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

Brian Mehling, MD Orthopedic Surgeon CMO, BHI Therapeutic Sciences

Umbilical Cord Mesenchymal Stem Cell Therapy for COVID 19

BHI Therapeutic Sciences (BHITS) is a healthcare consulting company with a unique concept that combines therapy, research, and philanthropy.

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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)

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)

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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

intervals described in the research protocol.

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Used Stem Cell Sources, Treatment Modalities and Outcome Measures

Stem Cell Quality

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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.

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FDA Endorsed Investigational New Drug Application: Evaluation of the Safety and Efficacy of HPC, Cord Blood in Subjects With Acute Ischemic Stroke

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. The study is registered on ClinicalTrials.gov ClinicalTrials.gov Identifier: NCT03735277 Protocol Number: BHI17-IS-A IND number: 018171 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

• f acceptability of chemistry, manufacturing, and controls (CMC) information and Pharmacology and Toxicology

information for Hemacord as indicated in the product labeling.

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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

• f 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.

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Published Clinical Studies of Mesenchymal Stem Cell Therapy for COVID-19

Citation Cells Administered Total Cell Dose (Dose Schedule) Indication Study Design

• No. of Patients

Efficacy Safety Leng, 2020 MSCs 1 × 106 cells/kg (one iv dose) COVID-19 Pneumonia Placebo controlled 3 control 7 treated

• Decrease in plasma C-reaction protein

level and increase in oxygen saturation.

• Elimination of overactivated cytokine-

secreting immune cells CXCR3+CD4+ T 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). No treatment-related AEs in clinical, laboratory, and radiological examination. Liang, 2020 hUC-MSCs 5×107cell (three iv doses) COVID-19 infection Case Report 1 treated

• Decrease in serum bilirubin, CRP,

and ALT/AST.

• Significant increase in CD3+ T cell,

CD4+ T cell, and CD8+ T cell.

• CT image indicate relief in both left and

right lung. No serious AEs reported.

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Published Clinical Studies of Human Umbilical Cord Mesenchymal Stem Cell Therapy for Pulmonary Disorders

Citation Cells Administered Total Cell Dose (Dose Schedule) Indication Study Design

• No. of Patients

Efficacy Safety Chang, 2014 hUCB-MSCs 1x107 cells/kg and 2x107 cells/kg (one intratracheal dose) Bronchopulmonary Dysplasia Phase I dose-escalation trial 9 treated (3 received low dose, 6 - high dose)

• Significant decrease in MMP-9,

IL-6, IL-8, TNF-a, and TGF-b levels compared with those at baseline or at day 3 post-transplantation (P < 0.05) No serious AEs reported. Significantly lower BPD severity in the MSC treatment group compared to historical control (P = 0.036). Zhang, 2017 hUC-MSCs 5x106-1x107/ml (one iv dose) Severe idiopathic pulmonary fibrosis Case Report 1 treated Reduction of LTOT requirement Improvements in physical performance, quality of life, and respiratory parameters at 12 months follow-up period No serious AEs reported Bich, 2020 hUC-MSCs 1 × 106 cells/kg (one iv dose) Chronic obstructive pulmonary disease Open-label single arm clinical study 25 treated Significant decrease in mMRC, CAT scores at 1, 3, and 6 months follow-up periods (P < 0.05) No serious AEs reported Han, 2014 hUC-MSCs Not included Pulmonary infection in haploidentical hematopoietic stem cell transplantation Open-labeled controlled 41 treated Not discussed UC-MSC infusions did not increase the infection rate in patients undergoing haplo- HSCT; no significant difference between two groups (P >0.05) Liu, 2012 hUC-MSCs 1 × 106 cells/kg Paraquat-induced lung injury Open-labeled controlled 5 treated Significantly lower maximum SOFA scores in the treatment group compared to control group at 15d after poisoning (P < 0.05) Significantly lower LISs in the treatment group compared to pre-treatment and to control group (P < 0.01) No serious AEs reported LTOT = long-term oxygen therapy; mMRC = Modified Medical Research Council; CAT = COPD Assessment Test; SOFA = Sequential Organ Failure Assessment; LIS = Lung Injury Score

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Wuhan Hamilton Biotechnology Co., Ltd: Umbilical Cord Mesenchymal Stem Cell Therapy for COVID 19

