QPI-1002, an siRNA targeting the p53 gene: clinical trials include a Phase I/ II study for the prevention of Delayed Graft Function (DGF) in deceased donor kidney transplant patients, and two Phase I studies in Acute Kidney Injury (AKI) following cardiac surgery. The drug has received Orphan Drug Designation from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) and Fast Track designation by the FDA for the DGF indication.

Quark is enrolling subjects in a pivotal Phase III study for the prevention and amelioration of DGF, following FDA Type C and Type B meetings and EU Scientific Advice (EU SAWP). parallel, Quark initiated a Phase II study for the prevention of AKI in patients undergoing major cardiovascular surgery. Novartis has an exclusive worldwide license option for QPI-1002.

The Drug Candidate

QPI-1002 (I5NP) is a nuclease-resistant, synthetic double-stranded RNA oligonucleotide designed to temporarily inhibit the expression of the pro-apoptotic gene p53, via activation of the RNA interference (RNAi) pathway. Its development is based on the proprietary concept for temporary and reversible inhibition of p53 for therapeutic purposes, first described by Quark and collaborators at the University of Illinois, Chicago in 1999 (Komarov et al.1999, Science 10:285). p53 is a stress-response gene activated by DNA damage, hypoxia, oxidative stress and other conditions, leading to the induction of cell cycle arrest, cell senescence or apoptosis (programmed cell death). In acute settings, the temporary inhibition of p53 at the time of injury may mitigate programmed cell death, which may allow time for repair of cellular damage, thereby preserving tissue and organ integrity and function. Systemic treatment with a siRNA targeting p53 significantly ameliorated acute kidney injury in several preclincial models, including renal vessel pedicle clamp, partial aortic clamp, cisplatin-induced AKI, and warm and cold ischemia models of kidney transplantation (Molitoris et al, J Am Soc Nephrol. 2009 Aug; 20(8): 1754–1764, PMCID: PMC2723992; Imamura et al, Cell Transplant. 2010;19(12):1659-70.).

Previous Clinical Studies

QPI-1002 was the first siRNA to be systemically administered to humans. The first-in-human Phase I study, QRK 002, “A Phase I, Randomized, Double-Blind, Dose Escalation Trial of the Safety and Pharmacokinetics of a Single Intravenous Injection of I5NP in Patients Undergoing Major Cardiovascular Surgery “(NCT00554359) the second Phase 1 study was QRK 004 “A Phase I, Randomized, Double-Blind, Dose Escalation Trial of the Safety and Pharmacokinetics of a Single Intravenous Injection of I5NP in Patients at High Risk of Acute Kidney Injury Undergoing Major Cardiovascular Surgery”( NCT00683553). Results from the AKI studies of QPI-1002 were presented at the “DIA/FDA Oligonucleotide-based Therapeutics 2012” conference.
Quark has completed a large Phase I/II study, QRK006A/QRK006B, a “Controlled, Randomized, Prospective, Double-Blind, Multicenter, Phase I/II, Dose-Escalation Study of the Safety, PK, and Clinical Activity of I5NP for Prophylaxis of Delayed Graft Function in Patients Undergoing Deceased Donor Kidney Transplantation (NCT00802347). The study evaluated the activity of QPI-1002 for prophylaxis of delayed graft function in ESRD dialysis-dependent patients undergoing deceased donor kidney transplantation, safety and pharmacokinetics (PK). Part B of the study included 331 treated (327 efficacy evaluable) patients and was conducted in 52 transplant centers across North America and Europe. The data were presented in the late-breaking session at the 2014 World Transplant Conference (WTC) 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. In this study treatment with QPI-1002 significantly reduced the risk for DGF, increased the dialysis free survival (time to first dialysis) in the first post-transplant month, reduced the mean duration of dialysis and reduced the number of dialysis sessions required in the first 30 days post-transplant. The best results were obtained in patients receiving kidneys from older donors.
No dose-limiting toxicities were reported in the Phase I clinical studies of QPI-1002, and the safety profile of QPI-1002 was consistent with that expected for the condition under study.

Delayed Graft Function in Kidney Transplant Patients

DGF, traditionally defined as need for dialysis within the first week after transplantation, is one of the most common complications of deceased donor organ transplantation. The rate of DGF reported for deceased donor transplants is in the 21-35% range depending upon varying degrees of recipient and donor risk factors in the patient populations and center-specific practices. DGF is associated with poorer graft outcomes as well as an increased risk of acute rejection, increasing morbidity of the transplant procedure and prolonging the initial hospitalization. DGF is thus associated with a significant economic burden both in the short and in the long term due to the extended hospital stay and costly patient management. DGF appears to be primarily related to ischemia-reperfusion (IR) injury resulting from organ preservation between the times of harvesting from the donor and reperfusion following vascular re-anastomosis in the recipient. The IR initiated chain of events can lead to acute tubular injury with renal tubular epithelial cell dysfunction and cell death.

Transplantation is the best available long-term treatment solution for ESRD patients. Due to severe organ shortage, the use of marginal and older kidneys is important to meet the growing organ demand but the risk for DGF is higher in these cases. DGF however is an unmet medical need and the best available treatment is dialysis. As shown in Phase II studies Quark’s QPI-1002 has the effect of reducing the DGF occurrence. In addition in patients that do experience DGF, QPI-1002 reduces the dialysis time and severity with a clear benefit to patients and to the healthcare system. Use of QPI-1002 potentially allows greater use of kidneys from high risk donors, reducing the discard rates currently high in the USA.

Acute Kidney Injury in Cardiac Surgery

AKI is a serious clinical disease that complicates approximately 5% of hospital admissions and up to 30% of admissions to intensive care units. In patients undergoing major cardiovascular surgery, post-surgical AKI develops within hours to days as a result of ischemic conditions caused by reduced local blood flow to the kidneys during surgery. The rate of AKI development in most patients undergoing cardiovascular surgery is low, but the rate can be as high as 22-39% in high-risk patients, depending upon AKI definition. The 30-day mortality rate following onset of AKI after surgery is greater than 50%. (Cardiorenal Med 2013;3:178-199, (DOI:10.1159/000353134)The prognosis among patients requiring dialysis after cardiac surgery is poor, with an increased mortality risk exceeding 60%, however, the risk of short and long term mortality is increased up to 4- fold in patients who develop non-dialysis requiring AKI (The Annals of Thoracic Surgery 93.1 (2012): 337–347. PMC. Web. 6 Sept. 2015). AKI is an unmet medical need, with no specific treatment available.

In models of ischemia-reperfusion induced AKI, the epithelium of proximal tubules is the primary cell type that undergoes damage, leading to acute tubular necrosis. In animal models, following intravenous administration QPI-1002 accumulates rapidly and predominantly in the kidney, specifically in proximal tubules, the intended target cells. Animals treated with a single injection of the animal analogue of QPI-1002 were significantly protected from AKI following either ischemia/reperfusion injury or cisplatin-induced nephrotoxicity (Molitoris et al., 2009 J Am Soc Nephrol. 8:1754) (PMID: 19470675). Preclinical pharmacokinetic, tissue distribution and toxicology studies indicate that QPI-1002 has an acceptable safety profile, a relatively short residence time and a pharmacodynamic effect in the kidney.