REP 2139 shows promise for people with hepatitis B and hepatitis delta co-infection

Liz Highleyman
Published:
16 November 2015

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 titres, according to findings from a small phase 2 study presented on Sunday at the 2015 AASLD Liver Meeting in San Francisco, USA. Participants fell into two distinct groups, with half being partial responders and half full responders.

Antiviral therapy using nucleoside/nucleotide analogues such as entecavir (Baraclude) or tenofovir (Viread) is the mainstay of treatment for chronic hepatitis B. While these drugs can effectively suppress hepatitis B virus (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 and HDV co-infection 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. 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 and HDV co-infection. (A previous study showed promising results in Asian patients with HBV mono-infection.)

This analysis includes 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 500mg 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 250mg once weekly for another 15 weeks plus 180 mcg/week pegylated interferon alfa-2a (Pegasys) continued for 48 weeks.

All participants experienced declines in serum HBsAg during REP 2139-Ca monotherapy, though responses were highly variable. Patients fell into two groups, with half considered partial responders and the other half full responders with larger HBsAg decreases (falling to < 1 IU/ml).

HBsAg levels remained stable or continued to decrease after adding pegylated interferon. After discontinuing REP-2139, partial responders saw an increase in serum HBsAg, while full responders maintained low levels.

All 12 patients experienced HDV RNA reductions – again quite variable – with 10 achieving undetectable levels. In most patients, reduced HDV levels led to rising HBV viral load, which the researchers attributed to 'de-repression'. HBV DNA fell again after adding interferon and discontinuing REP 2139.

Most participants had increased anti-HBs antibody levels during REP 2139 monotherapy. Full responders experienced substantial further anti-HBs increases after adding pegylated interferon, while the partial responders did not.

Full responders experienced ALT and AST increases – including some with substantial 'flares' – after adding pegylated interferon, while partial responders did not see this effect.

REP 2139-Ca was generally safe and well-tolerated. The most common adverse event was mild to moderate transient intravenous infusion reactions (fever, headache, injection site redness or itchiness) attributed to the IV tubing.

"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."

Reference

Bazinet M et al. Update on the safety and efficacy of REP 2139 monotherapy and subsequent combination therapy with pegylated interferon alpha-2a in chronic HBV/HDV co-infection in Caucasian patients. AASLD Liver Meeting, abstract 31, 2015.