A phase I, first-in-human study to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of MRG-001 in healthy subjects
Ali R Ahmadi, George Atiee, Bart Chapman, Laurie Reynolds, John Sun, Andrew M Cameron, Russell N Wesson, James F Burdick, Zhaoli Sun, Ali R Ahmadi, George Atiee, Bart Chapman, Laurie Reynolds, John Sun, Andrew M Cameron, Russell N Wesson, James F Burdick, Zhaoli Sun
Abstract
Preclinical studies demonstrate that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a fixed-dose drug combination (MRG-001) improves wound healing, promotes tissue regeneration, and prevents allograft rejection. In this phase I, first-in-human study, three cohorts receive subcutaneous MRG-001 or placebo, every other day for 5 days. The primary outcome is safety and tolerability of MRG-001. Fourteen subjects received MRG-001 and seven received a placebo. MRG-001 is safe over the selected dose range. There are no clinically significant laboratory changes. The intermediate dose group demonstrates the most significant white blood cell, stem cell, and immunoregulatory cell mobilization. PBMC RNA sequencing and gene set enrichment analysis reveal 31 down-regulated pathways in the intermediate MRG-001 dose group compared with no changes in the placebo group. MRG-001 is safe across all dose ranges. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration (ClinicalTrials.gov: NCT04646603).
Keywords: MRG-001; clinical trial; healthy volunteers; pharmacodynamics; pharmacokinetics; phase I; plerixafor; safety; stem cells; tacrolimus.
Conflict of interest statement
Declaration of interests A.R.A. is a consultant to MedRegen LLC. J.B. and J.S. are employees of MedRegen LLC. J.B. and Z.S. are shareholders in MedRegen LLC. Z.S. is also the founder of MedRegen LLC.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Figures
![Graphical abstract](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10518600/bin/fx1.jpg)
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10518600/bin/gr1.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10518600/bin/gr2.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10518600/bin/gr3.jpg)
Figure 4
Stem cell mobilization with MRG-001…
Figure 4
Stem cell mobilization with MRG-001 Subjects received SC injections every other day of…
Figure 5
Regulated molecular pathways by MRG-001…
Figure 5
Regulated molecular pathways by MRG-001 RNA sequencing transcriptome studies of PBMCs were performed…
- Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose denosumab in healthy Chinese volunteers: A randomized, single-blind, placebo-controlled study.Chen Q, Hu C, Liu Y, Song R, Zhu W, Zhao H, Nino A, Zhang F, Liu Y. Chen Q, et al. PLoS One. 2018 Jun 22;13(6):e0197984. doi: 10.1371/journal.pone.0197984. eCollection 2018. PLoS One. 2018. PMID: 29933364 Free PMC article. Clinical Trial.
- Mobilization of hematopoietic stem cells with the novel CXCR4 antagonist POL6326 (balixafortide) in healthy volunteers-results of a dose escalation trial.Karpova D, Bräuninger S, Wiercinska E, Krämer A, Stock B, Graff J, Martin H, Wach A, Escot C, Douglas G, Romagnoli B, Chevalier E, Dembowski K, Hooftman L, Bonig H. Karpova D, et al. J Transl Med. 2017 Jan 3;15(1):2. doi: 10.1186/s12967-016-1107-2. J Transl Med. 2017. PMID: 28049490 Free PMC article. Clinical Trial.
- Two Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Studies To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza A Virus Monoclonal Antibody, MHAA4549A, in Healthy Volunteers.Lim JJ, Deng R, Derby MA, Larouche R, Horn P, Anderson M, Maia M, Carrier S, Pelletier I, Burgess T, Kulkarni P, Newton E, Tavel JA. Lim JJ, et al. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5437-44. doi: 10.1128/AAC.00607-16. Print 2016 Sep. Antimicrob Agents Chemother. 2016. PMID: 27381392 Free PMC article. Clinical Trial.
- Safety, Pharmacokinetics and Pharmacodynamics of Multiple Escalating Doses of PEGylated Exenatide (PB-119) in Healthy Volunteers.Cui H, Zhao CY, Lv Y, Wei MJ, Zhu Y, Ma XZ, Xia YH, Tian JH, Ma Y, Liu Y, Zhang P, Xu M. Cui H, et al. Eur J Drug Metab Pharmacokinet. 2021 Mar;46(2):265-275. doi: 10.1007/s13318-020-00665-x. Epub 2021 Feb 12. Eur J Drug Metab Pharmacokinet. 2021. PMID: 33576936 Clinical Trial.
- Effect of high-dose plerixafor on CD34+ cell mobilization in healthy stem cell donors: results of a randomized crossover trial.Pantin J, Purev E, Tian X, Cook L, Donohue-Jerussi T, Cho E, Reger R, Hsieh M, Khuu H, Calandra G, Geller NL, Childs RW. Pantin J, et al. Haematologica. 2017 Mar;102(3):600-609. doi: 10.3324/haematol.2016.147132. Epub 2016 Oct 20. Haematologica. 2017. PMID: 27846612 Free PMC article. Clinical Trial.
