AL-034 / J&J, Sino Biopharm - LARVOL DELTA

Combination treatment of TLR7 agonist and anti-PD-L1 reconstitute protective immunity in virally suppressed chronic hepatitis B patients (EASL 2025) - " Totally 24 nucleos(t)ide analogues (NUCs)-treated CHB patients were randomized to receive Entecavir (ETV) monotherapy (n=6), ETV+TQA3334 dual therapy (n=9) or NA+TQA3334+TQB2450 triple therapy (n=9) for 24 weeks and then followed up for 24 weeks. The combination of TLR7 agonist and anti-PD-L1 could reconstitute antiviral immunity in virally suppressed CHB patients by inducing the production of ISGs, antiviral cytokines, and reinvigorating HBV-specific CD8+T cell response, thus potentially favouring improved clinical outcome."

Clinical • IO biomarker • Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation • CD8 • IFNA1 • IFNG • IL21 • ISG15 • MX1

Combination Treatment of TLR7 Agonist and Anti-PD-L1 Reconstitute Protective Immunity in Virally Suppressed Chronic Hepatitis B Patients (APASL 2025) - " Totally 24 nucleos(t)ide analogues (NUCs)-treated CHB patients were randomized to receive Entecavir (ETV) monotherapy (n=6), ETV+TQA3334 dual therapy (n=9) or NA+TQA3334+TQB2450 triple therapy (n=9) for 24 weeks and then followed up for 24 weeks. The combination of TLR7 agonist and anti-PD-L1 could reconstitute antiviral immunity in virally suppressed CHB patients by inducing the production of ISGs, antiviral cytokines, and reinvigorating HBV-specific CD8+T cell response, thus potentially favoring improved clinical outcome. Table and Figure:Figure 1.Dual or Triple therapy altered cytokines and ISGs level Figure 2.Triple therapy induces broader and stronger HBV specific CD8+T cells respons"

Clinical • IO biomarker • Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation • CD8 • IFNA1 • IFNG • IL21 • ISG15 • MX1 • PD-1 • TNFA

TQ-A3334-II-03: Evaluate TQ-A3334 Combined Nucleoside (Acid) Analogs in the First Treatment/Treatment of Chronic HBV Infection (clinicaltrials.gov) - P2 | N=116 | Recruiting | Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Evaluate TQ-A3334 Combined Nucleoside (Acid) Analogs in the First Treatment/Treatment of Chronic HBV Infection (clinicaltrials.gov) - P2 | N=116 | Not yet recruiting | Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

New P2 trial • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Clinical Trial of TQ-A3334 Tablet After Multiple Administration in Adult Subjects (clinicaltrials.gov) - P1 | N=40 | Completed | Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Recruiting ➔ Completed | N=90 ➔ 40 | Trial completion date: Dec 2024 ➔ Aug 2024

Enrollment change • Trial completion • Trial completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

COMBINATION THERAPY WITH TLR7 AGONIST TQ-A3334 AND ANTI-PD-L1 TQ-B2450 ENHANCE HBSAG DECLINE IN VIRALLY-SUPPRESSED PATIENTS WITH CHRONIC HEPATITIS B: OCEANCURE05 STUDY (AASLD 2024) - "The addition of PD-L1 antibody to the combination of NUC and TLR7 agonist enhanced HBsAg decline in virally-suppressed CHB patients. This effect might be attributed to the ability to counteract the upregulation of PD-L1 associated with TLR7 agonist. Early ALT elevation and HBsAg decline may predict sustained reduction in HBsAg after the triple therapy."

