miRagen Therapeutics announced new data from two Phase 1 clinical trials of MRG-110, miRagen’s microRNA-92 inhibitor, in which administration of MRG-110 was observed to increase angiogenesis, as demonstrated by increased perfusion and histological markers of neoangiogenesis, as well as reduce alpha-smooth muscle actin (α-SMA) expression, which has been show to correlate with activation of myofibroblasts. In addition, MRG-110 was safe and generally well-tolerated when given as a single intravenous dose or as three weekly intradermal doses.
“We believe these Phase 1 safety, tolerability, pharmacokinetics, and biomarker data may provide mechanistic proof-of-concept for use of MRG-110 in the treatment of cardiovascular disease and certain other conditions where vascular flow is compromised,” said Paul Rubin, M.D., Executive Vice President, R&D, of miRagen Therapeutics. “When combined with the preclinical data that we have accumulated for MRG-110 in a variety of potential therapeutic settings, we believe these initial human data support advancing MRG-110 into additional clinical studies.”
“MRG-110 is our third product candidate to have observed proof-of-drug mechanism in humans with a good safety and tolerability profile. We believe this adds to the growing body of evidence that microRNA targeting may be a new avenue to treat complex diseases,” William S. Marshall, President and CEO of miRagen Therapeutics, said.
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The two Phase 1 studies investigated MRG-110 in order to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple local administrations of MRG-110 in excisional wounds. In addition, one of the studies was a systemic dosing study assessing safety and tolerability in healthy volunteers.
In small, acute wounds on normal healthy volunteers, single and multiple doses of MRG-110 appeared to:
- Increase angiogenesis as assessed by CD31 immunostaining, a marker of new blood vessel growth;
- Increase peri-wound perfusion, as assessed by non-invasive Laser Speckle Perfusion Imaging;
- Demonstrate pharmacodynamic target engagement by increasing CD49e (ITGA5) expression; and
- Reduce α-SMA expression, as assessed by immunostaining.
In the intradermal multiple ascending dose study, the mean granulation tissue, or new connective tissue, area was decreased in subjects treated with MRG-110 when compared to placebo treated subjects’ wounds. miRagen believes that delayed granulation tissue formation may be related to the MRG-110 mediated decrease in α-SMA positive myofibroblasts, which are the predominant source of type I collagen and fibrogenic/inflammatory cytokines. The data also supported that delayed kinetics of granulation tissue formation was not detrimental to achieving full wound closure or appropriate collagen maturation.
miRagen believes that the data supports moving forward in cutaneous wounds of varying causes where increased perfusion may result in improved wound closure and reduced α-SMA expression may reduce scar formation and contracture. miRagen also believes that this mechanistic proof-of-concept study combined with the observed safety and tolerability of MRG-110 via systemic administration support additional clinical studies to evaluate the ability of the product candidate to enhance vascularization and function in the setting of heart failure.
In August 2019, miRagen announced that it had regained the rights to MRG-110 in all indications and all territories globally, including rights in the U.S. and Japan.