Abstract: Introduction & Objectives: MRG-106 is an oligonucleotide inhibitor of miR-155, a microRNA with a strong mechanistic link to CTCL. The goals of this first-in-human study are to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of MRG-106 in patients with mycosis fungoides (MF). Methods: This Ph 1 trial employs a dose-escalation design to evaluate the administration of MRG-106 via subcutaneous (SC) injection, 2-hour intravenous (IV) infusion, or IV rapid bolus injection (≤ 900 mg/dose). An additional cohort received intralesional injections (75 mg/dose) to evaluate tolerability and efficacy with local delivery. Subjects were required to have biopsy-proven MF stage I-III with plaque and/or tumor lesions. Subjects were permitted to remain on concurrent stable CTCL therapy. Subjects received 6 doses (SC/IV) in the first 26 days of the study followed by weekly or bi-weekly doses in patients who continued beyond the first cycle. Safety was monitored by physical exams, clinical laboratory tests, and assessment of adverse events (AEs). Immunophenotyping of peripheral blood was performed to measure the impact of MRG-106 on normal immune cell subsets. The PK properties of MRG-106 were compared between different routes of administration. The effect of MRG-106 on individual skin lesions or total skin disease was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score or the modified Severity Weighted Assessment Tool (mSWAT), respectively. Biopsies were collected from all subjects treated by intralesional injection and from a subset of subjects in the SC/IV cohorts to assess molecular and cellular responses to MRG-106. Baseline miR-155 expression and changes in gene expression and T cell repertoire (T cell receptor sequencing) in response to MRG-106 treatment were assessed. Results: 24 subjects (18M/6F, median age 62 yrs) have been in the study for up to 10 months (as of 7/31/2017). 4 subjects received only intralesional doses; 2 subjects were enrolled into both the intralesional and SC cohorts. 18 subjects received only SC injections or IV infusions/bolus injections of MRG-106. 22/26 subjects completed the first treatment cycle per protocol; 2 subjects are on-going. 2 subjects discontinued: one due to progressive disease found shortly after enrollment, and one due to an AE of worsening pruritus (Grade 3), judged as a dose-limiting toxicity at 900 mg SC. The drug was otherwise well-tolerated: of the other 48 drug-related AEs, all were Grade 1 or 2. The MTD has not been reached. 23/24 subjects (95%) showed improvement in either the individually treated lesion (intralesional cohort) or total skin disease (SC/IV cohorts) as measured by maximal change in CAILS or mSWAT. In the SC/IV-infusion cohorts, 17/18 subjects had an improvement in mSWAT score; 9/18 subjects (50%) reached a PR defined as ≥ 50% reduction in mSWAT score. Of the 9 subjects who received MRG-106 for & gt; 1 cycle, 78% reached a PR, suggesting that longer treatment may provide greater benefit. Improvements in mSWAT scores were observed as early as Study Day 19 (the 1st post-treatment assessment), and for all but one subject, improvements from baseline were maintained through the treatment period. Based on immunophenotyping of peripheral blood, absolute numbers and proportions of subjects' leukocyte subpopulations were not significantly altered with MRG-106 treatment, with the exception of transient increases in NK and NK T cells observed only at the highest dose. TCR sequencing of pre- and post-treatment biopsies showed that T cell clonality decreased with intralesional injection of MRG-106. miR-155 was elevated in the lesions of most subjects, drug accumulation was observed with all routes of administration, and gene expression changes were associated with inactivation of the STAT, NFκB, and PI3K/AKT pathways. Conclusions: These preliminary results suggest that MRG-106 is well-tolerated and has clinical activity as indicated by meaningful reductions in CAILS and mSWAT assessments. Exploratory analyses of lesion biopsies support the clinical activity of MRG-106 with reductions in T cell clonality and gene expression changes consistent with the known mechanism of miR-155. These encouraging data support the continued investigation of MRG-106 in MF patients and expansion of the study to include additional hematological malignancies in which miR-155 is known to be elevated and relevant. Disclosures Querfeld: Medivir: Honoraria; Actelion: Honoraria, Research Funding; MiRagen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Kyowa: Research Funding; Trillium Therapeutics: Research Funding; City of Hope: Employment; Mallinckrodt: Honoraria; Mindera: Consultancy. Foss: seattle genetics: Speakers Bureau; Eisai: Honoraria; spectrum: Honoraria, Speakers Bureau; immune design: Research Funding; celgene: Honoraria. Porcu: Tetralogic: Research Funding; Celgene: Research Funding; Cell Medica: Research Funding; Galderma: Research Funding; Kura: Research Funding; Innate Pharma: Research Funding; Miragen: Research Funding; Kiowa: Research Funding. Kim: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; miRagen: Research Funding; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Soligenix: