The microRNA inhibitor miravirsen induced a dose-dependent drop in hepatitis C virus RNA levels, according to a phase IIa clinical trial reported online March 28 in the New England Journal of Medicine.
The treatment reduced HCV RNA to undetectable levels in five patients. And there was no evidence of the virus developing resistance to miravirsen during the 18-week study, said Dr. Harry L. A. Janssen of Erasmus MC University Hospital, Rotterdam, the Netherlands, and his associates (N. Engl. J. Med. 2013 March 28 [doi:10.1056/NEJMoa1209026]).
MicroRNAs are small, endogenous RNA that are thought to regulate a wide variety of biologic processes, including cell growth and differentiation, apoptosis, and modulation of the host response to viral infection. Miravirsen inhibits microRNA-122, which is expressed at high levels in the liver "and is essential to the stability and propagation of HCV RNA," the investigators explained.
In primate studies, miravirsen induced long-lasting HCV suppression, with no evidence of viral mutations conferring resistance to the agent. In phase I human studies, no adverse events were reported in healthy volunteers who took miravirsen.
For the phase IIa study, 36 patients with treatment-naive, genotype 1chronic HCV infection were followed at seven international sites. They were randomly assigned in a double-blind fashion to receive 3-mg, 5-mg, or 7-mg/kg doses of miravirsen, or a matching placebo, injected subcutaneously in five weekly doses over 29 days.
The study patients were allowed to initiate therapy with pegylated interferon and ribavirin after completing the course of miravirsen, at the discretion of the study investigators. Twelve of the 36 patients did so.
At all three dosages, miravirsen induced declines in HCV RNA levels from baseline for the study’s 14 weeks beyond the initial 4-week treatment period.
The reduction was dose dependent: The mean maximum decrease in HCV RNA levels was 1.2 log for patients receiving 3 mg/kg, 2.9 log for those receiving 5 mg/kg, and 3.0 log for those receiving 7 mg/kg. In contrast, patients receiving placebo showed a decline of only 0.4 log.
In five patients, miravirsen decreased HCV RNA to undetectable levels. That suggests that miravirsen eventually might be appropriate as monotherapy in some patients, Dr. Janssen and his colleagues said.
However, four of those five patients showed a rebound in viral levels at the conclusion of the study, which indicates that five weekly injections were not sufficient to induce a sustained virologic response.
"It is not clear whether regimens of miravirsen of longer duration could achieve a sustained virologic response; we are currently testing the effect of a 12-week regimen," the investigators noted.
Overall, HCV RNA levels rebounded after miravirsen was discontinued in nine patients who had not begun receiving interferon plus ribavirin. That included one patient given the 3-mg dose, five patients given the 5-mg dose, and three patients given the 7-mg dose of miravirsen.
The study subjects were assessed for resistance-associated mutations in HCV RNA at week 5 and at the time of viral rebound. No such mutations were found.
"There were no dose-limiting toxic effects or treatment discontinuations because of adverse events" or laboratory abnormalities, Dr. Janssen and his associates said.
No systemic allergic reactions occurred. Five patients given miravirsen and two patients given placebo reported transient, moderately severe adverse events that may not have been related to the study drug. Those included headache, otitis, flulike symptoms, and syncope.
There was one serious adverse event: One patient fell, lost consciousness, and injured a pelvic bone 9 weeks after receiving the last 7-mg dose of miravirsen.
Lab studies showed a sustained reduction in serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase levels with miravirsen. There were no clinically significant changes in hemoglobin levels, total white-cell counts, prothrombin time, or activated partial thromboplastin time.
A "side benefit" of the treatment was a prolonged decrease in serum total cholesterol, which was expected because inhibition of microRNA-122 is known to disrupt cholesterol homeostasis.
The findings indicate that miravirsen should be considered a potential treatment for HCV infection, the study authors said. The injections can be given as infrequently as once a month, which encourages patient compliance. And unlike protease inhibitors, miravirsen "is not a substrate for cytochrome P-450 and is therefore not expected to have significant drug-drug interactions," the researchers said.
They added that antisense therapy "may also be relevant for diseases other than chronic HCV infection," including nonalcoholic fatty liver disease. Cancer, cardiovascular diseases, and autoimmune disorders also may respond to a strategy of inhibiting microRNAs that are associated with those diseases.
Santaris Pharma funded the study. Dr. Janssen and his associates reported ties to numerous industry sources.