The DANCE Trial · Christopher D. Owens, MD, MSc Associate Professor of Vascular and Endovascular Surgery University of California, San Francisco Section Chief, Vascular Surgery San

The DANCE Trial

Christopher D. Owens, MD, MSc Associate Professor of Vascular and Endovascular Surgery

University of California, San Francisco Section Chief, Vascular Surgery San Francisco VA Medical Center

Associate Chief, Surgery San Francisco VA Medical Center Director, Vascular Integrated Physiology and Experimental

Therapeutics (VipeRx) Laboratory

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Disclosure

Speaker name: Christopher D. Owens, MD

.................................................................................

I have the following potential conflicts of interest to report:

Consulting

Employment in industry

Stockholder of a healthcare company

Owner of a healthcare company

Other(s)

I do not have any potential conflict of interest

DANCE Trial Organization National Co-PIs Christopher Owens, MD, UCSF/SFVAMC

Mahmood Razavi, MD, St. Joseph’s, Orange, CA

Ultrasound Core Laboratory Vascore, Boston, MA Director: Michael Jaff, DO

Angiographic Core Laboratory CRF, New York, NY Director: Philippe Genereux, MD

Biomarker Laboratory Quest Diagnostics Clinical Trials

Sites: George Adams, MD – UNC Healthcare, Rex Hospital, Raleigh, NC Guarav Aggarwala, MD – Palestine Regional Medical, Palestine, TX Sam Ahn, MD – DFW Vascular Group, Dallas, TX Vaquar Ali – First Coast Cardiovascular Institute, Jacksonville, FL Gary Ansel, MD – OhioHealth - Riverside Methodist, Columbus, OH Ehrin Armstrong, MD – Denver VA, Denver, CO Nelson Bernardo – MedStar Washington Hospital Center, DC Ian Cawich, MD – Arkansas Heart Hospital, Little Rock, AR Michael Curi, MD – Rutgers Univ. Hospital – Newark, NJ Tom Davis, MD – St. John Providence Hospital, Detroit, MI Suhail Dohad, MD – Cardiovascular Research Foundation, Beverly Hills, CA

W. Britton Eaves, MD – Willis Knighton Medical Center, Bossier City, LA Andrey Espinoza, MD – Hunterdon Medical Center, Flemington, NJ Robert Feldman, MD – Munroe Regional Medical Center, Ocala, FL Stuart Harlan, MD – Coastal Vascular & Interventional Center, Pensacola, FL Donald Jacobs, MD – St. Louis University Hospital, St. Louis MO Richard Kovach, MD – Deborah Heart & Lung, Browns Mills, NJ Louis Lopez, MD – St. Joseph Hospital, Ft. Wayne, IN Amir Malik, MD – Plaza Med Ctr., Ft. Worth, TX Luke Marone, MD – UPMC, Pittsburgh, PA Christopher Metzger, MD – Wellmont Health, Kingsport, TN Christopher Owens, MD – UCSF / SFVAMC, San Francisco, CA John Pacanowski, MD – PIMA Vascular, Tucson, AZ Richard Powell – Dartmouth-Hitchcock Medical Center, Lebanon, NH

Anthony Pucillo, MD – Columbia Presbyterian, New York, NY Venkatesh Ramaiah, MD – Arizona Heart Hospital, Phoenix, AZ Mahmood Razavi, MD - St. Joseph Hospital of Orange Heart & Vascular Center, Orange, CA Bhavanada Reddy, MD – Alpine Research, Salt Lake City, UT Andrez Shanzer, MD – UMass Medical Ctr., Worcester, MA Immad Sadiq, MD – Hartford Hospital, Hartford CT Peter Soukas, MD – Miriam Hospital, Providence RI Cezar Staniloae, MD – Gotham Cardiovascular Research, New York, NY John Taggert, MD – Albany Vascular Group, Albany, NY Robert Wilkins, MD – Hattiesburg Clinic, Hattiesburg, MS John Winscott, MD – Univ of Mississippi Med Ctr., Jackson, MS Jason Yoho, MD – Mission Research - Guadalupe Regional, Seguin, TX 3

DANCE: Dexamethasone delivered to the Adventitia to eNhance Clinical Efficacy

• Open label, single arm trial

• Primary endpoints:

– Efficacy: 12 month patency (duplex ultrasound PSVR≤2.4 and lack of CD-TLR)

– Safety: MALE through 12 months, POD through 30 days

• Key eligibility criteria:

– Rutherford 2-4

– SFA or popliteal

– De novo or restenotic lesions ≤15 cm length

– ≤30% residual stenosis after revascularization

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DANCE Trial Enrollment and Design

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First 100 patients enrolled, 12 mo

interim data presented today

First 100 DANCE-ATX Patients Enrolled (Interim Data)

100 Enrolled 01 Nov 2014

to 07 Jan 2015

12 Withdrawn or Lost to Follow-Up

3 Deaths prior to endpoint

73 Analyzed for Primary Patency and TLR Endpoints

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12 Failed revascularization (per Core Lab analysis,

>33% angiographic stenosis at completion or not

patent at baseline ultrasound)

The Bullfrog® Micro-Infusion Device (Mercator MedSystems)

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20% contrast

80% dexamethasone

The Bullfrog Micro-Infusion Device is FDA 510(k)-cleared and CE-Marked

Interrupting the Cascade at Inflammation

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ATVB 2011;31:1530-

1539

Cell recruitment

Inflammation –

cytokine expression Proliferation

Neointima

Lumen Loss

DANCE Demographics

N 73

Age 68.9 ± 10.5

Male 52.1%

Caucasian 78.1%

African American 20.5%

Diabetes 43.1%

Coronary artery disease 66.7%

Hypertension 93.1%

Hyperlipidemia 76.4%

BMI (kg/m2) 31.6 ± 18.1

Creatinine (mg/dL) 1.04 ± 0.35

hsCRP, baseline (mg/dL) 5.2 ± 5.4

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DANCE Vascular Disease and Lesion Characteristics

