Hepatitis B cure: Several investigational drugs shoot at victory

Hope for a hepatitis B virus (HBV) cure becomes manifest as multiple drugs from recent clinical trials show potential in transforming the battle against the disease.

HBV can be prevented with a vaccine and treated with interferons and nucleos(t)ide analogues (NAs). These treatments suppress viral replication and reduce the risk of developing cirrhosis, liver failure, hepatocellular carcinoma (HCC), and death. However, they cannot eliminate the virus. [Hepatol Commun 2019;3:8-19]

In the hunt for curative treatment, current research has paid special attention to functional cure of HBV as a target. The endpoint would be loss of hepatitis B surface antigen (HBsAg), with or without seroconversion to hepatitis B surface antibody, off drugs. This is deemed a more realistic goal than a sterilizing cure or complete eradication of the virus in the body. [Clin Gastroenterol Hepatol 2020;18:548-550]

Presented at this year’s Digital International Liver Congress, data on emerging therapies explore different mechanisms as avenues for functional HBV cure. These include mechanisms that are directed to the virus, such as blockage of viral protein expression and inhibition of the HBV core protein directly, and act on the host’s immune system.

Stop virus replication

A strategy of inhibiting the ability of the virus to synthesize the components it needs to replicate has been evaluated in two studies of RNA interference (RNAi) therapies and two of antisense oligonucleotides.

In a phase IIa trial of the RNAi JNJ-3989, 40 patients (median age, 45 years; 73 percent male; 85 percent Asian) with chronic HBV were given with three monthly subcutaneous doses (100 mg, 200 mg, 300 mg, or 400 mg) of the drug in combination with NAs. All except one patient (97.5 percent) achieved a ≥1.0 log₁₀ IU/mL reduction in HBsAg at nadir, and 22 (56 percent) of them sustained suppression of HBsAg for about 9 months after the last dose of JNJ-3989. [ILC 2020, abstract GS10]

Likewise, another RNAi, VIR-2218, showed clinical activity in a phase II trial. Among the 24 chronic HBV patients given two subcutaneous shots of the drug (20, 50, 100, or 200 mg) in combination with NAs, those who received the 50-mg dose achieved maximal reductions in HBsAg at week 12, with a mean reduction of 1.5 log₁₀ IU/mL from baseline. These patients maintained viral suppression at a mean of 1.0 log₁₀ IU/mL through week 28. [ILC 2020, abstract AS068]

Both drugs were well-tolerated. There was only one case of elevated ALT (peak 136 U/L), which occurred in the JNJ-3989 trial.

Meanwhile, phase IIa data on the novel antisense oligonucleotide ISIS 505358 (now known as GSK3228836) showed positive results in a small sample of 24 chronic HBV patients either naïve to or receiving NAs. Compared with placebo, the investigational drug (dosed at 300 mg and administered subcutaneously twice weekly) significantly lowered HBsAg levels at day 29. Average reductions reached –1.56 log₁₀ IU/mL (p=0.001) in the NA-naïve group and –2.51 log₁₀ IU/mL in the NA-treated group (p=0.454). [ILC 2020, abstract AS067]

Overall, six patients had HBsAg reductions >3.0 log10 IU/mL, with levels dropping below the lower limit of quantification (0.05 IU/mL) in four individuals. There were meaningful declines in HBV DNA seen in NA-naïve patients who received ISIS 505358/GSK3228836. Tolerability profile was acceptable, and the most common adverse events (AEs) were injection-site reactions.

In a phase 1 study, the GalNAc LNA antisense oligonucleotide also showed positive results. The experimental drug was given at various doses and dosing intervals, over a 4-week period, in 59 chronic HBV patients (mean age, 45 years; 88 percent male; 90 percent Asian) on NA therapy. At nadir, largest mean HBsAg reductions of 0.5 log IU/mL were observed with the 3 mg/kg weekly dosing regimen. Seven patients developed injection-site reactions, but none had serious or severe AEs or discontinued treatment due to AEs. [ILC 2020, abstract AS069]

Hijack HBV core protein

In a phase IIa study, the novel oral HBV core inhibitor ABI-H0731 was evaluated as an adjunct treatment to NA. Twenty-six patients (mean age, 48 years; 62 percent male; 81 percent Asian) with HBeAg-negative chronic HBV who were virologically suppressed after a mean of 4 years on NA were randomized to receive either ABI-H0731 300 mg once daily or placebo for 24 weeks while maintaining their NA. [ILC 2020, abstract AS070]

ABI-H0731 resulted in deeper viral suppression with an accompanying increase in the proportion of patients with HBV DNA <5 IU/mL (undetectable using sensitive polymerase chain reaction methodology)—from 63 percent at baseline to 94 percent at week 24 as compared with 80 percent to 70 percent with placebo. HBsAg levels did not significantly change in both treatment groups. The drug was generally safe and well-tolerated.

Core protein inhibitors act at multiple steps of the viral life cycle. They block the formation of covalently closed circular (ccc)DNA, which serves as a template of HBV transcription and permits the persistence of infection. [J Hepatol 2009;51:581-592]

Trigger host’s immune response

Another potential way to induce functional cure is to promote a more complete immune response to the virus. This strategy was examined in a phase II trial of a toll-like receptor 8 (TLR8) agonist, selgantolimod. Forty-eight virally suppressed chronic HBV patients (mean age, 47 years; 75 percent male; 58 percent Asian; 50 percent HBeAg-positive) were randomized to receive oral selgantolimod at 1.5 mg (n=20) or 3.0 mg (n=19) or placebo (n=9) once weekly for 24 weeks.

According to week 48 responses in the combined selgantolimod arms, two patients exhibited loss of HBsAg, and three out of 19 HBeAg-positive patients had achieved HBeAg loss. HBsAg declines of ≥0.1 log₁₀ IU/mL were seen in 10 patients. [ILC 2020, abstract AS071]

Treatment was well-tolerated. The experimental drug produced dose-dependent increases in cytokines, and no cases of tachyphylaxis occurred. Selgantolimod was generally safe and well tolerated, and most treatment-related AEs (nausea and vomiting) were mild.

Noting the attention and energy in HBV cure research, European Association for the Study of the Liver Governing Board Member Dr Tobias Böttler from the University Hospital Freiburg, Germany, described the development of novel therapeutics for persistent HBV infection as one of the most vibrant fields in hepatology currently.

“With so many different approaches that show promising results regarding HBsAg decline, and even HBsAg loss, we appear to be edging closer to the development of a functional cure,” Böttler said.