Neucardin (recombinant human neuregulin-1β) / Zensun - LARVOL DELTA

ZS-01-210: Efficacy and Safety of Human Neuregulin-1 to Treat Stable Chronic Heart Failure (clinicaltrials.gov) - P2 | N=67 | Completed | Sponsor: Zensun Sci. & Tech. Co., Ltd. | Phase classification: P2a ➔ P2

Phase classification • Cardiovascular • Congestive Heart Failure • Heart Failure

Evaluation of the Effect of Injectable Neucardin on Cardiac Function and Reversal Ventricular Remodeling in Patients With Chronic Systolic Heart Failure (clinicaltrials.gov) - P3 | N=202 | Completed | Sponsor: Zensun Sci. & Tech. Co., Ltd. | Recruiting ➔ Completed | Trial primary completion date: Jun 2024 ➔ Aug 2024

Trial completion • Trial primary completion date • Cardiovascular • Congestive Heart Failure • Heart Failure

Evaluate the Effect of Injectable Neucardin on the Cardiac Function of Subjects With Chronic Systolic Heart Failure (clinicaltrials.gov) - P3 | N=154 | Completed | Sponsor: Zensun Sci. & Tech. Co., Ltd. | Active, not recruiting ➔ Completed | Trial completion date: May 2022 ➔ Apr 2024

Trial completion • Trial completion date • Cardiovascular • Congestive Heart Failure • Heart Failure

Survival Study of the Recombinant Human Neuregulin-1β in Subjects With Chronic Heart Failure. (clinicaltrials.gov) - P3 | N=1600 | Recruiting | Sponsor: Zensun Sci. & Tech. Co., Ltd. | Trial completion date: Feb 2023 ➔ Feb 2026 | Trial primary completion date: Feb 2022 ➔ Feb 2026

Trial completion date • Trial primary completion date • Cardiovascular • Congestive Heart Failure • Heart Failure

Evaluation of the Effect of Injectable Neucardin on Cardiac Function and Reversal Ventricular Remodeling in Patients With Chronic Systolic Heart Failure (clinicaltrials.gov) - P3 | N=198 | Recruiting | Sponsor: Zensun Sci. & Tech. Co., Ltd. | Trial primary completion date: Dec 2023 ➔ Jun 2024

Trial primary completion date • Cardiovascular • Congestive Heart Failure • Heart Failure

Evaluation of the Effect of Injectable Neucardin on Cardiac Function and Reversal Ventricular Remodeling in Patients With Chronic Systolic Heart Failure (clinicaltrials.gov) - P3 | N=198 | Recruiting | Sponsor: Zensun Sci. & Tech. Co., Ltd.

New P3 trial • Cardiovascular • Congestive Heart Failure • Heart Failure

Safety, Tolerability, and Pharmacokinetics of Recombinant Human Neuregulin-1 in Healthy Chinese Subjects. (PubMed, Am J Cardiovasc Drugs) - "It is concluded that rhNRG-1 is safe and well tolerated in healthy Chinese subjects at the dosing levels used in this study. The severity and frequency of adverse events did not increase with the prolongation of administration time."

Journal • PK/PD data • Cardiovascular • Congestive Heart Failure • Gastrointestinal Disorder • Heart Failure • NRG1

Evaluate the Effect of Injectable Neucardin on the Cardiac Function of Subjects With Chronic Systolic Heart Failure (clinicaltrials.gov) - P3; N=140; Active, not recruiting; Sponsor: Zensun Sci. & Tech. Co., Ltd.; Recruiting ➔ Active, not recruiting; N=84 ➔ 140; Trial completion date: Dec 2021 ➔ May 2022

Clinical • Enrollment change • Enrollment closed • Trial completion date • Cardiovascular • Congestive Heart Failure • Heart Failure • NPPB

Neuregulin 1 treatment improves glucose tolerance in diabetic db/db mice, but not in healthy mice. (PubMed, Arch Physiol Biochem) - "Diabetic mice showed altered NRG1-ErbB pathway in the liver compared with healthy mice. Moreover, chronic NRG1 treatment increased p38 phosphorylation in liver and improved glucose tolerance in diabetic mice, but not in control mice."

