discovery and preclinical characterization of AMG 650, a first-in-class inhibitor of kinesin KIF18A motor protein with potent activity against chromosomally unstable cancers (AACR 2023) - "Lastly, the combination of AMG 650 with PARP inhibitor Olaparib enhances anti-cancer activity relative to single agent alone in BRCA1- and CCNE1-altered tumor models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via AMG 650, a first-in-class KIF18A inhibitor."

Preclinical • Breast Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • CCNE1 • KIF18A • TP53

Preclinical Data on Volastra Therapeutics’ Two Novel and Differentiated KIF18A Inhibitors Presented at AACR 2023 (Businesswire) - "Volastra Therapeutics...released preclinical data from the company’s portfolio of KIF18A inhibitors at the 2023 American Association for Cancer Research (AACR) Annual Meeting....Sovilnesib findings, presented in a poste...demonstrate robust anti-cancer activity with evidence of durable tumor regressions in a subset of human ovarian and breast tumor models at well-tolerated doses....Findings for one of Volastra’s internally-developed KIF18A inhibitors are shown in a second poster....In this, in vivo data shows substantial, dose-dependent inhibition of tumor growth in multiple tumor models....Volastra will advance clinical development of both sovilnesib and the Volastra-developed KIF18A inhibitor VLS-1488 in 2023."

Clinical • Preclinical • Breast Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Study of AMG 650 in Adult Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=66 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed | N=140 ➔ 66

Enrollment change • Trial completion • Breast Cancer • Endometrial Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

Volastra Therapeutics In-Licenses Clinical Stage KIF18A Inhibitor and Secures $60 Million in Series A Funding to Further Advance Cancer-Focused Pipeline (Businesswire) - "Volastra Therapeutics...announced completion of the in-license of Amgen’s sovilnesib (AMG650), an oral, first-in-class small molecule inhibitor of KIF18A. In parallel, the company has closed a $60 million Series A financing. Under the terms of the licensing agreement, Volastra receives an exclusive worldwide license (ex-China) to develop and commercialize sovilnesib. In return, Amgen receives an upfront mix of cash and equity, as well as downstream milestones and royalties. The drug is currently in Phase 1 for the treatment of platinum-resistant high-grade serous ovarian cancer, triple-negative breast cancer and other solid tumors with TP53 mutations....Volastra will advance clinical development of both sovilnesib and VLS-1488 in 2023."

Financing • Licensing / partnership • Pipeline update • Breast Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer

Study of AMG 650 in Adult Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=140 | Active, not recruiting | Sponsor: Amgen | Trial completion date: Mar 2024 ➔ Feb 2023

Metastases • Trial completion date • Breast Cancer • Endometrial Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

Study of AMG 650 in Adult Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=140 | Active, not recruiting | Sponsor: Amgen | Trial completion date: Apr 2025 ➔ Mar 2024 | Trial primary completion date: Sep 2023 ➔ Oct 2022

Trial completion date • Trial primary completion date • Breast Cancer • Endometrial Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

Study of AMG 650 in Adult Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=140 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • Endometrial Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

Study of AMG 650 in Adult Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=140 | Recruiting | Sponsor: Amgen | Trial completion date: Apr 2024 ➔ Apr 2025

Trial completion date • Breast Cancer • Endometrial Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

Discovery of AMG 650, a first-in-class KIF18A inhibitor for the treatment of chromosomally unstable cancers (ACS-Sp 2022) - "AMG 650 binds to the complex formed by the motor domain of KIF18A and tubulin, exploiting unique interactions in this ternary complex. AMG 650 has advanced to Phase I clinical testing in patients with advanced solid tumors that harbor TP53 genetic mutations."

CNS Disorders • Oncology • Solid Tumor • TP53

Study of AMG 650 in Adult Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=140 | Recruiting | Sponsor: Amgen | Trial primary completion date: Oct 2022 ➔ Sep 2023

Trial primary completion date • Breast Cancer • Endometrial Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

[VIRTUAL] Trial in progress: A phase 1, multicenter, open-label, dose-exploration and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and efficacy of AMG650 in subjects with advanced solid tumors. (ASCO 2021) - P1 | "Continuous monitoring of toxicity is conducted . The study began enrolling pts in March 2020 and is ongoing."

Clinical • P1 data • PK/PD data • Breast Cancer • Endometrial Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • TP53

Study of AMG 650 in Adult Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=120; Recruiting; Sponsor: Amgen; Trial completion date: Oct 2023 ➔ Apr 2024; Trial primary completion date: Jun 2022 ➔ Oct 2022

Clinical • Trial completion date • Trial primary completion date • Breast Cancer • Endometrial Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer

Study of AMG 650 in Adult Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=120; Recruiting; Sponsor: Amgen; Trial completion date: Mar 2023 ➔ Oct 2023; Trial primary completion date: Nov 2021 ➔ Jun 2022

Clinical • Trial completion date • Trial primary completion date • Breast Cancer • Endometrial Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • HER-2

Study of AMG 650 in Adult Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=120; Recruiting; Sponsor: Amgen; Not yet recruiting ➔ Recruiting; Trial completion date: Nov 2023 ➔ Mar 2023; Trial primary completion date: Jul 2022 ➔ Nov 2021

Clinical • Enrollment open • Trial completion date • Trial primary completion date • HER-2

Study of AMG 650 in Adult Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=120; Not yet recruiting; Sponsor: Amgen

Clinical • New P1 trial