Angiogenesis. Biologic Therapy in the Treatment of Critical Limb Ischemia. Presenter Disclosure Information

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1 Biologic Therapy in the Treatment of Critical Limb Ischemia Richard J. Powell MD Section of Vascular Surgery Dartmouth-Hitchcock Medical Center 1 Presenter Disclosure Information Richard J Powell, MD FINANCIAL DISCLOSURE: Consultant AnGes Inc Aestrom Boston Scientific DSMB Aldagen EV3 CLEVER NIH NHLBI Current Grants/Research Support: NIH NHLBI 2 Angiogenesis Growth and proliferation of new blood vessels from existing vascular structures. Therapeutic Angiogenesis: promote the growth of new blood vessels for the treatment of disorders of inadequate tissue perfusion Vasculogenesis: De novo vascular development form stem cells Arteriogenesis: collateral blood vessel Angiogenic Therapy Critical Limb Ischemia Trials Delivery of angiogenic factor to ischemic limb Cell therapy Growth factor or transcription factor Gene therapy Plasmid Adenovirus Potential Complications Off Target angiogenesis Growth of occult tumor Progression of diabetic retinopathy development 3 4 1

2 Gene Therapy by Intramuscular Injection of Angiogenic Growth Factor ASO Gene Therapy using VEGF to Treat Peripheral Arterial Disease VEGF Gene Before GT 4W 8W 5 Isner J et al. Circulation TALISMAN 201 Trial NV1FGF Plasmid vs Placebo in CLI Primary end-point: rate of wound healing Secondary end-points, n= month Endpoint AFS Amputation Death NV1FGF 73% 16% 12% Placebo 52% 34% 23% p FGF Gene Transfer in CLI Proof of Concept 6 patients undergoing leg amputation treated with IM injection FGF -1 plasmid Amputation specimens positive for : Plasmid expression FGF-1 mrna expression FGF protein expression Proves that CLI patients injected with FGF plasmid express the FGF protein Nikol S et al, Molecular Therapy, 16, , Baumgartner I et al, Molecular Therapy; 17;914-21,

3 TAMARIS Trial NV1FGF Plasmid vs Placebo in CLI Pivotal Trial n= month Endpoint AFS Amputation Death NV1FGF 63% 26% 18% Placebo 67% 21% 15% p Belch et al. Lancet Anti-apoptosis Angiogenesis Molecular Mechanisms of HGF Action HGF c-met VEGF Flk Flt Collagenase (MMP-1) HGF Ets-1 upa upa-r MMP3 Ets-1 MMP9 Activation of prepro-hgf Sustained Gene Activation Anti-fibrosis 10 A Phase II Double Blind Placebo-Controlled Study to Assess the Safety and Efficacy of to Improve Perfusion in Critical Limb Ischemia HGF-STAT Trial Richard Powell, M.D. Principle Investigator Professor of Surgery Section of Vascular Surgery Dartmouth Medical School AG-CLI-0202 Treatment Arms Randomized, placebo-controlled, double-blind, multicenter Arm 1: Placebo (n=25) Arm 2: 0.4 mg on days 0, 14 and 28 (n=25) Arm 3: 4 mg on days 0 and 28 (n=25) Arm 4: 4 mg on days 0, 14 and 28 (n=25) Each administration as 8 x 2.0ml injections at predefined anatomical locations Powell et al, Circulation 118,

4 Inclusion Criteria Rest pain; or peripheral ischemic ulcer(s); or areas of gangrene TcPO 2 of < 40 mmhg Ankle systolic pressure of < 70 mmhg or toe systolic pressure < 50 mmhg Poor candidate for standard revascularization treatment options for peripheral arterial disease Rutherford TcPO 2 (dorsum of foot) ABI TBI Ulcer (mean cm2) Baseline Disease Status (Efficacy population) Placebo (n=24) 25% 75% x 0.4mg (n=25) 48% 52% x 4.0mg (n=21) 43% 57% x 4.0mg (n=23) 30% 70% Safety Assessment No safety concerns at 12 month follow-up 750 adverse events in 97 subjects equally distributed between groups 11 neoplasms (including benign) diagnosed and equally distributed between groups. Two colon cancers: Placebo and middle dose (2 x 4.0mg) groups No progression of retinopathy 15 mm Hg TcPO 2 at Baseline and at 6 Months Baseline TcPO 2 TcPO 2 6 months Placebo Low Dose Middle Dose High Dose #=p.014 vs placebo at 6 months # 16 4

