Increased Alanine Aminotransferase Research Articles

Phase I study of TQB3728 tablets, an oral inhibitor of apoptosis proteins in patients with advanced solid tumor.

e13104 Background: Apoptosis proteins are frequently upregulated in human cancers and are associated with resistance to therapeutic agents and poor outcomes. TQB3728 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby inhibiting NF-кB signaling pathways and promoting cancer cell death. This first-in-human study aims to evaluate the maximum-tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of TQB3728 in patients with advanced solid tumors after the failure of standard therapy. Methods: This study combined an accelerated dose titration design with a 3+3 dose escalation design. Three dosage schedules were explored. First of all, TQB3728 was given orally once a week, on a 28-day cycle (DS1). The starting dose of 25mg was escalated by 100% in a single patient until the third dose, then diverted to a 3+3 dose escalation design. The other two dosage schedules were TQB3728 given once daily on days 1-14 every 3 weeks (DS2) and daily every 4 weeks (DS3). The primary endpoint was safety, maximum tolerated or maximum administered dose (MTD), and the secondary endpoints were pharmacokinetics, pharmacodynamics, and tumor response per RECIST v1.1. Results: As of Dec 15, 2023, 23 patients (pts) received at least one dose of TQB3728 (dose range, 25 to 600mg). Based on the pharmacokinetics and safety of DS1, then DS2 (dose range, 100 to 200mg) and DS3 (dose range, 100 to 200mg) were investigated. The median follow-up period was 8.5m (range, 0.5 to 25m). No dose-limited toxicity and cytokine release syndrome were observed. The main treatment-related adverse events (TRAEs) were nausea (56.5%), lymphopenia (56.5%), dizziness (39.1%), hypersomnia (34.8%), increased aspartate aminotransferase (30.4%), increased alanine aminotransferase (26.1%), vomiting (26.1%), anemia (21.7%), decreased appetite (21.7%), and grade≥3 TRAE were lymphopenia (8.7%), anemia (4.4%). As for DS1, the average Tmax and t1/2 were 2 h and 9.6 h, respectively. The exposure did not increase with the dose above 150mg. Moreover, the average Tmax was about 2.3 h and 0.8 h, and t1/2 was 6.6 h and 7 h in DS2 and DS3, respectively. There was no significant accumulation with continuous medication. Additionally, Plasma MCP-1 increased at 3-6h postdose at high dose; cIAP-1 levels in PBMCs were undetected. Two pts (8.7%) had stable disease >6 weeks as the best treatment response. Conclusions: TQB3728 was well tolerated at doses up to 600mg but had limited anti-tumor activity in advanced solid tumor. According to the preliminary results, TQB3728 administered orally in combination with conventional chemo-radiotherapy is under exploration. Clinical trial information: NCT04523285 .

Phase 1 clinical trial of AMG 340, a prostate-specific membrane antigen (PSMA)-targeted T-cell engager with a novel low-affinity CD3 binding domain designed to mitigate toxicity for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

e14587 Background: PSMA, a transmembrane protein highly expressed on the surface of prostate cancer cells, is a validated target in prostate cancer; however, achieving a favorable therapeutic index has been challenging for PSMA-directed T-cell engagers (TCE’s). AMG 340, a PSMA-targeted TCE with a novel low-affinity CD3 binding domain specifically engineered to mitigate cytokine release syndrome (CRS) toxicity and maintain efficacy was investigated in a phase 1, open-label, dose-escalation study (NCT04740034). Methods: Patients (pts) with mCRPC who had received ≥2 prior lines of therapy were treated with AMG 340 monotherapy (1.5–800 mg intravenously every 3 weeks [Q3W]) during dose escalation. The primary outcome measures were dose-limiting toxicities, treatment-emergent adverse events (TEAEs), and pharmacokinetic profile. Secondary outcomes included prostate antigen specific (PSA) response and objective response per response evaluation criteria in solid tumors (RECIST). Results: As of September 6, 2023, a total of 42 pts (mean ± SD age, 68.5±7.8 years) received AMG 340 step up dosing across 11 cohorts. At doses up to 800 mg Q3W, AMG 340 had a manageable side effect profile. Any grade TEAEs reported in ≥30% of pts included CRS (52%), nausea (52%), vomiting (52%), fatigue (48%), diarrhea (38%), increased aspartate aminotransferase (36%), increased alanine aminotransferase (33%), and hypocalcemia (31%). Treatment-related toxicities included CRS (52%; Grade 1, 26%; Grade 2, 24%; Grade ≥3, 2%) and thrombocytopenia (24%; Grade 2, 10%; Grade ≥3, 14%). Step dosing was implemented at doses >40 mg and successfully mitigated CRS incidence and severity after the first dose. The maximal tolerated dose was not reached, as increasing the dose beyond 800 mg was predicted to minimally increase the potential AMG 340 activity. Exposure increased in an approximately dose-proportional manner with no evidence of clinically significant anti-drug antibodies. AMG 340 demonstrated evidence for pharmacodynamic engagement as shown by cytokine induction. Of the 41 PSA evaluable pts, PSA responses were seen across dose levels (PSA50, n=4), but were not dose dependent. Eight of 42 pts remained on treatment after 6 months. Among 27 RECIST evaluable pts, no RECIST responses were observed (n=14 stable disease, n=0 partial or complete response). Conclusions: Despite reaching high doses, no dose response was observed, and AMG 340 did not generate sufficient clinical activity to warrant further exploration. However, AMG 340 demonstrated manageable CRS toxicity showing that decreased CD3-binding strength mitigates CRS, the main toxicity of TCEs. Clinical studies are ongoing evaluating the PSMA protein as a molecular target for prostate cancer. Clinical trial information: NCT04740034 .

Updated survival results of BBCAPX-II: Sintilimab combined with bevacizumab and CapeOx as first-line treatment in patients with RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer.

