Slowing Progression of Cardiovascular Calcification With SNF472 in Patients on Hemodialysis: Results of a Randomized Phase 2b Study

BACKGROUND:The high cardiovascular morbidity and mortality in patients with end-stage kidney disease could be partially caused by extensive cardiovascular calcification. SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits the formation and growth of hydroxyapatite. METHODS:This doub...

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Published in:Circulation (New York, N.Y.) N.Y.), 2020-03, Vol.141 (9), p.728-739
Main Authors: Raggi, Paolo, Bellasi, Antonio, Bushinsky, David, Bover, Jordi, Rodriguez, Mariano, Ketteler, Markus, Sinha, Smeeta, Salcedo, Carolina, Gillotti, Kristen, Padgett, Claire, Garg, Rekha, Gold, Alex, Perelló, Joan, Chertow, Glenn M.
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container_issue 9
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container_title Circulation (New York, N.Y.)
container_volume 141
creator Raggi, Paolo
Bellasi, Antonio
Bushinsky, David
Bover, Jordi
Rodriguez, Mariano
Ketteler, Markus
Sinha, Smeeta
Salcedo, Carolina
Gillotti, Kristen
Padgett, Claire
Garg, Rekha
Gold, Alex
Perelló, Joan
Chertow, Glenn M.
description BACKGROUND:The high cardiovascular morbidity and mortality in patients with end-stage kidney disease could be partially caused by extensive cardiovascular calcification. SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits the formation and growth of hydroxyapatite. METHODS:This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium volume score and other measurements of cardiovascular calcification by computed tomography scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with end-stage kidney disease receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log coronary artery calcium volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least 1 dose of SNF472 or placebo and had an evaluable computed tomography scan after randomization. RESULTS:The mean change in coronary artery calcium volume score was 11% (95% CI, 7–15) for the combined SNF472 dose group and 20% (95% CI, 14–26) for the placebo group (P=0.016). SNF472 compared with placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5–24] versus 98% [95% CI, 77–123]; P
doi_str_mv 10.1161/CIRCULATIONAHA.119.044195
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SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits the formation and growth of hydroxyapatite. METHODS:This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium volume score and other measurements of cardiovascular calcification by computed tomography scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with end-stage kidney disease receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log coronary artery calcium volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least 1 dose of SNF472 or placebo and had an evaluable computed tomography scan after randomization. RESULTS:The mean change in coronary artery calcium volume score was 11% (95% CI, 7–15) for the combined SNF472 dose group and 20% (95% CI, 14–26) for the placebo group (P=0.016). SNF472 compared with placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5–24] versus 98% [95% CI, 77–123]; P&lt;0.001) but not in the thoracic aorta (23% [95% CI, 16–30] versus 28% [95% CI, 19–38]; P=0.40). Death occurred in 7 patients (4%) who received SNF472 and 5 patients (6%) who received placebo. At least 1 treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with SNF472 300 mg, SNF472 600 mg, and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of SNF472 300 mg, SNF472 600 mg, and placebo for 14%, 29%, and 20% of patients, respectively. CONCLUSIONS:Compared with placebo, SNF472 significantly attenuated the progression of coronary artery calcium and aortic valve calcification in patients with end-stage kidney disease receiving hemodialysis in addition to standard care. Future studies are needed to determine the effects of SNF472 on cardiovascular events. REGISTRATION:URLhttps://www.clinicaltrials.gov; Unique identifierNCT02966028.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/CIRCULATIONAHA.119.044195</identifier><identifier>PMID: 31707860</identifier><language>eng</language><publisher>United States: by the American College of Cardiology Foundation and the American Heart Association, Inc</publisher><ispartof>Circulation (New York, N.Y.), 2020-03, Vol.141 (9), p.728-739</ispartof><rights>by the American College of Cardiology Foundation and the American Heart Association, Inc.