Data from the PATENCY-1 trial indicate that the application of vonapanitase (Proteon Therapeutics) at the time of fistula surgery is associated with increased fistula survival and use for haemodialysis.
Steven Burke, chief medical officer for Proteon Therapeutics, told delegates at the 2017 Charing Cross Symposium (25–28 April, London, UK) that the vonapanitase safety profile was consistent with medical conditions experienced by kidney disease patients undergoing fistula surgery and was comparable to placebo.
Vonapanitase is an investigational recombinant human elastase, composed of 25 kilodalton serine protease that cleaves peptide bonds in the protein elastin. Elastin is the principal component of elastic fibres in blood vessels that impart elasticity. A single local application (for 10 minutes) of vonapanitase to the external surface of the fistula immediately after creation has led to no observed systemic effects since inactivated by the blood.
Vonapanitase’s mechanism of action is related to the concentration administered, and results in partial fragmentation of elastin fibres at the concentration studied in radiocephalic fistulae. Peptides in the adventitia act as chemo-attractants and may inhibit neointimal hyperplasia and promote outward vascular remodelling. Burke told the audience that vonapanitase has been shown to lead to vessel dilation when administered at a sufficient concentration, and higher concentrations—currently being studied for use in peripheral artery disease—may cause extensive elastin fragmentation, resulting in permanent vessel dilation.
PATENCY-1 is a phase 3 multicentre, randomised, double-blind, placebo-controlled trial involving 31 clinical sites following 313 patients out to one year. All patients had chronic kidney disease and were on or expecting to initiate haemodialysis and were undergoing surgical creation of a radiocephalic fistula. The primary endpoint for the trial was primary patency. Of the original 201-patient vonapanitase group, 85% completed one-year follow-up. In the placebo group, 85% of the initial 103 patients completed one-year follow-up.
There were no significant differences in demographics between the two treatment groups, and patients tended to be male (82.5%) and white (68.9%). There was also a high prevalence of diabetes (60% vonapanitase, 56% placebo), hypercholesterolaemia (71% vonapanitase, 70% placebo), and hypertension (98% vonapanitase, 95% placebo). The primary cause of chronic kidney disease in both groups was diabetes (43% vonapanitase, 39% placebo) followed by hypertension (23% vonapanitase, 25% placebo), while approximately 45% of all patients were on haemodialysis at the time of treatment.
Burke reported that patients treated with vonapanitase had a 42% rate of primary patency at one year compared with 31% for the placebo patients, although this was not clinically significant. There was a 17% reduction in the risk of primary patency loss, ie. thrombosis or procedure to restore or maintain patency (hazard ration 0.83, 95% CI 0.61–1.14, p=0.25). Secondary patency was also improved at one year, and for vonapanitase patients was 74% compared with 61% for placebo patients (HR 0.66, 95% CI 0.43–1, p=0.048).
Use of the fistula for haemodialysis was also increased by vonapanitase application, with a 45% increase compared with placebo (64% vs 44%, p=0.006), and a 56% increase compared with placebo for unassisted use (39% vs. 25%, p=0.035).
Burke told the audience that there was no evidence of immunogenicity when analysing the vonapanitase safety profile and that adverse events were consistent with medical conditions of kidney disease patients undergoing fistula surgery. He noted that adverse event rates were comparable for vonapanitase and placebo: the rate of vascular stenosis was 40.2% in the placebo group and 38.3% in the vonapanitase group; the rate of fistula thrombosis was 26.5% for placebo and 19.6% for vonapanitase; the rate of hypoaesthesia was 4.9% for placebo and 5.3% for vonapanitase; and the rate of procedural pain was 5.9% for placebo and 4.8% for vonapanitase group.
“Vonapanitase was associated with an improvement in fistula survival, secondary patency, and use for haemodialysis, while the safety profile was excellent,” Burke summarised. He went on to note that these results will now need to be confirmed in a second, ongoing phase 3 multicentre, randomised, doubled-blind, placebo-controlled clinical trial—PATENCY-2—enrolling 500 US and Canadian patients with co-primary endpoints of secondary patency and fistula use for haemodialysis.