Looking Toward a Shift From Paclitaxel to Limus Agents

Do we have enough evidence for limus devices to replace paclitaxel in peripheral arterial disease? Not yet, but we soon may have, according to Sahil Parikh, Director of Endovascular Services at Columbia University Irving Medical Center and Associate Professor of Medicine at the Columbia University College of Physicians and Surgeons in New York. On Tuesday afternoon, Dr Parikh reviewed the current research and presented a timeline illustrating when to expect new data from pivotal studies over the next few years.

Introducing his talk, Dr Parikh outlined the basis of the interest in limus devices as an alternative to paclitaxel. In his opinion, the paclitaxel mortality controversy is not a major factor here.

“We’re all aware of the controversy about the safety of paclitaxel agents, but that story has largely come and gone now,” he said. “Instead, the original value proposition for switching agents was to improve effectiveness. If you look back at the coronary literature over the last 20 years, it’s become clear that limus agents have proved superior in terms of efficacy.”

Since the first trials in the early 2000s comparing paclitaxel- to sirolimus-eluting stents in the coronary circulation, head-to-head comparisons have consistently demonstrated superior performance of limus agents as regards target lesion revascularization and restenosis. However, as Dr Parikh explained, this picture was not easily reproduced in the peripheral circulation due to differences in the pharmacokinetics and pharmacodynamics of drug delivery. In the larger and more elastic peripheral arteries, achieving and maintaining therapeutic drug levels is more challenging – and limus agents, being less stable than paclitaxel, must be protected from degradation.

“It’s difficult to deliver enough sirolimus to the surface area of the larger arteries in the legs. Consequently, we’ve seen several starts and stops with limus-based technologies, and paclitaxel has been preferred as it’s easier to work with,” he summarized. “But more recently there have been chemical modifications of sirolimus analogues to encapsulate them or otherwise protect them from being cleared before they’re bound to their targets. That technological evolution was what it took to make limus agents viable in the peripheral circulation.”

Now that limus agents are a viable option, Dr Parikh noted that this could open up new options for treatment below the knee (BTK), where paclitaxel devices have shown disappointing results. “Whereas we may have half a dozen or more paclitaxel balloons for above the knee, everything that’s been tried in the BTK circulation has so far failed,” he stated. “There’s a lot of speculation as to why, but the underlying feeling is that we need something different for the BTK circulation.” 

Given the poor performance of paclitaxel BTK, Dr Parikh observed that research into limus devices is particularly active here. While BTK lesions are notoriously difficult to treat, the competition above the knee raises challenges, he explained.

“Above the knee there are multiple paclitaxel options available, which the limus devices must equal or outperform. Plus innovation costs money, and new technology is generally more expensive. So the bar is pretty high for sirolimus in the superficial femoral artery – it has to be as good as paclitaxel and also similar in cost. In light of this, most limus devices have been tackling the BTK circulation either concomitantly or even ahead of the circulation above the knee.”

In his talk, Dr Parikh covered clinical trials relating to 2 drug-coated balloons (DCBs): the MagicTouch PTA sirolimus-coated balloon (Concept Medical) and the SELUTION SLR sirolimus-eluting balloon (MedAlliance). He first commented on MagicTouch, which uses a phospholipid microparticle carrier to enhance drug penetration and retention in the artery. 

The first-in-human study of this device was the XTOSI trial, a prospective single-arm study that enrolled 50 patients with femoropopliteal or BTK peripheral arterial occlusive disease; most treatments were performed for limb salvage. Initial outcomes were promising, with no early safety concerns and 80% 6-month primary patency (88.2% femoropopliteal; 74% BTK).¹ Thirty-six-month outcomes were presented at the 2022 VEITHsymposium, revealing low rates of re-intervention and high limb salvage: amputation-free survival was 63.3%, freedom from amputation 86.1%, and freedom from target lesion revascularisation 84.4%.² 

Given the encouraging outcomes from this initial single-arm study, larger randomized trials have been designed and are currently enrolling. Dr Parikh drew attention to the FUTURE-SFA and FUTURE-BTK trials, 2 multicenter randomized controlled trials comparing the MagicTouch DCB to standard percutaneous transluminal angioplasty in the femoropopliteal segment and below the knee, respectively.^3,4 

Dr Parikh also highlighted a particularly bold trial for the above-the-knee circulation: SIRONA, a prospective multicenter randomized non-inferiority trial comparing the MagicTouch DCB with a paclitaxel DCB for high-grade stenotic or occluded femoropopliteal lesions.⁵ “That’s a pretty ambitious study as it’s a head-to-head comparison above the knee,” he observed. “The trial should read out in a year or so, and it will be very interesting to see those results.”  

