In Reply to "Letter Regarding 'Dose-Response of Tenapanor in Patients With Hyperphosphatemia Undergoing Hemodialysis in Japan-A Phase 2 Randomized Trial'".
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SUBMITTER: Inaba M
PROVIDER: S-EPMC9263242 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionSimplified, but effective, hyperphosphatemia treatments with novel mechanisms of action, tolerable safety profiles, and low pill burden are needed for patients undergoing hemodialysis. Tenapanor is a calcium (Ca)-free, nonmetal, nonpolymeric drug that reduces phosphate absorption by selectively inhibiting intestinal sodium-hydrogen exchanger 3. As the serum phosphorus (P) level-lowering effect of tenapanor has not been evaluated in Japanese patients with hyperphosphatemia undergoing hemodialysis, we evaluated its efficacy and safety in this population.MethodsThis was a multicenter, phase 2, double-blind, placebo-controlled, parallel-group, dose-finding study. Change in serum P level from baseline at week 6 was the primary end point.ResultsOverall, 207 patients were randomized to 5 groups (placebo [n = 41] and tenapanor 5-mg taken twice daily [BID] [n = 42], 10-mg BID [n = 41], 30-mg BID [n = 42], and 30-mg BID dose-titration [n = 41]) and treated for 6 weeks. Mean changes from baseline at week 6 in serum P level were 0.64, -0.93, -1.36, -1.92, and -1.99 mg/dl in the placebo and tenapanor groups, respectively. Serum P level was significantly decreased from baseline in all tenapanor groups compared with placebo (P < 0.001, for each dose). Diarrhea was the most frequent drug-related adverse event (AE) with an incidence of 9.8%, 50.0%, 65.9%, 76.2%, and 65.9% in the respective placebo and tenapanor groups.ConclusionIn Japanese patients undergoing hemodialysis, tenapanor was found to have a dose-responsive, serum P level-lowering effect. Diarrhea was the most frequent drug-related AE; most cases were mild and generally tolerable. Tenapanor may become a first-in-class therapeutic agent for patients with hyperphosphatemia.
| S-EPMC8820999 | biostudies-literature
Project description:IntroductionPhosphate binders are used to treat hyperphosphatemia. Some patients have inappropriately controlled serum phosphorus levels, which may occur for many reasons, including a high pill burden and adverse events (AEs). Tenapanor selectively inhibits the passive paracellular transfer of phosphate in the gastrointestinal tract, thereby reducing serum phosphorus levels. This novel mechanism of action may contribute to improved phosphate management. The efficacy and safety of tenapanor have not been evaluated in Japanese patients with high serum phosphorus levels despite treatment with phosphate binders. This study aimed to assess the efficacy and safety of add-on tenapanor therapy for reducing serum phosphorus levels in this population.MethodsThis multicenter, double-blind, randomized, placebo-controlled trial enrolled patients with refractory hyperphosphatemia undergoing hemodialysis. Patients were randomly assigned in a 1:1 ratio to receive tenapanor or placebo as an add-on to their phosphate binder regimen for 6 weeks. Change in serum phosphorus levels at week 6 (day 43) compared with the baseline value (day 1, week 0) (primary endpoint), achievement of target serum phosphorus levels (serum phosphorus level ≤6.0 or ≤5.5 mg/dL), and safety, based on all AEs and drug-related AEs, were among the outcomes evaluated.ResultsIn total, 24 patients were randomly assigned to the placebo group and 23 to the tenapanor group. The mean serum phosphorus level decreased from 7.01 mg/dL on day 1 to 6.69 mg/dL on day 43 in the placebo group and from 6.77 mg/dL on day 1 to 4.67 mg/dL on day 43 in the tenapanor group. In the placebo and tenapanor groups (modified intent-to-treat population), the mean (standard deviation) change in the serum phosphorus level at day 43 (last observation carried forward [LOCF]) was 0.08 (1.52) mg/dL and -1.99 (1.24) mg/dL, respectively, with a between-group difference of -2.07 (95% confidence interval: -2.89, -1.26; p < 0.001). The target achievement rate (serum phosphorus level ≤6.0 mg/dL at week 6 [LOCF]) was 37.5 and 87.0% in the placebo and tenapanor groups, respectively. Diarrhea was the most common drug-related AE, and it occurred in 8.3 and 65.2% of patients in the placebo and tenapanor groups, respectively. No specific AEs were observed with add-on tenapanor or with phosphate binders.Discussion/conclusionTherapy with existing phosphate binders and add-on tenapanor resulted in a significant decrease in serum phosphorus level compared with the placebo group in patients with refractory hyperphosphatemia despite treatment with phosphate binders. No new safety signals were raised, and add-on tenapanor was generally well tolerated.
