beroterkib anhydrous (ASTX029)

P1/2, N=192, Completed, Taiho Oncology, Inc. | Active, not recruiting --> Completed | Trial completion date: Dec 2025 --> Mar 2025

P1/2, N=0, Withdrawn, M.D. Anderson Cancer Center | N=42 --> 0 | Trial completion date: May 2029 --> Mar 2025 | Suspended --> Withdrawn | Trial primary completion date: May 2027 --> Mar 2025

P1/2, N=190, Active, not recruiting, Taiho Oncology, Inc. | Trial primary completion date: Apr 2024 --> Aug 2024

P1/2, N=0, Withdrawn, M.D. Anderson Cancer Center | N=36 --> 0 | Initiation date: Jul 2024 --> Jan 2025 | Not yet recruiting --> Withdrawn

P1/2, N=190, Active, not recruiting, Taiho Oncology, Inc. | N=300 --> 190

P1/2, N=300, Active, not recruiting, Astex Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

P1/2, N=36, Not yet recruiting, M.D. Anderson Cancer Center

P1/2, N=42, Suspended, M.D. Anderson Cancer Center | Phase classification: P1b/2a --> P1/2 | Not yet recruiting --> Suspended

P1/2, N=42, Suspended, M.D. Anderson Cancer Center

In a PDX mouse model of post venetoclax/decitabine-relapsed AML, ASTX029+venetoclax treatment improved survival compared to vehicle (median survival 76.5 days vs. 50 days, p=0.0006) and venetoclax alone (median survival 76.5 days vs. 51.5 days, p=0.0065) (Figure 1) with corresponding reduction in leukemia burden in bone marrow (p<0.0001) and spleen (p<0.0001). The increased mitochondrial fission driven by ERK1/2 mediated phosphorylation of Drp1 contributes to venetoclax resistance in AML and inhibiting ERK1/2/Drp1 axis overcomes resistance to venetoclax by inhibiting mitochondrial fission (Figure 2). These data provide a strong rationale for the combination of ERK1/2 and Bcl-2 inhibitors in the treatment of AML.

ERK1/2 inhibition demonstrates strong synergy with venetoclax and overcomesresistance to venetoclax. This synergy is largely mediated through effects on mitochondrial structural and functional dynamics. Our findings provide a strong rationale for clinical development of ERK 1/2 inhibitor ASTX029 in the treatment of AML and highlights the impact of targeting mitochondrial dynamics.

2018), an analog of ASTX029, was highly synergistic with venetoclax at inducing apoptosis in AML. The inhibition of ERK1/2 alters mitochondrial metabolism and functional integrity to overcome resistance to venetoclax by causing apoptosis in venetoclax resistant AML cells. These data provide a strong rationale for the combination of ERK1/2 and Bcl-2 inhibitors in treatment of AML and warrant further investigation in the clinic.