Antiviral combination plus standard therapy achieves ‘controlled biological state’ in HBV



Agarwal K. Abstract GS010. Presented at: International Liver Congress; June 22-26, 2022; London (hybrid meeting).

The researchers report receiving research grants from Janssen Pharmaceuticals.

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LONDON — Therapy combining small interfering RNA, capsid assembly modulator and nucleotide analogue reduced HBsAg levels over 24 weeks compared with standard therapy, according to a presenter at the International Liver Congress.

Kosh Agarwal

“It’s important that we think about public health and global viruses and liver disease, and hepatitis B is a globally relevant virus,” Kosh Agarwal, MD, from the Institute of Liver Studies at King’s College Hospital in London, told attendees. “I believe the latest estimates suggest that almost 300 million people in the world are affected with hepatitis B, and almost every 30 seconds, someone dies of hepatitis B somewhere in the world.”

Steve Forrest/EASL

“We didn’t achieve a cure, but at the end of follow-up, a significant proportion of patients were in a ‘controlled biological state’ — is that good enough?” Kosh Agarwal, MD, attendees. “Is that going to be followed through when we report 48 weeks?” Source: Steve Forrest/EASL

He added: “We have good treatments that can control hepatitis B, but we do not have treatments that cure hepatitis B. On the back of the stunning success of hepatitis C, there is within the field, a wish to try and achieve cure of hepatitis B, and we characterize that by losing surface antigen, a marker of hepatitis B.”

In the phase 2b REEF-2 study, Agarwal and colleagues selected 130 non-cirrhotic HBeAg-negative hepatitis B patients with HBsAg greater than 100 IU/mL and nucleotide analogue treatment for at least 2 years, and randomly assigned them to add on an investigational small interfering RNA (siRNA; JNJ-3989, Arrowhead Pharmaceuticals) plus a capsid assembly modulator (JNJ-6379, Janssen Pharmaceuticals) or placebo.

The primary endpoint for the study was the proportion of patients who achieved HBsAg levels less than 0.05 IU/mL at follow-up week 24 without restarting nucleotide analogue therapy.

“The unique aspect of this study is that after 48 weeks, all treatment was stopped,” Agarwal said. “If you want to get to a cure, you have to think about a finite duration of therapy, and currently, we don’t have that.”

According to researchers, at baseline, 80% of patients in the combination therapy group had HBsAg levels of at least 1,000 IU/mL and a mean duration of previous nucleotide analogue use of 8.4 years, while 76% of the standard therapy group exhibited HBsAg levels of At least 1,000 IU/mL with prior mean nucleotide analogue use of 8.1 years.

Following the end of treatment, mean reductions in HBsAg from baseline were –1.89 (0.060) log10 IU/mL in the combination group and –0.06 (0.012) log10 IU/mL in the control group. In the combination group, 71.1% of patients achieved HBsAg of less than 100 IU/mL, 19.7% less than 10 IU/mL and 2.6% less than 1 IU/mL. In the control group, only 2.4% of patients achieved HBsAg of less than 100 IU/mL; However, no patient in either group achieved HBsAg seroclearance.

“After 24 weeks of follow up, no patients in this study lost their surface antigen — ie, were cured of hepatitis B — in either the active arm or the control arm,” Agarwal said. “However, there is evidence to show that the combination of these drugs, and one particular aspect of siRNA, shows a significant decrease in some of the markers that we are interested in for hepatitis B, and this is at 24 weeks.”

He added: “So we didn’t achieve a cure, but at the end of follow-up, a significant proportion of patients were in a ‘controlled biological state’ — is that good enough? Is that going to be followed through when we report 48 weeks? This will take us back to the drawing board to think about whether we need better antiviral treatments, whether we need to think about different combinations and whether stopping all treatment is the right strategy to take.”

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