Patiromer Study Published: Approval for Hyperkalemia Soon?

Marcia Frellick

July 17, 2015

Results of a phase 2 study testing a new oral potassium-binding agent patiromer have been published. The findings of the AMETHYST-DN trial, first reported at the American College of Cardiology meeting in San Diego earlier this year, show that treating patients with hyperkalemia and diabetic kidney disease with twice-daily doses of the agent significantly decreased blood potassium levels after 4 weeks, and the effects were sustained for a year.

The study, designed to determine the most effective starting-dose level of the drug, is published in the July 14 issue of the Journal of the American Medical Association.

"This is the first predictable, well-tolerated potassium binder that has come along…ever," lead author George L Bakris, MD, from the University of Chicago Medicine, Illinois, told Medscape Medical News. "What is available, Kayexalate, or sodium polystyrene, is not predictable, has varying effects on potassium, and is generally not well tolerated." Side effects of that drug include nausea, vomiting, and constipation, he said.

Patients were able to take patiromer for 1 year with minimal dropouts and side effects, his team found.

Based on these findings, the authors note a phase 3 study has been conducted in which patiromer demonstrated consistent efficacy ( N Engl J Med. 2015;372:211-221).

Relypsa, which is developing the agent, has now filed a new drug application with the US Food and Drug Administration (FDA), with a decision on approval expected by October 21 this year, according to Wolfgang Winkelmayer, MD, ScD, a nephrologist with Baylor College of Medicine in Houston, Texas, who has written an editorial accompanying the AMETHYST-DN publication.

FDA Approval Could Come This Year, but Concerns Remain…

Dr Winkelmayer writes that he expects the FDA to approve the drug, but he would like to see approval tied to a mandate to continue long-term examination of whether there is reduced progression of chronic kidney disease (CKD), deferral of dialysis, and better heart-failure outcomes.

"Once hyperkalemia drugs are approved based on trials of the surrogate marker of potassium concentration, it is uncertain if manufacturers will be motivated to conduct such crucial trials of the hard end points that patients care about," he observes.

"[A]s part of the approval process, the FDA and other agencies should consider mandating a sizable postmarketing trial and safety surveillance program to clearly establish whether the assumptions underlying the value proposition of chronic hyperkalemia treatments actually hold," he asserts.

Dr Bakris says, "The FDA, I'm sure, will have requested that, but they can't mandate it….I will tell you, to the company's credit, they have set up a global advisory board that is generating these types of studies."

Potential to Change Current Treatment Approach to Hyperkalemia

Hyperkalemia can be life-threatening, and those at highest risk are patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors with stage 3 or greater CKD, many of whom also have diabetes, heart failure, or both.

As previously reported, the AMETHYST-DN study divided just over 300 patients with CKD, type 2 diabetes, and hypertension who were taking RAAS inhibitors into groups according to their baseline potassium levels. About a third of the patients also had heart failure.

There were 222 patients classified as having mild hyperkalemia, and they were randomized to one of three starting doses of patiromer — 4.2 g, 8.4 g, or 12.6 g twice daily. Those with moderate hyperkalemia (84 patients) received 8.4 g, 12.6 g, or 16.8 g twice daily.

Patiromer was titrated to maintain a serum potassium level 5.0 mEq/L or lower.

After the baseline visit (day 1), patients returned for assessment at day 3 (48 hours after the first patiromer dose), then after 1 week and then each week during the 8-week treatment. During the 44-week maintenance phase, patients were seen once a month unless more visits were necessary.

The primary efficacy end point was mean change in serum potassium level from baseline to week 4 or prior to initiation of dose titration. Mean change in serum potassium level through 52 weeks was a secondary end point.

The mean reduction in serum potassium level at week 4 in patients with mild hyperkalemia was 0.35 mEq/L for the 4.2-g twice-daily starting dose group, 0.51 mEq/L for the 8.4-g group, and 0.55 mEq/L for the 12.6-g group.

In those with moderate hyperkalemia, reductions were greater — 0.87 mEq/L for the 8.4-g twice-daily starting group, 0.97 mEq/L for the 12.6-g group, and 0.92 mEq/L for the 16.8-g group.

In his editorial, Dr Winkelmayer says these findings "confirm previously published findings from a smaller and shorter trial of patiromer" and "have the potential to fundamentally change the current treatment approach for hyperkalemia."

But the "novelty of the present study lies in the secondary results: after the 8-week treatment phase, patients entered a 44-week maintenance phase and therefore were assessed while receiving patiromer treatment for a total of 52 weeks."

Mean potassium concentrations "remained essentially stable throughout the maintenance phase and were within the normokalemic range for the vast majority of patients," he adds.

And of note, after the end of the study (or after study withdrawal) patients' potassium concentrations increased quickly and significantly once again, confirming that control of potassium levels was not attributable to regression to the mean but rather was related to patiromer treatment.

Longer Observations Needed With Regard to Safety

With regard to safety, there were relatively high rates of hypomagnesemia (8.6%) and mild to moderate rates of hypokalemia (5.6%) as well as a variety of less serious gastrointestinal symptoms.

"Clearly, considerably longer person-time receiving the drug will be required to more adequately analyze and describe the safety of patiromer with regard to potentially severe but rare adverse events," Dr Winkelmayer observes.

Nevertheless, "these initial findings are encouraging and suggest that this agent may represent a viable new and effective approach to the management of hyperkalemia," he concludes.

He notes also that a second compound, sodium zirconium cyclosilicate (ZS Pharma), is close behind patiromer in the approval pathway.

The study was sponsored and funded by Relypsa. Dr Bakris reports receiving personal fees from AbbVie, Takeda, Medtronic, Relypsa, Daiichi-Sankyo, Janssen, Novartis, and Bayer and receiving grants from Takeda. Disclosures for the coauthors are listed in the article. Dr Winkelmayer reports serving as an adviser or consultant to Amgen, AstraZeneca, Bayer, Keryx, Medgenics, Medtronic, Mitsubishi-Tanabe, and Rockwell Pharma.

JAMA. 2015;314:151-161, 129-130. Article, Editorial


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