orca-t, a precision treg-engineered donor product ...orca-t standard of care 0 100 200 300 400 0 50...

Orca-T, a Precision Treg-Engineered Donor Product, Prevents Acute GvHD with Less Immunosuppression in an

Early Multicenter Experience with Myeloablative HLA-Matched Transplants.

Everett H Meyer, MD, PhD1, Rasmus Hoeg, MD2, Anna Moroz, MD, PhD1, Bryan Xei, BS1, Hsin-Hsu Wu, MD1, Rahul Pawar1,

Kartoosh Heydari, MD1, David B. Miklos, MD, PhD1, Parveen Shiraz, MD1, Lori S. Muffly, MD, MS1, Sally Arai, MD, MS1, Laura J.

Johnston, MD1, Robert Lowsky, MD, FRCP1, Andrew R. Rezvani, MD1, Judith A Shizuru, MD, PhD1, Wen-Kai Weng, MD, PhD1,

Nathaniel Fernhoff, PhD6, Gerhard Bauer2, Arpita Gandhi, MD, MS3, Amy Putnam6, J. Scott McClellan, MD, PhD6, Bronwen E.

Shaw, PhD, MRCP, FRCPath4, Joseph P. McGuirk, DO5, Mehrdad Abedi, MD2 and Robert S. Negrin, MD1

1Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA | 2Institute For Regenerative Cures (IRC),

University of California Davis, Sacramento, CA | 3Oregon Health Sciences University, Portland, OR | 4CIBMTR (Center for

International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI | 5Department of Blood and Bone Marrow Transplant, The University of Kansas Medical Center, Kansas City, KS | 6Orca Bio,

Menlo Park, CA

Conflicts of interest | Everett Meyer, MD, PhD

Co-founder, scientific advisor

Co-founder, scientific advisor

Scientific Advisory Board

Scientific Advisory Board

Sponsored Research Support

Graft versus Host Disease (GvHD) remains a major problem in hematopoietic stem cell transplantation (HSCT)

Day 0: Infusion into Patient

Day -2: Collection of Donor Cells

Conventional Graft

GvHD in HSCTs

• Donor T-cells drive GVHD pathophysiology

• 40 years of clinical research to control GVHD by controlling donor T cell

GvHD risk with reduced T-cell grafts remains significant

T-cell reduced grafts

• Previous studies employing T cell reduction of allografts alone still show significant acute and chronic GVHD with single-agent cyclosporin prophylaxis*

low

med

high

104 106 108

T cells per kg

Ris

k o

f G

vHD No PPX 1-agent PPX insufficient

T-cell reduced ConventionalT cell depleted

*Montero et al. BBMT 12:1318-1325 (2006)Nakamura et al. BJH 115:95-104 (2001)

Barrett et al. BMT 21: 543-551 (1998)

Tregs in hematopoietic stem cell transplantation

CellProcessing Tcons

Day +2

Day 0

Tregs &HSPCs

Day 0: Infusion into Patient


Conventional Graft

Conventional Transplant High-Precision Orca-T


Infusion into Patient

Eddinger et al. Nature Medicine 2003 Sep;9(9):1144-50. | Trzonkowski et al. Clin Immunol. 2009 Oct;133(1):22-6.

Di Ianni M, et al. Blood. 2011;117(14):3921–3928. | Brunstein, et al. Blood 2016 Feb 127 (8):1044-51. | Kellner H, et al.

Oncotarget 2018 Nov 2;9(86):35611-35622.

Orca-T

Evaluation of high-precision Orca-T to control GvHD

Orca-T + 1-agent PPX

• Yield of Treg from apheresis: 2-3 million Treg/kg

• Target ratio of T-cell to Treg: 1:1

• Conventional T-cell dose: 3 million/kg

• CD34 dose: >2 million/kg

low

med

high

104 106 108

T cells per kg

Ris

k o

f G

vHD

ConventionalT cell depleted

1-agent PPX

No PPX

Clinical protocol Orca-T

Meyer, E. H., Laport, G., et al. JCI INSIGHT. 2019; 4 (10)

MA Conditioning

Day 0: Infusion of HSPCs and Treg(cell dose: 3e6 Treg/kg)

Day +2: Infusion of Tcon(cell dose: 3e6 Tcells/kg)

Post-Transplant

Start Day +3: Single-agent Tacrolimus (4-6 ng/mL target)

Post-Transplant

Day 0: Infusion of Apheresis Product (cell dose: 10e8 – 10e9 Tcells/kg)