| S-EPMC8491508 | biostudies-literature
Project description:BackgroundElevated serum fibroblast growth factor 23 (FGF23) is strongly associated with cardiovascular risk and mortality. Tenapanor, an inhibitor of gastrointestinal sodium/hydrogen exchanger isoform 3, decreased serum phosphate in a randomized, double-blind, placebo-controlled Phase 2 trial (ClinicalTrials.gov identifier NCT02081534) of patients receiving hemodialysis with hyperphosphatemia. Here, we report a secondary analysis of effects on serum FGF23 during that study.MethodsAfter 1-3 weeks of washout of phosphate binders, 162 patients were randomized to receive 4 weeks of treatment with placebo or one of six tenapanor regimens (3 or 30 mg once daily, or 1, 3, 10 or 30 mg twice daily). Intact FGF23 concentrations were determined from serum samples collected at screening, post-washout and end of treatment, assayed in duplicate in a single batch at the end of the study.ResultsAfter phosphate-binder washout, serum FGF23 concentrations increased in all groups [range of geometric means: 1430-2605 pg/mL before, to 2601-6294 pg/mL after washout (P < 0.001 for all patients analyzed as a single group)]. Serum FGF23 concentrations subsequently decreased in tenapanor-treated patients (2030-3563 pg/mL), whereas they increased further in placebo-treated patients (6930 pg/mL). In an analysis of covariance, FGF23 decreased by 9.1-27.9% in tenapanor-treated patients and increased by 21.9% in placebo-treated patients (P ≤ 0.001-0.04).ConclusionsFollowing a marked increase in serum FGF23 in response to withdrawal of phosphate binders, tenapanor significantly decreased serum FGF23 in patients receiving hemodialysis with hyperphosphatemia. Further studies are required to explore the long-term effects of controlling FGF23 with tenapanor.
| S-EPMC6365767 | biostudies-literature
Project description:BackgroundThe efficacy and safety of tenapanor has not been confirmed in Chinese end-stage renal disease (ESRD) patients with hyperphosphatemia on haemodialysis (HD).MethodsThis was a randomised, double blind, phase 3 trial conducted at 26 dialysis facilities in China (https://www.chictr.org.cn/index.aspx; CTR20202588). After a 3-week washout, adults with ESRD on HD with hyperphosphatemia were randomised (1:1) using an interactive web response system to oral tenapanor 30 mg twice a day or placebo for 4 weeks. The primary endpoint was the change in mean serum phosphorous level from baseline to the endpoint visit (day 29 or last serum phosphorus measurement). Efficacy was analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drug.ResultsBetween 5 March 2021 and 8 June 2022, 77 patients received tenapanor and 73 received placebo. Tenapanor treatment (n = 75) resulted in a significantly greater least squares (LS) mean reduction in serum phosphate at the endpoint visit versus placebo (n = 72): LS mean difference -1.17 mg/dl (95% CI -1.694 to -0.654, P < .001). More patients receiving tenapanor achieved a serum phosphorous level <5.5 mg/dl at the endpoint visit (44.6% versus 10.1%). The most common treatment-related adverse event was diarrhoea [tenapanor 28.6% (22/77), placebo 2.7% (2/73)], which was mostly mild and led to treatment discontinuation in two patients receiving tenapanor.ConclusionsTenapanor significantly reduced the serum phosphorous level versus placebo in Chinese ESRD patients on HD and was generally well tolerated.
