AASLD 2015: REP 2139 Shows Promise for People with Hepatitis B and Hepatitis Delta Coinfection

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The nucleic acid-based polymer REP 2139, used first as monotherapy then combined with pegylated interferon, reduced hepatitis B surface antigen (HBsAg) levels, lowered hepatitis delta viral load, and increased anti-HBs antibody titers, according to findings from a small Phase 2 study presented at the AASLD Liver Meeting taking place this week in San Francisco. Participants fell into 2 distinct groups, with half being partial responders and half full responders.

Antiviral therapy using nucleoside/nucleotide analogs such as entecavir (Baraclude) or tenofovir (Viread) is the mainstay of chronic hepatitis B treatment. While these drugs can effectively suppress HBV replication during therapy, they usually do not lead to a cure, as indicated by HBsAg loss and development of anti-HBs antibodies (seroconversion).

Hepatitis delta (HDV) is a small virus that can only replicate in the presence of HBV; in turn, HDV appears to "repress" HBV replication. There is no standard treatment for HDV, although interferon promotes immune responses against both viruses. Liver disease progression is more rapid and complications are more common in people with HBV/HDV coinfection compared to those with HBV alone.

Montreal-based Replicor is developing nucleic acid polymers (NAPs) that interfere with assembly and release of HBV subviral particles, thereby lowering HBsAg levels in the blood; NAPs do not directly target complete HBV virions. Because HBsAg is required for hepatitis delta assembly, reducing HBsAg also suppresses HDV levels. Early studies showed that REP 2139 reduced serum HBsAg levels and HDV viral load.

At the Liver Meeting Replicor researchers presented an update on the safety and efficacy of REP 2139 assessed first as monotherapy and then with pegylated interferon in a Phase 2 trial (NCT02233075) of Caucasian patients with chronic HBV/HDV coinfection. A previous study showed promising results in Asian patients with HBV monoinfection.

This analysis include 12 participants in Moldova who had baseline serum HBsAg >1000 U/mL, were hepatitis B "e" antigen (HBeAg) negative, and had mild to moderate liver fibrosis but no cirrhosis.

Participants first received 500 mg once-weekly intravenous infusions of REP 2139-Ca (calcium chelate complex) for 15 weeks. This was followed by REP 2139-Ca at a reduced dose of 250 mg once-weekly for another 15 weeks plus 180 mcg/week pegylated interferon alfa-2a (Pegasys), which was continued for 48 weeks.

Results

"REP 2139-Ca is able to simultaneously reduce HBsAg and HDV RNA in patients with chronic HBV/HDV coinfection," the researchers concluded. "Increased anti-HBs production and/or liver flares correlated with the start of [pegylated interferon] exposure appears to be related to the extent of clearance of serum HBsAg."

The findings, they said, indicate that NAPs seem to have distinct antiviral activity against HDV in addition to blocking HBV subviral particles.

"Longer combination treatment with immunotherapy will likely result in a higher proportion of patients with a full HBsAg response (<1 IU/mL)," they suggested. "NAP-based antiviral therapy may become an important new treatment option for patients with HBV/HDV coinfection."

11/15/15

Reference

M Bazinet, V Pantea, V Cebotarescu, et al. Update on the safety and efficacy of REP 2139 mono- therapy and subsequent combination therapy with pegylated interferon alpha-2a in chronic HBV / HDV co-infection in Caucasian patients. AASLD Liver Meeting 2015. San Francisco, November 13-17, 2015. Abstract 31.