Umbilical Cord Mesenchymal Stem Cell Therapy for COVID 19 Brian - PowerPoint PPT Presentation

Umbilical Cord Mesenchymal Stem Cell Therapy for COVID 19 Brian Mehling, MD Orthopedic Surgeon CMO, BHI Therapeutic Sciences

BHI Therapeutic Sciences (BHITS) is a healthcare consulting company with a unique concept that combines therapy, research, and philanthropy. Our research studies designed to measure the safety and efficacy of intravenous, intra-articular, and intrathecal stem cell therapies. Our comprehensive stem cell protocols employ well-targeted combinations of autologous adipose stem cells, and allogeneic human umbilical cord blood and tissue stem cells that treat various medical conditions such as spinal cord injury, traumatic brain injury, and chronic inflammation. Locations: • Wuhan Hamilton Biotechnology Co., Ltd (Wuhan, China) • Malacky Hospital (Malacky, Slovakia) • BHITS Jamaica (The Village at Half Moon Montego Bay St.James, Jamaica Indies) 2

Previous BHITS Studies: Institutional Review Board (IRB) Approved Clinical Research Studies • Retrospective Chart Review Study of Human Umbilical Cord Blood Mononuclear Cell Therapy in Previously Treated Subjects with Brain Trauma (IRCM-2019-231, December 10, 2019). • Evaluation of The Long-Term Safety of Human Umbilical Cord Blood Derived Mononuclear Cell Therapy in Previously Treated Subjects with Chronic Inflammation (IRCM-2019-232, December 10, 2019). • Evaluation of the Safety and Efficacy of HPC, Cord Blood in Subjects with Acute Ischemic Stroke (IRCM-2018-188, July 13, 2018) • Retrospective Chart Review Study of Human Cord Blood Stem Cells in the Therapy of Symptoms Related to Chronic Inflammation (IRCM-2017-136, January 18, 2017) • Retrospective Chart Review Study of Human Adipose Tissue Derived Mesenchymal Stem Cell Therapy in Subjects with Musculoskeletal Conditions (IRCM-2017-137, January 18, 2017) • Retrospective Chart Review Study of Human Umbilical Cord Blood Derived Mesenchymal Stem Cell Therapy in Subjects with Stroke (IRCM-2017-135, January 18, 2017) • Umbilical Cord Blood Mononuclear Cell Therapy for Spinal Cord Injury – A Retrospective Cohort Study (Office of Research and Sponsored Programs. SC# 5488, “Spinal Cord Injury Stem Cell Therapy”, April 2, 2014) • Evaluation of Immune response to Intravenously Administered Human Cord Blood Stem Cells in the treatment of Symptoms related to Chronic Inflammation (IRCM 2014-040, December 17, 2014 ) 6

Used Stem Cell Sources, Treatment Modalities and Outcome Measures Stem Cell Sources: • Allogeneic Human Umbilical cord blood • Allogeneic Wharton's jelly • Autologous Bone Marrow • Autologous Adipose Tissue Treatment Modalities: • Intravenous Infusion • Intrathecal Injection • Intra-Articular Injection Treatment modalities, specific for the medical condition, descried in our Institutional Review Board-approved research protocols . Outcome Measures: • Safety evaluation – conduct of adverse events form, medical history, physical exam, specific blood tests at intervals described in the research protocol. • Assessment of efficacy – conduct of specific blood tests, exams and self-assessment questionnaires at 4 intervals described in the research protocol.

Stem Cell Quality Stem cells are tested for sterility, infectious diseases and have high cell count and viability. Every unit of Human Umbilical Cord Blood Mononuclear Cells and Human Umbilical Cord Mesenchymal Stem Cells has the Cell Quality Certificate with the following information: Virus Tests (Hepatitis B virus, Hepatitis C virus, Human Immunodeficiency virus and Treponema pallidum), Microbiological Tests (Bacteria, Fungus, Mycoplasma, Endotoxin), the cell count and viability. 7

FDA Endorsed Investigational New Drug Application: Evaluation of the Safety and Efficacy of HPC, Cord Blood in Subjects With Acute Ischemic Stroke Protocol Number: BHI17-IS-A IND number: 018171 The study is registered on ClinicalTrials.gov ClinicalTrials.gov Identifier: NCT03735277 The prospective, open-label, single-center, exploratory FDA endorsed IND study is designed to characterize the safety and efficacy profile of FDA-licensed Hematopoietic Progenitor Cell Cord Blood, when administered by intravenous infusion and intrathecal injection, in subjects who have sustained an acute ischemic stroke. In our study, we are one of the first to combine intrathecal and intravenous administrations to maximize the potential therapeutic benefit by accessing the central nervous system through the cerebrospinal fluid and the systemic circulation. To support an IND-enabling clinical investigation of the off-label use of FDA-licensed product for the treatment of ischemic stroke, the investigation has been relied on previous FDA findings of acceptability of chemistry, manufacturing, and controls (CMC) information and Pharmacology and Toxicology information for Hemacord as indicated in the product labeling. 6

