Lutonix’s scientific initiatives have focused on answering three fundamental questions about drug-coated balloons:

1. What is the optimal carrier molecule and formulation?

Which one most efficiently delivers a therapeutic dose with the lowest possible paclitaxel dose on the balloon in order to minimize systemic dose?

2. What does pre-clinical science reveal about the biological effects of drug-coated balloons?

What are the appropriate pharmacokinetic and histopathologic parameters?

3. What is the mechanism of action behind drug-coated balloons?

How do DCBs achieve a sustained anti-restenotic effect through a 30-second bolus delivery as compared to drug-eluting stents?

Pre-clinical science

Because clinical outcomes are influenced by both the drug and the specific drug carrier, extensive pre-clinical science for any drug-coated balloon is imperative. Utilizing the exact same formulation in pre-clinical research as is used in the clinical and commercial product is also important, as even a slight change in an individual variable can impact results significantly.

The Lutonix DCB drug-coated balloon catheter is supported by a solid scientific foundation encompassing in vitro studies, histopathologic research and extensive pharmacokinetic analyses. In order to identify the optimal Lutonix DCB formulation, more than 250 potential carrier molecules were screened through rigorous testing and analysis.

Following the molecular screening process, over 40 in vivo studies spanning arterial dose distribution to formulation stability were conducted to identify and optimize the most promising formulation candidates. GLP animal studies and three pilot human clinical studies demonstrated the safety of the final Lutonix DCB formulation.

Lutonix DCB’s mechanism of action

How does a drug-coated balloon provide a long-lasting therapeutic benefit with local bolus delivery? Where does the drug initially reside after the balloon is deflated and removed? How rapidly does it diffuse into the artery? Where in the arterial wall does the drug remain longer-term and for what duration of time? What is the optimal adhesion and release profile of a DCB coating?

These questions have been at the heart of the Lutonix scientific development process. Lutonix has applied empiric pharmacokinetic data and computational modeling in order to understand the mechanistic foundations underlying efficacy of the Lutonix DCB drug-coated balloon.

During the interventional procedure, Lutonix DCB is inflated for a minimum of 30 seconds. In a process that is highly carrier-dependent, Lutonix pharmacokinetic studies have demonstrated that paclitaxel is initially deposited onto the endoluminal surface of the treated artery. After the balloon is deflated and retracted, paclitaxel slowly diffuses into deeper layers of the arterial wall.

Drug dissolution from the surface deposition over time establishes therapeutic drug levels in deep layers of the arterial wall that are sustained for a period of months. Importantly, computational modeling has demonstrated that paclitaxel levels in the endothelium become sub-therapeutic much more rapidly. As a result, new endothelial cells are able to grow and re-line the lumen while the deeper arterial layers — the culprits of restenosis — are exposed to prolonged therapeutic drug levels.

This mechanistic framework is consistent with pre-clinical studies of Lutonix DCB, demonstrating by histopathology both healthy endothelial tissue and sustained drug effects in the media and adventitia. The prolonged therapeutic dose in the deep arterial wall continues to inhibit restenosis while allowing for re-endothelization.

Drug-coated balloons and drug-eluting stents

Drug-coated balloon (DCB) catheters are similar to drug-eluting stents (DES) in that they both deliver an anti-proliferative drug to the arterial wall for the purposes of preventing restenosis. However, several important differences exist with respect to mechanism of action.

Lutonix DCB delivers paclitaxel in a single inflation. The balloon is inflated for a minimum of 30 seconds and then removed. With DES, a permanent metal implant is left behind from which the Paclitaxel elutes.

Computational modeling has demonstrated that, unlike DES, the paclitaxel delivered by Lutonix DCB becomes sub-therapeutic in the endothelium while therapeutic levels are sustained in the deeper cell layers. As a result, re-endothelization can occur while the anti-proliferative effect is maintained in the deeper cell layers responsible for restenosis. Earlier re-endothelialization may allow for a shorter duration of anti-platelet therapy with DCB use.