Conges've Heart Failure Cardiopoie'c Regenera've Therapy (CHART-1): - - PowerPoint PPT Presentation

Conges've Heart Failure Cardiopoie'c Regenera've Therapy (CHART-1): Clinical Trial Primary Outcomes

Jozef Bartunek On behalf of CHART-1 Inves<gators and Study Group

Conflict Of Interest

Jozef Bartunek is member of an ins<tu<on which has been a co-founder of Cardio3Biosciences (now Celyad) All consultancy/speakers fees and research contracts are directed to Cardiovasculair Onderzoek and Cardiac Research Ins<tute, Aalst, BE

Background

• Advanced ischemic heart failure with cardiac enlargement leads to poor
• utcomes
• Cell therapy is a paradigm-shiMing interven<on that targets organ

restora<on

• Cardiopoie<c cells, derived by lineage specifica<on of pa<ent own

mesenchymal stem cells, show clinical promise as next genera<on therapy

Objec've

To validate the efficacy and safety of cardiopoie<c cells delivered via a reten<on-enhanced injec<on catheter in advanced ischemic heart failure

CHART-1 Trial Design

• Prospec<ve, mul<center, randomized, sham-controlled, pa<ent/evaluator-

blinded clinical trial executed in 39 centers

• Pa<ents with ischemic heart failure on standard-of-care randomized to:

Ø Ac#ve arm: endomyocardial cardiopoie<c cell therapy Ø Control arm: sham procedure

• Cell Product: C3BS-CQR-1, Celyad, Mont St Guibert, BE
• Delivery Catheter: C-Cathez, Celyad, Mont St Guibert, BE

CHART-1 Trial Criteria

Main Inclusion Criteria

• ≥18 and <80 years
• Ischemic heart failure with LVEF ≤35%
• Heart failure hospitaliza<on or

worsening within 12 months

• NYHA class >II at inclusion with NYHA

class III/IV or INTERMACS class >4 within 12 months

• On guideline heart failure therapy

Major Exclusion Criteria

• Recent myocardial infarc<on or

revasculariza<on prior to screening

• Severe uncontrolled heart failure

within past 1 month

• LeM ventricular thrombus or aneurysm
• LeM ventricular wall thickness < 8 mm

in > 50% of ventricular segments

• Primary efficacy end-point: Finkelstein Schoenfeld hierarchical composite where each pa<ent

was compared to every other pa<ent with respect to: All cause mortality: days alive out of 39 weeks (LVAD and Tx counted as cardiac death) Number of worsening heart failure events: 0, 1, or ≥ 2 Change in MLHFQ: ≥10 point improvement, ≥10 point deteriora<on, no change Change in 6MWD: ≥40m improvement, ≥40m deteriora<on, no change Change in LV ESV: ≥15mL improvement, ≥15mL deteriora<on, no change Change in LV EF: ≥4% improvement, ≥4% deteriora<on, no change Sta#s#cal power: 120 pa#ents per group to provide 87% power for Mann-Whitney es#mator, probability of beGer response in ac#ve, of 0.61 (value >0.5 favors ac#ve treatment)

• Safety assessment: all-cause mortality, aborted sudden death, cardiac transplanta<on,

myocardial infarc<on, stroke, hospitaliza<ons and incidence of adverse events

CHART-1 Clinical Trial

End-points at 39 Weeks

CHART-1 Pa'ent Flow

315 randomised

157 ac<ve 120 with baseline ac<ve procedure* 19 with baseline sham procedure* 158 control 151 with baseline sham procedure*

6 died 1 withdrew consent 18 not mee<ng release criteria, 1 contraindicated 10 died 6 contraindicated 2 withdrew consent

Treated set: 271 pa<ents analyzed for efficacy (120 ac<ve vs 151 sham control) Safety set: 290 pa<ents (120 ac<ve vs 170 sham procedure = 151 sham control + 19 sham procedure)

