Jim Kling

June 04, 2013

ISTANBUL, Turkey — The investigational drug PA21 controls hyperphosphatemia over the long term and has a lower pill burden than sevelamer carbonate, according to a phase 3 study.

The cardiovascular complication, which can result from renal failure, is often treated with phosphate binders, but they typically require a large number of pills each day to control potassium levels.

"Dialysis patients often have a dry mouth, and they tend to have problems swallowing big pills. This is why the number 1 problem we have is pill compliance," said Jürgen Floege, MD, professor of nephrology at the University of Aachen in Germany. "All the rest is more or less an academic discussion. We can talk about a binder's effect on vascular calcification, but if my patient doesn't take anything, it doesn't help him."

Dr. Floege presented the study results here at the European Renal Association-European Dialysis and Transplant Association 50th Congress.

In this long-term open-label study, Dr. Floege and his team compared PA21, which is a novel polynuclear iron(III)-oxyhydroxide phosphate binder, with sevelamer in patients undergoing hemo- or peritoneal dialysis who had hyperphosphatemia.

The researchers randomized 710 of the 1059 study participants to receive PA21 1.0 to 3.0 g/day and 349 to receive sevelamer 2.4 to 14.4 g/day. A 12-week period for dose titration was followed by 12 weeks of maintenance.

At 24 weeks, the effectiveness of PA21 and sevelamer was similar in hemodialysis and peritoneal dialysis patients.

The researchers then enrolled 658 patients in a 28-week safety extension study.

For the extension study, the baseline serum phosphate level was 1.7 mmol/L in both groups. This was maintained throughout; after 28 weeks, the serum phosphate level was 1.8 mmol/L in both groups.

For the number of pills required to maintain the serum phosphate-lowering effect, there was a significant difference between the PA21 and sevelamer groups (3.3 vs 8.7).

From the original to the extension study, treatment-emergent adverse events decreased in the PA21 group (83.2% vs 74.4%), but stayed the same in the sevelamer group (76.1% vs 76.8%).

Many of the treatment-emergent adverse events were gastrointestinal, but their incidence decreased with time in both groups.

Table. Treatment-Emergent Adverse Events in the Original and Extension Studies

Adverse Event PA21 Original (n = 707) Sevelamer Original (n = 348) PA21 Extension (n = 391) Sevelamer Extension (n = 267)
Any gastrointestinal disorder, % 45.1 33.6 25.6 19.1
Diarrhea, % 20.1 7.5 8.2 5.6
Discolored feces, % 15.4 0.3 0.8 0.4
Nausea, % 7.2 11.2 5.9 4.1
Constipation, % 3.8 7.2 2.8 1.9

 

PA21 does not cause a significant amount of iron absorption, which can occur with some other drugs, according to Dr. Floege. PA21 had a higher prevalence of gastrointestinal adverse effects than sevelamer, but Dr. Floege pointed out that diarrhea, in particular, could actually be a benefit. Most patients reported softened stools. "If anything, a dialysis patient has constipation," he explained. "I view this as a very interesting new phosphate binder."

The gastrointestinal effects are a concern, according to Christoph Wanner, MD, from the University Clinic Würzburg in Germany. He pointed out that the PA21 group had a higher dropout rate, despite the lower burden of pills.

The gastrointestinal adverse effects could be a problem, but physicians might be able to counter them by starting at a lower dose to allow the patient's intestine to adapt. "There are some benefits to PA21; we will see in the future whether this holds true over time. Nephrologists are very skeptical when new drugs enter the market," he told Medscape Medical News, "but these data look good."

This study was funded by Vifor Fresenius, which is developing PA21. Dr. Floege is an executive advisor to Vifor Fresenius. Dr. Wanner has disclosed no relevant financial relationships.

European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 50th Congress. Presented May 20, 2013.

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