cimaglermin alfa (GGF2) / PAION, Acorda - LARVOL DELTA

The Combination of a Human Biomimetic Liver Microphysiology System with BIOLOGXsym, a Quantitative Systems Toxicology (QST) Modeling Platform for Macromolecules, Provides Mechanistic Understanding of Tocilizumab- and GGF2-Induced Liver Injury. (PubMed, Int J Mol Sci) - "Tocilizumab exposure was associated with increased oxidative stress and extracellular/tissue remodeling, and GGF2 decreased bile acid secretion. BIOLOGXsym simulations, leveraging the in vivo exposure predicted by physiologically-based pharmacokinetic modeling and mechanistic toxicity data from the Liver Acinus Microphysiology System, reproduced the clinically observed liver signals of tocilizumab and GGF2, demonstrating that mechanistic toxicity data from microphysiology systems can be successfully integrated into a quantitative systems toxicology model to identify liabilities of biologics-induced liver injury and provide mechanistic insights into observed liver safety signals."

Journal • Hepatology • Liver Failure • HMGB1

Neuregulin (NRG-1β) Is Pro-Myogenic and Anti-Cachectic in Respiratory Muscles of Post-Myocardial Infarcted Swine. (PubMed, Biology (Basel)) - "We therefore assessed NRG-1β's effect on intercostal skeletal muscle gene expression in a swine model of heart failure using recombinant glial growth factor 2 (USAN-cimaglermin alfa), a version of NRG-1β that has been tested in humans with systolic heart failure...In vitro experiments with myoblast cell lines confirmed that NRG-1β induces ERBB-dependent differentiation. These findings suggest a NRG-1β-mediated anti-atrophic, anti-cachexia effect that may provide additional benefits to this potential therapy in heart failure."

Journal • Cachexia • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Infarction • HES1 • NRG1

Neuregulin-1β promotes myoblast differentiation and is anti-cachexic in respiratory muscles of post-infarcted swine. (PubMed, FASEB J) - "We therefore assessed NRG-1β's effect on skeletal muscle gene expression in a swine model of heart failure using recombinant Glial Growth Factor 2 (USAN - cimaglermin alfa), a version of NRG-1β currently being tested in humans with systolic heart failure...In vitro experiments with myoblast cell lines confirmed that NRG-1β induces skeletal muscle differentiation with an absolute requirement for ERBB signaling on myoblast differentiation. These findings suggest a NRG-1β-mediated anti-atrophic, anti-cachexia effect that may provide additional benefits to this potential therapy in heart failure."

Journal • Cachexia • Cardiovascular • Congestive Heart Failure • Heart Failure • HES1 • NRG1

Clinicopathologic Features and Response to Therapy of NRG1 Fusion–Driven Lung Cancers - Episode 4 NRG1 Fusion-Driven Lung Cancer: Future Directions in Care (Cancer Network) - "What do you think about these global registries and how it adds to the understanding of these rare fusions? You were a part author of this registry we should point out....Yes, that's a great point, especially with these rare entities. What do you think some of the next steps are?....The only challenge of this journey is this is rare. We say ALK is rare, but that's 4%; here, we're less than 1%. ALK used to be able to be tested with FISH [fluorescence in situ hybridization], which is was little bit more common than NGS [next-generation sequencing]...D. Ross Camidge, MD, PhD: The thing that I take away from it is, we are way past the tipping point for saying, 'What is that other thing we're supposed to test for?' All you have to do is make sure you have a panel. Have one time when you look through the list of things that you're supposed to be finding, and you check that it's all going to be detected, and then you're good."

Video

The Association between Urinary Glucose and Renal Uric Acid Excretion in Non-diabetic Patients with Stage 1-2 Chronic Kidney Disease. (PubMed, Endocr Res) - "The EurGF levels in the highest tertiles of UG, FEG and EgGF were higher than those in the lowest tertiles of UG, FEG and EgGF. Urinary glucose excretion is closely related to renal excretion of uric acid in non-diabetic patients with stage 1-2 CKD."

Clinical • Journal • Chronic Kidney Disease • Metabolic Disorders • Nephrology • Renal Disease

NG2-glia cell proliferation and differentiation by glial growth factor 2 (GGF2), a strategy to promote functional recovery after ischemic stroke. (PubMed, Biochem Pharmacol) - "It has been reported that the number of NG2-glia cells in the peri-infarction area significantly increases after ischemic stroke and glial growth factor (GGF2) administration promotes the proliferation and differentiation of NG2-glia cells as well as functional recovery after spinal cord injury. On the basis of the important roles of GGF2 in functional recovery and those of ID2 in NG2-glia cell proliferation and differentiation , we propose that after binding with the ErBb receptor on the surface of NG2-glia cells, GGF2 promotes NG2-glia cell proliferation and differentiation, thereby repairing BBB and white matter integrity and promoting neural functional recovery after ischemic stroke."

Journal • Review • Cardiovascular • Complement-mediated Rare Disorders • Ischemic stroke • Melanoma • Orthopedics • Reperfusion Injury • Solid Tumor

Transient Changes in Hepatic Physiology That Alter Bilirubin and Bile Acid Transport May Explain Elevations in Liver Chemistries Observed in Clinical Trials of GGF2 (Cimaglermin alfa). (PubMed, Toxicol Sci) - "GGF2 is a recombinant human neuregulin-1β in development for chronic heart failure. Additional studies conducted in sandwich-cultured human hepatocytes revealed a transient and GGF2 concentration-dependent decrease in hepatocyte bile acid content and biliary clearance of taurocholate without affecting biliary taurocholate efflux. Taken together, these data suggest that GGF2 does not cause significant hepatocellular death, but transiently modifies hepatic handling of bilirubin and bile acids, effects that may account for the elevations in serum bilirubin observed in the clinical trial subjects."

Journal • Biosimilar • Cardiovascular • Heart Failure

"Heart failure drug, cimaglermin, shows promise in first human trial - CBS News" - C. Michael Gibson MD, ‏@CMichaelGibson

Clinical

"Geneva Geeks shouts out to @GSK @JNJCares and others for leading in the private sector to ensure broad scale impact. https://t.co/gGf2tbFoyg"

Biosimilar

"In scrappy Cambodian casino town, Chinese plan future beyond coronavirus https://t.co/DU64yGgF2N" (@Reuters)

Potential of AAV-GGF2 Delivery in Gene Therapy of Heart Failure (ASGCT 2019) - "Traditional H&E staining of liver slices showed that all liver tissues from dead mice had various degrees of lymphocyte infiltration and sharply demarcated centrilobular necrosis with loss of hepatocyte cytologic details. Taken together, these results indicate that AAV8-mediated GGF2 expression causes hepatotoxicity and proper control of GGF2 expression level is essential for the clinical application of AAV-GGF2 delivery in heart failure."

Glial Growth Factor 2 Regulates Glucose Transport in Healthy Cardiac Myocytes and During Myocardial Infarction via an Akt-Dependent Pathway. (PubMed, Front Physiol) - "GGF2 treatment also increased GLUT4 translocation in healthy myocytes by 184% (P < 0.01), while ErbB 2/4 receptor blockade (by afatinib) abolished these effects. Our data demonstrate that acute GGF2 treatment increased glucose transport in cardiac myocytes by activating the ErbB 2/4 receptors and subsequent key downstream effectors (i.e., PDK-1, Akt, AS160, and PKC). These findings highlight novel mechanisms of action of GGF2, which warrant further investigation in patients with heart failure."

Clinical • Journal