INT-1B3 / InteRNA Tech - LARVOL DELTA

Wilms' Tumor 1 Functions As a Tumor Suppressor to Suppress FLT3-STAT Signaling and Epigenetic Remodeling in Acute Myeloid Leukemia (CALGB 8461, 9665 and 20202; Alliance) (ASH 2023) - P1 | "To overcome this, we tested a novel lipid-nanoparticle (LNP) formulation of miR-193a-3p (INT-1B3), currently being investigated in a phase I clinical trial (NCT04675996)...Loss-of-function WT1 mutations subvert the tumor suppressor function of WT1 via failure to maintain miR-193a expression, leading to increased FLT3 expression and STAT5 signaling, subsequently impairing differentiation, increasing proliferation and disease aggressiveness in AML (Figure 1). Our findings advocate for use of FLT3 inhibition and miR-193a supplementation for treatment of WT1mut patients, a subgroup with poor outcomes and no targeted treatment options."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Wilms Tumor • FLT3 • HOXA9 • MEIS1 • MIR193A • NPM1 • STAT5 • TET2 • WT1

INT-1B3, an LNP formulated miR-193a-3p mimic, promotes anti-tumor immunity by enhancing T cell mediated immune responses via modulation of the tumor microenvironment and induction of immunogenic cell death. (PubMed, Oncotarget) - "Live cell imaging demonstrated PBMC-mediated cytotoxicity against 1B3-transfected tumor cells. These data demonstrate for the first time that miR-193a-3p induces long-term immunity against tumor development via modulation of the tumor microenvironment and induction of immunogenic cell death."

Biomarker • Immunogenic cell death • Journal • Tumor microenvironment • Oncology • CD4 • CD8 • MIR193A

First-in-Human Study of INT-1B3 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=25 | Terminated | Sponsor: InteRNA | N=80 ➔ 25 | Trial completion date: Dec 2024 ➔ Mar 2023 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2023 ➔ Mar 2023; insufficient funding

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Oncology • Solid Tumor

TARGETING THE WT1MUT-MIR-193A TRANSCRIPTIONAL AXIS WITH INT-1B3, A NOVEL LIPID NANOPARTICLE-FORMULATED MIR-193A-3P MIMIC IN ACUTE MYELOID LEUKEMIA (EHA 2023) - P1 | "We uncover a previously unknown regulatory mechanism between WT1 mut and miR-193a in AML cells, which provides a novel therapeutic target for a miR-193a based therapeutic for AML patients. WT1, Immunomodulation, Acute myeloid leukemia, Nanoparticle"

Acute Myelogenous Leukemia • Hematological Malignancies • Immune Modulation • Immunology • Leukemia • Nephrology • Oncology • Solid Tumor • Transplantation • Wilms Tumor • HOXA9 • MEIS1 • MIR193A • WT1

Targeting the WT1mut-Mir-193a Transcriptional Axis with INT-1B3, a Novel Lipid Nanoparticle-Formulated Mir-193a-3p Mimic in Acute Myeloid Leukemia (ASH 2022) - P1 | "Biweekly i.v. treatments for 8 weeks of INT-1B3 or PBS after H9M cell transplantation prevented AML formation in the INT-1B3 arm, whereas all mice in the control arm succumbed to AML, highlighting the potent anti-leukemic activity of this miRNA based therapeutic. In summary, we uncover a previously unknown regulatory mechanism between WT1mut and miR-193a in AML cells, which provides a pre-clinical rationale for a miR-193a based therapeutic for AML patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Nephrology • Oncology • Solid Tumor • Transplantation • Wilms Tumor • HOXA9 • KIT • MEIS1 • MIR193A • WT1

InteRNA Technologies Announces U.S. FDA Clearance of IND Application for Phase I Clinical Trial with Lead microRNA Candidate INT-1B3 in Patients with Advanced Solid Tumors (Businesswire) - "InteRNA Technologies Announces U.S. FDA Clearance of IND Application for Phase I Clinical Trial with Lead microRNA Candidate INT-1B3 in Patients with Advanced Solid Tumors...The treatment of the first patient in the Phase Ib cohort is planned for the second half of 2022...The study is expected to enroll a total of up to 80 patients at up to 15 clinical centers in the United States and Europe....In the second part (Phase Ib) of the trial, approximately 50 patients with hepatocellular carcinoma or triple negative breast cancer will be enrolled in the United States and Europe. Topline results from the Phase Ia part of the study are expected in the first half of 2022."

