Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicle Infusion for the Treatment of Respiratory Failure From COVID-19

Abstract

BackgroundBone marrow mesenchymal stem cell (BM-MSC)-derived extracellular vesicles (ExoFlo) convey the immunomodulatory and regenerative properties of intact BM-MSCs. This study aimed to determine the safety and efficacy of ExoFlo as treatment for moderate to severe ARDS in patients with severe COVID-19.Research QuestionDo two doses of ExoFlo safely reduce mortality in COVID-19-associated moderate to severe ARDS compared with placebo?Study Design and MethodsA prospective phase 2 multicenter double-anonymized randomized placebo-controlled dosing trial was conducted at five sites across the United States with infusions of placebo, 10 mL of ExoFlo, or 15 mL of ExoFlo on days 1 and 4. Patients (N = 102) with COVID-19-associated moderate to severe ARDS were enrolled and randomized to treatment. Adverse events were documented throughout the study. The primary outcome measure was all-cause 60-day mortality rate. Secondary outcomes included time to death (overall mortality); the incidence of treatment-emergent serious adverse events; proportion of discharged patients at 7, 30, and 60 days; time to hospital discharge; and ventilation-free days.ResultsNo treatment-related adverse events were reported. Mortality (60-day) in the intention-to-treat population was reduced with 15 mL ExoFlo mixed with 85 mL normal saline (ExoFlo-15) compared with placebo (not significant, χ2, P = .1343). For the post hoc subgroup analyses, 60-day mortality was decreased with ExoFlo-15 compared with placebo (relative risk, 0.385; 95% CI, 0.159-0.931; P = .0340; n = 50). With ExoFlo-15, a relative risk of 0.423 (95% CI, 0.173-1.032; P = .0588; n = 24) was determined for participants aged 18 to 65 years with moderate to severe ARDS. Ventilation-free days improved with ExoFlo-15 (P = .0455; n = 50) for all participants aged 18 to 65 years.InterpretationThe 15 mL dose of ExoFlo was found to be safe in patients with severe or critical COVID-19-associated respiratory failure. In participants aged 18 to 65 years, the risk reduction in 60-day mortality was further improved from subjects of all ages in the intention-to-treat population after two doses of 15 mL of ExoFlo compared with placebo.Clinical Trial RegistrationClinicalTrials.gov; No.: NCT04493242; URL: www.clinicaltrials.gov. Bone marrow mesenchymal stem cell (BM-MSC)-derived extracellular vesicles (ExoFlo) convey the immunomodulatory and regenerative properties of intact BM-MSCs. This study aimed to determine the safety and efficacy of ExoFlo as treatment for moderate to severe ARDS in patients with severe COVID-19. Do two doses of ExoFlo safely reduce mortality in COVID-19-associated moderate to severe ARDS compared with placebo? A prospective phase 2 multicenter double-anonymized randomized placebo-controlled dosing trial was conducted at five sites across the United States with infusions of placebo, 10 mL of ExoFlo, or 15 mL of ExoFlo on days 1 and 4. Patients (N = 102) with COVID-19-associated moderate to severe ARDS were enrolled and randomized to treatment. Adverse events were documented throughout the study. The primary outcome measure was all-cause 60-day mortality rate. Secondary outcomes included time to death (overall mortality); the incidence of treatment-emergent serious adverse events; proportion of discharged patients at 7, 30, and 60 days; time to hospital discharge; and ventilation-free days. No treatment-related adverse events were reported. Mortality (60-day) in the intention-to-treat population was reduced with 15 mL ExoFlo mixed with 85 mL normal saline (ExoFlo-15) compared with placebo (not significant, χ2, P = .1343). For the post hoc subgroup analyses, 60-day mortality was decreased with ExoFlo-15 compared with placebo (relative risk, 0.385; 95% CI, 0.159-0.931; P = .0340; n = 50). With ExoFlo-15, a relative risk of 0.423 (95% CI, 0.173-1.032; P = .0588; n = 24) was determined for participants aged 18 to 65 years with moderate to severe ARDS. Ventilation-free days improved with ExoFlo-15 (P = .0455; n = 50) for all participants aged 18 to 65 years. The 15 mL dose of ExoFlo was found to be safe in patients with severe or critical COVID-19-associated respiratory failure. In participants aged 18 to 65 years, the risk reduction in 60-day mortality was further improved from subjects of all ages in the intention-to-treat population after two doses of 15 mL of ExoFlo compared with placebo. ClinicalTrials.gov; No.: NCT04493242; URL: www.clinicaltrials.gov. FOR EDITORIAL COMMENT, SEE PAGE 1343Take-home PointsStudy