Accutar Biotechnology's First-in-Class Oral PROTAC Degrader AC699 Granted IND Approval in China for ESR1-Mutated ER+/HER2- Metastatic Breast Cancer

▎Accutar Biotech Content Team Report

The role of estrogen receptor (ER) signaling in breast cancer development has been confirmed. For decades, endocrine therapy has been the primary treatment for patients with ER-positive advanced or metastatic breast cancer. Aromatase inhibitors, selective estrogen receptor modulators, and selective ER degraders (SERDs) have become integral components of treatment strategies for ER-positive breast cancer patients. However, due to issues such as drug resistance, there remains an unmet clinical need for this patient population.E3 Ligase Chimeric Degraders Represent a Technological Advance with the Potential to Induce Effective and Deeper ER Degradation。

AC699 is a novel chimeric degrader targeting ERα.It effectively links ER ligands to E3 ligase-recruiting ligands, bringing ERα close to the E3 ligase, which leads to the ubiquitination and subsequent degradation of ERα.Chimeric ER degraders have the unique advantage of degrading ER proteins while avoiding the risk of activating ER signaling. Additionally, these molecules do not degrade along with the target protein, allowing them to be efficiently recycled within the cell. This direct mechanism enables chimeric ER degraders to achieve stronger and more specific ER degradation.

In August 2024, Accutar Biotech announcedAC699 Granted FDA Fast Track Designation for ER-Positive, HER2-NegativeESR1Patients with mutant advanced or metastatic breast cancer whose disease has progressed during or after at least one endocrine-based therapy.

In 2024At the American Society of Clinical Oncology (ASCO) conference, researchers announcedAC699 TreatmentAdvanced or Metastatic Breast CancerPhase 1 Clinical Study Results: As of the data cutoff, a total of 22 patients across three dose groups (100, 200, and 300 mg) had received AC699 treatment. The median age of the patients was 61 years, with a median of 5 prior lines of therapy (range 2–10). Prior treatments included CDK4/6 inhibitors (100%), aromatase inhibitors (91%), fulvestrant (82%), novel oral SERDs or covalent antagonists (SERCA) (23%), and ER chimeric degraders (14%). No dose-limiting toxicities, dose reductions, or treatment-related discontinuations were observed, and the maximum tolerated dose was not reached.

In terms of efficacy, among 12 evaluable patients, 4 (33%) achieved partial response (PR), and the clinical benefit rate (CBR), including patients with stable disease ≥24 weeks, was 42% (5/12).Upon confirmationESR1In the evaluable patient subgroup with mutations, the ORR was 67% (4/6) and the CBR was 83% (5/6).The median treatment duration was 168 days (range 56-336), and 4 of the 7 patients were still receiving AC699 treatment. The researchers concluded that AC699 demonstrated good safety, tolerability, and anti-tumor activity at doses up to 300mg, administered orally once daily.

The approval of this innovative degrader for clinical trials in China means that the product is about to initiate clinical research in China.

References:

[1] Official website of the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of China.Retrieved Apr 8，2025, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c

[2]Accutar Biotechnology Receives FDA Fast Track Designation for AC699 in ER+ / HER2- Breast Cancer. Retrieved Aug 14, 2024 from https://www.accutarbio.com/accutar-biotechnology-receives-fda-fast-track-designation-for-ac699-in-er-her2-breast-cancer/

[3]Preliminary results from a phase 1 study of AC699, an orally bioavailable chimeric estrogen receptor degrader, in patients with advanced or metastatic breast cancer. Retrieved May 29, 2024 from https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3074