| S-EPMC10768776 | biostudies-literature
Project description: Not available
| S-EPMC10658421 | biostudies-literature
Project description:Hyperphosphatemia is common in chronic kidney disease (CKD) and associated with mortality and morbidity. We aimed to evaluate the dose-dependent efficacy and safety of PA21 (sucroferric oxyhydroxide), an iron-based phosphate binder, in Japanese hemodialysis patients with hyperphosphatemia.In this double-blind, multicenter, Phase II study, 183 patients were randomized to placebo or PA21 at doses of 250, 500, 750, or 1000 mg (based on iron content) three times/day for 6 weeks. The primary efficacy endpoint was the mean change in serum phosphorus levels from baseline to end of treatment in each group. Adverse reactions were evaluated.The change in serum phosphorus level was significantly greater in each PA21 group than in the placebo group (analysis of covariance: P < 0.001 for all groups). A dose-dependent change in serum phosphorus levels was observed in the PA21 groups. A notable decrease in mean serum phosphorus levels to the target level of ?6 mg/dL was shown starting at Week 1 in all PA21 groups. The cumulative achievement rates for target serum phosphorus level at the end of treatment were generally >80 % in all PA21 groups. The major adverse reaction reported was diarrhea; however, most cases were mild.PA21 was an effective and safe treatment that decreased serum phosphorus levels starting at 1 week of treatment when administered as one 250-mg tablet three times/day. PA21 demonstrated a dose-dependent phosphorus lowering effect up to 3000 mg/day. PA21 may be a new treatment alternative with relatively low pill burden for Japanese hemodialysis patients with hyperphosphatemia.
| S-EPMC5486467 | biostudies-literature
Project description:Hyperphosphatemia is common among patients with CKD stage 5D and is associated with morbidity and mortality. Current guidelines recommend lowering serum phosphate concentrations toward normal. Tenapanor is a minimally absorbed small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 that functions in the gut to reduce sodium and phosphate absorption. This randomized, double-blind, placebo-controlled trial assessed the effects of tenapanor on serum phosphate concentration in patients with hyperphosphatemia receiving hemodialysis. After a 1- to 3-week washout of phosphate binders, we randomly assigned 162 eligible patients (serum phosphate =6.0 to <10.0 mg/dl and a 1.5-mg/dl increase from before washout) to one of six tenapanor regimens (3 or 30 mg once daily or 1, 3, 10, or 30 mg twice daily) or placebo for 4 weeks. The primary efficacy end point was change in serum phosphate concentration from baseline (randomization) to end of treatment. In total, 115 patients (71%) completed the study. Mean serum phosphate concentrations at baseline (after washout) were 7.32-7.92 mg/dl for tenapanor groups and 7.87 mg/dl for the placebo group. Tenapanor provided dose-dependent reductions in serum phosphate level from baseline (least squares mean change: tenapanor =0.47-1.98 mg/dl; placebo =0.54 mg/dl; P=0.01). Diarrhea was the most common adverse event (tenapanor =18%-68%; placebo =12%) and frequent at the highest tenapanor doses. In conclusion, tenapanor treatment resulted in statistically significant, dose-dependent reductions in serum phosphate concentrations in patients with hyperphosphatemia receiving hemodialysis. Additional studies are required to clarify the optimal dosing of tenapanor in patients with CKD-related hyperphosphatemia.
| S-EPMC5461797 | biostudies-literature
Project description:IntroductionChronic kidney disease (CKD) has a prevalence of 9.1% globally, and frequently results in elevated serum phosphate, increasing cardiovascular morbidity and mortality risk in hemodialysis (HD) patients. DS-2330b, an oral NaPi-IIb inhibitor, reduced intestinal phosphate absorption in preclinical studies, but its effect in patients with CKD is unknown. This 2-part, randomized, placebo- and active-controlled, single- and repeated-dose, phase 1b study evaluated safety and efficacy of DS-2330b in patients with CKD on HD.MethodsPart A, a 2-period, 2-way study, evaluated safety and pharmacokinetics of DS-2330b 250 mg in solution and tablet formulations. Part B assessed the safety of DS-2330b in solution (chosen based on results of part A) and its effect on serum phosphate. Patients were randomized to placebo 3 times daily (TID), DS-2330b 400 mg TID, DS-2330b 400 mg with sevelamer 1.6 g TID, and sevelamer 1.6 g with placebo TID for 14 days. Safety endpoints included adverse event (AE) monitoring.ResultsSix patients completed part A. Two patients experienced serious AEs considered unrelated to DS-2330b treatment. Thirty-two patients enrolled and completed part B. Serum phosphate mean change from baseline ± SD was -2.2±1.5 mg/dl versus -1.9 ± 1.1 mg/dl for DS-2330b monotherapy versus placebo. Patients receiving DS-2330b with sevelamer or sevelamer with placebo experienced the greatest serum phosphate decrease from baseline. Nine patients (28.1%) experienced ≥1 treatment-emergent AE (TEAE); 7 patients experienced drug-related TEAEs. The TEAE incidence was comparable between DS-2330b and control groups.ConclusionsDS-2330b, alone or in combination with sevelamer, was safe and well tolerated but did not demonstrate clinically meaningful efficacy in HD patients.
