Two pharmaceutical companies have challenged to achieve a functional cure of chronic hepatitis B, which requires a lifetime of therapy, but only one of them made meaningful progress. A functional cure refers to a situation where a virus remains in the body but is controlled by the immune system without medication.
Assembly Biosciences, which developed vebicorvir, the first core inhibitor in the hepatitis B virus (HBV), tried discontinuing the treatment in a trial but failed to sustain the virologic response.
In contrast, GSK announced that it took one step closer to a “functional cure” of hepatitis B, as its antisense oligonucleotide (ASO) candidate GSK3228836 removed the hepatitis B surface antigen (HBsAg) and its DNA through a four-week treatment in a study.
Assembly Biosciences said on Thursday that its phase-2 extension study of vebicorvir failed to achieve its goal.
In the previous trials, vebicorvir, combined with a nucleotide analog reverse transcriptase inhibitor (NrtI), showed successful, deeper viral suppression. So, the company tested whether patients who had received at least 12-18 months of vebicorvir plus NrtI still had sustained virologic response (SVR) even after discontinuing the therapy.
Assembly Biosciences set the goal of SVR reaching 15 percent at week 24. However, at week 16, 39 out of 41 patients have relapsed.
Among the 23 patients who were HBeAg negative, 22 have relapsed, leading SVR at only 4 percent. Sixteen of them relapsed in the fourth week after stopping the treatment. Among 18 HBeAg positive patients, 17 relapsed in the fourth week after discontinuing the therapy, with SVR at 6 percent.
“As we had previously indicated, we believe an SVR24 rate of at least 15 percent would have marked a meaningful first advance in HBV finite therapy, but preliminary results have shown that we will fall short of that mark.” CEO and President of Assembly Biosciences John McHutchison said. “While we are just beginning to analyze the data and this is not the outcome we were hoping for, we firmly believe it was the right experiment to conduct, and the learnings will inform the field and our ongoing development programs.”
The company is preparing a phase-3 trial on vebicorvir with BeiGene in China, which has one-third of chronic HBV patients worldwide. The company plans to assess vebicorvir’s additional efficacy in patients who find conventional NrtI therapy insufficient.
Assembly Biosciences also has second- and third-generation core inhibitor candidates ABI-H2158 and ABI-H3733. However, given the failure of vebicorvir’s trial, it is unclear whether the company could pull off the development of second and third-generation core inhibitors, which have the same mechanism as vebicorvir.
Assembly Biosciences said it planned to begin triple combination, phase-3 trials combining vebicorvir with NrtI and an RNAi therapeutic from Arbutus in the first half of next year.
Unlike Assembly Biosciences, GSK said the RNAi therapeutic candidate GSK3228836 showed its potential to become a functional cure.
In late August, GSK announced the results of the Phase-2a study on the drug candidate at the Digital International Liver Congress organized by the European Association for the Study of the Liver.
The company said that the four-week treatment of GSK3228836 showed a superior effect in reducing HBsAg and DNA, compared to placebo, in patients who received conventional nucleoside or nucleotide analog (NA) and treatment-naïve chronic hepatitis B patients.
HBsAg is a “surrogate marker” of chronic hepatitis B, indicating the antiviral treatment's ending time. The U.S., Europe, and Korea recommend discontinuing the antiviral therapy after HBsAg loss (functional cure), but the recommendation is not supported with evidence because HBsAg losses are extremely rare.
However, GSK’s recent study showed that GSL3228836 could reduce HBsAg and increase long-term HBsAg loss.
In the GSK’s phase-2a study, researchers divided 31 patients into three groups to give them GSK3228836 150mg, 300mg, and placebo, for four weeks. After administering the last dose, all the patients took the conventional NA therapy, tenofovir or entecavir, for six months, for a follow-up.
The results showed that the GSK3228836 300mg group (16 patients) had a reduction in HBsAg. The decline appeared all in four patients with NA therapy history and NA-naïve 12 patients.
“The goal to achieve functional cure at an early age would potentially have a lower risk of liver-related complications and liver cancer,” Professor Man-Fung Yuen of the Queen Mary Hospital at the University of Hong Kong, who led the trial, said in a statement. “Besides, enhanced immune control associated with a functional cure would potentially allow patients to be free of long-term medications.”