beroterkib anhydrous (ASTX029) / Otsuka, Mosaic Therapeutics - LARVOL DELTA

ERK1/2 Inhibition Overcomes Resistance to Venetoclax in AML By Inhibiting Drp1 Dependent Mitochondrial Fission (ASH 2023) - "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."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • Solid Tumor • MCL1 • NRAS

ERK1/2 Inhibition Mediates Bax Dependent Proteolysis of OPA1 and Induces Mitochondrial Cristae Remodeling to Overcome Resistance to Venetoclax (ASH 2024) - P1/2 | "Our work with ASTX029 and Compound 27, inhibitors of ERK1/2, linked suppressed mitochondrial fission as a mechanism of overcoming MAPK driven resistance to ABT199 in AML. We demonstrated that ERK1/2 inhibition decreased phosphorylation of DRP1, a dynamin like GTPase that drives mitochondrial fission, induced apoptosis in combination with ABT199 in vitro and extended the survival of PDX mouse model of post-ABT199/decitabine relapsed AML (Sharma et al., Blood...Conclusion : Inhibition of ERK1/2, results in mitochondrial dysfunction and mediates Bax dependent proteolysis of Opa1 in AML, which alters mitochondrial cristae width and releases cytochrome C to overcome ABT199 resistance. The findings in this study provide a strong rationale for combining Bcl-2 and ERK1/2 inhibitors as part of an AML treatment protocol."

IO biomarker • Metabolic Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • BAX • BCL2 • KRAS • NRAS

Study of ASTX029 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=192 | Completed | Sponsor: Taiho Oncology, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Mar 2025

Trial completion • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • BRAF

A Phase 1B/2A Trial of Combination of ASTX727 With ASTX029 in Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: 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

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KRAS • NF1 • PTPN11

Study of ASTX029 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=190 | Active, not recruiting | Sponsor: Taiho Oncology, Inc. | Trial primary completion date: Apr 2024 ➔ Aug 2024

Trial primary completion date • Oncology • Solid Tumor

Phase I/II Study of a Combination of Decitabine and Cedazuridine (ASTX727) and ASTX029, an ERK Inhibitor, for Patients With RAS Pathway Mutant Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: M.D. Anderson Cancer Center | N=36 ➔ 0 | Initiation date: Jul 2024 ➔ Jan 2025 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial initiation date • Trial withdrawal • Hematological Malignancies • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology

Activity of ERK1/2 inhibitor ASTX029 in patients with gynecological malignancies harboring genomic alterations in the MAPK pathway (ESMO 2024) - P1/2 | "ASTX029 was well-tolerated and induced PR in four subjects (ORR of 12.5%). The response following MEKi therapy suggests further study in this population is warranted."

Clinical • Cervical Cancer • Colorectal Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • KRAS

Study of ASTX029 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=190 | Active, not recruiting | Sponsor: Taiho Oncology, Inc. | N=300 ➔ 190

Enrollment change • Metastases • Oncology • Solid Tumor

Study of ASTX029 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=300 | Active, not recruiting | Sponsor: Astex Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Oncology • Solid Tumor

Phase I/II Study of a Combination of Decitabine and Cedazuridine (ASTX727) and ASTX029, an ERK Inhibitor, for Patients With RAS Pathway Mutant Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms (clinicaltrials.gov) - P1/2 | N=36 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

New P1/2 trial • Hematological Malignancies • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology

A Phase 1B/2A Trial of Combination of ASTX727 With ASTX029 in Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=42 | Suspended | Sponsor: M.D. Anderson Cancer Center | Phase classification: P1b/2a ➔ P1/2 | Not yet recruiting ➔ Suspended

Phase classification • Trial suspension • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KRAS • NF1 • PTPN11

A Phase 1B/2A Trial of Combination of ASTX727 With ASTX029 in Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=42 | Suspended | Sponsor: M.D. Anderson Cancer Center

New P1/2 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KRAS • NF1 • PTPN11

ASTX029 is a dual mechanism ERK1/2 inhibitor with activity in models of MAPK-inhibitor resistance. (AACR-NCI-EORTC 2023) - No abstract available

