New drug ‘functionally cures’ many hepatitis B virus infections

A 6-month regimen of an experimental drug for the hepatitis B virus (HBV) added to standard antivirals has “functionally cured” 19% of people in two efficacy trials, meaning they can naturally control that virus without any further treatments. The results, published today in The New England Journal of Medicine (NEJM) and presented at Europe’s largest meeting on liver health, come from people whose chronic HBV infections were already relatively well controlled with the existing drugs, so its effectiveness in other populations that are more challenging to treat remains unknown. The findings are “remarkable” and “a major step” forward for the field, hepatologist Anna Lok of the University of Michigan Medical School wrote in an editorial accompanying the NEJM editorial—although she cautioned it was far from a solution to a major global problem. GSK in January had announced that its drug, called bepirovirsen (bepi), had positive results in two phase 3 efficacy trials that involved more than 1800 participants in 29 countries, but the company did not report any details. Many researchers anticipated that about 10% of trial participants would achieve natural suppression of HBV—what the field calls a functional cure—as that’s what was found in the earlier phase 2 bepi trials. The even more impressive result is “exciting news,” says Nick Walsh, an epidemiologist at Monash University who specializes in hepatitis diseases and was unconnected to the study. “This will certainly bring much needed attention to HBV and should accelerate further efforts to find a cure, which indeed needs to be urgently rolled out,” he says. But Walsh and other HBV researchers stress that bepi’s unprecedented powers may well have a limited impact for most of the 240 million people worldwide living with chronic HBV infections, which kill 1.1 million each year. The World Health Organization estimates only 27% of infected people have been diagnosed, and of those, fewer than 5% receive treatment. Chronic HBV infections can destroy the liver and ultimately kill if left unchecked.

They currently require lifelong treatment, and less than 1% of patients who receive existing drugs can control the virus after stopping treatments. The most commonly used HBV drugs disrupt the ability of the virus to make copies of its genes by introducing into infected cells defective analogs of the nucleosides or nucleotides—nukes—that make up its DNA. Bepi, in contrast, is an antisense oligonucleotide that derails viral replication by binding to HBV’s messenger RNA, preventing it from making needed proteins and triggering its destruction. The drug separately stimulates immune responses against the virus. The new phase 3 studies focused on the subset of the treated population for whom the standard drugs were working. Participants had relatively low levels of the viral surface protein, or antigen, in their blood and did not have HIV infections or liver scarring known as cirrhosis. Two-thirds of participants added bepi shots for 24 weeks to their daily nuke pills, while a control group added placebo shots. Everyone then continued with nukes for another 24 weeks. Six months after stopping all treatment, 233 of 1220 people who had received bepi had functional cures—both undetectable HBV DNA and surface antigen—versus zero of 614 participants in the placebo arm. The functional cure rate went up to 26% in participants who entered the study with the lowest levels of the viral surface antigen. Side effects were common, but rarely severe. When HBV infects adults, typically through sex or sharing needles during drug use, the immune system clears the virus about 90% of the time. In infants who become infected, mainly by mother-to-child transmission, their less mature immune systems falter more often—90% develop chronic infections. An infection becomes chronic when HBV integrates its DNA into human chromosomes and also forms an intractable miniature chromosome inside cells called cccDNA. Like the nukes, bepi doesn’t eliminate the embedded cccDNA—a “sterilizing” cure—but it helps suppress HBV levels to low enough levels for a long enough period to reinvigorate immune responses against the virus. Many researchers see the functional cure bepi provides as a more realistic goal than a sterilizing cure. The new results are “a long-awaited milestone in the journey toward curing HBV infection,” says Fabien Zoulim, a hepatologist at Claude Bernard University Lyon 1.

Whether a bepi-induced functional cure is lifelong remains a key issue. Zoulim notes that the durability of surface antigen loss “requires further assessment through extended follow-up.” Data from the much smaller phase 2 studies of the drug have shown viral suppression for up to 3 years in more than 90% of the functionally cured patients, according to Melanie Paff, a GSK scientist who spoke at a press briefing last week. GSK has already submitted the new phase 3 data to drug regulatory agencies in Europe, the United States, Canada, Japan, and China. The company expects at least some approvals to occur later this year. It has yet to announce how much the drug will sell for in wealthy countries and resource-limited ones. “We are committed to pricing which balances the value of innovation and patient access, and we’ll continue to work constructively with payers around the world to achieve this,” a GSK spokesperson told Science. Despite the promise of bepi, some hepatitis B researchers remain frustrated that pharmaceutical companies have not made more of an effort to design even better, truly curative drugs. “There have not been enough collaborations within industry—each company tries to work on its own,” Lok says, “and we expect that a cure, for many patients, will require a multiprong approach.”