Hepatitis B capsid inhibitors look promising in early studies

Two experimental drugs that interfere with assembly of the hepatitis B virus (HBV) capsid and prevent production of functional new virus demonstrated good safety and promising antiviral activity in early clinical trials, according to reports presented at the 2018 International Liver Congress last week in Paris.

Nucleoside/nucleotide antivirals such as tenofovir DF (Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude) can suppress HBV replication indefinitely during long-term therapy, but they seldom lead to a cure, typically defined as hepatitis B surface antigen (HBsAg) clearance.

Capsid inhibitors are among several novel agents being explored as finite treatments, potentially for use in combination therapy.

RO7049389, being developed by Roche, is a core protein allosteric modulator. It causes production of defective HBV core proteins that lead to assembly of a defective nucleocapsid, the shell that encloses viral genetic material. JNJ-379, being developed by Janssen, is a capsid inhibitor with a dual mode of action. It appears to interfere with both disassembly of the capsid when the virus enters a cell – necessary to release viral DNA – and assembly of capsids for newly produced HBV particles.

Edward Gane of Auckland Clinical Studies in New Zealand presented findings from a phase 1 study evaluating the safety, tolerability, pharmacokinetics and anti-HBV activity of RO7049389.

Part 1 of the study, which enrolled 65 healthy volunteers without HBV, looked at the safety and pharmacokinetics of single ascending oral doses ranging from 150mg to 2000mg, with and without food, and multiple ascending doses ranging from 200mg to 600mg twice daily for 14 days. All were men, about 70% were white, 16% were Asian and the median age was approximately 25 years.

The second part, enrolling people with chronic HBV infection, is assessing the drug's antiviral activity at multiple doses. Gane reported findings from the first cohort of six patients treated with 200mg RO7049389 twice daily for 28 days plus one placebo recipient. Five were men, six were Asian, one was white and the median age was 40 years; three were hepatitis B 'e' antigen (HBeAg) positive, which is more difficult to treat. They were not currently on HBV treatment, did not have liver cirrhosis or high ALT elevation and had a viral loads of least 2000 IU/ml if HBeAg negative or 20,000 IU/ml if HBeAg positive.

RO7049389 had a favourable pharmacokinetic profile, with a half-life of 5.5 hours. Treatment was well tolerated by both healthy volunteers and people with HBV. Only three people had adverse events that were considered drug-related (nausea, abdominal upset, skin rash and headache) and all were mild. There were no clinically meaningful changes in laboratory results.

All participants with hepatitis B who took RO7049389 for four weeks experienced "rapid and profound" viral load suppression, Gane reported. The median HBV DNA decline was -2.7 log₁₀ and the maximum decline was -3.4 log₁₀. The three HBeAg-negative people, who started with lower viral levels, became undetectable; viral load was still declining in the HBeAg-positive participants.

Gane did not report changes in HBsAg or HBeAg levels, but preclinical studies showed that higher doses of RO7049389 reduced HBsAg and HBeAg in mice.

"These preliminary data support the further development of RO7049389 as a potential component of a novel combination HBV cure regimen," the researchers concluded.

Gane said that other cohorts in this ongoing study will evaluate higher doses and a once-daily dosing schedule.

In a related presentation, Lu Gao and colleagues of the Roche Innovation Centre in Basel reported findings from a mouse study testing RO7049389 in combination with the toll-like receptor 7 (TLR7) agonist RO7020531, a drug that activates T cells, B cells and natural killer cells.

The combination produced sustained HBV DNA suppression that lasted for six weeks after the drug was stopped in four of the seven treated mice. It also led to HBsAg loss in five mice and some developed anti-HBs antibodies.

Fabien Zoulim of INSERM Cancer Research Institute in Lyon, France, and colleagues evaluated the safety, pharmacokinetics and antiviral activity of multiple ascending doses of JNJ-56136379 (JNJ-379 for short) in people with chronic hepatitis B.

This ongoing phase 1b trial study enrolled 36 people with previously untreated chronic hepatitis B and had HBV DNA levels above 2000 IU/ml. Most (83%) were men, three-quarters were white and the median age was approximately 43 years. A quarter were HBeAg positive and a majority had HBV genotype D. Most had absent or mild liver fibrosis; people with cirrhosis and highly elevated ALT were excluded.

Participants were randomly assigned to receive JNJ-379 at once-daily doses of 25mg (starting with a 100mg loading dose), 75mg or 150mg, or a placebo, for 28 days; a 250mg cohort is still underway.

After 28 days of treatment, HBV DNA declined by -2.16, -2.89 and -2.70 log₁₀ in the 25mg, 150mg and 75mg dose groups, respectively. HBV RNA levels fell by -2.3, -1.85 and -1.67 log₁₀,. There were no relevant changes in HBsAg levels, which Zoulim said was to be expected for such a short treatment period.

Again, treatment was safe and well tolerated. Only one person in the highest dose group experienced a severe adverse event and stopped treatment for this reason.

A phase 2a study of both previously untreated and virally suppressed people with chronic hepatitis B is underway to further evaluate JNJ-379 alone and in combination with nucleoside/nucleotide analogues.