Recombinant Human Elastase Treatment of Cephalic Veins

Wong, Marco D.; Bingham, Karen; Moss, Emma; Warn, J. D.; Smirnov, Igor; Bland, Kimberly S.; Starcher, Barry; Franano, F. Nicholas; Burke, Steven K.

doi:10.4172/2329-6607.1000178

Cited by 3 publications

(3 citation statements)

References 16 publications

(30 reference statements)

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“…19 Vonapanitase applied topically immediately following fistula creation rapidly enters the outermost adventitial vessel layer where it fragments elastin fibers. 20,21 Elastin fragmentation by endogenous elastases (matrix metalloproteinases) is an early and essential component of outward vascular remodeling in animal fistula models. 22 Previous clinical trials had shown that vonapanitase, when administered at doses that partially fragment elastin in human arm veins, may increase fistula and arteriovenous graft blood flow 23,24 and improve fistula maturation, patency, and use for hemodialysis.…”

Section: Introductionmentioning

confidence: 99%

PATENCY-2 trial of vonapanitase to promote radiocephalic fistula use for hemodialysis and secondary patency

et al. 2021

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Objective: Arteriovenous fistulas created for hemodialysis often fail to become usable and are frequently abandoned. This prospective trial evaluated the efficacy of vonapanitase, a recombinant human elastase, in increasing radiocephalic fistula use for hemodialysis and secondary patency. Methods: PATENCY-2 was a randomized, double-blind, placebo-controlled trial in patients on or approaching the need for hemodialysis undergoing radiocephalic arteriovenous fistula creation. Of 696 screened, 613 were randomized, and 603 were treated (vonapanitase n = 405, placebo n = 208). The study drug solution was applied topically to the artery and vein for 10 min immediately after fistula creation. The primary endpoints were fistula use for hemodialysis and secondary patency (fistula survival without abandonment). Other efficacy endpoints included unassisted fistula use for hemodialysis, primary unassisted patency, fistula maturation and unassisted maturation by ultrasound criteria, and fistula procedure rates. Results: The proportions of patients with fistula use for hemodialysis was similar between groups, 70% vonapanitase and 65% placebo, ( p = 0.33). The Kaplan–Meier estimates of 12-month secondary patency were 78% (95% confidence interval [CI], 73–82) for vonapanitase and 76% (95% CI, 70–82) for placebo ( p = 0.93). The proportions with unassisted fistula use for hemodialysis were 46% vonapanitase and 37% placebo ( p = 0.054). The Kaplan–Meier estimates of 12-month primary unassisted patency were 50% (95% CI, 44–55) for vonapanitase and 43% (95% CI, 35–50) for placebo ( p = 0.18). There were no differences in the proportion of patients with fistula maturation or in fistula procedure rates. Adverse events were similar between groups. Vonapanitase was not immunogenic. Conclusions: Vonapanitase treatment did not achieve clinical or statistical significance to meaningfully improve radiocephalic fistula surgical outcomes. Outcome in the placebo group were better than in historical controls. Vonapanitase was well-tolerated and safe. TRIAL REGISTRATION: clinicaltrials.gov: NCT02414841 ( https://clinicaltrials.gov/ct2/show/NCT02414841 )

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Section: Introductionmentioning

confidence: 99%

PATENCY-2 trial of vonapanitase to promote radiocephalic fistula use for hemodialysis and secondary patency

et al. 2021

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“…19 When vonapanitase is applied locally during fistula creation, it is rapidly absorbed into the outermost vessel layer, where it fragments elastin fibers. 20,21 Elastin fragmentation by endogenous elastases (matrix metalloproteinases) is an early and essential component of outward vascular remodeling in animal fistula models. 22 Elastin fragments (peptides) created by CELA1 have chemotactic properties that may inhibit cell migration to the intima.…”

mentioning

confidence: 99%

A randomized trial of vonapanitase (PATENCY-1) to promote radiocephalic fistula patency and use for hemodialysis

