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A phase II study found that 19% of patients given the highest dose of the investigational siRNA therapy HRS-5635 met the study’s functional-cure definition 24 weeks after treatment ended. The result is promising but preliminary: follow-up was short, the trial excluded people with cirrhosis, and an extension study and phase III trial are ongoing.
In a phase II trial, 19% of patients given the highest dose of HRS-5635, an investigational small interfering RNA (siRNA) therapy, met the study’s definition of a functional cure for chronic hepatitis B 24 weeks after treatment ended. The results, presented by Xieer Liang of Southern Medical University at the American Association for the Study of Liver Diseases meeting in Denver, are preliminary; participants also received an existing antiviral, and longer-term outcomes are not yet known.
The trial included people with chronic hepatitis B who were taking stable nucleos(t)ide analogue therapy. Participants had hepatitis B surface antigen (HBsAg) levels above 100 and below 3,000 IU/mL and suppressed hepatitis B virus (HBV) DNA. They did not have cirrhosis. All received tenofovir amibufenamide during 48 weeks of HRS-5635 treatment and were assigned to one of four doses: 50, 100, 200 or 400 milligrams.
At week 12, all four dose groups met the study’s primary endpoint of reducing HBsAg from baseline. Average reductions ranged from 1.26 log10 IU/mL at 50 mg to 2.12 log10 IU/mL at 400 mg, indicating a stronger average response at the highest dose. In that 400-mg group, all 32 participants had HBsAg below 100 IU/mL after 48 weeks of treatment; 88% remained below that level 24 weeks after treatment ended.
The study 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. By that measure, 16% of the 400-mg group had reached the endpoint at the end of treatment, rising to 19% at follow-up. The 19% figure applies to the highest-dose group, not all participants or people with chronic hepatitis B generally.
A Potential Route to Surface Antigen Clearance
Chronic hepatitis B can cause liver damage, cirrhosis and liver cancer, and treatment often suppresses the virus without clearing HBsAg. The study’s results matter because persistent HBsAg clearance, alongside sustained suppression of HBV DNA, is used here as a functional-cure measure. Such an outcome may offer some patients a different treatment goal from ongoing viral suppression alone, though the trial does not establish that HRS-5635 can reliably produce a lasting cure.
The results also add to research into nucleic acid-based treatments for HBV. HRS-5635 is an siRNA therapy, while the source report notes that the FDA approved the antisense oligonucleotide bepirovirsen last month for certain patients taking antiviral therapy. Those drugs use different approaches, and results from separate trials should not be treated as a direct comparison. The HRS-5635 findings remain from a phase II study rather than a completed confirmatory trial.
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How the Trial Measured Response
Chronic HBV affects an estimated 240 million people worldwide, including about 640,000 U.S. adults, according to the report. U.S.-approved treatments include antivirals and immune modulators; regimens can last from six months to more than a year. The trial tested HRS-5635 as an addition to an existing antiviral regimen, so its findings do not show that the siRNA therapy worked on its own.
Participants could be hepatitis B e antigen (HBeAg) positive or negative, and most in each dose group were HBeAg negative. In the highest-dose group, 45% of participants who were HBeAg positive became negative after 48 weeks of treatment; that proportion was 27% 24 weeks after treatment ended. Among high-dose participants who were HBeAg negative at baseline and had HBsAg below 1,000 IU/mL, 33% met the study’s functional-cure measure. These subgroup findings may help guide further research, but they do not establish who will benefit most.
“A dose-dependent antiviral response was observed with HRS-5635.”
— Xieer Liang, PhD, of Southern Medical University, presenting the study
Durability and Safety Need More Follow-Up
The key uncertainty is whether HBsAg clearance and viral suppression will persist beyond 24 weeks after treatment. Liang cautioned that this follow-up was relatively short, and the report did not provide longer-term cure rates. The trial also excluded people with cirrhosis and enrolled patients whose HBV DNA was already suppressed on background antiviral therapy, limiting how broadly its results can be applied.
Safety findings were reported across the four dose groups: 46.9% to 60% had a treatment-related adverse event. There were two treatment-related events graded 3 or higher, no serious adverse events attributed to treatment and no deaths. Upper respiratory tract infections were the most common reported adverse event, occurring in 25% to 33.3% of participants. Alanine transaminase elevations occurred in up to 6.7%; Liang said levels were generally stable during treatment and none reached grade 3. The available report does not establish the longer-term risk profile or how the treatment compares with other options in a head-to-head trial.
Extension and Phase III Studies Continue
A longer-duration extension study is ongoing, along with a phase III trial, according to the report. Those studies should provide more evidence about whether responses remain after treatment, how often patients meet the functional-cure measure in a larger group and how safety holds up with additional observation.
Until those results are available, HRS-5635 should be regarded as an investigational therapy rather than an established cure. The reported findings do not show that patients should stop or change existing hepatitis B treatment. Decisions about antiviral therapy should be made with a qualified clinician.
Key Questions
What did the HRS-5635 study find?
In the 400-mg group, 19% met the trial’s functional-cure definition 24 weeks after treatment ended. All participants also received tenofovir amibufenamide during HRS-5635 treatment.
What did researchers mean by functional cure?
The study defined it as sustained HBV DNA suppression and HBsAg clearance below 0.05 IU/mL, with or without seroconversion, maintained for 24 weeks after treatment.
Is HRS-5635 an approved hepatitis B treatment?
The source report describes HRS-5635 as an investigational siRNA therapy studied in a phase II trial. It does not report that HRS-5635 has been approved.
How long did the study follow patients after treatment?
Researchers reported outcomes through 24 weeks after treatment ended. They cautioned that this was a relatively short follow-up period; a longer-duration extension study is ongoing.
What happens next for HRS-5635?
A longer-term extension study and a phase III trial are ongoing. Their results will help clarify durability, safety and the treatment’s performance in a larger study population.
Source: medpagetoday.com
