Novel Hepatitis B Drug Hints at Long-Term 'Functional Cure' for Some in Early Trial

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WASHINGTON -- Investigational antisense RNA-based therapy bepirovirsen sustained clearance of both hepatitis B virus (HBV) DNA and surface antigen (HBsAg) for a modest proportion of patients out to 6 months after injections stopped, a phase IIb trial showed.

Levels remained below the level of detection or quantification at that point for 9% of chronic HBV infection patients who got either of two 24-week dose regimens for subcutaneous injections of bepirovirsen along with nucleoside analogues (NA) and for 10% not taking NA but on the highest bepirovirsen dose for 24 weeks.

Shorter, 12-week courses of bepirovirsen with placebo for the other 12 weeks yielded clearance by both measures in no more than 3% regardless of NA use at the 6-month post-treatment follow-up, reported Man-Fung Yuen, MD, PhD, of the University of Hong Kong, at the annual Liver Meeting sponsored by the American Association for the Study of Liver Diseases. The findings were published simultaneously in the New England Journal of Medicine (NEJM).

These 6-month post-treatment rates were substantially lower than seen in interim results of the B-Clear trial reported at the completion of 24 weeks of treatment, when the proportions of patients with undetectable HBsAg and HBV DNA levels reached 28% and 29% in the higher dose 24-week regimen group on and not on NA, respectively.

Nine to 10% rates at the end of follow-up are good -- "it's not zero" -- commented Jay Hoofnagle, MD, of the NIH in Bethesda, Maryland, who served as moderator for the late-breaking trial session where Yuen presented the results and also authored an editorial on the results in NEJM.

"This is very promising, this is what we've been waiting for in hepatitis B for a long time; it's not ready for prime time, but it's marvelous when these drugs come along," he told MedPage Today following Yuen's presentation.

Still, Hoofnagle asked: "Will they remain negative and healthy in the long term? Can those taking nucleosides get off of them?"

Once a patient is taking nucleosides, Hoofnagle explained, they have to be taken for life or patients face a high risk of mortality. "What is needed is a regimen that would lead to clearance of both HBV DNA and HBsAg and allow for withdrawal of therapy without a risk of relapse, an end point colloquially known as a 'functional' cure," he wrote in the editorial.

"I have a patient that's been on nucleosides for 30 years," he said. "We really need a finite treatment, and this really is a promissory note. It's a lot like the first breakthrough in hepatitis C in 2012 -- it looked good, but it took a while to get the best drug combination and the best duration."

Bepirovirsen is an antisense oligonucleotide that targets all HBV messenger RNAs and acts to decrease levels of viral proteins. The aim of the trial was to test bepirovirsen as a functional cure, offering long-term virus suppression after a fixed course of treatment.

The phase IIb trial enrolled 457 patients who had chronic HBV infection for at least 6 months, had alanine aminotransferase (ALT) greater than three times the upper limit of normal, HBV DNA over 2,000 IU/mL, and HBsAg over 100 IU/mL. The composite primary endpoint was an HBV DNA below the lower limit of quantification and HBsAg below the limit of detection for 6 months after the end of treatment.

Participants included individuals who continued on their preexisting NA and those not on NA for at least 6 months prior to enrollment. They were assigned to four treatment groups in two parallel randomizations:

• Bepirovirsen 300 mg per week for 24 weeks
• Bepirovirsen 300 mg for 12 weeks then 150 mg for 12 weeks
• Bepirovirsen 300 mg for 12 weeks followed by placebo for 12 weeks
• Placebo for 12 weeks followed by bepirovirsen 300 mg for 12 weeks

The proportion of men across treatment groups ranged from 46% to 60%. Mean age was around 42 years old. More than half of patients were Asian, and about one-third were white.

Mean HBsAg at baseline averaged 3.65 to 3.76 log 10 IU/mL.

"Participants with low baseline surface antigen were more likely to achieve the primary outcome than those with high baseline surface antigen, particularly the 16% of patients with baseline surface antigen lower than three logs," Yuen said in his presentation.

Hoofnagle also drew attention to this factor, noting a primary outcome response of 19% for participants with baseline HBsAg levels at 3,000 IU/mL or below in the study arm where participants received the 300-mg weekly dose for 24 weeks, as compared with "only 7% of those who had higher baseline levels."

Other than body mass index, no other variables appeared to be independent predictors of response, Yuen noted.

No monotherapy patients in the arm that got placebo for 12 weeks then 12 weeks of 300-mg bepirovirsen achieved the primary endpoint at the end of the 6-month follow-up.

Treatment-related adverse events were reported in 65-79% of patients across the groups. During the first 12 weeks when three groups were on bepirovirsen and one group was on placebo only, adverse events more common with the drug included injection-site reactions, pyrexia, fatigue, and increased ALT levels. There were no adverse events that led to treatment discontinuation.

"Of most concern were increased ALT levels, which were more common in patients not receiving NA therapy than in those receiving it (41% vs 17%)," Hoofnagle noted. "Two serious instances of acute hepatitis resulting in hospitalization arose in participants not receiving NA therapy, which suggests that bepirovirsen should be combined with NA therapy."

HBV is vaccine-preventable, but only about 30% of the U.S. adult population has been vaccinated, according to the CDC. The CDC's Advisory Committee on Immunization Practices recently recommended all adults age 19-59 get vaccinated, citing the fact that while infections have been reduced during the past four decades, the incidence of infection has stopped declining in recent years.