- Induction of Skin Allograft Chimerism by Pharmacological Mobilization of Endogenous Bone Marrow-Derived Stem Cells.Ahmadi AR, Wesson RN, Huang J, Harmon J, Burdick JF, Cameron AM, Sun Z. Ahmadi AR, et al. J Burn Care Res. 2024 Jan 5;45(1):234-241. doi: 10.1093/jbcr/irad153. J Burn Care Res. 2024. PMID: 37801462
-
- Okabayashi T., Cameron A.M., Hisada M., Montgomery R.A., Williams G.M., Sun Z. Mobilization of host stem cells enables long-term liver transplant acceptance in a strongly rejecting rat strain combination. Am. J. Transplant. 2011;11:2046–2056. doi: 10.1111/j.1600-6143.2011.03698.x. - DOI - PMC - PubMed
-
- Lin Q., Wesson R.N., Maeda H., Wang Y., Cui Z., Liu J.O., Cameron A.M., Gao B., Montgomery R.A., Williams G.M., Sun Z. Pharmacological mobilization of endogenous stem cells significantly promotes skin regeneration after full-thickness excision: the synergistic activity of AMD3100 and tacrolimus. J. Invest. Dermatol. 2014;134:2458–2468. doi: 10.1038/jid.2014.162. - DOI - PMC - PubMed
-
- Brave M., Farrell A., Ching Lin S., Ocheltree T., Pope Miksinski S., Lee S.L., Saber H., Fourie J., Tornoe C., Booth B., et al. FDA review summary: Mozobil in combination with granulocyte colony-stimulating factor to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation. Oncology. 2010;78:282–288. doi: 10.1159/000315736. - DOI - PubMed
-
- Hu X., Okabayashi T., Cameron A.M., Wang Y., Hisada M., Li J., Raccusen L.C., Zheng Q., Montgomery R.A., Williams G.M., Sun Z. Chimeric Allografts Induced by Short-Term Treatment With Stem Cell-Mobilizing Agents Result in Long-Term Kidney Transplant Survival Without Immunosuppression: A Study in Rats. Am. J. Transplant. 2016;16:2055–2065. doi: 10.1111/ajt.13706. - DOI - PMC - PubMed
-
- Cameron A.M., Wesson R.N., Ahmadi A.R., Singer A.L., Hu X., Okabayashi T., Wang Y., Shigoka M., Fu Y., Gao W., et al. Chimeric Allografts Induced by Short-Term Treatment With Stem Cell Mobilizing Agents Result in Long-Term Kidney Transplant Survival Without Immunosuppression: II, Study in Miniature Swine. Am. J. Transplant. 2016;16:2066–2076. doi: 10.1111/ajt.13703. - DOI - PubMed
- Clinical Trial, Phase I
- Research Support, Non-U.S. Gov't
- Healthy Volunteers
- Humans
- Leukocytes, Mononuclear*
- Stem Cells*
- Transplantation, Homologous
- ClinicalTrials.gov/NCT04646603
- Full Text Sources
- Medical
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10518600/bin/gr4.jpg)
Figure 5
Regulated molecular pathways by MRG-001…
Figure 5
Regulated molecular pathways by MRG-001 RNA sequencing transcriptome studies of PBMCs were performed…
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10518600/bin/gr5.jpg)
References
- Okabayashi T., Cameron A.M., Hisada M., Montgomery R.A., Williams G.M., Sun Z. Mobilization of host stem cells enables long-term liver transplant acceptance in a strongly rejecting rat strain combination. Am. J. Transplant. 2011;11:2046–2056. doi: 10.1111/j.1600-6143.2011.03698.x.
- Lin Q., Wesson R.N., Maeda H., Wang Y., Cui Z., Liu J.O., Cameron A.M., Gao B., Montgomery R.A., Williams G.M., Sun Z. Pharmacological mobilization of endogenous stem cells significantly promotes skin regeneration after full-thickness excision: the synergistic activity of AMD3100 and tacrolimus. J. Invest. Dermatol. 2014;134:2458–2468. doi: 10.1038/jid.2014.162.
- Brave M., Farrell A., Ching Lin S., Ocheltree T., Pope Miksinski S., Lee S.L., Saber H., Fourie J., Tornoe C., Booth B., et al. FDA review summary: Mozobil in combination with granulocyte colony-stimulating factor to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation. Oncology. 2010;78:282–288. doi: 10.1159/000315736.