5 % Increase in TcPO 2 to > 30 mmhg at 6 Months Ischemic Ulcer Venous Ulcer Placebo Low Dose Middle Dose High Dose p= TBI HGF 0205 Change in Toe Brachial Index Baseline 3 months 6 months HGF P=.06 P=.05 VAS HGF 0205 Change in Pain Score by Visual Analogue Scale (VAS) Baseline 3 months 6 months HGF P=.21 P=.04 Placebo Placebo Powell et al, J Vasc Surg, Dec Powell et al, J Vasc Surg, Dec

6 AG-CLI-0205 Baseline Ulcer Severity Summary of Japanese Phase III Clinical Trial ASO Study Efficacy : Dose Group Subjects Subjects Improvement Improved Unimproved Rate HGF % Placebo % Total 40 Subjects 21 Shigematsu et al. Gene Therapy 2010 MH Analysis P= Summary of HGF Trial Results Bone Marrow Derived Stem Cells Bone Marrow Stromal Cells Well tolerated, no safety concerns Cardiac Muscle Skeletal Muscle improved limb perfusion and wound healing in patients with CLI Phase III trial to start 2012 Hematopoietic and Endothelial Stem Cells Macrophages, Lymphocytes & other Blood Cells Endothelial Precursor Cells Blood Vessels Bone Cells (Osteoblasts) Neurons & Glial Cells Epithelial Cells Fat Cells

7 Harvest Technologies Phase 2 Trial Bone Marrow Aspirate Concentrate in CLI 48 patients End point at 3 months Bone Marrow Concentrate (34) Control (14) Major Amputation 17.6% 28.6% (p=.45) Improved Pain 44% 25% (p=.54) Improved ABI 32% 7% (p=.08) Improved Rutherford Classification 35% 14% (p=.18) Results from a Randomized, Placebo Controlled, Double-Blind Multi-Center Phase II Trial Comparing Expanded Autologous Bone Marrow Treatment in Patients with Critical Limb Ischemia RESTORE-CLI Trial Richard J. Powell1, Anthony J. Comerota2, Elmar R. Burchardt3,4, Scott A. Berceli5, Judith W. Douville3, Timothy D. Henry6, Edith Tzeng7, and Omaida Velazquez8 1-Dartmouth-Hitchcock Medical Center Lebanon, NH; 2-Jobst Vascular Center, Toledo, OH; 3- Aastrom Biosciences Inc., Ann Arbor, MI; 4-University of Witten-Herdecke, Germany; 5-Malcolm Randall VAMC and University of Florida, Gainesville, FL; 6-Minneapolis Heart Institute at Abbott Northwestern, Minneapolis, MN; 7-University of Pittsburgh, Pittsburgh, PA; 8-University of Miami Medical School, Miami, FL Iafrati et al. J Vasc Surg Dec Powell et al. J Vasc Surg 54: , 2011 Powell et al. Mol Therapy, March Study Protocol Time to First Occurrence of Treatment Failure 2:1 randomization Tissue repair cells placebo injection (acellular vehicle) One-time set of 20 intramuscular injections 0.5 ml each Lower thigh Calf Foot 12 month follow-up Major amputation All-cause mortality Doubling in wound size De novo gangrene Revascularization

8 Bone Marrow Harvest (50 ml) Cells Undergo Expansion in Bioreactor Starting Bone Marrow Ixmyelocel-T Cell Expansion RBCs Lymphocytes T + B CD45 CD90 Granulocytes Monocytes Mesenchymal Stem Cells Cell Reduction Cell Amplification ~300 million cells Expansion Process RBC extraction 0.1% remaining -5X -5X +200X +50X CD 14 Macrophage ixmyelocel-t ~150 million cells Therapeutic Effect Remodelling of ischemic tissue Modulation of inflammation Promotion of angiogenesis Safety Overview: All Aspirated Patients (N=77) Time to First Occurrence of Treatment Failure All Treated Patients (N=72) Safety Parameter N (%) with Adverse Events N (%) Serious Adverse Event N (%) withdrawal due to AE Ixmyelocel- T N = 53 Control N = 24 P- value ** 47 (89) 23 (96) (43) 12 (50) (4) 0 (0) N (%) Deaths * 3 (6) 2 (8) * An additional ixmyelocel-t patient died ~100 days after completing study. ** Based on Fisher s Exact Test % risk reduction: HR 0.38, 95%CI = ( ) 32 8

