Discussion
inflammation, deaths, TEAE, TEAEs
CRITICALLY ILL, ADVERSE EVENTS, INFLAMMATION, INFLAMMATORY DISORDER, EVENTS, DISEASES, ACUTE RESPIRATORY DISTRESS SYNDROME
In this first-in-human study, MRG-001 was safe and well tolerated at doses of up to 0.02 mL/kg administered every other day subcutaneously SC in the three multiple ascending dose cohorts in healthy subjects. There were no deaths, serious adverse events, or severe TEAE. Most TEAE were mild, and there was a dose-dependent increase in TEAE frequency; 68% of TEAEs (26/38) including four moderate TEAEs were observed in the high-dose cohort. These events were temporary and all were resolved within 24–48 h. No clinically significant laboratory changes were observed besides the expected mobilization of different lineages of WBCs.After multiple dose administration, plasma plerixafor and tacrolimus CThe action of MRG-001 in animal models of human diseases is to mobilize bone marrow stem cells and immunoregulatory cells to the peripheral blood and recruit mobilized stem cells and immunoregulatory cells into the injured sites.All cell populations returned to baseline levels before the next injection, consistent with there being no accumulative effect. As expected, control subjects who received placebo showed no evidence of diurnal variation of leukocyte subset levels across the measured timepoints. In animal models of human diseases, mobilized stem cells and immunoregulatory cells are recruited into the injured organ or tissues and promoted tissue repair and regeneration.Foxp3Circulating hematopoietic stem and progenitor cells (HSPCs) including CD34Notably, mobilizing stem cells and immune Tregs are associated with changes in gene expression of PBMCs. RNA sequencing of PBMCs and the GSEA revealed 27 common down-regulated pathways in the mid-dose cohort and 4 common down-regulated pathways in the high-dose cohort, compared with the placebo group or pre-dose expression profiles (Higher numbers of mobilized stem cells and immunoregulatory T cells in peripheral blood are correlated with more down-regulated pathways in PBMCs. However, the kinetics of gene expression changes did not correspond to kinetic changes of stem cells and/or immunoregulatory T cells. For example, circulating immune cells and stem cells fell back to placebo levels at 48 h in the high-dose cohort, but six down-regulated pathways remained. The mid-dose, not high-dose, mobilized more stem cells and immunoregulatory T cells and down-regulated more pathways. The peak levels of tacrolimus (2–3 ng/mL) in the middle dose cohort (More than a decade of animal studies led to the development of MRG-001. Because of its immunoregulatory and regenerative therapeutic properties discovered from animal studies and its safety in healthy subjects, MRG-001 is being tested in a phase II trial for efficacy and safety in severely, critically ill, COVID-19 patients who suffer from acute respiratory distress syndrome (NCT04646603). A second IIa study will soon be initiated to study the safety and efficacy of MRG-001 in wound healing in pre-abdominoplasty surgical excisions (NCT05844527).In summary, multiple doses of MRG-001 up to 0.02 mL/kg (every other day, SC injection) were safe and well tolerated in healthy participants in this study. The 0.01 mL/kg MRG-001 dose may be a promising and safe dosage for mobilizing bone marrow stem cells, immune Tregs, and down-regulating pathways related to inflammation and other diseases. Further studies in phase II clinical trials are warranted to investigate the efficacy and safety of MRG-001 in patients with inflammatory disorders, wounds, and organ transplantation.