RG-101 Targeting miR-122 for HCV

Hepatitis C is a 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. According to the World Health Organization, up to 170 million people are chronically infected with HCV worldwide, and more than 350,000 people die from HCV annually. The CDC estimates that there are currently approximately 3.2 million persons infected with HCV in the United States.

We have nominated RG-101 as our first microRNA clinical candidate for the treatment of HCV. RG-101, which is wholly-owned by us, is a hepatocyte-targeted GalNAc-conjugated anti-miR targeting microRNA-122, or miR-122. miR-122 is the most abundant microRNA in liver hepatocytes and HCV has evolved to utilize it as a viral replication factor such that the stability and propagation of HCV is dependent on the interaction of miR-122 and the HCV genome.

We believe that RG-101 has several attractive properties that make our approach to treating HCV unique and differentiated among the current therapies:

  • RG-101 employs a unique mechanism of action by targeting a host factor.
    • We believe by targeting a host factor there is a lower likelihood for the virus to develop resistance, which has been observed with direct-acting antivirals. In addition, because of its unique mechanism of action, we believe that RG-101 will have minimal to potentially no negative drug-drug interactions with current and future direct-acting antiviral treatment regimens.
  • RG-101 has the potential to be a pan-genotypic agent.
    • The miR-122 binding site of the HCV genome is one of the most highly conserved regions across all HCV genotypes. Therefore, RG-101 is expected to be active against all viral genotypes. In preclinical studies, RG-101 has demonstrated activity across a broad spectrum of HCV genotypes and against the most commonly identified HCV mutations detected in patients being treated with direct-acting antiviral therapy.
  • RG-101 has a convenient dosing regimen.
    • The pharmacological activity of RG-101 has been shown in animal models to be sustained for more than 28 days after a single dose administration. These data suggest the feasibility of a convenient subcutaneous dosing regimen, to be administered during a patient’s regularly scheduled physician visit.
  • RG-101 is potent and has a favorable safety profile to date.
    • In pharmacology studies using a human liver chimeric mouse model to assess potency against HCV, RG-101 demonstrated significant lowering of viral titer load. These experiments are helping us refine the initial starting dose for clinical trials in humans and assess the therapeutic index. Further, we did not identify any adverse effects that would preclude the development of RG-101 for the treatment of HCV.

Phase 1 Trial Design

The Phase I clinical study of RG-101 will have four parts; (i) a single ascending-dose study in healthy volunteer subjects; (ii) a multiple-ascending dose study in healthy volunteer subjects; (iii) a single-dose drug-drug interaction study of RG-101 in combination with an approved oral direct-acting antiviral (“DAA”) in healthy volunteer subjects; and (iv) a single-dose study in HCV patients to assess the safety and viral load reduction, which is designed to demonstrate human proof-of-concept. The primary objective of the Phase I clinical study of RG-101 is to evaluate safety and tolerability and the secondary objectives are to evaluate pharmacokinetics, viral load reduction and any impact an oral DAA may have on the pharmacokinetics of RG-101. A total of approximately 80 healthy volunteer subjects and HCV patients are planned to be enrolled in the Phase I study, which is being conducted in the Netherlands, and dosing is expected to commence in the near term.