Selepressin

Selepressin (FE 202158; [Phe(2),Ile(3),Hgn(4),Orn(iPr)(8)]vasopressin; CAS 876296-47-8; molecular formula C46H73N13O11S2; molecular weight 1048.29) is a synthetic nonapeptide analog of arginine vasopressin (AVP) and a potent, selective, short-acting full agonist of the human vasopressin type 1a receptor (V1aR), developed by Ferring Pharmaceuticals for the treatment of vasodilatory hypotension in septic shock. The compound was identified through a systematic structure-activity relationship campaign at the Ferring Research Institute in San Diego, in which modifications at positions 2, 4, and 8 of the vasopressin backbone were explored to dissociate V1a-mediated vasoconstriction from the V2-receptor-mediated antidiuresis, V1b-mediated corticotropin release, and oxytocin-receptor-mediated uterotonic effects that complicate clinical AVP administration [1, 2]. Selepressin activates the human V1a receptor with an EC50 of 2.4 nanomolar in functional assays, producing a selectivity ratio of 1:142:1107:440 relative to V1b, V2, and oxytocin receptors, respectively [2]. This selectivity profile confers three pharmacological advantages over AVP in the septic shock setting: absence of V2-receptor-mediated free water retention and consequent fluid overload; absence of V2-receptor-mediated release of von Willebrand factor and consequent procoagulant risk [3]; and absence of V2-receptor-mediated exacerbation of capillary leak through endothelial aquaporin-2 trafficking. Preclinical pharmacology in ovine fecal peritonitis, ovine Pseudomonas aeruginosa pneumonia, canine hemodynamic, and rabbit endotoxemia models demonstrated that selepressin maintains mean arterial pressure comparably to AVP, reduces cumulative fluid requirements, attenuates pulmonary edema, preserves mesenteric perfusion more favorably than AVP, and improves survival relative to both AVP and norepinephrine when administered early in the septic course [4, 5, 6, 7]. In vitro, selepressin protects human lung microvascular endothelial barrier integrity against thrombin, vascular endothelial growth factor, angiopoietin-2, and lipopolysaccharide challenge through V1a-receptor-dependent activation of p53, suppression of RhoA/myosin light chain 2 signaling, and activation of the Rac1 GTPase barrier-protective pathway [8]. A Phase IIa randomized, double-blind, placebo-controlled trial in 53 patients with early septic shock (Russell et al. 2017) demonstrated that selepressin at 2.5 nanograms per kilogram per minute effectively substituted for norepinephrine, reduced 7-day cumulative norepinephrine dose from 761 to 249 micrograms per kilogram, lowered cumulative net fluid balance from day 5 onward, and increased ventilator-free days [9]. The pivotal SEPSIS-ACT adaptive Phase 2b/3 randomized clinical trial (Laterre et al. 2019, JAMA) enrolled 868 adults with septic shock across 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States. Three selepressin dosing regimens (starting infusion rates of 1.7, 2.5, and 3.5 nanograms per kilogram per minute) were compared to placebo. The trial was stopped for futility at the completion of Part 1: the primary endpoint of ventilator- and vasopressor-free days within 30 days was 15.0 days with selepressin versus 14.5 days with placebo (difference 0.6 days; 95 percent confidence interval, negative 1.3 to 2.4; P equals 0.30), and 90-day mortality was 40.6 percent versus 39.4 percent [10]. Selepressin did produce statistically significant reductions in cardiovascular Sequential Organ Failure Assessment score at 24 hours (difference negative 0.42; P less than 0.001) and in hourly fluid balance at 24 hours (81 versus 107 milliliters per hour; P less than 0.001), confirming the hemodynamic and fluid-sparing pharmacodynamic effects observed in Phase IIa. The compound is not approved by any regulatory authority. It is available from chemical suppliers as a research-grade peptide. This monograph reviews the chemistry and structure-activity relationships, the receptor pharmacology and selectivity, the comprehensive preclinical evidence base across multiple sepsis models, the human pharmacokinetic profile, the Phase IIa and Phase 2b/3 clinical evidence, sourcing and reconstitution considerations, stack-interaction implications, adverse-event signal, and a comparative assessment of five vasopressor alternatives on five competency standards.