Efficacy and safety of evocalcet in Japanese peritoneal dialysis patients

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Abstract

Background

Secondary hyperparathyroidism (SHPT) is a serious and common complication in patients receiving peritoneal dialysis (PD). Cinacalcet is currently the recommended therapy for SHPT; however, gastrointestinal (GI)-related symptoms can result in low adherence and high discontinuation rates. Evocalcet is a novel calcimimetic agent that has non-inferior efficacy while providing a more tolerable safety profile.

Methods

This was a multicenter, intra-subject dose-adjustment treatment study evaluating the efficacy and safety of 1–8 mg evocalcet orally administered once daily for 32 weeks for the treatment of SHPT in PD patients. Patients then entered a 20-week extension period (dose range 1–12 mg). The primary endpoint was the proportion of patients who achieved a mean intact parathyroid hormone (iPTH) level of 60–240 pg/mL during the evaluation period (weeks 30–32). Secondary efficacy endpoints included the proportion of patients achieving ≥ 30% decrease in iPTH levels.

Results

A total of 39 Japanese PD patients with SHPT received evocalcet. The target mean iPTH level of 60–240 pg/mL was achieved by 71.8% (28/39) of patients during the evaluation period and 83.3% (20/24) of patients at week 52. The proportion of patients who achieved ≥ 30% decrease in iPTH levels from baseline was 74.4% (29/39) during the evaluation period and 87.5% (21/24) at week 52. Adverse drug reactions occurred in 46.2% (18/39) of patients, with most being of mild-to-moderate severity including GI-related events.

Conclusion

This study shows the long-term efficacy and safety of evocalcet when orally administered to PD patients with SHPT once daily.

Clinical trial registration

ClinicalTrials.gov: NCT02549417, https://clinicaltrials.gov/ct2/show/NCT02549417; JAPIC: JapicCTI-153016, http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-153016.

Electronic supplementary material

The online version of this article (10.1007/s10157-019-01692-y) contains supplementary material, which is available to authorized users.

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Most cited references 15

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Head-to-head comparison of the new calcimimetic agent evocalcet with cinacalcet in Japanese hemodialysis patients with secondary hyperparathyroidism

Masafumi Fukagawa, Ryutaro Shimazaki, Tadao Akizawa (2018)

Secondary hyperparathyroidism (SHPT) leads to cardiovascular calcification, which affects survival and quality of life in patients with chronic kidney disease. Cinacalcet is used to control SHPT, but it may induce gastrointestinal symptoms, resulting in lower adherence and insufficient dosages. Therefore, a need exists to develop new calcimimetics that cause fewer gastrointestinal symptoms. Here we conducted a phase 3, randomized, double-blind, double-dummy trial for a head-to-head comparison of the efficacy and safety of evocalcet, a new oral calcimimetic, to the established cinacalcet. Japanese patients with SHPT on hemodialysis were randomized to receive evocalcet or cinacalcet (317 patients each) for 30 weeks. The primary efficacy endpoint was non-inferiority of evocalcet to cinacalcet in the proportion of patients achieving a mean intact parathyroid hormone level of 60 to 240 pg/mL from week 28 to 30 (non-inferiority margin, -15%, per protocol set analyses). In the evocalcet and cinacalcet groups, 72.7% and 76.7%, respectively, achieved the target intact parathyroid hormone level (between-group difference: -4.0% [95% confidence interval -11.4%, 3.5%], for non-inferiority). The incidence of gastrointestinal-related adverse events was 18.6% and 32.8%, respectively (between-group difference: -14.2% [-20.9%, -7.5%], significant for superiority). Thus, the non-inferiority of evocalcet to cinacalcet in suppressing intact parathyroid hormone with fewer gastrointestinal-related adverse events was demonstrated. Hence, evocalcet may be a favorable alternative to existing calcimimetics for management of SHPT.

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A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro

Takehisa Kawata, Shin Tokunaga, Miki Murai … (2018)

Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin.