The second family of trials that Dr Parikh discussed relate to the SELUTION SLR drug-eluting balloon. In this device, a biodegradable polymer is mixed with sirolimus, creating spherical micro-reservoirs that enable controlled and sustained drug release. The first-in-human SELUTION SLR trial reported 88.4% 6-month primary patency in the femoropopliteal area – interestingly very similar to the 88.2% found in the XTOSI trial for MagicTouch, although the trial populations were not directly comparable as SELUTION SLR enrolled patients with Rutherford scores of 2 and 3, vs predominantly 5 or 6 in XTOSI.⁶

As for MagicTouch, there are several randomized trials currently enrolling to assess the safety and efficacy of this technology, comparing the device to either uncoated or paclitaxel-coated balloons. Dr Parikh drew particular attention to the SELUTION4SFA and the SELUTION4BTK trials, 2 randomized multicenter studies enrolling 300+ patients that will compare the SELUTION SLR device to uncoated balloon angioplasty in patients with femoropopliteal and BTK lesions, respectively.^7,8

Summarizing the picture regarding SELUTION SLR and MagicTouch, Dr Parikh highlighted the importance of these large ongoing trials. “For both of these devices we have encouraging data so far, but the really pivotal trials will be ongoing in the year forthcoming.” 

Dr Parikh then moved on to discuss limus-eluting stents. In his talk, he outlined the trials in progress, including the LIFE-BTK trial, for which he is one of the principal investigators. This landmark global randomized trial is comparing the safety and efficacy of the Esprit BTK everolimus-eluting bioresorbable scaffold (Abbott Vascular) to standard percutaneous transluminal angioplasty.⁹ This technology has great promise, Dr Parikh explained, as the scaffold allows fine-tuned control of the drug release kinetics, while its resorbable nature preserves future options. 

Considering the research landscape as a whole, Dr Parikh emphasized the encouraging amount of study in this area and also the work left to do. “There’s so much activity, and yet there’s not one FDA-approved limus device for the peripheral arteries,” he reflected. “That’s very telling, because we’re still a fair way from the clinic. But there’s a lot of data on the horizon – there’ll be LIFE-BTK this year, we might have some of the DCB trials in the next 18 months, and then we’ll see some of the head-to-heads probably a couple of years after that. So the next 3 years at least will be an explosive time of growth and we’ll be watching what happens with bated breath.”

Looking ahead, Dr Parikh is hopeful that limus devices will lead to an improvement in patient outcomes. “I’m very optimistic that as with the coronaries we’ll see an effectiveness signal showing that these agents are at least as good if not superior to paclitaxel,” he concluded. “But I’m not worried about paclitaxel’s safety – it’s not dangerous, we just need something better for our patients.“

REFERENCES

1. Choke E, Tang TY, Peh E, et al. MagicTouch PTA sirolimus coated balloon for femoropopliteal and below the knee disease: results from XTOSI pilot study up to 12 months. J Endovasc Ther. 2022;29(5):780-789. 

2. Choke E; results presented at VEITH 22. Available at: https://www.youtube.com/watch?v=2xokmMuhzuc 

3. Sirolimus Coated Balloon Versus Standard Balloon for SFA and Popliteal Artery Disease (FUTURE-SFA). ClinicalTrials.gov Identifier NCT04511234. Available at: https://clinicaltrials.gov/ct2/show/NCT04511234 

4. Sirolimus Coated Balloon for the Treatment of Below The Knee Arterial Disease (FUTURE-BTK). ClinicalTrials.gov Identifier NCT04511247. Available at: https://clinicaltrials.gov/ct2/show/NCT04511247

5. Sirolimus- vs. Paclitaxel-Drug Coated Balloons in Patients with Peripheral Artery Disease (SIRONA) trial. ClinicalTrials.gov Identifier NCT04475783. Available at: https://clinicaltrials.gov/ct2/show/NCT04475783 

6. Zeller T, Brechtel K, Meyer DR, et al. Six-month outcomes from the first-in-human, single-arm SELUTION sustained-limus-release drug-eluting balloon trial in femoropopliteal lesions. J Endovasc Ther. 2020;27(5):683-690. 

7. SELUTION4BTK Trial. ClinicalTrials.gov Identifier NCT05055297. Available at: https://clinicaltrials.gov/ct2/show/NCT05055297

8. SELUTION4SFA Trial. ClinicalTrials.gov Identifier NCT05132361. Available at: https://clinicaltrials.gov/ct2/show/NCT05132361

9. LIFE-BTK Randomized Controlled Trial. ClinicalTrials.gov Identifier NCT04227899. Available at: https://clinicaltrials.gov/ct2/show/NCT04227899