P1404A PHASE 2 OPEN-LABEL, SINGLE-ARM, FIRST JAPANESE STUDY OF TENAPANOR, A NOVEL PHOSPHATE ABSORPTION INHIBITOR, FOCUSING ON PILL BURDEN DECREASE IN PATIENTS WITH HYPERPHOSPHATEMIA UNDERGOING HEMODIALYSIS
Authors: Akizawa Tadao , Kanda Hironori , Takanuma Masayuki , Kinoshita Jun , Fukagawa Masafumi 
Published: June 2020

Abstract

Background and Aims
Phosphate binders (PB) are usually prescribed to dialysis patients with hyperphosphatemia. Several studies have reported that higher PB pill burden may reduce adherence and lead to insufficient phosphorus control. Tenapanor is an investigational, minimally absorbed, orally administered, non-binder, small-molecule that inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) in development for the control of serum phosphorus. A previous Ph3 study sponsored by Ardelyx, Inc. (NCT02675998) showed a significant phosphorus decrease compared to the placebo in patients with hyperphosphatemia undergoing hemodialysis (HD) in the US. Tenapanor was expected to reduce PB pill burden since it is administered as one small pill, taken twice a day. This was the first study in Japanese HD patients, which aimed to confirm whether tenapanor reduces the pill burden of PB.

Method
This was a multicenter, open-label, single-arm Ph2 study. The study consists of a screening period, a 3-week observation period, and a 26-week treatment period. Patients whose serum phosphorus level was ≥ 3.5 and ≤ 7.0 mg/dL, taking at least two PB pills three times a day were enrolled. The patients started to receive 30 mg of tenapanor twice daily. The tenapanor dose could be reduced in a step-wise manner (60, 40, 20 and 10 mg/day) at the investigator’s discretion, based on GI tolerability. PB treatment was continued according to individual regimens, however, the dose could be adjusted appropriately to maintain serum phosphorus level within ±0.5 mg/dL from the baseline. The primary endpoint was an achievement of at least a 30% decrease in the mean of the total number of PB and tenapanor pills compared to the number of PB pills at baseline. The proportion of patients who achieved at least a 30 % decrease were tested using binomial test with a threshold level of 20% and a one-sided significance level of 0.025. The analysis was conducted using the data as of Dec25, 2019.

Results
The primary endpoint was met. Of 67 enrolled patients at the timing of analysis, 48 patients (71.6%, [95% CI: 59.3% - 82.0%], p&lt;0.001) achieved a 30% decrease in the total number of PB and tenapanor pills, and of those, 35 patients (52.2%, [95% CI: 39.7% - 64.6%]) achieved a 50% decrease and 18 patients (26.9%) no longer required the use of any PB at week 26. Mean phosphorus levels were maintained during the study from 5.2 mg/dL at the baseline to 4.7 mg/dL at week 26. The most frequent adverse event was diarrhea (76.1%), which was mostly mild to moderate. Only four patients discontinued the study due to diarrhea. Serious adverse events were reported in five patients, only two of which were related to tenapanor (diarrhea and acute myocardial infarction).

Conclusion
Tenapanor was able to provide phosphorus control with significantly fewer pills compared to PB. AE profile was similar to previous US studies. This result suggests that tenapanor, a non-binder, phosphate absorption inhibitor that provides a novel approach to the management of hyperphosphatemia, could potentially improve drug adherence by reducing PB pill burden while maintaining effective phosphorus control.