Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease.
Hypoxia inducible factor (HIF) stabilization by HIF-prolyl hydroxylase (PHD) inhibitors may improve ischemic conditions such as peripheral artery disease (PAD). This multicenter, randomized, placebo-controlled study evaluated the safety and efficacy of GSK1278863 (an oral PHD inhibitor) in subjects with PAD. The study assessed two active treatment paradigms: single dosing and subchronic daily dosing (300 mg single dose and 15 mg daily for 14 days, respectively). Neither regimen improved exercise performance compared with placebo (change from baseline in the 6-minute walk test (6MWT; feet), (GSK1278863, placebo): single dose (-46, -44), p=0.96; repeat dose (9, 8), p=0.99; change in number of contractions to onset of claudication (goniometry): single dose (4, -1), p=0.053; repeat dose (-2, 1), p=0.08). A calf-muscle biopsy substudy showed no increases in mRNA or protein levels of HIF target genes. More subjects receiving GSK1278863 than placebo experienced adverse events, particularly following the 300 mg single dose. Thus, assessing the safety of GSK1278863 in this setting would require a larger population exposed to the agent for a longer duration. These data do not support a benefit of GSK1278863 in PAD using the regimens tested. CLINICALTRIALSGOV IDENTIFIER NCT01673555:
GlaxoSmithKline, King of Prussia, PA, USA eric.j.olson@gsk.com.
Eric
E
Olson
GlaxoSmithKline, King of Prussia, PA, USA.
Laura
L
Demopoulos
GlaxoSmithKline, King of Prussia, PA, USA.
Thomas F
TF
Haws
GlaxoSmithKline, King of Prussia, PA, USA.
Erding
E
Hu
GlaxoSmithKline, King of Prussia, PA, USA.
Zixing
Z
Fang
GlaxoSmithKline, King of Prussia, PA, USA.
Kelly M
KM
Mahar
GlaxoSmithKline, King of Prussia, PA, USA.
Pu
P
Qin
GlaxoSmithKline, King of Prussia, PA, USA.
John
J
Lepore
Division of General Internal Medicine and CPC Clinical Research, University of Colorado School of Medicine, Aurora, CO, USA.
Timothy A
TA
Bauer
Division of Cardiology and CPC Clinical Research, University of Colorado School of Medicine, Aurora, CO, USA.
William R
WR
Hiatt
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005080:Exercise Test; D005260:Female; D006801:Humans; D007383:Intermittent Claudication / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects; D058729:Peripheral Arterial Disease / Q000188:drug therapy*; D064800:Prolyl-Hydroxylase Inhibitors / Q000627:therapeutic use*; D011788:Quality of Life; D013997:Time Factors; D016896:Treatment Outcome; D016138:Walking / Q000502:physiology
D064800:Prolyl-Hydroxylase Inhibitors
6-minute walk test; GSK1278863; HIF target genes; HIF-prolyl hydroxylase inhibitors; claudication (see intermittent claudication); exercise performance; peripheral artery disease; subchronic dosing