ALBERT

Description: Treatment-resistant hematological malignancies remain an area of high unmet need and novel therapeutic approaches will be required. microRNAs are small (~ 22 nt) non-coding RNAs that act as negative regulators of gene expression. These small RNAs impact expression of a substantial fraction of the genome, and have powerful effects on cellular phenotypes and physiological processes. miR-155-5p is a well-described oncomiR associated with poor prognosis in multiple malignancies, particularly lymphoma and leukemia. Cutaneous T-cell lymphoma (CTCL) is a rare hematological malignancy with limited treatment options and a strong mechanistic link to increased miR-155-5p. Because of the accessibility of cutaneous lesions, CTCL provides a unique opportunity to determine if inhibition of miR-155-5p has therapeutic potential in lymphomas associated with elevated miR-155-5p. We optimized a LNA-modified oligonucleotide inhibitor of miR-155-5p, MRG-106, based on the ability to de-repress canonical miR-155-5p targets in multiple cell types in vitro. In mycosis fungoides (MF) cell lines, MRG-106 does not require additional formulation to achieve maximum pharmacodynamic efficacy. Inhibition of miR-155-5p resulted in transcriptome changes consistent with miR-155-5p target gene modulation, reduction in cell proliferation, and activation of the programmed cell death pathway. The gene expression and phenotypic effects were inhibitor dose-dependent and sequence-specific. Based on an informatics approach for the expression profiling of MF cell lines treated with MRG-106, a set of 600 genes was identified to represent the translational pharmacodynamic biomarker signature, both direct and downstream of miR-155-5p. GLP preclinical safety studies have been completed in rats and non-human primates, demonstrating an acceptable safety profile for MRG-106. We plan to initiate a 4-week first-in-human clinical trial in CTCL (MF) patients. The trial design is two-part, with Part A testing the effect of direct intra-tumoral injection of MRG-106 into plaque and nodular skin lesions, and Part B testing the effect of systemic (subcutaneous) administration of higher doses of MRG-106. The primary objective of Part A is to profile the pharmacodynamic effect of MRG-106 on the miR-155-5p gene expression signature, establishing a PK/PD model to guide future development. The primary objective of Part B is to establish the safety, tolerability, PK and skin deposition of MRG-106 after systemic delivery. Exploratory objectives include measures for clinical response, immune system effects, and biomarker validation. Disclosures Seto: miRagen Therapeutics: Employment, Equity Ownership. Beatty:miRagen Therapeutics: Employment, Equity Ownership. Pestano:miRagen Therapeutics: Employment, Equity Ownership. Dickinson:miRagen Therapeutics: Employment, Equity Ownership. Warren:miRagen Therapeutics: Consultancy. Rodman:miRagen Therapeutics: Employment, Equity Ownership. Jackson:miRagen Therapeutics: Employment, Equity Ownership.

Description: 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.

Description: 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 〉 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.