FDA Approves Bepirovirsen for Chronic Hepatitis B. In Phase 3, 19 Percent Reached Functional Cure Off Treatment.
Hibsago, approved Oct. 20, is the first antisense oligonucleotide for chronic hepatitis B. In the pooled B-Well trials, 233 of 1,220 treated patients reached functional cure versus none on placebo, and the label carries a boxed warning for hepatic flares and thrombocytopenia.
Idea in Brief
The Approval
On Oct. 20 the FDA approved bepirovirsen (Hibsago, GSK) with nucleos(t)ide analog therapy for adults without cirrhosis who are virally suppressed after at least six months of that therapy and have HBsAg of 3,000 IU/mL or less.
The Evidence
In B-Well 1 and B-Well 2, functional cure 24 weeks after stopping all hepatitis B treatment occurred in 20 percent and 19 percent of treated patients, and in none on placebo.
The Caveats
About four in five treated patients did not reach the endpoint, response was lower with higher baseline HBsAg, and the label requires close liver, platelet and kidney monitoring.
On Oct. 20, the Food and Drug Administration approved bepirovirsen (Hibsago, GSK) for chronic hepatitis B; in two phase 3 trials, 19 percent of treated patients had a functional cure 24 weeks after stopping all hepatitis B therapy.
Bepirovirsen is the first antisense oligonucleotide approved for the disease, the FDA said in its announcement. It targets the viral RNA used to make new virus and viral proteins, lowering hepatitis B surface antigen (HBsAg). Functional cure, as GSK defines it, means undetectable HBV DNA and HBsAg for at least 24 weeks after all treatment stops. GSK says about 1.7 million people in the United States have chronic hepatitis B.
Who is eligible under the label?
The indication is narrow. According to the prescribing information, bepirovirsen is used with nucleos(t)ide analog therapy in adults without cirrhosis who have been on that therapy for at least six months, have suppressed HBV DNA and have HBsAg of 3,000 IU/mL or less on an FDA-authorized test. The FDA also authorized the Roche Elecsys HBsAg II quant II RxDx assay as a companion diagnostic.
The label calls for quantitative HBsAg, HBV DNA, ALT, AST, bilirubin, platelet count, urine albumin-creatinine ratio and estimated glomerular filtration rate before the first dose. Dosing is 300 mg subcutaneously twice weekly in weeks 1 and 2, then once weekly through week 24, the maximum duration. The first dose is given under a clinician's supervision; patients or caregivers may inject later doses after training.
What did B-Well 1 and B-Well 2 show?
Both were randomized 2:1, double-blind and placebo-controlled, with identical designs, and together enrolled 1,838 patients in 29 countries. Patients stayed on their antiviral through week 48, and those who met prespecified criteria then stopped it. The primary endpoint, read at week 72, was sustained HBV DNA suppression with HBsAg not detected 24 weeks after stopping all hepatitis B treatment.
Per the label, the endpoint was met by 20 percent of treated patients in B-Well 1 (127 of 650) and 19 percent in B-Well 2 (106 of 570), and by none on placebo. The common rate differences were 17 percentage points (95% CI, 14.6 to 20.3) and 13 points (95% CI, 10.4 to 16.1). Pooled, that is 233 of 1,220 versus 0 of 614. In the key secondary group with baseline HBsAg of 1,000 IU/mL or less, 26 percent (200 of 768) reached functional cure. The FDA said 24 percent of treated patients qualified to stop their existing medicine.
Response was lower with higher baseline HBsAg, HBeAg positivity and age 65 or older. About 92 percent of participants were HBeAg-negative, roughly two-thirds were Asian, and 6 to 7 percent were enrolled in the United States or Canada.
Roughly four in five eligible patients did not reach functional cure. For most, this is a time-limited attempt to come off antivirals, not a replacement for long-term care.
Clinical Pearls
- Bepirovirsen is the first FDA-approved antisense oligonucleotide for chronic hepatitis B and is given with, not instead of, nucleos(t)ide analog therapy.
- A quantitative HBsAg level of 3,000 IU/mL or less on an FDA-authorized test is required; the FDA authorized the Roche Elecsys HBsAg II quant II RxDx assay as a companion diagnostic.
- Pooled functional cure was 19 percent (233 of 1,220) versus 0 of 614 on placebo, and 26 percent (200 of 768) in patients with baseline HBsAg of 1,000 IU/mL or less.
- The boxed warning covers on-treatment hepatic flares, with ALT rises above 20 to 40 times the upper limit of normal, and thrombocytopenia that can be sudden and life-threatening.
- The drug is contraindicated with a baseline platelet count below 100 x 10^9/L and in patients with cirrhosis or acute hepatic impairment.
- Maximum treatment duration is 24 weeks, and the label allows considering early cessation if HBsAg is not below 1 IU/mL by week 12.
What are the safety and monitoring requirements?
The boxed warning covers on-treatment hepatic flares, with ALT rises above 20 to 40 times the upper limit of normal as HBsAg falls, mostly in the first 12 weeks, and thrombocytopenia that can be sudden and life-threatening. The drug is contraindicated with a baseline platelet count below 100 x 10^9/L and in patients with cirrhosis or acute hepatic impairment. Platelets are checked weekly during treatment, more often below 75 x 10^9/L, and the drug is stopped for good below 50 x 10^9/L. Further warnings cover worsening kidney function, inflammatory effects including vasculitis, and harm from improper injection.
In the pooled safety data through week 36, injection site reactions occurred in 57 percent of treated patients versus 15 percent on placebo, pyrexia in 20 versus 4 percent and fatigue in 16 versus 8 percent, the label states. ALT rose to five times the upper limit of normal or more in about 14 percent of treated patients. Three percent stopped treatment for adverse events, versus under 1 percent on placebo.
“Hibsago provides a new treatment approach that gives some patients the possibility of maintaining control of the virus after all chronic HBV treatment has ended,” said Wendy Carter, DO, acting director of the Office of Infectious Diseases in the FDA's Center for Drug Evaluation and Research, in the agency's release.
What it means in clinic
Most patients on tenofovir or entecavir will not qualify, and the trials excluded people with platelets below 140 x 10^9/L, an eGFR of 60 or less, or coinfection with hepatitis C, hepatitis D or HIV. GSK's release does not give a price or launch date.
This week, list patients who have been suppressed on nucleos(t)ide therapy for six months or more without cirrhosis, check whether a recent quantitative HBsAg is in the chart, and confirm platelet, liver and kidney baselines before referral to hepatology. For a related hepatitis B prevention question, see our report on the Annals birth-dose model.
Reported, fact-checked and edited by The Script Pad's editorial staff.
This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.
