Tiny Kitov Pharmaceuticals Holdings Ltd. made a big splash in the drug development world with news that its lead candidate, KIT-302, met the primary efficacy endpoint of reducing blood pressure as a combo drug that also treats osteoarthritic (OA) pain during a double-blind, placebo-controlled phase III trial that received a special protocol assessment from the FDA.

KIT-302 combines the FDA-approved drugs celecoxib (Celebrex), the COX-2 inhibitor that targets OA pain, and amlodipine besylate, a calcium channel blocker that targets hypertension. The drug would command a unique niche as the first to treat both indications at once.

KIT-302 could even change a major treatment paradigm by overcoming a problem that dogged COX-2 inhibitors – the selective nonsteroidal anti-inflammatory drugs (NSAIDs) that target cyclooxygenase-2 – and led to the voluntary market withdrawal of Merck & Co. Inc.'s approved drug, Vioxx (rofecoxib), after studies revealed that COX-2 inhibitors could raise blood pressure and increase the risk of cardiovascular events. (See BioWorld Today, Oct. 28, 2004.)

"We will get at the very top of our labeling that our drug will be indicated not only to treat pain and blood pressure but to prevent heart attack, stroke and death," J. Paul Waymack, Kitov's co-founder, chairman and chief medical officer, told BioWorld Today.

The commercial potential wasn't lost on investors, who jumped on the company's shares (NASDAQ:KTOV), listed in the U.S. just last month. The stock closed Tuesday at $4.47 for a gain of 90 cents, or 25.2 percent, on volume of 10.4 million shares.

Kitov also is traded on the Tel Aviv Stock Exchange, where shares (KTOV) were listed in 2013.

Waymack and two other former FDA officials founded Tel Aviv-based Kitov in 2010 to leverage their regulatory and clinical trial expertise by targeting late-stage drug development using combinations of approved compounds to lower scientific and regulatory risks. Given the enormity of the OA market, they started with that indication, reasoning that the addition of a calcium channel blocker to a COX-2 inhibitor could mitigate potential cardiovascular problems without affecting pain control.

The trial protocol, in fact, was designed solely to quantify the decrease in hypertension among patients who received KIT-302. The U.K.-based trial enrolled 152 patients – the FDA required only 120 to meet statistical significance but the company took a conservative approach to enhance the statistical power – in four groups of 26 to 49 patients, each treated over a two-week period. One group was treated with the combo KIT-302, a second only with the anti-hypertensive amlodipine besylate, a third only with celecoxib and the fourth with a double placebo.

The primary efficacy endpoint was designed to show that the combination of drugs in KIT-302 lowered daytime systolic blood pressure by at least 50 percent of the reduction in blood pressure achieved in patients treated with amlodipine besylate alone. Results showed a mean reduction of 8.8 mm Hg in daytime systolic blood pressure in patients treated with amlodipine besylate alone compared to a mean reduction of 10.6 mm Hg in daytime systolic blood pressure in patients treated with KIT-302, meeting the study goal (p = 0.001).

The trial began in June 2014 and was completed last month. Waymack said company officials are still sifting through additional findings on secondary endpoints such as changes in nighttime and 24-hour systolic blood pressure as well as changes in daytime and nighttime ambulatory diastolic blood pressure, plasma concentrations of amlodipine and celecoxib and other measures.

Adverse events, which were studied but not disclosed, will be graded according to World Health Organization Toxicity Criteria, according to Cortellis Clinical Trials Intelligence.

"The big finding here is that we met the FDA's criteria," Waymack said. "Everyone was thinking that Celebrex would somewhat decrease the amlodipine effect. To our great pleasure, it actually increased it."

'WE THINK THIS IS A MAJOR SCIENTIFIC ADVANCE'

NSAIDs are "the most widely consumed class of medications on the planet" and "the treatment of choice in osteoarthritis," Waymack pointed out, despite the cardiovascular risks associated with COX-2 inhibitors and the gastrointestinal bleeds that can result from aspirin and related COX-1 inhibitors. With OA affecting 27 million individuals in the U.S. alone – including half of those over age 50 – and at least half of the U.S. population over age 50 diagnosed with hypertension, KIT-302 addresses "a major medical need," he said.

"We think this is a major scientific advance as well as an advance for Kitov, in that we now know if you're on a nonsteroidal and you have high blood pressure, you also need to be on a calcium channel blocker," Waymack added.

Because KIT-302 was advanced through the 505(b)(2) pathway, the drug would have a minimum of three years of exclusivity in the U.S. and seven to 10 years in Europe. Kitov has filed basic patents on the drug combination and an additional patent on the drug's formulation, which required some "creative workarounds" to manufacture the celecoxib component of the drug, according to CEO Isaac Israel. Patent approval could extend the drug's marketing exclusivity.

Also thanks to the 505(b)(2) pathway, the only additional data the FDA requires from Kitov prior to a new drug application (NDA) filing is a pharmacokinetic bioequivalence study in healthy volunteers. The company plans to request a pre-NDA type B meeting in January, which Waymack expects to occur in March, before finalizing details of the NDA, which he expects the company to file in the second half of 2016.

That chain of events would set up potential approval in 2017. With that goal in mind, the company will begin partnering talks next month at the J.P. Morgan Healthcare Conference in San Francisco, according to Israel. The company's strategy "from the beginning" was to reach out to major players – big pharma and specialty pharma – only after data were in hand.

Kitov expects to sign a licensing deal in 2016, but the company is in no hurry to accept the first proposal that comes down the pike. The company has only seven full-time employees and sufficient cash to take KIT-302 to approval, Israel said.

Kitov raised approximately $9.3 million through a series of public offerings prior to last month's listing on Nasdaq, when the company landed another $13 million.

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