Direct Temsirolimus Delivery Promising in BTK: TANGO Phase II Study

Adventitial delivery of temsirolimus appears to safely reduce neointimal hyperplasia and target lesion failure after endovascular revascularization of below-the-knee (BTK) arteries, according to a phase II dose-escalation study. The results, though preliminary, can inform the design of a phase III trial testing the drug and technology, researchers say.

“Current infrapopliteal treatments continue to lack long-term durability,” Ehrin Armstrong, MD (Rocky Mountain Regional VA Medical Center, Denver, CO), said when sharing TANGO’s results with media. Drug-coated balloons haven’t shown consistent benefits in BTK lesions, he pointed out. “This is likely due to a number of factors but it may include heavy calcification, difficulty with drug effusion in this segment, more dense and bulky plaque.”

TANGO, presented Sunday at TCT Connect 2020, employs the Bullfrog micro-infusion device (Mercator MedSystems). Direct delivery of therapy to the adventitia, confirmed by contrast media, can provide a “shortcut” to the disease. Injections are performed approximately every 40 mm along the lesion length using a single balloon. Temsirolimus, the active metabolite of sirolimus, is an “ideal agent based on its confirmed efficacy and safety in the coronary circulation,” he said.

Peter Schneider, MD (University of California, San Francisco), a press conference discussant, said the concept is appealing.

“[With] the hostile environment of the lower-extremity arteries—and especially below-the-knee, long, diffusely diseased, slow-flow arteries—I think the idea that some kind of a drug-eluting stent paradigm is going to be successful there in anything but the shorter lesions is [unlikely],” he explained. “That leaves us with: how else can we deliver the drug? And we know that we’ve had trouble delivering sirolimus from a balloon.

“So this gives the potential to inject it directly. The more drug you get into the media or periadventitial space, just conceptually the higher the chance of the drug effect being successful, or so it would seem,” Schneider commented. “I think we’re seeing a hint of that here.” In a larger phase III trial, “this therapy may really show itself as beneficial,” he predicted.

TANGO

For the double-blind TANGO trial, researchers prospectively enrolled 61 patients undergoing endovascular revascularization of at least one angiographically significant BTK lesion. All had Rutherford class 3 to 5 symptoms, and most had diabetes. Mean lesion length was 10.9 cm in the treatment groups and 12.7 cm in controls. Around half of the lesions were TASC II C or D, and slightly more than one-third had total occlusion at baseline

After intervention, patients were randomly assigned to saline control, low-dose temsirolimus (0.1 mg/mL), or high-dose temsirolimus (0.4 mg/mL).

TANGO’s primary endpoint is 6-month angiographic transverse view area loss (TVAL), which Armstrong explained is a 3-D representation of the neointimal hyperplasia that’s “really useful as a biologic signal with regards to restenosis.”

After exclusion of short and nonoccluded TASC A lesions, which could potentially dilute a treatment effect, TVAL was 24% with temsirolimus and 46% with saline, “essentially a 50% reduction in the neointimal hyperplasia volume along the treated segment, consistent with a reduction in the overall restenosis and inflammatory signal in the treated vessels,” Armstrong reported.

At 12 months, target lesion failure (clinically driven TLR, ischemia-related major amputation, or clinically relevant target lesion occlusion) had occurred in 70.2% of the treated TASC B-D group and 31.0% of controls.

“Below-the-knee drug treatment must pass through excessive tissue barriers, and while many drug-coated balloons and drug-eluting stents are in development, positive results up to this point have been limited to short, focal segments,” Armstrong concluded, referring to the TANGO outcomes as “robust.” Next up is a phase III trial, he added.

What Lies Ahead

Robert Lookstein, MD (Mount Sinai Health System, New York, NY), in the media briefing, called TANGO a “very provocative study” on a treatment that would be welcome if it pans out.

Lookstein told Armstrong that his “one concern . . . is how do you take a therapy which, at least on its surface, can only be administered every 40 mm or so and translate that to real-world lesions [that can be] 20 cm long? . . . Should the Bullfrog be modified before we go to a pivotal phase III trial?”

Armstrong acknowledged that “those are good questions.” The 40-mm distance is based on the visualization provided by contrast, he said. “You really can ‘paint’ the vessel. With longer lesions, of course, it does require multiple injections, sometimes on the order of five or six injections.” That said, he stressed that Bullfrog has advantages over balloons, among them torqueability that allows for the device to go around calcium for drug delivery.

Asked about the therapy’s durability, Armstrong pointed out that while patients with infrapopliteal disease may well go on to have restenosis and need repeat revascularization, the 6- and 12-month marks here are clinically relevant. “Typically we’re trying to assist with wound healing and prevent major amputation in these settings,” he told TCTMD, noting that they’d likely include 24- and 36-month follow-up in a subsequent trial.

Jihad A. Mustapha, MD (Advanced Cardiac & Vascular Centers for Amputation Prevention, Lansing, MI), in an interview, outlined TANGO’s limitations—among them the unusually short length of treated lesions. “It’s a promising technology and has a great future if it’s done properly with an RCT that’s 1:1, adjudicated, [etc],” he said, adding that the current report is hard to interpret, given how the two doses are combined. Mustapha also observed that this delivery device has been tested for many years and has yet to show decisive results.

Before TANGO, the Bullfrog was tested in the DANCE and LIMBO-PTA studies, which applied steroid dexamethasone in femoropopliteal and BTK lesions, respectively.

Mahmood K. Razavi, MD (St. Joseph Heart & Vascular Center, Orange, CA), an investigator involved in all of the above studies, gave TCTMD a progress report on the technology.

For him, what’s most appealing is multidrug treatment involving both an anti-inflammatory that would work early in the pathologic process as well as an antiproliferative drug to target restenosis. The TAP-DANCE trial, with Razavi as principal investigator, is testing the combo approach in superficial femoral artery disease. Whether the next step for BTK lesions in a phase III study will be dual therapy or temsirolimus alone is under discussion, he said.