3563 Background: Microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) patients are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Sintilimab plus bevacizumab and CapeOX (BBCAPX) has proved its efficacy and safety in above unresectable mCRC patients (Ying Yuan et al. ASCO 2023 and Xuefeng Fang et al. ASCO 2022). Here, we report updated survival results of this single arm, open-label, phase 2 trial. Methods: Eligible patients were aged 18 to 75 years with histologically confirmed unresectable metastatic colorectal adenocarcinoma by multidisciplinary team, and had RAS gene mutation and confirmed MSS status. All patients received treatment with sintilimab (200 mg, day 1) plus bevacizumab (7.5mg/kg, day 1) and oxaliplatin (135 mg/m2, day 1) and capecitabine (1g/m2, bid, day 1-14) of each 21-day cycle. The primary endpoint included objective response rate (ORR) and adverse events. Secondary endpoint was disease control rate (DCR) and progression-free survival (PFS). Results: From April 2021 to December 2021, 25 patients were enrolled. The ORR was 84% and the DCR was 100%. Six (24%) patients underwent surgical treatment and unexpectedly achieved no evidence of disease status. At the data cut-off day (January 26, 2024), the median PFS in the full analysis set was 17.9 months (95% CI, 8.84-27), and the median PFS in the per-protocol set was 9.79 months (95% CI, 6.44-24.3). Median PFS was 23.7 months (95% CI, 4.8-NA) in the patients with only liver metastasis and 11.5 months (95% CI, 4.83-24.3) in the patients with other metastasis. The PFS rate at 6 months was 84% (95% CI, 70.8-99.7). The PFS rate at 12 months was 56% (95% CI, 39.6-79.3). The most frequent grade 3 or 4 TRAEs were neutropenia (3/25) and increased alanine transaminase (2/25). No grade 5 adverse events occurred during the study. Conclusions: The combination of sintilimab plus bevacizumab and CapeOx showed promising antitumor activity and manageable toxicity in RAS-mutant, MSS, unresectable mCRC. Patients with liver metastases presented better prognosis compared other metastases. Furthermore, we are currently launching a phase III, randomized, open-label, multicentric clinical trial (NCT05171660) to further analyze the effects, safety, and prognostic biomarkers of this regimen. Clinical trial information: NCT04194359 . [Table: see text]

Tucatinib and trastuzumab for previously treated HER2−mutated metastatic breast cancer (SGNTUC−019): A phase 2 basket study.

1105 Background: Approximately 2-5% of breast cancers harbor HER2 mutations, often occurring in hormone receptor-positive (HR+) disease. There are currently no approved treatment options for patients (pts) with HER2-mutated metastatic breast cancer (HER2-mut MBC). Tucatinib (TUC) is a tyrosine kinase inhibitor highly selective for HER2 and is approved for previously treated HER2+ MBC with or without brain metastases in combination with trastuzumab (Tras) and capecitabine. Here, we report the efficacy and safety results of TUC combined with Tras in pts with previously treated HER2-mut MBC. Methods: SGNTUC-019 (NCT04579380) is an open-label phase 2 basket study evaluating efficacy, safety, and tolerability of TUC and Tras in pts with metastatic HER2-altered solid tumors. Pts in the HER2-mut MBC cohort must have HER2 mutations determined locally by tissue- or blood-based next-generation sequencing, not be HER2+ per local testing, been previously treated with ≥1 systemic therapy in the locally advanced, unresectable, or metastatic setting, and if HR+, have received a CDK4/6 inhibitor. Pts were treated in 21-day cycles with TUC (300 mg orally twice a day) and Tras (8 mg/kg IV followed by 6 mg/kg every 3 wks). Pts with HR+ disease also received fulvestrant (F; 500 mg IM once every 4 wks starting from cycle 1 day 1, and cycle 1 day 15). Disease status was determined based on RECIST v1.1 with assessments performed every 6 wks for 24 wks and every 12 wks thereafter. The primary endpoint is cORR per investigator assessment. Secondary endpoints include OS, DCR, DOR, PFS, and safety. Results: As of Nov 1, 2023, 31 pts were enrolled in the HER2-mut MBC cohort. The median duration of follow-up for OS was 15.0 months. Twenty-seven (87%) pts had HR+ disease and 18 (58%) had lobular histology. The pts received a median of 4 prior lines of systemic therapy in any setting. cORR was 41.9% (90% CI, 26.9-58.2) with 13 responses including 2 complete responses. Median DOR was 12.6 months (90% CI, 4.7, not estimable), DCR was 80.6% (n=25; 90% CI, 65.3-91.2), median PFS was 9.5 months (90% CI, 5.4-13.8), and median OS was 20.1 months (90% CI, 15.9 to not estimable). The most common treatment-emergent adverse events (TEAEs) reported were diarrhea (64.5%) and nausea (35.5%). The most common grade ≥3 TEAEs reported were diarrhea (13%), alanine aminotransferase increase (10%), and hypertension (10%). Two (6.5%) pts discontinued TUC due to TEAEs, but these pts continued Tras. No deaths were due to TEAEs. Additional biomarker analyses will be included in the presentation. Conclusions: The investigational combination of TUC and Tras, plus F in pts with HR+ disease, was well tolerated and had clinical activity in pts with previously treated HER2-mut MBC. The results support further evaluation of the combination of TUC and Tras as a potential treatment option for this pt population. Clinical trial information: NCT04579380 .

Tucidinostat plus toripalimab in patients with unresectable or metastatic melanoma: An open-label, single-arm phase II study.

e21527 Background: Acral and mucosal melanoma respond poorly to anti–PD-1 monotherapy. Tucidinostat, a benzamide class of histone deacetylase (HDAC) inhibitor, potentially augments immunotherapy with PD-1 blockade. We therefore conducted a phase II study to investigate the safety and efficacy of tucidinostat plus toripalimab in unresectable or metastatic melanoma. Methods: This was a single center, single arm phase II clinical trial. Patients with pathologically confirmed locally advanced unresectable or metastatic melanoma were enrolled and received 30 mg tucidinostat orally twice a week and 240 mg toripalimab every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was the confirmed ORR per RECIST v1.1. Secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. Results: Between October 2022 and May 2023, a total of 21 patients(pts) were enrolled. All pts were included in the safety analysis set and 18 pts were included in the full analysis set (FAS) for efficacy analysis. In the FAS, the median age was 56.0 years (range: 49 to 60), 6 pts (33.3%) were acral melanoma, 9 (50.0%) mucosal melanoma, 1 (5.6%) cutaneous melanoma and 2 (11.1%) unknown primary melanoma. 15 pts were treated as first-line, and 3 pts were as second-line. By Dec 2023, the median follow-up was 8.8 mo (95% CI:7.6-10.4) , Confirmed ORR was 27.8% (95% CI:9.7-53.5%). The DCR was 61.1% (95% CI:35.7-82.7%). Median progression-free survival was 4.1 months (95%CI: 1.4-NR) ,OS was not reached. Subgroup analysis showed that, in acral and mucosal melanoma pts, the confirmed ORR was 50.0%(95%CI:11.8-88.2%) and 22.2%(95%CI: 2.8-60.0%), respectively. The incidence of treatment-related adverse events (TRAEs) was 90.5% (19/21). The most common ≥3 grade TRAEs were neutrophil reduction (28.6%), white blood cell count reduction (9.5%), alanine aminotransferase increase (9.5%), platelet count reduction (9.5%), aspartate aminotransferase increase (9.5%), and γ-glutamyl transferase increase (9.5%). No treatment-related deaths occurred. Conclusions: The combination of tucidinostat and toripalimab showed acceptable safety and encouraging efficacy in patients with unresectable or metastatic melanoma. Further research is warranted. Clinical trial information: NCT05478473 .

