The World Health Organization estimates that in 2024, 240 million people were living with chronic hepatitis B virus worldwide. That same year, HBV claimed 1.1 million lives. Current treatments for HBV include oral nucleoside or nucleotide analogues, and they are rarely curative. They are effective at suppressing viral replication and decreasing the risk of cirrhosis and complications like hepatocellular carcinoma. However, cure rates are dismal – approximately 3% after being on treatment for a decade or so.
The Phase 3 results of two studies that looked at an antiviral with a novel mechanism of action were published in the New England Journal of Medicine. Bepirovirsen is an antisense oligonucleotide that targets all HBV transcripts and terminates them early. As such, it decreases HBV DNA and HBsAg. Simultaneously, it stimulates the immune response through cytokine induction and immune cell activation.
In these two double-blind trials, noncirrhotic patients with chronic HBV who were on stable oral nucleoside/nucleotide analogue therapy were randomized 2:1 to receive 300 mg of bepirovirsen subcutaneous weekly or placebo for 24 weeks. Patients were 18 years or older with HBsAg of 100-3,000 IU/mL and HBV DNA of < 90 IU/mL, and alanine aminotransferase of no more than two times the upper limit of normal. Patients with hepatitis C virus, hepatitis D virus or HIV coinfection were excluded.
Patients received dual therapy for 24 weeks, then bepirovirsen was stopped, and oral therapy was continued through 48 weeks. Patients with HBV DNA < 20 IU/mL and no detectable HBsAg between weeks 26 and 48 were eligible to stop oral therapy at 48 weeks. Treatment response was assessed at 72 weeks, which was 24 weeks after stopping all HBV therapy.
A total of 1,220 patients received bepirovirsen, and 714 received placebo. At 48 weeks, 24% of bepirovirsen patients were eligible to discontinue oral therapy. Zero patients in the placebo arm were eligible. The percentage of patients with a functional cure at 72 weeks was around 20% in the bepirovirsen group, and none of the placebo patients achieved a functional cure. Grade 3 adverse events were noted in 16% of the treatment arm and 3% of placebo, with the most common being alanine aminotransferase increase (in 6%).
A functional cure of 20% doesn’t seem like much until you remember the comparator arm was zero. I remember the early days of hepatitis C virus direct-acting antivirals and how they opened the floodgates to more and more effective regimens — and now cure rates hover around 95%. I hope that we see a similar trajectory for HBV treatment in the years to come.