</rights><rights>2020 by the American College of Cardiology Foundation and the American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4165-5646e29bc00e40e64251a1fb7679babdd9e3d9889f1e0d6b837417e76b639e5e3</citedby><cites>FETCH-LOGICAL-c4165-5646e29bc00e40e64251a1fb7679babdd9e3d9889f1e0d6b837417e76b639e5e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31707860$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Raggi, Paolo</creatorcontrib><creatorcontrib>Bellasi, Antonio</creatorcontrib><creatorcontrib>Bushinsky, David</creatorcontrib><creatorcontrib>Bover, Jordi</creatorcontrib><creatorcontrib>Rodriguez, Mariano</creatorcontrib><creatorcontrib>Ketteler, Markus</creatorcontrib><creatorcontrib>Sinha, Smeeta</creatorcontrib><creatorcontrib>Salcedo, Carolina</creatorcontrib><creatorcontrib>Gillotti, Kristen</creatorcontrib><creatorcontrib>Padgett, Claire</creatorcontrib><creatorcontrib>Garg, Rekha</creatorcontrib><creatorcontrib>Gold, Alex</creatorcontrib><creatorcontrib>Perelló, Joan</creatorcontrib><creatorcontrib>Chertow, Glenn M.</creatorcontrib><title>Slowing Progression of Cardiovascular Calcification With SNF472 in Patients on Hemodialysis: Results of a Randomized Phase 2b Study</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>BACKGROUND:The high cardiovascular morbidity and mortality in patients with end-stage kidney disease could be partially caused by extensive cardiovascular calcification. SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits the formation and growth of hydroxyapatite. METHODS:This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium volume score and other measurements of cardiovascular calcification by computed tomography scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with end-stage kidney disease receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log coronary artery calcium volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least 1 dose of SNF472 or placebo and had an evaluable computed tomography scan after randomization. RESULTS:The mean change in coronary artery calcium volume score was 11% (95% CI, 7–15) for the combined SNF472 dose group and 20% (95% CI, 14–26) for the placebo group (P=0.016). SNF472 compared with placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5–24] versus 98% [95% CI, 77–123]; P&lt;0.001) but not in the thoracic aorta (23% [95% CI, 16–30] versus 28% [95% CI, 19–38]; P=0.40). Death occurred in 7 patients (4%) who received SNF472 and 5 patients (6%) who received placebo. At least 1 treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with SNF472 300 mg, SNF472 600 mg, and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of SNF472 300 mg, SNF472 600 mg, and placebo for 14%, 29%, and 20% of patients, respectively. CONCLUSIONS:Compared with placebo, SNF472 significantly attenuated the progression of coronary artery calcium and aortic valve calcification in patients with end-stage kidney disease receiving hemodialysis in addition to standard care. Future studies are needed to determine the effects of SNF472 on cardiovascular events. 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SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits the formation and growth of hydroxyapatite. METHODS:This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium volume score and other measurements of cardiovascular calcification by computed tomography scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with end-stage kidney disease receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log coronary artery calcium volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least 1 dose of SNF472 or placebo and had an evaluable computed tomography scan after randomization. RESULTS:The mean change in coronary artery calcium volume score was 11% (95% CI, 7–15) for the combined SNF472 dose group and 20% (95% CI, 14–26) for the placebo group (P=0.016). SNF472 compared with placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5–24] versus 98% [95% CI, 77–123]; P&lt;0.001) but not in the thoracic aorta (23% [95% CI, 16–30] versus 28% [95% CI, 19–38]; P=0.40). Death occurred in 7 patients (4%) who received SNF472 and 5 patients (6%) who received placebo. At least 1 treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with SNF472 300 mg, SNF472 600 mg, and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of SNF472 300 mg, SNF472 600 mg, and placebo for 14%, 29%, and 20% of patients, respectively. CONCLUSIONS:Compared with placebo, SNF472 significantly attenuated the progression of coronary artery calcium and aortic valve calcification in patients with end-stage kidney disease receiving hemodialysis in addition to standard care. Future studies are needed to determine the effects of SNF472 on cardiovascular events. REGISTRATION:URLhttps://www.clinicaltrials.gov; Unique identifierNCT02966028.</abstract><cop>United States</cop><pub>by the American College of Cardiology Foundation and the American Heart Association, Inc</pub><pmid>31707860</pmid><doi>10.1161/CIRCULATIONAHA.119.044195</doi><tpages>12</tpages></addata></record>
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title Slowing Progression of Cardiovascular Calcification With SNF472 in Patients on Hemodialysis: Results of a Randomized Phase 2b Study
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