Tenapanor for the Treatment of Hyperphosphatemia in Japanese Hemodialysis Patients: A Randomized Phase 3 Monotherapy Study With an Up-titration Regimen

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.1Komaba H. Fukagawa M. Phosphate-a poison for humans?.Kidney Int. 2016; 90: 753-763https://doi.org/10.1016/j.kint.2016.03.039Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 2Taniguchi M. Fukagawa M. Fujii N. et al.Serum phosphate and calcium should be primarily and consistently controlled in prevalent hemodialysis patients.Ther Apher Dial. 2013; 17: 221-228https://doi.org/10.1111/1744-9987.12030Crossref PubMed Scopus (117) Google Scholar, 3Ketteler M. Block G.A. Evenepoel P. et al.Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters.Kidney Int. 2017; 92: 26-36https://doi.org/10.1016/j.kint.2017.04.006Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar, 4Fukagawa M. Yokoyama K. Koiwa F. et al.Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder.Ther Aphr Dial. 2013; 17: 247-288https://doi.org/10.1111/1744-9987.12058Crossref PubMed Scopus (289) Google Scholar 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.5Japanese Society for Dialysis Therapy Renal Data Registry2019 Annual Dialysis Data Report.https://docs.jsdt.or.jp/overview/file/2019/pdf/05.pdfDate accessed: October 19, 2022Google Scholar 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.6Jacobs J.W. Leadbetter M.R. Bell N. et al.Discovery of tenapanor: a first-in-class minimally systemic inhibitor of intestinal Na+/H+ exchanger isoform 3.ACS Med Chem Lett. 2022; 13: 1043-1051https://doi.org/10.1021/acsmedchemlett.2c00037Crossref PubMed Scopus (3) Google Scholar, 7Spencer A.G. Labonte E.D. Rosenbaum D.P. et al.Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans.Sci Transl Med. 2014; 6: 227ra36https://doi.org/10.1126/scitranslmed.3007790Crossref PubMed Scopus (122) Google Scholar, 8Labonté E.D. Carreras C.W. Leadbetter M.R. et al.Gastrointestinal inhibition of sodium-hydrogen exchanger 3 reduces phosphorus absorption and protects against vascular calcification in CKD.J Am Soc Nephrol. 2015; 26: 1138-1149https://doi.org/10.1681/ASN.2014030317Crossref PubMed Scopus (85) Google Scholar Here, we sought to confirm the efficacy and safety of tenapanor. Based on results from a Japanese dose-response study,9Inaba M. Une Y. Ikejiri K. et al.Dose-response of tenapanor in patients with hyperphosphatemia undergoing hemodialysis in Japan-a phase 2 randomized trial.Kidney Int Rep. 2021; 7: 177-188https://doi.org/10.1016/j.ekir.2021.11.008Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar 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.10Block G.A. Rosenbaum D.P. Yan A. Chertow G.M. Efficacy and safety of tenapanor in patients with hyperphosphatemia receiving maintenance hemodialysis: a randomized phase 3 trial.J Am Soc Nephrol. 2019; 30: 641-652https://doi.org/10.1681/ASN.2018080832Crossref PubMed Scopus (78) Google Scholar 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) (Fig 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) (Fig 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) (Fig 1A). Tenapanor significantly lowered serum phosphorus levels regardless of baseline characteristics of patients (Fig 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 (Fig 1B and 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 (Fig 1D, Fig 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. 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 cases of 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 (Fig S5). No clinically significant events occurred in either group during the study.Table 1Summary of Adverse Events and Drug-Related Adverse EventsTenapanor (N = 82)Placebo (N = 82)N(%)N(%)Any AE with an incidence >5%76(92.7)54(65.9)Serious AE4(4.9)5(6.1) Death02(2.4) Serious AE other than death4(4.9)3(3.7)Any AE with an incidence >5% Diarrhea61(74.4)16(19.5)SeverityMild56(91.8)13(81.3)Moderate5(8.2)3(18.7)Severe0—0—Discontinuation2(2.4)0— Pyrexia5(6.1)6(7.3) Shunt stenosis5(6.1)3(3.7) Feces soft5(6.1)4(4.9)Any drug-related AE with an incidence >5%62(75.6)13(15.9) Diarrhea62(75.6)8(9.8)Drug-related serious AE0—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 owing 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).Abbreviation: AE, adverse event. Open table in a new tab 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 owing 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). Abbreviation: AE, adverse event. 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.10Block G.A. Rosenbaum D.P. Yan A. Chertow G.M. Efficacy and safety of tenapanor in patients with hyperphosphatemia receiving maintenance hemodialysis: a randomized phase 3 trial.J Am Soc Nephrol. 2019; 30: 641-652https://doi.org/10.1681/ASN.2018080832Crossref PubMed Scopus (78) Google Scholar 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. Study design, data acquisition, data analysis/interpretation, and statistical analysis: all authors; supervision or mentorship: MF, TA. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved. This research was funded by Kyowa Kirin Co., Ltd. MF received lecture fees, and TA received consulting fees and lecture fees from the study sponsor. The study sponsor contributed to the study design, data collection, and statistical analysis. Keyra Martinez Dunn, MD, of Edanz (www.edanz.com) provided medical writing support, which was funded by Kyowa Kirin Co., Ltd., in accordance with Good Publication Practice guidelines (https://www.ismpp.org/gpp-2022). Masafumi Fukagawa received consulting fees from Sanwa Kagaku and Ono Pharmaceutical, and received lecture fees from Bayer Japan and Kissei Pharmaceutical. Tadao Akizawa received consulting fees from Kissei Pharmaceutical, Ono Pharmaceutical, Torii Pharmaceutical, Astellas, Bayer Japan, and Sanwa Kagaku, and received lecture fees from Kissei Pharmaceutical, Ono Pharmaceutical, Torii Pharmaceutical, Astellas, Bayer Japan, and Sanwa Kagaku. Natsuki Urano, Kazuaki Ikejiri, Jun Kinoshita, and Kaoru Nakanishi are employees of Kyowa Kirin. The authors are thankful to the patients, investigators, and cooperating staff at the study sites. The datasets generated and/or analyzed during the study sponsored by Kyowa Kirin are available in the Vivli repository, https://vivli.org/ourmember/kyowa-kirin/, as long as conditions of data disclosure specified in the policy section of the Vivli website are satisfied. Received October 27, 2022. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and a Deputy Editor who served as Acting Editor-in-Chief. Accepted in revised form March 28, 2023. The involvement of an Acting Editor-in-Chief was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies. Download .pdf (.43 MB) Help with pdf files Supplementary File (PDF)Figures S1-S5, Item S1, Tables S1-S2