ZN-c5

After fully profiling the compound, we nominated compound 4 (ZN-c5) for clinical development. Compound 4 advanced into Phase 1/2 clinical trials, which demonstrated high human exposure upon dosing patients with 50 mg once a day.

Our strategy to convert the acrylic acid-containing motif of ZN-c5 to a basic amine-containing tail resulted in compounds with much improved brain penetration and excellent ER degradation activity. Further optimization led to the discovery of compound 5 with excellent in vitro and in vivo efficacy. Compound 5 showed good in vitro ADME properties, good oral bioavailability in mouse, rat, and dog, as well as superior brain penetration, which translated into excellent efficacy in multiple brain metastasis breast cancer mouse models.

P1/2, N=181, Completed, Zeno Alpha Inc. | Active, not recruiting --> Completed | Trial completion date: Jun 2024 --> Dec 2022

P1b, N=14, Completed, Zeno Alpha Inc. | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Oct 2022 | Trial primary completion date: Apr 2023 --> Oct 2022

P1, N=35, Completed, Zeno Alpha Inc. | Recruiting --> Completed

P1/2, N=181, Active, not recruiting, Zeno Alpha Inc. | Recruiting --> Active, not recruiting | N=458 --> 181 | Trial primary completion date: Dec 2023 --> Apr 2022

P1b, N=14, Active, not recruiting, Zeno Alpha Inc. | Recruiting --> Active, not recruiting

In the ER-positive MCF-7 efficacy model, ZN-c3 demonstrated anti-tumor activity as a single agent as well as in combinations with a CDK4/6 inhibitor (Palbociclib) or ZN-c5, a selective estrogen receptor degrader (SERD). In the MDA-MB-436, a triple negative breast cancer tumor xenograftmodel, ZN-c3 demonstrated efficacy as a single agent and in combination with the PARP inhibitors Olaparib or Niraparib...Moreover, ZN-c3 can overcome the acquired resistance to PARP inhibitors and trastuzumab. ZN-c3 is currently in clinical trials for several indications and has demonstrated promising clinical activity and good tolerability.

P1b, N=24, Active, not recruiting, Zentera Therapeutics HK Limited | Recruiting --> Active, not recruiting

Although fulvestrant binds and degrades the ER and shows anti-tumor activity in patients with advanced breast cancer, intramuscular injection is inconvenient and precludes achievement of higher and potentially more efficacious exposure. Conclusions : In this first-in-human study, ZN-c5 monotherapy was well tolerated and showed clinical benefit, including confirmed PRs, in subjects with advanced ER+/HER2- breast cancer. These data warrant further evaluation of ZN-c5 as monotherapy and in combination with palbociclib.

Although fulvestrant binds and degrades the ER and shows anti-tumor activity in this population, intramuscular injection is inconvenient, associated with injection-site reactions, and precludes achievement of higher and potentially more efficacious exposures. Correlations between biomarkers and clinical outcomes will be explored. Subject recruitment is ongoing.

Combination therapy of fulvestrant or letrozole with palbociclib, a CDK4/6 inhibitor, significantly improved progression-free survival compared to ET alone in phase 3 trials.Trial designThis phase 1/2, open-label, multicenter study is evaluating the safety, pharmacokinetics, and anti-tumor activity of ZN-c5 alone and in combination with palbociclib. Biomarkers and pharmacodynamic effects of therapy will be explored. Subject recruitment is ongoing.