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A phase II trial found that 19% of patients receiving the highest dose of the siRNA drug HRS-5635 met the study’s definition of functional cure 24 weeks after treatment ended. The result is an early signal, not proof of a durable cure: follow-up was short, and a longer extension study and phase III trial are underway.
In a phase II study of adults with chronic hepatitis B, 19% of patients given the highest dose of the experimental siRNA drug HRS-5635 met the trial’s definition of functional cure 24 weeks after treatment ended, researchers reported November 10 at the American Association for the Study of Liver Diseases meeting in Denver. The finding is an early clinical signal; it does not establish that the effect will last longer or that the drug can broadly cure hepatitis B.
The study tested four HRS-5635 doses, from 50 mg to 400 mg, in people whose HBV was suppressed on stable nucleos(t)ide analogue therapy. Participants also received tenofovir amibufenamide during 48 weeks of HRS-5635 treatment. They had surface antigen (HBsAg) levels above 100 and below 3,000 IU/mL, HBV DNA below 20 IU/mL, and no cirrhosis. Patients could be positive or negative for hepatitis B e antigen (HBeAg).
All four dose groups met the primary endpoint: reduction in HBsAg from baseline by week 12. The mean reductions ranged from 1.26 log10 IU/mL at 50 mg to 2.12 log10 IU/mL at 400 mg, a pattern the study presenter described as dose-dependent. In the 400-mg group, all patients had HBsAg below 100 IU/mL at week 48; 88% remained below that level 24 weeks after treatment ended.
Researchers defined functional cure as sustained HBV DNA suppression and HBsAg clearance below 0.05 IU/mL, with or without seroconversion, maintained for 24 weeks after treatment. In the highest-dose group, 16% met that threshold at the end of treatment, rising to 19% at the 24-week follow-up. The report said the figure was 33% among high-dose patients who were HBeAg negative and had baseline HBsAg below 1,000 IU/mL; that subgroup result does not describe all trial participants.
Chronic hepatitis B can lead to liver damage, cirrhosis and liver cancer, while existing treatment often focuses on suppressing the virus rather than clearing HBsAg. A functional-cure result could mean sustained viral suppression and loss of this surface antigen, but it is not the same as proving eradication of every trace of HBV or eliminating the need for monitoring.
The HRS-5635 findings add to research into nucleic acid-based treatments, including siRNA therapies that target viral material. They are relevant because some patients in this selected study reached the specified endpoint after treatment stopped. However, the trial’s size, patient criteria and limited follow-up mean the result cannot yet show how often the outcome would occur in broader patient populations or how durable it will be.
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How HRS-5635 Fits HBV Treatment
The trial enrolled people already receiving stable antiviral therapy and with low HBV DNA, so its results concern an add-on treatment strategy rather than HRS-5635 used alone. The source report estimates that about 240 million people worldwide and roughly 640,000 U.S. adults have chronic HBV. It also notes that five antivirals and two immune modulators are approved in the United States.
Another nucleic acid-based drug, bepirovirsen, was approved by the U.S. Food and Drug Administration the month before the report, according to MedPage Today. In the B-Well 1 and B-Well 2 trials, 19% to 20% of patients with HBsAg levels from 100 to 3,000 IU/mL met a functional-cure endpoint at week 72 while taking bepirovirsen. Those results come from different trials and time points, so the percentages should not be treated as a direct comparison with HRS-5635.
“A dose-dependent antiviral response was observed with HRS-5635.”
— Xieer Liang, PhD, of Southern Medical University in Guangzhou, presenting the findings
Durability and Safety Still Under Study
The reported post-treatment follow-up lasted 24 weeks, which the presenter described as relatively short. It is not yet known whether the functional-cure outcomes will persist over longer periods, how the results will hold up in a larger and more varied population, or whether some patients may need additional treatment. The supplied report does not provide the total number of participants across all groups or detailed statistical comparisons for the reported outcomes.
Treatment-related adverse events occurred in 46.9% to 60% of participants across the dose groups. The report recorded two treatment-related events graded 3 or higher, no serious adverse events attributed to treatment and no deaths. Upper respiratory infections were most common, and alanine transaminase elevations occurred in up to 6.7%; none reached grade 3. These trial findings do not settle the drug’s longer-term safety profile.
Extension and Phase III Trials
A longer-duration extension study is ongoing, along with a phase III trial, according to the report. Those studies should provide more information about the persistence of HBsAg clearance after treatment, safety over a longer period and the results in a larger group of patients. Until those data are reported, HRS-5635 remains an investigational treatment and the phase II findings should be viewed as preliminary.
Key Questions
What does functional cure mean in this study?
Researchers defined it as sustained HBV DNA suppression together with HBsAg clearance below 0.05 IU/mL, with or without seroconversion, maintained for 24 weeks after treatment. It does not by itself establish complete eradication of the virus.
How many patients reached the study’s functional-cure endpoint?
In the 400-mg HRS-5635 group, 16% met the endpoint at the end of 48 weeks of treatment and 19% did so 24 weeks after treatment ended. The report gives a 33% rate for a subgroup with HBeAg-negative status and baseline HBsAg below 1,000 IU/mL.
Was HRS-5635 tested without other treatment?
No. Participants were on stable nucleos(t)ide analogue therapy and also received tenofovir amibufenamide during the 48 weeks of HRS-5635 treatment. The reported findings therefore reflect the study regimen, not HRS-5635 on its own.
Is HRS-5635 approved for hepatitis B?
The source describes HRS-5635 as an investigational drug being tested in clinical trials. It does not report an approval. A phase III trial and longer extension study are ongoing.
Source: medpagetoday.com
