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 combinestherapy, research, and philanthropy.

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Our research studies designed to measure the safety and efficacy of intravenous, intra-articular, and intrathecalstem cell therapies. Our comprehensive stem cell protocols employ well-targeted combinations of autologousadipose stem cells, and allogeneic human umbilical cord blood and tissue stem cells that treat various medicalconditions 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) 6

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

of 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

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.

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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 MesenchymalStem 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