Hepatitis E virus infections in German blood donors: results of 8 years of screening, 2015 to 2022.

BackgroundAwareness of transfusion-transmitted hepatitis E raised in recent years led to the mandatory testing of blood donations in some European countries for hepatitis E virus (HEV) RNA. However, little is known about the epidemiology of HEV infections.AimTo and describe and analyse the epidemiology of HEV infections in blood donors in Germany.MethodsData from routine testing of therapeutic blood products donated between January 2015 and December 2022 at the Uni.Blutspendedienst OWL were analysed at the Institute of Laboratory and Transfusion Medicine, Heart and Diabetes Centre North Rhine-Westphalia. A total of 731,630 allogenic blood donations from 119,610 individual blood donors were tested for HEV RNA in minipools of 96 samples. The HEV RNA-positive donations were analysed for the presence of anti-HEV IgM and IgG. The HEV strains were genotyped and various clinical liver-specific parameters were determined.ResultsA total of 497 HEV-positive blood donations were identified, resulting in a yearly incidence of 1:1,474, from which 78.4% of the donations were RNA-only positive. Increased alanine aminotransferase activity was determined in 26.6% of HEV RNA-positive donors and was associated with the detection of IgG antibodies (1.2% anti-HEV IgM-positive, 11.9% anti-HEV IgM- and IgG-positive and 8.5% anti-HEV IgG-positive). An average incidence of 0.084-0.083% HEV RNA-positive donations in June and July in all years was observed, and a higher proportion of HEV RNA-positive men compared with women. All isolated HEV sequences corresponded to genotype 3.ConclusionOur results underline the necessity of HEV RNA screening in blood donations.

Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Initial safety and efficacy of phase 1b/2 study (RAMP 205).

4140 Background: More than 90% of pancreatic ductal adenocarcinomas (PDAC) harbor an activating KRASmutation .Avutometinib (avuto) is an oral RAF/MEK clamp. Defactinib (defact) is an oral selective FAK inhibitor. Avuto/defact combined with gemcitabine/paclitaxel have shown synergistic antitumor activity in preclinical PDAC models. RAMP 205 (NCT05669482) is a Phase 1b/2 study assessing the safety and efficacy of avuto/defact + gemcitabine/nab-paclitaxel (GnP) in first-line metastatic PDAC. Methods: Eligible patients (pts) were enrolled and treated in 3+3 cohorts with escalating doses of avuto orally (PO) twice weekly (BIW) and defact PO twice daily (BID), both 3 out of 4 weeks, in combination with GnP dosed intravenously (IV) on a D1, D8, D15 or D1, D15 (modified) 4wk schedule (Table 1). Key eligibility criteria include histologically confirmed newly diagnosed metastatic PDAC with measurable disease, ECOG performance status (PS) ≤1, adequate organ function, and no prior treatment. Results: At the 24Jan2024 data cutoff, 18 pts were enrolled, 44% were male, 65 y median age, and 61% ECOG PS 1. Pts were enrolled to DL-1 (n=3), DL1 (n=6), DL1a (n=6), and DL2a (n=3). No dose-limiting toxicities (DLTs) were reported and the majority of treatment related adverse events (TRAEs) were mild to moderate. The most frequently reported TRAEs of any grade in the safety population (N=18) were nausea (50%), alopecia (44%), fatigue (39%), maculo-papular rash (33%), and peripheral edema (28%). The most common grade ≥3 TRAEs included alanine aminotransferase increase (17%), neutropenia (17%), peripheral edema (11%), anemia (11%), and sepsis (11%). Four patients experienced serious AEs (SAEs). Grade ≥3 treatment emergent SAEs included pulmonary embolism (n=2; unrelated), sepsis (n=2), febrile neutropenia (n=1; did not meet DLT criteria), and neutropenia (n=1). One patient discontinued treatment due to TRAE (febrile neutropenia and blood bilirubin increased). All efficacy evaluable pts (n=8) experienced a reduction in target lesions (100% disease control rate) and partial responses were observed in 6/8 (75%), 3 being confirmed at data cutoff. All efficacy evaluable pts with an elevated CA19-9 at baseline (n=7) had a ≥60% CA19-9 reduction from baseline. Conclusions: Avuto/defact and GnP are combinable and show notable preliminary efficacy in first-line metastatic PDAC based on RECIST v.1.1 criteria and CA19-9 levels. No DLTs were reported across the 4 dosing cohorts/schedules and safety signals were consistent with previous clinical data. Updated safety and efficacy will be reported. Clinical trial information: NCT05669482 . [Table: see text]

Effects of acute carbon monoxide poisoning on liver damage and comparisons of related oxygen therapies in a rat model

