Core protein inhibitor shows promising activity against hepatitis B

An experimental hepatitis B virus (HBV) core protein inhibitor led to greater reductions in HBV viral load and residual HBV genetic material when added to nucleoside/nucleotide analogues, which could lead to a functional cure with longer follow-up, according to a study presented at the 2019 International Liver Congress last week in Vienna.

ABI-H0731, from Assembly Biosciences, was well tolerated, and the rapid, deep declines in HBV DNA and HBV RNA could promote the loss of cccDNA (covalently closed circular DNA), an intermediate form that persists in the nucleus of liver cells and presents a barrier to a cure, said Dr Jay Lalezari of Quest Clinical Research in San Francisco.

HBV cccDNA can lie dormant in liver cells, establishing a reservoir of viral genetic material that evades both the immune system and standard treatment. Over years or decades, chronic HBV infection can lead to liver cirrhosis, hepatocellular carcinoma and end-stage liver failure requiring a transplant.

Nucleoside/nucleotide antivirals such as tenofovir disoproxil fumarate (Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude) can suppress HBV replication during long-term therapy but they do not completely eliminate the virus, do not prevent formation of cccDNA and usually do not lead to a cure, as indicated by hepatitis B surface antigen (HBsAg) loss.

ABI-H0731 is a core protein allosteric modifier (CpAM) that targets the HBV core protein and interferes with multiples steps of the viral lifecycle, including cccDNA formation.

Dr Lalezari presented interim findings from a pair of phase IIa studies evaluating ABI-H0731 in people with chronic hepatitis B and absent to moderate (stage F0-F2) liver fibrosis.

Study 201 included 47 hepatitis B 'e' antigen (HBeAg) positive and 26 HBeAg negative people on nucleoside/nucleotide analogues (mostly tenofovir) with suppressed HBV DNA. They were randomised to add either once-daily oral ABI-H0731 or placebo.

Study 202 included 25 previously untreated HBeAg positive people with unsuppressed HBV. They were randomised to receive entecavir plus either ABI-H0731 or placebo. After 24 weeks, people in both studies could opt to join an ongoing open-label extension study (Study 211).

In both studies, the combination regimen led to faster, steeper and larger declines in HBV viral load starting at week 2. In Study 201, people who added ABI-H0731 had a mean HBV RNA decline of 2.34 log₁₀ at 12 weeks, compared with 0.05 log₁₀ in the placebo group. Although most people had not yet reached this time point, the declines at 24 weeks were 2.20 log₁₀ and 0.15 log₁₀, respectively.

In Study 202 – those who started treatment with unsuppressed virus – HBV DNA declined by 4.54 log₁₀ at week 12 and by 5.94 log₁₀ at week 24 in the combination therapy group, compared with 3.29₁₀ log and 3.99 log₁₀, respectively, in the entecavir monotherapy group. Looking at HBV RNA, levels fell by 2.27 log₁₀ at week 12 and 2.54 log₁₀ at week 12 in the combination group versus 0.44 log₁₀ and 0.61 log₁₀, respectively, in the entecavir-only group.

Among Study 201 participants who reached the 24-week time point, sensitive tests to detect low-level HBV DNA, capable of measuring down to 2-5 IU/ml, showed that residual virus was not eliminated using nucleoside/nucleotide analogues alone, but fell below the level of detection in five of six people who added ABI-H0731.

Treatment was generally safe and well tolerated and no serious adverse events, treatment interruptions or treatment-related discontinuations were reported.

Eliminating residual HBV DNA will likely be required to prevent new cccDNA formation, and this will be a critical milestone for a cure, according to Lalezari. He said that decay of cccDNA and declines in HBeAg and and HBsAg are anticipated to follow the elimination of residual virus, and this will be explored in the extension study.

"Although decreases in HBeAg and HBsAg in some individuals have been observed in both studies, it is too early to draw meaningful conclusions about this endpoint," Lalezari said in a conference press release. "The accelerated decline and significant loss of baseline RNA and DNA viraemia suggest that combination therapy with a core inhibitor plus [nucleoside/nucleotide analogues] may enhance loss of cccDNA and viral antigen once residual viraemia has been fully cleared."

Despite these promising findings, Assembly has reportedly decided not to further develop ABI-H0731 in favour of more potent core protein inhibitors including ABI-H2158 and ABI-H3733. A late-breaking poster at the conference reported that ABI-H2158 was well tolerated and demonstrated favourable pharmacokinetics in a Phase Ia trial; a Phase Ib dose-finding study is underway. ABI-H3733 is expected to enter Phase Ia studies early next year, according to the company.