HH2853

P1/2, N=100, Recruiting, Haihe Biopharma Co., Ltd. | Trial primary completion date: Apr 2025 --> Oct 2025

HH2853 is a novel dual EZH1/2 inhibitor that exhibits superior antitumour activity compared to tazemetostat across various preclinical models. A phase II trial of HH2853 in patients with ES is underway. The Science, Technology and Economic Commission of Shanghai Pudong New Area Municipality and Shanghai Haihe Biopharma Co., Ltd.

The selective EZH1/2 dual inhibitor HH2853 demonstrated acceptable and manageable safety profiles and promising efficacy in r/r PTCL patients, indicating its therapeutic potential for this difficult-to-treat patient population.

P1/2, N=100, Recruiting, Haihe Biopharma Co., Ltd.

Dual-target inhibitors, exemplified by EZH1/2 inhibitor HH-2853(28), offer enhanced efficacy and reduced adverse effects. This review highlights recent advancements in dual inhibitors targeting EZH2 and other proteins like BRD4, PARP1, and EHMT2, emphasizing rational design, structure-activity relationships, and safety profiles, suggesting their potential in clinical applications.

P1/2, N=254, Recruiting, Haihe Biopharma Co., Ltd. | N=168 --> 254

P1/2, N=168, Recruiting, Haihe Biopharma Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

The 6-month OS rates was 91.97% (95%CI: 71.50%, 97.93%). Conclusions The selective EZH1/2 dual inhibitor HH2853 demonstrated good safety and promising efficacy in r/r PTCL patients, indicating its potential as a therapeutic option for this difficult to treat patient population.

We have discovered a novel EZH1/2 inhibitor HH2853 with a better antitumor effect than EPZ-6438 in preclinical studies. On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor; co-treatment with ferroptosis inducer erastin effectively overrode the resistance of DLBCL to EZH2i in vitro and in vivo. Altogether, this study reveals iron-dependent resistance evoked by EZH2i in DLBCL cells, and suggests that combination with ferroptosis inducer may be a promising therapeutic strategy.

Tazemetostat (an EZH2 inhibitor) has been approved by FDA for clinical use in ES. HH2853 showed an acceptable safety profile and promising anti-tumor activity in heavily pretreated ES pts with a wide therapeutic window, providing evidence for further investigation. Clinical trial information: NCT04390737.

HH2853 is a novel selective EZH1/2 dual inhibitor, which has demonstrated superior anti-tumor efficacy to tazemetostat (EZH2 inhibitor approved by FDA) in various preclinical models. This is a first-in-human, open-label, multi-center, phase (Ph) I/II study of HH2853 in patients (pts) with relapsed/refractory (r/r) non-Hodgkin lymphomas (NHLs) or advanced solid tumors. This first-in-human study of HH2853 showed a manageable safety profile and promising anti-tumor activity in multiple tumor types, supporting further exploration in NHLs and solid tumors after recommended Ph II dose is determined.Clinical trial information: NCT04390737

Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell lymphoma with a poor prognosis. Several other dual EZH1/2 inhibitors such as HH2853, HM97594, and HM97662 have also demonstrated potential in treating malignant tumors. Dual targeting EZH1/2 may have promising antitumor action in hematological malignancies and solid tumors.