On June 16, 2023, the 68th Annual Meeting of the Japanese Society for Dialysis Therapy was held in Kobe, Japan, with the theme of " Unity of Knowledge and Action: Utilizing Skills and Putting Knowledge Into Practice ". Every year, about 20,000 professionals in the field of dialysis participated in the conference to exchange the latest cutting-edge dialysis technologies and therapies. The China Phase 3 results (study number: TEN C-03-002) of phosphorus-lowering drug (Tenapanor) licensed-in by Fosun Pharma, was selected for oral presentation at the conference, and Professor Gan Liangying of Peking University People's Hospital will represent the research group as a speaker to exchange detailed study data with the peers during the annual meeting.

Session Name: Oral Presentation Session 3  Time: June 16, 2023 10:30-11:20

Source: //www.jsdt.or.jp/

Tenapanor is an oral intestinal sodium/hydrogen exchanger 3 (NHE3) inhibitor licensed by Fosun Pharma from Ardelyx, Inc., Fosun Pharma is responsible for the exclusive clinical development and commercialization of Tenapanor in Chinese mainland, Hong Kong SAR and Macao SAR. Tenapanor can reduce intestinal sodium ion absorption, increase the water in the intestinal lumen, promote intestinal peristalsis and the frequency of normal bowel movements, and has been approved by the US FDA in 2019 for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults. In addition, studies have demonstrated that Tenapanor can also inhibit the absorption of phosphate in the paracellular pathway of the intestine, thereby reducing serum phosphorus. The therapeutic use of Tenapanor for hyperphosphatemia in patients with end-stage renal disease (ESRD) is also under development. Several phase II and III studies in the United States and Japan have shown that Tenapanor significantly reduces elevated serum phosphorus (sP) levels in hemodialysis patients, and also shown its therapeutic tolerability in the study of treatment duration up to 52 weeks^1,2,3.

The TEN C-03-002 study (registration number: CTR20202588) is a randomized, double-blind, placebo-controlled, multi-center phase III clinical study conducted in China to evaluate the efficacy and safety of Tenapanor in ESRD hemodialysis patients with hyperphosphatemia. This study enrolled 150 patients on maintenance haemodialysis and randomized to receive either 30 mg bid Tenapanor or placebo at a 2:1 ratio for 4 weeks. The primary efficacy endpoint was the difference in the changed sP levels from baseline between the Tenapanor group and the placebo group at the end of the 4-week treatment or early termination of the visit (study endpoint) in the intention-to-treat analysis (ITT) population. At the endpoint, the difference in the least squares mean of changed sP levels from baseline between the Tenapanor group and the placebo group was -1.17 mg/dL (95% CI: -1.694, -0.654, p<0.001), and 44.59% and 10.14% of patients in the two groups achieved the target of sP levels <5.5 mg/dL, respectively. In subgroup analyses of age (<45 years, ≥45~<65 years, ≥65 years), sex, and baseline sP levels (<7.5 mg/dL or ≥7.5 mg/dL), the reduction of sP levels from baseline in the Tenapanor group was better than that in the placebo group. Treatment emergent adverse events (TEAEs) were reported in 51.9% and 41.1% of patients treated with Tenapanor and placebo, respectively, with most being mild to moderate severity. The results of this study are consistent with previous studies in the United States and Japan.

In the AMPLIFY study, combination of Tenapanor and phosphorus binders further improved the control of hyperphosphatemia4. Another previous Japanese study also demonstrated that the add-on Tenapanor not only synergistically reduced sP levels, but also reduced the pill burden of phosphorus binders⁵. In addition, no clinically relevant drug interactions between phosphorus binders and Tenapanor were observed in human trials⁶. Although phosphorus binders are widely used in China, the sP control in most dialysis patients does not reach the target level recommended by KDIGO guidelines. The mechanism of the existing phosphorus binders is similar, the blindly incremental dosing can’t bring better efficacy. Moreover, the high incidence of gastrointestinal adverse reactions and high pill burden of phosphorus binders (studies have shown that the average tablets number of phosphorus binders in CKD patients with hyperphosphatemia is about 11 tablets/day⁷) resulted in poor patient compliance. Tenapanor as a new phosphorus-lowering drug under development has been highly anticipated, which inhibits the absorption of phosphate in the intestinal paracellular pathway to achieve the purpose of reducing sP. Its tablet size is small and easy to take, in the meantime of the phosphorus lowering can also improve the symptoms of constipation by soften the feces. China Phase 3 results of Tenapanor provide an evidence base for its future application in Chinese dialysis patients with hyperphosphatemia. As a novel phosphorus-lowering therapy used alone or in synergy with existing phosphorus binders, Tenapanor is anticipated to be marketed in China and hope to bring more benefits to Chinese patients.

Compliance coding：NP-MA-20230605-CN-TEN-00001

Reference：

1.    Block GA, Rosenbaum DP, Yan A, Chertow GM. Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial. J Am Soc Nephrol 2019; 30: 641–52.

2.    Inaba M, Une Y, Ikejiri K, Kanda H, Fukagawa M, Akizawa T. Dose-Response of Tenapanor in Patients With Hyperphosphatemia Undergoing Hemodialysis in Japan-A Phase 2 Randomized Trial. Kidney Int Rep 2021; 7: 177–88.

3.    Block GA, Bleyer AJ, Silva AL, et al. Safety and Efficacy of Tenapanor for Long-term Serum Phosphate Control in Maintenance Dialysis: A 52-Week Randomized Phase 3 Trial (PHREEDOM). Kidney360 2021; 2: 1600–10.

4.    Pergola PE, Rosenbaum DP, Yang Y, Chertow GM. A Randomized Trial of Tenapanor and Phosphate Binders as a Dual-Mechanism Treatment for Hyperphosphatemia in Patients on Maintenance Dialysis (AMPLIFY). J Am Soc Nephrol 2021; 32: 1465–73.

5.    Shigematsu T, Une Y, Ikejiri K, Kanda H, Fukagawa M, Akizawa T. Therapeutic Effects of Add-On Tenapanor for Hemodialysis Patients with Refractory Hyperphosphatemia. Am J Nephrol 2021; 52: 496–506.

6.    Johansson S, Leonsson-Zachrisson M, Knutsson M, et al. Preclinical and Healthy Volunteer Studies of Potential Drug-Drug Interactions Between Tenapanor and Phosphate Binders. Clin Pharmacol Drug Dev 2017; 6: 448–56.

7.    Steven N Fishbane, et al. Phosphate Absorption and Hyperphosphatemia Management in Kidney Disease: A Physiology-Based Review. Kidney Med. 2021 Aug 27;3(6):1057-1064.