Torapsel

Gaber AO, Mulgaonkar S, Kahan BD, Woodle ES, Alloway R, Bajjoka I, Jensik S, Klintmalm GB, Patton PR, Wiseman A, Lipshutz G, Kupiec‐Weglinski J, Gaber LW, Katz E, Irish W, Squiers EC, Hemmerich S. YSPSL (rPSGL‐Ig) for improvement of early renal allograft function: A double‐blind, placebo‐controlled, multi‐center Phase IIa study. 
Clin Transplant 2011: 25: 523–533. © 2010 John Wiley & Sons A/S.Abstract: Introduction: Recombinant P‐selectin glycoprotein ligand IgG fusion protein, rPSGL‐Ig (YSPSL), a fusion protein of human P‐selectin ligand and IgG1‐Fc, blocks leukocyte adhesion and protects against ischemia reperfusion injury (IRI) in animal models.Patients and Methods: This randomized 15‐center, double‐blind, 59‐patient Ph2a study assessed YSPSL’s safety in recipients of deceased‐donor kidney allografts and its potential efficacy in improving early graft function. Two doses and two dosing modalities were evaluated.Results: No drug‐specific toxicities or increased adverse event rates were noted. Two YSPSL‐treated patients died of causes determined as unrelated to study drug. YSPSL did not reduce the incidence of dialysis within the first week post‐transplant (41% in treated vs. 20% in placebo patients). Renal function endpoints scored at post‐operative days 1 & 2 were also not impacted by YSPSL. However, at day 5, the fraction of patients with serum creatinine above 6 mg/dL was lower in the YSPSL vs. placebo group (26% vs. 55%, p = 0.043). Large variations in the dialysis‐delayed graft function (DGF) rates were observed between centers, independently of treatment assignment, indicating subjectivity of this endpoint.Conclusion: In this first Ph2a study in kidney transplantation, YSPSL was safe but did not impact the dialysis‐DGF rate. Further studies with more objective efficacy endpoints are required to define the impact of YSPSL on early renal allograft function.

The selectin antagonist known as recombinant P-selectin glycoprotein ligand IgG (rPSGL-Ig) blocks leukocyte adhesion and protects against transplantation ischemia reperfusion injury (IRI) in animal models. This randomized (1:1) single-center double-blind 47-patient phase 2 study with 6-month follow-up assessed rPSGL-Ig's safety and impact on early graft function at 1 mg/kg systemic dose with pretransplant allograft ex vivo treatment in deceased-donor liver transplant recipients. Safety was assessed in all patients, whereas efficacy was assessed in a prospectively defined per-protocol patient set (PP) by peak serum transaminase (TA) and bilirubin values, and normalization thereof. In PP patients, the incidence of poor early graft function (defined as peak TA >2500 U/L or bilirubin >10 mg/dL), average peak liver enzymes and bilirubin, normalization thereof and duration of primary and total hospitalization trended consistently lower in the rPSGL-Ig group compared to placebo. In patients with donor risk index above study-average, normalization of aspartate aminotransferase was significantly improved in the rPSGL-Ig group (p < 0.03). rPSGL-Ig treatment blunted postreperfusion induction versus placebo of IRI biomarker IP-10 (p < 0.1) and augmented cytoprotective IL-10 (p < 0.05). This is the first clinical trial of an adhesion molecule antagonist to demonstrate a beneficial effect on liver transplantation IRI and supported by therapeutic modulation of two hepatic IRI biomarkers.