Phase 1 trial evaluating MRG-106, a synthetic inhibitor of microRNA-155, in patients with cutaneous t-cell lymphoma (CTCL).

Abstract

7564 Background: MRG-106 is an oligonucleotide inhibitor of miR-155, a microRNA with a strong mechanistic link to CTCL, selected based on its activity in mycosis fungoides (MF) cell lines. The objective of this first-in-human study is to evaluate the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary efficacy of MRG-106 in MF patients. Methods: This Phase 1 trial employs a dose-escalation design to evaluate either intratumoral (IT, 75 mg/dose) or subcutaneous (SC, ≤ 900 mg/dose) administration of MRG-106. Patients were required to have biopsy-proven stage I-III MF and plaque- or tumor-stage lesions. Results: Fifteen patients (12M/3F, median age 59 years) have been dosed over 1-4 weeks. All patients tolerated the IT or SC administrations well with only minor local injection reactions in 8 patients. Thirteen of 15 patients completed dosing as scheduled. There were no clinically significant MRG-106 related adverse events with the exception of one grade 3 pruritus. The MTD has not yet been reached. In the IT cohort, a reduction of ≥50% in the baseline Composite Assessment of Index Lesion Severity (CAILS) score was observed in the MRG-106 treated lesions in all 4 evaluable patients who completed dosing; such responses were maintained to the End of Study visit (Day 28 or 35). Histological examination of pre- and post-treatment biopsies of the MRG-106-injected lesion from most patients revealed a trend in reduction in neoplastic cell density and depth; 1 patient had a complete loss of the neoplastic infiltrate. Gene expression analysis of the pre- and post-treatment biopsies showed reduction of the PI3K/AKT, JAK/STAT, and NFkB survival pathways and increased cell death consistent with the expected MRG-106 mechanism of action. In the SC cohorts, 3/8 patients had a maximal decrease in their modified Severity-Weighted Assessment Tool (mSWAT) of > 39% indicative of a significant response. One patient at the 900 mg SC dose level had a possible flare of their disease after 3 doses that resolved after 3 weeks. Conclusions: Based on favorable clinical safety, efficacy and PK data, additional patients are being accrued. Updated results will be presented as available. Clinical trial information: NCT02580552.

Noncoding RNAs in Myelodysplastic Syndromes

“…In 2012, the first cancer-targeted miRNA drug, MRX34 (a liposome-based miR-34 mimic), entered phase I clinical trials in patients with advanced hepatocellular carcinoma, and this mimic has attracted considerable attention from both academic researchers and pharmaceutical companies [82]. MRG-106, a synthetic antagonist of miRNA-155, is currently being tested by MIRagen Therapeutics in patients with cutaneous T-cell lymphoma [83]. However, testing miRNAs as potential therapeutic agents or targets in MDS therapy still requires initial exploration in in vitro models before evolving to future clinical trials.…”

Coordinated AR and microRNA regulation in prostate cancer

“…Other trials of miRs/inhibitors suggest they are well tolerated, even long-term, with no serious adverse effects , e.g. Santaris phase II trials of anti-miR-122 (NCT01200420, NCT02508090) [ [169] , [170] , [171] ], miRagen phase II for anti-miR-155 (NCT02580552) after successful phase I [ 172 ], also phase I for miR-29 mimic (NCT02603224). Oligonucleotides are hailed as the 3rd major drug-development platform (after small molecules and biologics) with predicted market worth of USD 4.6 billion by 2022 [ 173 , 174 ].…”

Oligonucleotides Targeting Telomeres and Telomerase in Cancer

“…However, MRG-106 is an oligonucleotide antimiRNA of miR-155 and is currently undergoing Phase I clinical trials. A recent Phase I study using MRG-106 showed that cutaneous T-cell lymphoma patients demonstrated improvement in either individual lesions or total skin disease over the course of the study, prompting application of this therapy to other malignancies [ 82 ]. Studies inhibiting oncogenic miRNAs that enhance telomerase activity has not yet progressed to clinical trials, but further studies targeting these miRNAs using in vivo models warrant further investigation of this therapeutic approach for the development of clinical applications.…”