Acute carbon monoxide (CO) poisoning may cause liver damage and liver dysfunction. Therefore, in this study, we aimed to compare the efficiency of normobaric oxygen (NBO) and high-flow nasal cannula oxygen (HFNCO) treatments on liver injury. For that purpose, 28 male Wistar albino rats were divided into four groups (Control, CO, CO + NBO, and CO + HFNCO). The control group was allowed to breath room air for 30 min. Acute CO poisoning in CO, CO + NBO, CO + HFNCO was induced by CO exposure for 30 min. Thereafter, NBO group received 100% NBO with reservoir mask for 30 min. HFNCO group received high-flow oxygen through nasal cannula for 30 min. At the end of the experiment, all animals were sacrificed by cardiac puncture under anesthesia. Serum liver function tests were measured. Liver tissue total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) levels, tissue histomorphology and immunoexpression levels of Bax, Caspase 3, TNF-α, IL-1β, and NF-κB were also examined. Our observations indicated that acute CO poisoning caused significant increases in blood COHb, serum aminotransferase (AST), alanine aminotransferase (ALT0, alkaline phosphatase (ALP), total protein, albumin, and globulin levels but a decrease in albumin to globulin ratio (all, p < 0.05). Furthermore, acute CO poisoning significantly increased the OSI value, and the immunoexpresssion of Bax, Caspase 3, TNF-α, IL-1β, and NF-κB in liver tissue (all, p < 0.05). These pathological changes in serum and liver tissue were alleviated through both of the treatment methods. In conclusion, both the NBO and HFNCO treatments were beneficial to alleviate the acute CO poisoning associated with liver injury and dysfunction.

A real-world pharmacovigilance study of FDA adverse event reporting system events for Capmatinib

Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world evidence is very limited, this study evaluated capmatinib-induced adverse events through data mining of the FDA Adverse Event Reporting System database. Four disproportionality analysis methods were employed to quantify the signals of capmatinib-related adverse events. The difference in capmatinib-associated adverse event signals was further investigated with respect to sex, age, weight, dose, onset time, continent, and concomitant drug. A total of 1518 reports and 4278 adverse events induced by capmatinib were identified. New significant adverse event signals emerged, such as dysphagia, dehydration, deafness, vocal cord paralysis, muscle disorder, and oesophageal stenosis. Notably, higher risk of alanine aminotransferase and aspartate aminotransferase increases were observed in females, especially when capmatinib was combined with immune checkpoint inhibitors. Compared with Europeans and Asians, Americans were more likely to experience peripheral swelling, especially in people > 65 years of age. Renal impairment and increased blood creatinine were more likely to occur with single doses above 400 mg and in Asians. This study improves the understanding of safety profile of capmatinib.

Organokines and liver enzymes in adolescent girls with polycystic ovary syndrome during randomized treatments.

Polycystic ovary syndrome (PCOS) is often associated with metabolic-associated fatty liver disease (MAFLD). MAFLD has been associated with altered hepatic function, systemic dysmetabolism, and abnormal circulating levels of signaling molecules called organokines. Here, we assessed the effects of two randomized treatments on a set of organokines in adolescent girls with PCOS and without obesity, and report the associations with circulating biomarkers of liver damage, which were assessed longitudinally in the aforementioned studies as safety markers. Liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT)] were assessed as safety markers in previous randomized pilot studies comparing the effects of an oral contraceptive (OC) with those of a low-dose combination of spironolactone-pioglitazone-metformin (spiomet) for 1 year. As a post hoc endpoint, the organokines fibroblast growth factor-21 (FGF21), diazepam-binding protein-1 (DBI), and meteorin-like protein (METRNL) were assessed by ELISA after 6 months of OC (N = 26) or spiomet (N = 28). Auxological, endocrine-metabolic, body composition (using DXA), and abdominal fat partitioning (using MRI) were also evaluated. Healthy, age-matched adolescent girls (N = 17) served as controls. Circulating ALT and GGT levels increased during OC treatment and returned to baseline concentrations in the post-treatment phase; in contrast, spiomet treatment elicited no detectable changes in ALT and GGT concentrations. In relation to organokines after 6 months of treatment, (1) FGF21 levels were significantly higher in PCOS adolescents than in control girls; (2) DBI levels were lower in OC-treated girls than in controls and spiomet-treated girls; and (3) no differences were observed in METRNL concentrations between PCOS girls and controls. Serum ALT and GGT levels were directly correlated with circulating METRNL levels only in OC-treated girls (R = 0.449, P = 0.036 and R = 0.552, P = 0.004, respectively). The on-treatment increase in ALT and GGT levels occurring only in OC-treated girls is associated with circulating METRNL levels, suggesting enhanced METRNL synthesis as a reaction to the hepatic changes elicited by OC treatment. https://doi.org, identifiers 10.1186/ISRCTN29234515, 10.1186/ISRCTN11062950.

Long-term thermal stress induces hepatic injury and alters the thermotolerance response in Hong Kong catfish (Clarias fuscus)

Global climate change has a significant impact on fish survival and the aquaculture industry. Even highly adaptable organisms like Siluriformes fish are susceptible to these effects. This study investigates the consequences of extreme high temperature on Hong Kong catfish (Clarias fuscus), a species known for its long-term habitation in tropical and subtropical regions. In this study, C. fuscus were cultivated for 90 days at high temperature (HT, 34 °C) and normal temperature (NT, 26 °C), followed by subjecting the two groups to high temperature stress (34 °C) and temperature recovery (26 °C). The hepatic histology, biochemical, and transcriptomic characteristics of the species were examined before acute high temperature stress (NT-C, HT-C), after acute high temperature stress (NT-T, HT-T), and after temperature recovery (NT-R, HT-R). The histological analysis revealed that long-term heat stress damaged the liver tissue of C. fuscus. Furthermore, significant damage was observed in the liver tissues of the NT group under acute high temperature stress, while no further damage was observed in the HT group. The biochemical analysis showed that 90 days of heat stress altered the body's immune and oxidative balance, resulting in an increase in alkaline phosphatase (ALP), alanine aminotransferase (ALT), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities, and a decrease in malondialdehyde (MDA) content. Upon acute heat stress, the liver function of the NT group was disordered and unable to produce enough total-bilirubin (T-BIL), while the aspartate aminotransferase (AST) activity of the HT group was more susceptible to being affected. Long-term heat stress led to significant changes in gene expression, with the NT group showing three times more differentially expressed genes (DEGs) identified in the liver compared to the HT group under acute heat stress conditions. Analysis of DEG enrichment during the same treatment period in both groups revealed significant differences in amino acid metabolism and lipid metabolism pathways. These results suggest that long-term heat stress caused liver tissue damage in C. fuscus, altering immune and oxidative balance, enzyme activity sensitivity, as well as the body's response to acute heat stress pathways and intensity. This study lays the groundwork for future investigations into fish adaptability to sudden temperature changes and aquaculture strategies to mitigate heat stress in fish facing extreme temperatures.

