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Quark Kidney Drug Misses Phase II Endpoint, but Phase III Still On Track

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NEW YORK (GenomeWeb) – Quark Pharmaceuticals this week presented data from a Phase II trial of QPI-1002, an siRNA-based drug for the prevention of delayed graft function (DGF) in kidney transplant patients. While the study's primary endpoint was not reached, patient outcomes were favorable enough that the company is now planning a Phase III trial that could begin as soon as early next year.

Meanwhile, Quark is planning a full-fledged Phase II trial of QPI-1002 as a preventative of acute kidney injury in patients undergoing cardiovascular surgery, following positive Phase I/IIa data.

QPI-1002 comprises siRNAs designed to silence p53, and its development stems from preclinical data showing that temporary inhibition of this stress-response gene can prevent cellular injury stemming from ischemia/reperfusion. Novartis currently holds an option to license the drug.

In the newly completed Phase II trial, 331 end-stage kidney disease dialysis-dependent patients received kidneys from deceased donors. They were then treated with either a single 10 mg/kg bolus intravenous dose of the drug or placebo 30 minutes after circulatory reperfusion was achieved in the transplanted organ.

The study's primary endpoint was a 30 percent reduction in the risk of DGF, as defined by the need for dialysis within the first seven days following transplant excluding dialysis in the first 24 hours due to hyperkalemia/hypervolemia.

Although the safety profile of QPI-1002 in the trial was similar in both treated and placebo groups, the drug failed to achieve its main objective, and treatment was associated with only a 15.1 percent reduction in the relative risk of DGF.

To Quark President and CEO Daniel Zurr, however, the 30 percent reduction threshold was an "artificial" goal set by the company, and "not necessarily the best endpoint." Notably, the study's data show that QPI-1002 achieved the 30 percent DGF risk reduction in all patients who received transplants from individuals 35 years and older — a group that represented 86 percent of the total study population.

According to Quark, this finding is consistent with animal studies from other groups showing stronger p53 activation following reperfusion of older kidneys.

Further, after six months, all patients in the study experienced a 1.5-fold reduction in the number of dialysis sessions needed compared with those receiving placebo.

Zurr said that the study results, which were presented at the 2014 World Transplant Conference in San Francisco, justify the continued development of QPI-1002. He added that Quark is moving quickly to meet with the US Food and Drug Administration to identify the protocols for Phase III development. He stressed that while the exact endpoints of the upcoming trial have yet to be determined, the company does not intend to limit patients to those receiving transplants from older donors.

"We have [met] enough of our [Phase II] secondary endpoints that we are justified to go for the total population," he said. "We are not going to segregate; we will go for all pieces of the kidney transplantation" market.

The data on the impact of kidney age on treatment outcomes, he added, has also provided further validation of Quark's strategy to develop QPI-1002 for acute kidney injury. Similar to kidney transplantation, a patient's kidneys are often injured during cardiovascular surgery as a result of the ischemia and reperfusion associated with cardiopulmonary bypass. Given that such surgeries are rarely performed in young individuals, QPI-1002 may prove particularly effective for this indication.

Given the positive results of a Phase I/IIa trial, Quark is also gearing up to begin a Phase II study of the drug in acute kidney injury. Assuming a positive outcome of discussion with regulators, the company expects this study will run in parallel with the Phase III trial in DGF, likely in the first quarter of 2015, Zurr said.

Meanwhile, Quark continues to explore additional cases where transient p53 inhibition might offer a therapeutic benefit. Among these, Zurr said, is the damage to the heart caused by the ischemia/reperfusion that accompanies myocardial infarction. He said that animal testing in this indication is underway.

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