Peginterferon-alpha-2a add-on to treatment with siRNA JNJ-73763989 in virologically suppressed chronic hepatitis B: The phase II PENGUIN study.

Background & Aims: Previous studies showed that combination treatment with short interfering RNA JNJ-73763989 (JNJ-3989) ± capsid assembly modulator bersacapavir (JNJ-56136379) and nucleos(t)ide analogs (NAs) was well tolerated by patients with chronic HBV (CHB), with JNJ-3989 dose-dependent reductions in viral markers, including HBsAg. The open-label, single-arm phase IIa PENGUIN study (NCT04667104) evaluated this regimen plus pegylated interferon alpha-2a (PegIFN-α2a) in patients with virologically suppressed CHB. Methods: Patients who were either HBeAg-positive or -negative virologically suppressed and taking NAs were included; all received JNJ-3989 ± bersacapavir for 24 weeks (some either did not start or discontinued bersacapavir as a result of protocol amendment) with PegIFN-α2a added during the final 12 weeks of treatment. The primary endpoint was the proportion of patients with ≥2 log Results: In total, 48 patients (HBeAg positive, n = 11; HBeAg negative, n = 37) were enrolled; 47 reached follow-up week 48 (FUW48). Of the 48 patients, 31 (64.6%) achieved the primary endpoint; one achieved HBsAg seroclearance (<0.05 IU/ml) at both W24 and FUW48 after stopping NA. Mean HBsAg changes from baseline were -1.43, -2.18, and -0.71 log Conclusions: Treatment with JNJ-3989 ± bersacapavir + NA and PegIFN-α2a was generally well tolerated. Most patients had pronounced HBsAg reductions from baseline, no additional benefit from PegIFN-α2a, and did not achieve functional cure. Clinical Trials registration: The study is registered at ClinicalTrials.gov (NCT04667104). Impact and implications: Previous studies with JNJ-73763989 (JNJ-3989) ± bersacapavir (JNJ-56136379) and nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B (CHB) have demonstrated JNJ-3989 dose-dependent and robust reductions in viral markers; however, functional cure was only rarely achieved. The current study assessed whether the addition of pegylated interferon alpha-2a (PegIFN-α2a) to a JNJ-3989-based regimen after HBsAg levels were reduced would lead to further HBsAg declines and improved outcomes during off-treatment follow-up. Study results confirmed pronounced HBsAg reductions from baseline in virologically suppressed patients with HBeAg-positive or -negative CHB. However, the addition of PegIFN-α2a to JNJ-3989 ± bersacapavir and NA for the final 12 weeks of a 24-week treatment period did not appear to improve antiviral activity in the studied population. Studies in other CHB groups, including treatment-naïve, HBeAg-positive patients, could help elucidate whether this or other treatment regimens including JNJ-3989 and NA can lead to functional cure in a larger proportion of patients.