- Category: HCV Treatment
- Published on Friday, 04 May 2012 00:00
- Written by Liz Highleyman
Miravirsen, the first microRNA therapy for hepatitis C, was well-tolerated and demonstrated prolonged antiviral activity lasting past the end of dosing in a proof-of-concept study of previously untreated HCV genotype 1 patients presented at the 47th International Liver Congress (EASL 2012) last month in Barcelona.
Miravirsen is the first microRNA-targeted drug to enter human clinical trials, according to its developer, Santaris Pharma. MicroRNAs work by binding to small pieces of genetic material and blocking their normal activity. Miravirsen targets microRNA-122 (miR-122), a liver-specific sequence involved in cholesterol metabolism that hepatitis C virus (HCV) requires for replication. Preclinical studies showed that miravirsen has long-lasting activity against all HCV genotypes (all of which have conserved miR-122 biding sites), with a high genetic barrier to resistance.
Henk Reesinkfrom the University of Amsterdam presented final results from a Phase 2a multiple ascending-dose trial evaluating the antiviral activity, safety, and pharmacokinetics of miravirsen.
The study included 36 treatment-naive chronic hepatitis C patients with difficult-to-treat HCV genotype 1. The majority were men, most were white, and the average age was approximately 50 years. About two-thirds had HCV subtype 1a (which predicts poorer response to some HCV direct-acting antivirals) and half had IL28B non-CC gene patterns (associated with poorer response to interferon). People with hepatitis B or HIV coinfection were excluded.
Participants were randomly allocated into 4 treatment arms. Three groups received once-weekly subcutaneous injections of miravirsen at doses of 3 mg/kg, 5mg/kg, or 7 mg/kg for 4 weeks. The 3 mg/kg group was eligible to start pegylated interferon/ribavirin 3 weeks after the last dose of miravirsen, while the 5 mg/kg and 7 mg/kg groups could do so 6 weeks after the last dose. The control arm received pegylated interferon/ribavirin alone. Follow-up continued through week 18.
- Out of 36 patients enrolled, 35 completed the study; 1 person in the 7 mg/kg miravirsen arm was lost to follow-up.
- Miravirsen demonstrated dose-proportional plasma concentrations, with levels building up in the liver over time.
- Miravirsen recipients in all dose groups experienced significant maximum declines in HCV RNA (-1.2, -2.9, and -3.0 log IU/mL) relative to the control group (-0.5 log).
- 4 out of 9 people who received the highest miravirsen dose achieved undetectable HCV RNA.
- Overall, viral load decreases were sustained until about week 10-14 -- that is, 6 to 10 weeks after the last miravirsen dose.
- However, response curves varied substantially among individual patients.
- There was no clear trend in miravirsen-induced viral load decline according to either HCV subtype or patient IL28B status.
- No escape mutations were detected in the HCV miR-122 binding region in any arm.
- Most participants experienced some, mostly mild, adverse events, but frequency was similar across all arms (78%-89%).
- There were no dose-limiting toxicities or discontinuations due to adverse events, and injection site reactions were uncommon (2 patients).
- More cases of nasopharyngitis occurred among miravirsen recipients (7 in the 3 arms combined vs 1 placebo recipient).
- ALT, AST, and GGT liver enzymes tended to decrease in all miravirsen dose groups.
Based on these findings, the researchers concluded, "Miravirsen has the potential to eradicate chronic HCV infection as part of non-interferon regimens or as monotherapy."
"These data provide clinical evidence that miravirsen's unique mechanism-of-action offers a high barrier to viral resistance and the potential for cure with monotherapy," Reesink stated in a press release issued by Santaris. "Due to its ability in targeting miR-122, miravirsen has the potential to change the way hepatitis C is treated. These data show that longer duration of miravirsen monotherapy has the potential to produce sustained virological responses."
Further trials are planned to test miravirsen in people with all HCV genotypes, using longer durations, and in combination with direct-acting antivirals.
HW Reesink, HLA Janssen, S Zeuzem, et al. Final Results - Randomized, Double-blind, Placebo-controlled Safety, Anti-viral Proof-of-Concept Study of Miravirsen, an Oligonucleotide Targeting miR-122, in Treatment-naive Patients with Genotype 1 Chronic HCV Infection. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012. Abstract 58.
Santaris Pharma. Santaris Pharma A/S presents final Phase 2a study results for miravirsen showing dose-dependent, prolonged antiviral activity in Hepatitis C patients. Press release. April 19, 2012.