9 First Event Contributed to Treatment Failure All Treated Patients (N=72) Amputation-Free Survival All Treated Patients (N=72) Ixmyelocel-T N = 48 Control N = 24 Endpoint (n) Major amputation 6(12%) 4(17%) All-cause mortality 2(4%) 1(4%) Doubling in total wound surface area* 5(10%) 7(29%) De novo gangrene 6(12%) 4(17%) Total n(%) 19 (39.6%)** 16 (66.7%)** *For wound size doubling: patient must have come into the study with a wound to be eligible to contribute to this event. ** p = , Fisher s exact test % risk reduction: HR 0.68, 95%CI = ( ) 34 TTF and AFS Baseline Wound Patients (N=45) Conclusions from RESTORE-CLI Safety of TRC s in CLI patients. Improved outcomes based on objective clinical endpoints. Significant improvement in composite endpoint (major amputation, all-cause mortality, doubling in wound size, de novo gangrene) Differences in outcome of patients with rest pain vs tissue loss Early results promising Larger pivotal trial warranted 77% risk reduction: HR = % CI = (0.103, 0.490) Cox PH p = % risk reduction: HR = % CI = (0.131, 1.164) Cox PH p=

10 Ongoing Cellular Therapy Trials Autologous Aastrom Phase 3 Harvest Technology Phase 3 - IDE Biomet Phase 3- IDE Allogeneic Pluristem: placental derived Phase 1 trial complete 37 Conclusions Potentially a disruptive technology No currently completed pivotal trial supports use of biologic therapy in CLI Large number of trials in progress with improved trial design 38 Interest from other Thought Leaders: PAD Pipeline Cell-based therapy Gene therapy Fibroblast GF Patient Demographics All Treated Patients (n=72) Treprostinil Vascugel Autologous Stem Cell (Baxter) AS-013 (JPN) Parogrelil/ INDI-702(JPN) PVS (France) Prostagladin agonist Stem-cell therapy Fibroblast stimulant PDE-5 inhibitor P-selectin inhibitor Nitric oxide donor Other MoA Parameter* (Mean values) Ixmyelocel-T N = 48 Control N = 24 % Male Age ALO 212 PLX-PAD SPI 017 (JPN) Phase I MultiGene Angio LA 419 (Spain) EG 016 (EU) AMG 0001 ALD 301 ANGX 1039 Trans-Sodium Crocetinate Ixmyelocel-T SLX 2101 (EU) RG-1512 Phase II Albumin-bound paclitaxel Ferumoxytol VM 202 HIF-1 alpha Marketed for Anaemia NV1-FGF Phase III MQX 503 Pre-Registration 39 % Current, % Past smokers 17, 67 38, 46 % Current, % Past alcohol 44, 23 29, 33 BMI Creatinine mg/dl N (%) with known Diabetes 21 (44) 15 (63) *No significant differences 40 10

11 Demographics (Study population) Angiogenic Growth Factors Age (yrs) Male (%) Race(%) White Black Other Diabetes (%) # Creatinine >1.5 Smoking (%) Placebo (n=26) % 77% 15% 8% 65% 35% 85% 3 x 0.4mg (n=26) % 92% 8% 0% 54% 8% 77% 2 x 4.0mg (n=25) % 88% 8% 0% 36% 12% 72% 3 x 4.0mg (n=27) % 85% 7% 7% 41% 26% 85% Vascular Endothelial Growth Factor (VEGF) Fibroblast Growth Factor (FGF) Hypoxia Inducible Factor -1a (HIF-1a) Hepatocyte Growth Factor (HGF) #: p=