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A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients

Masafumi Fukagawa, Keitaro Yokoyama, Takashi Shigematsu … (2017)

Abstract Background Secondary hyperparathyroidism (SHPT) is a major complication associated with chronic kidney disease. We evaluated the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, in Japanese haemodialysis patients with SHPT. Methods In this phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study, etelcalcetide was administered three times per week at an initial dose of 5 mg, and subsequently adjusted to doses between 2.5 and 15 mg at 4-week intervals for 12 weeks. A total of 155 SHPT patients with serum intact parathyroid hormone (iPTH) levels ≥300 pg/mL were assigned to receive etelcalcetide (n = 78) or placebo (n = 77). The primary endpoint was the proportion of patients with decreased serum iPTH to the target range proposed by the Japanese Society for Dialysis Therapy (60–240 pg/mL). The major secondary endpoint was the proportion of patients with ≥30% reductions in serum iPTH from baseline. Results The proportion of patients meeting the primary endpoint was significantly higher for etelcalcetide (59.0%) versus placebo (1.3%). Similarly, the proportion of patients meeting the major secondary endpoint was significantly higher for etelcalcetide (76.9%) versus placebo (5.2%). Serum albumin-corrected calcium, phosphorus and intact fibroblast growth factor-23 levels were decreased in the etelcalcetide group. Nausea, vomiting and symptomatic hypocalcaemia were mild with etelcalcetide. Serious adverse events related to etelcalcetide were not observed. Conclusions This study demonstrated the efficacy and safety of etelcalcetide. As the only available intravenous calcium-sensing receptor agonist, etelcalcetide is likely to provide a new treatment option for SHPT in haemodialysis patients.

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Author and article information

Contributors

Kazuhiko Tsuruya: +81-744-29-8865 , tsuruya@naramed-u.ac.jp

Journal

Journal ID (nlm-ta): Clin Exp Nephrol

Journal ID (iso-abbrev): Clin. Exp. Nephrol

Title: Clinical and Experimental Nephrology

Publisher: Springer Singapore (Singapore )

ISSN (Print): 1342-1751

ISSN (Electronic): 1437-7799

Publication date (Electronic): 6 April 2019

Publication date PMC-release: 6 April 2019

Publication date (Print): 2019

Volume: 23

Issue: 6

Pages: 739-748

Affiliations

[1 ]ISNI 0000 0004 0372 782X, GRID grid.410814.8, Department of Nephrology, , Nara Medical University, ; 840 Shijo-cho, Kashihara, Nara 634-8521 Japan

[2 ]ISNI 0000 0004 1789 3108, GRID grid.473316.4, R&D Division, Kyowa Hakko Kirin Co., Ltd., ; 1-9-2 Otemachi, Chiyoda-ku, Tokyo, 100-0004 Japan

[3 ]ISNI 0000 0001 1516 6626, GRID grid.265061.6, Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, , Tokai University School of Medicine, ; 143 Shimokasuya, Isehara, Kanagawa 259-1193 Japan

[4 ]ISNI 0000 0000 8864 3422, GRID grid.410714.7, Division of Nephrology, Department of Medicine, , Showa University School of Medicine, ; Namics 301, 4-24-51 Takanawa, Minato-ku, Tokyo, 108-0074 Japan

Article

Publisher ID: 1692

DOI: 10.1007/s10157-019-01692-y

PMC ID: 6586709

PubMed ID: 30955188

SO-VID: 497bd40b-96b9-495c-8a25-6248a1a87408

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

History

Date received : 31 July 2018

Date accepted : 6 January 2019

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ScienceOpen disciplines: Nephrology

Keywords: evocalcet,calcimimetic,peritoneal dialysis,parathyroid hormone,secondary hyperparathyroidism,phase iii study

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ScienceOpen disciplines: Nephrology

Keywords: evocalcet, calcimimetic, peritoneal dialysis, parathyroid hormone, secondary hyperparathyroidism, phase iii study

Efficacy and safety of evocalcet in Japanese peritoneal dialysis patients

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Abstract

Background

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Conclusion

Clinical trial registration

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Karger: Nephrology

Most cited references 15

Head-to-head comparison of the new calcimimetic agent evocalcet with cinacalcet in Japanese hemodialysis patients with secondary hyperparathyroidism

A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro

A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients

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