Improved Sirolimus-Analog Adventitial Delivery to Enhance Outcomes in Below-the-Knee Peripheral Artery Disease

PROJECT SUMMARY Peripheral artery disease (PAD) affects 1 in 16 individuals over age 40 (approximately 10 million Americans) [2]. The end stage of lower-extremity PAD, critical limb-threatening ischemia (CLTI), is estimated to affect 1.3% of those over age 40 (approximately 2 million Americans) [3]. Left untreated, up to 40% of patients with CLTI will require major (above the ankle) amputation within 6 months [4]. CLTI is often associated with multivessel below-the-knee (BTK) arterial occlusion, necessitating surgical bypass or endovascular intervention to restore blood flow. Endovascular (catheter-based) procedures, which are likely to occur in approximately 220,000 cases in the U.S. in 2025 [5], are often preferred over surgery in CLTI patients due to high-surgical-risk comorbidities, but they have historically produced suboptimal results. Failure of the first intervention is typically 50% or greater in the first year. After that initial failure and over the 5-year period following reintervention, patients often progress toward a need for multiple re-interventions, major amputation in more than half of patients, and 5-year survival rates less than 40% (as in a recent study of 1,134 patients with average age of 59 years) [6]. Drug-coated balloons and drug-eluting stents have invariably had negative clinical trial results for reducing restenosis below the knee, possibly because significant disease in these smaller vessels may be hindering drug elution kinetics from the solid-drug elution devices. Meanwhile, adventitial and perivascular delivery of liquid formulations have proven quite effective. The TANGO trial, an FDA Phase 2, dual-blinded, randomized, controlled trial of temsirolimus injected with Mercator’s Bullfrog® Micro-Infusion Device was funded in part by the prior Phase II SBIR grant. TANGO was performed to determine safety and efficacy endpoints and strength of signal in the improvement in treating BTK arterial occlusion. The rate of clinically relevant target lesion failure after treatment was reduced by a relative 51.3% in comparison to controls. Based on this signal, the Phase 3 trial has been designed and negotiated with FDA. The proposed research aims include the finalization of development and production of a research batch of lyophilized temsirolimus and its corresponding placebo under current good manufacturing practices (cGMP), completing the negotiation of a special protocol assessment (SPA) with the FDA, and carrying out the Phase 3 clinical trial up to its interim analysis. Beyond the scope and timeframe of this grant, the Phase 3 trial will be completed, with meaningful clinical endpoints to achieve NDA approval from FDA and a J-code for drug reimbursement from the Centers for Medicare and Medicaid Services (CMS). The significance of this proposal lies in the fact that (a) a recalcitrant clinical problem is being addressed, (b) perivascular or adventitial therapy may be used as an adjunct to several common interventional revascularization techniques and (c) therapeutic success in BTK PAD could be translated into ATK applications soon thereafter. With the success of this Phase 3 trial, FDA approval for the novel combination therapy will be sought.