IND • P1 data • Trial status • Breast Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

[VIRTUAL] Phase I/Ib study with INT-1B3, a novel LNP-formulated micro-RNA (miR-193a-3p mimic) therapeutic for patients with advanced solid cancer. (ASCO 2021) - P1 | "infusions twice a week in 21-day cycles . The first patient was enrolled on January the 14th 2021."

Clinical • IO biomarker • P1 data • Breast Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD4 • CD8 • FOXP3 • IFNG • IL2 • LAG3

InteRNA Technologies Publishes Preclinical Data from Investigational microRNA INT-1B3 Program in Molecular Therapy – Nucleic Acids and Oncotarget (Businesswire) - “InteRNA Technologies…announced that preclinical data investigating the Company’s lead candidate, INT-1B3, have been published in the peer-reviewed journals Molecular Therapy – Nucleic Acids and Oncotarget. INT-1B3 is a mimic of the tumor suppressor miRNA-193a-3p and has the potential to address multiple hallmarks of cancer at the same time. The published results include data from tumor cell lines and experimental tumor models and support the high therapeutic potential of INT-1B3 in solid tumor indications….These preclinical results contributed to the decision by InteRNA to initiate a first-in-human clinical study with INT-1B3 in patients with advanced solid tumors…topline results from the dose escalation part of the study are expected by the end of 2021.”

P1 data • Preclinical • Oncology • Solid Tumor

Multi-modal effects of 1B3, a novel synthetic miR-193a-3p mimic, support strong potential for therapeutic intervention in oncology. (PubMed, Oncotarget) - "Importantly, a novel lipid nanoparticle-based formulation of 1B3, INT-1B3, demonstrated marked anti-tumor activity as a single agent following systemic administration in tumor-bearing mice. Together, these data strongly support the development of 1B3 as a novel therapeutic agent for treatment of human cancer."

Journal • Oncology

InteRNA Technologies Awarded € 2.7M Clinical Innovation Credit from Dutch Government (Businesswire) - “InteRNA Technologies…announced that it was awarded a Clinical Innovation Credit of € 2.7 Million from the Dutch government. This award will support the clinical validation of the Company’s lead candidate, INT-1B3, for the treatment of solid tumors. The funding is granted by the ‘Rijksdienst voor Ondernemend Nederland’/The Netherlands Enterprise Agency (RVO), an agency of the Dutch Ministry of Economic Affairs and Climate Policy….Recently, InteRNA announced the dosing of the first patient in the first-in-human trial for INT-1B3, which is conducted in several clinical study centers located in the Netherlands and Belgium. Topline results from the dose escalation part of the study are expected by the end of 2021.”

Financing • Grant • P1 data • Oncology • Solid Tumor

First-in-Human Study of INT-1B3 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=80; Recruiting; Sponsor: InteRNA; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Oncology • Solid Tumor

InteRNA Technologies Announces Dosing of First Patient in First-in-Human Trial of microRNA Drug Candidate INT-1B3 in Patients with Advanced Solid Tumors (Businesswire) - “InteRNA Technologies announced today that the first patient has been dosed in the first cohort of its first-in-human Phase I study with the Company’s lead microRNA candidate, INT-1B3. The trial will evaluate safety and initial signs of efficacy of INT-1B3, a microRNA-mimic of the endogenous tumor suppressor miR-193a-3p formulated in next-generation lipid nanoparticles, in patients with advanced solid tumors….Topline results from the dose escalation part of the study are expected by the end of 2021.”

