clinical evidence for immune reprogramming with ......clinical evidence for immune reprogramming...

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Clinical Evidence for Immune Reprogramming with Extracorporeal Mesenchymal Stromal Cell Therapy Barcia, Rita N., PhD1, Nguyen, Sunny, BS1, Brian O’ Rourke , PhD1, Igo, Peter, BS1, Tilles, Arno W., MD, MSBE1, Elizabeth Lapointe1, Chris Gemmiti, PhD 1, Brian LK Miller, MS, MBA1, Parekkadan, Biju, PhD1,2,3 1Sentien Biotechnologies, Inc. 99 Hayden Ave, Suite 140, Lexington, MA 02421 2 Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854 3Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Boston, MA 02114 3Harvard Stem Cell Institute, Cambridge, MA 02138 An interim analysis was performed on the low dose cohort (n=4 in each group). Product Concept: Sentien is developing a combination product (SBI-101) that integrates allogeneic MSCs within an extracorporeal, blood contacting device to fundamentally change the administration route. Instead of bringing MSCs to the blood, our product brings blood to the MSCs. Bioactive molecules secreted by MSCs are the primary source of activity of these therapeutically promising cells. We have engineered a system to maximize delivery of therapy from MSCs to circumvent the half-life issues that have hindered MSC transplantation. This system overcomes the dosing constraints of IV infusion and potentiates a broad range of biological responses unparalleled in single molecule therapeutics. The Sentien Approach: Bringing blood to the MSCs Ex-vivo MSC therapy using SBI-101 technology shows promise for severe COVID-19 Grant Funding Agencies: NIDDK 5R44DK085766 NHLBI 4R44HL128659 SBI-101 Clinical Data in AKI Reflects Broad Immunomodulation Phase I/II: Double blind, randomized, controlled, study at 2 doses to establish safety and pharmacologic POC (NCT03015623) Miller et al., Kidney Int Rep. 2018 SBI-101 Acute Kidney Injury (AKI) trial 2. MSCs secrete therapeutic molecules creating concentrated, sustained microenvironment in SBI-101 3. SBI-101 modulates immune cells leading to a systemic anti-inflammatory response 1. Blood is continuously exposed to MSCs in SBI-101 SBI-101 8-10 US based clinical sites CRRT only (control) CRRT + 250M cells (low dose) CRRT + 750M cells (high dose) Endpoints: 1: Safety 2: Renal specific efficacy Exploratory: PK/PD biomarkers Monocytes T cells B cells Accelerated Kidney Repair MSC Secreted Factors à Systemic Immunomodulation à Immune Cell Reprogramming Therapeutic Hypothesis of MSC-Mediated Blood Reprogramming All patients were on Continuous Renal Replacement Therapy (CRRT) SBI-101 AKI Results are Consistent with Immune Reprogramming *Huang C, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; published online Jan 24. TNF-, MCP-1, and IFN-y are all highly increased in COVID-19 ICU patients* COVID-19 Patient data Screen B Pre-Dose End of Tx Day 1 Day 3 Day 7 0.0 0.5 1.0 1.5 2.0 Change over pre treatment TNFa Tx SBI-101 AKI Patient data Screen B Pre-Dose End of Tx Day 1 Day 3 Day 7 0 1 2 3 4 Change over pre treatment IFNy Tx Screen B Pre-Dose End of Tx Day 1 Day 3 Day 7 0.0 0.5 1.0 1.5 Change over pre treatment MCP-1 Tx Low dose SBI-101 Sham Immunomodulation observed in SBI-101 AKI Clinical Data Supports Therapeutic Hypothesis in COVID-19 **ZHOU, et al., Aberrant pathogenic GM-CSF+T cells and inflammatory CD14+CD16+monocytes in severe pulmonary syndrome patients of a new coronavirus, pre print Healthy control (n=10) ICU (n= 12) Non - ICU (n= 21) Screen B Pre-Dose End of Tx Day 1 Day 3 Day 7 0 1 2 3 Fold Change from Pre-Dose Total Monocytes Tx Inflammatory monocytes have positive correlations with severe pulmonary syndrome in patients infected 2019-nCoV** SBI-101 Sham * Inhibited Activated * Septic subject that got better has pathway profile similar to SBI-101 treatment Phase 1b data suggests that SBI-101 broadly inhibits immune-mediated inflammatory pathways, including: T cell response Maturation of lymphocytes Activation of lymphocytes Immune response of leukocytes Quantity of leukocytes Inflammation of Organ Known MSC biology is very well suited to address the hyper- inflammation associated with severe COVID-19. By addressing a broad array of immune-mediated inflammatory pathways, MSCs can simultaneously address multiple aspects of the inflammatory cascade. SBI-101 therapy allows for extended delivery of MSC secreted factors, harnessing the potential of MSC therapy for systemic inflammatory diseases such as COVID-19. Adapted from From Li, et al. Molecular immune pathogenesis and diagnosis of COVID-19, Journal of Pharmaceutical Analysis, Pre proof MSCs Therapy Ideally Suited for Severe COVID-19 [email protected]

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Page 1: Clinical Evidence for Immune Reprogramming with ......Clinical Evidence for Immune Reprogramming with Extracorporeal Mesenchymal Stromal Cell Therapy Barcia, Rita N., PhD1, Nguyen,

Clinical Evidence for Immune Reprogramming with Extracorporeal Mesenchymal Stromal Cell TherapyBarcia, Rita N., PhD1, Nguyen, Sunny, BS1, Brian O’ Rourke , PhD1, Igo, Peter, BS1, Tilles, Arno W., MD, MSBE1, Elizabeth Lapointe1, Chris Gemmiti, PhD 1, Brian LK Miller, MS, MBA1, Parekkadan, Biju, PhD1,2,3

1Sentien Biotechnologies, Inc. 99 Hayden Ave, Suite 140, Lexington, MA 02421 2 Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854 3Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Boston, MA 02114 3Harvard Stem Cell Institute, Cambridge, MA 02138

An interim analysis was performed on the low dose cohort (n=4 in each group).

