“Portable Normothermic Ex Vivo Lung Perfusion to Reduce Warm Ischemia Time

and Increase Graft Usage "

Gabriel Loor, MD Baylor St. Luke’s Medical CenterSurgical Director Lung TransplantationCo-chief Section of Adult Cardiac Surgery

Disclosures

• Grant support from Transmedics for involvement in EVLP clinical and

translational trials

• Travel reimbursement for study related travel

• United Therapeutics grant support for translational research

• Receive grant support from Maquet for an ECMO in lung transplantation

registry

End stage lung disease

4

15-30% of patients die on the waitlist

Critical organ shortage

5

Donor lungswastedDonor lungsused

20%

80%

Critical organ shortage

Primary Graft Dysfunction

Ex Vivo Lung Perfusion

XPS –Novel Trial

Static Perfusion Systems

Vivo Line –Develop UK Trial

Portable Ex-vivo Lung Perfusion (EVLP)“Breathing Lung Transplantation”

§ Organ Care System Lung (OCS Lung)

§ Portable EVLP platform

§ Normothermic, blood based perfusion, ventilation, monitoring and recruitment

§ Additives – steroids, antibiotics, glucose, multivitamins, insulin

Critical Trends

Pump Flow

VR (Vascular Resistance)

SaO2 & SvO2

Tidal Volume

PAP (Pulmonary Artery Pressure)

PAWP (Peak Airway Pressure)PEEP (Positive End Expiratory Pressure)

Monitoring

12

13

INSPIRE trial

§ Standard Criteria Donors§ PaO2:FiO2 >300mmHg§Age < 65§Organ suitable for either cold storage or OCS§No active pulmonary disease§Non DCD

14

INSPIRE trial

Physiologic parameters on portable EVLP

Total ischemic time and total cross clamp time

Donor lung splitting

• Reduces ischemic exposure even further

• Increases options for size reduction and single lungs to expand the donor pool

18

PGD3 within 72 hours

Resource utilization

20

Survival

21

Summary of portable EVLP in standard donors

• Safe, FDA approved • Mean clamp times of 8 hours, despite lower ischemic

times• Less PGD 3 – better graft function• Trends towards decreased resource utilization• Costs include modules and stationary console • Survival at 12 months and 24 months are similar to ice

storage• CLAD data is not yet available

Can we extrapolate this to extended criteria lungs?

23

Donor lungswastedDonor lungsused

20%

80%

Critical organ shortage

24

The OCS Lung EXPANDI International Trial Results

G. Loor, G. Warnecke, M. Villavicencio, M. Smith, J. Kukreja, J. Moradiellos, A. Varela, J. Madsen, A. Haverich, M. Hertz, A. Ardehali, D. Van Raemdonck

U. Minnesota, Minneapolis, USA; Hannover Medical School, Germany; Massachusetts General Hospital, Boston, USA; St. Joseph’s Medical Center, Phoenix, USA; University of California San

Francisco, USA; University Hospital Puerta de Hierro, Madrid, Spain; Ronald Reagan UCLA Medical Center, Los Angeles, USA; University Hospital Leuven, Leuven, Belgium

• Objective: To evaluate the safety and effectiveness of the OCS™

Lung System to recruit, preserve and assess non-standard donor lungs that may not meet current standard donor lung acceptance criteria for transplantation

• Trial Design: Prospective single arm multi-center international pivotal trial focusing on improving utilization of non-ideal donor lungs for double lung transplantation

OCS Lung EXPANDI Trial

EXPAND Lung Donor Eligibility

Inclusion ExclusionDonor PaO2/FiO2 ≤ 300 mmHg

Expected Ischemic time > 6 hours

DCD Donors

Donor Age ≥ 55 years

Moderate/Severe Lung Injury

Presence of Active Pneumonia

History of Active Lung Disease

Blood Transfusion >10 pRBCs

ABO Incompatibility

Tobacco history >20 pack years

EXPAND I Trial

Did Not Meet Tx Criteria on OCS N=12

Recipient Txed. with OCS Lungs N= 79

Met Transplant Criteria on OCS N=81

OCS Perfused Donor Lungs N=93

Not TransplantedN=1 Recipient dx. lung CaN=1 No surgeon available

87% Yield Rate

30

DCD + other (N=6, 50%)

Age > 55 yo(N=4, 33%)

DCD isolated (N=1, 8%)Anticipated ischemic time > 6 hrs(N=1, 8%)

Lungs screened out on OCS

31

Donor lung inclusion characteristic(s)

Percentage of donor entries

PF < 300 25%DCD 33%Anticipated ischemic time > 6 hours

32%

Age > 55 yo 39%> 1 inclusion 27%

52 U.S. Transplanted Donors in EXPAND had an Avg. of 39

Declines by other U.S. Centers in UNOS Match Run

Donor lung inclusion characteristics

32

Transplanted Recipients with OCS LungsN=79

Age (years) (Mean ± SD) 55.6 ± 10.6 (32 – 74)Female Gender 33 (42%)Male Gender 46 (58%)LAS Score (Range) 42 ± 13 (31 – 93)Primary Diagnosis

