Although doing so isn’t necessary for the a 505(b)(2) regulatory pathway, Ardelyx Inc. is conducting phase II and phase III trials with its potassium binder to win a package insert that competes well, President and CEO Mike Raab told BioWorld Today.
He acknowledged that the Fremont, Calif.-based company has been “somewhat quiet about this” until lately. “Given the backgrounds of all the people in the company, we wanted to make a better binder [using] our collective experiences, and we think what we’re embarking on is exactly that,” he said.
Ardelyx is starting a phase III trial with RDX7675 against hyperkalemia (HK, high potassium) in patients with cardiorenal disease, along with a phase II onset-of-action study with oral, non-absorbed potassium-binding polymer. The drug will be tested in a randomized, single-blind, three-part experiment to test the efficacy and safety in about 300 adult patients with hyperkalemia and includes a long-term, open-label safety extension. A separate, single-blind, placebo-controlled study will research the safety and efficacy as well as how fast RDX7675 starts working in 60 patients with the condition.
RDX7675 was developed to improve on sodium polystyrene sulfonate, or SPS, which as Kayexalate has been the standard of care for the treatment of HK for more than 50 years. Ardelyx eliminated sodium and sorbitol, optimized binding capacity and improved palatability over Kayexalate, distributed in the U.S. by Covis Pharmaceuticals Inc., of Cary, N.C., and elsewhere by Paris-based Sanofi SA.
Kayexalate “tastes terrible,” Raab said, and “uses sodium as a counter-ion, which is a really bad idea if you’re going to be treating chronic kidney disease [CKD] patients or heart failure patients. That’s not what you’d want to do as a clinician.” Ardelyx “took advantage of the fact that the backbone we used, polystyrene sulfonate, is an extraordinary well-characterized, well-known polymer,” made by the metric ton, which will reduce the cost of goods, he said. Because of “the unique chemistry Ardelyx was able to bring to bear,” the company won a patent last year that provides protection “well out to 2034 without any kind of extension,” he added.
“It’s really kind of sad,” Raab said, characterizing the situation for patients. “When patients present with elevated potassium – and this is by protocol – the first thing the physician says is, ‘OK, stop eating kale,’ and other things that are actually good for you. And if your potassium levels are still too high, they cut your antihypertensives, the renin-angiotensin system inhibitors, in half. And if your potassium is still too high, they stop [them].”
Hope for HK patients came in the form of 2015’s approval of potassium binder Veltassa (patiromer) from Redwood City, Calif.-based Relypsa Inc., followed by bad news in the space in May 2016 by way of a complete response letter (CRL) for Astrazeneca plc, of London. The CRL related to the NDA for sodium zirconium cyclosilicate, an oral suspension for hyperkalemia. The candidate, better known as ZS-9, was Astrazeneca’s prize in the acquisition of San Mateo, Calif.-based ZS Pharma Inc. for $2.7 billion. “Astrazeneca knows how to build markets,” Raab said, pointing to the pharma giant’s work with proton pump inhibitors. “Arguably, they did that better than anybody else,” and Ardelyx may eventually benefit from the path to be made in HK, though the CRL for ZS-9 is a challenge for Astrazeneca. “There is already an adequate market,” he said. (See BioWorld Today, Oct. 23, 2015, Nov. 15, 2015, and May 31, 2016.)
TRIPLE FILINGS POSSIBLE NEAR TERM
RDX7675 bears a “very small particle size, 35 microns,” compared to Veltassa’s 120, Raab said. “Your teeth are exquisitely sensitive to particles – these are tiny and soft, kind of like tapioca.”
Ardelyx conducted trials with professional taste testers who evaluated flavor and mouthfeel, he said. “This goes back to experiences with Renagel (sevelamer)” the non-absorbed phosphate binder that Cambridge, Mass.-based Genzyme Corp. acquired from Geltex Pharmaceuticals Inc., of Waltham, Mass., in 1997. Sanofi bought Genzyme – where Raab built the Renagel sales force – in 2011.
”It’s really hard to get people to take as much polymer as they’re supposed to take, when they’re supposed to take it,” he said. Ardelyx compared RDX7675 to Kayexalate. Taking the latter is “literally like putting a couple of tablespoons of sand in your mouth.” (See BioWorld Today, June 19, 1997, and Feb. 17, 2011.)
In August 2015, Relypsa entered a two-year co-promotion agreement with Paris-based Sanofi for Veltassa, which comes in powder form and is mixed with water. Under the terms, Sanofi’s nephrology sales force is complementing the 120-member sales team of Relypsa and will be paid a service fee plus potential incentive payments. There’s also an ex-U.S. (and outside-of-Japan) marketing deal with Vifor Fresenius Medical Care Renal Pharma Ltd., of St. Gallen, Switzerland, for which Vifor paid $40 million up front and agreed to $125 million in regulatory and sales-based milestones, plus tiered double-digit royalties. “We’re the last man standing on our own,” Raab noted.
Also at the phase III stage, Ardelyx has tenapanor, a minimally systemic small-molecule inhibitor of NHE3, a sodium transporter present on the epithelial surface of the gastrointestinal (GI) tract, for irritable bowel syndrome with constipation and for hyperphosphatemia in end-stage renal disease. Ardelyx expects to file for approval of all three candidates in the 2019-2020 time frame.
Still preclinical is the RDX013 program, aimed at discovering and evaluating small-molecule, oral drug candidates that modulate the transport of potassium in the GI tract. Specifically, agents are designed to enhance potassium secretion in the colon and correct HK in CKD patients, which would eliminate the need for binders altogether, Raab said.