Clinical • Combination therapy • IO biomarker • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Clinical Study to Evaluate the Tolerance, Pharmacokinetics and Efficacy of TQ-A3334 Tablets (clinicaltrials.gov) - P1/2 | N=30 | Terminated | Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

Metastases • New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A novel oral TLR7 agonist orchestrates immune response and synergizes with PD-L1 blockade via type I IFN pathway in lung cancer. (PubMed, Int Immunopharmacol) - "Furthermore, combining TQ-A3334 with anti-PD-L1 treatment exceeded tumor control, with a further increase in CD8+ TIL frequency compared to monotherapy. These findings suggest that TQ-A3334 can mobilize innate immunity and promote T cell recruitment into the tumor microenvironment; a combination of TQ-A3334 and anti-PD-L1 antibodies can intensify the sensitivity of tumors to anti-PD-L1 therapy, which demonstrates significant potential for treating poorly immune-infiltrated lung cancer."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Oral Cancer • Solid Tumor • CD8 • CXCL10 • IFNA1

Efficacy of Combination Treatment of TLR7 Agonist and Anti-Pd-L1 in Virally Suppressed CHB Patients (APASL 2024) - "The combination of NA, TQA3334 and TQB2450 induced greater HBsAg decline in viral-suppressed CHB pts with good safety. Moreover, high dose of TQA3334 promoted HBsAg reduction in triple therapy."

Clinical • Endocrine Disorders • Hepatitis B

A Clinical Trial of TQ-A3334 Tablet After Multiple Administration in Adult Subjects (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Clinical Trial of TQ-A3334 Tablet After Multiple Administration in Adult Subjects (clinicaltrials.gov) - P1 | N=90 | Not yet recruiting | Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

New P1 trial • Hepatitis B • Hepatology • Infectious Disease • Inflammation

EFFICACY AND SAFETY OF COMBINATION TREATMENT OF TLR7 AGONIST TQA3334 AND ANTI-PD-L1 TQB2450 IN VIRALLY SUPPRESSED CHRONIC HEPATITIS B PATIENTS: A PILOT RCT PHASE II STUDY (OCEAN cure05 STUDY) (AASLD 2023) - "The combination of NA, TQA3334 and TQB2450 induced greater and more durable HBsAg decline in viral-suppressed CHB patients with good safety and tolerability. Moreover, high dose of TQA3334 promoted HBsAg reduction in triple therapy."

Clinical • P2 data • Endocrine Disorders • Hematological Disorders • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Neutropenia • IFNA1

A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral immune cells in healthy adults. (PubMed, Antivir Ther) - "JNJ-4964 administration led to changes in transcriptional profiles and immune cell activation phenotype, particularly for NK cells and B cells. Together, these changes could represent a set of biomarkers for the characterization of the immune response in CHB patients receiving TLR7 agonists."

Immune cell • IO biomarker • Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation • CD69 • CD86 • CXCL10 • IFNA1 • TNFRSF4 • TNFRSF9 • TNFSF10

Population pharmacokinetic/pharmacodynamic models of JNJ-64794964, a toll-like receptor 7 agonist, in healthy adult participants. (PubMed, Antivir Ther) - "PK/PD models well characterized the time course of immune system markers in healthy adults. Our results supported sex and race as covariates on JNJ-4964 responsiveness, as well as circadian rhythms and negative feedback as homeostatic mechanisms that are relevant in TLR7-induced type I IFN responses."

IO biomarker • Journal • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • CXCL10 • IFNA1 • IFNG

Phase Ib study of the TLR7 agonist TQ-A3334 monotherapy or combined with Anlotinib or PD-L1 inhibitor in treatment of advanced metastatic non-small cell lung cancer (ESMO-IO 2021) - P1/2 | "Methods The study was a multi-center, Phase 1b study of TQ-A3334 as monotherapy and combination with Anlotinib or TQ-B2450 in advanced metastatic NSCLC with ≥2 prior chemotherapy lines, including TQ-A3334 (q1w) dose escalation, followed by expansion into indication specific arms to test for efficacy in defined patient cohorts. Funding Chia Tai Tianqing Pharmaceutic Group Co. Ltd."

