Relypsa Inc. CEO John Orwin told BioWorld Today it’s “probably not appropriate” to make comparisons between his firm’s just-approved Veltassa (patiromer) for high blood potassium and the FDA-pending compound from ZS Pharma Inc., since no head-to-head trials have been done. “Ultimately, it’s going to depend on what their package insert looks like.”

Speculation went ahead anyway, as analysts scrutinized the label for Redwood City, Calif.-based Relypsa’s hyperkalemia therapy, which includes a warning about drug-drug interactions (DDIs) that Orwin called “unexpected.” The compound is not to be used within six hours of any other oral drug. “We specifically looked for evidence of any clinical DDIs,” he said, and experimented with meds such as those for diabetes and hypertension. “We saw no suggestion of that.”

With the warning, the FDA is “relying exclusively on in vitro studies that we did,” which showed that Veltassa binds not only to potassium but to “about half the drugs that we studied,” Orwin said. “What we don’t know is whether that in vitro binding will translate into any human DDI effect.” Research designed to find out will report data “early in the coming year,” which is also when Veltassa becomes available, he said.

Shares of Relypsa (NASDAQ:RLYP) closed Thursday at $11.76, down $4.39, or 27.2 percent, probably due to the label warning and possibly due to confusion caused by a botched press release from the FDA about the approval. The misleading phraseology was passed along in an email alert to investors Wednesday night from J.P. Morgan analyst Cory Kasimov, who quoted the agency’s release. “While the approval is not unexpected, there are a couple interesting points in the label (as highlighted in the FDA’s press release),” he wrote, “including the recommendation that Veltassa use ‘is not appropriate for rapid correction of severe hyperkalemia because lowering of serum potassium may take hours to days,’ and the boxed warning that recommends ‘taking it and any other orally administered medication at least six hours apart,’ because Veltassa binds many other orally administered drugs.”

Asserting that Veltassa should not be used in severe cases is “not what [the FDA] intended,” Orwin said, “because those are the patients we studied. The actual limitation of use is that the drug should not be used as an emergency treatment for life-threatening hyperkalemia, because of its delayed onset of action, and that’s consistent with what we’ve always said.” The screw-up “certainly has made a difficult time” for Relypsa, he added. “It’s a really important distinction, and it’s one that was discussed extensively with the FDA. As you could imagine, word choice was very specific and deliberate and theirs was not intended to exclude the use in the hospital setting or in patients who are severely hyperkalemic. The concern they’re trying to solve for is that these medications are not to be used in place of infusional therapies, which can correct potassium within a matter of minutes, albeit transiently.” Anyway, he said, Relypsa does “see the bigger opportunity in the chronic outpatient setting. That’s really where the major unmet need is. The existing products can be used intermittently but they’re not tolerated well enough to be used on a chronic basis.”

The FDA corrected its press release later.

In August, Relypsa entered a two-year co-promotion agreement with Paris-based Sanofi SA 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.

Relypsa said the treatment will be available to patients in the first week of January 2016 by way of Veltassa Konnect, a centralized patient support center. Morgan’s Kasimov said the implications of Veltassa’s approval for San Mateo, Calif.-based ZS Pharma, also of Redwood City – which has submitted its new drug application for ZS-9, an insoluble, non-absorbed zirconium silicate, to the FDA with an action date of May 26, 2016 – are “positive overall . . . perhaps even best case. Our current thinking is that it’s good that Veltassa was approved, but even better for ZS-9 that the door could be open to have a superior label.” He cited ZS-9’s “faster onset of action and greater magnitude of reduction in serum potassium (ZS-9 had a reduction in serum potassium of 0.4 mmol per liter, 0.6, 0.7, 1.5 at one, two, four, 48 hours [respectively] vs. Veltassa’s reduction of 0.2 at seven hours, 0.3 at 12 hours, 0.4 at 20 hours, 0.6 at 34 hours, 0.8 at 48 hours. This is from a similar baseline of 5.93 but still obviously not a head-to-head comparison,” he conceded.

Shares of ZS (NASDAQ:ZSPH) ended the day at $63.92, up $10.52, or 19.7 percent.