Oncology

Study of ASTX029 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=300 | Recruiting | Sponsor: Astex Pharmaceuticals, Inc. | Trial completion date: Dec 2023 ➔ Dec 2025 | Trial primary completion date: Jun 2023 ➔ Jun 2024

Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

ERK1/2 INHIBITION OVERCOMES RESSITANCE TO BCL2 INHIBITION IN ACUTE MYELOID LEUKEMIA BY IMPACT ON MITOCHONDRIAL DYNAMICS AND FUNCTION (EHA 2023) - "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."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2 • CD34 • FLT3 • KRAS • MAP2K1 • MCL1 • PTPRC

ERK1/2 inhibition overcomes resistance to venetoclax in AML by altering mitochondrial metabolism (AACR 2023) - "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."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • CD44 • GLI2 • KRAS • MYC • NRAS

[VIRTUAL] Immune modulation by the dual-mechanism ERK inhibitor, ASTX029, in MAPK-activated tumor models (AACR 2021) - P1/2 | "Approaches targeting the immune system have elicited durable responses and led to the approval of checkpoint inhibitors such as the anti-PD1 therapy, pembrolizumab, in indications where MAPK pathway activation is often observed, such as melanoma...Further, preclinical studies have demonstrated that in addition to inhibiting MAPK activity in tumor cells, MAPK pathway inhibitors such as the BRAFV600E inhibitor dabrafenib or MEK inhibitor trametinib have promoted a more proinflammatory TME leading to upregulated antigen presentation on tumor cells, increased CD8+ T cell infiltration and tumor cell killing. Similar preclinical results were recently reported for a KRASG12C inhibitor, AMG 510, where treatment of in vivo models led to an increase in tumor infiltrating lymphocytes, macrophages, dendritic cells and an increase in active immune gene signatures leading to tumor immunity...Our results were consistent with increased immune activation, including increased..."

IO biomarker • Preclinical • Melanoma • Oncology • Solid Tumor • CD8 • KRAS

Transcriptomics-based stratification of response to MAPK inhibition in vitro better predicts sensitivity to single agent and combination treatment than MAPK genomic alteration status alone (AACR 2022) - P1/2 | "Targeted MAPK pathway inhibitors have been approved as therapies in patient populations with genomic alterations to MAPK pathway genes (e.g. dabrafenib in BRAF-mutant melanoma), with multiple other MAPK-targeted therapies in development...However, MAPK oncogene status alone is not a universal indicator of sensitivity, nor is it clear that genomic markers of sensitivity to single agent inhibition represent the optimal approach to predicting response to MAPK targeted agents in the combination setting (e.g. sotorasib + trametinib)...The sensitivity was further increased when considering response to the combination of an ERK and SHP2 inhibitor compared to the ERK inhibitor as a single agent.This analysis demonstrates the potential use of MAPK pathway-related transcriptomics-based scores for the stratification of MAPK pathway inhibitor response. ASTX029 is currently undergoing clinical development in advanced solid tumours (NCT03520075) and transcriptomics-based..."

Preclinical • Melanoma • Oncology • Solid Tumor • BRAF

ERK1/2 Inhibition Overcomes Resistance in Acute Myeloid Leukemia (AML) and Alters Mitochondrial Dynamics (ASH 2021) - P1/2 | "It is a close analog of ASTX029, a dual-mechanism ERK inhibitor currently under clinical investigation in solid tumors (NCT03520075). ERK inhibition by Compound 27 synergizes with 5-azacitidine, ABT-199 and AC220 and can overcome primary or acquired resistance. The impact on mitochondrial dynamics suggests a potential impact on leukemia stem cells. Additional mechanistic confirmatory work is in progress."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2L1 • CCNB1 • CCND1 • CD34 • CD44 • CDK4 • CXCR4 • FLT3 • MCL1 • MYC • NRAS • PTPRC

ERK1/2 Inhibition Overcomes Resistance to Venetoclax in AML By Altering Drp1-Dependent Mitochondrial Fission and Metabolism (ASH 2022) - P1/2 | "2018) a close analog of ASTX029, which is currently under clinical investigation in solid tumors (NCT03520075), was highly synergistic with venetoclax at inducing apoptosis in AML cells. ERK1/2 inhibition alters Drp1 dependent mitochondrial dynamics and metabolism, resulting in mitochondrial defects and overcoming 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."

