Making good on preclinical whispers heard at last year's American Association for the Study of Liver Diseases meeting, Regulus Therapeutics Inc. disclosed interim phase I proof-of-concept data showing that one subcutaneous 2 mg/kg dose of its hepatitis C virus (HCV) candidate RG-101 knocked down HCV RNA in a diverse group of patients.

The La Jolla, Calif.-based company's shares roared Wednesday to close at $13.75, up $6.98, or 103 percent, after trading as high as $15.37.

Regulus CEO Kleanthis Xanthopoulos told investors during a conference call that next steps "obviously are under consideration, given the extraordinary results that we've seen today," which suggest the "potential to have a disruptive agent" in HCV. "Those plans will be finalized over the next few months," Xanthopoulos said, and will include a combination study with direct-acting antivirals. RG-101 is an N-acetylgalactosamine (GalNAc)-conjugated anti-microRNA (miR) that targets host factor miR-122.

Included in the HCV patients to benefit in the phase I experiment were those who had relapsed after interferon (IFN) regimens. Specifically, in the first dose cohort of part IV of the study, 16 HCV patients were enrolled with multiple genotypes: 10 with GT1, five with GT3 and one with GT4. Fourteen patients – eight treatment-naïve and six who experienced viral relapse after a prior IFN-containing regimen – got the drug as monotherapy and two were given placebo.

In the 14 patients, researchers found a mean viral load reduction of 4.1 log10 at day 29 (range -5.8 log10 to -2.3 log10). Six had HCV RNA levels below the limit of quantification at day 29 and the three patients from that group who had reached day 57 still had HCV RNA levels below the limit of quantification.

Viral load reduction happened within the first 96 hours and virologic response was not influenced by the interleukin-28 genotype, the company said. As a result of the encouraging results, Regulus has amended the study protocol to follow patients for up to six months after dosing as a way of exploring the chance that certain patients might reach viral cure after a single dose of the drug.

"We have not seen data as impressive, particularly after a single dose" of an RNA-targeting antiviral in development by other firms, Xanthopoulos said. "The only direct reference we can make is the data from Santaris. They were focusing exclusively on the GT1a naïve patients, which of course are much easier to treat than other genotypes, particularly GT3," he said, noting that Horsholm, Denmark-based Santaris A/S injected 3 mg/kg, 5 mg/kg and 7 mg/kg weekly for five weeks, and followed patients for up to 12 weeks. The 3-mg/kg dose had "very little effect," and the other two doses got 2.3-2.9 log reductions, "nowhere close to what we've seen here, and certainly not as fast-acting or long-acting effect that we see with RG-101."

In early August, Basel, Switzerland-based Roche AG made known its plan to buy partner Santaris for $250 million up front plus $200 million in potential milestone payments. (See BioWorld Today, Aug. 5, 2014.)

No drug-drug interactions turned up from part III of Regulus' ongoing study in which RG-101 was combined with Olysio (simeprevir, Medivir AB/Johnson & Johnson), the oral DAA protease inhibitor approved by the FDA late last year, and the combination had no effect on the pharmacokinetic profile of RG-101 or Olysio. RG-101 is safe and well tolerated so far, with no serious adverse events, and Regulus backers hope the compound might eventually be used in combination with therapies such as Olysio. (See BioWorld Today, Nov. 26, 2013.)

'CORE AGENT' IN HCV

The phase I trial with RG-101 consists of four parts: a single-ascending-dose study in healthy volunteers; a multiple-ascending-dose study in healthy volunteers; a single-dose study in combination with Olysio; and a single-dose monotherapy study in patients with HCV.

Regulus' target profile in the trial is a 2 log or greater viral load reduction after one shot, and interim data suggest RG-101 is well on its way. But the company needs to generate longer-term data in the competitive HCV field, where it goes up against such formidable players as the just-approved Harvoni, from Foster City, Calif.-based Gilead Sciences Inc. The first oral therapy for GT1 HCV to eliminate the need for both interferon and ribavirin, once-daily Harvoni combines a dose of sofosbuvir, the active ingredient in Gilead's blockbuster HCV drug Sovaldi, with ledipasvir, a direct-acting macrocyclic antiviral agent and an inhibitor of NS5A serine protease. (See BioWorld Today, Oct. 13, 2014.)

Responding to questions, Paul Grint, Regulus' chief medical officer, acknowledged the spectrum of responses shown in the study and said more work will have to be done in order to explain the differences. "It's a great question – are there predictive markers that would allow you to identify those patients who are going to respond better than others? Exactly the type of question you ask and a lot more I can think of" will be answered when more experiments can be analyzed, he said. So far, though, the success is "directly related to the GalNAc conjugate design," he said. "You can get much more efficient delivery to the hepatocyte."

Xanthopoulos noted that "what we do know is that, whether you're [treatment-]naïve or experienced, your chance of responding is equal. This could be the core agent in all kinds of patients" across genotypes.