JNJ-3989 reduces HBsAg, may improve immune control in patients with chronic HBV infection
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Key takeaways:
- Up to 19% of patients who received JNJ-3989 achieved nucleos(t)ide analogue-stopping criteria.
- There were “substantial reductions” in mean hepatitis B surface antigen among the JNJ-3989 groups vs. control.
The small-interfering RNA JNJ-3989 induced a dose-dependent response for meeting nucleos(t)ide analogue-stopping criteria in patients with chronic hepatitis B virus infection, although hepatitis B surface antigen seroclearance was rare.
“JNJ-73763989 (JNJ-3989) is a subcutaneously injected, liver-targeted small interfering RNA composed of two triggers designed to treat chronic hepatitis B,” Man-Fung Yuen, DSc, of the department of medicine at Queen Mary Hospital and State Key Laboratory of Liver Research at the University of Hong Kong, and colleagues wrote in The Lancet Gastroenterology & Hepatology.
They continued, “Results from the phase 2a clinical trial showed that short-term JNJ-3989 treatments at doses from 100 mg to 400 mg, in combination with nucleos(t)ide analogues, led to similar HBsAg reductions, whereas lower doses (25 mg and 50 mg) led to smaller HBsAg declines.”
Researchers conducted the multicenter, double-blind, phase 2b REEF-1 study to characterize the dose-response relationship for JNJ-3989 on antiviral activity and the efficacy of JNJ-3989 with or without bersacapavir and nucleos(t)ide analogues in chronic HBV infection.
They included 470 patients (mean age, 43 years; 66% men; 52% white) who were assigned to one of six groups: oral nucleos(t)ide analogues once daily with placebo (control group; n = 45); oral bersacapavir 250 mg daily with nucleos(t)ide analogues (bersacapavir dual group; n = 48); nucleos(t)ide analogues with subcutaneously injected JNJ-3989 40 mg (JNJ-3989 dual 40 mg group; n = 93), 100 mg (JNJ-3989 dual 100 mg group; n = 93) or 200 mg (JNJ-3989 dual 200 mg group; n = 96) every 4 weeks; or bersacapavir 250 mg plus JNJ-3989 100 mg every 4 weeks with nucleos(t)ide analogues (triple group; n = 95) for 48 weeks.
Median HBsAg values ranged from 3.6 log10 IU/mL to 3.9 log10 IU/mL at baseline, researchers reported. Further, 70% were hepatitis B e antigen-negative at screening and 63% were virologically suppressed.
The primary endpoint was the proportion of patients who met predefined nucleos(t)ide analogue-stopping criteria, which was defined as alanine aminotransferase values less than three times the upper limit of normal, HBV DNA below the lower limit of quantitation, HBeAg-negative and HBsAg less than 10 IU/mL.
At 48 weeks, 5% (90% CI, 2-11) of patients in the JNJ-3989 dual 40 mg group, 16% (90% CI, 10-24) in the JNJ-3989 dual 100 mg group, 19% (90% CI, 13-27) in the JNJ-3989 dual 200 mg group, 9% (90% CI, 4-15) in the triple group and 2% (90% CI, 0-10) in the control group met nucleos(t)ide analogue-stopping criteria. No patients in the bersacapavir dual group met the criteria. Of those who met the primary endpoint, 81% were virologically suppressed and HBeAG-negative at baseline.
Further analysis showed “substantial reductions” in mean HBsAg among all JNJ-3989 groups vs. control and bersacapavir dual groups, with 57% of those in the triple group, 69% in the dual 100 mg group and 75% in the dual 200 mg group achieving HBsAg concentrations of less than 100 IU/mL at 48 weeks.
“The combinations of antiviral therapies used in this study were insufficient to achieve functional cure,” Yuen and colleagues concluded. “However, most patients treated with JNJ-3989 had substantial HBsAg reductions that are believed to establish a liver environment that supports better immune control and might allow a better response to immune-modulating therapies.”
They continued: “Combination studies aiming for functional cure of chronic hepatitis B involving different mechanisms of action, including immune modulators, are ongoing.”
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