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Nucleic acid polymer REP 2139-Ca shows promising activity against hepatitis B and hepatitis delta

Liz Highleyman
15 May 2015
Andrew Vaillant of Replicor. Photo by Liz Highleyman,

The nucleic acid-based polymer REP 2139-Ca lowered hepatitis B surface antigen (HBsAg) levels and significantly reduced hepatitis B and hepatitis delta viral loads when combined with immunotherapy, according to presentations at the European Association for the Study of the Liver (EASL) 50th International Liver Congress last month in Vienna, Austria.

Over years or decades, chronic hepatitis B virus (HBV) infection can lead to advanced liver disease including cirrhosis and liver cancer. Disease progression is more rapid and complications are more common in people with hepatitis delta virus (HDV) co-infection, a small virus that can only replicate in the presence of HBV.

Antiviral therapy using nucleoside/nucleotide analogues 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). There is no standard treatment for hepatitis D, although interferon can stimulate the body's immune response to both HBV and HDV.



Chemical "messengers" exchanged between immune cells that affect the function of the immune system. Interleukins such as IL-2 are a particular type of cytokine.

Researchers are working on another treatment approach using nucleic acid polymers (NAPs), oligonucleotides with broad-spectrum antiviral activity. Montreal-based Replicor is developing NAPs for the treatment of both hepatitis B and hepatitis delta. According to the company, NAPs have a safety advantage because their activity is not sequence-dependent, so they can be engineered to retain antiviral activity without undesirable side-effects.

Preclinical research showed that NAPs target both entry and post-entry steps of the viral lifecycle. They block HBV and HDV entry into hepatocytes (liver cells) and also interfere with assembly and release of HBV subviral particles, thereby lowering HBsAg levels in the blood. As HBsAg is required for HDV assembly, reducing HBsAg also suppresses HDV. NAPs do not directly target replication of HBV virions (complete viral particles) like existing antiviral agents.

Early studies found that REP2139-Ca lowered HBsAg levels and HBV and HDV blood viral load, as well as HBV covalently closed circular DNA (cccDNA) in the liver – an intermediate form that persists in the cell nucleus and presents a barrier to a cure.

Replicor chief scientific officer Andrew Vaillant presented late-breaking finding from a phase 2 study (REP 301) evaluating the safety and efficacy of REP 2139-Ca in Caucasian patients with chronic HBV/HDV co-infection. A previous study (REP 102) tested REP 2139-Ca in Asian patients with HBV mono-infection.

Vaillant's study included 12 Caucasian people with HBV/HDV co-infection in Moldova. At the start of treatment, they had serum HBsAg >1000 U/ml, were hepatitis B 'e' antigen (HBeAg)-negative and had mild-to-moderate liver fibrosis (no cirrhosis).

REP 2139-Ca was administered first as monotherapy, 500mg once-weekly intravenous infusions for 15 weeks. This was followed by REP 2139-Ca at a dose of 250mg once-weekly for another 15 weeks in combination with pegylated interferon alfa-2a (180 mcg/week), which was continued for 48 weeks.

Virus levels (HBV DNA, HDV RNA, HBsAg and anti-HBs antibodies) were measured every two weeks. Vaillant reported results obtained between week 20 and 25, while participants were still taking both REP 2139-Ca and interferon; monitoring will continue through 24 weeks post-treatment.

All participants experienced reductions in serum HBsAg during REP 2139-Ca monotherapy, but they fell into two groups. One group saw decreases of around 1-2 log10, while the second group saw drops of 4-5 log10 or more. HBsAg levels remained stable or continued to decrease after adding pegylated interferon.

Anti-HBs antibody levels remained undetectable or rose slightly in most patients, but the individuals who experienced the greatest HBsAg declines saw substantial antibody gains, which accelerated after the addition of interferon.