Bleyer

Scavo

Wilson

et al. 2019

Journal of Vascular Surgery

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Objective: Arteriovenous fistulas created in patients with chronic kidney disease often lose patency and fail to become usable. This prospective trial evaluated the efficacy of vonapanitase, a recombinant human elastase, in promoting radiocephalic fistula patency and use for hemodialysis. Methods: PATENCY-1 was a double-blind, placebo-controlled trial that enrolled 349 patients on or approaching hemodialysis and being evaluated for radiocephalic arteriovenous fistula creation. Of these, 313 were randomized and 311 treated. Patients were assigned to vonapanitase (n ¼ 210) or placebo (n ¼ 103). The study drug solution was applied topically to the artery and vein for 10 minutes immediately after fistula creation. The primary and secondary end points were primary patency (time to first thrombosis or corrective procedure) and secondary patency (time to abandonment). Tertiary end points included use of the fistula for hemodialysis, fistula maturation by ultrasound, and procedure rates. Results: The Kaplan-Meier estimates of 12-month primary patency were 42% (95% confidence interval [CI], 35-49) and 31% (95% CI, 21-42) for vonapanitase and placebo (P ¼ .25). The Kaplan-Meier estimates of 12-month secondary patency were 74% (95% CI, 68-80) and 61% (95% CI, 51-71) for vonapanitase and placebo (P ¼ .048). The proportions of vonapanitase and placebo patients were 39% and 25% (P ¼ .035) with unassisted use for hemodialysis and 64% and 44% (P ¼ .006) with unassisted plus assisted use. Conclusions: Vonapanitase treatment did not significantly improve primary patency but was associated with increased secondary patency and use for hemodialysis. Further research is needed to evaluate these end points.

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“…However, it failed to show a reduction in NH at 21 days in a 12‐pig AVG study (Burke et al, 2009), and recently failed to achieve statistical significance on both of its coprimary endpoints in a second Phase III clinical trial (PATENCY‐2) seeking to improve maturation and patency of AVFs. These results may underpin the importance of providing a more sustained effect with an external sheath, perhaps with a slowly biodegradable SMP wrap that promotes MMP‐12 expression periadventitially, rather than with a therapeutic that may exude only short‐term effects (catalytic activity of 1–4 hr) (Wong et al, 2016). Further in‐depth studies are required to confirm and elucidate the role that MMP‐12 might play in the neovascular, inflammatory, and fibrogenic responses to these macroporous SMP scaffolds.…”

Section: Discussionmentioning

confidence: 99%

Effect of pore size and spacing on neovascularization of a biodegradble shape memory polymer perivascular wrap

Boire

Himmel

et al. 2020

J Biomedical Materials Res

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Neointimal hyperplasia (NH) is a main source of failures in arteriovenous fistulas and vascular grafts. Several studies have demonstrated the promise of perivascular wraps to reduce NH via promotion of adventitial neovascularization and providing mechanical support. Limited clinical success thus far may be due to inappropriate material selection (e.g., nondegradable, too stiff) and geometric design (e.g., pore size and spacing, diameter). The influence of pore size and spacing on implant neovascularization is investigated here for a new biodegradable, thermoresponsive shape memory polymer (SMP) perivascular wrap. Following an initial pilot, 21 mice were each implanted with six scaffolds: four candidate SMP macroporous designs (a–d), a nonporous SMP control (e), and microporous GORETEX (f). Mice were sacrificed after 4 (N = 5), 14 (N = 8), and 28 (N = 8) days. There was a statistically significant increase in neovascularization score between all macroporous groups compared to nonporous SMP (p < .023) and microporous GORETEX (p < .007) controls at Day 28. Wider‐spaced, smaller‐sized pore designs (223 μm‐spaced, 640 μm‐diameter Design c) induced the most robust angiogenic response, with greater microvessel number (p < .0114) and area (p < .0055) than nonporous SMPs and GORETEX at Day 28. This design also produced significantly greater microvessel density than nonporous SMPs (p = 0.0028) and a smaller‐spaced, larger‐sized pore (155 μm‐spaced, 1,180 μm‐sized Design b) design (p = .0013). Strong neovascularization is expected to reduce NH, motivating further investigation of this SMP wrap with controlled pore spacing and size in more advanced arteriovenous models.

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Recombinant Human Elastase Treatment of Cephalic Veins

Cited by 3 publications

References 16 publications

PATENCY-2 trial of vonapanitase to promote radiocephalic fistula use for hemodialysis and secondary patency

PATENCY-2 trial of vonapanitase to promote radiocephalic fistula use for hemodialysis and secondary patency

A randomized trial of vonapanitase (PATENCY-1) to promote radiocephalic fistula patency and use for hemodialysis

Effect of pore size and spacing on neovascularization of a biodegradble shape memory polymer perivascular wrap

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