Abstract PO2-03-05: Neoadjuvant anthracycline followed by Toripalimab combined with nab-paclitaxel in patients with stage IIA-IIIC triple negative breast cancer (NeoTENNIS): efficacy and safety results of a phase II study

Abstract Background: Immune checkpoint inhibitors(ICIs)have shown promising antitumor activity in triple negative breast cancer (TNBC) patients. Toripalimab, a novel PD-1 antibody, has been approved for the treatment in multiple solid tumors. However, the neoadjuvant use of toripalimab with chemotherapy has not been evaluated in TNBC patients. In addition, whether chemotherapy could sensitize the ICI treatment has not drawn conclusion yet. In this phase II trial, a sequential use of chemotherapy and anti-PD1 therapy was given in a neoadjuvant setting. The efficacy and safety of toripalimab were evaluated. Patients and methods: Female patients with histologically confirmed stage IIA to IIIC TNBC were included. Eligible patients received neoadjuvant therapy with four cycles of epirubicin-cyclophosphamide every 2 weeks followed by toripalimab (240 mg) every 3 weeks plus nab-paclitaxel weekly for 12 weeks. The primary endpoint was pathologic complete response (tpCR; ypT0/is ypN0) rate. Key secondary endpoints were breast pCR (bpCR; ypT0/is) rate, biomarker analysis, and safety. Results: Among 70 enrolled patients (median age, 51 years; 62.9% stage III), 66 patients completed study treatment without progression and received surgery after study treatment. Overall, the percentages of patients with a tpCR and bpCR were 55.7% (39 of 70 patients) and 58.6 % (41 of 70 patients), respectively. For women with CD8–positive and negative tumors, the tpCR rates were 66.0% and 30.0% (P = 0.006), respectively. Significant upregulation of CD8 positive cells after 4 cycles of epirubicin-cyclophosphamide induction chemotherapy (P = 0.011) were shown in sequential biopsy samples. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 30 patients (42.9%), the most common of which were neutropenia (15.7%), leukopenia (14.3%) and alanine aminotransferase increase (4.3%). Most common immune-related AEs were hepatobiliary disorders (Grade 3, 7.2%), creatinine increase (all Grade 1-2, 2.8%) and hypothyroidism (all Grade 1-2, 2.8%). Conclusions: The addition of toripalimab to neoadjuvant chemotherapy is efficacious and safe in patients with locally advanced TNBC. Anthracycline-based chemotherapy could sensitize the ICI treatment with upregulated tumor immune response. The event-free survival results are expected with further follow up. Mechanisms of chemotherapy sensitization are still under investigation (ClinicalTrials.gov number: NCT04418154). Citation Format: Min He, Linxiaoxi Ma, Shuang Hao, Benlong Yang, Bingqiu Xiu, Ya-Yun Chi, Ruo-Hong Shui, Zhong-Hua Wang, Zhi-Ming Shao, Jiong Wu. Neoadjuvant anthracycline followed by Toripalimab combined with nab-paclitaxel in patients with stage IIA-IIIC triple negative breast cancer (NeoTENNIS): efficacy and safety results of a phase II study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-03-05.

Incidence of Elevated Liver Enzyme Levels in Patients Receiving Remdesivir and Its Effective Factors.

Emergency use of remdesivir was approved for COVID-19 in some countries. Based on the promising results of remdesivir, the most common side effects were nausea, worsening respiratory failure, increased alanine aminotransferase levels, and constipation. The aim of this study was to determine the incidence of elevated liver enzymes in patients with COVID-19 receiving remdesivir. In this retrospective study, information was collected from patients' files. The study population included patients with moderate to severe COVID-19 who were admitted to Rouhani Babol Hospital. For daily patient selection, the list of patients was extracted from the system, and based on the census, the patient file was selected. Data were analyzed using Stata 16. 620 patients suffering from moderate to severe COVID-19 were included in this study, 43% of whom were men. Of these patients, 120 were selected as the control group who did not receive remdesivir. The increase in liver enzymes in patients receiving remdesivir compared with the control, for alanine transaminase (ALT) and aspartate transaminase (AST), respectively, was 6.20 and 3.64 times, but it was not statistically significant for alkaline phosphatase (ALP). Also, the increase in bilirubin levels in patients receiving remdesivir was not statistically significant. The recipients of remdesivir had high liver enzymes, which is one of the possible side effects of this drug. The intensity of the enzymes was mild and moderate, and they were not dangerous to the health of any of the consumers. Deaths in patients with COVID-19 were not due to drug-induced liver complications but to other factors such as disease-related complications.

Role of L-, N- and T-type Calcium Channels in Achieving Maximum Analgesic and Minimum Toxic Effect of Tramadol

The aim of the study was to investigate the effects of lacidipine, amlodipine and benidipine on the analgesic activity and toxicity of tramadol. Rats (n=6/each group) were divided into five groups as control(CG), tramadol(TRD), lacidipine+tramadol(LTRD), amlodipine+tramadol(ATRD) and benidipine+tramadol(BTRD). Tramadol was administered once at a dose of 50 mg/kg and lacidipine, amlodipin, benidipin were administered at a dose of 4 mg/kg orally, once a day for 10 days. After the animals were sacrificed malondialdehyde(MDA) and total glutathione(tGSH) levels were measured in brain, heart, liver and kidney tissues. Troponin I(Tp I), alanine aminotransferase(ALT), aspartate aminotransferase(AST), blood urea nitrogen(BUN), and creatinine levels were determined in serum. Paw pain thresholds were measured 1 hour before and after drug administration. Analgesic effect of tramadol was increased the most by benidipine, while amlodipine and lacidipine increased it equally. Lacidipine failed to suppress MDA increase and tGSH decrease in brain tissue. Benidipine suppressed MDA increase and tGSH decrease in brain tissue better than amlodipine. All three drugs suppressed cardiac tissue oxidative stress and the release of TP I into the circulation. Lacidipine and amlodipine could not prevent tramadol-induced oxidative stress in liver and kidney tissues, whereas benidipine prevented excessive MDA increase and tGSH decrease. Benidipine significantly suppressed the increase of ALT, AST, BUN, and creatinine. Analgesic activity was 35.1% in TRD, 43.7% in LTRD 50.4% in ATRD and 67,5% in BTRD. Study results show that benidipine and tramadol co-treatment is better than co-treatment with lacidipine or amlodipine in achieving minimal toxic effects and maximum analgesia.