- Hu X., Okabayashi T., Cameron A.M., Wang Y., Hisada M., Li J., Raccusen L.C., Zheng Q., Montgomery R.A., Williams G.M., Sun Z. Chimeric Allografts Induced by Short-Term Treatment With Stem Cell-Mobilizing Agents Result in Long-Term Kidney Transplant Survival Without Immunosuppression: A Study in Rats. Am. J. Transplant. 2016;16:2055–2065. doi: 10.1111/ajt.13706.
- Cameron A.M., Wesson R.N., Ahmadi A.R., Singer A.L., Hu X., Okabayashi T., Wang Y., Shigoka M., Fu Y., Gao W., et al. Chimeric Allografts Induced by Short-Term Treatment With Stem Cell Mobilizing Agents Result in Long-Term Kidney Transplant Survival Without Immunosuppression: II, Study in Miniature Swine. Am. J. Transplant. 2016;16:2066–2076. doi: 10.1111/ajt.13703.
- Sun Z., Williams G.M. Host stem cells repopulate liver allografts: reverse chimerism. Chimerism. 2011;2:120–122. doi: 10.4161/chim.2.4.19177.
- Ray K. Transplantation: Host stem cells boost tolerance of liver grafts. Nat. Rev. Gastroenterol. Hepatol. 2011;8:601. doi: 10.1038/nrgastro.2011.178.
- Carney E.F. Transplantation: Reverse chimerism enables graft acceptance. Nat. Rev. Nephrol. 2016;12:125. doi: 10.1038/nrneph.2016.8.
- Tolar J., McGrath J.A. Augmentation of cutaneous wound healing by pharmacologic mobilization of endogenous bone marrow stem cells. J. Invest. Dermatol. 2014;134:2312–2314. doi: 10.1038/jid.2014.209.
- Qi L., Ahmadi A.R., Huang J., Chen M., Pan B., Kuwabara H., Iwasaki K., Wang W., Wesson R., Cameron A.M., et al. Major Improvement in Wound Healing Through Pharmacologic Mobilization of Stem Cells in Severely Diabetic Rats. Diabetes. 2020;69:699–712. doi: 10.2337/db19-0907.
- Zhai R., Wang Y., Qi L., Williams G.M., Gao B., Song G., Burdick J.F., Sun Z. Pharmacological Mobilization of Endogenous Bone Marrow Stem Cells Promotes Liver Regeneration after Extensive Liver Resection in Rats. Sci. Rep. 2018;8:3587. doi: 10.1038/s41598-018-21961-2.
- Iwasaki K., Ahmadi A.R., Qi L., Chen M., Wang W., Katsumata K., Tsuchida A., Burdick J., Cameron A.M., Sun Z. Pharmacological Mobilization and Recruitment of Stem Cells in Rats Stops Abdominal Adhesions After Laparotomy. Sci. Rep. 2019;9:7149. doi: 10.1038/s41598-019-43734-1.
- Li X., Sun Z. 2022. Methods of Treating Inflammatory Bowel Disease with AMD3100 and Tacrolimus.
- Peiffer B.J., Qi L., Ahmadi A.R., Wang Y., Guo Z., Peng H., Sun Z., Liu J.O. Activation of BMP Signaling by FKBP12 Ligands Synergizes with Inhibition of CXCR4 to Accelerate Wound Healing. Cell Chem. Biol. 2019;26:652–661.e4. doi: 10.1016/j.chembiol.2019.01.011.
- Notta F., Doulatov S., Laurenti E., Poeppl A., Jurisica I., Dick J.E. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011;333:218–221. doi: 10.1126/science.1201219.
- Lucey M.R., Terrault N., Ojo L., Hay J.E., Neuberger J., Blumberg E., Teperman L.W. Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl. 2013;19:3–26. doi: 10.1002/lt.23566.
- Astellas Pharma US Inc . 2018. Prograft (Tacrolimus) Package Insert.
- Pantin J., Purev E., Tian X., Cook L., Donohue-Jerussi T., Cho E., Reger R., Hsieh M., Khuu H., Calandra G., et al. Effect of high-dose plerixafor on CD34(+) cell mobilization in healthy stem cell donors: results of a randomized crossover trial. Haematologica. 2017;102:600–609. doi: 10.3324/haematol.2016.147132.
- Wing J.B., Tanaka A., Sakaguchi S. Human FOXP3(+) Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer. Immunity. 2019;50:302–316. doi: 10.1016/j.immuni.2019.01.020.
- Ni X., Wang Q., Gu J., Lu L. Clinical and Basic Research Progress on Treg-Induced Immune Tolerance in Liver Transplantation. Front. Immunol. 2021;12 doi: 10.3389/fimmu.2021.535012.
- Muñoz-Rojas A.R., Mathis D. Tissue regulatory T cells: regulatory chameleons. Nat. Rev. Immunol. 2021;21:597–611. doi: 10.1038/s41577-021-00519-w.
