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

> **NIH NIH R44** · MERCATOR MEDSYSTEMS, INC. · 2024 · $1,000,000

## Abstract

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 re...

## Key facts

- **NIH application ID:** 10798046
- **Project number:** 2R44HL102998-04
- **Recipient organization:** MERCATOR MEDSYSTEMS, INC.
- **Principal Investigator:** Kirk Seward
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,000,000
- **Award type:** 2
- **Project period:** 2010-08-15 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798046

## Citation

> US National Institutes of Health, RePORTER application 10798046, Improved Sirolimus-Analog Adventitial Delivery to Enhance Outcomes in Below-the-Knee Peripheral Artery Disease (2R44HL102998-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10798046. Licensed CC0.

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