Differential Protective Effect of Zinc and Magnesium for the Hepatic and Renal Toxicity Induced by Acetaminophen and Potentiated with Ciprofloxacin in Rats.

Background and Objectives: The purpose of this study was to investigate the influence induced by magnesium chloride (MgCl2) and zinc gluconate (ZnG) supplementation on liver and kidney injuries experimentally induced with acetaminophen (AAPh) and potentiated by a ciprofloxacin addition in rats. Material and Methods: The experiment was performed on five animal groups: group 1-control, treated for 6 weeks with normal saline, 1 mL/kg; group 2-AAPh, treated for 6 weeks with AAPh, 100 mg/kg/day; group 3-AAPh + C, treated for 6 weeks with AAPh 100 mg/kg/day and ciprofloxacin 50 mg/kg/day, only in the last 14 days of the experiment; group 4-AAPh + C + Mg, with the same treatment as group 3, but in the last 14 days, MgCl2 10 mg/ kg/day was added; and group 5-AAPh + C + Zn, with the same treatment as group 3, but in the last 14 days, zinc gluconate (ZnG), 10 mg/kg/day was added. All administrations were performed by oral gavage. At the end of the experiment, the animals were sacrificed and blood samples were collected for biochemistry examinations. Results: Treatment with AAPh for 6 weeks determined an alteration of the liver function (increases in alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, and gamma-glutamyl transferase) and of renal function (increases in serum urea and creatinine) (p < 0.001 group 2 vs. group 1 for all mentioned parameters). Furthermore, the antioxidant defense capacity was impaired in group 2 vs. group 1 (superoxide dismutase and glutathione peroxidase activity decreased in group 2 vs. group 1, at 0.001 < p < 0.01 and 0.01 < p < 0.05, respectively). The addition of ciprofloxacin, 50 mg/kg/day during the last 14 days, resulted in further increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, and creatinine (0.01 < p < 0.05, group 3 vs. group 2). MgCl2 provided a slight protection against the increase in liver enzymes, and a more pronounced protection against the increase in serum urea and creatinine (0.001 < p < 0.01 group 4 vs. group 3). MgCl2 provided a slight protection against the decrease in superoxide dismutase (0.01 < p < 0.05 group 4 vs. group 3), but not against decrease of glutathione peroxidase. The improvement of mentioned parameters could also be seen in the case of ZnG, to a higher extent, especially in the case of alanine aminotransferase and lactic dehydrogenase (0.01 < p < 0.05 group 5 vs. group 4). Conclusions: This study presents further proof for the beneficial effect of magnesium and zinc salts against toxicity induced by different agents, including antibacterials added to the analgesic and antipyretic acetaminophen; the protection is proven on the liver and kidney's function, and the antioxidant profile improvement has a key role, especially in the case of zinc gluconate.

Abstract CT147: Phase I clinical study of Bruton’s tyrosine kinase inhibitor (BTKi) HBW-3220 capsules in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL)

Abstract Purpose: This clinical study is to evaluate HBW-3220, a novel reversible BTK inhibitor (BTKi) with an improved in vitro profile than the existing non-covalent drugs pirtobrutinib (LOXO-305, approved) and MK-1026 (Phase III). HBW-3220 shows superior inhibition against BTK wild-type and several common mutants, such as C481S, C481R, T474I, T316A, and L528W (the one predominantly enriched in patients resistant to the newer-generation BTKis), and hematopoietic cell kinase (HCK), a key contributor to the development of ibrutinib resistance associated with kinase-defective BTK. Methods: This phase I clinical study was conducted in R/R B-NHL patients who had received two or more prior lines of treatments. The dose escalation study adopts accelerated titration and a "3+3" design, with a daily single dose of 15, 30, 60, 90, 120, or 150 mg. During the dose escalation phase, the sponsor and investigators determined whether to expand the cohort of the previous dose based on the existing data. Adverse events (AEs) were assigned according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response assessment was based on the iwCLL 2018 guidelines, the IWWM-7 consensus, or the Lugano 2014 guidelines, according to the respective disease type. Results: 28 patients have been enrolled so far, and the dose escalation study has been completed. No dose-limiting toxicity (DLT) occurred in any patient, implicating good tolerability. Adverse events (AEs), similar to other BTKis, were mostly Grade 1 or 2, including fever (38%), diarrhea (35%), headache (19%), anemia (42%), infectious pneumonia (23%), decreased neutrophils (42%), decreased platelet count (27%), increased alanine aminotransferase (23%), etc. Drug-related Grade 3 AEs included neutrophil count decreased (n=3, 11%), increased lymphocyte count (n=2, 7%), and infectious pneumonia (n=2, 7%). 21 patients underwent at least 1 response assessment (4 chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); 4 marginal zone lymphoma (MZL); 5 mantle cell lymphoma (MCL); 3 diffuse large B-cell lymphoma (DLBCL); 5 other B-NHL), and the results are 1 complete response (CR), 6 partial response (PR), and 1 partial response with lymphocytosis (PR-L). The overall response rate (ORR) in CLL/SLL (all with prior irreversible BTKi treatment, and 2 of them with additional BCL2 inhibitor treatment), MZL, MCL, and DLBCL patients were 75% (3/4, including 1 PR-L), 50% (2/4), 40% (2/5) and 33% (1/3), respectively. Among the ORR (including CR, PR, and PR-L), 88% (7/8) were in the 90 mg and above dose group, regardless of previous BTKi treatment history or mutation status of p53 and BTK C481S. In the 90 mg and above dose group, the ORR is 47%. After oral administration, the drug exposures showed dose-dependent increases. The time to maximum plasma concentration (Tmax) was 2 hours, and the elimination half-life (T1/2) was 19 hours. Conclusions: The current data show that HBW-3220 is well tolerated, showing no DLT occurred at daily doses up to 150 mg, and has good efficacy in patients with CLL/SLL, MZL, and MCL. Citation Format: Ning Lee, Yingfu Li, Yong Mao, Guanfeng Liu, Jiang Li, Qingchun Liu. Phase I clinical study of Bruton’s tyrosine kinase inhibitor (BTKi) HBW-3220 capsules in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT147.

