BOSTON — Two nucleic acid polymers — REP-2165 and REP-2139 — used individually in triple combination with tenofovir disoproxil fumarate and pegylated interferon were efficacious and tolerable in patients with hepatitis B e antigen-negative hepatitis B virus infection, according to a Late Breaker presented at The Liver Meeting.
“This data reproduces the effects of [nucleic acid polymers] in our previous proof-of-concept trials where we have continually increased the frequency of achieving functional control in patients, both in our initial trials in Bangladesh in antigen-positive patients and our more recent protocol in coinfected patients,” Andrew Vaillant, PhD, chief scientific officer at Replicor Inc., said during his presentation.
In this trial, known as the REP-401 protocol, researchers randomly assigned 40 patients 300 mg of tenofovir disoproxil fumarate (TDF, Gilead Sciences) prior to a randomized regimen of either 48 weeks of TDF, 180 mg of pegylated interferon (PEG-IFN) and 250 mg of REP-2139 (Replicor Inc.) or Rep-2165 (Replicor Inc.) administered via IV, for 48 weeks. For a control group, patients will receive TDF plus PEG-IFN for 58 weeks, and then switch to 48 weeks of either experimental drug if there was no 3 log drop in hepatitis B surface antigen after 24 weeks of PEG-IFN. According to Vaillant, most of the patients were around 40 years of age, male, had genotype D and mild fibrosis.
To date, 29 patients have received at least 12 weeks of treatment in the control and experimental groups. After treatment with TDF for 48 weeks, most patients showed HBV DNA levels less than 10 IU/mL prior to PEG-IFN treatment. Vaillant said before cross-over to the experimental drugs, TDF “did its job” to suppress HBV DNA in blood of patients in both groups.
The triple therapy was well-tolerated in all patients, with no evidence of infusion reactions due to treatment with either experimental drug. To date, in both groups of patients, reduced HBsAg, increases in anti-HBs or alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transpeptidase (GGT) flares were absent or negligible during TDF-only therapy prior to the initiation of therapy with REP-2165 or REP-2139.
“We get a very dramatic and rapid clearance of surface antigen … and we expect all of these patients to become surface antigen negative very soon thereafter,” Vaillant said, adding that activity is comparable between the two drugs, but may be more retardant in the REP-2165 group due to tissue clearance.
At this point, there is a 100% response rate in the 2139 group, one patient needs to be initiated treatment, Vaillant said.
After only 4 weeks of therapy, two patients treated with REP-2139 experienced reductions in HBsAg. One patient who received REP-2165 also experienced reductions in HBsAg after 4 weeks of therapy.
Vaillant noted that the HBsAg reductions because of REP-2139 or REP-2165 therapy were accompanied by asymptomatic ALT, AST and GGT flares at an increased rate compared with patients in the control group. He noted that two patients who had flares, one had HBsAg reduction and one did not. Vaillant said all liver function was normal is patients who experienced flares, calling the flares “therapeutic in nature.”
“Early clearance in HBsAg … suggests NAP-mediated HBsAg clearance improves the efficacy of pegylated interferon in this patient population,” Vaillant said.
He concluded: “These preliminary data demonstrate the tolerability and efficacy of REP-2139 and REP-2165 when used in combination with pegylated interferon and TDF in patients with HBeAg-negative chronic HBV,” adding that the antiviral effect of REP-2165 is more rapid compared with REP-2139.
More data will be presented at upcoming medical conferences in 2017, according to Vaillant.- by Melinda Stevens
Bazinet M, et al. Abstract LB-7. Presented at: The Liver Meeting; Nov. 11-15, 2016; Boston.
Disclosures: Vaillant is employed by Replicor Inc.