Umbilical Cord Mesenchymal Stem Cell Therapy for COVID 19 Mesenchymal Stem Cells (MSCs) have been widely used in cell-based therapy, from basic research to clinical trials . MSC-based therapy of lung diseases has rapidly progressed over the past decade. Many studies have shown that MSCs have immunomodulatory, antimicrobial, anti-inflammatory and tissue repair functions, being a great potential for the prevention and treatment of viral diseases. It is believed that one of the causes of the severity of lung symptoms in patients with COVID-19 is cytokine storm . The immunomodulatory effects of MSCs occur primarily through inhibiting the proliferation and cytokine secretion of immune cells. Wharton’s Jelly is the connective tissue that surrounds the umbilical vessels. MSCs obtained from Wharton’s Jelly are easily culture expanded and can be collected in a non -invasive manner. An advantage of the use of culture-expanded hUC- MSCs from Wharton’s Jelly is that one donated or cryogenically stored umbilical cord, through culture expansion will supply enough MSCs to treat hundreds of patients. 7

Published Clinical Studies of Mesenchymal Stem Cell Therapy for COVID-19 Citation Cells Total Cell Indication Efficacy Safety Administered Dose Study Design (Dose No. of Patients Schedule) 1 × 10 6 cells/kg Leng, 2020 MSCs COVID-19 - Decrease in plasma C-reaction protein No treatment-related AEs (one iv dose) Pneumonia level and increase in oxygen saturation. in clinical, laboratory, and Placebo controlled - Elimination of overactivated cytokine- radiological examination. 3 control secreting immune cells CXCR3+CD4+ T 7 treated cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells. -Decrease in CD14+CD11c+CD11bmid regulatory DC cell population. -Decrease in pro-inflammatory cytokine TNF- α (p<0.05). -Increase in anti-inflammatory IL-10 (p<0.05). 5 × 10 7 cell (three Liang, 2020 hUC-MSCs COVID-19 infection -Decrease in serum bilirubin, CRP, No serious AEs reported. iv doses) Case Report and ALT/AST. 1 treated -Significant increase in CD3+ T cell, CD4+ T cell, and CD8+ T cell. -CT image indicate relief in both left and 8 right lung.

Published Clinical Studies of Human Umbilical Cord Mesenchymal Stem Cell Therapy for Pulmonary Disorders Citation Cells Total Cell Indication Efficacy Safety Administered Dose Study Design (Dose No. of Patients Schedule) 1x10 7 cells/kg and Chang, hUCB-MSCs Bronchopulmonary Dysplasia -Significant decrease in MMP-9, No serious AEs reported. 2014 2x107 cells/kg (one Phase I dose-escalation trial IL-6, IL-8, TNF-a, and TGF-b levels compared with those at Significantly lower BPD severity intratracheal dose) 9 treated (3 received low dose, 6 - baseline or at day 3 post-transplantation (P < 0.05) in the MSC treatment group high dose) compared to historical control (P = 0.036). 5x10 6 -1x10 7 /ml Zhang, hUC-MSCs Severe idiopathic pulmonary fibrosis Reduction of LTOT requirement No serious AEs reported 2017 (one iv dose) Case Report Improvements in physical performance, quality of life, and 1 treated respiratory parameters at 12 months follow-up period 1 × 10 6 cells/kg (one Bich, hUC-MSCs Chronic obstructive pulmonary Significant decrease in mMRC, CAT scores at 1, 3, and 6 No serious AEs reported 2020 iv dose) disease months follow-up periods (P < 0.05) Open-label single arm clinical study 25 treated Han, hUC-MSCs Not included Pulmonary infection in haploidentical Not discussed UC-MSC infusions did not 2014 hematopoietic stem cell increase the infection rate in transplantation patients undergoing haplo- Open-labeled controlled HSCT; no significant difference 41 treated between two groups (P >0.05) 1 × 10 6 cells/kg Liu, hUC-MSCs Paraquat-induced lung injury Significantly lower maximum SOFA scores in the treatment No serious AEs reported 2012 Open-labeled controlled group compared to control group at 15d after poisoning (P < 5 treated 0.05) Significantly lower LISs in the treatment group compared to pre-treatment and to control group (P < 0.01) LTOT = long-term oxygen therapy; mMRC = Modified Medical Research Council; CAT = COPD Assessment Test; SOFA = Sequential Organ Failure Assessment; LIS = Lung Injury 9 Score