Treatment with QPI-1002, a Short Interfering (SI) RNA for the Prophylaxis of Delayed Graft Function.

Abstract

Introduction: Delayed graft function (DGF) can adversely affect deceased donor renal transplant outcomes, particularly in recipients of expanded criteria donor (ECD) kidneys. We report first results of a large Phase 2 study with QPI-1002 (NCT#00802347), a siRNA that transiently suppresses p53 mediated apoptosis and that was previously shown to improve outcomes after acute kidney injury and renal transplantation in preclinical models. Methods: 332 patients (pts) were randomized 1:1 to single dose QPI-1002, 10.0 mg/kg IV, or Placebo in double-blind fashion post-allograft reperfusion. DGF was defined as the need for dialysis ≤7 days post-transplant (Tx) (except for dialysis on Day 1 for hyperkalemia or hypervolemia). Pts were prospectively allocated to 4 strata by donor type (ECD or SCD) and preservation [cold-stored (CS) or machine-perfused (MP)]. Estimated cold ischemia time (CIT)>26 hrs was required in all but the ECD/CS stratum. Results: In 327 (164 QPI-1002; 163 Placebo) efficacy-evaluable pts, mean age, %male, %of African descent, pt weight, BMI, peak %PRA, prior transfusion status, HLA mismatch, mean CIT and donor terminal serum creatinine, % with hypertension and cause of death did not differ between groups (p=ns). Pre-Tx DGF risk was 35% in QPI-1002 and 36% in Placebo pts (p=ns), in whom DGF occurred in 50 (30.9%) and 60 (36.4%; p=0.349). In the largest stratum (ECD/CS, n=177), DGF rates were 27.3% and 39.3% for QPI-1002 (n=88) and Placebo (n=89), respectively (30.5% relative reduction, p=0.111), mean duration of dialysis (13.4 vs 25.3 days) was shorter (p=0.292), mean number of dialysis sessions (6.0 vs 11.2.) was lower (p=0.271); and time-to-first post-Tx dialysis (hazard ratio 0.626, log-rank p=0.045) and mean Day 30 measured (m)GFR (34.8 vs. 21.1 mL/min/1.73 m2, p=0.035) were significantly improved following QPI-1002. The overall safety profile was consistent with that expected in Tx recipients and similar in both groups. Conclusions: Treatment with QPI-1002 resulted in a relative reduction of DGF and significantly improved time to first dialysis and Day 30 mGFR in the largest stratum (ECD/CS) in this Phase 2 study. QPI-1002 may reduce the need for dialysis in ECDs, possibly due to increased expression of p53 following reperfusion in older kidneys, as has recently been demonstrated in preclinical studies. DISCLOSURE:Budde, K.: Grant/Research Support, Quark Pharmaceuticals. Polinsky, M.: Employee, Quark Pharmaceuticals, Inc. Squiers, E.: Employee, Quark Pharmaceuticals, Inc. Erlich, S.: Employee, Quark Pharmaceuticals, Inc.