Novel concept for drug delivery in infrapopliteal arteries The LIMBO trial Prof. Dr. med. Dierk Scheinert Division of Interventional Angiology University Hospital Leipzig, Germany 1
Disclosure Advisory Board /Consultant: Abbott, Biotronik, Boston Scientific, Cook Medical, Cordis, CR Bard, Gardia Medical, Medtronic/Covidien, TriReme Medical, Trivascular, Upstream Peripheral Technologies
Unmet Needs in BTK Arteries Addition of drug to SFA and popliteal segments has dramatically improved patency DES has shown improvements in shortsegment BTK disease However, well-controlled clinical trials of DCB in BTK arteries have been inconsistent or disappointing Flaking of drug from balloons may have negative outflow consequences 3
The Bullfrog Micro-Infusion Device (Mercator MedSystems) 20% contrast 80% dexamethasone 4
Interrupting the Cascade at Inflammation Cell recruitment ATVB 2011;31:1530-1539 Inflammation cytokine expression Proliferation Neointima Lumen Loss 5
Background Data from DANCE (Adventitial DEX in SFA/Pop) Interim: 73 DANCE Atherectomy Subjects Rutherford 2 23.3% Rutherford 3 61.6% Rutherford 4 15.1% Severe Calcification 26.6% Popliteal Involvement 20.5% TASC II Classification 36% A; 59% B; 6% C Restenosis 8.2% Lesion Length (cm) 8.8 ± 5.2 %DS (Pre) 69% ± 17% Total Occlusions 15.4% Grade B-D Dissection 25.0% Stent Utilization 34.2% Safety (0-360 Days) Device-related SAE 0/83 (0%) Drug-related SAE 0/83 (0%) Major Adverse Limb Events Amputation Bypass Thrombolysis 0/83 (0%) 2/83 (2.4%) 0/83 (0%) Death 0-30 Days 0/97 (0%) Death 0-360 Days 5/88 (5.7%) Efficacy (Interim update as of 3/4/2016) TLR at 360 Days 8.3% Patency at 360 Days 85.3% TLR at 390 Days 8.6% %DS (Post) 20% ± 7% Patency at 390 Days 82.2% 6
Moving to BTK: LIMBO Trials Below-Knee 2 trials: Adventitial Dexamethasone added to PTA (Germany) or atherectomy (U.S.) LIMBO-PTA PI: Dierk Scheinert, MD, University Hospital Leipzig, Germany (Began January 2016) LIMBO-ATX co-pis: George Adams, MD, UNC-Rex, Raleigh, NC Don Jacobs, MD, St. Louis University, MO LIMBO-ATX Baseline angiogram and biomarker blood draw 60 controls LIMBO-PTA 120 ATX (U.S.) 120 PTA (Germany) 60 DEX 60 controls 60 DEX 24-hour blood draw for biomarkers 1-month blood draw for biomarkers Clinical, hemodynamic and angiographic follow-up at 6 months 7
LIMBO Key Eligibility Criteria Male or female 18 years of age Single or multiple atherosclerotic lesion(s) 70% diameter stenosis in at least one infrapopliteal target vessel with possible extension into the distal popliteal (P3) Target lesion up to 30 cm in length Target vessel diameter of 2 mm and 8 mm 8
LIMBO Endpoints Primary Transverse-view vessel area loss percentage (TVAL%) of the target lesion at 6 months by quantitative vascular angiography (QVA) or prior to any TLR of the target lesion before 6 months Secondary Safety (including MALE-POD and CD-TLR), effectiveness (including patency, wound healing, biomarkers), healthcare economics, technical success, and revascularization success 9
Novel LIMBO Endpoints - Biomarkers C-Reactive Protein (CRP) Normalized CRP Change in Median from Baseline to 24 Hours After Interventions 600% 500% 400% 514% No Dex 300% Circulating levels rise in response to inflammatory cytokines (e.g. IL-6) expressed in response to local triggers (e.g. inflammation) Physiologic role: bind to dead or dying cells to activate the complement system via C1Q complex Elevations tied to restenosis [Schillinger et al. Radiology 2002; 225:21-26.] 200% 100% 0% Bullfrog/Dex 37% % Change from Baseline to 24 hours Non-Dex Control (DANCE-Partner Atherectomy, N=9) Dex Treatment (DANCE Atherectomy, N=42) 10
Novel LIMBO Endpoints - Biomarkers Monocyte Chemoattractive Protein-1 (MCP-1) Normalized MCP-1 Change in Median from Baseline to 24 Hours After Interventions 30% 20% 10% 23% No Dex 0% -10% Recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection Dexamethasone destabilizes the mrna that codes for MCP-1, shutting off its production Elevations tied to restenosis [Cipollone F, et al. Arterioscler Thromb Vasc Biol 2001;21:327-334.] -20% -30% -40% -50% Bullfrog/ Dex -46% % Change from Baseline to 24 hours Non-Dex Control (DANCE-Partner Atherectomy, N=9) Dex Treatment (DANCE Atherectomy, N=39) 11
Novel LIMBO Endpoints - TVAL TVAL: Transverse-view Vessel Area Loss A measurement of AREA opacified by contrast, rather than the narrowest cross-section, which LLL defines BASELINE FOLLOW-UP MLD baseline TL TL TVA baseline TVA f/u MLD follow-up LLL = MLD baseline MLD follow-up (in mm) TVA = shaded area within TL end constraints (in mm 2 ) TVAL = 100% - (TVA f/u / TVA baseline ) Courtesy of Kirk Seward, PhD, Mercator MedSystems 12
Looking Forward Bullfrog delivery of dexamethasone after atherectomy in SFA and popliteal arteries reduces production of inflammatory biomarkers versus atherectomy alone and had demonstrated good patency results of 82.2% at 390 days in a highly diseased population (15% Rutherford 4, 59% TASCII B lesions) The early results of steroidal micro-infusion in peripheral revascularization looks promising, particularly given the inherently low risks of proven and approved steroids Bullfrog delivery into the BTK area has shown technical feasibility The study of Bullfrog delivery of Dexamethasone BTK is incorporating new endpoints to gain more granular information related to the disease state (inflammatory biomarkers) and the resulting outcomes (TVAL) 13
Novel concept for drug delivery in infrapopliteal arteries The LIMBO trial Prof. Dr. med. Dierk Scheinert Division of Interventional Angiology University Hospital Leipzig, Germany 14