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

Diameter Stenosis Pre-Revascularization 69% ± 17%

Total Occlusions 15.4%

Grade B-D Dissection 25.0%

Stent Utilization 34.2%

Residual Stenosis Post-Revascularization 20% ± 7% 10

DANCE Safety and Efficacy Endpoints

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SAFETY

Device-related SAE 0-360 Days 0/83 (0%)

Drug-related SAE 0-360 Days 0/83 (0%)

Major Adverse Limb Events 0-360 Days 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

TLR at 360 Days 8.3%

Patency at 360 Days 85.0%

TLR at 390 Days 8.8%

Patency at 390 Days 81.5%

Putting DANCE into Perspective versus Published Drug Delivery

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85% 78% 82%

52% 65%

53%

0%

20%

40%

60%

80%

100%

DANCE(Atherectomy +

Bullfrog/Dex)

DEFINITIVE-LE(Atherectomy)

In.Pact SFA(PTX DCB)

In.Pact SFA(PTA)

Levant 2(PTX DCB)

Levant 2(PTA)

12 Month Patency

Lesion Length 8.8 cm 7.5 cm 8.9 cm 8.8 cm 6.3 cm 6.3 cm

Ruth 4 % 15.1% 0% 5.0% 5.4% 7.9% 8.1%

TASCII A:B:C % 36:59:6 57:31:12 63:27:11 76:22:2 76:24:1

Popliteal % 20.5% 15.3% 6.8% 7.1% 9.8% 7.5%

Severe Ca2+ % 26.6% 8.1% 6.2% 10.4% 8.1%

DANCE Clinical Endpoints

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* Statistically significant (P<0.05) improvement versus baseline screening exam

0

1

2

3

4

Screening 4wk 6mo 12mo

Rutherford Classification

*

* *

0

10

20

30

40

50

60

70

80

90

100

Screening 4 wk 6 mo 12 mo

Walking Impairment Questionnaire Scores

* * *

Novel DANCE Endpoints - Biomarkers

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• Circulating levels rise in

response to local triggers (e.g.

inflammation)

• Primitive antibody

• Elevations tied to restenosis

[Schillinger et al. Radiology

2002; 225:21-26.]

C-Reactive Protein (CRP)

• Recruits inflammatory cells to the

site of injury

• Elevations tied to restenosis

[Cipollone F, et al. Arterioscler

Thromb Vasc Biol 2001;21:327-

334.]

Monocyte Chemoattractive

Protein-1 (MCP-1)

Inflammatory Biomarker Reductions

-50%

-40%

-30%

-20%

-10%

0%

10%

20%

30%

% Change from Baseline to 24 hours

Normalized MCP-1 Change in Median from

Baseline to 24 Hours After Interventions

Non-Dex Comparator (PTA or Stenting of SFA;Heider, JVS 2006;43:969, N=32)

Dex Treatment (DANCE Atherectomy, N=39)15

0%

50%

100%

150%

200%

250%

300%

350%

400%

% Change from Baseline to 24 hours

Normalized CRP Change in Median from Baseline

to 24 Hours After Interventions

Non-Dex Control (DANCE-PartnerAtherectomy, N=7)

Dex Treatment (DANCE Atherectomy, N=42)

Summary

• Bullfrog delivery of GR-agonist (dexamethasone) after atherectomy reduces production of pro-inflammatory cytokines and acute phase reactants versus atherectomy alone

• The first 73 eligible patients reaching their endpoint in the atherectomy group of DANCE have demonstrated strong patency results, with 85% remaining patent at 360 days and 81.5% remaining patent at 390 days

• The DANCE trial enrolled a challenging cohort with a high representation of Rutherford 4 (15%), severe calcification (27%), popliteal involvement (21%), and TASCII B lesions (59%)

• The early results of GR-agonist micro-infusion in peripheral arteries at the time of atherectomy appears promising, particularly given the inherent safety profile of currently approved steroids

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Conclusions

• The DANCE trial is a proof-of-principle study which supports a paradigm shift in anti-restenosis therapy away from intimal delivery platforms

• Adventitial delivery of powerful GR-agonist therapy results in the nuclear immunomodulation of the vascular injury response to reduce restenosis while permitting the unimpeded re-establishment of vascular endothelium

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Next Phase: LIMBO Trials

• Below-Knee

• 2 trials: Adventitial

Dexamethasone added to

PTA (Germany) or

atherectomy (U.S.)

• Anticipated start: Q1 2016

• LIMBO-PTA PI: Dierk

Scheinert, MD, University

Hospital Leipzig, Germany

• LIMBO-ATX coPIs: George

Adams, MD, UNC-Rex,

Raleigh, NC

Don Jacobs, MD, St. Louis

University, MO

60 controls

Baseline angiogram and biomarker blood draw

24-hour blood draw for biomarkers

Clinical, hemodynamic and angiographic follow-up at 6 months

1-month blood draw for biomarkers

LIMBO-PTA

120 ATX (U.S.) 120 PTA (Germany)

60 DEX 60 controls 60 DEX

LIMBO-ATX

The DANCE Trial

Christopher D. Owens, MD, MSc Associate Professor of Vascular and Endovascular Surgery

University of California, San Francisco Section Chief, Vascular Surgery San Francisco VA Medical Center

Associate Chief, Surgery San Francisco VA Medical Center Director, Vascular Integrated Physiology and Experimental

Therapeutics (VipeRx) Laboratory

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