Dr. Alexander Lyon Senior Lecturer and Consultant Cardiologist Clinical Lead in Cardio-Oncology Royal Brompton Hospital, London UK

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1 Advanced heart failure - devices, mechanical circulatory support and cardiac transplantation Monday 30 January 2017 Stem cell and gene therapies for heart failure Dr. Alexander Lyon Senior Lecturer and Consultant Cardiologist Clinical Lead in Cardio-Oncology Royal Brompton Hospital, London UK

2 Overview Gene therapy Stem cell therapy Different stem cell subtypes Clinical trials hesc and hips to deliver cardiomyocytes Controversies

3 SERCA2a protein Gene Therapy in Cardiac Failure

4 Cardiomyocyte Calcium Physiology Excitation-Contraction Coupling Image from Bers D. Nature :

5 N=14 High Dose N=9

6 Randomised, double blind, placebo controlled 250 pts with NYHA III-IV chronic systolic HF due to ischemic or dilated cardiomyopathy (LVEF <35%) + 1 of 2 high risk factors for HF High NTproBNP or BNP HF hospitalisation in last 6 months Optimal medical and device HF therapy AAV ab negative* Randomised 1:1 to high dose AAV1.SERCA2a gene therapy vs placebo (1x10 13 drp)

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8 CUPID2 Trial Primary Endpoint no benefit

9 Possible explanations Wrong hypothesis Wrong vector Inadequate delivery of SERCA2a enzymatic activity Vector dose too low False positive CUPID 1 re high dose Detectable vector DNA levels low (20-200copies in n=3) Infusion strategy inadequate Posttranscriptional barrier (mirs) Posttranslational barrier (oxidation, SUMOlyation) Disease severity and duration Duration of functional effect

10 Stem Cell Therapy Cardiac Recovery, Repair or Regeneration? Poss et al Science 2002 Orlic et al Nature 2001

11 Scientific Background 3 basic mechanisms to support the paradigm that stem cell therapy can be used as an effective treatment for HF Cardiogenesis = Myocardial Regeneration very limited numbers (if any) differentiate and engraft into myocardium Angiogenesis = Vascular Regeneration By activating endogenous endothelial progenitor cells Only a small fraction of EPCs may be capable of neovasculogenesis No convincing proof Paracrine Most likely Secretion of cardioprotective factors Vascular growth / remodeling, fibrosis attenuation, modulation of inflammatory pathways, resident stem cells / progenitor cell recruitment

12 Scientific Background Nguyen PK, Rhee JW, Wu JC. JAMA Cardiol Oct 1;1(7):

13 Delivery Routes

14 Clinical Trials

15 Trial BMNSCs Phase Publication date Clinical Stem Cell Trials in Heart Failure Details Registered number Patients Aetiology Endpoints Results Delivery route ixcell-dcm phase 2b 2016 Randomised, double-blind NCT Ischaemic dilated All-cause death, cardiovascular hospital admission, unplanned clinic visits Composite end point met Intramyocardial REGENERATE- DCM phase Randomised, double-blind NCT Non-ischaemic dilated LVEF Improvement in LVEF, NYHA, NTpro BNP Intracoronary FOCUS-CCTRN phase LVESV, maximal oxygen Randomised, double-blind NCT Ischaemic consumption, SPECT reversibility No significant changes Intramyocardial MSCs POSEIDON phase 1/ Randomised, open label NCT Ischaemic Serious adverse events Low incidence of events Intramyocardial C-CURE phase Randomised, open label NCT Ischaemic LVEF Improvement in LV function Intramyocardial PROMETHEUS Phase 1/ Randomised, double-blind NCT Ischaemic Serious adverse events / LV remodellng Improvement in LV function Intramyocardial CDCs CADUCEUS phase Randomised, open label NCT Ischaemic Composite of multiple endpoints including MACE, MRI ventricular assessment Increase in viable mass observed by MRI Intracoronary SCIPIO phase Randomsied, open label NCT Ischaemic Adverse events including death, ventricular tachycardia; MRI ventricular assessment Improvement in LV function / reduction in LV infarct size Intracoronary

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17 CHART - 1 Randomised double blind trial assessing autologous cultured MSCs Symptomatic ischaemic heart failure LVEF <35%, NYHA II-IV Recent HHF or high NT-proBNP The primary efficacy endpoint was a hierarchical composite all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. 484 patients screened n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion n = 315 achieved > 24 million mesenchymal stem cells from BM harvest Randomized 1:1 to autologous cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Bartunek J. Eur Heart J Dec 23. pii: ehw543. doi: /eurheartj/ehw543

18 CHART-1 Results at 39 weeks The primary outcome was neutral (P = 0.27). No difference was observed in serious adverse events. Bartunek J. Eur Heart J Dec 23. pii: ehw543. doi: /eurheartj/ehw543

19 Other Stem Cells Can we deliver cardiomyocytes? Human embryonic stem cell-derived CMs (hesc-cms) Human inducible pluripotent stem cell-derived CMs (hipsc-cms) Shi Y, Inoue H, Wu JC, Yamanaka S. Nat Rev Drug Discov Dec 16. doi: /nrd

20 Landmark Preclinical Studies hesc-cms Seven pigtail macaques (Macaca nemestrina) Intra-myocardial delivery of 1 billion hesc-cms generated significant remuscularization of the infarcted heart Chong JJ. Nature 2014 Jun 12;510(7504):273-7.

21 Clinical Trial with hesc-cms Ongoing trial world first Prof Menasche PI hesc-derived CD15+, Isl-1+ progenitors in addition to CABG and/or mitral valve procedure Ischaemic heart failure Single arm, open label Sheet of cells with fibrin patch 6 patients End-points change in LVEF, viability of grafted area, functional status, MACE

22 Landmark Preclinical Studies ipsc-cms Five HT4 heterozygous monkeys were subjected to myocardial infarction followed by direct intra-myocardial injection of ipsc-cms (4 x 10 8 ipsc-cms) The grafted cardiomyocytes survived for 12 weeks No evidence of immune rejection in monkeys treated with methylprednisolone and tacrolimus Electrical coupling with host cardiomyocytes Ventricular arrhythmias increased Y Shiba et al. Nature 1 4 (2016) doi: /nature19815

23 Controversy

24 Controversy

25 Controversy

26 Summary First gene therapy trials for HF have been completed Safe with AAV vector at dose studied No benefit Clinical trials to date with BMSCs, MSCs and CPCs Paracrine effects Very small or no improvement hesc and hipsc probably best source of new CMs Large animal studies show promise but highlight arrhythmia risk FIM study underway using tissue engineering approach Judge on clinical outcomes and maintain high scientific scrutiny