Quark Pharmaceuticals, Inc. reported data from a randomised, double-blinded, placebo-controlled multicenter phase II clinical trial (QRK.006B; ClinicalTrials.gov identifier: NCT00802347) of QPI-1002, a synthetic chemically modified siRNA acting to reduce p53 RNA and protein levels, for the prophylaxis of delayed graft function (DGF) in deceased donor kidney transplant patients.

The data were presented in the late-breaking session at the 2014 World Transplant Conference (WTC) in San Francisco, CA by Dr. V. Ram Peddi, Director of Kidney Transplant Research at California Pacific Medical Center in San Francisco, on behalf of the QPI-1002 DGF Study Investigator Group.

The study, which included 331 treated (327 efficacy evaluable) patients, was conducted in 52 transplant centers across North America and Europe. The primary objectives of the study were to assess the efficacy of QPI-1002 in the prevention of DGF and to further assess its safety and pharmacokinetics. The primary study endpoint was to achieve at least 30 per cent relative risk reduction of DGF (defined as the need for dialysis within the first 7 days post-transplant, excluding dialysis in the first 24 hours due to hyperkalemia/hypervolemia) in QPI-1002-treated patients compared to placebo.

The overall QPI-1002 safety profile was consistent with the expected profile for transplant recipients, and similar in both treated and placebo groups. While the primary endpoint for the study was not met in the total study population (15.1per cent relative risk reduction of DGF), the data presented at the WTC showed that treatment with QPI-1002 resulted in 30.5per cent relative risk reduction in patients included in the largest of the prospectively defined study strata - Expanded Criteria Donor kidneys entirely Cold Stored (ECD/CS, n=177,). The same relative risk reduction of approximately 30per cent was obtained, in post hoc analysis of the results, in all recipients of kidney grafts from donors older than 45 or 35 years of age, n=252; 77per cent and n=283; 86per cent respectively of all efficacy evaluable patients, regardless of the predefined graft strata classification (data for older than 35 not presented at the WTC).

Furthermore, in the ECD/CS stratum, QPI-1002 treatment significantly increased the dialysis free survival (time to first dialysis) in the first post-transplant month (Log rank p=0.04), reduced the mean duration of the first course of dialysis (13.4 vs 25.3 days); and reduced the number of dialysis sessions required in the first 30 days post-transplant (6.0 vs 11.2). Similar results were obtained in all recipients of kidney grafts from donors older than 45 and in patients receiving kidneys of donors older than 35 years of age, regardless of the predefined graft strata classification (data for older than 35 not presented at the WTC). By the end of 6-month study observation period, the total number of dialysis sessions in all efficacy evaluable patients treated with QPI-1002 was 1.5-fold lower compared to placebo group (375 vs. 561 p=0.059).

The improved outcomes associated with QPI-1002 treatment in the function of kidney grafts from older donors is consistent with recently published studies showing stronger activation of p53, the target of QPI-1002, following reperfusion of older kidneys in animal models. Altogether, the trial findings justify continued development of QPI-1002 for the prevention and amelioration of DGF, an unmet medical need. In addition, increased impact of kidney age on treatment outcomes of QPI-1002 indicates that this drug may be useful for prophylaxis of acute kidney injury in patients undergoing major cardiac surgery given the higher prevalence of this procedure in aging population. Quark believes that QRK.006B is the first ever well-controlled clinical trial involving hundreds of patients in which a systemically administered siRNA-based drug has shown clinical activity.

"Delayed graft function adversely affects outcomes following deceased donor kidney transplantation and is a significant problem for which there is no approved treatment.” Quark Pharmaceuticals’ study with QPI-1002 is a very large double blind randomized study in patients at risk for DGF," Dr. Peddi observed. "The findings of this study showing QPI-1002 decreases DGF, especially in older donor transplants, are exciting and warrant further study with this investigational agent that could improve outcomes from older kidneys”.

Dr. A. Osama Gaber, F.A.C.S, Professor of Surgery of the Houston Methodist J.C.Walter Jr. Transplant Center, an investigator in the study who previously presented the Phase I QPI-1002 results, stated, “QPI-1002, represents a truly unique approach by directly targeting p53-dependent cell death, an underlying trigger of the injury that causes DGF, and the findings in older donors support the rationale for a QPI-1002 treatment effect based on p53 expression in older kidneys. The positive findings in this large trial merit further study, and suggest we may have a promising investigational agent for DGF”.

The QRK.006B Phase II study was a multicenter placebo-controlled, randomized, prospective, and double-blinded for evaluating the clinical activity of QPI-1002 (administered as 10 mg/kg single bolus IV dose at 30 minutes after  circulatory reperfusion is achieved to the transplanted organ) in end-stage kidney disease dialysis-dependent patients undergoing deceased donor kidney transplantation. The primary objectives of the study were to assess the efficacy of QPI-1002 in the prevention of DGF and to further assess its safety and pharmacokinetics. The incidence of DGF (defined as the need for dialysis within first 7 post-transplant days excluding dialysis in the first 24 hours due to hyperkalemia/hypervolemia) was the primary study endpoint, whereas secondary endpoints included other definitions of DGF, and parameters evaluating DGF severity and kidney function in the post transplant period. The patients were prospectively grouped into 4 strata by the type of donor - expanded or standard criteria donors (ECD or SCD); and graft preservation - cold-stored (CS) or machine-perfused (MP) with protocol specified cold ischemia time (CIT requirements).

DGF results from ischemia-reperfusion injury to the graft tissue associated with transplantation procedure when blood flow is re-established to the kidney following transplantation and initiates a chain of events that can lead to severe renal damage. DGF not only significantly increases the risk of delayed allograft rejection, but also adds to the cumulative cost of renal transplantation by increasing the time of hospital stay, the number of tests and the use of dialysis facilities. The increasing shortage of suitable kidney donors led to the necessity of incorporating expanded criteria donor kidneys (mainly from older deceased donors) into the donor pool. However, such kidneys are at increased risk of DGF. There is no currently marketed drug therapy for the prevention or treatment of DGF.

QPI-1002, the first systemic siRNA drug to enter human clinical trials and to complete a well-controlled clinical trial with clinical efficacy endpoints that was conducted in hundreds of patients. It is an investigational drug designed to temporarily inhibit the expression of the pro-apoptotic gene, p53, to protect normal cells from acute injury. Preclinical studies have shown that p53-targeted siRNAs can protect kidneys from ischemia/reperfusion injury in a variety of clinically relevant animal models. QPI-1002 has been granted Orphan Drug designation in the USA and Europe for the prevention of DGF in kidney transplant patients. Under an August 2010 agreement, Novartis has an exclusive worldwide license option for the development and commercialisation QPI-1002.