HDV RNA levels also fell across the board, with considerable variability between patients. Individuals with the greatest HBsAg declines saw the largest and most rapid drops in HDV viral load. Decreases ranged up to 7 log10 and five people reached undetectable HDV RNA. But even some people with smaller HBsAg declines eventually experienced substantial HDV RNA reductions, suggesting that REP 2139-Ca may have multiple antiviral effects against HDV, Vaillant said.

Treatment with REP 2139-Ca was generally safe and well-tolerated. During the monotherapy phase, before adding interferon, all adverse events were mild to moderate and were associated with intravenous infusion (fever, headache, injection site redness). These side-effects typically became less frequent as treatment progressed and resolved after completion of the infusions.

"REP 2139-Ca is able to simultaneously reduce HBsAg and HDV RNA in patients with chronic HBV/HDV coinfection," the researchers summarised. "[The] pharmacologic effect on serum HBsAg observed in Asian patients is replicated in Caucasian patients." Combing REP 2139-Ca with pegylated interferon "may provide additional productive antiviral response," they added.

"NAP-based antiviral therapy may become an important new treatment option for patients with HBV/HDV coinfection," they concluded.

At an earlier session, Louis Jansen from Academic Medical Centre in Amsterdam presented findings from the aforementioned phase 2 study of Asian chronic hepatitis B patients treated with REP 2139-Ca plus immunotherapy. This study included 12 HBV monoinfected participants who were HBeAg-positive and had detectable HBV DNA (mean 6.7 log) at study entry, were previously untreated for hepatitis B and did not have cirrhosis.

Participants were initially treated with 500mg once-weekly REP 2139-Ca monotherapy for 20-24 weeks. People who were good HBsAg responders then added either pegylated interferon or thymosin alfa-1 (Zadaxin) for 13-26 weeks, while non-responders started entecavir.

A majority of participants saw declines in HBsAg, HBV DNA and HBV RNA levels after starting REP 2139-Ca monotherapy. Nine participants were considered responders, having at least a 2-log10 decline in HBV RNA and large declines in HBsAg levels. At week 20-24 eight of these patients had undetectable HBV RNA. Four of the nine responders experienced HBsAg loss and anti-HBs antibody seroconversion during post-treatment follow-up – far higher than the response rates seen in people treated with antivirals alone or antivirals plus pegylated interferon.

In contrast, the three people without substantial declines in HBV RNA at week 20-24 showed no notable reduction in HBsAg or HBV DNA levels. They then started entecavir and their HBV DNA levels declined significantly, but the antiviral "didn't do much for [HBV] RNA levels," Jansen said.

"Treatment of chronic hepatitis B patients with REP 2139-Ca resulted in a pronounced decline of serum HBV RNA in nine of 12 patients," the researchers concluded. "In three of 12 patients (non-responders), HBV RNA levels were unaffected, both before and after treatment with entecavir."

A retrospective analysis from the same study looked at changes in cytokines, or immune cell chemical messengers, and found evidence that REP 2139-Ca may help restore immune responses against HBV.

Vaillant indicated that studies of REP 2139-Ca are ongoing. He noted that the drug has poor oral bioavailability, but Replicor expects it can be given by once-weekly subcutaneous injection rather than the two-hour infusions used in these trials. The company is also testing another NAP candidate, REP 2165.


Bazinet M et al. Significant reduction of HBsAg and HDV RNA by the nucleic acid polymer REP 2139 in Caucasian patients with chronic HBV/HDV co-infection. EASL 50th International Liver Congress, Vienna, abstract LO2, 2015.

Jansen L et al. Serum HBV-RNA levels decline significantly in chronic hepatitis B patients dosed with the nucleic-acid polymer REP 2139-Ca
. EASL 50th International Liver Congress, Vienna, abstract O114, 2015.

Stelma F et al. 
Cytokine responses in chronic hepatitis B patients dosed with the nucleic-acid polymer REP 2139-Ca
. EASL 50th International Liver Congress, Vienna, abstract P0659, 2015.