Hepatitis B capsid assembly modulators show good antiviral activity

Liz Highleyman
Published:
21 December 2018

Experimental drugs that interfere with hepatitis B virus (HBV) capsid assembly continue to show promise as a new approach to antiviral treatment, according to research presented at the AASLD Liver Meeting last month in San Francisco.

Nucleoside/nucleotide antivirals such as tenofovir DF (Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude) can suppress HBV replication indefinitely during long-term therapy. They seldom lead to a cure, however, and researchers are exploring new approaches that might be more effective alone or in combination.

Capsid assembly modulators (CAMs) interfere with the HBV core protein, which plays a role in packaging viral genetic material into a nucleocapsid shell. This leads to the production of defective virus that is unable to replicate. CAMs also inhibit formation of HBV covalently closed circular DNA (cccDNA), probably by interfering with capsid disassembly, an early step in viral replication.

JNJ-56136379 (JNJ-6379 for short) is a CAM being developed by Janssen. Fabien Zoulim of INSERM Cancer Research Institute in Lyons, France, reported findings from a study evaluating the antiviral activity, safety, pharmacokinetics of JNJ-6379 given for 4 weeks, followed by 8 weeks of follow-up, in people being treated for hepatitis B for the first time.

This phase 1b trial enrolled 48 people with chronic HBV infection and HBV DNA levels above 2000 IU/ml. More than 80% were men, most were white and the median age was approximately 40 years. About a quarter were hepatitis B 'e' antigen (HBeAg) positive. They mostly had absent or mild liver fibrosis (stage F0-F1); none had advanced fibrosis or cirrhosis.

Participants were assigned to receive JNJ-6379 at doses of 25mg (after a 100mg loading dose), 75mg, 150mg, 250mg or a placebo once daily for 4 weeks.

At this year's EASL International Liver Congress in April, Zoulim reported early results from the first three groups. After 4 weeks of treatment, HBV DNA declined by -2.16, -2.89 and -2.70 log10 in the 25mg, 150mg and 75mg dose groups, respectively. At The Liver Meeting, he reported that HBV DNA also fell by -2.70 log10 in the 250mg group at 4 weeks. At the end of treatment, 38% in the 75mg and 150mg groups and 56% in the 250mg group had undetectable HBV DNA.

Viral levels began to rise after stopping treatment. Those in the 25mg group saw their HBV DNA return almost to the baseline level. The rise was slower in the intermediate dose groups and the level remained low in the highest dose group. At the end of 8 weeks of follow-up (4 on and 4 off treatment), HBV DNA levels were -0.27, -1.71, -1.51 and -2.19 log10 below baseline in the respective dose groups.

HBV RNA levels showed the opposite pattern, falling by -2.30, -1.85, -1.83 and 1.43 log10 in the respective groups. At the end of treatment, 75% in the 75mg and 150mg groups and 89% in the 250mg group had undetectable HBV RNA, but the number of patients with RNA data was small.

Viral DNA and RNA levels changed little in the placebo group (-0.11 and -0.02 log10, respectively). After 4 weeks of treatment, no placebo recipients had HBV DNA below the level of quantification, though 36% had undetectable HBV RNA

No notable changes in hepatitis B surface antigen (HBsAg) or HBeAg levels were observed, which Zoulim said was to be expected with such a short treatment period.

Treatment was generally well tolerated. Three people had severe (grade 3-4) adverse events. One person in the 150mg group stopped treatment early due to liver enzyme elevation.

JNJ-6379 "demonstrated potent antiviral activity by reducing HBV DNA and HBV RNA," the researchers concluded.

Noting that there was a limited increase in antiviral activity at higher doses, Jordan Feld of University Health Network in Toronto, who presented a 'debrief' of viral hepatitis studies at The Liver Meeting, suggested that a higher dose may be needed to disrupt formed capsids and prevent replenishment of cccDNA.

Another research team presented findings from a phase 1b trial of another core inhibitor CAM known as ABI-H0731. This study mostly enrolled Asian men. Again, participants were assigned to receive one of four doses of the drug or a placebo for 4 weeks.

Man-Fung Yuen of Queen Mary Hospital in Hong Kong reported that HBV DNA decreased by about -1.5, about -2.0 and nearly -3.0 log10 , respectively, in the 100mg, 200mg and 300mg dose groups. Those who were HBeAg negative saw larger declines than those who were HBeAg positive. Although there were only two evaluable patients in the 400mg group, they had an impressive mean -3.9 log10 drop. Here, HBV RNA reductions corresponded with HBV DNA declines. Again no significant changes in HBeAg or HBsAg levels were seen.

Yuen's team likewise concluded that ABI-H0731 conferred "potent antiviral activity" and warranted further study.

Many experts believe that a combination approach will be needed to achieve a functional cure for hepatitis B. Based on these findings, phase 2 trials of JNJ-6379 and ABI-H0731 plus nucleoside/nucleotide analogue antivirals are currently underway.

Reference

Zoulim F et al. Safety, pharmacokinetics and antiviral activity of a novel hepatitis B virus (HBV) capsid assembly modulator, JNJ-56136379, in patients with chronic hepatitis B (CHB). AASLD Liver Meeting, abstract 0074, 2018.

View the abstract.

Yuen MF et al. Final results of a phase 1b 28-day study of ABI-H0731, a novel core inhibitor, in non-cirrhotic viremic subjects with chronic hepatitis B. AASLD Liver Meeting, abstract 0073, 2018.

View the abstract.

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