P1 data • Trial status • Oncology • Solid Tumor

InteRNA Technologies Extends Series B Financing Round Totaling EUR 18.5M (Businesswire) - “The funding will enable the clinical evaluation of the Company’s microRNA lead candidate, INT-1B3, in patients with advanced solid tumors. Furthermore, the proceeds will be used to develop and advance additional proprietary preclinical drug candidates adressing a variety of cancer indications thereby expanding the Company’s pipeline.”

Commercial • Oncology • Solid Tumor

First-in-Human Study of INT-1B3 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=80; Not yet recruiting; Sponsor: InteRNA

Clinical • New P1 trial • Oncology • Solid Tumor

InteRNA Technologies receives regulatory approval for initiation of phase I clinical trial of INT-1B3 in patients with advanced solid tumors (Businesswire) - "InteRNA Technologies announced today regulatory approvals in the Netherlands and Belgium for the initiation of the first-in-human (Phase I) clinical trial testing its lead microRNA candidate, INT-1B3, in patients with advanced solid tumors…Due to the ongoing COVID-19 pandemic, clinical trial initiation has been delayed and is now anticipated to start during H2 2020… Initial data readout from the Phase Ia study is expected in the end of 2021."

European regulatory • P1 data • Trial initiation date • Oncology • Solid Tumor

A synthetic miR-193a-3p mimic (INT-1B3) suppresses primary tumor growth and prolongs animal survival by enhancing T-cell mediated immune response in murine TNBC 4T1 orthotopic model (CIMT 2019) - "Among those CD73, CD39, PD-L1, KRAS, KIT, HMGB1, CDK4, CDK6, uPA, TGFB2 and FAK are a few examples that play a key role in modulation of T-cell mediated immune response via control of cytotoxic- and regulatory- T-cells as well as myeloid-derived suppressor cells ratios, regulation of adenosine generation and cytokine signaling, and blockade of immune checkpoint. Taken together, these results indicate a strong immune-oncology potential for INT-1B3 as monotherapy with triggering of long-term T-cell mediated immune response memory against tumor antigens."

IO Biomarker • PD(L)-1 Biomarker

A synthetic miR-193a-3p mimic (INT-1B3) suppresses primary tumor growth and prolongs animal survival by enhancing T-cell mediated immune response in murine TNBC 4T1 orthotopic model (CIMT 2019) - "Among those CD73, CD39, PD-L1, KRAS, KIT, HMGB1, CDK4, CDK6, uPA, TGFB2 and FAK are a few examples that play a key role in modulation of T-cell mediated immune response via control of cytotoxic- and regulatory- T-cells as well as myeloid-derived suppressor cells ratios, regulation of adenosine generation and cytokine signaling, and blockade of immune checkpoint. Taken together, these results indicate a strong immune-oncology potential for INT-1B3 as monotherapy with triggering of long-term T-cell mediated immune response memory against tumor antigens."

IO Biomarker • PD(L)-1 Biomarker

Pronounced antitumor activity upon systemic treatment with INT-1B3 - a synthetic miR-193a-3p mimic – in a wide range of syngeneic experimental tumor models, distinct from immune checkpoint inhibitors (CIMT 2019) - "Baseline immune-cell profile was an imperfect predictor of response to INT-1B3 as INT-1B3 not only hampered tumor growth in tumors with highly immunogenic TME, but also showed a pronounced anti-tumor response in tumors with poorly immunogenic TME such as B16-F10, B16-BL6 and LL/2. Taken together, these results, supported by observed modulation of relevant gene expression and impact on gene network and signaling pathways, strongly suggest a distinct anti-tumor efficacy for INT-1B3 monotherapy as compared to selected ICIs, due to the effect of INT-1B3 not only as a TME modulator, but also via targeting multiple other hallmarks of cancer."

Checkpoint inhibition • IO Biomarker • PD(L)-1 Biomarker • Preclinical