NTX-301 / PinotBio, Aston Sci., Korea University - LARVOL DELTA

Epigenetic therapy shows promise against treatment-resistant AML (Eurekalert) - "In preclinical models, NTX-301, a hypomethylating agent, was more effective than standard hypomethylating therapy and retained anti-leukemia activity in therapy-resistant and TP53-mutant AML. Researchers also found that the therapy activated the Hippo pathway through targeted epigenetic changes, revealing a previously unrecognized mechanism that may contribute to its anti-leukemia effects."

Preclinical • Acute Myelogenous Leukemia

The novel hypomethylating agent NTX-301 reprograms epigenetic and Hippo signaling pathways and exhibits pre-clinical activity in venetoclax-resistant and TP53-mutant AML. (PubMed, Clin Cancer Res) - "Data suggest that NTX-301 exerts potent anti-leukemia activities superior to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML, in part by suppressing DNMT1 and inducing DNA damage responses and apoptosis, by inducing p53 signaling and demethylating LATS1/2, thus activating Hippo signaling."

IO biomarker • Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CASP8 • DNMT1 • LATS1 • TP53

ORAL HYPOMETHYLATING AGENT NTX-301 DEMONSTRATES POTENT ANTI-LEUKEMIC ACTIVITY AND ENHANCES RESPONSE TO VENETOCLAX IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) (EHA 2026) - "Methods Primary CMML cells were cultured in cytokine-supplemented suspension assays and treated with NTX-301 alone or in comparison with clinically relevant agents including venetoclax, trametinib, decitabine, azacitidine, and hydroxyurea. Summary/Conclusion NTX-301 demonstrates potent anti-leukemic activity in primary CMML cells and robust efficacy in two CMML-PDX models. The observed synergy with venetoclax and the consistent reduction of leukemic burden support further clinical development of NTX-301 as a promising therapeutic strategy for CMML."

Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • CD14 • FUT4 • NDUFA2 • PTPRC

NTX-301 in MDS/AML (clinicaltrials.gov) - P1 | N=22 | Completed | Sponsor: University of Alabama at Birmingham | Active, not recruiting ➔ Completed

Trial completion • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology

Exploring new approaches to widening of the therapeutic index of ADCs with dual-payload design and combination with a novel HMA (AACR 2025) - "Recent approvals of ADCs such as trastuzumab deruxtecan, sacituzumab govitecan have significantly improved patient treatment options, underscoring the clinical potential of this therapeutic class...One promising approach involves the combination of the ADC with NTX-301, a novel 4′-thio-modified analog of decitabine (DAC)...In this study, we present novel strategies to enhance the therapeutic index of ADCs through a dual-payload design and combination with NTX-301. These results highlight the potential of both approaches for further development in cancer treatment."

ADC • Gastric Cancer • Oncology • Solid Tumor • HER-2

Novel Hypomethylating Agent Ntx-301 Exhibits Anti-Leukemia Activity in Venetoclax-Resistant and TP53-Mutant AML (ASH 2023) - "Additionally, NTX-301 treatment increased caspase-8 and cleaved-caspase-8 in AML cells independent of TP53 mutation status, consistence with reports showing caspase-8 hypermethylation in AML and supporting that activation of caspase-8-mediated extrinsic apoptosis as a mechanism of NTX-301 action. In conclusion, our data suggest that NTX-301 has more potent anti-leukemia activities compared to current HMA in clinic and synergizes with venetoclax in venetoclax-resistance and TP53-mutant AML and AML stem/progenitor cells, and warrants clinical evaluation"

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CASP8 • CD34 • CD38 • DNMT1 • FLT3 • MCL1 • MDM2 • PTPRC • TP53

NTX-301 in MDS/AML (clinicaltrials.gov) - P1 | N=22 | Active, not recruiting | Sponsor: University of Alabama at Birmingham | Recruiting ➔ Active, not recruiting | Trial completion date: Mar 2028 ➔ Mar 2026 | Trial primary completion date: Dec 2027 ➔ Mar 2026

Enrollment closed • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology

Pinotbio completes P1a study for its blood cancer therapy NTX-301 (Korea Biomedical Review) - P1a | N=20 | NCT04167917 | "Pinotbio...said Tuesday that it has completed the phase 1a clinical trial for its targeted cancer therapy, NTX-301, in the U.S....The trial focused on patients with hematologic malignancies, particularly those with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) who had no other treatment options. Using a 3+3 design, the trial gradually increased the dosage from 2mg to a maximum of 24mg across 12 patients. The results showed no dose-limiting toxicities (DLTs) or significant adverse reactions, even at the highest dose. The company said the drug's safety and tolerability were demonstrated by the absence of common side effects of existing DNMT1 inhibitors, including neutropenia....Based on these findings, Pinot Bio plans to commence phase 1b/2a trials immediately next month..."

