QPI-1002 (I5NP) is a synthetic siRNA designed to temporarily inhibit expression of the pro-apoptotic protein, p53. Its development is based on the proprietary method 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) (PMID: 10481009)
QPI-1002 is being developed by Quark for the prevention of AKI following major cardiovascular surgery, and for the prophylaxis of DGF following deceased donor renal transplantation. Phase I studies in both of these patient populations have been completed and an independent Data Safety Monitoring Board (DSMB) recommended that clinical development of QPI-1002 in both indications continue to the next phase of development. Phase II clinical studies
have been initiated. In August 2010 Quark granted to Novartis
an option for a worldwide exclusive license to QPI-1002 for all indications.
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 delays the induction of cell death, allowing natural repair mechanisms to restore normal DNA and cellular integrity, thereby preserving organ and tissue function. In ischemia-reperfusion induced AKI, the epithelium of proximal tubules is the primary cell type that undergoes damage, leading to acute tubular necrosis. Following intravenous administration, QPI-1002 accumulates rapidly and predominantly in the kidney, specifically in proximal tubules, hence providing the necessary protection to 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 a favorable safety profile and a relatively short residence time and pharmacodynamic effect in the kidney. AKI
is a clinically devastating disease that complicates approximately 5% of hospital admissions and up to 30% of admissions to intensive care units. The incidence of AKI is rising. 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 the time the patient is on cardiopulmonary bypass. Reperfusion of the kidneys upon removal of the patient from bypass initiates a chain of events that can lead to renal damage. The rate of AKI development in most patients undergoing cardiovascular surgery is low, but rate can be as high as 22% in high-risk patients. The 30-day mortality rate following onset of AKI after surgery is greater than 50%. AKI is an unmet medical need. DGF
is one of the most common complications during the immediate postoperative period in renal transplantation and affects 25-40% of the deceased donor renal transplants. DGF results most often from ischemia-reperfusion injury that occurs when blood flow is re-established to the transplanted kidney, initiating a chain of events that can lead to severe renal damage. DGF is associated with longer hospital stays, higher rates of graft rejection, patient morbidity, and shortened survival time of the transplanted kidney. DGF is an unmet medical need, and the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) granted Orphan designation of QPI-1002 for prophylaxis of DGF in kidney transplantation. Orphan designation provides various regulatory and patent or market exclusivity incentives to the sponsor.
The method of temporary and reversible inhibition of p53 for therapeutic purposes is covered by several patent families, including early intellectual property generated in joint research performed by Professor Andrei Gudkov at the 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. Quark’s IP covers siRNA products inhibiting the p53 gene, pharmaceutical compositions, and use of the product for treatment of various diseases. For QPI-1002, the Company has RNAi structure-related technology licenses from Silence Therapeutics and from Alnylam Pharmaceuticals.