QPI-1002 (formerly AKIi-5 or I5NP) is an siRNA drug candidate designed to temporarily inhibit the expression of human p53. Its development is based on the proprietary concept of temporary and reversible inhibition of p53 for therapeutic purposes, first described by Quark’s collaborators from University of Illinois, Chicago in 1999 and Quark’s scientists in Science magazine (Science. 1999 Sep 10; 285).
Quark is conducting two Phase I/IIa dose escalation trials of the safety and pharmacokinetics of a single intravenous injection of QPI-1002 in patients undergoing major cardiovascular surgery. Both Phase I/IIa clinical trials, one in moderate to high risk patients and the other in very high risk patients, are multi-center, double-blind, placebo controlled, dose-escalation trial recruiting patients in multiple sites in the United States, Switzerland and Israel. Based on publicly available information, Quark believes that these are the first human clinical trials involving the systemic delivery of siRNA.
p53 is a stress-response gene activated e.g., by DNA damage, hypoxia, oxidative stress and other conditions, leading to the triggering of cellular pathways that induce either cell cycle arrest, cell senescence, or apoptosis in damaged cells. In acute cell damaging settings, the temporary inhibition of p53 at the time of injury delays the induction of cell death, thereby allowing natural repair mechanisms to restore normal DNA and cellular integrity. In ischemia-reperfusion induced acute kidney injury (AKI), the epithelium of proximal tubules is the primary cell type that undergoes damage. Following intravenous administration, QPI-1002 accumulates rapidly and predominantly in kidneys, specifically in proximal tubules, , hence providing necessary protection to the target cells. Quark has conducted pre-clinical studies of QPI-1002 for the prevention of AKI in rats. Rats treated with a single bolus injection of QPI-1002 were significantly protected from ischemia/reperfusion-induced acute kidney injury and effectively prevented the development of acute renal failure. QPI-1002 was also effective in attenuation of cisplatin-induced kidney injury. Quark’s pharmacokinetic, distribution, and toxicity studies in rats and monkeys indicate that QPI-1002 has a favorable safety profile and a relatively short residence time and pharmacodynamic effect in the kidney.
The concept of temporary/reversible p53 inhibition for therapeutic purposes is covered by several patent families, including early intellectual property generated in joint research performed by Prof. Andrei Gudkov at that time at University of Illinois (UIC) with Quark researchers and exclusively licensed to Quark. Issued US patents broadly cover the method of temporary inhibition of p53 to treat diseases associated with the death of normal cells following a variety of stresses, including hair loss associated with cancer therapy or cell death in central nervous system (e.g., after stroke). Patent applications cover siRNA products inhibiting the p53 gene including composition of matter, pharmaceutical compositions comprising same and to the use of the product for treatment of various specified diseases and conditions including acute kidney injury and kidney transplant. The Company has RNAi structure related technology licenses from Silence Therapeutics and from Alnylam Pharmaceuticals.
Post-surgical AKI develops rapidly (within hours to days) when ischemic conditions caused by reduced local blood flow to the kidneys, followed by rapid reperfusion upon removal of the patient from cardiopulmonary bypass, initiate a chain of events that can lead to renal damageI. AKI develops in up to 22% high-risk patients. The mortality rate following onset of AKI following surgery is reportedly 65% - 88%. No specific drug therapy or preventive therapy is available for AKI.
** QUARK is conducting A Dose Escalation Trial of the Safety and Pharmacokinetics of a Single Intravenous Injection in Patients Undergoing Major Cardiovascular Surgery. This study is currently recruiting participants: clinicaltrials.gov