About RG-012

Regulus is developing RG-012, a single stranded, chemically modified oligonucleotide that binds to and inhibits the function of miR-21 for the treatment of Alport syndrome. Alport syndrome is a life-threatening genetic kidney disease with no approved therapies.

In preclinical studies, RG-012 has demonstrated potent inhibition of miR-21 in vitro and in vivo, and in an experimental model of Alport syndrome demonstrated a decrease in the rate of progression of renal fibrosis, an increase in the lifespan of the mice by up to fifty percent, and an additive benefit in combination with an emerging standard of care therapy.  Further, RG-012 has received orphan drug status from the U.S. Food and Drug Administration and European Commission as a therapeutic in development for the treatment of Alport syndrome.

In December 2015, Regulus completed a Phase I first-in-human randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the safety, tolerability and pharmacokinetics of subcutaneous RG-012 in healthy volunteers in the United States. Forty healthy volunteer subjects were enrolled and RG-012 was well-tolerated. No serious adverse events were reported and all forty subjects successfully completed the study. Regulus expects to use the results of this Phase I study, as well as those of its ongoing ATHENA Natural History Study to inform the design of a Phase II therapeutic intervention study of RG-012 for the treatment of patients with Alport Syndrome.

RG-012 is being developed by Regulus in a strategic alliance with Genzyme, a Sanofi company, for the treatment of Alport syndrome. Regulus is responsible for advancing RG-012 to proof-of-concept. At that stage of development, Sanofi has an exclusive option exercisable after proof-of-concept to assume worldwide development and commercialization of RG-012 subject to a co-promote right in the United States by Regulus.

ATHENA Natural History Study and Phase II Therapeutic Intervention Study for Patients with Alport Syndrome

Currently, there is little known information on exactly how Alport syndrome progresses, although miR-21 is known to play a role in the disease progression.  miR-21 is up-regulated in Col4A3 deficient mouse models of Alport syndrome, other renal fibrosis models and human CKD patients.  The role of miR-21 has been validated through genetic knock-out models and anti-miRs targeting miR-21 have reduced the severity of fibrosis in two distinct preclinical rodent models.

In September 2014, Regulus initiated ATHENA ( a natural history of disease study to gather greater information about the progression of Alport syndrome, particularly the rate of decline in renal function in Alport syndrome patients over time. To our knowledge, this is the first-ever prospectively designed natural history study in patients with Alport Syndrome.

Regulus aims to enroll up to 120 Alport syndrome patients who are 16 years and older with a GFR between 30-75ml/min at planned clinical sites in the United States, Australia, Canada and Europe. Data from the ATHENA study will provide the clinical basis for the design of a Phase II study to evaluate the therapeutic effect of RG-012 on the decline in renal function in Alport syndrome patients. Regulus expects that many patients enrolled in ATHENA will be eligible to enroll in a Phase II therapeutic intervention study, which Regulus expects to initiate by the middle of 2016.

About Alport Syndrome

Alport syndrome is an inherited form of kidney disease caused by mutations in the type IV collagen genes (Col4A3, Col4A4 and Col4A5). The prevalence of mutations in the collagen IV family of genes is estimated to be 1 in 5,000 individuals (Pirson, 1999). Type IV collagen is important for maintaining the integrity of the glomerular basement membrane (GBM), a vital component in the kidney structure and filtration process. The genetic mutation in the collagen gene results in thickening in the GBM and impairment of glomerulus filtration.

Alport syndrome patients experience a progressive loss of kidney function, which ultimately leads to end stage renal disease requiring dialysis or kidney transplantation often by early adulthood, or even death (Cosgrove, 2012; Jais et al., 2000; Oka et al., 2014). Patients with Alport syndrome are thought to account for approximately 2.5% of all renal transplants in the US. Alport syndrome can also cause hearing loss and eye abnormalities during late childhood or early adolescence because the collagen IV isotypes are also expressed in the inner ear and eye. The major clinical concern, however, is the loss of renal function.

Although not an approved therapy for Alport syndrome, ACE (angiotensin-converting enzyme) inhibitors are often used in patients with Alport syndrome to treat proteinuria, or abnormal amounts of protein in the urine, an indicator of chronic kidney disease.  However, with no approved therapies, Alport syndrome is a disease with an urgent unmet medical need.