8.2 Drug Delivery for BTK Interventions: Which Drug and What Platform Will Get the Job Done?

These proceedings summarize the educational activity of the 16th Biennial Meeting of the International Andreas Gruentzig Society held January 31-February 3, 2022 in Punta Cana, Dominican Republic

Faculty Disclosures     Vendor Acknowledgments

2022 IAGS Summary Document

Statement of the problem or issue

Patients with peripheral arterial disease often present late in the disease course, often with critical limb ischemia. These patients generally exhibit anatomically advanced disease, with long, calcified lesions and chronic total occlusions (CTOs). Vessels typically are small—2.0-3.5 mm—and diabetics especially can have microvascular distal pruning disease. Vessel access can be very problematic, which has led to retrograde pedal artery access techniques just to reach and cross the target lesions. Distal emboli arising from lesions and/or flaked material coatings can be catastrophic and lead to amputation. Restenosis is common with conventional balloon angioplasty (POBA) and stenting, and this has evolved into a “no metal left behind” approach. Drug-coated balloons (DCBs) have so far not proven beneficial: In.Pact Deep, BioLux P-II, and Lutonix BTK clinical trials all had negative primary outcomes. Atherectomy with directional or orbital devices have not directly improved outcomes, but may be useful techniques for lesion preparation. Interestingly, laser angioplasty, and even more recently Shockwave lithoplasty, have both shown some promise in preparing the target lesion.

Gaps in our current knowledge

While drug delivery to target lesions below the knee seems to offer promise, there are many challenges to this approach. With drug-coated materials, there is increased risk of emboli from flaking off of large coating particles; this can lead to drug loss in transit to the target site, which in some models exceeds 50%. The goal is to deliver the full drug dose to the target lesion while navigating through the vasculature, protecting the drug from loss during transit while avoiding particulate emboli and potential downstream ischemia. Beyond this, the goals are to ensure timely, consistent, and accurate drug delivery/transfer from balloon to target lesion with full, intended, and consistent dosing.

Other knowledge-gap questions:

• Can the full drug dose be deployed to the target lesion during angioplasty?

• Can we ensure mural uptake of therapeutic drug doses?

• How can we prevent rapid drug degradation and/or diffusion away from target site?

• How can we sustain drug release over the critical time period required?

• Can we mimic the drug-release pharmacokinetics of efficacious permanent implants (DES)?

• Are there better ways to deliver antiproliferative agents to the vessel wall for more durable results?

• Would a bioabsorbable vascular scaffold (ABSORB) offer benefits?

• How can we access the intracellular space with sufficient drug levels to exert desired therapeutic effects?

Possible solutions and future directions

This will be a potent area of research over the next 3 years. Below are 3 examples of novel technologies moving through the clinical pathway towards device approval.

(1) Virtue SAB: sirolimus-weeping balloon (Orchestra BioMed)

• Proprietary weeping balloon technology that protects drug during transit to prevent potential for downstream ischemia from particulate debris.

• Performs angioplasty using standard catheter techniques.

• Consistently delivers intended dose and enables focal drug uptake.

• Provides extended focal release through the critical healing period.

(2) Selution SLK: sirolimus-eluting balloon with sustained release (MedAlliance)

• Proprietary microreservoirs with cell-adherent technology.

• Creates microreservoirs combining sirolimus and biodegradable polymer via a proprietary amphipathic lipid technology with binds microreservoirs to the balloon surface.

• Contains and protects microreservoirs during insertion and inflation.

• Enhances drug retention and bioavailability, allowing for a lower drug dose concentration on the balloon surface (1 μg/mm).

(3) ESPRIT BVS: bioabsorbable vascular scaffold (Abbott)

• Updated thinner BVS from the coronary Absorb BVS.

• PLLA slowly degradable polymer loaded with everolimus.

• 99 micron strut thickness with sizes from 2.5-4.0 mm.

• Scaffold lengths up to 38 mm.

• Delivers everolimus to the vessel wall over many months.

• Polymer slowly degrades over 2 years.