FDA's Clinical Hold on Investigational HCV Drug Continues

Earlier this month, the US Food and Drug Administration (FDA) announced that a clinical hold that was placed on a hepatitis C (HCV) drug back in the summer of 2016 due to adverse effects will continue.

Acccording to Regulus Therapeutics Inc., RG-101 is a “GalNAc-conjugated anti-mir targeting miR-122” designed to treat HCV infections. This new therapeutic agent targets all HCV genotypes, as well as the strain responsible for causing increased resistance to direct-acting antivirals. A single dose of 2 mg/kg or 4 mg/kg of RG-101 administered subcutaneously was found to cause “significant and sustained viral load reductions in all treated HCV patients” in a phase 1 study. As a monotherapy, RG-101 was successful in reducing viral load in individuals with difficult-to-treat genotypes, as well as in those who previously relapsed after treatment with interferon-containing therapy.

However, in June 2016, during clinical trials for RG-101, reports of a second case of jaundice prompted the FDA to place the drug on clinical hold. According to the press release, this patient had “end-stage renal disease [and was] on dialysis,” and presented with jaundice 117 days after one dose of the drug, during the phase 1 US study.

Jaundice is usually diagnosed in infants; however, it can develop in adults who have viral infections, including chronic HCV. Jaundice refers to discoloration of the skin and whites of the eyes, which usually become of a yellowish hue due to higher than normal levels of bilirubin. In addition to the discoloration, some infected individuals may present with fever, stomach pains, chills, and symptoms usually associated with influenza infection.

Exactly one month after announcing the clinical hold, the FDA provided Regulus with a list of data to be submitted to the FDA for review, with the outcome to be provided to Regulus after 30 days.

According to the press release, the requested data were as follows:

• Detailed safety data analysis from preclinical studies
• Exploration of potential mechanisms of hepatotoxicity in non-clinical models
• Review and input from independent hepatotoxicity experts
• Additional PK data from the US phase 1 study
• Risk/benefit assessment for the proposed therapeutic regimens containing RG-101

Regulus submitted the requested data to the FDA in late 2016.

In a recent press release from the pharmaceutical company, Regulus noted that the submitted report “included identification of a potential mechanism of hyperbilirubinemia.” They later “submitted a proposal to mitigate this risk.” Nonetheless, before the clinical hold can be lifted Regulus must submit “final safety and efficacy data from on-going RG-101 clinical and pre-clinical studies,” as well as “additional expert review of safety data in light of the proposed mechanism of hyperbilirubinemia” to the FDA.

According to Regulus, the additional data requested by the FDA cannot be submitted before “the current study protocols are complete through 48 weeks of follow up, which is anticipated in the fourth quarter” of 2017.

In the press release, Chief Research and Development Officer of Regulus Therapeutics Inc., Timothy M. Wright, MD, said, “While we are disappointed that the clinical hold was not lifted at this time, we plan to continue to work with the FDA to address their additional requests as we seek the removal of the clinical hold.”