| S-EPMC7938184 | biostudies-literature
Project description:IntroductionThe current management of hyperphosphatemia with phosphate binders is associated with insufficient phosphorus control and a significant pill burden. Tenapanor, a first-in-class, phosphate absorption inhibitor, is expected to control phosphorus and decrease pill burden because of its small pill size and twice daily dosing regimen. This study evaluated tenapanor effectiveness on reducing the phosphate binder pill burden during a 26-week treatment period in Japanese hemodialysis patients.MethodsIn this multicenter, open-label, single-arm study, hemodialysis patients whose serum phosphorus level was 3.5 to 7.0 mg/dl received tenapanor 30 mg twice daily orally added to their phosphate binder regimen. The phosphate binder dosage was adjusted to achieve a serum phosphorus level within the baseline range of ±0.5 mg/dl. The primary end point was the percentage of patients who achieved a ≥30% decrease in the number of phosphate binders and tenapanor tablets prescribed daily compared with the number of phosphate binder tablets at baseline.ResultsOf the 67 patients enrolled, 43 completed the study. At baseline, the mean total number of phosphate binder tablets per day was 14.7, which decreased to 3.0 tablets per day at week 26. The primary end point was achieved in 71.6% of patients (P < 0.001). The phosphate binder was completely switched to tenapanor in 28.4% of patients (P < 0.001). The mean phosphorus levels were relatively well controlled (5.19 and 4.71 mg/dl at baseline and week 26, respectively). The most frequent drug-related adverse event (AE) was diarrhea (74.6%).ConclusionTenapanor provided effective phosphorus control and decreased the number of phosphate binder tablets. The management of drug-related diarrhea will facilitate more widespread use of tenapanor.
| S-EPMC8418975 | biostudies-literature
Project description:Background and objectivesInterdialytic weight gain in patients on hemodialysis is associated with adverse cardiovascular outcomes and increased mortality. The degree of interdialytic weight gain is influenced by sodium intake. We evaluated the effects of tenapanor (AZD1722 and RDX5791), a minimally systemically available inhibitor of the sodium/hydrogen exchanger isoform 3, on interdialytic weight gain in patients with CKD stage 5D treated with hemodialysis.Design, setting, participants, & measurementsThis phase 2, randomized, double-blind study (NCT01764854; conducted January to September of 2013) enrolled adults on maintenance hemodialysis with interdialytic weight gain ≥3.0% of postdialysis weight and ≥2 kg. Patients were randomly assigned (1:1) to receive tenapanor or placebo. The primary end point was change in mean interdialytic weight gain (percentage of baseline postdialysis weight) from baseline (mean across a 2-week run-in period) to week 4. In a subgroup of inpatients, 24-hour stool sodium and stool weight were assessed for 1 week.ResultsSixteen patients received 1 week of inpatient treatment (tenapanor, eight; placebo, eight), and 72 patients received 4 weeks of treatment in an outpatient setting (tenapanor, 37; placebo, 35; completers: tenapanor, 31; placebo, 33). In the outpatient cohort, no significant effect on interdialytic weight gain was detected; least squares mean changes in relative interdialytic weight gain from baseline to week 4 were tenapanor, -0.26% (95% confidence interval, -0.57% to 0.06%) and placebo, -0.23% (95% confidence interval, -0.54% to 0.07%; P=0.46). During week 1 (inpatient cohort only), compared with placebo, tenapanor treatment resulted in higher stool sodium content (mean [±SD]: tenapanor, 36.6 [±21.8] mmol/d; placebo, 2.8 [±2.7] mmol/d; P<0.001) and higher stool weight (tenapanor, 172.5 [±68.1] g/d; placebo, 86.3 [±30.0] g/d; P<0.01). A similar safety profile was observed across treatment groups with the exception of diarrhea, which occurred more frequently with tenapanor treatment.ConclusionsTenapanor treatment increased stool sodium and weight over placebo in patients undergoing hemodialysis. However, over 4 weeks of treatment, there was no difference in interdialytic weight gain between patients treated with tenapanor and those receiving placebo.
| S-EPMC5012484 | biostudies-literature