Gane Edward, Janczewska Ewa, Takehara Tetsuo, Chuang Wan-Long, Peng Cheng-Yuan, Hlebowicz Maria, Asahina Yasuhiro, Chang Ting-Tsung, Kalmeijer Ronald, Jezorwski John, Kim Gloria, Anastasiou Zacharias, Kakuda Thomas N, Verbinnen Thierry, Pehlivanov Nonko, Bakala Adam, Lenz Oliver, Biermer Michael
University of Auckland, Auckland, New Zealand.
ID Clinic, Myslowice, Poland.
JHEP Rep. 2025 Jul 9;7(10):101516. doi: 10.1016/j.jhepr.2025.101516. eCollection 2025 Oct.
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.
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 IU/ml HBsAg reduction from baseline at week 24 (W24). Safety, tolerability, and proportion of patients meeting predefined NA stopping criteria were assessed. After 24 weeks of treatment, NA was stopped when stopping criteria were met; all patients were followed for 48 weeks. Efficacy and safety endpoints were summarized using descriptive statistics.
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 logIU/ml at W12, W24, and FUW48, respectively. At W24, 15/48 (31.3%) patients met NA stopping criteria; 11/15 (73.3%) remained off NA by FUW48. One patient achieved functional cure at FUW48. Adverse events were consistent with known PegIFN-α2a safety profiles.
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.
The study is registered at ClinicalTrials.gov (NCT04667104).
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.
既往研究表明，慢性乙型肝炎（CHB）患者对短干扰RNA JNJ - 73763989（JNJ - 3989）±衣壳组装调节剂贝萨卡韦（JNJ - 56136379）与核苷（酸）类似物（NAs）的联合治疗耐受性良好，JNJ - 3989可使包括HBsAg在内的病毒标志物呈剂量依赖性降低。开放标签、单臂IIa期企鹅研究（NCT04667104）评估了该方案联合聚乙二醇化干扰素α - 2a（PegIFN - α2a）用于病毒学抑制的CHB患者的疗效。
纳入病毒学抑制且正在服用NAs的HBeAg阳性或阴性患者；所有患者接受JNJ - 3989±贝萨卡韦治疗24周（部分患者因方案修订未开始或停用贝萨卡韦），并在治疗的最后12周加用PegIFN - α2a。主要终点为第24周（W24）时HBsAg较基线降低≥2 log IU/ml的患者比例。评估安全性、耐受性以及达到预定义NA停药标准的患者比例。治疗24周后，达到停药标准时停用NA；所有患者随访48周。使用描述性统计总结疗效和安全性终点。
共纳入48例患者（HBeAg阳性11例，HBeAg阴性37例）；47例患者完成48周随访（FUW48）。48例患者中，31例（64.6%）达到主要终点；1例患者在停用NA后的W24和FUW48均实现HBsAg血清清除（<0.05 IU/ml）。W12、W24和FUW48时，HBsAg较基线的平均变化分别为 - 1.43、 - 2.18和 - 0.71 logIU/ml。在W24时，15/48（31.3%）患者达到NA停药标准；至FUW48时，11/15（73.3%）患者仍未服用NA。1例患者在FUW48时实现功能性治愈。不良事件与已知的PegIFN - α2a安全性特征一致。
JNJ - 3989±贝萨卡韦 + NA与PegIFN - α2a联合治疗总体耐受性良好。大多数患者的HBsAg较基线有显著降低，PegIFN - α2a未带来额外益处，且未实现功能性治愈。
该研究已在ClinicalTrials.gov注册（NCT04667104）。
既往关于JNJ - 73763989（JNJ - 3989）±贝萨卡韦（JNJ - 56136379）与核苷（酸）类似物（NAs）用于慢性乙型肝炎（CHB）患者的研究表明，JNJ - 3989可使病毒标志物呈剂量依赖性且显著降低；然而，功能性治愈仅很少实现。本研究评估了在HBsAg水平降低后，在基于JNJ - 3989的方案中加用聚乙二醇化干扰素α - 2a（PegIFN - α2a）是否会导致HBsAg进一步下降，并改善停药后随访期间的结局。研究结果证实，病毒学抑制的HBeAg阳性或阴性CHB患者的HBsAg较基线有显著降低。然而，在24周治疗期的最后12周，在JNJ - 3989±贝萨卡韦和NA的基础上加用PegIFN - α2a似乎并未改善研究人群的抗病毒活性。对其他CHB群体的研究，包括初治HBeAg阳性患者，可能有助于阐明该方案或其他包括JNJ - 3989和NA的治疗方案是否能使更大比例的患者实现功能性治愈。