New P1/2 trial • P1 data • Trial completion • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

Clinical activity, pharmacokinetics, and pharmacodynamics of oral hypomethylating agents for myelodysplastic syndromes/neoplasms and acute myeloid leukemia: A multidisciplinary review. (PubMed, J Oncol Pharm Pract) - "Treatment with oral HMAs has the potential to improve quality of life, treatment adherence, and disease outcomes versus parenteral HMAs. Better education of multidisciplinary teams on the factors affecting HMA treatment selection may help to improve treatment outcomes in patients with MDS or AML."

Journal • PK/PD data • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Preclinical evaluation of NTX-301, a Novel DNA Hypomethylating Agent in Ovarian Cancer. (PubMed, Clin Cancer Res) - "NTX-301 is active in OC models. Our findings point to a new mechanism by which epigenetic blockade disrupts lipid homeostasis and promotes cancer cell death."

Journal • Preclinical • Oncology • Ovarian Cancer • Solid Tumor

Preclinical evaluation of NTX-301, a Novel DNA Hypomethylating Agent in Ovarian Cancer (Clin Cancer Res) - "In vivo, monotherapy with NTX-301 significantly inhibited OC and patient derived xenograft (PDX) growth (p<0.05). Decreased SCD levels and increased oxidized lipids were detected in NTX-301-treated xenografts."

Preclinical • Ovarian Cancer

NTX-301 in MDS/AML (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: University of Alabama at Birmingham | Trial completion date: Mar 2025 ➔ Mar 2028 | Trial primary completion date: Dec 2023 ➔ Dec 2027

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

NTX301, a novel DNA hypomethylating agent, targets lipid metabolism in ovarian cancer (AACR 2023) - "Treatment with NTX301 induced significant downregulation of the DNA methyltransferases (DNMTs) 1-3 expression in SKOV3 and OVCAR5 cells compared with decitabine (p<0.05). NTX301 is a potent HMA active in OC models. Our findings point to a new mechanism by which epigenetic blockade disrupts lipid homeostasis and promotes cancer cell death."

Oncology • Ovarian Cancer • Solid Tumor • POU5F1 • SOX2

Integrative Analyses Reveal the Anticancer Mechanisms and Sensitivity Markers of the Next-Generation Hypomethylating Agent NTX-301. (PubMed, Cancers (Basel)) - "Recently, we described the superior therapeutic efficacy of a novel HMA, namely, NTX-301, when used as a monotherapy and in combination with venetoclax in the treatment of acute myeloid leukemia. Multiomics analyses revealed the mechanisms of action (MoAs) of NTX-301 and linked these MoAs to markers of sensitivity to NTX-301 and to the demethylation activity of NTX-301 with high concordance. In conclusion, our findings provide a rationale for currently ongoing clinical trials of NTX-301 and will help guide the development of novel therapeutic options for cancer patients."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor

A phase 1 study of NTX-301, an oral DNMT1 inhibitor, in patients with MDS and AML (trial in progress). (ASCO 2022) - P1 | "NTX-301 offers an improvement over traditional DNA methyltransferase inhibitors (azacitidine, decitabine) by virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity. After the MTD/BED is identified, the safety and efficacy of NTX-301 will be explored further in selected myeloid malignancies. The study began enrolling patients in January 2021 and is still recruiting."

Clinical • P1 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Myelomonocytic Leukemia • Hematological Disorders • Myelodysplastic Syndrome • Transplantation • DNMT1

NTX-301 in MDS/AML (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: University of Alabama at Birmingham | Trial primary completion date: Mar 2023 ➔ Dec 2023

Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

NTX-301 Monotherapy in Advanced Solid Tumours and in Combination With Platinum-based Chemotherapy in Advanced Ovarian & Bladder Cancer and in Combination With Temozolomide in High-grade Glioma (clinicaltrials.gov) - P1/2 | N=12 | Terminated | Sponsor: Xennials Therapeutics Australia Pty Ltd | N=125 ➔ 12 | Trial completion date: Nov 2023 ➔ Nov 2022 | Recruiting ➔ Terminated | Trial primary completion date: Aug 2023 ➔ Nov 2022; Study was terminated by IP Holder (collaborator), PinotBio Inc.

