Bepirovirsen Becomes the First Hepatitis B Drug to Deliver a Functional Cure

The FDA signed off on bepirovirsen on October 20, 2026, and JAMA flagged that US approval in a news piece published November 13. Japan moved first, approving the drug on August 24, 2026, and it came with a Sakigake pioneering designation — the first approval under that system, according to the report. Japan then listed it for reimbursement and launched it on October 14.

The evidence comes from two Phase 3 trials, B-Well 1 and B-Well 2. A functional cure — HBsAg loss plus HBV DNA suppression held after all treatment stopped — landed in 127 of 650 patients (19.5%) in B-Well 1 and 106 of 570 (18.6%) in B-Well 2, or 233 of 1,220 (19%) pooled. Placebo produced nothing: zero cases out of 328 and 286. The FDA says 24% of the bepirovirsen group hit the criteria to stop nucleoside/nucleotide analogs, and 19% kept viral control for 24 weeks after quitting them.

Response leans hard on starting HBsAg levels. Patients at 1,000 IU/mL or below cured at 24.6% and 27.8% across the trials, while those between 1,000 and 3,000 IU/mL managed 9.8% and 4.8%. Japan's electronic package insert warns rates trend lower for people 65 and older, HBeAg-positive patients, HBsAg above 1,000 IU/mL and genotype C — a genotype common in Japan, making patient selection critical.

Pooled data to 72 weeks show adverse events in 91% of the bepirovirsen arm versus 73% on placebo, serious events in 7% versus 4%, and Grade 3 or worse events during treatment in 16% versus 3%. The most common Grade 3 problem was ALT elevation, at 6% on bepirovirsen. The US label carries a boxed warning for on-treatment hepatic flares (ALT more than 20 to 40 times the upper limit of normal) and low platelets, while Japan's insert skips the warning section but bars patients with cirrhosis or pre-treatment platelets under 100,000/μL. Platelets are checked weekly in the US and every two weeks in Japan.

Dosing is a 300 mg subcutaneous injection: twice weekly every three to four days in weeks 1–2, then once weekly from weeks 3 to 24, for 26 doses total. Nucleoside/nucleotide analogs stay on board and continue for 24 weeks after the last bepirovirsen dose. If there's no early response at week 12 — under 1 IU/mL when baseline HBsAg was 1,000 IU/mL or less, under 0.05 IU/mL when it was higher — stopping should be considered. Eligible patients are adults already on analogs for at least six months with HBsAg of 3,000 IU/mL or less and HBV DNA under 90 IU/mL at the start; cirrhosis rules them out.

Durability data landed at AASLD in November 2026: at 96 weeks, 90% (114 of 127) of B-Well 1 functional cures and 92% (97 of 105) in B-Well 2 held. The caveats are real — the trials covered selected non-cirrhotic patients only, never directly measured liver cancer, liver failure or death, and looked no further than 96 weeks. Even when HBsAg vanishes, cccDNA or integrated HBV DNA can linger in the liver, so surveillance shouldn't be dropped just because a functional cure was declared. A syringe costs 183,015 yen, and 26 doses of two syringes each runs about 9.52 million yen.