Discussion
hyperphosphatemia, diarrhea
SECONDARY, HYPERPHOSPHATEMIA
After 52 weeks of tenapanor administration, the most common drug-related AE was diarrhea, occurring in approximately 55% of patients. The severity of diarrhea was classified as mild in 74.8%. The increase in Bristol Stool Form Scale score and stool frequency was similar to that reported in another Japanese phase 3 studyBicarbonate levels decreased during 52-week administration in this study. Although there is a possible mechanism by which tenapanor might enhance chloride excretion by inhibiting NHE3 because sodium and hydrogen exchange is closely conjugated with chloride and bicarbonate exchange in the intestinal tractPhosphate binders may be used while expecting secondary effects characteristic of each type, such as a decrease in total cholesterol and low-density lipoprotein cholesterol, replenishment of calcium, or iron supplementation. In this study, AEs associated with a decrease in phosphate binders were not observed. Similar to the findings reported in a 26-week phase 2 studyOver 75% of patients achieved a ≥ 30% reduction in the total daily pill number of phosphate binders and tenapanor from baseline, which was the key secondary endpoint. Furthermore, the mean daily pill number of phosphate binders decreased from 11.4 to 3.1; thus, adding tenapanor reduced the mean number of pills taken by eight or more. Even when accounting for the addition of tenapanor (a daily dose of two tablets), the total number of pills per day was 5.1 at Week 52. Consequently, administration of tenapanor resulted in a ≥ 50% decrease in the mean daily pill burden of hyperphosphatemia treatment at Week 52 compared with baseline. Moreover, the mean daily volume of phosphate binders and tenapanor at Week 52 decreased by approximately 70% from baseline; significant reductions in both the volume and number of pills were noted. It is conceivable that the high serum phosphorus-lowering effect was a result of the additive effect associated with the difference between the mechanism of action of tenapanorEven though the pill burden was reduced, mean serum phosphorus levels were well controlled within the target range (3.5–6.0 mg/dl) proposed by the Japanese Society for Dialysis TherapyThis study indicated a favorable effect on reducing phosphate binders regardless of the number of phosphate binder types taken at baseline. More than 70% of patients in this study received multiple types of phosphate binders at baseline. It is plausible that a similar effect on pill burden decrease could be shown in clinical practice, where many patients take multiple phosphate bindersSome limitations of this study were, first, the single-arm, open-label design, meaning the findings were not validated against a placebo comparator. Second, only Japanese patients were included, precluding generalizability to other settings. Third, approximately 75% of patients took a combination of multiple phosphate binders at baseline. Phosphate binder dosing was adjusted according to the investigator’s judgment, which may have introduced bias regarding the types of phosphate binders to be reduced and by how many pills.In conclusion, diarrhea was commonly reported, albeit cases tended to be mild in severity. No other safety issues were observed at a high incidence, suggesting long-term treatment safety and tolerability of tenapanor. In this population of patients whose serum phosphorus levels were controlled, many patients successfully reduced the use of phosphate binders by adding tenapanor. These findings suggest that, even in patients with refractory hyperphosphatemia and a high pill burden, tenapanor could potentially achieve the dual goals of reducing the pill number of phosphate binders and controlling serum phosphorus levels while contributing to ameliorating polypharmacy and medication adherence.