Research Funding; Portola: Consultancy, Research Funding; Neumedicine: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Halwani: Kyowa Hikko Kirin: Research Funding; Bristol Myers Squib: Research Funding; Seattle Genetics: Research Funding; Roche/Genentech Inc.: Research Funding; Genetech Inc.: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Immune Design: Research Funding; Miragen: Research Funding. Seto: miRagen Therapeutics: Employment, Equity Ownership, Patents & Royalties: Inventor on patents. Pestano: Sanofi: Equity Ownership; Cascadian Therapeutics: Equity Ownership; miRagen Therapeutics: Employment, Equity Ownership. Jackson: miRagen Therapeutics: Employment, Equity Ownership. Williams: miRagen Therapeutics: Employment, Equity Ownership. Dickinson: miRagen Therapeutics: Employment, Equity Ownership. Ruckman: miRagen Therapeutics: Employment, Equity Ownership. Gordon: Syndax: Consultancy; Taiho: Consultancy; Pre-cell: Consultancy; Bayer: Consultancy; ElevenP15: Consultancy; Clinipace: Consultancy; Ruesch Center for the Cure of Gastrointestinal Cancer: Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy; Heron Therapeutics: Consultancy; Themis: Consultancy; Caring for Colorado Foundation: Membership on an entity's Board of Directors or advisory committees; TEQ laboratories: Membership on an entity's Board of Directors or advisory committees; GLPI: Consultancy, Equity Ownership; Industrial Laboratories: Membership on an entity's Board of Directors or advisory committees; Axion: Membership on an entity's Board of Directors or advisory committees; Globavir: Consultancy; miRagen Therapeutics: Consultancy; IGM: Consultancy; Cleave Pharmaceuticals: Consultancy; Flugen: Consultancy; Inovio: Consultancy. Rubin: miRagen Therapeutics: Employment, Equity Ownership. Marshall: Colorado BioScience Association: Membership on an entity's Board of Directors or advisory committees; Atlas Venture: Consultancy; AmideBio: Consultancy, 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; miRagen Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor on various patents.

Abstract: Background: Cobomarsen (MRG-106) is an inhibitor of miR-155, a microRNA with a strong link to cutaneous T cell lymphoma (CTCL) pathogenesis. The goals of this first in human study are to evaluate the safety, tolerability, pharmacokinetics, and efficacy of cobomarsen in mycosis fungoides (MF) patients. Methods: This Phase 1 trial evaluated cobomarsen given via intralesional injection (75 mg/dose), subcutaneous (SC), IV rapid bolus injection, or 2-hour IV infusion (300, 600 or 900 mg/dose). Patients must have MF stage I-III with plaques and/or tumors and could remain on concurrent stable CTCL therapy. Patients received 6 doses, either subcutaneous or intravenous, in the first 26 days of the study followed by weekly or bi-monthly doses. Safety was monitored by physical exams, clinical lab tests, and reported adverse events (AEs). Efficacy was assessed by CAILS and by the modified Severity Weighted Assessment Tool (mSWAT). The effect of cobomarsen on quality of life was assessed by Skindex-29. Results: 38 subjects receiving IV or SC treatment (25 male/13 female, median age 59 years) have been on study for up to 22 months. As of the data cut off, no serious AEs have been attributed to cobomarsen. The most common AEs reported in greater than 15% of subjects were: fatigue, neutropenia, injection site pain, nausea, pruritus, and headache. Two AEs were deemed dose limiting toxicities (DLTs): Grade 3 worsening pruritus and Grade 3 tumor flare. The maximum tolerated dose (MTD) has not yet been reached. In the subcutaneous and IV cohorts, 29 out of 32 (91%) evaluable subjects had improvement in mSWAT score. Skin improvements were observed as early as the first assessment (Day 17). The best improvements were observed after more than 1 month of treatment. Eleven out of twenty-one (52%) patients receiving more than one month of dosing (6 doses) achieved greater than 50% reduction in mSWAT score. The mean duration of response (n=11) was 213 days, as of data cut off. Eight patients achieved a partial response meeting the criteria for ORR4, an objective response rate lasting at least four months in duration. The overall skin response in patients who received cobomarsen as monotherapy or cobomarsen with concurrent stable therapy were not significantly different. Improvement in quality of life (QOL), as measured by the Skindex-29 total score, correlated with reductions in mSWAT score during the treatment phase. Conclusions: These results demonstrate that cobomarsen is well-tolerated, has clinical activity, and has the potential to impact MF quality of life. These encouraging data support the continued investigation of cobomarsen in the CTCL population. The study is expanded to enroll patients with other hematologic malignancies in which miR-155 is elevated and relevant, including chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), and adult T cell lymphoma/leukemia (ATLL). Final safety and efficacy data on CTCL mycosis fungoides will be presented. Disclosures Foss: Seattle genetics: Consultancy; Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Mallinkrodt: Consultancy.