mRNA-2416 / Moderna - LARVOL DELTA

First-in-human phase I/II, open-label study of mRNA-2416 alone or combined with durvalumab in patients with advanced solid tumors and ovarian cancer. (PubMed, Oncologist) - P1/2 | "mRNA-2416 alone or with durvalumab was well tolerated. Pharmacodynamic analyses support Itu mRNA proof-of-concept. Predefined primary efficacy endpoints were not met in an exploratory cohort of ovarian cancer. Additional research is warranted to further inform this therapeutic approach."

Clinical • IO biomarker • Journal • P1/2 data • Hematological Malignancies • Lymphoma • Oncology • Ovarian Cancer • Solid Tumor • PD-L1 • TNFSF4

Dose Escalation and Efficacy Study of mRNA-2416 for Intratumoral Injection Alone and in Combination With Durvalumab for Participants With Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=79 | Terminated | Sponsor: ModernaTX, Inc. | N=117 ➔ 79 | Trial completion date: Sep 2022 ➔ Aug 2021 | Active, not recruiting ➔ Terminated | Trial primary completion date: Sep 2022 ➔ Aug 2021; This study was halted prematurely because the efficacy endpoints were not met for either treatment arm.

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Hematological Malignancies • Lymphoma • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • BRCA

A Phase 1, open-label, multicenter, dose escalation study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection to patients with advanced Malignancies (SITC 2018) - P1; "Conclusions mRNA-2416 is tolerable at all dose levels studied, and yielded productive expression of OX40L protein. Translational data continues to be collected and analyzed."

Clinical • IO biomarker • P1 data • Head and Neck Cancer • Leukemia • Lung Cancer • Lymphoma • Melanoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Sarcoma • Thoracic Cancer

[VIRTUAL] A phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies (AACR-I 2020) - "Intratumoral mRNA-2416 is tolerable at all dose levels studied when given as monotherapy and analyses of tumor post-treatment demonstrate increased OX40L protein expression, elevated PD-L1 levels and pro-inflammatory activity. Taken together with the observation of preclinical in vivo synergy with PD-L1 blockade, these data support the evaluation of a combination of intratumoral mRNA-2416 with the anti-PD-L1 inhibitor durvalumab in solid tumors, which is ongoing in part B of this study."

Clinical • Combination therapy • IO Biomarker • P1/2 data • CD8 • GEP • TNFA • TNFRSF4

Spatial mapping and immunomodulatory role of the OX40/OX40L pathway in human non-small cell lung cancer. (PubMed, Clin Cancer Res) - "The OX40 pathway is expressed in a fraction of NSCLCs and is associated with a favorable immune contexture. Although OX40L is uncommonly expressed in NSCLC and serous malignancies, it is associated with better prognosis and can be introduced using exogenous mRNA."

IO biomarker • Journal • Immune Modulation • Inflammation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • CD4 • CD8 • EGFR • KRAS

Dose Escalation and Efficacy Study of mRNA-2416 for Intratumoral Injection Alone and in Combination With Durvalumab for Participants With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=117; Active, not recruiting; Sponsor: ModernaTX, Inc.; Recruiting ➔ Active, not recruiting; Trial completion date: Mar 2023 ➔ Sep 2022; Trial primary completion date: Mar 2023 ➔ Sep 2022

Clinical • Combination therapy • Enrollment closed • Trial completion date • Trial primary completion date • Breast Cancer • Hematological Malignancies • Lymphoma • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • BRCA • PCR

Moderna Reports Second Quarter Fiscal Year 2021 Financial Results and Provides Business Updates (Businesswire) - “Discontinued further development of mRNA-2416, our standalone OX40L candidate; focus shifted to the development of mRNA-2752, which comprises mRNAs for OX40L plus two cytokines, IL23 + IL36γ.”

Clinical • Discontinued • Oncology

Dose Escalation and Efficacy Study of mRNA-2416 for Intratumoral Injection Alone and in Combination With Durvalumab for Participants With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=117; Recruiting; Sponsor: ModernaTX, Inc.; Trial completion date: Mar 2022 ➔ Mar 2023; Trial primary completion date: Sep 2021 ➔ Mar 2023

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • Hematological Malignancies • Lymphoma • Oncology • Ovarian Cancer • Solid Tumor • BRCA • PCR

Immune gene expression in head and neck squamous cell carcinoma patients. (PubMed, Eur J Cancer) - "OX40L and PDGFRB overexpression was associated with poor outcomes, whereas PD-1 overexpression was associated with good prognosis in patients with HNSCC treated with primary surgery, suggesting their relevance as potential prognostic biomarkers and major therapeutic targets."

Biomarker • Clinical • IO Biomarker • Journal • Head and Neck Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

AACR 2020 – Changing the immunotherapy paradigm - "Dr. Antonio Jimeno...presented clinical data for novel mRNA-based lipid nanoparticle therapeutic agent named as mRNA-2416 that expresses the wild type human OX40L. By directly inserting the beads inside the tumor, the group plans to activate OX40 signaling locally. Unpublished preclinical data showed promising anti-tumor activity for mRNA-2416."

