Navigating How to Initiate Tenapanor Therapy in the Real World
如何在现实世界中启动特纳帕诺疗法

Hyperphosphatemia is a common complication of kidney failure and is associated with vascular calcification and mortality. Strategies to control hyperphosphatemia include dietary phosphate restriction, the use of phosphate binders, and ensuring adequate dialysis.¹ However, adequate control of serum phosphate levels remains a challenge because of the limited efficacy of phosphate binders, variable adherence to taking these pills, and the difficulty of dietary phosphate restriction. Tenapanor is a potential new option for the treatment of hyperphosphatemia. Unlike conventional phosphate binders, it directly inhibits intestinal phosphate absorption by selectively inhibiting sodium/hydrogen exchanger isoform 3, which most likely induces a conformational change in tight junction proteins leading to inhibition of paracellular phosphate transport.²
高磷血症是肾衰竭的常见并发症，与血管钙化和死亡率有关。¹ 然而，由于磷酸盐结合剂的疗效有限、服用磷酸盐结合剂的依从性不一以及限制饮食中磷酸盐的难度较大，因此充分控制血清磷酸盐水平仍是一项挑战。特纳帕诺是治疗高磷血症的潜在新选择。与传统的磷酸盐结合剂不同，它通过选择性抑制钠/氢交换器同工酶3来直接抑制肠道对磷酸盐的吸收，这很可能会诱导紧密连接蛋白的构象变化，从而抑制细胞旁磷酸盐的转运。

The efficacy of tenapanor in controlling hyperphosphatemia has been demonstrated in several clinical studies. Previous studies have shown that tenapanor monotherapy significantly reduced serum phosphate levels compared with placebo or sevelamer in dialysis patients.^3–5 Subsequent studies have further demonstrated the efficacy of combination therapy with tenapanor and phosphate binders in controlling serum phosphate levels.^6,7 In these studies, tenapanor was started at a dose of 30 mg twice daily, but subsequent studies in Asian dialysis patients using a protocol that gradually increased the dose from 5 mg twice daily also confirmed a significant benefit in phosphate control.⁸ Tenapanor is known to cause soft stools or diarrhea as a result of sodium/hydrogen exchanger isoform 3 inhibition but has shown an acceptable safety and tolerability profile in previous studies.^3–8
多项临床研究证明，替那帕诺能有效控制高磷血症。先前的研究表明，与安慰剂或西维拉姆相比，替那帕诺单药治疗可显著降低透析患者的血清磷酸盐水平。^6,7 在这些研究中、但随后在亚洲透析患者中进行的研究证实，采用从每日两次、每次 5 毫克开始逐渐增加剂量的方案，对控制磷酸盐也有显著疗效。⁸ 特纳帕诺因抑制钠/氢交换异构体3而导致软便或腹泻，但在以前的研究中显示其安全性和耐受性是可以接受的。^3-8

In the May issue of Kidney360, Sprague and colleagues report the results of the OPTIMIZE study,⁹ which used three different initiation strategies for tenapanor. The primary target population was dialysis patients with serum phosphate levels >5.5 mg/dl despite the use of conventional phosphate binders. Participants were randomized to either a complete switch from phosphate binders to tenapanor (straight switch group) or to a regimen in which the phosphate binder dosage was reduced by more than 50% with the addition of tenapanor (binder reduction group). The study also included dialysis patients who were not receiving phosphate binders and had phosphate levels >4.5 mg/dl, in whom tenapanor was initiated as monotherapy (binder-naive group). In all groups, participants received 30 mg of tenapanor twice daily for 10 weeks, followed by an optional 16-week open-label extension.
在五月份的Kidney360杂志上，Sprague及其同事报告了OPTIMIZE研究的结果，⁹ 该研究采用了三种不同的替那帕诺起始策略。主要目标人群是使用传统磷酸盐结合剂后血清磷酸盐水平仍大于 5.5 mg/dl 的透析患者。参与者被随机分配到完全从磷酸盐结合剂改用替那帕诺（直接改用组）或磷酸盐结合剂用量减少 50% 以上并添加替那帕诺的治疗方案（减少结合剂组）。该研究还包括未接受磷酸盐结合剂治疗且磷酸盐水平>4.5 mg/dl的透析患者，这些患者开始接受替那帕诺单药治疗（未接受结合剂治疗组）。在所有组别中，参与者均接受了为期 10 周、每天两次、每次 30 毫克的替那帕诺治疗，随后可选择接受为期 16 周的开放标签延长治疗。

