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Therapeutic Angiogenesis with FGF-2 For Intermittent Claudication Brian H. Annex, MD Duke University School of Medicine

TRAFFIC Phase II, multi-center, randomized, double-blind, placebo-controlled, regimen finding study comparing placebo, one, or two doses of rFGF-2 Investigators: PARC (www.arterial.org) PI:    Brian Annex & Robert Lederman Sponsor:    Chiron Corporation CC:    DCRI

Spectrum of Peripheral Artery Disease

Peripheral Artery Disease 15% of adults > 55 years (ABI < 0.9) Manifestations Intermittent claudication Critical limb ischemia 150,000 annual arterial reconstructive surgeries in US alone Vast majority do not undergo revascularization

Walking Impairment in Claudication 2/3 have difficulty walking 150 ft 1/3 have difficulty walking around home Maximum walking speed 1-2 mph Normal 3.3 mph » NYHA Class III CHF

Background: rFGF-2 Preclinical Studies angiogenic agent in multiple ischemia models Clinical Trials with rFGF-2 Chiron Phase I CAD study: defined MTD Chiron Phase II CAD study NIH-NHLBI Phase I PAD & CAD

Hypotheses for TRAFFIC Intra-arterial rFGF-2 improves exercise capacity in patients with intermittent claudication due to infra-inguinal PAD Repeat administration of rFGF-2 at 30 days is superior to single administration 80% powered to detect a 60” increase for SINGLE and a 90” increase for DOUBLE

TRAFFIC Overall Enrollment

TRAFFIC Lead Enrollers

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Major Selection Criteria INCLUSION Age > 40 years Exercise limited by claudication Paired baseline PWTs within 20% of each other Index ABI < 0.8 at rest Patent femoral inflow Medically stable for > 4 mos Informed consent EXCLUSION Suspicion of malignancy (screening per ACS guidelines) Creatinine > 2.0 mg/dL Urine protein ³ 2+ or > 300 mg/day Proliferative retinopathy Other conditions impacting safety or compliance

TRAFFIC Baseline Findings and Safety Results

Demographics, n=190

Baseline Findings

Angiographic Distribution of Stenoses*

Patient Follow-up

Safety: Adverse Events

TRAFFIC Primary Endpoint = Change in PWT at 90 days Primary Efficacy Analysis = ANOVA (null hypothesis)

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Primary Endpoint:  Change in PWT at 90 days

Primary Analysis vs Intent to Treat

Primary Endpoint:  Change in PWT at 90 days

Secondary Efficacy Variables

Change in PWT at 180 days

“Responders”: % Patients with > 2 min increase in PWT

Walking Impairment Questionnaire (WIQ) Claudication Severity Modest favorable results day 90 No difference day 180 Stair Climbing Baseline mismatch among groups Modest favorable results day 90 No difference day 180 Walking speed No difference days 90, 180 Walking distance No difference days 90, 180

Short Form-36 (SF-36): Physical Component

TRAFFIC PCSS in perspective

Change in Claudication Onset Time

Ankle Brachial Index at days 1, 90

Ankle Brachial Index at days 1, 90, 180

TRAFFIC Summary 1 A single intra-arterial infusion of rFGF-2 improves peak walking time at 90 days (pairwise p=0.026 vs placebo) Prespecified 3-way ANOVA p=0.075 3-way ANOVA of Ranks p=0.035 TRAFFIC was powered for DOUBLE being superior to  SINGLE.  Therefore, it was underpowered to detect a 60s benefit in both treatment groups. Repeat infusion at 30 days is not better than single

TRAFFIC Summary 2 Clinical improvement is Supported by ABI, WIQ (severity & stair climbing), SF-36 (physical summary) Not supported by COT, WIQ (distance & speed) Relative improvement at 180d is diminished Large improvement in placebo at 180d

TRAFFIC Summary 3 Acceptable Safety Profile Malignancy: 1 in placebo group Hypotension during dosing: < 6% (2, 4, 5) Proteinuria: < 5% (2, 6, 7) Death + Cardiac SAEs (4, 4, 3) Revascularizations (3, 2, 3) Repeat administration after 30 days

TRAFFIC:  Conclusions rFGF-2 is associated with a clinically-relevant increase in PWT in single dose group compared with placebo. Repeat infusion at 30 days is not better. IA infusion of rFGF-2 appears safe. TRAFFIC is a phase II trial and is the first large, randomized, placebo-controlled, therapeutic angiogenesis study to show benefit in its primary efficacy measure.