Abstract CT144: Safety and efficacy of HMPL-523 (Syk inhibitor) in patients with relapsed or refractory lymphoma

Abstract Background: HMPL-523, a selective oral Syk inhibitor, demonstrated encouraging benefit-risk profile in 2 Phase 1 (P1) studies in relapsed/refractory (R/R) lymphoma patients (pts) in USA/Europe (NCT03779113) and China (NCT02857998). In the 16 response-evaluable pts in the dose-escalation portion (Part 1) of study NCT03779113, 4 responses were noted, including complete responses (CRs) in R/R hodgkin lymphoma (HL) and follicular lymphoma (FL) pts (Strati et al. Blood 2021). Here, we report the results from the dose expansion portion (Part 2) of the study NCT03779113. Methods: Safety and efficacy of HMPL-523, at the recommended phase 2 dose (RP2D) of 700 mg QD, was evaluated in lymphoma pts who have exhausted all approved therapy options. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v5.0. Responses were assessed by investigators at weeks 8, 16, and 24, and then every 12 weeks. Results: As of 14 July 2023, 47 pts were enrolled in the Part 2 [25 HL, 9 Peripheral T cell lymphoma (PTCL), 7 Chronic lymphocytic leukemia (CLL), 2 each of FL and Mantle cell lymphoma (MCL), and 1 each with Marginal zone lymphoma (MZL) and Waldenström's macroglobulinemia (WM)]. Median age was 57 (Range:21-93) years, 55% were males, 85% were Caucasian, 47% had ECOG status of 1, 81% were disease stage ≥3 and 17% had B-symptoms at study entry. Median prior lines of therapy was 4 (range 1 - 12); 86% of CLL pts were prior BTK treated and 88% of HL pts had both a PD-1 inhibitor and Brentuximab vedotin. With a median drug exposure of 2.9 months, the overall response rate (ORR) among 41 efficacy evaluable pts was 26.8% and disease control rate (DCR) was 65.9% [4 CR (9.8%), 7 PR (17.1%) and 16 SD (39.0%)]. The median time-to-response was 1.9 months. Among HL pts (N=24), ORR was 25.0% and DCR was 66.7% [2 CR (8.3%), 4 PR (16.7%) and 10 SD (41.7%)]. Among PTCL pts (N=7), ORR and DCR were 42.9% [2 CR (28.6%) and 1 PR (14.3%)]. The median duration of response (DOR) was not reached for HL pts and was 5.7 months (2.0 - NR) in PTCL. Two pts (one each with HL and PTCL) with disease control were taken off treatment to be consolidated with allogenic stem cell transplant. At cut-off, 1 pt each with CLL (N=5 ) and WM (N=1) demonstrated a PR. Serious TEAEs occurred in 18 pts (38.3%), of which 4 (8.5%) were considered treatment-related (TRAE). Grade≥3 TRAEs were noted in 15 pts (31.9%); the most common Grade≥3 TRAEs (&amp;gt;5%) were alanine aminotransferase increase 4 (8.5%) and febrile neutropenia 3 (6.4%). Dose interruption due to TEAEs occurred in 23 pts (48.9%) and dose reduction in 4 pts (8.5%). Two pts (4.3%), 1 each with TEAE of thrombocytopenia and pruritis had drug discontinued. Conclusion: HMPL-523 was well tolerated at the RP2D of 700 mg QD in R/R lymphoma pts. Encouraging proof of activity was demonstrated in heavily pre-treated HL and PTCL pts. Additional studies are needed to evaluate the value of SYK-inhibitor as either monotherapy or combination in these high unmet-need population. Citation Format: Paolo Strati, Eva Gonzalez-Barca, Daniel Morillo, Sairah Ahmed, Dominik Chraniuk, Sirpa Leppa, Fatima de la Cruz Vicente, Piotr Centkowski, Rathi N. Pillai, Shivani Nanda, Alisha Khullar, Marjo Hahka-Kemppinen, Vijayvel Jayaprakash, Giuseppe Gritti. Safety and efficacy of HMPL-523 (Syk inhibitor) in patients with relapsed or refractory lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT144.

Abstract CT192: A first-in-human phase 1 study of TQB2916, a novel CD40 agonist antibody for advanced malignancies

Abstract Background: CD40 receptor is a member of the tumor necrosis factor receptor family that plays a prominent role in immune responses. TQB2916, a humanized IgG2 CD40 monoclonal antibody, has demonstrated CD40 agonistic activity and promising anti-tumor activity in preclinical studies. A first-in-human study of TQB2916 single agent in advanced solid tumors and lymphomas is ongoing (NCT05213767). Methods: Patients with an ECOG performance status of 0 or 1, adequate hematologic and organ function and refractory to standard therapies met inclusion criteria. TQB2916 was given intravenously every 3 weeks until progression or unacceptable toxicity. Bayesian optimal interval (BOIN) design was used to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). The objective is to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of TQB2916. Results: From April 2022 to November 2023, 18 patients with solid tumors and 2 with lymphoma have been treated with TQB2916 monotherapy, and were assigned to 7 cohorts (0.5 mg n=1, 2.5 mg n=1, 12.5 mg n=3, 60 mg n=3, 200 mg n=7, 300 mg n=2, and 400 mg n=3). Three dose limiting toxicities (DLTs) were observed: one with grade 3 pneumonia and one with grade 4 lipase/amylase increase in the 400 mg cohort; one with grade 3 pancreatitis in the 300 mg cohort. All patients experienced at least one treatment-related adverse event (TRAE). The most common TRAEs were lipase increase (n=15, 75%), amylase increase (n=14, 70%), lymphocyte count decrease (n=13, 65%), alanine aminotransferase (ALT) increase (n=12, 60%), alkaline phosphatase (ALP) increase (n=12, 60%), aspartate aminotransferase (AST) increase (n=11, 55%), hypoalbuminemia (n=11, 55%), and anorexia (n=11, 55%). Serious TRAEs occurred in 5 (25%) patients. Most of TRAEs were of grade 1 or grade 2 and manageable. Sixteen patients were evaluated for efficacy, and 3 of them achieved stable disease as per immune response evaluation criteria in solid tumors (iRECIST) and lymphoma response to immunomodulatory therapy criteria (LYRIC). The pharmacokinetics were well-behaved with increasing exposure dose-proportionally and no accumulation occurred after repeated dosing. The Cmax, AUC(0-t) and T1/2 of 400 mg single dosing were 109±21.8 μg/ml, 611±228 d*µg/mL and 5.54±3.37 d. Dose-dependent occupancy of CD40 was detected of 0.5 mg and above doses. Reduction in peripheral B cells and increasing in cytokines secretion were also observed. Conclusions: Pharmacodynamics analysis suggested that TQB2916 treatment achieved CD40 occupancy and immune activation with the changes in cytokines. Considering the safety profile and efficacy, 200 mg was determined as the preliminary expansion dose as it was well tolerated. Studies of TQB2916 in combination with immune checkpoint inhibitors and/or other anti-cancer therapies are ongoing. Citation Format: Yi Ba, Huilai Zhang, Ting Deng, Tao Ning, Qian Fan. A first-in-human phase 1 study of TQB2916, a novel CD40 agonist antibody for advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT192.

