Two-Part Phase 1 Study to Evaluate the Taste Profile of Novel Belumosudil Oral Suspensions and Assess the Relative Bioavailability and Food Effect of the Selected Belumosudil Oral Suspension Compared With Oral Tablet Reference in Healthy Male Participants.

Belumosudil is a selective rho-associated coiled-coil-containing protein kinase 2 inhibitor in clinical use for the treatment of chronic graft-versus-host disease. The current tablet formulation may be inappropriate for children or adults with dysphagia and/or upper gastrointestinal manifestations of chronic graft-versus-host disease. This study (NCT04735822) assessed the taste and palatability of oral suspensions of belumosudil, evaluated the relative bioavailability of an oral suspension versus the tablet formulation, and characterized the effect of food on the pharmacokinetics of an oral suspension.

Radiological Evaluation of OrthAlign-A Novel Handheld Navigation System used in Total Knee Replacement.

Background: The goal of this research is to determine how well OrthAlign, a novel portable navigation system for total knee replacement, helps surgeons make accurate incisions. When comparing OrthoAlign, a portable accelerometer-based technique, to the gold standard of extramedullary jigs, the results are promising. This study aimed to evaluate the accuracy of distal femoral and proximal tibial cuts in total knee arthroplasty.

Evaluation of the clinical molecule anti-human-PD-L1/IL-15 KD033 in the human-PD-1/PD-L1-expressing murine model demonstrates PD-L1 targeting of IL-15 in vivo.

KD033 is a clinical-stage immunocytokine composed of a high-affinity anti-human-PD-L1 antibody and the human IL-15/ IL-15 receptor sushi-domain complex. We have previously shown that KD033-surrogate, the anti-mouse-PD-L1/IL-15 immunocytokine, was efficacious in several syngeneic murine tumor models including those that were refractory to anti-PD-1/PD-L1 checkpoint blockers. KD033-surrogate showed better efficacy than the combination treatment of its component, anti-PD-L1 antibody with the non-targeting IL-15.

A Phase 1 Thorough QT/QTc Study of Therapeutic and Supratherapeutic Doses of Belumosudil in Healthy Subjects.

Belumosudil is a selective Rho-associated, coiled-coil-containing protein kinase-2 inhibitor. In this crossover design thorough QT/QTc study, single therapeutic (200 mg) and supratherapeutic (1000 mg) oral doses of belumosudil, moxifloxacin (positive control), and placebo were administered to 34 subjects. Twelve-lead electrocardiograms and serial pharmacokinetic sampling were acquired.

Phase 1 Studies to Evaluate the Food Effect and Relative Bioavailability of Tablet and Capsule Formulations of Belumosudil in Healthy Adult Subjects.

Belumosudil is a selective Rho-associated coiled-coil containing protein kinase 2 inhibitor. A capsule formulation was used during early clinical development of belumosudil; it was later replaced by a tablet formulation, which mimicked the capsule's release properties and facilitated manufacturing scalability. To assess belumosudil's pharmacokinetics, including potential food effects, and evaluate the relative bioavailability of the 2 formulations, 2 phase 1 clinical trials were conducted.

Absolute Bioavailability, Mass Balance, and Metabolic Profiling Assessment of [ C]-Belumosudil in Healthy Men: A Phase 1, Open-Label, 2-Part Study.

Belumosudil is a selective Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor. ROCK2 has been shown to drive proinflammatory response and fibrosis that occurs with chronic graft-versus-host disease; therefore, inhibition of ROCK2 has emerged as a therapeutic target for chronic graft-versus-host disease. In this phase 1 two-part study, the pharmacokinetics, mass balance, and metabolic profile of belumosudil were evaluated after single doses of unlabeled belumosudil oral tablets (200 mg), radiolabeled belumosudil intravenous (IV) microtracer infusions (100 μg), and radiolabeled oral capsules (200 mg).

A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors.

