The Japanese study
Phosphorus load is associated with the risk of cardiovascular events and all-cause death in patients with chronic kidney disease (CKD), and thus regulation of serum phosphorus level is one of the most important treatment strategies for CKD–mineral and bone disorders (MBD).1, 2, 3, 4 However, approximately 30 % of Japanese patients requiring hemodialysis (HD) do not achieve the target range of serum phosphorus levels proposed by the Japanese Society for Dialysis Therapy, despite the use of phosphate binders.5 Tenapanor is a novel drug for the management of hyperphosphatemia that selectively inhibits sodium/hydrogen exchanger 3 (NHE3) on the luminal side of intestinal epithelial cells, thereby blocking the paracellular influx of phosphate.6, 7, 8 Here, we sought to confirm the efficacy and safety of tenapanor. Based on results from a Japanese dose-response study,9 we adopted an up-titration regimen starting from the lowest effective dose in the present study, rather than the down-titration regimen used in a US phase 3 study.10. ( my emphasis )
We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study (NCT04767581) at 34 facilities in Japan. The study included a screening period, a phosphate binder washout period (up to 3 weeks), and a treatment period (8 weeks) (Figure S1). Patients whose serum phosphorus levels were within the target range with a stable dose of phosphate binders were pre-enrolled at a screening period according to the inclusion/exclusion criteria (Item S1). Pre-enrolled patients were subsequently enrolled if their serum phosphorus levels increased by ≥1.0 mg/dL to 6.1-9.9 mg/dL during the washout period. Enrolled patients received tenapanor or placebo twice daily (BID) for 8 weeks. Tenapanor was titrated step-wise starting from 5 mg BID, up to 10 mg, 20 mg, or 30 mg BID with ≥2-week intervals based on serum phosphorus level. During the study, serum samples were obtained before dialysis at the first session of the week, and the samples at baseline were collected on Day 1 (Week 0) before administration. The primary endpoint was the change in serum phosphorus level from baseline at Week 8.
Of the 216 pre-enrolled patients, 164 initiated the treatment period (82 per group) and 123 completed the study (tenapanor group: 65, placebo group: 58) (Figure S2). Baseline characteristics were well balanced between the groups (Table S1).
The changes in serum phosphorus levels at Week 8 from baseline in the tenapanor and placebo groups were -1.89 mg/dL and 0.05 mg/dL, respectively, with a significant difference of -1.95 mg/dL (95% confidence interval: -2.37, -1.53) (P <0.0001) (Figure 1A). Tenapanor significantly lowered serum phosphorus levels regardless of baseline characteristics of patients (Figure S3). In the tenapanor group, the mean serum phosphorus level decreased by 1.3 mg/dL, and >50% of patients achieved the target range immediately after administration (Figure 1B, C). These results indicate that the starting dose of tenapanor 5 mg BID has a relevant serum phosphorus-lowering effect. Additionally, the serum phosphorus level was decreased further by up-titration after Week 2. At Week 7, the mean dose of tenapanor reached 18.1 mg and the breakdown of dose levels was as follows: 5 mg, 13.8%; 10 mg, 33.8%; 20 mg, 16.9%; 30 mg, 35.4%; 69.2% of patients achieved the target range (Figure 1D, Figure S4). Furthermore, tenapanor did not affect the serum levels of any minerals such as calcium, sodium, potassium or magnesium, unlike other phosphate binders (Table S2). These data suggest the potential of tenapanor to control serum phosphorus levels when administered as monotherapy.
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Figure 1Least-squares mean change in serum phosphorus level from baseline to Week 8 (A), time course of mean serum phosphorus level (B), proportion of patients who achieved the target serum phosphorus level (≥3.5 mg/dL and ≤6.0 mg/dL) at each time point (C), and time course of mean prescribed tenapanor dose (D). Error bars represent standard deviation.
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In each group, the most common adverse event was diarrhea (tenapanor group: 74.4%, placebo group: 19.5%) (Table 1). Among patients receiving tenapanor, most diarrhea (91.8%) cases were classified as mild and few patients (2.4%) discontinued the study because of diarrhea, suggesting that most diarrhea caused by tenapanor may be tolerable to Japanese patients. In the tenapanor group, the mean Bristol Stool Form Scale score and bowel movements per week slightly increased immediately after administration and remained constant thereafter (Figure S5). No clinically significant events occurred in either group during the study.
Table 1Summary of AEs and drug-related AEs
Tenapanor (n = 82) Placebo (n = 82)
n (%) n (%)
Any AE with an incidence >5% 76 (92.7) 54 (65.9)
Serious AE 4 (4.9) 5 (6.1)
Death 0 2 (2.4)
Serious AE other than death 4 (4.9) 3 (3.7)
Any AE with an incidence >5%
Diarrhea 61 (74.4) 16 (19.5)
Severity
Mild 56 (91.8) 13 (81.3)
Moderate 5 (8.2) 3 (18.7)
Severe 0 0
Discontinuation 2 (2.4) 0
Pyrexia 5 (6.1) 6 (7.3)
Shunt stenosis 5 (6.1) 3 (3.7)
Faces soft 5 (6.1) 4 (4.9)
Any drug-related AE with an incidence >5% 62 (75.6) 13 (15.9)
Diarrhea 62 (75.6) 8 (9.8)
Drug-related serious AE 0 0
The attending physician determined the severity according to the following definitions:
Mild: signs or symptoms present but not interfering with daily activities.
Moderate: interferes with daily activities due to discomfort or affects the clinical status.
Severe: inability to engage in daily activities or significant impact on clinical status.
In the case of discontinuation at the patient’s request, the tabulation was based on the information gathering by monitoring (no information gathering by electronic data capture).
AE, adverse event
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In the present study, 74.4% of patients receiving tenapanor experienced diarrhea, which is more than in the 30-mg down-titration group in a US study.10 Based on a relatively high incidence of diarrhea even in the placebo group in this study (19.5%), Japanese patients may be more sensitive to diarrhea than patients of other ethnicities.
The main limitation of this study was the short treatment period. Another phase 3 study conducted to confirm the long-term efficacy and safety of tenapanor would address this limitation.
In conclusion, in this phase 3 study with an up-titration regimen from the lowest dose, 5 mg BID, tenapanor significantly reduced the serum phosphorus level compared with placebo and was well tolerated in Japanese patients receiving HD. Thus, tenapanor administration with an up-titration regimen could be considered a new treatment option for hyperphosphatemia.
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