Combination therapy • Enrollment change • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Bladder Cancer • Brain Cancer • CNS Tumor • Genito-urinary Cancer • Glioblastoma • Glioma • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer

The preclinical efficacy of the novel hypomethylating agent NTX-301 as a monotherapy and in combination with venetoclax in acute myeloid leukemia. (PubMed, Blood Cancer J) - No abstract available

Combination therapy • Journal • Monotherapy • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

NTX301 targets platinum resistant ovarian cancer (AACR 2022) - "Treatment with NTX301 induced more significant downregulation of the DNA methyltransferases (DNMTs) 1-3 expression in SKOV3 and OVCAR5 cells compared with decitabine (p<0.05)...We next tested the effects NTX301 in cisplatin (CDDP) resistant OC cells, developed by repeated treatments with CDDP... Our data indicate that NTX301 is a potent HMA which targets ovarian CSCs and re-sensitizes OC cells to chemotherapy, supporting its further development in OC."

Oncology • Ovarian Cancer • Solid Tumor • CASP3 • SLFN11 • SOX2

A Study on Preclinical Efficacy, Underlying Mechanisms, and Sensitivity Markers of a Novel Hypomethylating Agent Ntx-301 in Acute Myeloid Leukemia (ASH 2021) - "As an alternative option, less intensive hypomethylating agents (HMAs), decitabine (DAC) and azacitidine (AZA), are currently being used in these unfit patients...Strikingly, the combined NTX-301 (0.5-2.0 mg/kg) + venetoclax (50 mg/kg) achieved complete tumor remission, no notable toxicity, and prolonged survival benefits over AZA (2.5 mg/kg) + venetoclax (50 mg/kg) in preclinical models of AML... Our study demonstrated an improved therapeutic index of NTX-301 over traditional HMAs, providing a rationale for further clinical development of the agent as a single-agent or in combination with other agents. We also believe that our study for MoAs and biomarkers will improve our understanding of NTX-301."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

NTX-301 Monotherapy in Advanced Solid Tumours and in Combination With Platinum-based Chemotherapy in Advanced Ovarian & Bladder Cancer and in Combination With Temozolomide in High-grade Glioma (clinicaltrials.gov) - P1/2; N=125; Recruiting; Sponsor: Xennials Therapeutics Australia Pty Ltd; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Monotherapy • Bladder Cancer • Brain Cancer • Genito-urinary Cancer • Glioblastoma • Glioma • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer

NTX-301 Monotherapy in Advanced Solid Tumours and in Combination With Platinum-based Chemotherapy in Advanced Ovarian & Bladder Cancer and in Combination With Temozolomide in High-grade Glioma (clinicaltrials.gov) - P1/2; N=125; Not yet recruiting; Sponsor: Pinotbio, Inc.

New P1/2 trial • Bladder Cancer • Brain Cancer • Genito-urinary Cancer • Glioblastoma • Glioma • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer

NTX-301 in MDS/AML (clinicaltrials.gov) - P1; N=20; Recruiting; Sponsor: University of Alabama at Birmingham; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology

Pinobio enters 3 clinical trials…ADC platform technology is being developed [Google translation] (Hankyung) - "Pinobio...announced that it will enter the clinical trials of the expansion cohort of NTX-303, a solid cancer treatment, from the first half of next year. NTX-303 is undergoing phase 1 and 2 clinical trials led by the National Cancer Institute (NCI)...'The blood cancer treatment NTX-301 will be conducting phase 1a clinical trials in Korea from the second half of next year.'"

New P1 trial • New trial • Trial status • Hematological Malignancies • Oncology • Solid Tumor

Pinobio, attracted 20 billion won investment in pre-IPO.. "Development of anticancer drugs" [Google Translation] (Biospectator) - "Pinobio has secured clinical research funding by completing a pre-IPO worth 20 billion won...Pinobio plans to use the funds secured this time for clinical and research and development...'NTX-301'...is currently being recruited for patients with Myeloplastic Syndrome (MDS) in the United States, and is expected to be administered for the first time within this year."

Enrollment status • Financing • Hematological Malignancies • Myelodysplastic Syndrome • Oncology