Novel Hep B Drug Delivers Functional Cures in Late-Stage Trials

Treatment with the investigational antisense oligonucleotide bepirovirsen led to functional cure in one in five patients with chronic hepatitis B virus (HBV) infection, the phase III B-Well 1 and B-Well 2 trials showed.

Among patients taking stable nucleoside or nucleotide analogue (NA) therapy, 20% and 19% of those taking bepirovirsen in the two trials, respectively, had a functional cure at week 72 compared with no patients taking placebo, reported Seng-Gee Lim, MD, of the National University Health System in Singapore, at the European Association for the Study of the Liver annual meeting in Barcelona.

The common risk difference between bepirovirsen and placebo was 17.5 percentage points in B-Well 1 (95% CI 14.6-20.3) and 13.3 percentage points in B-Well 2 (95% CI 10.4-16.1; P<0.001 for both comparisons).

The twin trials’ findings, which were published simultaneously in the New England Journal of Medicine, “will change the landscape of hepatitis B treatment,” Lim said during his presentation.

In an accompanying editorial, Anna Lok, MD, of the University of Michigan in Ann Arbor, noted that the B-Well studies’ results were “remarkable” and “represent a major step toward a functional cure for HBV infection.”

While the studies show that bepirovirsen is an attractive option for selected patients, Lok added, their results can’t be generalized to the patients who weren’t included in the trials: those with cirrhosis, HIV coinfection, or hepatitis B surface antigen (HBsAg) levels greater than 3,000 IU/mL.

“The durability of HBsAg loss has to be confirmed with longer follow-up, and alternative therapies are needed for other patients,” Lok cautioned.

A functional cure for chronic HBV infection is defined as an HBV DNA level below the lower limit of quantification (less than 20 IU/mL or not detected) and the loss of HBsAg (level less than 0.05 IU/mL) for at least 24 weeks after fixed-duration therapy ends. Reaching a functional cure makes further NA therapy unnecessary.

HBsAg loss is linked with better clinical outcomes compared with HBV DNA suppression alone, but treatment with NA therapies or pegylated interferon rarely achieves HBsAg loss. After 8 to 10 years of NA therapy, only about 3% of patients reach HBsAg loss. An estimated 8% to 11% of those treated with pegylated interferon achieve HBsAg loss 3 years after treatment.

The identically designed B-Well 1 and B-Well 2 double-blind trials included patients from 29 countries, enrolling adults with chronic HBV infection who were on stable NA therapy for at least 6 months. Trial participants had HBsAg levels between 100 and 3,000 IU/mL, an HBV DNA level below 90 IU/mL, and alanine aminotransferase (ALT) levels no more than twice the upper limit of the normal range. Exclusion criteria included cirrhosis and coinfection with hepatitis C, hepatitis D, or HIV.

Across the two trials, mean age was 49-50, 69-73% were men, 67-70% were Asian, 24-27% were white, 4-5% were Black, and 5-12% were Hispanic or Latino.

Patients were randomized 2:1 to either weekly subcutaneous injections of 300-mg bepirovirsen or placebo from week 1 to week 24. All patients received NA therapy from week 1 to week 48. Those who reached an HBV DNA level below the lower limit of quantification, HBsAg loss, and ALT values no more than twice the normal range’s upper limit from week 24 to week 48 stopped NA therapy. In both trials, 24% of those in the bepirovirsen groups discontinued NA therapy at week 48, while no placebo patients did.

The study’s primary outcome was functional cure at week 72, 24 weeks after eligible patients stopped all HBV treatment.

Among patients with lower HBsAg levels (100-1,000 IU/mL), 25% and 28% of bepirovirsen patients in B-Well 1 and B-Well 2, respectively, reached functional cure, compared with no placebo patients (P<0.001 in both trials).

Functional cure rates fell as HBsAg levels rose. In those with higher HBsAg levels (>1,000 to ≤3,000 IU/mL), functional cure was reached by 10% and 5% of B-Well 1 and B-Well 2 bepirovirsen patients, respectively, while no placebo patients with higher HBsAg levels in either trial achieved functional cure.

In a pooled analysis of both trials, 91% of bepirovirsen patients and 73% of placebo patients reported adverse events by week 72, with 7% and 4%, respectively, reporting severe adverse events. Grade 3 or higher adverse events occurred in 16% of those in the bepirovirsen groups and 3% of those in the placebo groups during the trials’ treatment periods, with increases in ALT level being the most common grade 3 adverse events with bepirovirsen (6%). Three percent of bepirovirsen patients stopped treatment because of adverse events.

Lim noted that 24% of patients in the bepirovirsen groups had ALT levels rise more than three times above the normal range’s upper limit. Those who had these increases had an 85% chance of HBsAg loss. Those with ALT levels below that threshold had only a 35% chance of HBsAg loss.

“Clearly, those flares are important from an efficacy viewpoint,” Lim said. “It was probably an effect of efficacy of the drug.”

Study limitations included the relatively small number of patients in some racial and ethnic groups such as Black and Hispanic or Latino patients, which could limit the findings’ generalizability. In addition, the studies’ central stratification may have led to different average HBsAg baseline levels in different countries.