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Phase-I Study of ETA Receptor Antagonist Ambrisentan in Sickle Cell Disease

Endothelin-1 (ET1) is a potent vasoconstrictor, mitogen, proinflammatory mediator and a mediator of nociception. Its synthesis is increased by hypoxia, ischemia, shear stress, oxidative stress and reduced nitric oxide (NO) bioavailability, all of which are well documented mechanisms in the pathophysiology of sickle cell disease. Two distinct receptors, ETA and ETB mediate opposing actions of ET1; while ETA mediates vasoconstriction, inflammation, cellular adhesion and vascular remodeling, ETB stimulation leads to increased NO production, vasodilatation, anticoagulation and anti-adhesion. We studied the role of ET1 in SCD in transgenic mouse models, and showed that selective ETA receptor blockade with ambrisentan provides renal protection by preventing the development of glomerular hyperfiltration, and preventing proteinuria (Kasztan et al, 2017; Taylor et al, 2019; Kasztan & Pollock, 2019).Additionaly, ETA receptor blockade was shown to decrease pulmonary inflammation in response to different stimuli, including hypoxia/reoxygenation and LPS (Meiler et al). Lutz et al (2018) showed that pharmacologic inhibition, or neuron specific knockdown of ETA receptor in primary sensory neurons of dorsal root ganglia in Berk mice alleviated basal and post-hypoxia evoked pain hypersensitivity.
 We then conducted a Phase 1, double blind, placebo controlled study to elucidate the role of ET-1 in 26 patients with SCD (SS or Sb0thal); patients were randomized to either ambrisentan 5 mg/day (N=13) or placebo (N=13) for 12 weeks. The primary end point was safety and tolerability. We also measured microalbuminuria, pressure pain threshold, transcranial doppler (TCD), echocardiograms (TR jet velocity), vascular endothelial function by flow mediated dilation (FMD), and inflammatory cytokines. Urine specimens were collected for measurement of markers of glomerular and tubular injury (NGAL, KIM-1, netrin and nephrin) at baseline and at the end of study (Day 85). Ambrisentan was well tolerated without any adverse events or fluid retention. No change in systolic and diastolic blood pressures were observed in either group (p=0.88, and p=049, respectively). No significant change in weight or serum creatinine was observed in the ambrisentan group (69.1→68.6 Kg, p=0.99, and 0.74→0.69 mg/dl, p=0.43). In the ambrisentan group, there was a tendency toward reduced microalbuminuria, (-36.6 mg/g Cr, vs +91.6), especially in the subgroup of patients who had been on a stable dose of ACE or ARB for 6 months (n=6, 286.1 mg/g Cr at baseline to 197.7 mg/g on day 85, p=0.06). FMD measurements showed increased arterial diameter, and improved microvascular function. Data collected for secondary end points including, TCD, TRV, inflammatory cytokines, markers of glomerular and tubular injury, quantitative sensory testing (QST) with pressure pain measurements, and von Frey monofilament readings, as well as quality of life measures (ASCQMe) are in the process of being analyzed. These data suggest that ETA receptor blockade is safe, well tolerated and has the potential to impact various aspects of disease pathophysiology in SCD.
 
 
 Kutlar: Novartis: Consultancy; Global Blood Therapeutics, Inc. (GBT): Research Funding; Bluebird Bio: Other: DSMB Member; Novo Nordisk: Research Funding; Micelle Biopharma: Other: DSMB Chair.
 
 
 
 Ambrisentan is an approved FDA drug used for treatment of another condition but it is expected that it will also help improve and/or prevent kidney damage that can be caused by sickle cell disease.