IO biomarker • Acute Myelogenous Leukemia • Gastrointestinal Cancer • Hematological Malignancies • Hepatology • Leukemia • Metabolic Disorders • Oncology • Pancreatic Cancer • Solid Tumor • CD34 • CD44 • GLI2 • KRAS • MCL1 • MYC • NRAS • PTPN11

Inhibition of ERK1/2 Reverses Venetoclax-Induced Autophagy to Overcome Resistance in Acute Myeloid Leukemia (ASH 2022) - P1/2 | "2018), a close analog of ASTX029, which is a dual-mechanism ERK1/2 inhibitor currently under clinical investigation in solid tumors (NCT03520075). Mechanistically, our results indicate that pharmacological inhibition of ERK1/2 impairs autophagy and sensitizes venetoclax-resistant AML cells to apoptosis, thus overcoming primary and secondary resistance to venetoclax. In addition, combination treatment induced apoptosis of LICs and reduced clonogenic potential and markers of stem cell function. 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."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ATF4 • BECN1 • CASP3 • CD34 • CD44 • MYC • NRAS

[VIRTUAL] Anti-Tumor Activity of ASTX029, a Dual Mechanism Inhibitor of ERK1/2, in Preclinical AML Models (ASH 2020) - P1/2 | "In summary, the ERK inhibitor, ASTX029, has potent activity against MAPK-activated tumor models, including AML models, and is now being tested in a Phase 1/2 clinical trial in advanced solid tumors (NCT03520075). These data highlight its therapeutic potential for the treatment of AML in patients with mutations leading to MAPK pathway activation and support further investigation in these patient populations."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Melanoma • Oncology • Solid Tumor • BRAF • HRAS • KRAS • NRAS

A combination vertical inhibition approach with inhibitors of SHP2 and ERK provides improved activity in KRAS-mutant pancreatic and colorectal cancer models (AACR-NCI-EORTC 2022) - P1/2 | "We have previously presented data on a large-scale combination cell panel screen using the combination of ASTX029, a dual-mechanism ERK inhibitor which is currently undergoing clinical development in a Phase 1/2 trial in advanced solid tumors (NCT03520075), with an inhibitor of SHP2 that we developed using structure-guided drug design...Conclusions These data support our hypothesis that the combination of SHP2 and ERK inhibitors enhances inhibition of cell growth over the single agents in KRAS-mutant PDAC and CRC cell lines. Our data provide a strong rationale for the use of a vertical inhibition approach with SHP2 and ERK inhibitors in KRAS-mutant PDAC and CRC and warrants further investigation in the clinic."

Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MIA

[VIRTUAL] The clinical candidate, ASTX029, is a novel, dual mechanism ERK1/2 inhibitor and has potent activity in MAPK-activated cancer cell lines and in vivo tumor models. (AACR-NCI-EORTC 2020) - P1/2 | "Discussion The ERK inhibitor, ASTX029 has potent activity against MAPK-activated tumor models and is now being tested in a Phase 1/2 clinical trial. These data highlight the therapeutic potential of the compound for the treatment of MAPK-activated cancers and support its further investigation in the clinic."

Melanoma • Oncology • Solid Tumor • BRAF • KRAS • MAPK1

[VIRTUAL] Combined inhibition of SHP2 and ERK enhances anti-tumour effects in preclinical models (AACR-NCI-EORTC 2020) - P1/2 | "Materials and methods The ERK inhibitor, ASTX029, currently in a Phase I-II clinical trial (NCT03520075), and an advanced SHP2 inhibitor from our internal program were used...Conclusions Combining SHP2 and ERK inhibitors enhanced inhibition of cell growth over single-agent therapies in a range of cell lines with similar effects observed in an in vivo xenograft model. These data suggest that this combined targeting of the MAPK pathway could be effective in several different tumor types and warrants further investigation in the clinic."

Preclinical • Oncology • KRAS