Intratumoral mRNA-2416 monotherapy appears safe for patients with solid tumors (Healio) - P1/2, N=39; '"Of note, the majority of patients with ovarian cancer included in the study achieved a best overall response of stable disease along with noted clinical observation of tumor regression in injected as well as uninjected lesions, which supports further investigation of this tumor type,' Antonio Jimeno, MD, PhD...said during a presentation."

Media quote • P1/2 data

"At #AACR20, Dr Jimeno presents data on mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding OX40L, made for tumor injection, given alone or with the PD-L1 inhibitor durvalumab." (@Jbauml)

Oncology

Effect of Blocking the OX40/OX40L Signaling Pathway by siRNA Interference on Animal Experimental Study of Allergic Rhinitis. (PubMed, Arch Med Res) - "Blockage of the OX40/OX40L signaling pathway with siRNA-OX40L interference can inhibit allergic reactions and relieve allergic symptoms in AR mice. The underlying mechanism may be related to correcting Th2 immune deviation, inducing immune tolerance, and promoting Treg production."

IO Biomarker • Journal • Preclinical • Allergic Rhinitis • Allergy • Immunology

Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs. (PubMed, Sci Transl Med) - "Last, combining triplet mRNA with checkpoint blockade led to efficacy in models otherwise resistant to systemic immune checkpoint inhibition. Human cell studies showed similar cytokine responses to the individual components of this mRNA mixture, suggesting translatability of immunomodulatory activity to human patients."

IO Biomarker • Journal

Relative Expression of OX40, OX40L mRNA, and OX40L Serum Levels in Women with Recurrent Spontaneous Abortion. (PubMed, Immunol Invest) - "In conclusion, our findings demonstrated that the expression of OX40 mRNA and OX40L mRNA was similar between women with a history of RSA and the control group. The elevation of serum OX40L level may be considered as a risk factor for RSA."

Clinical • IO Biomarker • Journal

Dose Escalation and Efficacy Study of mRNA 2416 for Intratumoral Injection Alone and in Combination With Durvalumab for Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=117; Recruiting; Sponsor: ModernaTX, Inc.; N=78 ➔ 117; Trial completion date: Oct 2020 ➔ Mar 2022; Trial primary completion date: Jun 2020 ➔ Sep 2021

Clinical • Combination therapy • Enrollment change • Trial completion date • Trial primary completion date

Moderna provides business updates and reports second quarter 2019 financial results (Market Watch) - "OX40L (mRNA-2416): Dosing is ongoing at the highest levels (8 mg) in the Phase 1/2 open-label, multi-center, dose escalation and efficacy study of intratumoral injections of mRNA-2416 in patients with advanced malignancies. A Phase 2 expansion cohort in patients with advanced ovarian carcinoma is preparing to start enrollment; this will include the combination of intratumoral mRNA-2416 with durvalumab (IMFINZI®)."

Enrollment status

Increased Expressions of OX40 and OX40 Ligand in Patients with Primary Immune Thrombocytopenia. (PubMed, J Immunol Res) - "...The percentage of OX40CD4T cells among CD4T cells was analyzed by flow cytometry, and the expression levels of OX40 and OX40L mRNA were analyzed by quantitative real-time PCR...Additionally, the mRNA expression levels of OX40 and OX40L in PBMCs from ITP patients were also notably greater than those from HCs, and the expression levels of OX40 and OX40L were significantly different in ITP patients with positive and negative antiplatelet autoantibodies. These data indicated that increased expression levels of OX40 and OX40L were involved in the pathogenesis of ITP, and OX40 and OX40L may be valuable therapeutic targets for ITP."

Clinical • IO Biomarker • Journal

Dose Escalation and Efficacy Study of mRNA 2416 for Intratumoral Injection to Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=78; Recruiting; Sponsor: ModernaTX, Inc.; Phase classification: P1 ➔ P1/2; Trial completion date: Jul 2019 ➔ Oct 2020; Trial primary completion date: Jul 2019 ➔ Jun 2020

Clinical • Phase classification • Trial completion date • Trial primary completion date

"#JPM19 $MRNA Ph1 mRNA-2416 in OvCan pts. N=25 max dose: 8mg (wow, quite high) Not meeting RESCIST response" (@BursatilBiotech)

Clinical

Moderna announces recent progress in its immuno-oncology and rare disease programs and highlights corporate objectives (Businesswire) - "Based on previously reported clinical observations in two patients with advanced ovarian carcinoma in its Phase 1 study, Moderna has submitted an Investigational New Drug (IND) amendment to the U.S. Food and Drug Administration (FDA) and to the study’s clinical research sites to commence a Phase 2 cohort of mRNA-2416 as a monotherapy in advanced ovarian carcinoma within its current Phase 1 study....Moderna and Merck are planning a randomized Phase 2 study comparing PCV and KEYTRUDA® against KEYTRUDA alone....Merck will lead an open-label, multi-center, dose-escalation and dose-expansion Phase 1 study to evaluate the safety and tolerability of mRNA-5671 administered as an intramuscular injection both as a monotherapy and in combination with KEYTRUDA. KRAS is a frequently mutated oncogene in epithelial cancers, primarily in non-small cell lung, colorectal and pancreatic cancers."

IND • New P1 trial • New P2 trial