- Rigato M., Bittante C., Albiero M., Avogaro A., Fadini G.P. Circulating Progenitor Cell Count Predicts Microvascular Outcomes in Type 2 Diabetic Patients. J. Clin. Endocrinol. Metab. 2015;100:2666–2672. doi: 10.1210/jc.2015-1687.
- Fadini G.P., Rigato M., Cappellari R., Bonora B.M., Avogaro A. Long-term Prediction of Cardiovascular Outcomes by Circulating CD34+ and CD34+CD133+ Stem Cells in Patients With Type 2 Diabetes. Diabetes Care. 2017;40:125–131. doi: 10.2337/dc16-1755.
- Hayek S.S., MacNamara J., Tahhan A.S., Awad M., Yadalam A., Ko Y.A., Healy S., Hesaroieh I., Ahmed H., Gray B., et al. Circulating Progenitor Cells Identify Peripheral Arterial Disease in Patients With Coronary Artery Disease. Circ. Res. 2016;119:564–571. doi: 10.1161/CIRCRESAHA.116.308802.
- Werner N., Kosiol S., Schiegl T., Ahlers P., Walenta K., Link A., Böhm M., Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. N. Engl. J. Med. 2005;353:999–1007. doi: 10.1056/NEJMoa043814.
- Rigato M., Avogaro A., Fadini G.P. Levels of Circulating Progenitor Cells, Cardiovascular Outcomes and Death: A Meta-Analysis of Prospective Observational Studies. Circ. Res. 2016;118:1930–1939. doi: 10.1161/CIRCRESAHA.116.308366.
- Patel R.S., Li Q., Ghasemzadeh N., Eapen D.J., Moss L.D., Janjua A.U., Manocha P., Kassem H.A., Veledar E., Samady H., et al. Circulating CD34+ progenitor cells and risk of mortality in a population with coronary artery disease. Circ. Res. 2015;116:289–297. doi: 10.1161/CIRCRESAHA.116.304187.
- Moazzami K., Lima B.B., Hammadah M., Ramadan R., Al Mheid I., Kim J.H., Alkhoder A., Obideen M., Levantsevych O., Shah A., et al. Association Between Change in Circulating Progenitor Cells During Exercise Stress and Risk of Adverse Cardiovascular Events in Patients With Coronary Artery Disease. JAMA Cardiol. 2020;5:147–155. doi: 10.1001/jamacardio.2019.4528.
- Fadini G.P., Schiavon M., Cantini M., Baesso I., Facco M., Miorin M., Tassinato M., de Kreutzenberg S.V., Avogaro A., Agostini C. Circulating progenitor cells are reduced in patients with severe lung disease. Stem Cell. 2006;24:1806–1813. doi: 10.1634/stemcells.2005-0440.
- Bonora B.M., Fogar P., Zuin J., Falaguasta D., Cappellari R., Cattelan A., Marinello S., Ferrari A., Avogaro A., Plebani M., et al. Hyperglycemia, Reduced Hematopoietic Stem Cells, and Outcome of COVID-19. Diabetes. 2022;71:788–794. doi: 10.2337/db21-0965.
- Muggeridge D., Dodd J., Ross M.D. CD34(+) progenitors are predictive of mortality and are associated with physical activity in cardiovascular disease patients. Atherosclerosis. 2021;333:108–115. doi: 10.1016/j.atherosclerosis.2021.07.004.
- Yang C.C., Sung P.H., Cheng B.C., Li Y.C., Chen Y.L., Lee M.S., Yip H.K. Safety and efficacy of intrarenal arterial autologous CD34+ cell transfusion in patients with chronic kidney disease: A randomized, open-label, controlled phase II clinical trial. Stem Cells Transl. Med. 2020;9:827–838. doi: 10.1002/sctm.19-0409.
- Salama H., Zekri A.R.N., Bahnassy A.A., Medhat E., Halim H.A., Ahmed O.S., Mohamed G., Al Alim S.A., Sherif G.M. Autologous CD34+ and CD133+ stem cells transplantation in patients with end stage liver disease. World J. Gastroenterol. 2010;16:5297–5305. doi: 10.3748/wjg.v16.i42.5297.
- Bonora B.M., Cappellari R., Mazzucato M., Rigato M., Grasso M., Menegolo M., Bruttocao A., Avogaro A., Fadini G.P. Stem cell mobilization with plerixafor and healing of diabetic ischemic wounds: A phase IIa, randomized, double-blind, placebo-controlled trial. Stem Cells Transl. Med. 2020;9:965–973. doi: 10.1002/sctm.20-0020.
- Duffy M.J., O'Grady S., Tang M., Crown J. MYC as a target for cancer treatment. Cancer Treat Rev. 2021;94 doi: 10.1016/j.ctrv.2021.102154.
Source: PubMed