MTL-CEBPA / MiNA Therap - LARVOL DELTA

Small activating RNA AW1-51 (CEBPA-51) elicits targeted DNA demethylation to promote gene activation. (PubMed, bioRxiv) - "AW1-51 (also referred to as CEBPA-51), the first small activating RNA therapeutic to enter clinical evaluation, has demonstrated biological activity and safety in Phase II trials for hepatocellular carcinoma, both as monotherapy and in combination with sorafenib, and in Phase 1a/1b in combination with pembrolizumab for patients with advanced solid tumors. In this study, we uncovered the molecular basis for AW1-51-induced transcriptional reactivation of CCAAT enhancer-binding protein alpha demonstrating that by directly promoting DNA demethylation of its promoter restores its expression, protein synthesis, and consequently cell differentiation. These findings unveil AW1-51 as a prototype for RNA-based precision medicine enabling conditional expression of CCAAT enhancer-binding protein alpha in diseases characterized by aberrant gene silencing and extending its potential therapeutic impact beyond cancer."

Journal • Hepatocellular Cancer • Solid Tumor • CEBPA

Small Activating RNA-Mediated Induction of HBG Via Liposome Delivery for In Vivo Treatment of Sickle Cell Disease and Beta-Thalassemia (ASH 2024) - P1 | "Notably, equivalent in vivo delivery efficiency was observed in peripheral blood monocytes, where the activity of another NOV340 formulation (MTL-CEBPA) was previously reported in clinical studies...Collectively, these studies establish that in vivo-delivered saRNA oligonucleotides hold promise for best-in-class in vivo HbF induction, with the potential to achieve protective levels of HbF in a significant proportion of patients. This approach offers significant improvements in safety, tolerability, and accessibility over current gene editing and small molecules therapies in development."

Preclinical • Anemia • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CD34 • CEBPA • HBB

Small Activating RNA-Mediated Induction of HBG Via Liposome Delivery for In Vivo Treatment of Sickle Cell Disease and Beta-Thalassemia (ASH 2024) - P1 | "Notably, equivalent in vivo delivery efficiency was observed in peripheral blood monocytes, where the activity of another NOV340 formulation (MTL-CEBPA) was previously reported in clinical studies...Collectively, these studies establish that in vivo-delivered saRNA oligonucleotides hold promise for best-in-class in vivo HbF induction, with the potential to achieve protective levels of HbF in a significant proportion of patients. This approach offers significant improvements in safety, tolerability, and accessibility over current gene editing and small molecules therapies in development."

Preclinical • Anemia • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CD34 • CEBPA • HBB

A phase I study of MTL-CEBPA, atezolizumab (atezo) and bevacizumab (bev) in advanced hepatocellular carcinoma (HCC) (ESMO 2025) - P1 | "Conclusions The combination was well tolerated, with encouraging early clinical activity. RP2D was defined as MTL-CEBPA 70 mg/m 2 Q3W."

Metastases • P1 data • Hepatocellular Cancer • Oncology • Solid Tumor • CEBPA

Phase I Study of RNA Oligonucleotide, MTL-CEBPA, Atezolizumab and Bevacizumab in Patients With Advanced Hepatocellular Carcinoma. (clinicaltrials.gov) - P1 | N=33 | Active, not recruiting | Sponsor: National University Hospital, Singapore | Recruiting ➔ Active, not recruiting

Enrollment closed • Tumor mutational burden • Hepatocellular Cancer • Oncology • Solid Tumor

RNA activation of CEBPA improves leukemia treatment. (PubMed, Mol Ther Nucleic Acids) - "Importantly, MTL-CEBPA enhances the efficacy of commonly prescribed FLT3 inhibitor, gilteritinib, both in vitro and in vivo. All together, these findings support RNAa of CEBPA as a potential adjuvant therapy for FLT3-mutated AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CEBPA • FLT3

TIMEPOINT, a phase 1 study combining MTL-CEBPA with pembrolizumab, supports the immunomodulatory effect of MTL-CEBPA in solid tumors. (PubMed, Cell Rep Med) - P1 | "Collectively, these data support a role for MTL-CEBPA in reducing immunosuppression in the TME. This study was registered at ClinicalTrials.gov (NCT04105335)."

IO biomarker • Journal • P1 data • Immunology • Oncology • Solid Tumor • CEBPA

RNAa: Mechanisms, therapeutic potential, and clinical progress. (PubMed, Mol Ther Nucleic Acids) - "Notably, MTL-CEBPA, the first saRNA drug candidate, shows promise in hepatocellular carcinoma treatment, while RAG-01 is being explored for non-muscle-invasive bladder cancer, highlighting clinical advancements in RNAa. This review synthesizes our current understanding of the mechanisms of RNAa and highlights recent advancements in the study of mi-RNAa and the therapeutic development of saRNAs."