*3 months between randomiza<on and baseline procedure

CHART-1 Clinical Trial: Baseline Characteris'cs

Ac've (N = 120) Control (N = 151) Age (years) 61.6±8.6 62.1±8.7 Male sex, n (%) 107 (89.2 %) 136 (90.1%) NYHA class II, n (%) 23 (19.2 %) 36 (23.8 %) NYHA class III, n (%) 96 (80.0 %) 114 (75.5 %) NYHA class IV, n (%) 1 (0.8 %) 1 ( 0.7 %) Time from HF diagnosis to screening (months) 44.11 (12.32 - 100.10) 46.27 (15.96 - 97.73) LV Ejec'on frac'on (%) LV end-diastolic volume (mL) MLWHFQ score 27 (23-32) 239.9 (197.4-294.0) 48.8 (39.8-64.8) 28 (24-32) 246.4 (198.2-285.6) 46.5 (37-60) 6 min walk distance (m) 332.5 (282.0-366.8) 332.5 (282.5-367.0) NT-proBNP pg/mL 1083.1 (450-2648.1) 1077.6 (483.7-2260.6) ACE or AR1 blockers, n (%) Betablockers, n (%) Loop diure'cs, n (%) Aldosterone blockers, n (%) Vitamin K antagonists, n (%) ICD/AICD, n (%) CRT, n (%) 109 (90.8) 107 (89.2) 104 (86.7) 94 (78.3) 42 (35) 46 (38.3) 25 (20.8) 137 (90.7) 135 (89.4) 123 (81.5) 109 (72.2) 60 (39.7) 63 (41.7) 25 (16.6)

CHART-1 Clinical Trial

Primary Efficacy Outcome at 39 weeks

Components of the Primary Outcome in Overall Study Pa'ents

Ac've (N = 120) Control (N = 151) P-value All-cause mortality, n (%) 11 (9.2%) 12 (7.9%) 0.696 Number of WHF events, n (%) 0.724 100 (83.3%) 128 (84.8%) 1 11 (9.2%) 14 (9.3%) ≥ 2 9 (7.5%) 9 (6.0%) Change in MLHFQ score from baseline, n (%) 0.116 ≥ 10-point improvement 64 (59.3%) 66 (48.5%) No change 37 (34.3%) 60 (44.1%) ≥ 10-point deteriora'on 7 (6.5%) 10 (7.4%) Change in 6MW distance from baseline, n (%) 0.070 ≥ 40 m improvement 50 (46.3%) 40 (30.5%) No change 39 (36.1%) 69 (52.7%) ≥ 40 m deteriora'on 19 (17.6%) 22 (16.8%) Change in LV ESV from baseline, n (%) 0.259 ≥ 15 mL improvement 51 (50.0%) 56 (45.2%) No change 33 (32.4%) 36 (29.0%) ≥ 15 mL deteriora'on 18 (17.6%) 32 (25.8%) Change in LV EF from baseline, n (%) 0.730 ≥ 4% absolute improvement 69 (67.6%) 82 (66.1%) No change 28 (27.5%) 33 (26.6%) ≥ 4% absolute deteriora'on 5 (4.9%) 9 (7.3%)

Sudden or aborted sudden death: HR 0.16, 95% CI 0.02-1.23, p = 0.04

Safety Assessment Through 39 Weeks

Ac've (N = 120) Control (N = 170) Total deaths (n, Kaplan Meier %) 10 (8.3%)* 14 (8.2%) Peri-procedural death Cardiovascular – Aor<c dissec<on 1 (0.8%) Post-procedural death Cardiovascular Death (n, Kaplan Meier %) 9 (7.6%) 12 (7.1%) Heart Failure or Cardiogenic Shock( n, Kaplan Meier %) 6 (5.0%) 7 (4.2%) Sudden Cardiac Death (n, Kaplan Meier %) 4 (2.4%) Acute Myocardial Infarc<on (n), Kaplan Meier %) 1 (0.9%) Stroke (n, Kaplan Meier %) 1 (0.9%) Undetermined Cause (n, Kaplan Meier %) 1 (0.9%) 1 (0.6%) Non Cardiovascular Death (n, Kaplan Meier %) 2 (1.2%) Peri-procedural unblinded adverse events (n, Kaplan Meier %) 25 (20.8%) 9 (5.3%) Post-procedural blinded adverse events (n, Kaplan Meier %) 62 (52.5%) 90 (53.0%) Safety endpoints Cardiac transplanta<on (n, Kaplan Meier %) 1 (0.9%) Myocardial infarc<on (n, Kaplan Meier %) 1 (0.9%) 1 (0.6%) Stroke (n, Kaplan Meier %) 3 (2.6%) 2 (1.2%) Aborted sudden death (n, Kaplan Meier %) 1 (0.9%) 5 (3.0%)

* One LVAD not counted for safety

• Modifying effect of baseline markers of heart failure severity
• Impact of treatment intensity (number of Injec<ons)

CHART-1 Clinical Trial Exploratory Analyses

CHART-1 Clinical Trial: Exploratory Analyses

Primary Outcome according to Baseline Markers of HF Severity

Exploratory Analysis using the HF Severity Marker

Subpopula'on Treatment Effect Pahern Plot by Baseline LVEDV

STEPP Analysis: subpopula#on treatment effect paGern plot using progressive subgroups of 70 pa#ents with 25 pa#ent overlap .