Question: Do two doses of ExoFlo safely reduce mortality in severe COVID-19-associated moderate to severe ARDS compared with placebo?Results: No adverse events or serious adverse events related to the investigational product were reported. For participants aged 18 to 65 years with respiratory failure, 60-day mortality was significantly decreased with ExoFlo-15 compared with placebo (relative risk, 0.385; 95% CI, 0.159-0.931; P = .0340).Interpretation: Two doses of ExoFlo safely and significantly reduced mortality in patients aged 18 to 65 years with respiratory failure caused by critical or severe COVID-19. FOR EDITORIAL COMMENT, SEE PAGE 1343 Study Question: Do two doses of ExoFlo safely reduce mortality in severe COVID-19-associated moderate to severe ARDS compared with placebo? Results: No adverse events or serious adverse events related to the investigational product were reported. For participants aged 18 to 65 years with respiratory failure, 60-day mortality was significantly decreased with ExoFlo-15 compared with placebo (relative risk, 0.385; 95% CI, 0.159-0.931; P = .0340). Interpretation: Two doses of ExoFlo safely and significantly reduced mortality in patients aged 18 to 65 years with respiratory failure caused by critical or severe COVID-19. Optimal management of ARDS morbidity remains critical. ARDS develops in 33% to 42% of hospitalized patients with COVID-19 and in 61% to 81% of patients admitted to the ICU. Patients with COVID-19-associated ARDS exhibit pathologic changes of diffuse alveolar damage similar to those of classic ARDS.1Tian S. Xiong Y. Liu H. et al.Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies.Modern Pathol. 2020; 33: 1007-1014Abstract Full Text Full Text PDF PubMed Scopus (639) Google Scholar,2Xu Z. Shi L. Wang Y. et al.Pathological findings of COVID-19 associated with acute respiratory distress syndrome.Lancet Respir Med. 2020; 8: 420-422Abstract Full Text Full Text PDF PubMed Scopus (6173) Google Scholar Pooled mortality estimates of ARDS cases in patients with COVID-19 showed similar mortality to patients with non-COVID-19 ARDS.3Hasan S.S. Capstick T. Ahmed R. et al.Mortality in COVID-19 patients with acute respiratory distress syndrome and corticosteroids use: a systematic review and meta-analysis.Expert Rev Respir Med. 2020; 14: 1149-1163Crossref PubMed Scopus (159) Google Scholar Bone marrow mesenchymal stem cells (BM-MSCs) show promise for the treatment of ARDS. The phase 1 Human Mesenchymal Stem Cells for ARDS Treatment (START) trial monitored outcomes for 60 days following a single IV administration to patients with moderate to severe ARDS; no serious adverse events (SAEs) were observed following infusion of allogeneic BM-MSCs.4Wilson J.G. Liu K.D. Zhuo H. et al.Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial.Lancet Respir Med. 2015; 3: 24-32Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar Transplantation of healthy donor BM-MSCs into patients with COVID-19 pulmonary disease improved functional outcomes without any observed adverse effects, and serum level changes in tumor necrosis factor alpha and IL-10 suggest that BM-MSCs may inhibit cytokine storm.5Leng Z. Zhu R. Hou W. et al.Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia.Aging Dis. 2020; 11: 216-228Crossref PubMed Scopus (871) Google Scholar MSCs from other tissue sources also exhibit efficacy.6Kirkham A.M. Bailey A.J.M. Shorr R. Lalu M.M. Fergusson D.A. Allan D.S. Systematic review and meta-analysis of randomized controlled trials of mesenchymal stromal cells to treat coronavirus disease 2019: is it too late?.Cytotherapy. 2023; 25: 341-352Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar However, the challenges of cryodamage, fresh product distribution, cell product heterogeneity, immunogenicity, thrombotic events, and scalability make BM-MSC technology impractical for global delivery.4Wilson J.G. Liu K.D. Zhuo H. et al.Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial.Lancet Respir Med. 2015; 3: 24-32Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar,7Matthay M.A. Calfee C.S. Zhuo H. et al.Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial.Lancet Respir Med. 2019; 7: 154-162Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar,8Zhou T. Yuan Z. Weng J. et al.Challenges and advances in clinical applications of mesenchymal stromal cells.J Hematol Oncol. 2021; 14: 24Crossref PubMed Scopus (192) Google Scholar ExoFlo (Direct Biologics) is an extracellular vesicle (EV) product manufactured per Current Good Manufacturing Practice regulations from a single-donor BM-MSC culture that conveys the immunomodulatory and regenerative properties of BM-MSCs without cellular therapy limitations.9De Jong O.G. Van Balkom B.W. Schiffelers R.M. Bouten C.V. Verhaar M.C. Extracellular vesicles: potential roles in regenerative medicine.Front Immunol. 