No option-patients : Is angiogenesis with gene or cell therapy still an option?

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1 No option-patients : Is angiogenesis with gene or cell therapy still an option? Professor Sigrid Nikol Clinical and Interventional Angiology Asklepios-Klinik St. Georg Hamburg, Germany

2 Angiogenic gene therapy trials: randomized placebo-controlled phase II TRIAL Disease targeted Growth factor Route of delivery Pt. # included Result RAVE PAD claudication VEGF 121 intramuscular 105 negative for peak walking distance WALK PAD claudication Hif-1a intramuscular 287 negative for peak walking distance DELTA-1 PAD claudication Del-1 intramuscular 105 negative for peak walking distance VEGF PVD PAD CLI VEGF 165 local catheter-mediated 54 positive for angiogr. increase of collaterals Groningen trial PAD CLI VEGF 165 intramuscular 54 positive for hemodynamics TALISMAN 201 PAD CLI FGF-1 intramuscular 125 positive for amputation HGF-STAT PAD CLI HGF intramuscular 104 positive for TcPO2 HGF-CLI PAD CLI HGF intramuscular 40 Postive for rest pain and ulcer size

3 Primary outcome event rate (%) Belch J, Hiatt WR, Baumgartner I, Driver IV, Nikol S, Norgren L, Van Belle E; Lancet. 377(9781): , 2011 TAMARIS Primary Endpoint Time to Major Amputation or Death NV1FGF 30 Placebo Placebo N=259 NV1FGF N=266 Hazard ratio (95% CI) P 5 Major amputation or death 86 (33.20%) 96 (37.07%) 1.11 (0.83, 1.49) 0.48 Number at Risk Months since randomization Placebo NV1FGF

4 Cell therapy any better?

5 Effect via growth factors released by human endothelial progenitor cells Human EPCs were transplanted into immunocompromised nude mice, and the levels of cytokines were measured by both human- and mouse-specific primers and probes. Cho HJ J Exp Med. 204: , 2007

6 Clinical trials for PAD: Bone marrow-derived cells Study level: 1a, double-blind; 1b, randomised, non-blinded controlled trial; 2, controlled trial; 3, cohort study/historical controls; 4. patient series/uncontrolled trial Lawall H et al, Thromb Haemost 2010; 103:

7 Clinical trials in PAD: Mobilised mononuclear blood cells Study level: 1a, double-blind; 1b, randomised, non-blinded controlled trial; 2, controlled trial; 3, cohort study/historical controls; 4. patient series/uncontrolled trial Lawall H et al, Thromb Haemost 2010; 103:

8 Powell et al. J Vasc Surg 2011 Autologous bone marow cells RESTORE CLI 1st prospective, randomized double-blind, placebo-controlled multicenter trial 79 pt. Time to first occurence of therapy failure: combined endpoint for major amputation, doubeling of ulcer size, occurence of new gamgrene or death positive Amputation-free survival

9 Teraa M et al, Circulation Jan 7. [Epub ahead of print] Effect of Repetitive Intra-Arterial Infusion of Bone Marrow Mononuclear Cells in Patients With No-Option Limb Ischemia: The Randomized, Double-Blind, Placebo-Controlled JUVENTAS Trial. negative 160 patients with severe, non-revascularizable limb ischemia to prevent major amputation Repetitive (3x; 3-weeks interval) intra-arterial infusion of BMMNC or placebo. Primary endpoint major amputation at 6 months: - 19% in the BMMNC vs. 13% in the placebo group (Relative risk [RR] 1.46; 95% confidence interval [CI] 0.62 to 3.42), not significantly different Safety endpoints at 6 months: - all-cause mortality, occurrence of malignancy or hospitalization due to infection) not significantly different between the groups (RR 1.46; 95%CI 0.63 to 3.38) - all-cause mortality at six months with 5% vs. 6% (RR 0.78; 95%CI 0.22 to 2.80). Secondary outcomes: - quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up with no significant differences between the groups.

10 Forest plot with 95% CIs pain (after 4-8 weeks, 12 weeks, 24 weeks and 48 weeks) in the RCT group (A) and the non-rct group (B) Wang Z-X J Atheroscler Thromb, 2014; 21:1183

11 Forest plot with 95% CIs pain (after 4-8 weeks, 12 weeks, 24 weeks and 48 weeks) in the RCT group (A) and the non-rct group (B) Wang Z-X J Atheroscler Thromb, 2014; 21:1183

12 Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials Teraa M et al. Ann Surg Dec;258(6):922 Meta-analysis of all randomized controlled trials (RCTs) - BM-derived cell therapy compared to standard care with or without placebo - in CLI patients - Major amputation and amputation-free survival were considered as the primary endpoints - 12 RCTs jointly including 510 CLI patients When only the placebo-controlled RCTs were considered, major amputations rates were considerably reduced and nonsignificant (RR = 0.78; 95% CI, ; P = 0.46). Amputation-free survival did not significantly differ between the BM treated and the control group (RR = 1.16; 95% CI, ; P = 0.22). CONCLUSIONS: Results of placebo-controlled and non-placebo-controlled RCTs seem to diverge, which stresses the necessity to use placebo in the control arms of these trials as well as long-term follow-up data to assess durability of treatment effects.

13 With inceasing cardiovascular risk less progenitor cells are available! The number of EPCs correlates inversely with the Framingham risk score of each individual patient Hill JM et al. N Engl J Med, 348: , 2003

14 Lower circulating progenitor cell levels in CLI patients Teraa M et al. PLoS One. 2013; 8(1): e55592

15 Teraa M et al. irc Res. 2014;114:311 Critical limb ischemia (CLI) is associated with decreased microvascular density Microscopic photographs of -human bone marrow from control (A), -CLI-diabetes mellitus (DM)+ (B), -and CLI-DM (C) donors, stained for microvascular marker CD34. A distinction was made between microvessels (MVs) and nonvessel structures, most likely hematopoietic stem cells (HSCs).

16 EPC levels and mobilization in diabetes Diminished mobilization response in diabetes Westerweel PE et al. PLoS One. 2013;8(3):e60357

17 Other sources of allogenic cells possible??

18 PLX- Placenta-derived stem cells for Peripheral Artery Disease

19 The PLX Manufacturing Platform Placenta Adherent stromal cells (ASCs) at the 2D growth phase Carrier Bioreactor 19

20 Angiogenesis PLX Secrete Angiogenic Factors VEGF (pg/ml) PLX PLX + TGFb PD B03 PD270611AS1 PD B04 P150811R01 P060711R02 PLX-1 PLX-2 PLX-3 PLX-4 PLX-5 186B02 VEGF is secreted by PLX TGF beta stimulates VEGF secretion in PLX

21 Angiogenesis Tube Formation EGM (positive control) EBM2 EBM2 +PLX CM PLX conditioned media induce tube formation in endothelial cells

22 Drug Delivery Platform PLX cells are administered Intramuscularly Ongoing randomized trial in claudicants Randomized trial in CLI being prepared

23 Other Options? Yes! - Neuronal stem cells - Mesenchymal stem cells - Genetically modified cells - Induced stem cells - Germline stem cells -...

24 Thank-you