In the fast-advancing hepatitis C virus (HCV) space, to make a splash isn't easy, as Regulus Therapeutics Inc. proved by unveiling phase I data that hold promise but were met by Wall Street with a lukewarm, wait-and-see attitude.

"We think that there is a potential to have a disruptive agent in HCV in RG-101, so we are currently looking very intensively to develop a plan that moves RG-101 forward in combination with direct[-acting] antivirals for a variety of patients," CEO Kleanthis Xanthopoulos told Regulus backers during a conference call in October, when the first proof-of-concept data with the compound surfaced, and it's apparently more news about just such combos that investors are waiting for.

The La Jolla, Calif.-based firm's stock (NASDAQ:RGLS) closed Monday at $15.64, down $1.22, after top-line data were disclosed from the 4 mg/kg cohort along with more results from the 2 mg/kg cohort in a study evaluating subcutaneously given RG-101, a GalNac-conjugated anti-microRNA therapy that targets microRNA-122 for HCV.

RG-101's "true value" will be unlocked in a combo regimen, Deutsche Bank analyst Alethia Young predicted in an email alert to investors, calling the new monotherapy outcomes "interesting proof-of-concept for the asset and their platform overall." The compound is likely best used as a booster to a month of HCV pills, in her view, since any type of patient seems responsive to RG-101, though Xanthopoulos said during an updating conference call Monday that RG-101 could prove worthy in "certain underserved patient populations" as well.

Treatment with a single subcutaneous dose of 4 mg/kg of RG-101 as monotherapy resulted in significant and sustained viral load reductions in all patients, including difficult-to-treat genotypes, various liver fibrosis status and those who relapsed after an interferon-containing regimen, Regulus said.

The data showed a greater response at 4 mg/kg (mean viral load reduction 4.8 logs) vs. 2 mg/kg (mean viral load reduction of 4.1 logs), with both responses durable at two months and no safety signals. All patients have responded to therapy, too, no matter what their genotype and fibrosis score. "We intended of course all along to have once-a-month dosing, but the data have been amazingly strong," Xanthopoulos said. Two patients relapsed at about day 57, possibly because they had only 6 percent drug levels in their tissues by then, the company speculated.

Young acknowledged that "the key pushback here is that the HCV market is over with all the discounts and greater volume," but she argued that in time "RG-101 may fit in the HCV combo regimen, if the simplicity of their regimen with pills still holds up. We think players in the HCV market will continue to have the same development strategy." The full dataset from the proof-of-concept experiment is likely to roll out in April during the 50th Annual Congress of The European Association for the Study of the Liver in Vienna. Meanwhile, "the proof of principle for microRNA biology from RG-101 remains unappreciated," according to Young.

FOCUS ON REGULATOR TALKS

Specifically, in the 4 mg/kg dose cohort yielding the latest results, 16 HCV patients were enrolled: 14 patients, 12 treatment-naive along with two patients who experienced viral relapse after an interferon-containing regimen, received a single dose of 4 mg/kg of RG-101 as monotherapy, and two patients received placebo. In the 14 treated HCV patients, there was a mean viral load reduction of 4.8 log10 at day 29 (range -5.8 to -3.0); and nine out of 14 patients had HCV RNA levels below the limit of quantification (BLOQ, or <15 IU/ml) at day 57. These patients will be followed for up to six months to investigate the potential for viral cures following the single administration of 4 mg/kg, Regulus said.

As for the 2 mg/kg dose cohort, this was the subject of the October interim efficacy and safety results and its first human proof-of-concept outcomes. At day 85, four out of 14 treated patients with varied genotypes, liver fibrosis status and treatment history were determined "target not detected." Two of the treated patients, previously noted, that were BLOQ at day 57 relapsed shortly thereafter. Due to the longevity of the viral responses that turned up, Regulus amended the protocol to add a year of follow-up.

During Monday's call, Young questioned Paul Grint, Regulus' chief medical officer, about whether the combo strategy still looks the same, given the latest data. "I don't think it's really changed much," Grint said. "Based on the data and what we're seeing, clearly it's important for us to better characterize what monotherapy does," and the firm is "becoming more sensitive to the practicalities out there in the real world."

Regulus has a relationship that began in 2010 with Paris-based Sanofi SA, which is aimed at discovering microRNA-based drugs in fibrosis. The Sanofi deal involves three microRNAs regarding which the pharma firm can opt in, once proof-of-concept data are in hand. Young wrote that Regulus believes it has "freedom to operate if it were the case of something strategic on RG-101 [arising] with another developer in the space."

For now, Xanthopoulos said the firm is staying focused on talks with the FDA and the EMA with an eye to phase II trials. Regulus wants "a little more than proof-of-concept [data]" before making further moves, he said. (See BioWorld Today, June 23, 2010.)