Journal • Preclinical • Diabetes • Metabolic Disorders • EGFR • ERBB3 • ERBB4 • FOXO1 • NRG1

ZS-01-210: Efficacy and Safety of Human Neuregulin-1 to Treat Stable Chronic Heart Failure (clinicaltrials.gov) - P2a; N=67; Completed; Sponsor: Zensun Sci. & Tech. Co., Ltd.; N=120 ➔ 67

Clinical • Enrollment change • Cardiovascular • Congestive Heart Failure • Heart Failure

Evaluate the Effect of Injectable Neucardin on the Cardiac Function of Subjects With Chronic Systolic Heart Failure (clinicaltrials.gov) - P3; N=84; Recruiting; Sponsor: Zensun Sci. & Tech. Co., Ltd.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Cardiovascular • Congestive Heart Failure • Heart Failure

Evaluate the Effect of Injectable Neucardin on the Cardiac Function of Subjects With Chronic Systolic Heart Failure (clinicaltrials.gov) - P3; N=84; Not yet recruiting; Sponsor: Zensun Sci. & Tech. Co., Ltd.; Trial completion date: Sep 2021 ➔ Dec 2021; Initiation date: Sep 2020 ➔ Dec 2020; Trial primary completion date: Sep 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial initiation date • Trial primary completion date • Cardiovascular • Congestive Heart Failure • Heart Failure

Evaluate the Effect of Injectable Neucardin on the Cardiac Function of Subjects With Chronic Systolic Heart Failure (clinicaltrials.gov) - P3; N=84; Not yet recruiting; Sponsor: Zensun Sci. & Tech. Co., Ltd.

Clinical • New P3 trial • Cardiovascular • Congestive Heart Failure • Heart Failure

Models of Heart Failure Based on the Cardiotoxicity of Anticancer Drugs. (PubMed) - "Blockade of the neuregulin-1/ErbB4/ErbB2, vascular endothelial growth factor (VEGF)/VEGF receptor and platelet-derived growth factor (PDGF)/PDGF receptor pathways by trastuzumab, sorafenib and sunitinib is proposed as paradigm of CTHF associated with alterations of myocardial paracrine pathways. Finally, anthracyclines and trastuzumab are also presented as examples of antitumor agents that induce HF by affecting the CPC population."

Journal • Review • Biosimilar • Heart Failure • Oncology

ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in HNSCC. (PubMed, PLoS One) - "...Here we show that the molecular components required for ErbB3 activation, including its ligand neuregulin-1 (NRG1), are highly prevalent in HNSCC and that HER2, but not EGFR, is the major activating ErbB3 kinase partner. We demonstrate that cetuximab treatment primarily inhibits the ERK signaling pathway and KTN3379, an anti-ErbB3 monoclonal antibody, inhibits the AKT signaling pathway, and that dual ErbB receptor inhibition results in enhanced anti-tumor activity in HNSCC models...Although ErbB3 and EGFR activation are uncoupled at the receptor level, their respective signaling pathways are linked through co-expression of their respective ligands. We propose that NRG1 expression and EGFR activation signatures may enrich for improved efficacy of anti-ErbB3 therapeutic mAb approaches when combined with EGFR-targeting therapies in HNSCC."

Biomarker • Journal • Biosimilar • Head and Neck Cancer

An ERBB1-3 Neutralizing Antibody Mixture With High Activity Against Drug-Resistant HER2+ Breast Cancers With ERBB Ligand Overexpression. (PubMed, J Natl Cancer Inst) - "...HER2+ cell lines and xenografts (n ≥ 6 mice per group) were treated with the ERBB1-3 antibody mixture Pan-HER, trastuzumab/lapatinib (TL), trastuzumab/pertuzumab (TP), or T-DM1...Post-TP and post-T-DM1 recurrent tumors expressed higher levels of neuregulin-1 (NRG1), HER3 and P-HER3 (all P < .05)...These data suggest that upregulation of a NRG1-HER3 axis can mediate escape from anti-HER2 therapies. Further, multitargeted antibody mixtures, such as Pan-HER, can simultaneously remove and/or block targeted ERBB receptor and ligands, thus representing an effective approach against drug-sensitive and -resistant HER2+ cancers."

Journal • Biosimilar • HER2 Breast Cancer

Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway. (PubMed) - "Neuroprotective and anti-inflammatory effects of NRG-1 are associated with the differential regulation of NF-kB signaling pathways in microglia. Taken together, these findings suggest that NRG-1 may be a potential therapeutic treatment for treating stroke and other neuroinflammatory disorders."

Journal • Biosimilar • Cardiovascular • Gene Therapies • Immunology • Reperfusion Injury • Venous Thromboembolism

Alterations of myelin morphology and oligodendrocyte development in early stage of Alzheimer's disease mouse model. (PubMed) - "Furthermore, we find active-caspase-6 can cleave neuregulin-1 type III at the cytoplasmic region. Given together, this study indicates the alterations of myelin morphology and oligodendrocytes development in 2-month-old APP/PS1 mouse, which might be highly associated with neuregulin-1 type III and active-caspase-6."