Product Concept: Sentien is developing a combination product (SBI-101) that integrates allogeneic MSCs within an extracorporeal, bloodcontacting device to fundamentally change the administration route. Instead of bringing MSCs to the blood, our product brings blood to the MSCs.

Bioactive molecules secreted by MSCs are the primary source of activity of these therapeutically promising cells. We have engineered a systemto maximize delivery of therapy from MSCs to circumvent the half-life issues that have hindered MSC transplantation. This system overcomesthe dosing constraints of IV infusion and potentiates a broad range of biological responses unparalleled in single molecule therapeutics.

The Sentien Approach: Bringing blood to the MSCs

Ex-vivo MSC therapy using SBI-101 technology shows promise for severe COVID-19Grant Funding Agencies:NIDDK 5R44DK085766NHLBI 4R44HL128659

SBI-101 Clinical Data in AKI Reflects Broad Immunomodulation

Phase I/II: Double blind, randomized, controlled, study at 2 doses to establish safety and pharmacologic POC (NCT03015623) Miller et al., Kidney Int Rep. 2018

SBI-101 Acute Kidney Injury (AKI) trial

2. MSCs secrete therapeutic molecules creating concentrated, sustained microenvironment in SBI-101

3. SBI-101 modulates immune cells leading to a systemic anti-inflammatory response

1. Blood is continuously exposed to MSCs in SBI-101

SBI-101

8-10 US based clinical sitesCRRT only (control)CRRT + 250M cells (low dose)CRRT + 750M cells (high dose)

Endpoints:1: Safety2: Renal specific efficacyExploratory: PK/PD biomarkers

Monocytes

T cells

B cells

Accelerated Kidney Repair

MSC Secreted Factors à Systemic Immunomodulation à Immune Cell Reprogramming

Therapeutic Hypothesis of MSC-Mediated Blood

Reprogramming

All patients were on Continuous Renal Replacement Therapy (CRRT)

SBI-101 AKI Results are Consistent with Immune Reprogramming

*Huang C, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; published online Jan 24.

TNF-⍺, MCP-1, and IFN-y are all highly increased in COVID-19 ICU patients*

COVID-19Patient data

Scree

n B

Pre-D

ose

End of T

x

Day 1

Day 3

Day 7

0.0

0.5

1.0

1.5

2.0

Cha

nge

over

pre

trea

tmen

t

TNFa

24hr 250M

Sham

Tx

SBI-101 AKI Patient

data

Scree

n B

Pre-D

ose

End of Tx

Day 1

Day 3

Day 7

0

1

2

3

4

Cha

nge

over

pre

trea

tmen

t

IFNy

24hr 250M

PLTx

Scree

n B

Pre-D

ose

End of T

x

Day 1

Day 3

Day 7

0.0

0.5

1.0

1.5

Cha

nge

over

pre

trea

tmen

t

MCP-1

Tx

Low dose SBI-101

Sham

Immunomodulation observed in SBI-101 AKI Clinical Data Supports Therapeutic Hypothesis in COVID-19

**ZHOU, et al., Aberrant pathogenic GM-CSF+T cells and inflammatory CD14+CD16+monocytes in severe pulmonary syndrome patients of a new coronavirus,

pre print

Healt

hy co

ntro

l (n=

10)

ICU

(n=

12)

Non-

ICU

(n=

21)

Scree

n B

Pre-D

ose

End of T

xDay

1Day

3Day

70

1

2

3

Fold

Cha

nge

from

Pre

-Dos

e

Total MonocytesSham LD 24hrTx

Inflammatory monocytes have positive correlations with severe pulmonary

syndrome in patients infected 2019-nCoV**

SBI-101 Sham

*

InhibitedActivated

* Septic subject that got better has pathway profile similar to SBI-101 treatment

Phase 1b data suggests that SBI-101 broadly inhibits immune-mediated inflammatory pathways, including:

• T cell response• Maturation of lymphocytes• Activation of lymphocytes• Immune response of leukocytes• Quantity of leukocytes• Inflammation of Organ

Known MSC biology is very well suited to address the hyper-inflammation associated with severe COVID-19. By addressing a broad array of immune-mediated inflammatory pathways, MSCs can simultaneously address multiple aspects of the inflammatory cascade.

SBI-101 therapy allows for extended delivery of MSC

secreted factors, harnessing the potential of MSC therapy for

systemic inflammatory diseases such as COVID-19.

Adapted from From Li, et al. Molecular immune pathogenesis and diagnosis of COVID-19, Journal of Pharmaceutical Analysis, Pre proof

MSCs Therapy Ideally Suited for Severe COVID-19

[email protected]