Journal • Review • Alzheimer's Disease • Bladder Cancer • CNS Disorders • Genito-urinary Cancer • Hepatocellular Cancer • Metabolic Disorders • Oncology • Otorhinolaryngology • Solid Tumor • CEBPA

OUTREACH: First-in-Human Safety, Tolerability and Antitumour Activity Study of MTL-CEBPA in Patients With Advanced Liver Cancer (clinicaltrials.gov) - P1 | N=75 | Active, not recruiting | Sponsor: Mina Alpha Limited | Trial completion date: Dec 2024 ➔ Jul 2025 | Trial primary completion date: Jan 2024 ➔ Jul 2025

Trial completion date • Trial primary completion date • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CEBPA

A Study of MTL-CEBPA in Combination With a PD-1 Inhibitor in Patients With Advanced Solid Tumours (TIMEPOINT) (clinicaltrials.gov) - P1 | N=50 | Completed | Sponsor: Mina Alpha Limited | Active, not recruiting ➔ Completed | N=108 ➔ 50 | Trial completion date: Jun 2024 ➔ Jan 2025 | Trial primary completion date: Dec 2023 ➔ Jan 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Biliary Tract Cancer • Glioblastoma • Lung Cancer • Melanoma • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • CEBPA • PD-L1

OUTREACH2: Radomised Phase II Study of MTL-CEBPA Plus Sorafenib or Sorafenib Alone (clinicaltrials.gov) - P2 | N=8 | Completed | Sponsor: Mina Alpha Limited | Active, not recruiting ➔ Completed | N=150 ➔ 8 | Trial completion date: May 2025 ➔ Jan 2025

Enrollment change • Trial completion • Trial completion date • Hepatitis B • Hepatitis C • Hepatocellular Cancer • Hepatology • Infectious Disease • Oncology • Solid Tumor • CEBPA

OUTREACH2: Radomised Phase II Study of MTL-CEBPA Plus Sorafenib or Sorafenib Alone (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: Mina Alpha Limited | Recruiting ➔ Active, not recruiting

Enrollment closed • Gastrointestinal Cancer • Hepatitis B • Hepatitis C • Hepatocellular Cancer • Hepatology • Infectious Disease • Oncology • Solid Tumor • CEBPA

OUTREACH: First-in-Human Safety, Tolerability and Antitumour Activity Study of MTL-CEBPA in Patients With Advanced Liver Cancer (clinicaltrials.gov) - P1 | N=75 | Active, not recruiting | Sponsor: Mina Alpha Limited | N=51 ➔ 75 | Trial completion date: Jan 2023 ➔ Dec 2024 | Trial primary completion date: Nov 2022 ➔ Jan 2024

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CEBPA

MiNA Therapeutics Highlights Preclinical Research on RNA Activation (RNAa) Therapeutics Presented at the Oligonucleotide Therapeutics Society (OTS) Annual Meeting (Businesswire) - "MiNA Therapeutics Limited...highlights preclinical research presented by academic partners at the annual meeting of the Oligonucleotide Therapeutics Society (OTS) in Barcelona, Spain. RNAa therapeutics are a revolutionary new class of medicines that can restore or boost normal function of genes and thereby protein-modulated pathways in cells....Finally, the presentation...detailed findings that identified the potential of MTL-CEBPA to treat acute myeloid leukemia (AML), an aggressive blood cancer with low survival rates and high burden of chemotherapeutic treatment side effects."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Transcriptional Upregulation of ɑ-L-iduronidase Utilizing Small-Activating RNA Following Bone Marrow Transplant in a Murine Model of Hurler Syndrome (ASGCT 2023) - "In the current study, it was hypothesized that following bone marrow transplant, MPS I mice treated with an saRNA targeting CEBPA (MTL-CEBPA) would increase Idua expression, and thus enzymatic activity...These results demonstrate the power and flexibility that saRNA-based therapies can provide for patients who have previously received HSCT by transiently over-expressing the therapeutic gene in the engrafted and derived cells. This targeted approach by saRNA opens a new avenue of therapeutic development for not only lysosomal disorders such as MPS I, but all disorders where transcriptional activation or enhancement of a gene could provide therapeutic benefits."

Preclinical • Bone Marrow Transplantation • Gastrointestinal Cancer • Gene Therapies • Genetic Disorders • Hepatocellular Cancer • Hurler Syndrome • Oncology • Pain • Solid Tumor • Transplantation • CEBPA

MTL-CEBPA in combination with pembrolizumab converts an immune desert to an inflamed TME in solid tumors resistant to checkpoint blockade (AACR 2023) - "MTL-CEBPA has shown favorable safety and promising clinical activity in combination with tyrosine kinase inhibitors (Sorafenib) in hepatocellular carcinoma (NCT-02716012) [Hashimoto et al, CCR 2021; Sarker et al, CCR 2020]. We observe a significant positive correlation between the change in cytotoxic T cells and HLA-DR+ myeloid cells post treatment (P=0.004). These effects are most pronounced in cold tumors."