Exploratory Analysis

Primary Outcome as a Func'on of HF Severity Marker

Ac've (N = 66) Control (N = 96) P-value All-cause mortality, n (%) 3 (4.5) 6 (6.2) 0.658 Number of WHF events, n (%) 58 (87.9) 79 (82.3) 0.342 1 4 (6.1) 9 (9.4) ≥ 2 4 (6.1) 8 (8.3) Change in MLHFQ score from baseline, n (%) ≥ 10-point improvement 43 (68.3) 44 (49.4) 0.043 No change 15 (23.8) 39 (43.8) ≥ 10-point deteriora'on 5 (7.9) 6 (6.7) Change in 6MWT distance from baseline, n (%) ≥ 40 m improvement 27 (42.9) 21 (24.7) 0.116 No change 25 (39.7) 51 (60.0) ≥ 40 m deteriora'on 11 (17.5) 13 (15.3) Change in LV ESV from baseline, n (%) ≥ 15 mL improvement 36 (57.1) 41 (48.2) 0.168 No change 18 (28.6) 23 (27.1) ≥ 15 mL deteriora'on 9 (14.3) 21 (24.7) Change in LVEF from baseline, n (%) ≥ 4% absolute improvement 42 (66.7) 56 (65.9) 0.759 No change 19 (30.2) 22 (25.9) ≥ 4% absolute deteriora'on 2 (3.2) 7 (8.2)

Components of the Primary Outcome in Pa'ents with Baseline LV EDV 200-370 mL

Exploratory Analysis

Change in LV ESV as a Func'on of Treatment Intensity (number of Injec'ons)

• 30
• 25
• 20
• 15
• 10
• 5

5

13 26 39

Change from Baseline, mL

Study Week

C3BS-CQR-1 (N=120) C3BS-CQR-1 (Inject. <= 19) (N=64) C3BS-CQR-1 (Inject. >19) (N=56) P=0.03

Exploratory Analysis

Primary Efficacy Outcome as a Func'on of Baseline LV EDV and Treatment Intensity

≤ < ≤

Ac've (N = 35) Control (N = 96) P-value All-cause mortality*, n (%) 0 (0) 6 (6.2) 0.134 Number of WHF events, n (%) 34 (97.1) 79 (82.3) 0.027 1 1 (2.9) 9 (9.4) ≥ 2 0 (0) 8 (8.3) Change in MLHFQ score from baseline, n (%) ≥ 10-point improvement 25 (71.4) 44 (49.4) 0.055 No change 7 (20.0) 39 (43.8) ≥ 10-point deteriora'on 3 (8.6) 6 (6.7) Change in 6MWT distance from baseline, n (%) ≥ 40 m improvement 15 (42.9) 21 (24.7) 0.122 No change 15 (42.9) 51 (60.0) ≥ 40 m deteriora'on 5 (14.3) 13 (15.3) Change in LV ESV from baseline, n (%) ≥ 15 mL improvement 25 (71.4) 41 (48.2) 0.014 No change 7 (20.0) 23 (27.1) ≥ 15 mL deteriora'on 3 (8.6) 21 (24.7) Change in LVEF from baseline, n (%) ≥ 4% absolute improvement 28 (80.0) 56 (65.9) 0.091 No change 7 (20.0) 22 (25.9) ≥ 4% absolute deteriora'on 0 (0) 7 (8.2)

Components of the Primary Outcome in Pa'ents with Baseline LVEDV 200-370 mL and ≤19 Injec'ons

* Mortality in efficacy analysis defined as death, LVAD or urgent cardiac transplant.

CHART-1 Clinical Trial

Summary

• The largest clinical trial tes<ng cardiopoie<c cells in advanced ischemic heart

failure successfully conducted in a mul<site/mul<na<onal sesng

• The primary efficacy endpoint was neutral in the en<re trial popula<on
• Exploratory analyses suggested a benefit of cell therapy:

– In a large subset popula<on defined by degree of LV dila<on – Driven by consistent trends on clinical end points, quality of life and physical fitness – Treatment intensity with lower number of injec<ons may poten<ate

• utcome

• The CHART-1 trial iden<fied a clinically relevant pa<ent popula<on with

elevated baseline end-diastolic volume that benefited from cardiopoie<c cell treatment

• Op<mized treatment intensity together with disease severity-targeted

pa<ent selec<on should be considered for future trials and/or poten<al cell therapy applica<on in heart failure

