A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Pharmacokinetics, Immunogenicity, Safety, and Tolerability After Subcutaneous Administration of Tozorakimab in Healthy Chinese Participants.

Tozorakimab is a high-affinity human immunoglobulin G1 monoclonal antibody that neutralizes interleukin (IL)-33, an IL-1 family cytokine. This phase 1, single-center, randomized, double-blind, placebo-controlled, single ascending dose study (NCT05070312) evaluated tozorakimab in a healthy Chinese population. Outcomes included the characterization of the pharmacokinetic (PK) profile and immunogenicity of tozorakimab. Safety outcomes included treatment-emergent adverse events (TEAEs) and clinical laboratory, electrocardiogram, and vital sign parameters. Healthy, non-smoking, male, and female Chinese participants aged 18-45 years with a body mass index 19-24 kg/m2 were enrolled. In total, 36 participants across 2 cohorts of 18 participants were randomized 2:1 to receive a single subcutaneous dose of tozorakimab (300 mg [2 mL] or 600 mg [4 mL]) or matching placebo (2 or 4 mL). Tozorakimab showed dose-dependent serum PK concentrations with an approximate monophasic distribution in serum over time and a maximum observed peak concentration of 20.1 and 33.7 µg/mL in the 300- and 600-mg cohorts, respectively. No treatment-emergent anti-drug antibodies for tozorakimab were observed in any of the participants. There were no clinically relevant trends in the occurrence of TEAEs across the treatment groups. There were no clinically relevant trends over time in clinical laboratory (hematology, clinical chemistry, and urinalysis), electrocardiogram, or vital sign parameters in any treatment group. Overall, tozorakimab demonstrated dose-dependent systemic exposure in healthy Chinese participants and was well tolerated, with no safety concerns identified in this study.

A Randomized Phase I Study of the Anti-Interleukin-33 Antibody Tozorakimab in Healthy Adults and Patients With Chronic Obstructive Pulmonary Disease.

Tozorakimab is a human monoclonal antibody that neutralizes interleukin (IL)-33. IL-33 is a broad-acting epithelial "alarmin" cytokine upregulated in lung tissue of patients with chronic obstructive pulmonary disease (COPD). This first-in-human, phase I, randomized, double-blind, placebo-controlled study (NCT03096795) evaluated the safety, tolerability, pharmacokinetics (PKs), immunogenicity, target engagement, and pharmacodynamics (PDs) of tozorakimab. This was a 3-part study. In part 1, 56 healthy participants with a history of mild atopy received single escalating doses of either intravenous or subcutaneous tozorakimab or placebo. In part 2, 24 patients with mild COPD received multiple ascending doses of subcutaneous tozorakimab or placebo. In part 3, 8 healthy Japanese participants received a single intravenous dose of tozorakimab or placebo. The safety data collected included treatment-emergent adverse events (TEAEs), vital signs, and clinical laboratory parameters. Biological samples for PKs, immunogenicity, target engagement, and PD biomarker analyses were collected. No meaningful differences in the frequencies of TEAEs were observed between the tozorakimab and placebo arms. Three tozorakimab-treated participants with COPD experienced treatment-emergent serious adverse events. Subcutaneous or intravenous tozorakimab demonstrated linear, time-independent PKs with a mean half-life of 11.7-17.3 days. Treatment-emergent anti-drug antibody frequency was low. Engagement of tozorakimab with endogenous IL-33 in serum and nasal airways was demonstrated. Tozorakimab significantly reduced serum IL-5 and IL-13 levels in patients with COPD compared with placebo. Overall, tozorakimab was well tolerated, with a linear, time-independent serum PK profile. Additionally, biomarker studies demonstrated proof of mechanism. Overall, these data support the further clinical development of tozorakimab in COPD and other inflammatory diseases.

Factores de estrés y su asociación con los biomarcadores del síndrome metabólico

Introducción: el síndrome metabólico es considerado como un conjunto de factores de riesgo para desarrollar enfermedades cardiovasculares y diabéticas, en adición a esto, los biomarcadores determinan un diagnóstico del síndrome metabólico. Existen diversos factores que pueden causar el síndrome metabólico, uno de ellos, el estrés, que se concibe como la reacción de un individuo ante eventos o situaciones que exceden los mecanismos de adaptación. Objetivos: explorar la literatura científica existente para identificar y sintetizar los diferentes factores de estrés fisiológico que se han investigado en relación con el síndrome metabólico, y evaluar críticamente la evidencia disponible sobre la asociación entre los factores de estrés identificados y los biomarcadores específicos del síndrome metabólico. Además, realizar un análisis de la calidad metodológica de los estudios incluidos en la revisión para evaluar la validez y la fiabilidad de los resultados obtenidos. Materiales y Métodos: se realizó una revisión sistemática usando bases de datos como PubMed, Redalyc, SciELO y Google Scholar, en donde se incluyeron investigaciones que busquen establecer una relación entre el estrés y los biomarcadores del síndrome metabólico en publicaciones desde enero del 2017 a noviembre del 2022. Se tomaron en cuenta criterios de la Declaración PRISMA. Resultados: se incluyeron un total de 32 artículos, en donde se pudo observar que los biomarcadores del estrés oxidativo que influyen en el padecimiento del síndrome metabólico son diversos y pueden afectar de múltiples formas al ser humano, generando enfermedades como la diabetes, enfermedades cardiovasculares, pulmonares y hasta neuropsicológicas. Conclusiones: los biomarcadores del estrés oxidativo influyen de manera directa en el padecimiento de síndrome metabólico y son identificados como un factor determinante para diagnosticar enfermedades desencadenantes de este síndrome.

Introduction: Metabolic syndrome is considered as a set of risks factors for developing cardiovascular and diabetic diseases. Additionally, biomarkers determine a diagnosis of metabolic syndrome. Several of them can cause metabolic syndrome, and one of them, stress, is conceived as an individual's reaction to events or situations that exceed adaptation mechanisms. Materials and methods: A systematic review was carried out using database such as PubMed, Redalyc, Scielo and Google Scholar, which included research that relates oxidative stress to biomarkers of metabolic syndrome in publications from January 2017 to November 2022. The criteria considered were those of the PRISMA Declaration. Results: A total of 32 articles were included, and it was possible to observe that the biomarkers of oxidative stress that influence the condition of metabolic syndrome are diverse and can affect humans in multiple ways, generating diseases such as diabetes, cardiovascular, pulmonary, and even neuropsychological. Conclusions: Oxidative stress biomarkers have a direct influence on suffering from metabolic syndrome and are identified as a determining factor in diagnosing diseases that trigger this syndrome.