GSK is pulling back the curtain on the phase 3 success of its chronic hepatitis B drug bepirovirsen, revealing that nearly one-fifth of all treated patients across two trials were functionally cured of the virus.
The B-Well studies focused on patients already receiving daily standard-of-care treatment with nucleos(t)ide analogue tablets, which block the virus’ ability to replicate. Though this cuts down viral numbers, the approach often stops short of eliminating the pathogen entirely.
After treatment with bepirovirsen, however, 19% of patients achieved the strictly defined “functional cure” criteria. For the subset of patients who already had levels of hepatitis B virus (HBV) surface antigen—a protein on the virus’ outer shell—below 1,000 international units per milliliter, functional cure rates hit 26%.
The results were published today in the New England Journal of Medicine.
“Chronic hepatitis B affects over 240 million people worldwide, and is the leading cause of liver cancer,” Melanie Paff, Ph.D., GSK’s medical development leader for hep B, said during a May 22 call with journalists. “These data are a significant step forward for patients offering functional cure and the potential to substantially reduce the risk of long-term liver complications.”
Bepirovirsen or placebo was administered weekly by injection for 24 weeks, followed by 24 or 48 weeks of standard treatment. Functional cure status was assessed at the 72-week mark. The B-Well 1 and B-Well 2 trials together enrolled 1,838 patients.
“We’ve not had a treatment that’s come to this level of cure,” Seng Gee Lim, M.D., director of hepatology at the National University Health System of Singapore and one of the B-Well lead investigators, said during the journalist call. Nucleos(t)ide analogues, which include medicines like BMS’ Baraclude and Gilead’s Viread, only lead to a functional cure less than 1% of the time, Lim added.
GSK’s trial results are “remarkable,” Anna Lok, M.D., director of clinical hepatology at the University of Michigan Medical School, wrote in a related editorial. “The B-Well trials represent a major step toward a functional cure for HBV infection, and bepirovirsen is an attractive option for selected patients.”
Safety first
More patients had adverse events above grade 3 in the bepirovirsen arm than in the placebo arm, with the most common being a spike in liver enzyme levels. Such side effects can be serious, Lok noted, and require “stringent monitoring” and procedures for pausing treatment until they subside.
To Lim, increases in liver enzymes like alanine aminotransferase (ALT) are a sign that bepirovirsen is working as intended.
“Four patients had to stop therapy because of ALT flares,” he said on the call with journalists, “but ALT rises were actually seen relatively commonly in bepirovirsen-treated patients.”
This, he said, is “probably a mark of efficacy,” because elevated ALT was associated with lower levels of HBV’s surface antigen.
Bepirovirsen is an antisense oligonucleotide, a molecule meant to bind to the virus’ RNA and disrupt its life cycle. GSK licensed the candidate from Ionis Pharmaceuticals back in 2019 and has since made it the star of its HBV pipeline.
The trial researchers are now keen to understand why some patients are functionally cured and others are not, Lim said, with plans to study the liver microenvironment to better understand how bepirovirsen works.
At the moment, bepirovirsen’s annihilation of hep B seems to be driven by three factors, GSK’s Paff said.
“It stops DNA replication because it breaks down pre-genomic RNA,” Paff explained, referring to the RNA that serves as an intermediate step when the virus copies its DNA genome. “It stops the production of S antigen because it breaks down the messenger RNA that makes that protein, and third, it acts as an innate immune stimulation mechanism.”
This immune reinvigoration, Paff added, seems to be bepirovirsen’s “secret sauce,” counteracting HBV’s ability to exhaust the immune system by constantly pumping empty virus shells into the bloodstream. These decoys don’t help the virus replicate, but still attract attention from the immune system.
GSK has already submitted bepirovirsen for approval in the U.S., Japan, Europe and China, with the FDA set to make a decision by October, Paff said.
“We are taking advantage of every regulatory pathway to accelerate the access of this medicine to patients,” she said.
Though bepirovirsen has produced functional cure rates far above other medicines, it still leaves the majority of chronic hep B patients uncured. GSK has plans to both increase cure rates and expand the reach of its HBV medicines to patients with higher and higher viral loads, Paff told Fierce during the call.
Paff specifically highlighted a small interfering RNA (siRNA) candidate called JNJ-3989 or DAP/TOM, licensed in 2023 from Johnson & Johnson’s Janssen unit via Arrowhead Pharmaceuticals.
Currently in a phase 2 trial, DAP/TOM “does a really good job of lowering S antigen,” Paff explained, even in patients with very high levels of the protein. The British pharma is testing whether DAP/TOM can bring virus levels down to a “sweet spot” where bepirovirsen can then take over and “have its maximum effect.”
The company also has a suite of other chronic hep B candidates in earlier stages of development, including the siRNA GSK5637608, the PAPD5/PAPD7 inhibitor GSK3965193 and the TLR8 agonist GSK5251738.