CHART-1 Clinical Trial

Clinical Insights

We wish to thank pa'ents and their families for par'cipa'ng in the study Collabora've effort of the CHART-1 team and inves'gators is greatly acknowledged: Steering Commihee: William Wijns, Aalst, Belgium (Chair); Andre Terzic, Rochester, MN, USA (Co-Principal Inves'gator); Jozef Bartunek, Aalst, Belgium (Co-Principal Inves'gator); Gerasimos Filippatos, Athens, Greece; Bernard Gersh, Rochester, MN, USA; Roger Hajjar, New York, NY, USA; Timothy Henry, Los Angeles, CA, USA; Thomas Povsic, Durham, NC, USA; Marco Metra, Brescia, Italy; Michal Tendera, Katowice, Poland Clinical Events Commihee: John R. Teerlink, San Francisco, CA, USA (Chair); Tom De Poher, Aalst, Belgium; Jeffrey Zimmet, San Francisco, CA, USA; Gert-Jan Laarman, Tilburg, The Netherlands (peri-procedural event adjudica'on) Data Safety Monitoring Board: Scoh Waldman, Philadelphia, PA, USA (Chair); Jan Tijssen, Amsterdam, The Netherlands; Adriaan A. Voors, Gronigen, The Netherlands; Cecilia Linde, Stockholm, Sweden Inves'ga'onal sites and their principal inves'gators: Belgium: ZOL Genk: J. Dens; Hôpital Civil de Charleroi: D. Dolatabadi; CHU Mont-Godinne UCL: A. Guedes; AZ Glorieux: A. Heyse; Domaine Universitaire du Sart Tilman: V. Legrand; Cardiovascular Center Aalst: M. Vanderheyden; Bulgaria: Tokuda Hospital Sofia: V. Gelev; City Hospital Clinic Cardiology Center: I. Petrov; Alexandrovska University Hospital, Sofia: D. Vassilev; Hungary: Gohsegen György Országos Kardiológiai Intézet: P. Andreka; Debreceni Egyetem Orvos- és Egészségtudományi Centrum Általános Orvostudományi Kar Kardiológia Intézet: I. Edes; Pécsi Tudományegyetem Klinikai Központ Szívgyógyásza' Klinika: I. Horvath; Semmelweis Egyetem Városmajori Szív- és Érgyógyásza' Klinika: B. Merkely; MH Egészségügyi Központ Kardiológiai Osztály: N. Nyolczas; Ireland: HRB Clinical Research Facility: F. Sharif, Israel: Western Galilee Hospital: S. Atar; Ziv Medical Center: M. Halabi; Barzilai Medical Center: A. Katz; Nazareth Hospital EMMS: M. Omory; Hillel Yaffe Medical Center: M. Shochat, Italy: A.O. Spedali Civili di Brescia: M. Metra; AOUI Verona – Borgo Trento Hospital: C. Vassanelli; Poland: Uniwersyteckie Centrum Kliniczne: M. Gruchala; Biegański Hospital: J. Kasprzak; Krakowski Szpital Specjalistyczny im. Jana: P. Musialek; Górnośląskie Centrum Medyczne Śląskie j Akademii Medycznej: W. Wojakowski ; Serbia: Clinical Hospital Center Zvezdara, Cardiology Clinic: A. Arandjelovic; Clinical Centre of Serbia, Cardiology Clinic: B. Beleslin, P. Seferovic; Clinical Center of Kragujevac: N. Jagić; Clinical Hospital Center Bezanijska Kosa; Cardiology Department: S. Radovanovic; Clinic

• f Emergency Internal Medicine, Military Medical Academy: S. Obradović; Spain: Hospital Universitario Germans Trias I Pujol: A. Bayes Genis; Hospital General Universitario Gregorio

Maranon: F. Fernandez-Aviles; Hospital Clinico Universitario Virgen de la Victoria: J. M. Hernandez-Garcia; Hospital Clinico San Carlos: P. Jimenez-Quevedo; Sweden: Karolinska University Hospital: A. Mansson-Broberg; Switzerland: CardioCentro Ticino, Lugano, Switzerland: T. Mocce‚; United Kingdom: Kings College Hospital, London: J. Hill Interven'onal proctors: Jozef Bartunek, Guy Heyndrickx , Dariouch Dolatabadi, Ricardo Sanz-Ruiz, Wojtek Wojakowski, Branko Beleslin, Warren Sherman Data management and analyses : Momentum Research Interna'onal (MRI), Durham, NC, USA. MRI supervised 4Clinics, Waterloo, Belgium (responsible for data management and analysis

• f biomarker and safety data) and Harvard Clinical Research Ins'tute, Boston, MA, USA (responsible for analysis of efficacy data)

Central laboratories: Cardiac enzymes analyzed at Clinical Reference Laboratory (CRL) Europe LTD, Fordham, United Kingdom, Echocardiograms analyzed at BioClinica, Princeton, NJ, USA

Acknowledgment