REP 2139 combination therapy leads to functional control of hepatitis B virus

A majority of people with chronic hepatitis B treated with a nucleic acid polymer (REP 2139 or REP 2165) plus tenofovir and pegylated interferon were able to achieve 'functional control' of hepatitis B virus (HBV) for at least six months after stopping treatment, according to a late-breaking poster presentation at the 2017 AASLD Liver Meeting last month in Washington, DC.

A majority of study participants achieved HBV DNA suppression, hepatitis B surface antigen (HBsAg) loss and normalisation of liver enzymes, which were maintained for up to 24 weeks after the end of therapy, suggesting a potential functional cure.

Over years or decades chronic HBV infection can lead to advanced liver disease including cirrhosis and liver cancer. Nucleoside/nucleotide antivirals such as tenofovir disoproxil fumarate (DF) (Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude) can suppress HBV replication during therapy. But they usually do not lead to a cure – as indicated by HBsAg loss and anti-HBs antibody seroconversion – and long-term treatment may be required.

Montreal-based Replicor is developing nucleic acid polymers (NAPs) that interfere with assembly and release of HBV subviral particles from infected liver cells, which make up most of the HBsAg in the blood. Lower HBsAg levels lead to stronger immune responses and enhance the activity of immune-based therapy such as interferon. This can trigger liver enzyme 'flares' – sharp increases in alanine and aspartate transaminase (ALT and AST) levels – and lead to HBV control in some individuals.

Andrew Vaillant, Replicor's chief scientific officer, and colleagues presented the latest interim findings from the REP 401 trial (NCT02565719), evaluating the safety and efficacy of two NAPs, REP 2139 and REP 2165, used in combination with tenofovir disoproxil fumarate and pegylated interferon for the treatment of chronic hepatitis B.

This study included 40 previously untreated hepatitis B 'e' antigen (HBeAg)-negative chronic hepatitis B patients in Moldova. Most were men, all were Caucasian and the average age was about 38 years. Most had mild to moderate liver fibrosis (stage F0-F2) and they did not have hepatitis delta, hepatitis C or HIV co-infection.

All participants in this open-label study started taking once-daily tenofovir DF (300mg). After 24 weeks they were randomly assigned to add either weekly 250mg intravenous infusions of REP 2139 or REP 2165 plus weekly injections of pegylated interferon alfa-2a (180 mcg/week), or only pegylated interferon, for 48 weeks. People who did not achieve at least a 3 log₁₀ decline in HBsAg after 24 weeks on dual therapy – which turned out to be all of them – then crossed over and added REP 2139 or REP 2165.

All participants showed a reduction in HBV DNA after starting tenofovir DF. HBsAg levels did not decline with tenofovir alone or during dual therapy with tenofovir plus pegylated interferon, but did so during triple therapy.

In the REP 2139 triple therapy arm, 8 of 10 people saw their HBsAg fall below 1 IU/ml by the end of treatment, including 7 people with undetectable HBsAg (< 0.01 IU/ml). These responders saw large increases in anti-HBs antibody titres and strong ALT and AST flares.

All 8 responders maintained functional control (defined as HBsAg < 1 IU/ml and HBV DNA < 10 IU/ml) for 4 to 24 weeks after stopping all treatment. ALT and AST normalised during follow-up. Among people with the longest follow-up, 4 so far have met the new AASLD/EASL endpoints for a functional cure of hepatitis B: HBsAg loss and HBV DNA < 1000 copies/ml for 6 months after the end of treatment. Vaillant suggested that this number would likely rise as further data become available.

In the REP 2165 triple therapy arm, 6 of 10 participants had HBsAg below 1 IU/ml (all also < 0.01 IU/ml) by the end of treatment. Five of these responders maintained functional control for 4 to 24 weeks post-treatment. Another 3 people saw their HBsAg drop by at least 1 log₁₀ from baseline during treatment, but it did not fall below 1 IU/ml and rebounded after stopping therapy.

People who crossed over from dual therapy to REP 2139 or REP 2165 triple therapy did not see such consistent HBsAG declines, anti-HBs increases or ALT and AST flares, suggesting that starting all three types of therapy at the same time is a more effective strategy.

Treatment was generally safe and well tolerated. ALT and AST flares were asymptomatic and other liver function biomarkers (bilirubin, albumin, blood clotting time) remained stable. Only one participant discontinued treatment early due to an adverse event (depression attributed to pegylated interferon).

As expected, pegylated interferon was associated with side-effects including weakness, neutropenia (low white blood cells) and thrombocytopenia (low platelets), but these did not differ according to whether or not REP 2139 or REP 2165 were also used. Kidney function (a potential concern with tenofovir DF) remained normal throughout treatment.

"Clearance of HBsAg uniquely occurs with NAP exposure. In the presence of [pegylated interferon], HBsAg clearance is accompanied by dramatic increases in circulating anti-HBs and the increased prevalence and magnitude of otherwise asymptomatic transaminase flares," the researchers concluded.

"Recent clinical studies have shown that [tenofovir DF] and [pegylated interferon] combined achieve HBsAg clearance in less than 10% of patients," Vaillant said in a Replicor press release. "The addition of REP 2139’s unique ability to clear circulating HBsAg improves this outcome in a striking fashion, achieving functional control in 80% of patients not only during treatment but persisting after treatment is withdrawn. Equally important is the normalization of liver function during follow-up in all these patients, even those with significantly elevated liver enzymes at the start of therapy."