Over the course of the study, there was a different pattern of the longitudinal changes in serum phosphate levels between the binder reduction and straight switch groups. In the binder reduction group, there was a large decrease in serum phosphate levels 1 week after starting tenapanor, and the low levels were maintained until week 9, after which there was an increasing trend. In the straight switch group, the initial decrease in phosphate levels after starting tenapanor was relatively small, but there was a gradual decrease in serum phosphate levels throughout the period. As a result, serum phosphate levels at the end of week 10 were comparable, with a mean level of 6.0–6.5 mg/dl in both groups. In the binder-naive group, serum phosphate levels decreased significantly immediately after starting tenapanor, and the mean serum phosphate level at the end of week 10 was 5.0–5.5 mg/dl, with more than 60% of patients achieving phosphate levels ≤5.5 mg/dl. As expected, the most common adverse event was diarrhea, but the incidence was approximately 40%, which is lower than in previous studies, and few patients discontinued tenapanor because of diarrhea.
在研究过程中，减少粘合剂组和直接转换组的血清磷酸盐水平出现了不同的纵向变化。在减少粘合剂组，开始服用替那帕诺 1 周后血清磷酸盐水平大幅下降，低水平一直维持到第 9 周，之后呈上升趋势。在直接转换组中，开始服用替那帕诺后，血清磷酸盐水平最初的下降幅度相对较小，但在整个期间，血清磷酸盐水平逐渐下降。因此，在第 10 周结束时，两组的血清磷酸盐水平相当，平均水平均为 6.0-6.5 mg/dl。在无粘合剂组，开始服用替那帕诺后血清磷酸盐水平立即显著下降，第10周末的平均血清磷酸盐水平为5.0-5.5 mg/dl，超过60%的患者磷酸盐水平低于5.5 mg/dl。不出所料，最常见的不良反应是腹泻，但发生率约为40%，低于以往的研究，而且很少有患者因腹泻而停用替那潘诺。

Phosphate binders are widely used as the only currently available drugs to control hyperphosphatemia, and an important question is how to use tenapanor in combination with or without phosphate binders. A unique feature of the OPTIMIZE study⁹ was that it evaluated three different strategies for initiating tenapanor, each of which appears to be appropriate for real-world clinical practice. Importantly, the study protocol allowed the dose of the phosphate binder to be reduced as serum phosphate levels declined while maintaining the dose of tenapanor at 30 mg twice daily, in contrast to the AMPLIFY study,⁶ which reduced tenapanor at low phosphate levels while maintaining the dose of the phosphate binder. Thus, it could be said that the OPTIMIZE study positioned tenapanor, rather than phosphate binders, as the mainstay of treatment for hyperphosphatemia.
磷酸盐结合剂作为目前唯一可用于控制高磷酸盐血症的药物被广泛使用，一个重要的问题是如何将替那帕诺与磷酸盐结合剂或不与磷酸盐结合剂联合使用。OPTIMIZE 研究的一个独特之处⁹ 在于它评估了三种不同的替那帕诺起始策略，每种策略似乎都适合现实世界的临床实践。重要的是，该研究方案允许随着血清磷酸盐水平的下降而减少磷酸盐粘合剂的剂量，同时将替那帕诺的剂量维持在每天两次，每次30毫克，这与AMPLIFY研究⁶ 形成鲜明对比，后者在磷酸盐水平较低时减少替那帕诺的剂量，同时维持磷酸盐粘合剂的剂量。因此可以说，OPTIMIZE 研究将替那潘诺而非磷酸盐结合剂定位为治疗高磷酸盐血症的主要药物。