Yet to be published preliminary data from our associate in Wuhan, China, Dr. Dongcheng Wu (Wuhan Hamilton Biotechnology Co., Ltd), has shown promise in the treatment of hospitalized patients with COVID-19 pneumonia. The clinical trial, conducted by Puren Hospital Affiliated to Wuhan University of Science and Technology and Wuhan Hamilton Biotechnology Co., Ltd (Hubei, China) is aimed to evaluate the safety and efficacy of UC-MSCs in 48 patients with pneumonia caused by 2019 novel coronavirus. Preliminary results indicate that UC-MSC therapy is safe and effective in therapy of patients with pneumonia caused by 2019 novel coronavirus. Nine intensive care unit patients showed significant improvement with no adverse reactions. ClinicalTrials.gov Identifier: NCT04293692 The UC-MSCs complies with the requirements of the “Volume Ⅲ of the Pharmacopoeia of the People’s Republic of China (2015 Edition)”, and passed the quality test of China National Institutes of Food and Drug Control (Wuhan Hamilton Biotechnology Co., Ltd is currently the only stem cell institution in Hubei province that the stem cells product has passed the review of China National Institutes of Food and Drug Control). BHITS received IRB approval on the study conducted by Wu et al in China “Retrospective Case Series Study of Umbilical Cord Mesenchymal Stem Cell Therapy in Previously Treated Subjects with Pneumonia Caused by 2019 Novel Coronavirus”. Protocol number: BHITS20- 2019-nCoV IRB approval number: IRCM-2020-243

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BHITS Study of Umbilical Cord Mesenchymal Stem Cell Therapy for COVID 19

Product Name: Human Umbilical Cord Mesenchymal Stem Cells (hUC-MSCs) Chemical name and structure The clinical grade hUC-MSCs will be supplied by Wuhan Hamilton Biotechnology Co., Ltd. (Wuhan, China). The cell product has been certified by the National Institutes for Food and Drug Control of China. The final cell product of the human umbilical cord mesenchymal stem cells (UC-MSCs) is presented as cell suspension for infusion containing 0.5 × 10^6 cells/kg UC-MSCs in 100mL 1% human albumin saline. Specifications: Active ingredient: human umbilical cord mesenchymal stem cells (UC-MSCs) Cell viability: ≥85% Surface antigen molecules:

• positive rates of CD73, CD90, CD105 ≥95%
• positive rates of CD31, CD34, CD45, HLA-DR≤2%.
• Product supplements: 0.9% sodium chloride injection (saline) containing 1% human serum albumin.
• Each dose of stem cell preparation contains 25-50×10^6 UC-MSCs/100ml/ bag

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The Rationale and Proposed Indications

The rationale for this clinical study is the further characterization of the safety and efficacy of UC-MSCs, delivered via an intravenous route of administration, for treatment of symptomatic COVID-19 pneumonia in hospitalized patients and continued respiratory disability after acute COVID-19 Infection. Proposed Indications: Evaluation of the Safety and Efficacy of Human Umbilical Cord Mesenchymal Stromal Cells (hUC-MSCs) in the Treatment of Hospitalized Subjects with Severe COVID-19 Pneumonia Evaluation of the Safety and Efficacy of Human Umbilical Cord Mesenchymal Stromal Cells in the Treatment of Continued Respiratory Disability after Acute COVID-19 Infection

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Previous Submissions

In April 2020, two clinical study proposals for hUC-MSCs in the Treatment of Hospitalized Subjects with Severe COVID-19 Pneumonia and Continued Respiratory Disability after Acute COVID-19 Infection were submitted to medicalcountermeasures.gov to request the U.S. government Coronawatch Meeting. The email acknowledging the receipt of our submission was received from TechWatch. The study is currently under review. In April 2020, two clinical study proposals for hUC-MSCs in the Treatment of Hospitalized Subjects with Severe COVID-19 Pneumonia and Continued Respiratory Disability after Acute COVID-19 Infection were submitted to a special emergency program created by FDA - Coronavirus Treatment Acceleration Program (CTAP). The study is currently under review.

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(1) BHITS Collaboration with DataRevive USA LLC

The study package, prepared by our associate in Wuhan, China, Dr. Dongcheng Wu (Wuhan Hamilton Biotechnology Co., Ltd) for the clinical trial of human umbilical cord mesenchymal stem cells in the treatment of novel coronavirus's severe pneumonia, was shared with us with intention to use this information for our IND application. DataRevive will support BHITS with the following:

• Review and assessment of the manufacturing process for the umbilical cord stem cell product described in

the study package, provided by Wuhan Hamilton Biotechnology.

• Determination of acceptability of Chemistry, Manufacturing, and Control (CMC), and Pharmacology and

Toxicology studies performed by Wuhan Hamilton Biotechnology for our IND application.

• Identification of the potential deficiencies from a scientific and regulatory perspective in the program.
• If CMC and Pharmacology and Toxicology studies conducted by Wuhan Hamilton Biotechnology are not

sufficient for our IND application, determination of further actions in the project.

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(2) BHITS Collaboration with DataRevive USA LLC

DataRevive will support BHITS with the following: If CMC and Pharmacology and Toxicology studies conducted by Wuhan Hamilton Biotechnology are sufficient for our IND application, support with the following: Preparation for Pre-IND meeting (if necessary) IND application support: Module 1—Administrative Information: Module 2—Summaries:

• Section 2.2—Introduction
• Section 2.3— Quality overall summary
• Section 2.4—Nonclinical Overview
• Section 2.5—Clinical Overview

Module 3 – CMC Module 4 – Nonclinical (Pharmacology and Toxicology) Module 5 – Clinical