Regulus’ wholly-owned lead product candidate is RG-101, a GalNAc-conjugated anti-miR targeting miR-122 for the treatment of hepatitis C virus (HCV) infection. miR-122 is the most abundant miR in the liver and is essential for HCV stability, replication and translation in hepatocytes. Regulus believes that its miR-122 antagonist, RG-101, has the potential to become a powerful new agent in the treatment of HCV infection.
RG-101 has several important properties which may differentiate it from other therapies currently on the market for the treatment of HCV.
- A novel mechanism of action
- Activity against all genotypes
- Activity against HCV strains with mutations that cause resistance to oral direct-acting antivirals (DAAs)
- Ability to be safely combined with and potentially enhance the efficacy and/or shorten the required treatment period of existing oral DAA therapies.
In a completed Phase I clinical study, Regulus demonstrated that treatment with a single subcutaneous dose of either 2 mg/kg or 4 mg/kg of RG-101 as monotherapy resulted in significant and sustained viral load reductions in all treated HCV patients, including patients with difficult to treat genotypes, various liver fibrosis status and those who have experienced viral relapse after a prior IFN-containing regimen.
In an ongoing Phase II clinical study, interim data showed that two injections of 2 mg/kg of RG-101 combined with just 4 weeks of commercially-available oral DAAs achieves high virologic response rates. The study enrolled 79 treatment naïve genotype 1 and 4 HCV patients (Harvoni® arm, n=27, Olysio® arm, n=27, Daklinza™ arm, n=25). Among the 38 patients with data through 8 weeks of follow up, 97% (37/38) had HCV RNA viral load measurements below the limit of quantification. For those patients through 12 weeks of follow-up, 100% remained below the limit of quantification (14/14).
To date, RG-101 has been generally well tolerated in patients with the majority of adverse events considered mild or moderate, and with no adverse events leading to study discontinuations in any study.
Ongoing RG-101 Clinical Trials
Regulus’ Phase II program and development strategy for RG-101 includes evaluating RG-101 (1) in combination studies with different approved direct-acting anti-HCV agents (DAAs); (2) in combination with investigational oral DAAs that can be formulated into long acting injections providing the potential for a single-visit therapy; and (3) in certain underserved HCV patient populations.
- Enrollment has been completed in an ongoing Phase II study evaluating the combination of RG-101 with multiple approved DAAs. Treatment-naïve patients chronically infected with genotypes 1 or 4 were randomized to one of three treatment arms (n=78). Patients receive a single subcutaneous injection of 2 mg/kg of RG-101, followed by 28 days of once/daily DAAs Harvoni®, Olysio®, or Daklinza®, followed by an additional subcutaneous injection of 2 mg/kg of RG-101 on Day 29. Positive interim results were reported in mid-February 2016, with primary endpoint results for virologic response at 12 weeks following conclusion of treatment anticipated in late Q2 2016.
- In early November 2015, Regulus announced that the company entered into a clinical trial collaboration agreement with GlaxoSmithKline (“GSK”) to evaluate an HCV combination regimen. In March 2016, Regulus initiated a multi-center, open-label Phase II study evaluating the combination of a single subcutaneous injection of 4 mg/kg of RG-101 and daily oral administrations of 20 mg of GSK2878175, an investigational non-nucleoside NS5B polymerase inhibitor, for up to 12 weeks in treatment-naïve patients chronically infected with HCV genotypes 1 and 3. Concurrently, GSK will work on developing a long-acting parenteral (“LAP”) formulation of GSK2878175 as a single intra-muscular injection, providing the potential for a single-visit therapy for HCV that could improve patient compliance through reduced dosing intervals and potentially extend opportunities for HCV therapeutic intervention. This LAP formulation of GSK2878175 may be used in additional clinical trials together with RG-101 following completion of the planned Phase II study, although any additional studies are not currently contemplated by the collaboration agreement. Regulus expects to report safety and efficacy data from the GSK Phase II study before the end of 2016.
- In addition to the combination studies, Regulus has commenced enrollment of patients in a multi-center, open label, non-randomized Phase I study to compare the safety, tolerability, pharmacokinetics, and pharmacodynamics of 2 mg/kg of RG-101 in subjects with severe renal insufficiency or end-stage renal disease (ESRD) to healthy control subjects, and further explore RG-101 in hepatitis C infected subjects with severe renal insufficiency or ESRD. The Phase I study is designed to have three treatment arms (n=24): (i) healthy volunteers (n=8); (ii) patients with severe renal impairment or ESRD (n=8); and (iii) HCV patients with severe renal impairment or ESRD (n=8). Enrollment is expected to be complete in the first half of 2016 with efficacy data from the HCV/severe renal impairment or ESRD arm anticipated in the second half of 2016.
About Hepatitis C Infection
Hepatitis C is the result of a hepatocyte-specific infection induced by the virus known as HCV. Chronic HCV may lead to significant liver disease, including chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Approximately 185 million people are chronically infected with HCV worldwide. An estimated 10 million people in the United States, European Union, and Japan have chronic HCV infection. According to the World Health Organization, more than 500,000 people die from HCV annually. The CDC estimates that there are currently approximately 3.5 million persons infected with HCV in the United States.
The field of HCV treatments is changing rapidly with the introduction of new direct acting antiviral (DAA) drugs in several classes – protease inhibitors, polymerase inhibitors, NS5A inhibitors, and combinations of these – with superior efficacy and tolerability compared to interferon-based or prior generation protease inhibitor-based regimens. However, despite the advances made in recent years, there remain underserved populations of infected individuals who do not respond to current treatments, who relapse following successful treatment, who are not compliant over up to 12 weeks of daily treatment, or who poorly tolerate one or more drugs used in the new standard-of-care cocktails. Resistance to antiviral therapy is a major problem associated with the high mutation rate of HCV and is seen even with combinations of drugs working through multiple mechanisms. Thus, new therapeutic strategies based on novel mechanisms of action, with an aim towards achieving higher efficacy, pan-genotypic activity, shortened treatment durations, and simplified administration leading to improved tolerability and patient adherence, are areas of high unmet medical need in HCV.