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

Award Number: R44HL102998
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2010
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,000,000 )
2025	2025	MERCATOR MEDSYSTEMS, INC.	520 MCCORMICK ST	SAN LEANDRO	CA	94577	ALAMEDA	USA	Cardiovascular Diseases Research	000	5	3/7/2025	NON-COMPETING CONTINUATION	$1,000,000
														Subtotal = $1,000,000

Issue Date FY: 2024 ( Subtotal = $1,000,000 )
2024	2024	MERCATOR MEDSYSTEMS, INC.	520 MCCORMICK ST	SAN LEANDRO	CA	94577	ALAMEDA	USA	Cardiovascular Diseases Research	000	4	12/29/2023	COMPETING CONTINUATION	$1,000,000
														Subtotal = $1,000,000

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2014	MERCATOR MEDSYSTEMS, INC.	1900 POWELL ST STE 800	EMERYVILLE	CA	94608	ALAMEDA	USA	Cardiovascular Diseases Research	000	3	7/11/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2014	MERCATOR MEDSYSTEMS, INC.	1900 POWELL ST STE 800	EMERYVILLE	CA	94608	ALAMEDA	USA	Cardiovascular Diseases Research	000	3	8/1/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2014	MERCATOR MEDSYSTEMS INC	3077 TEAGARDEN STREET	SAN LEANDRO	CA	94577	ALAMEDA	USA	Cardiovascular Diseases Research	000	3	5/31/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $1,088,602 )
2014	2014	MERCATOR MEDSYSTEMS INC	3077 TEAGARDEN STREET	SAN LEANDRO	CA	94577	ALAMEDA	USA	Cardiovascular Diseases Research	000	3	4/23/2014	NON-COMPETING CONTINUATION	$1,088,602
														Subtotal = $1,088,602

Issue Date FY: 2013 ( Subtotal = $960,118 )
2013	2013	MERCATOR MEDSYSTEMS INC	3077 TEAGARDEN STREET	SAN LEANDRO	CA	94577	ALAMEDA	USA	Cardiovascular Diseases Research	000	2	7/15/2013	COMPETING CONTINUATION	$960,118
														Subtotal = $960,118

Grand Total All Awards = $4,048,720

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

Award Number: R44HL102998

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2010

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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