RG-012 is an experimental therapy being developed by Regulus Therapeutics. to treat Alport syndrome. It has received orphan drug designation from the both the U.S. Food and Drug Administration and the European Commission as a potential therapy for a rare disease.

How RG-012 works

Alport syndrome is a condition caused by mutations or defects in the collagen genes. Collagen is essential for maintaining the integrity of kidney structure. These defects cause scarring of a structure called the glomerular basement membrane (GLM), which is necessary in helping the kidneys filter blood. Such scarring results in a progressive loss of kidney function, eventually requiring the patient to undergo frequent dialysis or a kidney transplant.

According to new research, the process of fibrosis in Alport syndrome involves a small molecule called microRNA-21 (miR-21). MicroRNAs regulate many processes in the body by reducing the levels of specific proteins. MiR-21 represses proteins in the PPARα signaling pathway, which could have a protective function in the kidneys.

RG-012, a complementary molecule to miR-21, binds and inhibits it from working. By blocking miR-21, the drug removes repression of the PPARα pathway and could reduce Alport symptoms.

RG-012 in clinical trials

RG-012 has shown promising results in pre-clinical trials. In a mouse model of Alport syndrome, RG-012 has been shown to successfully silence miR-21, thereby slowing the rate of thickening of the GLM, improving kidney function and boosting life expectancy by up to 50 percent.

San Diego-based Regulus is now running a randomized, double-blind, placebo-controlled Phase 2 clinical trial (NCT02855268) called the HERA study, in collaboration with Sanofi Genzyme. Its aim is to assess the safety and efficacy of RG-012 in Alport patients, compared to a placebo. Participants will be injected with either 110 mg or 220 mg of RG-012 or placebo once weekly, for 48 weeks (up from the initial 24 weeks). Researchers will monitor all patients for adverse effects during the trial, which has been delayed but should produce results by mid-2018.

The delay followed a decision by Regulus to carry out a Phase I multiple ascending dose study on healthy participants, to provide vital data on the drug’s safety. Results are expected this year.

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