TOSCA-5: Collagenase Injection May Ease Chronic-Occlusion PCI, but Early Days

Patrice Wendling

November 07, 2016

WASHINGTON, DC — Injecting chronic total occlusions (CTOs) with bacterial collagenase before angioplasty appeared to increase wire-crossing success rates in a phase 2 trial but also raised questions about the novel strategy[1].

MZ-004 (Matrizyme) is produced by fermentation of Clostridium histolyticum and thought to facilitate PCI by degrading collagen, a key component of CTOs, and softening the fibrous proximal cap.

Dr Christopher Buller

Using this investigational biochemical approach doubled crossing rates in an animal model and allowed successful crossing in 15 of 20 patients with prior crossing failure in a first-in-human study, TOSCA-5 principal investigator Dr Christopher Buller (St Michael's Hospital, Toronto, ON) explained at TCT 2016.

To extend these findings and inform the design of a larger pivotal trial, the investigators enrolled 75 patients undergoing clinically driven CTO procedures targeting a single native-vessel occlusion not more than 25 mm in length and using exclusively an antegrade wire escalation. Initially the protocol required a documented failed attempt, but this was amended to a simple 1-minute guidewire tap test due to slower-than-expected enrollment.

The randomly assigned treatment was given the day before PCI by hand injection over 12 minutes through a microcatheter embedded in the proximal cap of the occlusion.

At 30 days, soft wire crossing rates were significantly higher in patients receiving MZ-004 900 µg and 1200 µg rather than placebo (17% vs 29% vs 0%; P=0.03).

There were no significant differences, however, between the 900-µg, 1200-µg, and placebo groups in rates of guidewire crossing (73% vs 74% vs 64%; NS) or successful PCI by quantitative coronary arteriography (60% vs 65% vs 64%; NS).

Session moderator Dr Gary S Mintz (Cardiovascular Research Foundation, Washington DC) called out the roughly 65% success rate, saying, "My CTO colleagues would sort of look at this with crossed eyes; was there a reason?"

Buller responded that they forbid formal reentry or retrograde procedures, and failures were brought forward beyond the 30-day end point and then offered a "full-on hybrid" procedure. "So this was not reflective, I think, of the overall practice of these sites that include many high-end hybrid operators."

PCI Procedural Efficiency, Safety Results

Notably, there were no significant differences in PCI procedural efficiency between groups, although several aspects were higher in the 1200-µg group.

Characteristics Placebo 900 µg 1200 µg
Fluoro time to cross (min) 17.1 16.7 17.3
Total fluoro time 36.6 34.7 44.6
Radiation (Gy) 2.1 2.8 2.5
Contrast during PCI (mL) 244 268 339
Total stented length (mm) 68 70 74

During a press briefing, however, Dr Christopher Metzger (Wellmont CVA Heart Institute, Kingsport, TN) commented on the "strikingly longer" procedure times in patients receiving the highest dose of collagenase.

Buller said some of it is "play of chance" but added that "more than half, maybe two-thirds of the procedure is after wiring; so as you increase your wiring success, you obligate yourself to doing a lot more angioplasty down the road. So there's a paradox here."

As to safety, there were no deaths, no repeat revascularizations, and one major adverse cardiac event, an MI in a placebo-treated patient.

Periprocedural myonecrosis was reported in two patients in the placebo group, two in the 900-µg group, and four in the 1200-µg group—all were associated with either a small side-branch occlusion (<2 mm diameter) or perforation.

Perforations and significant effusions were numerically higher in patients receiving the highest collagenase dose; and all perforations associated with stiff wires occurred in this group.

  Placebo 900 µg 1200 µg P
Perforation
Ellis 2 1 1 1  
Ellis 3 0 0 3  
Ellis 2 or 3 1 (7%) 1 (3%) 4 (13%) 0.56
Significant effusion
Moderate 1 1 1  
Large 0 0 0  
Moderate to large 1 (7%) 1 (3%) 1 (3%) 0.99
Ellis 2/3 or significant effusion 1 (7%) 2 (7%) 4 (13%) 0.87

"The safety profile appears generally favorable, with low rates of adverse events both immediately following administration and at subsequent PCI; the caveat is the need to continue to monitor the combination of 1200-µg doses with the use of stiff wires in future trials," Buller said.

Discussants also questioned whether the collagenase could migrate outside the CTO and permeate other caps in other vessels.

Buller replied; "There is a µg measurable level in the plasma of collagenase after injection for a couple of hours that theoretically could have that effect, as well as effects elsewhere, of course, since it's in plasma. But we've not yet seen any sign of that, and angiographically on the day-1 procedures when the agent is marinating, so to speak, in the heart for 24 hours, we saw no angiographic changes in other vessels whatsoever."

The study was sponsored by Matrizyme Pharma. Buller reported research funding from Abbott Vascular and Matrizyme Pharma, consultancy for Abbott, Volcano, and Aegis Medical; intellectual property license with Vascular Solutions; and equity/stock ownership in Soundbite Medical and Atrius Medical. Mintz reported grant support/research contract with Boston Scientific, St Jude Medical, and Volcano; and consultant fees/honoraria/speaker's-bureau affiliation with Boston Scientific and Volcano. Metzger reported consultant fees/honoraria/speaker's bureau affiliation with Abbott Vascular, Bard Medical, Boston Scientific, Endologix, and CSI.

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