Day -1: Tacrolimus

Days +1, +3, +6, +11: Methotrexate prophylaxis

MA Conditioning

SOC

Orca-T

Day-10 to Day-2:MA Conditioning

Day-10 to Day-2:MA Conditioning

Clinical protocol Orca-T

Eligible Patients

High risk, MRD+, active disease

Leukemia, Lymphoma, MDS, MPN

Myelodysplastic syndrome

KPS >70

Age

Patient demographics Orca-T and SOC control cohortOrca-T* SOC Control Cohort

Cohort size 50 144

Median age (range) 47 (20-65) 48 (20-64)

% Male 52% 49%

Race White 60% 44%

African American 2% 2%

Asian 14% 19%

Unspecified 26% 30%

Primary Disease % AML 42% 53%

ALL 28% 26%

CML 4% 7%

B-cell lymphoma 2% 6%

MDS/MF 16% 22%

Other (e.g. mixed phenotype acute leukemia)

8% 2%

Graft source HLA-matched siblings/URD 62%/38% 56%/44%

% with active leukemia at time of transplant 23% 21%

Median f/u (days) 223 days (30 – 1561 days) 886 days (55-1783 days)

* subjects with ≥ 30 days f/u. Data from NCT04013685 and

NCT01660607

Orca-T manufacturing and supplyVein-to-vein times of less than 72 hours across the continental United States

NMDP Apheresis Centers

Mfg & Supply Summary• Manufacturing and logistics carried out by

Orca Bio • 12+ participating clinical sites in the

continental US across 3 studies• Product sourced from MRD and MUDs• Consistent vein-to-vein time of less than 72

hours• No manufacturing nor logistic failures to

date (90+ patients treated across all studies)

Clinical center

Orca Bio GMP

Treg Cell Dose

(by CD45+ Moxi count)

(in millions of cells/kg)

0

1

2

3

4

Treg

cell

do

se (

millio

n c

ells

/kg

)

HSPC DP Cell Dose

(by CD45+ Moxi count)

(in millions of cells/kg)

0

5

10

15

20

HSPC

cell

do

se (

millio

n c

ells

/kg

)

Treg % Purity

Surface Stain

80

85

90

95

100

Treg

% C

D4

5+

ce

lls

Orca-T manufacturing and supply Central manufacturing with consistent quality and performance to date

Treg Cell Doses %Treg PurityCD34

Orca-T Standard of Care

0

10

20

30

40

5060

80

100

Da

ys

****

Orca-T Standard of Care

0

10

20

30

Da

ys

****

More rapid engraftment & hospital discharge with Orca-T

Median 15 vs 17 days; p=0.01

Time to Platelet Engraftment (Days) Time from Day 0 Hospital Discharge (Days)Time to Neutrophil Engraftment (Days)

Median 11 vs 17 days; p

0

10

0

20

0

30

0

40

0

0

10

20

30

40

50

Days

Pe

rce

nt

wit

h E

xte

nsi

ve c

GV

HD Standard of Care

Orca-T

0

50

10

00

10

20

30

40

Days

Pe

rce

nt

wit

h G

rad

e

2 a

GV

HD

Orca-T

Standard of Care

Profound reduction of GVHD with Orca-T

Chronic GvHDGrade ≥2 Acute GvHD

10%p=0.005

30%

3%

p=0.0002

46%

0 100 200 300 400

0

5

10

15

20

25

Days

TR

M

Orca-T

Standard of Care

0 100 200 300 400

0

50

100

Days

GR

FS

(%

)

Standard of Care

Orca-T

Significant improvement in GVHD-free relapse-free survival with Orca-T

GVHD (≥ grade 3) and Relapse-Free SurvivalTreatment-Related Mortality

11%

75%

p=0.04

p=0.001

0%

31%

Durable disease control demonstrated with Orca-T

Orca retains GvT effect• Despite markedly reduced GVHD rates

with Orca-T, early data suggests that GvTeffect is preserved

• Patients at relapse or with at least 180 days of follow up.

Deceased

Active/refractory disease/PR

CR, MRD+

CR, MRD-

Pre-Orca-T Day 90 Day 180 Day 356

Orca-T presentation summary

Disease control demonstrated in several patients with active disease at time of Tx

Central GMP laboratory production with no manufacturing/distribution failures

Vein-to-vein times of less than 72 hours across the continental United States

No Transplant Related Mortalities observed to date.

GRFS GvT

GvHD

TRM

1-yr GVHD relapse-free survival (GRFS) more than doubled compared to SOC.

Dramatically reduced acute and chronic GvHD compared to SOC despite reduced use of immunosuppressive meds.

Orca-T has been granted Regenerative medicine advanced therapy (RMAT) by the FDA

Improved time-to-engraftment compared to SOC.

Engraft

Questions?

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