Belumosudil is a selective Rho-associated protein kinase 2 inhibitor. Inhibition of Rho-associated protein kinase 2 has emerged as a promising treatment for chronic graft-versus-host disease by restoring immune homeostasis and reducing fibrosis. In vitro assessments have suggested that metabolism of belumosudil is primarily dependent on cytochrome P450 (CYP) 3A4 activity and that the solubility of belumosudil is pH dependent.

Functional antibody characterization via direct structural analysis and information-driven protein-protein docking.

Detailed description of the mechanism of action of the therapeutic antibodies is essential for the functional characterization and future optimization of potential clinical agents. We recently developed KD035, a fully human antibody targeting vascular endothelial growth factor receptor 2 (VEGFR2). KD035 blocked VEGF-A, and VEGF-C-mediated VEGFR2 activation, as demonstrated by the in vitro binding and competition assays and functional cellular assays.

ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease.

Purpose: The rho-associated coiled-coil-containing protein kinase-2 (ROCK2) signaling pathway regulates the Th17/regulatory T cells balance and controls profibrotic pathways. Selective ROCK2 inhibition with belumosudil (KD025) may offer a novel approach to the management of chronic graft-versus-host disease (cGVHD).

Patients And Methods: A phase IIa, open-label, dose-finding study of belumosudil enrolled 54 patients with cGVHD who had received one to three prior lines of therapy (LOTs).

Single-Dose Anti-PD-L1/IL-15 Fusion Protein KD033 Generates Synergistic Antitumor Immunity with Robust Tumor-Immune Gene Signatures and Memory Responses.

Immunocytokines hold great potential as anticancer agents, as they use a specific antitumor antibody to deliver an immune-activating cytokine directly to the immunosuppressive tumor microenvironment (TME). We have developed a novel immunocytokine (KD033) composed of a fully human, high-affinity antiprogrammed death-ligand 1 (PD-L1) linked to the sushi-domain of the human IL-15/IL-15 receptor alpha (IL-15/IL-15Rα) complex. A murine PD-L1 cross-reactive KD033 surrogate (srKD033) and a nontargeting antibody (ntKD033) were also developed to investigate mechanism of action in murine tumor models.

Modulation of neuronal CXCR4 by the micro-opioid agonist DAMGO.

The chemokine receptor CXCR4 regulates neuronal survival and differentiation and is involved in a number of pathologies, including cancer and human immunodeficiency virus (HIV). Recent data suggest that chemokines act in concert with neurotransmitters and neuropeptides, such as opioids. This study aimed to determine whether mu-opioid agonists alter the effect of CXCL12 (the specific CXCR4 ligand) on central neurons.

Human immunodeficiency virus gp120-induced apoptosis of human neuroblastoma cells in the absence of CXCR4 internalization.

The chemokine receptor CXCR4 functions as human immunodeficiency virus (HIV)-1 coreceptor and is involved in acquired immunodeficiency virus (AIDS) neuropathogenesis. CXCR4 is expressed by most cell types in the brain, including microglia, astrocytes, and neurons. Studies have shown that the HIV envelope protein gp120 binds to neuronal CXCR4 and activates signal transduction pathways leading to apoptosis.

Regulation of neuronal P53 activity by CXCR 4.

Abnormal activation of CXCR 4 during inflammatory/infectious states may lead to neuronal dysfunction or damage. The major goal of this study was to determine the coupling of CXCR 4 to p53-dependent survival pathways in primary neurons. Neurons were stimulated with the HIV envelope protein gp120(IIIB) or the endogenous CXCR 4 agonist, SDF-1 alpha.

Apoptotic and antiapoptotic effects of CXCR4: is it a matter of intrinsic efficacy? Implications for HIV neuropathogenesis.

CXCR4, the specific receptor for the chemokine SDF-1 alpha that also binds CXCR4-using HIV gp120s, affects survival of different cell types, including neurons. However, current data show that the outcome of CXCR4 activation on neuronal survival may vary depending on the ligand and/or the cellular conditions. In this study, we have systematically compared the effects of SDF-1 alpha and gp120(IIIB) (with or without CD4) on several intracellular pathways involved in cell survival, including MAP kinases and Akt-dependent pathways.