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AASLD 2016: Nucleic Acid Polymers Reduce HBsAg Levels and Improve Control of Hepatitis B Virus

The nucleic acid polymers REP 2139 and REP 2165 led to hepatitis B surface antigen (HBsAg) reduction or clearance when combined with tenofovir and pegylated interferon, according to early results from a small study presented as a late-breaker at the AASLD Liver Meeting this month in Boston. This combination may potentially enable functional control of hepatitis B if confirmed in larger studies.

Over years or decades chronic hepatitis B virus (HBV) infection can lead to advanced liver disease including cirrhosis and liver cancer.Antiviral therapy using nucleoside/nucleotide analogs such as entecavir (Baraclude) or tenofovir disoproxil fumarate (Viread) is the mainstay of treatment for chronic hepatitis B. While these drugs can suppress HBV replication during therapy, and can thereby reduce the risk of liver disease progression, they usually do not lead to a cure -- as indicated by HBsAg loss and anti-HBs antibody seroconversion -- and long-term treatment is generally needed.

Researchers are therefore looking at other approaches to more curative hepatitis B treatment. Montreal-based Replicor, Inc. is developing nucleic acid polymers (NAPs) that interfere with the assembly and block the release of HBV subviral particles from infected hepatocytes. Unlike nucleoside/nucleotide analogs, NAPs do not directly target fully formed HBV virions.

Andrew Vaillant from Replicor presented the latest findings from a study of the safety and efficacy of a pair of NAPs -- REP 2139 and REP 2165 -- used in combination with tenofovir DF and pegylated interferon for the treatment of hepatitis B "e" antigen (HBeAg)-negative chronic hepatitis (REP 401/NCT02565719).

Blocking release of HBV subviral particles leads to lower HBsAg levels in the blood, Vaillant noted as background. This in turn reduces HBsAg-mediated immune suppression, and the resulting stronger immune response can lead to liver enzyme flares and eventual establishment of hepatitis B control in some individuals. This may also enhance the effectiveness of immunotherapy such as interferon.

Early studies showed that NAPs reduced HBsAg and HBV DNA levels in serum 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. At last year's EASL International Liver Congress Vaillant reported that REP 2139 lowered levels of HBsAg, HBV DNA, and hepatitis delta, a small virus that can only replicate in the presence of HBV.

Study REP 401 evaluated REP 2139 and the related drug REP 2165, which appears to have similar antiviral activity but with less accumulation in the liver. Investigators used REP 2139 and REP 2165 formulated as magnesium chelate complexes (known as REP 2139-Mg and REP 2165-Mg) to improve their administration tolerability. 

This open-label study enrolled 40 chronic hepatitis B patients in Moldova. Most were men and the mean age was about 38 years. They were HBeAg-negative, had baseline serum HBsAg >1000 U/mL and HBV DNA >7500 copies/mL, and most had HBV genotype D. They were non-cirrhotic with mostly mild to moderate liver fibrosis (stage F0-F2) and they were not coinfected with hepatitis delta, hepatitis C, or HIV.

All participants started taking once-daily oral tenofovir DF (300 mg) for 24 weeks. They were then randomly assigned to 2 treatment arms. Those in the experimental arm stayed on tenofovir DF and received weekly intravenous infusions of either REP 2139-Mg or REP 2165-Mg (250 mg) plus weekly injections of pegylated interferon alfa-2a (Pegasys; 180 mcg/week) for 48 weeks. The control arm stayed on tenofovir DF and added pegylated interferon alone; after 24 weeks on dual therapy those with less than a 3 log decline in HBsAg also added REP 2139-Mg or REP 2165-Mg.

The primary study endpoints were serum HBsAg reduction, appearance of anti-HBs antibodies, and functional control after stopping treatment, defined as HBsAg <1 IU/mL and HBV DNA <1000 copies/mL for at least 6 months. Vaillant presented data for 29 patients followed for more than 12 weeks after randomization, including 9 who received REP 2139 and 9 who got REP 2165.

Results

• All participants experienced gradual declines in serum HBV DNA after starting tenofovir DF.
• HBsAg levels did not decline during treatment with tenofovir DF alone, or with tenofovir plus pegylated interferon, but dropped steeply after adding REP 2139 or 2165.
• 9 of 9 patients who received REP 2139 had a >1 log decrease in HBsAg, as did 6 of 9 who received REP 2165.
• 3 people taking REP 2139 and 2 people taking REP 2165 saw their HBsAg levels fall below the lower limit of quantification.
• Increases in anti-HBs antibodies correlated with the extent of HBsAg reduction after patients added either REP 2139 or REP 2615.
• REP 2165 had antiviral activity similar to that of REP 2139 despite more rapid tissue clearance.
• Treatment with REP 2139 or EP 2165 was generally safe and well-tolerated.
• Serum alanine and aspartate transaminase (ALT and AST) levels rose in most patients after adding REP 2139 or REP 2165 plus pegylated interferon, and a few saw increases on pegylated interferon alone.
• ALT and AST increases correlated with HBsAg reduction and mostly resolved with continued therapy.
• Liver function was otherwise normal during these ALT and AST flares, with bilirubin, albumin, and blood clotting time (INR) remaining stable.
• Kidney function also remained generally stable in all treatment arms.
• Platelet and white blood cell levels dropped after adding interferon -- a known side effect -- but did not decline further with the addition of REP 2139 or REP 2165.
• Administration of REP 2139 and REP 2165 was generally asymptomatic, though 1 patient had infusion reactions after the 20th dose of REP 2165-Mg.
• As expected, pegylated interferon was associated with adverse events including weakness, neutropenia, and thrombocytopenia, but this did not differ based on whether REP 2139 and REP 2165 were also used.
• There was 1 drug-related serious adverse event, profound weakness attributed to pegylated interferon.

The researchers concluded that NAP therapy in combination with tenofovir DF and pegylated interferon is associated with multi-log reduction or clearance of serum HBsAg, increases in serum anti-HBs antibodies, and increased incidence and magnitude of serum transaminase flares that were otherwise asymptomatic and self resolving.

Vaillant said that the ALT and AST flares -- markers of liver inflammation -- were not due to liver toxicity, but rather were "therapeutic," indicating that the decline in HBsAg was likely leading to strengthened immune response against HBV.

11/22/16

Source

M Bazinet, A Vaillant, V Pantea, et al. Preliminary safety and efficacy of REP 2139-Mg or REP 2165-Mg used in combination with tenofovir disoproxil fumarate and pegylated interferon alpha 2a in treatment naive Caucasian patients with chronic HBeAg negative HBV infection. AASLD Liver Meeting. Boston, November 11-15, 2016. Abstract LB-7.