2014; 5: 608Crossref PubMed Scopus (256) Google Scholar, 10Kaspi H. Semo J. Abramov N. et al.MSC-NTF (NurOwn®) exosomes: a novel therapeutic modality in the mouse LPS-induced ARDS model.Stem Cell Res Ther. 2021; 12: 72Crossref PubMed Scopus (28) Google Scholar, 11Krishnan A. Muthusamy S. Fernandez F.B. Kasoju N. Mesenchymal stem cell-derived extracellular vesicles in the management of COVID19-associated lung injury: a review on publications, clinical trials and patent landscape.Tissue Eng Regen Med. 2022; 19: 659-673Crossref PubMed Scopus (6) Google Scholar, 12Tang Y. Zhou Y. Li H.J. Advances in mesenchymal stem cell exosomes: a review.Stem Cell Res Ther. 2021; 12: 71Crossref PubMed Scopus (118) Google Scholar Extensive characterization of ExoFlo EVs reveals an absence of immunogenic surface epitopes that would cause acute immune reactions. The BM-MSCs used to manufacture ExoFlo are fully characterized to meet the International Society for Cellular Therapy definition of possessing trilineage differentiation capability (bone, adipose, and cartilage) and to be positive for the surface markers CD90 and CD166 but negative for CD45. The cells are evaluated by, and have a master file on record, with the US Food and Drug Administration that includes information about the chemistry, manufacturing, and control requirements for an approved phase 2 Investigational New Drug Application clinical study. The efficacy and safety potential of ExoFlo were evidenced by an investigator-initiated safety study treating patients with COVID-19-associated ARDS.13Sengupta V. Sengupta S. Lazo A. Woods P. Nolan A. Bremer N. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19.Stem Cells Develop. 2020; 29: 747-754Crossref PubMed Scopus (423) Google Scholar These findings combine with the acellular nature, homogeneity, and scalability of ExoFlo to increase its potential as a practical therapeutic option for respiratory failure from COVID-19.13Sengupta V. Sengupta S. Lazo A. Woods P. Nolan A. Bremer N. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19.Stem Cells Develop. 2020; 29: 747-754Crossref PubMed Scopus (423) Google Scholar,14Sengupta V. Sengupta S. Lazo Jr., A. Hicok K.C. Moseley T. Response to Lim et al. re: "Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19.".Stem Cells Develop. 2020; 29: 879-881Crossref PubMed Scopus (20) Google Scholar To further evaluate the safety and efficacy of ExoFlo for the treatment of hospitalized patients with respiratory failure from severe or critical COVID-19, a randomized controlled trial (Extracellular Vesicle Infusion Treatment for COVID-19 [EXIT COVID-19]) was conducted. We hypothesized that ExoFlo would be safe in the treatment of patients with severe and critical COVID-19 and compared the safety and efficacy of two doses of ExoFlo vs placebo. A prospective multicenter phase 2 randomized double-anonymized placebo-controlled trial was conducted. Enrollment for EXIT COVID-19 began September 24, 2020, and was completed May 22, 2021. Five clinical trial sites in the United States actively participated in patient recruitment and enrollment. Patients with severe or critical COVID-19 as defined by blood oxygen saturation < 94% on room air at sea level, < and a respiratory per or lung were included The trial was approved by the review at a as and by a and safety that was fully of study and by other was from patient or the patient was to 1 a of of patient and and 1 a of the clinical trial Patients (N = 102) were randomized by the clinical trial sites to ExoFlo 15 ExoFlo 10 or placebo on ExoFlo is and treatment was to that were to the the are on a of and with or patients and of ExoFlo and In the and of EVs and the of an for and are are with to show that the of is of ExoFlo was on the the COVID-19 ExoFlo V. Sengupta S. Lazo A. Woods P. Nolan A. Bremer N. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19.Stem Cells Develop. 2020; 29: 747-754Crossref PubMed Scopus (423) Google the phase 1 trial IV administration of BM-MSCs for safety at to and a dose of 10 of EVs per and 60 to from the trial dose an IV ExoFlo dose of and 15 mL and 10 mL of IV ExoFlo were determined as and dosing and per enrolled patients a mL IV infusion 60 on Treatment mL normal saline 10 mL ExoFlo mixed with mL normal saline and 15 mL ExoFlo mixed with 85 mL normal saline A of the study treatment on the patient oxygen saturation on room air or patients were for 60 or hospital or of the treatment patients were to hospital was no the ExoFlo-15 and placebo for of and and and and of and per P. 