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At the forefront of fibrosis
BOULDER, Colo.—Biopharmaceutical company miRagen Therapeutics Inc. recently debuted encouraging new preclinical data related to pulmonary disease for one of its lead candidates, MRG-201, at this year’s European Respiratory Society International Congress in Milan, Italy. The compound is being advanced in several indications related to fibrosis.
MRG-201 is what is known as a microRNA-29 “mimic,” which emulates the activity of microRNA-29 and decreases the expression of collagen and other proteins associated with scar formation—previous studies have indicated that microRNA-29 might regulate production of the extracellular matrix. One the various microRNAs that miRagen is pursuing is microRNA-29, which plays a role in fibrogenesis. Levels of this microRNA are extremely low in several pathological fibrotic conditions, such as cutaneous, cardiac, renal, hepatic, pulmonary and ocular fibrosis, as well as systemic sclerosis.
“We discovered the linkage between microRNA-29 and fibrosis originally in the setting of myocardial infarction,” explains Dr. William S. Marshall, president and CEO of miRagen. “Any time you have an injury to an organ or a cut on your skin, the fibrotic response is really intended to stabilize the organ or close the cut so that you’re not subject to sepsis. What we found was that right after myocardial infarction, levels of this microRNA drop, and then over a period of a couple weeks it comes back up. When we did some bioinformatic analysis to understand the predicted targets that are regulated by the microRNA, what was really compelling to us was that the microRNA had the likelihood of controlling the expression of many different genes that are involved in fibrogenesis, so everything from things like TGF beta, PDGF and other growth factors were all controlled by microRNA-29.”
The preclinical safety and feasibility data shared in Milan focused on MRG-201’s potential in the area of pulmonary fibrosis, or scarring of the lungs; miRagen reported that they were able to successfully nebulize the compound for inhaled delivery in rodents while maintaining its chemical integrity. (The study featured a nose-only inhalation exposure system with Lovelace Respiratory Research Institute for this investigation.) In addition, exposure within lung tissue was high following inhalation, but low in tissues beyond the lung, implying that this form of MRG-201 has a localized effect with limited effect on the broader system. The nebulized form of the compound proved capable of down-regulating pharmacodynamic and mechanistic biomarkers linked to fibrotic tissue deposition.
“What we subsequently recognized was that in the setting of pathological fibrosis, in essentially all the forms that have been looked at today, there’s a mechanism that leads to the persistent down-regulation of the microRNA,” says Marshall. “And so rather than going through the regular healing cycle, where you would deposit extracellular matrix and as inflammation resolves you turn off the process, there’s a couple of interesting publications that have now shown that persistent inflammation, in addition to pathological matrix, actually feedback to reinforce the dampening of expression of microRNA-29. And when you do that, you set up a vicious cycle where you reinforce more and more fibrogenesis and more and more extracellular matrix deposition, which is really a hallmark of pathologic fibrosis—uncontrolled fibrotic tissue deposition. And what we were able to do in a variety of preclinical studies was show that in the setting of the decrease of microRNA-29, if we use a synthetic replacement of this microRNA, we can control all the genes in the fibrogenesis pathway.”
Cutaneous fibrosis in another area in which miRagen is advancing MRG-201. A recent Phase 1 study in healthy volunteers consisted of making two small incisions, one that was treated with MRG-201 and one that was treated with placebo, then studying the healing process and taking a biopsy of the incision site.
The study was focused on MRG-201’s safety, tolerability and pharmacokinetics, but also was what Marshall called a “foothold” approach, in that it also looked at biomarker-driven activity and whether the compound resulted in any changes in gene expression or “histopathological changes associated with clinical benefit.” This approach enabled miRagen to confirm that “the biomarker set that we identified is in fact fully regulated, so we can say at a molecular level that that is controlling fibrogenesis in man. Fibrogenesis is a highly conserved process. So an important purpose of this initial study was to demonstrate that we can control this pathway in man, independent of whether it’s cutaneous manifestations or other manifestations. It really helps to de-risk the compound.”
“In the human setting, we’ve now been able to show that the drug, when administered at the site of induced fibrosis in an incisional wounding setting, is able to invert a variety of biomarkers in fibrogenesis,” Marshall adds. “That then culminates in a reduction in fibroplasia, which is a marker of fibrotic tissue deposition, but it doesn’t affect the ability of the wound to heal.”
Looking forward, Marshall tells DDNews that miRagen is interested in advancing MRG-201 in several areas of fibrosis as it relates to healing. Keloid scars are one such target. These scars are typified by an excess of scar tissue, and while the main method for treating them is to remove the scar tissue, it grows back 70 percent of the time, Marshall explains. Hypertrophic scars and burns are also indications they hope to pursue, noting that “If you have a product candidate that really is able to prohibit scar tissue formation but not affect wound healing, it has rather broad implications in incisional wounds.”
He says they are “absolutely” looking to continue advancing in the area of pulmonary fibrosis as well, noting that “Pulmonary fibrosis, cutaneous fibrosis, fibrotic conditions in the eye, liver and kidney are all areas of interest for MRG-201 or other microRNA-29 mimics.” He adds that the company is planning to move into the necessary studies for filing an IND to advance MRG-201 into the clinic in the indication of idiopathic pulmonary fibrosis.