COPD 31 (39%)IPF 23 (29%)CF 12 (15%)Sarcoidosis 2 (2%)Other 11 (14%)

Secondary Pulmonary Hypertension 22 (28%)Transplanted on CPB 38 (48%)

Recipient characteristics

Reduced Cold Ischemic Times Despite Extended Total Clamp Times

8.510.1

2.63.9

0

2

4

6

8

10

12

14

1st Lung 2nd Lung

Total Out of Body Time Total Ischemic Time

Mean Time(Hours)

EXPAND Lung Trial – EVLP Physiology

351

320

100

150

200

250

300

350

400

Initial OCS Assessment

Final OCS Assessment

1211

0

2

4

6

8

10

12

14

Initial OCS Assessment

Final OCS Assessment

378409

100

150

200

250

300

350

400

450

Donor Assessment

Final OCS Assessment

Vascular Resistance (dyn·s/cm5 ) Peak Airway Pressures (CmH2O) PaO2/FiO2 Ratio

EXPAND I Trial

Post-Transplant Patient Survival

Patient Survival 1, 6 and 12 months98.7%

93.7% 91.1%

0%

20%

40%

60%

80%

100%

Proportion (%)

1 month 6 months 12 months

Patient Survival EXPANDI vs INSPIRE Cohorts98.7

93.7 91.199.5

90.887

0

10

20

30

40

50

60

70

80

90

100

30 Days 6 Months 12 Months

EXPAND Trial (Extended Criteria Donors) INSPIRE Trial Control (Standard Criteria Donors)

37

Proportion (%)

EXPAND Patient Survival vs Standard of Care98.7

93.7 91.199.5

90.8 90.296.2

90.285

0

10

20

30

40

50

60

70

80

90

100

30 Days 6 Months 12 Months

EXPAND Trial (Extended Criteria) INSPIRE Trial Control (Standard Criteria) US National UNOS Data

Proportion (%)

EXPAND I Trial

Primary Graft Dysfunction Grade 3

EXPAND I Trial PGD3 Rates

40.5%

16.5%

9.0%6.4%

0%

10%

20%

30%

40%

50%

Proportion (%)

T0 T24 T48 T72

44.30%

0%

10%

20%

30%

40%

50%

PGD3 Within Initial 72 Hours

PGD3 Rates EXPAND (ECD) vs INSPIRE (SOC)

40.5

16.5

96.4

20.7

10.9

6.6 5.5

0

10

20

30

40

50

T0 T24 T48 T72

EXPAND I Trial INSPIRE Trial Control

Proportion (%)

44.3%

28.8%

0%

10%

20%

30%

40%

50%

PGD3 Within Initial 72 Hours

EXPAND Trial INSPIRE Trial Control

Incidence of PGD3 Within 72 hours Incidence of PGD3 At Each Timepoint

PGD3 in EXPAND (OCS) and DEVLOP UK Trial (Static)

42

Proportion (%) 40.5%

16.5%9.0% 6.4%

88.9%

44.4%38.9%

27.8%

0%

20%

40%

60%

80%

100%

T0 T24 T48 T72

EXPAND Trial DEVELOP UK TrialFisher A, et al.; An observational study of donor ex-vivo lung perfusion in UK lung transplantation: DEVELOP-UK

HTA 2016 Vol20, No. 85

PGD3 Stratified by Donor Inclusion Criteria

40% 41%48%

61%

0%

20%

40%

60%

80%

100%

PF Ratio <300mmHg

Age > 55 YO Ischemic Time >6hours

DCD Donors

Proportion (%)

PGD3 Rates in EXPAND (OCS) and NOVEL Extension (XPS) by Donor Inclusion

15.4%

7.7% 7.7%

50.0%

29.2%25.0%

0%

20%

40%

60%

T24 T48 T72

EXPAND Trial NOVEL Extension

17.0%

9.6%5.8%

21.1%

12.7%8.5%

0%

20%

40%

60%

T24 T48 T72EXPAND Trial NOVEL Extension

44

Proportion (%)

Whitson, B.A., et al. Ex-Vivo Lung Perfusion in Donation after Circulatory Death Lung Transplantation Increases Donor Utilization: Analysis of the NOVEL Extension Trial, No. 355, ISHLT 2018 Annual Meeting, Nice, France.

Incidence of PGD3 DCD Donor Population Incidence of PGD3 DBD Donor Population

Portable EVLP in Extended Criteria Donors

• Excellent survival with Extended Criteria Donors (EXPAND)

• But still have a burden of PGD with Extended Criteria Donors

• Static platform also FDA approved – need to further understand options.

4 8 12 16 20 24

Perfusion Time (hrs)

StandardDonor run (INSPIRE)

Extended criteriaDonor run (EXPAND)

Ris

k of

PG

D

Effects of time on portable EVLP on incidence of PGD remain unknown

Does this curve change if the parameters are excellent on EVLP??

THANK YOU!JLH Foundation grantMcDonald GrantUniversity of Minnesota Lillehei InstituteUnited TherapeuticsRobert and Sonja Steinberg FoundationUniversity of Minnesota CollaboratorsVisible Heart Lab OCS Investigators collaborators