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New Data Shows Higher Dose of Regulus HCV Drug Offers Better Viral Load Reductions

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NEW YORK (GenomeWeb) – Regulus Therapeutics today released additional data from a recently completed Phase I trial of its microRNA-targeting hepatitis C therapy RG-101, showing that a single 4 mg/kg dose of the subcutaneously administered drug — the highest yet tested — triggers greater viral load reductions.

Further, the data indicate that the viral load reductions, which are on par or better than existing treatments, can be achieved in patients regardless of their disease genotype, the extent of their liver fibrosis, or if they had previously experienced a relapse after prior treatment with other therapies. RG-101 continues to appear safe and well-tolerated.

The study results were not all positive, however, and Regulus noted that two patients whose viral loads had fallen below the limit of quantification 57 days after treatment "relapsed shortly thereafter."

Company officials said during a conference call held to discuss the new data that there are a number of possible reasons behind the relapses, but that there is not enough data to draw any firm conclusions.

RG-101 is an antagonist of miR-122, the most abundant miRNA in the liver and one that has been show to play a key role in HCV replication and infection. It is delivered using Alnylam Pharmaceuticals' GalNAc conjugate delivery technology, which targets the asialoglycoprotein receptors expressed on the surface of hepatocytes.

The Phase I trial comprises four stages, with the first three examining single and multiple doses of the drug, as well as single doses in combination with the approved oral direct-acting antiviral agent Olysio.

The closely watched fourth arm of the study tested single doses of RG-101 ranging from 2 mg/kg, 4 mg/kg, and 8 mg/kg in a variety of HCV patients including ones with genotypes 1, 3, and 4, as well as treatment-naive patients and ones who have experienced viral relapse after receiving interferon (IFN)-containing treatments.

In October, Regulus released data on 14 patients in the 2-mg/kg-dose group, which showed that treatment resulted in a virological response, with a mean 4.1-log viral load reduction at day 29. Six of the patients had HCV RNA levels fall below the limit of quantification (BLOQ) by day 29, with three patients from this group still experiencing these undetectable levels at day 57.

Today, Regulus presented extended follow-up data from the 2 mg/kg cohort showing that at day 85, four of the 14 patients treated were deemed "target not detected," which is defined as "no presence of HCV RNA as detected by the Roche Cobas [HCV] assay 2.0," Regulus CMO Paul Grint said during the call.

Due to the longevity of the viral load reductions, Regulus said that it was amending the trial's protocols to follow the 2 mg/kg patients for an additional year to "investigate the potential for viral cures with one single administration" of RG-101.

Not all the data were positive, however. Two of the six patients who were BLOQ at day 57 experienced a relapse, an occurrence that company officials were at a loss to explain.

Regulus President and CEO Kleanthis Xanthopoulos said during the call that the relapse may have been due to the lower levels of drug in remaining in liver tissue after roughly two months.

Grint added that the patients' starting viral loads — a factor that is known to influence the efficacy of other HCV therapeutics — may also have contributed to the relapses, but stressed that this cannot be known for certain with such a small number of patients.

Regulus also unveiled top-line data from the 4 mg/kg cohort, which consisted of 12 treatment-naive patients and two patients who had relapsed after previous IFN treatment. In all the patients, there was a mean viral load reduction of 4.8 log at day 29. The range of viral load reductions among these patients was 5.8 to 3.0.

Nine of the patients were BLOQ at day 57, and Regulus said they will be followed for up to six months to see whether the single dose can result in a cure.

During the conference call, Grint noted that the new data include previously unreleased information about the extent of liver fibrosis among the study participants in the 2 mg/kg cohort, which included five patients in the advanced stages of fibrosis. A similar number of patients with advanced fibrosis were in the 4 mg/kg cohort.

"Given the severity of some of the fibrosis scores … we believe that [the] significant and sustained responses … are that much more impressive," Grint said.

Looking ahead

Regulus CSO Neil Gibson added that because patient response does not appear to be influenced by HCV genotype or the extent of liver fibrosis, the company is exploring the possible relationship between viral responses and starting viral loads.

"Patients with viral loads equal to or less than 2 x 106 may show hypersensitivity to RG-101 or go below the limit of quantification faster," he said. "This finding may help us predict response to RG-101 prior to treatment, and we expect to test this hypothesis in additional patients."

Gibson said that Regulus is also profiling serum samples from treated patients to identify miRNA signatures that may allow the company to predict patient response to treatment.

In light of the data, Gibson said Regulus remains on track with its dual-development approach for RG-101, under which the drug will be tested both as a monotherapy and in combination with a direct-acting antiviral.

In the second quarter of this year, the company aims to start Phase II studies to test multiple doses of the drug both alone and as part of a combination therapy. Interim data from these trials are expected by year end.

Regulus also plans to release full Phase I data next quarter.

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