Discussion
nausea, diarrhea, HD, constipation, PD, hyperphosphatemia
EVENTS, SECONDARY, HYPERPHOSPHATEMIA
Although several clinical studies of tenapanor have been conducted for dialysis patients with hyperphosphatemia, studies in PD patients have been limited to date. In this phase 3, open-label, multicenter, single-arm clinical trial, the efficacy and safety of tenapanor for PD patients with hyperphosphatemia were assessed.The main findings of the study were as follows: treatment with tenapanor for 8 weeks (the primary endpoint) and 16 weeks (the secondary endpoint) resulted in a mean change in serum phosphorus level (LOCF) of − 1.18 mg/dL (95% CI: − 1.54, − 0.81 mg/dL) and − 1.65 mg/dL (95% CI: − 2.08, − 1.22 mg/dL), respectively. Serum phosphorus significantly decreased from the baseline value of 7.65–6.14 mg/dL at week 8, and to 5.44 mg/dL at week 16, respectively. Furthermore, a total of 46.3% (19 cases/41) at week 8, and 76.5% (26 cases/34) at week 16, achieved the guideline range of serum phosphorus level (3.5–6.0 mg/dL).The most common AE was diarrhea, occurring in 74.1% of patients. All events of diarrhea were considered either mild or moderate in severity. Expected increases were noted in the BSFS score (softening of stools) and stool frequency per week by week 2 of tenapanor treatment, after which there were no remarkable changes.Previous studies of tenapanor in dialysis patients mainly focused on HD patients. In the phase 3 study in HD patients conducted in Japan [After completing the week 8 evaluation, phosphate binder use was allowed only if the dose of tenapanor could not be increased any further and the serum phosphorus level was 6.1 mg/dL or higher. Thirteen of 41 patients (25.0%) who completed the week 8 evaluation received rescue treatment after week 8. In addition to increasing the dose of tenapanor, the concomitant use of only one type of phosphate binder could achieve phosphorus target levels in nearly 80% of cases and equivalent serum phosphorus levels before the washout period. Since tenapanor has a different mechanism of action from phosphate binders, combining tenapanor and other phosphate binders suggests that tenapanor may have an additive effect with a phosphate binder and decreases serum phosphorus.The characteristics of the non-calcium agent tenapanor are clinically important. It is well known that increased serum phosphorus levels result in increased levels of Ca × P product [In addition to the pill burden associated with phosphate binder therapy, the occurrence of abdominal symptoms (e.g., reportedly diarrhea, constipation, and nausea) associated with phosphate binder therapy is a serious issue for patients [This study had some limitations. First, it was a single-arm study with a small sample size, a short study period, and no randomization. Thus, the results could not be compared with findings with a placebo or other comparators. Second, kidney function and diet records were not collected in this study, and it was not possible to examine the influence of those factors on serum phosphorus levels. Finally, as this study included only Japanese patients, the generalizability of these results is limited because of cultural differences in diet.Despite the study limitations, we consider that tenapanor administration for PD patients with hyperphosphatemia resulted in clinically meaningful decreases in serum phosphorus levels and achievement of the target serum phosphorus levels per current guidelines (3.5–6.0 mg/dL). Treatment with tenapanor for 16 weeks was considered safe and tolerable for PD patients, with all cases of diarrhea being mild or moderate and occurring at the beginning of treatment. The serum phosphorus level tends to decrease with increasing tenapanor doses. Tenapanor may be a first-in-class drug, as it has a different mechanism of action from existing phosphate binder options for patients undergoing PD.