Новый препарат бепировирсен показал эффективность функционального излечения гепатита B у 20% пациентов

The novel antisense oligonucleotide bepirovirsen targeting hepatitis B virus (HBV) transcripts holds promise of a functional cure, at least in the short term, according to phase 3 results from the twin B-Well 1 and B-Well 2 trials reported recently in The New England Journal of Medicine. One in 5 patients on the drug achieved a functional cure at week 72 after therapy discontinuation compared with zero placebo patients: in the B-Well 1 trial, 127 of 650 patients (20%) vs zero of 328 patients); in the B-Well 2 trial, 106 of 570 patients (19%) vs zero of 286 patients. The common difference in risk between the treatment group and the placebo group was 17.5 percentage points in B-Well 1 (95% CI, 14.6-20.3) and 13.3 percentage points in B-Well 2 (95% CI, 10.4-16.1; P < .001 for both) Cure was defined as at least 24 weeks of a sustained HBV DNA level below the lower limit of quantification and hepatitis B surface antigen (HBsAg) loss after fixed-duration therapy, according to international investigators led by Jinlin Hou, MD, of the Department of Infectious Diseases at Nanfang Hospital, Southern Medical University, in Guangzhou, China. Standard therapy typically requires long-term, often lifelong, therapy with nucleos(t)ide analogues (NAs), and functional cures have been rare, coauthor Norah Terrault, MD, MPH, a professor of medicine and chief of Gastroenterology and Liver Diseases at Keck School of Medicine at University of Southern California in Los Angeles, told Medscape Medical News. “Thus, there has been great interest to find therapies that can increase the rates of HBsAg loss and to do so with finite therapy. Individuals who achieve functional cure have very low risk for liver cancer, especially if they achieve functional cure prior to development of cirrhosis.” Given that the historical rate of HBsAg loss on NA is about 1% per year, the trials’ 20% rate of functional cure with 24 weeks in selected patients is a major step forward, she added but not a universal cure strategy. “Still, B-Well is the most credible phase 3 signal to date that finite HBV functional-cure therapy is achievable, but it will initially be a selected-patient strategy rather than a replacement for standard NA treatment.” Trial Details From December 2022 to May 2025, 1838 adult patients with documented HBV infection and without cirrhosis were recruited to B-Well 1 (n = 981) and B-Well 2 (n = 857), identical in design and conducted in 29 countries across Europe, the Asia Pacific region, and the Americas. About 70% of patients overall were Asian. Participants had been on stable NA therapy for at least 6 months before screening and no regimen changes were planned during the trial. All had an HBsAg level of 100-3000 IU/mL, an HBV DNA level < 90 IU /mL, and an alanine aminotransferase (ALT) level of no more than twice the upper limit of the normal. In a pooled analysis at 72 weeks, adverse events were reported in 91% of the bepirovirsen groups and in 73% of the placebo groups, with serious adverse events in 7% and 4% of the two groups, respectively. During the treatment period, adverse events of grade 3 or higher were reported in 16% on bepirovirsen vs 3% on placebo. Elevated ALT was the most common grade 3 adverse event in the treatment group, affecting 6%. Commenting on the trials for Medscape Medical News but not involved in them, Joseph K. Lim, MD, a professor of medicine and director of clinical hepatology at Yale School of Medicine in New Haven, Connecticut, referred to the study findings as “landmark, compelling, unequivocally groundbreaking, and a potential transformative shift” in confirming the efficacy of a 24-week course of bepirovirsen for functional cure. “However, it’s important to clarify that this is a functional cure rather than a sterilizing cure,” he cautioned. “And although the ability to achieve functional cure is very exciting, only a subset of patients with chronic HBV will be eligible for consideration.” Lim added that bepirovirsen may be the first in a new generation of novel agents targeting functional cure. Additional studies are needed to clarify optimal combinations of HBsAg-lowering approaches such as RNA interference, immunomodulators, and antivirals, which may further augment functional cure of chronic HBV. In a related editorial, Anna S. Lok, MD, of the Department of Gastroenterology and Hepatology at University of Michigan in Ann Arbor, Michigan, called the B-Well trials remarkable and agreed they represent a major step toward a functional HBV cure. “Not only did these phase 3 trials aim at a cure for HBV infection, but they also had encouraging results that involved adding only one investigational agent,” she wrote. Lok cited, however, the need to confirm the durability of HBsAg loss with longer follow-up and to find alternate therapies for patients with cirrhosis or HBsAg levels above 3000 units per milliliter. “Ultimately, curative therapies must be simple, safe, accessible, and affordable to benefit the 240 million persons worldwide who are living with chronic HBV infection.” Terrault agreed that long-term durability beyond week 72 is a big question. “Additionally, there is need to confirm that functional cure achieved by patients with bepi yields the same long-term benefits of reduction in cirrhosis and liver cancer as those who achieve functional cure naturally or with NA therapy,” she said. The next research step would likely involve a broader group of patients and real-world data, Terrault added. “Clearly, it would be ideal to also study this in patients with early or compensated cirrhosis, but this must be undertaken carefully given the recognized occurrence of ALT flares with bepi treatment, which is believed to reflect a positive treatment effect but can be a risk for decompensation in patients with cirrhosis.” Lim agreed that the optimal application of bepirovirsen to real-world clinical practice, including for important subgroups not included in the B-Well trials, needs research. Other important questions are optimal patient selection, treatment monitoring, patient/payor access, and adverse effect management. GlaxoSmithKline (GSK) funded the trials and provided the investigational medication. Terrault reported consulting and having board membership for GSK and Vir Biotech as well as having book royalties from Elsevier. Lim reported having relationships with Abbott Diagnostics, Aligos Therapeutics, Arbutus, Assembly Biosciences, AusperBio, Eisai, F. Hoffmann-La Roche, Gilead Sciences, GSK, Grifols, IRnovate, Janssen Biotech, and Sysmex Inostics. Lok disclosed having ties to Chroma Medicine, Flagship Pioneering, GSK, Grifols, Moderna, Novo Nordisk, Pfizer, Precision BioSciences, Virion, and Zenas BioPharma.