There are several possible explanations for the notable differences in longitudinal changes in serum phosphate between the straight switch and binder reduction groups. In the straight switch group, serum phosphate levels decreased relatively little, presumably because phosphate binders were discontinued with the initiation of tenapanor, but there was a slow but steady decrease in serum phosphate levels with the resumption and gradual increase of phosphate binders. In the binder reduction group, serum phosphate levels decreased more rapidly, presumably because the effect of initiating tenapanor exceeded that of reducing phosphate binders by half. The reason for the subsequent gradual increase in phosphate levels is unknown, but given the continued administration of tenapanor and phosphate binders, this may be explained by a decrease in adherence or a relaxation of the dietary phosphate restriction.
对于直接转换组和减少粘合剂组之间血清磷酸盐纵向变化的显著差异，有几种可能的解释。在直接转换组中，血清磷酸盐水平下降相对较少，这可能是因为在开始使用替那帕诺时停用了磷酸盐结合剂，但随着磷酸盐结合剂的恢复和逐渐增加，血清磷酸盐水平出现了缓慢但稳定的下降。在减少磷酸盐结合剂组，血清磷酸盐水平下降得更快，这可能是因为开始使用替那帕诺的效果比减少磷酸盐结合剂的效果高出一半。随后磷酸盐水平逐渐升高的原因尚不清楚，但鉴于持续服用替那帕诺和磷酸盐结合剂，其原因可能是坚持服用的人数减少或饮食中磷酸盐限制的放松。

The comparable efficacy at the end of the study between the straight switch and binder reduction groups has implications for the use of tenapanor in clinical practice. The results suggest that the choice between the two approaches should be individualized based on patient preference and phosphate control. For example, for patients with uncontrolled hyperphosphatemia and a high pill burden or poor adherence, it may be reasonable to choose the straight switch approach and advise the patient to be sure to take tenapanor, with resumption of phosphate binders as needed. On the other hand, for patients with good adherence but inadequate control of hyperphosphatemia, it may be reasonable to choose the binder reduction approach or to add tenapanor without reducing phosphate binders. In addition, although not tested in this study, the use of tenapanor may improve patient satisfaction and nutritional status even in patients with well-controlled hyperphosphatemia by reducing pill burden and relaxing dietary phosphate restrictions. The use of tenapanor may also be considered in patients with vascular calcification, as a recent study demonstrated the benefit of intensive phosphate control in attenuating the progression of vascular calcification.¹⁰ In the future, individualizing the use of tenapanor appears to be an important step in managing phosphate levels in clinical practice.
研究结束时，直接换药组和减少粘合剂组的疗效相当，这对在临床实践中使用替那帕诺具有重要意义。研究结果表明，应根据患者的偏好和磷酸盐控制情况在两种方法之间做出个性化选择。例如，对于高磷血症未得到控制、药片负担较重或依从性较差的患者，选择直接换药法可能是合理的，建议患者务必服用替那帕诺，并根据需要恢复磷酸盐结合剂的服用。另一方面，对于依从性较好但高磷血症控制不佳的患者，选择减少磷酸盐结合剂的方法或在不减少磷酸盐结合剂的情况下添加替那帕诺可能是合理的。此外，尽管本研究未对替那帕诺进行测试，但即使是对高磷血症控制良好的患者，使用替那帕诺也可通过减轻药片负担和放宽饮食磷酸盐限制来提高患者满意度和改善营养状况。血管钙化患者也可考虑使用替那潘诺，因为最近的一项研究表明，强化磷酸盐控制有利于减轻血管钙化的进展。¹⁰ 未来，在临床实践中，个性化使用替那潘诺似乎是控制磷酸盐水平的重要一步。

Because patient initiative is critical to controlling serum phosphate levels, patient preference for phosphate-lowering treatment is a very important issue. In this study,⁹ the majority of participants in the straight switch and binder reduction groups responded to the patient experience questionnaires, with more than 80% in both groups reporting an improvement in their phosphate management routine. In addition, approximately 70% reported that their phosphate management was much less or somewhat less difficult. Given that patient preferences are likely to influence medication adherence and treatment efficacy, these data are meaningful and support the practical value of tenapanor.
由于患者的主动性对于控制血清磷酸盐水平至关重要，因此患者对降磷治疗的偏好是一个非常重要的问题。在这项研究中，⁹ 直接换药组和减少粘合剂组的大多数参与者都对患者体验问卷做出了回应，两组中都有超过 80% 的人表示他们的磷酸盐管理常规有所改善。此外，约有 70% 的人表示他们的磷酸盐管理难度大大降低或有所降低。鉴于患者的偏好可能会影响用药依从性和治疗效果，这些数据非常有意义，并支持替那帕诺的实用价值。