Monotherapy • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IFNA1 • IL12A • TNFA

Safety, tolerability, pharmacokinetics, and pharmacodynamics of oral JNJ-64794964, a TLR-7 agonist, in healthy adults. (PubMed, Antivir Ther) - "In healthy adults, JNJ-4964 was generally well-tolerated, exhibited dose-proportional pharmacokinetics and induced cytokines/ISGs, with possible anti-HBV activity."

Journal • PK/PD data • IL1R1 • MX1

JNJ-64794964 (AL-034/TQ-A3334), a TLR7 agonist, induces sustained anti-HBV activity in AAV/HBV mice via non-cytolytic mechanisms. (PubMed, Antiviral Res) - "In these animals, HBsAg-specific CD8 T cells were detectable. Throughout the study, normal levels of alanine aminotransferase were observed, with no hepatocyte cell death (end of treatment and 4 weeks later) and minimal infiltrations of B and T cells into the liver, suggesting induction of cytokine-mediated, non-cytolytic mechanisms."

IO biomarker • Journal • Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation • CD4 • CD8 • IFNG

Safety, Pharmacokinetics, and Pharmacodynamics of TQ-A3334, an Oral Toll-Like Receptor 7 Agonist, in Healthy Individuals. (PubMed, Expert Opin Investig Drugs) - "Oral doses of 0.2-1.8 mg appeared to be safe and tolerated. PD activity was seen at doses ranging from 1.0 to 1.8 mg, indicating its possible future use to treat CHB."

Clinical • Journal • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Pain

[VIRTUAL] POPULATION PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) MODELS OF JNJ-64794964, A TOLL-LIKE RECEPTOR (TLR)-7 AGONIST, IN HEALTHY ADULT SUBJECTS (AASLD 2020) - "A set of population PK/PD models for JNJ-4964 effects on IFN-a, IP-10, ISG15, neopterin and lymphocytes have been constructed from data in healthy adults. Modeling of combined data has allowed to better characterize the impact of gender and race on EC50 for the TLR-7 agonist JNJ-4964."

Clinical • IO Biomarker • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • IFNG

[VIRTUAL] A once-per-week or every-two-week dosing regimen is more efficacious for the TIR7 agonist JNJ-64794964 (JNJ-4964) to induce an anti-hepatitis B virus (HBV) effect and HBV-specific immune responses in AAV-HBV mice (EASL-ILC-I 2020) - "JNJ-4964 dosing frequency impacted the extent of immune stimulation and anti-HBV effect that JNJ-4964 may trigger in AAV-HBV mice. To trigger adaptive immune responses, as well as an indirect anti-HBV effect, the QW dosing frequency was overall more efficient than the BIW, Q2W and Q4W dosing frequencies. Dosing frequency did not impact safety in AAV-HBV mice."

IO Biomarker • Preclinical • Hepatitis B • Hepatology • Infectious Disease • CXCL10 • IFNA1 • IFNG

A Study to Evaluate the Tolerance, Pharmacokinetics and Efficacy of TQ-A3334 Tablets (clinicaltrials.gov) - P1/2; N=40; Recruiting; Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.; Initiation date: Mar 2020 ➔ Jul 2020

Clinical • Trial initiation date • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • EGFR

A Study to Evaluate the Tolerance, Pharmacokinetics and Efficacy of TQ-A3334 Tablets (clinicaltrials.gov) - P1/2; N=40; Recruiting; Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

Clinical • New P1/2 trial • EGFR

Combination of ETV, TQ-A3334 and TQ-B2450 for CHB (Neptune Study) (clinicaltrials.gov) - P2; N=30; Not yet recruiting; Sponsor: Tongji Hospital

New P2 trial

A Study of TQ-A3334 Combined With Entecavir in the Treatment of Chronic Hepatitis B (clinicaltrials.gov) - P2a; N=12; Recruiting; Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

A Study of TQ-A3334 Combined With Entecavir in the Treatment of Chronic Hepatitis B (clinicaltrials.gov) - P2a; N=12; Not yet recruiting; Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

Clinical • New P2a trial