Response to Controlled-release Interferon Alfa-2b (Locteron) in Genotype 1 Hepatitis C Patients

By Liz Highleyman

In an attempt to improve the quality of life of patients undergoing treatment for chronic hepatitis C, researchers have explored longer-lasting forms of interferon that can be administered less often.

On such agent, controlled-release recombinant interferon alfa 2b (brand name Locteron), is being developed by Biolex Therapeutics in collaboration with OctoPlus. Locteron is expected to be effective at a dosing frequency of once every 2 weeks. In comparison, conventional interferon alfa is given 3 times weekly and pegylated interferon alfa (Pegasys or PegIntron) is administered once weekly.

As reported at the 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008) last month in Milan, researchers evaluated the efficacy, safety, and viral kinetics of Locteron in SELECT-1, a Phase 2a open-label, dose-ranging study in treatment naive patients with genotype 1 chronic hepatitis C.

A total of 32 patients were randomly assigned to receive subcutaneous injections of Locteron at doses of 160, 320, 480, and 640 mcg once every 2 weeks for 12 weeks. All participants also received weight-based ribavirin.

The investigators mathematically modeled viral kinetics over the first 4 weeks. Dynamics of alanine aminotransferase (ALT), 2'5'-oligoadenylate synthetase (OAS), and neopterin concentrations were also assessed.

Results

• The percentages of patients who achieved early virologic response, defined as at least a 2 log reduction in HCV RNA at week 12, were as follows:

• 100% in the 640 and 480 mcg dose cohorts;
• o 88% in the 320 mcg dose cohort;
• 38% in the 160 mcg dose cohort.

• The average reduction in HCV RNA at week 12 ranged from 4.2 to 4.7 logs with the 640, 480, and 320 mcg doses, compared to 1.8 logs with the 160 mcg dose.

• Locteron was generally well tolerated at all doses.

• There were no serious adverse events in the 160, 320, or 480 mcg dose cohorts, and 1 case of serious ear inflammation in the 640 mcg cohort.

• Modeling of viral kinetics demonstrated mean and maximum efficiency of blocking viral production of:

• 42% and 54%, respectively, in the 160 mcg cohort;
• 58% and 71% in the 320 mcg cohort;
• 72% and 85% in the 480 mcg cohort;
• 75% and 80% in the 640 mcg cohort.

• This reflects a clear dose-dependent effect on mean and maximum efficiency (P = 0.003 and P = 0.006, respectively).

• The median half-life of HCV RNA was 2 hours and the median half-life of infected cells was 2.8 days.

• Neopterin and OAS increased early during treatment.

• There was a dose-dependent effect in terms of faster and more pronounced neopterin and OAS increases in the higher dose groups.

• ALT dynamics typically showed a short intermediate increase, followed by a decline, falling from 105 U/L at baseline to 57, 58, 46, and 28 U/L in the 160, 320, 480, and 640 mcg cohorts, respectively, at week 4.

Conclusion

"Locteron demonstrated significant and dose-dependent virologic response with decrease of ALT levels," the researchers concluded. "Furthermore, OAS levels and neopterin concentrations increased dose-dependently early during treatment."

In February 2008, Biolex announced the commencement of dosing in the PLUS study, a U.S. Phase 2a clinical trial of Locteron in hepatitis C patients designed to expand upon the favorable results from SELECT-1.

Saarland University, Homburg/Saar, Germany; J.W. Goethe-University Hospital, Frankfurt, Germany; P.L. Shupyk National Medical Academy of Postgraduate Education, Kiev, Ukraine; M.I. Pyrogov Vinnitsa National Medical University, Vinnitsa, Ukraine; M. Gorky Donetsk State Medical University, Donetsk, Ukraine; OctoPlus N.V., Leiden, the Netherlands; Biolex Therapeutics, Pittsboro, NC.

5/23/08

Reference
E Herrmann, S Zeuzem, I Dzyublyk, and others. Viral kinetics during treatment with a controlled-release recombinant interferon alfa 2b in genotype 1 chronic hepatitis C patients. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

Additional source
Biolex Therapeutics. Biolex Therapeutics researchers present Locteron Phase 2a hepatitis C trial results at EASL Conference. Press release. April 4, 2008.