The results in the binder-naive group are also important because it was the first to evaluate the efficacy of tenapanor in patients not treated with phosphate binders. Similar to previous studies, tenapanor was shown to be effective in this population, supporting its potential as a first-line treatment. However, the choice between tenapanor and phosphate binders as initial treatment requires further consideration. If the cost of tenapanor is higher than that of existing phosphate binders, as is the case in Japan, starting with phosphate binders would make more sense from a health economic perspective.
未使用磷酸盐结合剂组的研究结果也很重要，因为这是首次评估替那帕诺对未使用磷酸盐结合剂治疗的患者的疗效。与之前的研究相似，替那帕诺在这一人群中也被证明是有效的，这支持了其作为一线治疗的潜力。然而，在选择替那帕诺还是磷酸盐结合剂作为初始治疗时还需要进一步考虑。如果替那帕诺的成本高于现有的磷酸盐结合剂（日本的情况就是如此），那么从健康经济的角度来看，首先使用磷酸盐结合剂会更有意义。

In terms of safety, the incidence of diarrhea was approximately 40%, which was lower than in previous studies, and few patients discontinued tenapanor because of diarrhea.⁹ As the authors also suggest, it is likely that pretrial education about the side effects of tenapanor helped reduce the incidence of diarrhea and drug discontinuation. These findings support the notion that education before the use of tenapanor is important to reduce patient anxiety, maintain adherence, and maximize efficacy in real-world clinical practice. It is also interesting to note that that the incidence of adverse events was lower in the binder-naive group. It would be worthwhile to investigate whether and how concurrent use of phosphate binders affects the incidence or severity of diarrhea associated with tenapanor.
在安全性方面，腹泻发生率约为40%，低于以往的研究，很少有患者因腹泻而停用替那帕诺。⁹ 作者还指出，有关替那帕诺副作用的试验前教育很可能有助于降低腹泻和停药的发生率。这些研究结果支持这样一种观点，即使用替那帕诺前的教育对于减少患者焦虑、保持依从性以及在实际临床实践中最大限度地提高疗效非常重要。此外，值得注意的是，未使用粘合剂组的不良反应发生率较低。值得研究的是，同时使用磷酸盐结合剂是否会影响替那帕诺相关腹泻的发生率或严重程度，以及影响的程度如何。

Finally, while this study confirmed the efficacy of tenapanor, it should be noted that only 30%–40% of patients in the binder reduction and straight switch groups achieved serum phosphate levels of ≤5.5 mg/dl at the end of the study.⁹ This finding was similar to that observed in the AMPLIFY study,⁶ in which tenapanor was added to phosphate binder therapy. These results underscore the challenge of controlling serum phosphate levels, even with the use of tenapanor, in patients with uncontrolled hyperphosphatemia who often have high dietary phosphate intake and poor medication adherence. Further efforts are needed to establish a more optimized approach to improve phosphate management in treatment-resistant populations.
最后，虽然这项研究证实了替那帕诺的疗效，但需要注意的是，在研究结束时，只有30%-40%的粘合剂减少组和直接转换组患者的血清磷酸盐水平达到了≤5.5 mg/dl。⁹ 这一结果与AMPLIFY研究中观察到的结果相似、⁶ 该研究在磷酸盐缓冲剂疗法中加入了替那帕诺。这些结果凸显了即使使用替那帕诺，也难以控制高磷血症患者的血清磷酸盐水平，因为这些患者的饮食磷酸盐摄入量通常较高，而且服药依从性较差。我们需要进一步努力，建立一种更优化的方法来改善耐药人群的磷酸盐管理。

In conclusion, this study evaluated three different approaches to tenapanor initiation and provided important evidence for its clinical application by demonstrating the efficacy of multiple ways to use tenapanor. To further establish the clinical value of tenapanor, the next critical step will be testing the efficacy in the real-world setting.
总之，本研究评估了三种不同的替那潘诺启动方法，并通过证明多种替那潘诺使用方法的疗效，为其临床应用提供了重要证据。要进一步确定替那潘诺的临床价值，下一步关键是在实际环境中测试其疗效。

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