Preliminary Results of a Phase 1 Trial Evaluating MRG-106, a Synthetic microRNA Antagonist (LNA antimiR) of microRNA-155, in Patients with CTCL

Abstract

Introduction and Objectives: microRNAs are small, non-coding RNAs that regulate expression of multiple genes which impact physiological processes and cellular phenotypes. miR-155-5p is a well-described onco-miR with a strong mechanistic link to cutaneous T-cell lymphoma (CTCL). A LNA-modified oligonucleotide inhibitor of miR-155-5p, MRG-106, was selected based on its ability to de-repress canonical miR-155-5p targets in multiple mycosis fungoides (MF) cell lines in vitro. In preclinical models, MRG-106 showed significant pharmacodynamic activity without requiring additional formulation. The objective of this first-in-human study is to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of MRG-106 in patients with mycosis fungoides (MF). Methodology: This Phase 1 trial employs a dose-escalation design to evaluate both intratumoral and subcutaneous administration of MRG-106 at doses of 75 mg and up to 900 mg per injection, respectively. Patients were required to be ≥ 18 years old, have a confirmed diagnosis of MF, be clinical stage I-III with plaques or tumors, be on a stable treatment regimen or without any concomitant therapy for MF, and have no other major illness. The first 6 patients were dosed with four or five 75 mg intratumoral injections of MRG-106 over 2 weeks. In addition, 4 patients received saline injections in a second lesion on the same schedule. Skin biopsies were taken from MRG-106 and saline treated lesions for molecular, bioanalytical, and histological analyses, before the first dose and after the last dose. Results: Six patients (5M/1F, median age 61 years, 5 Caucasian/ 1 African-American) were dosed intratumorally. All tolerated the administrations well with only minimal erythema at the site of injection noted in one patient. One patient was discontinued from the trial due to rapid progression of disease, which was considered not related to the study drug. There were no clinically significant adverse events or laboratory abnormalities. To date, the first cohort of 6 patients has either completed the dosing period (5 patients) or discontinued due to progressive disease (1 patient). All patients showed a reduction in the baseline Composite Assessment of Index Lesion Severity (CAILS) score in both MRG-106-treated and saline-treated lesions. The maximal reduction was on average 55% [range: 33% to 77%] in the MRG-106 treated lesion and 39% [range:13% to 75%] in the saline treated lesions). In all the subjects that completed dosing, the MRG-106 treated lesions had a CAILS score reduction of ≥ 50% which was maintained to the end of study; in contrast, a ≥ 50% reduction was observed in only one saline treated lesion. Most patients noted a marked decrease in systemic pruritus. Histological examination of pre-treatment and post-treatment biopsies of the same lesion injected with MRG-106 from five evaluable patients revealed that one patient had a complete loss of the neoplastic infiltrate, two patients had a reduction in neoplastic cell infiltrate density and depth, one patient had fewer CD30+ large atypical cells, and one patient demonstrated no change. After the first dose, MRG-106 had a mean t1/2 in plasma of 4.4 hours, and a mean Cmaxof 1.4 µg/mL. The drug was detectable 24 hours after the last dose in the MRG-106-injected lesions that were biopsied. Gene expression analysis of the pre- and post-treatment biopsies showed transcript changes consistent with the expected mechanism of action of MRG-106. Conclusions: These promising preliminary results in this first-in-human study in 6 MF patients show that intratumoral injection of MRG-106 was well-tolerated, and demonstrated encouraging therapeutic improvements in cutaneous lesions, based on CAILS scores and histological findings. In addition, reductions in CAILS scores in other lesions as well as decreases in systemic symptoms such as pruritus were observed. Preliminary biomarker analysis indicates that MRG-106 induces transcriptional changes consistent with on-target activity and molecular proof of concept. The trial is ongoing and additional results will be presented as available. Disclosures Querfeld: Actelion: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foss:Seattle Genetics: Consultancy, Speakers Bureau; Spectrum Pharmaceuticals: Consultancy; Eisai: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau. Halwani:Bristol-Myers Squibb: Research Funding; Abbvie: Consultancy, Research Funding; Amgen: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Research Funding; Kyowa Hakko Kirin: Research Funding; Immune Design: Research Funding. Porcu:miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Seto:miRagen: Employment. Ruckman:miRagen Therapeutics, Inc: Employment. Landry:Accera, Inc: Consultancy; miRagen: Consultancy. Jackson:miRagen: Employment. Pestano:miRagen Therapeutics: Employment. Dickinson:miRagen Therapeutics: Employment. Sanseverino:miRagen Therapeutics: Employment. Rodman:Nivalis: Employment, Equity Ownership; miRagen Therapeutics: Consultancy. Gordon:GLPI: Consultancy, Equity Ownership; IGM: Consultancy; Globavir: Consultancy; Pre-cell: Consultancy; Industrial Laboratories: Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy; Flugen: Consultancy; Bayer: Consultancy; miRagen Therapeutics: Consultancy; Clinipace: Consultancy; Caring for Colorado Foundation: Membership on an entity's Board of Directors or advisory committees; Ruesch Center for the Cure of Gastrointestinal Cancer: Membership on an entity's Board of Directors or advisory committees; Axion: Membership on an entity's Board of Directors or advisory committees; TEQ laboratories: Membership on an entity's Board of Directors or advisory committees. Marshall:miRagen Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: inventor on various patents; BiOptix: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fluorofinder: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AmideBio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Colorado BioScience Association: Membership on an entity's Board of Directors or advisory committees; Atlas Venture: Consultancy.

SATB1 in Malignant T Cells

“…Because other Th2 cytokines (IL-4 and IL-13) are also implicated in CTCL pathogenesis, studies have been undertaken to address whether expressions of these cytokines are also regulated by the miR-155/SATB1 pathway. Based on our present observations, this vicious cycle based on JAK3/STAT5/ miR155 and SATB1 signaling in MF progression may be broken by JAK3 inhibitors such as tofacitinib (Damsky and King, 2017) and miR-155 inhibitors like MRG-106, which are currently in clinical development for treatment of MF patients (Querfeld et al, 2016). JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, and psoriasis.…”

Targeted delivery of anti-miR-155 by functionalized mesoporous silica nanoparticles for colorectal cancer therapy

“…5 Currently, many miRNAbased therapeutics are in the preclinical stage, 6 and several miRNA-based drugs have already entered clinical trials for the treatment of cancer and Hepatitis C virus (HCV) infection. [7][8][9][10] However, effective and safe delivery of anti-miRs or miRNA mimics to the tissue of interest remains a main challenge for the clinical applications of miRNAbased therapeutics. 11 MicroRNA-155 (miR-155) is one of the most salient oncogenic microRNA (oncomiR), which is upregulated in many human cancers.…”

Enhancer control of miR-155 expression in Epstein-Barr virus infected B cells

“…It therefore represents an important therapeutic target. The first in human phase I trial of a synthetic locked nucleic acid anti-miR to miR-155 has been initiated and preliminary results show that the inhibitor is well tolerated in patients with cutaneous T cell lymphoma when injected intratumorally (39). Inhibition of miR-155 expression through indirect transcriptional repression has also been tested in acute myeloid leukemia cells using an inhibitor of the NEDD8-activating enzyme (40).…”