A nonpharmaceutical approach to hepatitis C (HCV) treatment demonstrated promising efficacy and safety results in an early stage trial, researchers reported.
Blocking the liver-expressed microRNA-122 (miR-122) led to dose-dependent and persistent declines in HCV, according to Harry Janssen, MD, PhD, of the University Health Network in Toronto, and colleagues.
The antisense oligonucleotide miravirsen, which binds miR-122, had no dose-limiting adverse events and did not appear to give rise to resistance, Janssen and colleagues reported online in the New England Journal of Medicine.
The researchers noted that miR-122 binds to two sites in the HCV genome – an attachment that is essential for the "stability and propagation" of the virus. Miravirsen, in turn, binds to miR-122, making it unavailable to HCV.
Their findings – from a randomized, double blind, placebo-controlled, Phase IIa study – suggest that miravirsen might play a role in treating chronic HCV infection, the researchers concluded.
But exactly what that role is will depend on further study, experts outside the industry-supported study commented.
The results so far are "very exciting," according to Stacey Rizza, MD of the Mayo Clinic in Rochester, Minn.
"One of the challenges in hepatitis C is always resistance," she told MedPage Today. "These microRNA (inhibitors) are targeting very conserved parts of the hepatitis virus so the chance of resistance is much lower."
But, she cautioned, "It's still very early, we don't know if it's actually going to lead to the outcomes we need it to lead to -- i.e. cure – and we're not sure yet long-term whether this is going to be safe."
Indeed, the long-term safety of the substance may be important, since one of the functions of miR-122 is to act as a tumor suppressor, commented Judy Lieberman, MD, PhD, of Harvard Medical School, and Peter Sarnow, PhD, of Stanford University in Palo Alto, Calif.
But, they concluded in an accompanying editorial in the journal, "pending satisfactory answers to the questions regarding safety," miravirsen or other microRNAs might be useful in a cocktail of anti-HCV agents that would have various targets.
Miravirsen, Janssen and colleagues reported, suppressed HCV in animal studies and showed no adverse events in healthy volunteers. To advance the clinical trials, they enrolled 36 treatment-naïve patients with genotype 1 HCV and randomly assigned them to placebo or one of three doses of miravirsen -- 3, 5, or 7 milligrams per kilogram of body weight.
Patients got five subcutaneous injections over a 29-day period and were followed for 18 weeks.
Miravirsen, they reported, led to dose-dependent reduction in HCV RNA, Specifically, the average maximum drop in HCV RNA (in log10 IU per milliliter) was:
- 1.2 for patients receiving 3 milligrams per kilogram, a change that was significant (P=0.01).
- 2.9 for those getting 5 milligrams per kilogram ( P=0.003).
- 3.0 for patients given 7 milligrams per kilogram, (P=0.002).
- 0.4 in the placebo group.
During the 14 weeks of follow-up after the end of treatment, HCV was not detected at some points in one patient in the 5-milligram group and in four patients in the 7-milligram group.
Several of those patients had viral rebound, suggesting that 4 weeks of miravirsen is not enough to lead to sustained virological responses, Janssen and colleagues reported.
Only two of the 112 adverse events reported miravirsen patients were above grade 2, the researchers reported, but none was dose limiting.
As well, the researchers reported that they found no mutations in the miR-122 binding sites of the HCV genome that would lead to resistance.
Rizza told MedPage Today that therapy for HCV is advancing rapidly, to the point where investigational all-oral regimens are possible that avoid the standard but difficult-to-take pegylated interferon and ribavirin.
But even those novel regimens may not be useful in all patients, so a therapy like miravirsen is likely to find a role, she said.
Primary source: New England Journal of Medicine
Source reference: Janssen HLA, et al "Treatment of HCV infection by targeting microRNA" N Engl J Med 2013; DOI: 10.1056/NEJMoa1209026.
Additional source: New England Journal of Medicine
Source reference: udy Lieberman,Peter Sarnow "Micromanaging hepatitis C virus" N Engl J Med 2013; DOI: 10.1056/NEJMe1301348.