Checkpoint block • Checkpoint inhibition • Combination therapy • IO biomarker • Late-breaking abstract • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CD8 • CEBPA • CXCL9

MiNA Therapeutics Presents Late-Breaking Positive Phase 1b Data for MTL-CEBPA in Combination with an Anti-PD1 Checkpoint Inhibitor at the Annual American Association of Cancer Research (AACR) Meeting (Businesswire) - P1 | N=108 | TIMEPOINT (NCT04105335) | Sponsor: Mina Alpha Limited | "MiNA Therapeutics Limited, the pioneer in small activating RNA (RNAa) therapeutics, will present positive updated biomarker data from its Phase 1a/b TIMEPOINT study of MTL-CEBPA in combination with the anti-PD1 checkpoint inhibitor, pembrolizumab, in adults with advanced solid tumors at the annual meeting of the American Association of Cancer Research (AACR) in Orlando, Florida....Interim data from an open-label, multi-center study demonstrated the safety, tolerability, immunological and clinical activity of MTL-CEBPA in combination with pembrolizumab."

P1 data • Oncology • Solid Tumor

Preliminary results of a first-in-human, first-in-class phase I study of MTL-CEBPA, a small activating RNA (saRNA) targeting the transcription factor C/EBP- in patients with advanced liver cancer. (ASCO 2018) - P1; "Once weekly MTL-CEBPA therapy was well tolerated, shows promising PD and initial clinical response in patients with advanced HCC. Updated results for the dose escalation will be presented."

Clinical • P1 data • Hepatocellular Cancer

Interim results for Phase 1b dose expansion of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumour malignancies (SITC 2022) - "Conclusions MTL-CEBPA in combination with pembrolizumab is safe and well tolerated, with encouraging early signs of activity in heavily pre-treated patients across multiple tumour types. Treatment was associated with intratumoural changes supporting the hypothesis of immunomodulation by MTL-CEBPA and further investigation in combination with ICI is warranted."

Clinical • Combination therapy • IO biomarker • P1 data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CEBPA

A phase 1 study of myeloid modulating agent MTL-CEBPA in combination with pembrolizumab in adult patients with advanced solid tumours (SITC 2021) - P1 | "Enrolment into the dose expansion is ongoing. Trial Registration This study was registered with ClinicalTrials.gov, number NCT04105335."

Clinical • Combination therapy • P1 data • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Mesothelioma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • CEBPA

OPEN LABEL, RANDOMISED, PHASE 2 STUDY TO EVALUATE THE SAFETY AND EFFICACY OF SORAFENIB WITH OR WITHOUT MTL-CEBPA, AN IMMUNE-MODULATORY SARNA UPREGULATING C/EBP-A, AS SECOND LINE TREATMENT IN ADVANCED HEPATOCELLULAR CARCINOMA (OUTREACH 2 (ILCA 2022) - P2 | "Introduction: There is a paucity of clinical outcome data relating to second line treatment options for unresectable HCC in patients who have progressed on atezolizumab and bevacizumab. As of March 2022 the study is open to recruitment in the first two countries (USA and Singapore) with the first two patients randomised. Updated study results will be provided. This study was registered with ClinicalTrials.gov, identifier: NCT04710641; EudraCT Number: 2021- 005431-23"

Clinical • P2 data • Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Immune Modulation • Infectious Disease • Inflammation • Oncology • Solid Tumor • CEBPA

Safety, tolerability, and efficacy of a combination of MTL-CEBPA and sorafenib in patients with advanced liver cancer with a viral background. (clinicaltrialsregister.eu) - P2 | N=150 | Ongoing | Sponsor: MiNA Alpha Limited

Combination therapy • New P2 trial • Gastrointestinal Cancer • Hepatitis B • Hepatitis C • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Liver Cancer • Oncology • Solid Tumor • CEBPA

OUTREACH: First-in-Human Safety, Tolerability and Antitumour Activity Study of MTL-CEBPA in Patients With Advanced Liver Cancer (clinicaltrials.gov) - P1 | N=51 | Active, not recruiting | Sponsor: Mina Alpha Limited | Trial completion date: Jan 2022 ➔ Jan 2023 | Trial primary completion date: Nov 2021 ➔ Nov 2022

Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CEBPA

A Study of MTL-CEBPA in Combination With a PD-1 Inhibitor in Patients With Advanced Solid Tumours (TIMEPOINT) (clinicaltrials.gov) - P1 | N=108 | Active, not recruiting | Sponsor: Mina Alpha Limited | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Biliary Tract Cancer • Gastrointestinal Cancer • Glioblastoma • Lung Cancer • Melanoma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Renal Cell Carcinoma • Solid Tumor • CEBPA • PD-L1

OUTREACH2: Radomised Phase II Study of MTL-CEBPA Plus Sorafenib or Sorafenib Alone (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Mina Alpha Limited | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Gastrointestinal Cancer • Hepatitis B • Hepatitis C • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Oncology • Solid Tumor • CEBPA