Relevance of PNPLA3, TM6SF2, HSD17B13, and GCKR Variants to MASLD Severity in an Egyptian Population.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a frequent clinical condition globally. Single nucleotide polymorphisms (SNPs) associated with NAFLD have been proposed in the literature and based on bioinformatic screening. The association between NAFLD and genetic variants in Egyptians is still unclear. Hence, we sought to investigate the association of some genetic variants with NAFLD in Egyptians. Egyptians have been categorized into either the MASLD group (n = 205) or the healthy control group (n = 187). The severity of hepatic steatosis and liver fibrosis was assessed by a Fibroscan device. TaqMan-based genotyping assays were employed to explore the association of selected SNPs with MASLD. PNPLA3 rs738409 C>G variant is associated with the presence of MASLD with liver fibrosis, the severity of both hepatic steatosis and liver fibrosis, increased systolic and diastolic blood pressure and increased alanine aminotransferase (all p < 0.05), while the TM6SF2 rs58542926 C>T, HSD17B13 rs9992651 G>A, and GCKR rs1260326 T>C variants were not (all p > 0.05). The TM6SF2 rs58542926 T allele is associated with increased fasting blood glucose and a decreased waist circumference. The GCKR rs1260326 C allele is associated with decreased aspartate transaminase and diastolic blood pressure (all p < 0.05). Only after adjusting for the risk factors (age, sex, BMI, WC, HDL, TG, diabetes mellitus, and hypertension) F2 liver fibrosis score is negatively correlated with the HSD17B13 rs9992651 GA genotype. This study offers evidence for the association of the PNPLA3 rs738409 C>G variant with MASLD among Egyptians and for the association of the PNPLA3 rs738409 G allele, the TM6SF2 rs58542926 T allele, and the GCKR rs1260326 C allele with some parameters of cardiometabolic criteria.

JNJ-73763989 and bersacapavir treatment in nucleos(t)ide analogue-suppressed patients with chronic hepatitis B: REEF-2

Functional cure for chronic hepatitis B (CHB) requires finite treatment. Two agents under investigation with the goal of achieving functional cure are the small-interfering RNA JNJ-73763989 (JNJ-3989) and the capsid assembly modulator JNJ-56136379 (JNJ-6379; bersacapavir). REEF-2, a phase IIb, double-blind, placebo-controlled, randomized study, enrolled 130 nucleos(t)ide analogue (NA)-suppressed hepatitis B e-antigen (HBeAg)-negative patients with CHB who received JNJ-3989 (200mg subcutaneously every 4 weeks) + JNJ-6379 (250mg oral daily) + NA (oral daily; active arm) or placebos for JNJ-3989 and JNJ-6379+active NA (control arm) for 48 weeks followed by 48 weeks off-treatment follow-up. At follow-up Week 24, no patients achieved the primary endpoint of functional cure (off-treatment hepatitis B surface antigen [HBsAg] seroclearance). No patients achieved functional cure at follow-up Week 48. There was a pronounced on-treatment reduction in mean HBsAg from baseline at Week 48 in the active arm vs. no decline in the control arm (1.89 vs. 0.06 log10IU/ml; p= 0.001). At follow-up Week 48, reductions from baseline were >1 log10IU/ml in 81.5% vs. 12.5% of patients in the active and control arms, respectively, and 38/81 (46.9%) patients in the active arm achieved HBsAg <100IU/ml vs. 6/40 (15.0%) patients in the control arm. Off-treatment HBV DNA relapse and alanine aminotransferase increases were less frequent in the active arm, with 7/77 (9.1%) and 11/41 (26.8%) patients in the active and control arms, respectively, restarting NAs during follow-up. Finite 48-week treatment with JNJ-3989 + JNJ-6379 + NA resulted in fewer and less severe post-treatment HBV DNA increases and alanine aminotransferase flares, and a higher proportion of patients with off-treatment HBV DNA suppression, with or without HBsAg suppression, but did not result in functional cure. Achieving a functional cure from chronic hepatitis B (CHB) with finite treatments is a major unmet medical need. The current study assessed the rate of functional cure and clinical outcome after controlled nucleos(t)ide analogue (NA) withdrawal in patients with low levels of HBsAg induced by 48 weeks of treatment with the small-interfering RNA JNJ-3989 and the capsid assembly modulator JNJ-6379 plus NA vs. patients who only received NA treatment. Though functional cure was not achieved by any patient in either arm, the 48-week treatment regimen of JNJ-3989, JNJ-6379, and NA did result in more patients achieving pronounced reductions in HBsAg, with clinically meaningful reductions maintained for up to 48 weeks off all treatments, as well as fewer off-treatment HBV DNA increases and alanine aminotransferase flares. These findings provide valuable insights for future studies investigating potential finite treatment options, while the reported efficacy and safety outcomes may be of interest to healthcare providers making treatment decisions for patients with NA-suppressed HBeAg-negative CHB. NCT04129554.