Journal • Alzheimer's Disease • Biosimilar • CNS Disorders • Oncology • Solid Tumor

Electrical Stimulation Using Conductive Polymer Polypyrrole Counters Reduced Neurite Outgrowth of Primary Prefrontal Cortical Neurons from NRG1-KO and DISC1-LI Mice. (PubMed) - Sci Rep - "Deficits in neurite outgrowth, possibly involving dysregulation of risk genes neuregulin-1 (NRG1) and disrupted in schizophrenia 1 (DISC1) have been implicated in psychiatric disorders including schizophrenia. Additionally, the use of the Ppy substrate normalised the synaptophysin and PSD95 protein and mRNA expression whereas both are usually reduced by NRG1-KO or DISC1-LI. Our findings support the utility of Ppy mediated electrical stimulation to prevent the reduction of neurite outgrowth and related synaptic protein expression in the primary PFC neurons from NRG1-KO and DISC1-LI mice, providing proof-of-concept for treating neurodevelopmental diseases including schizophrenia."

Journal • Biosimilar • CNS Disorders • Schizophrenia

Uniting the neuro developmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia. (PubMed, Sci Rep) - "In healthy controls, ErbB activation was associated with a marked production of IL-10, which was dampened in schizophrenia. These results indicate that the stimulation of TLR4 and ErbB induces opposite pro-inflammatory cytokine responses in schizophrenia."

Journal • Biosimilar • CNS Disorders • Schizophrenia

Neuroinflammation-Induced Downregulation of Hippocampacal Neuregulin 1-ErbB4 Signaling in the Parvalbumin Interneurons Might Contribute to Cognitive Impairment in a Mouse Model of Sepsis-Associated Encephalopathy. (PubMed) - Inflammation - "Notably, minocycline treatment attenuated neuroinflammation and mimicked the beneficial effects of NRG1 treatment. In summary, we provided additional evidence that the disruption of NRG1-ErbB4 signaling in the parvalbumin interneurons mediated by neuroinflammation might lead to abnormal gamma oscillations and thus contribute to cognitive impairment in a mouse model of SAE."

Journal • Alzheimer's Disease • Biosimilar • Immunology

Stromal neuregulin-1 modulates the response to MEK inhibitors in WT BRAF/WT NRAS (WT/WT) melanomas. (SMR 2016) - "In order to determine the potential contribution of the tumor microenvironment (TME) to resistance, we tested the effects of five growth factors on WT/WT melanoma growth in the presence of the MEK inhibitor (MEKi) trametinib. Knockdown of SOX10 in WT/WT melanoma cell lines reduced ErbB3 expression and NRG1 effects on cell growth. Together our results provide a rationale for the treatment of WT/WT melanomas expressing SOX10 and NRG1 with the combination of MEK inhibitors and ErbB3/ErbB2 antibodies."

Tumor microenvironment • Biosimilar • Hematological Malignancies • Melanoma • Multiple Myeloma • Oncology

Can ERBB4 induce nuclear YAP in High Grade Glioma? (COSA 2017) - "...Western blots were employed to assess the phosphorylation and cleavage of ERBB4 in response to its principal ligand, neuregulin-1β (NRG-1β), in a panel of ERBB4-positive HGG cell lines...Collectively, these findings suggest that ERBB4 is not a key orchestrater of nuclear YAP in HGG. We are planning further experiments to explain the cause and significance of non-responsive ERBB4 in patient-derived HGG cell lines."

Breast Cancer • Oncology • Solid Tumor

Schwann cell-specific deletion of the endosomal PI 3-kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2-ErbB3 tyrosine kinase signaling. (PubMed, Glia) - "...In Vps34(SCKO) nerves, ErbB3 was hyperphosphorylated on a tyrosine known to be phosphorylated in response to neuregulin 1 exposure...Our findings suggest that the loss of Vps34 alters the trafficking of ErbB2/3 through endosomes. Abnormal ErbB2/3 signaling to downstream targets may contribute to the hypomyelination observed in Vps34(SCKO) mice."

Journal • Biosimilar • CNS Disorders • Gene Therapies • Pain

Neuregulin expression in solid tumors: Prognostic value and predictive role to anti-HER3 therapies. (PubMed) - Oncotarget - "NRG expression is not associated with either OS or PFS, but is a predictor of benefit from anti-HER3 antibodies."

Journal • Biosimilar • Complement-mediated Rare Disorders • Oncology