‘Wrinkle’ to come out in the wash

Cowen and Co. analyst Eric Schmidt took Veltassa’s measure against ZS-9 and found “nearly all the competitive arguments discredited,” leaving only the DDI issues for the Relypsa product to contend with. “We note that this is a very unusual boxed warning, as it represents only a theoretical risk,” he wrote in a research report. “The vast majority of boxed warnings refer to known severe adverse events,” and in this case U.S. regulators “erred on the side of caution and simplicity,” in his opinion. “Interestingly, the labels of most other binders such as Renvela [sevelamer carbonate, Sanofi SA unit Genzyme], Welchol [colesevelam hydrochloride, Daiichi Sankyo Co. Ltd.] and Fosrenol [lanthanum carbonate, Shire plc] include references (but not boxed warnings) against numerous DDIs, yet this has not substantially limited their adoption.”

CEO Orwin predicted the same for Veltassa, the first new hyperkalemia therapy to reach the market in more than 50 years. Relypsa tried out the language of the label warning on 20 physicians and the “vast majority of the folks we talked to” said they would find a way to use the drug. “While they didn’t really understand why six-hour separation should be necessary, they would simply give the drug at lunchtime and give the other medication either morning or morning and night,” he said. People on three to four medications per day might find Veltassa tricky, but the company examined 1,000 patient records from a syndicated report and found that about 97 percent were taking meds once or twice per day, with the tiny percentage taking theirs more often. “Even in those cases, other once or twice-a-day medicines are available” for their conditions, he said.

“The FDA was very clear with us that they did not want the use of the product precluded from patients in the hospital,” Orwin said. “We expect that pretty much wherever Kayexalate [sodium polystyrene sulfate, Covis Pharma Sarl/Sanofi SA] is being used today, Veltassa will be used and will be preferred.” Standard-of-care Kayexalate, an old drug prescribed about half-and-half in-hospital and outpatient, brings gastrointestinal [GI] side effects that can be as serious as bowel perforation and colonic necrosis.

Veltassa was approved by the FDA based on a phase III program that included the Opal-HK study, showing the potassium binder knocked down levels in hyperkalemic chronic kidney disease patients taking renin-angiotensin-aldosterone system , or RAAS, inhibitors (mean decrease of -1.01 ± 0.03 mEq/L from baseline; p<0.001). At four weeks, 76 percent of patients had potassium levels in the target range (3.8 to <5.1 mEq/L). During the second part of the trial, patients taking Veltassa had no change in median potassium from baseline (0.00 mEq/L), but in the placebo group potassium levels rose (0.72 mEq/L; p<0.001).

Regarding ZS-9, Lifesci Capital analyst Jerry Isaacson noted that it’s “an inorganic compound that is selective for potassium and is formulated without excipients. Thus, the potential for direct interactions is low. No interactions have been observed in clinical studies to date. This is consistent with ZS-9 being restricted to the GI tract, which is unlikely to interfere with absorption of other drugs. Excipients such as sorbitol have been shown to interfere with absorption and polymers can interact with drugs due to organic-organic binding or non-specific ion binding,” he wrote in a research report.

Relypsa said as many as several million patients with stage 3 or 4 chronic kidney disease and/or heart failure may benefit from the likes of Veltassa and ZS-9. Such a patient population and unmet need “will support multiple products in the marketplace,” Orwin said, and companies need to increase awareness and educate doctors about the need to treat hyperkalemia. “We view [options] as good for patients,” he said, although “I do think the products are clearly differentiated both in terms of what they are and how they work.”

Cowen’s Schmidt “identified four key specifications that we believe carry commercial advantage for Veltassa: (1) a broad label indicating use in hyperkalemia (2) no restrictions based on the severity of the disease (3) no limitations on the duration of dosing and (4) once daily dosing.”

Orwin, of Relypsa, said “once it all settles down and people realize what the label says and what the implications of the label are,” the outlook for Veltassa likely will brighten. Schmidt seemed to agree. “Despite this added wrinkle [of the boxed label warning], we continue to view Veltassa as an excellent therapeutic option for a large unmet need and model peak sales in excess of $500 million.”