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The mortality placebo and ExoFlo-15 was by the and a with 95% a and by a No mortality with a 60-day was for the (P = or the 95% CI, the suggest an reduction in the mortality risk time with ExoFlo-15 compared with placebo. The relative in mortality across the with time from ExoFlo-15 was placebo at at 30, and at of were observed with vs placebo. Mortality for ExoFlo-15 and by 60 and the mortality for at 60 days was similar to that of placebo. The of subjects discharged was for ExoFlo-15 by and placebo The time to hospital was to be days for ExoFlo-15, days for and by placebo evaluated with The a time to from placebo to to ExoFlo-15, was for the (P = or the 95% CI, as by a time vs hospital ExoFlo-15 and placebo. In the were for ExoFlo-15 and similar for and placebo The in ExoFlo-15 and placebo to P = in in of of the population that were post hoc were conducted in patients aged 18 to 65 years with respiratory failure or moderate to severe ARDS. with respiratory failure a 60-day mortality of in the placebo and in the ExoFlo-15 risk reduction of and a relative risk of (95% CI, 0.159-0.931; P = For for moderate to severe 60-day mortality was in the placebo and in the ExoFlo-15 an risk reduction of and a relative risk of 0.423 (95% CI, 0.173-1.032; P = These findings a Mortality for Patients 18 to 65 With or to Severe 15 = mortality mortality (95% = mortality with mortality with for failure to severe or critical COVID-19, aged to severe ARDS subgroup all to severe ARDS defined per the definition in moderate ARDS is < and severe ARDS is to severe ARDS subgroup aged to severe ARDS defined per the definition in moderate ARDS is < and severe ARDS is = = mortality mortality = mortality with mortality with to severe ARDS defined per the definition in moderate ARDS is < and severe ARDS is in a = For the aged 18 to 65 years, the of with ExoFlo-15 was improved P = compared with placebo A was observed for in moderate and severe ARDS in moderate and severe and This prospective double-anonymized randomized placebo-controlled phase 2 trial is the to show that BM-MSC EVs are safe and exhibit potential for efficacy on post hoc subgroup in the treatment of severe or critical COVID-19. 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In mortality in the ExoFlo-15 and improved with time from This safety is to the to and 2021; PubMed Scopus Google J. mortality and in COVID-19 patients with systematic review and 2021; PubMed Scopus Google Scholar 60-day mortality in the population was with ExoFlo-15 and with placebo. significant, findings are with the findings of the investigator-initiated trial and of for of extracellular vesicles in patients with COVID-19 associated ARDS. of Scholar two of ExoFlo-15 in a mortality reduction patients hospitalized with severe or critical COVID-19. the of ExoFlo-15 included of mortality to time to hospital and were observed in the population for 60-day mortality mortality time to and In the subgroup of patients aged 18 to 65 years with moderate or severe showed a with ExoFlo-15 placebo. the phase trial This study was for a mortality treatment a mortality risk reduction was in subjects aged 18 to 65 years respiratory failure to COVID-19, and a similar risk reduction was in with moderate to severe ARDS. In the subgroup of patients aged 18 to 65 years the for moderate to severe mortality was for ExoFlo-15 = compared with = in the placebo was a 60-day mortality risk reduction of and a relative risk of 0.423 (95% CI, of may be to in the population is a factor that subjects aged 65 years to treatment on or to the and a for a mortality in the ARDS is that ExoFlo may have a in patients and those at the time of the of ExoFlo in a patient that ExoFlo be in are to a in as the treatment was too to is the completed prospective randomized placebo-controlled trial of an product for the treatment of respiratory failure from COVID-19, other randomized clinical trials have conducted with and immunomodulatory for the treatment of P. 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In to be improved in the patient with ARDS. on with ExoFlo, the US Food and Drug Administration a regenerative therapeutic and also with a phase clinical trial that is to the the approved with mortality of phase trial be critical to the treatment of patients with ARDS. of efficacy respiratory failure from COVID-19 disease by ExoFlo would a in to reduce morbidity and mortality caused by for study was by

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