Etelcalcetide for the treatment of secondary hyperparathyroidism

Hamano, Naoto; Komaba, Hirotaka; Fukagawa, Masafumi

doi:10.1080/14656566.2017.1303482

Cited by 33 publications

(14 citation statements)

References 27 publications

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“…Recently developed calcimimetic agent for intravenous use, etelcalcetide, may be a solution, especially for low adherance, however, in head to head study, it evoked GI events as frequent as by cincalcet [ 27 ]. Thus, there is an unmet need for a calcimimetic agent with less GI events and fewer drug-drug interaction [ 28 ]. Evocalcet is a newly synthesized calcimimetic compound for oral administration designed with the aim of alleviating these adverse effects of cinacalcet.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…Even considering the potential interference of the pharmaceutical industry in enhancing positive reports, the drug seems a major advance in the care of a challenging clinical problem [51][52][53][54][55][56][57][58][59][60][61][62][63][64]. Pharmacokinetic studies, animal data and expert opinions indicate that the new agent has obvious advantages over the oral drug in improving compliance (IV on dialysis instead of orally once or twice daily); it seems to have a better efficacy profile and appears to increase stability in the blood levels of calcium, phosphate and PTH, in keeping with a longer duration of action and lack of interference with food intake; its side effects are similar to those caused by earlier products, and can generally be avoided with a strict control policy [65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84].…”

Section: Discussionmentioning

confidence: 99%

New Intravenous Calcimimetic Agents: New Options, New Problems. An Example on How Clinical, Economical and Ethical Considerations Affect Choice of Treatment

Piccoli

Trabace

Chatrenet

et al. 2020

IJERPH

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Background. Dialysis treatment is improving, but several long-term problems remain unsolved, including metabolic bone disease linked to chronic kidney disease (CKD-MBD). The availability of new, efficacious but expensive drugs (intravenous calcimimetic agents) poses ethical problems, especially in the setting of budget limitations. Methods. Reasons of choice, side effects, biochemical trends were discussed in a cohort of 15 patients (13% of the dialysis population) who stared treatment with intravenous calcimimetics in a single center. All patients had previously been treated with oral calcimimetic agents; dialysis efficacy was at target in 14/15; hemodiafiltration was employed in 10/15. Median Charlson Comorbidity Index was 8. The indications were discussed according to the principlist ethics (beneficience, non maleficience, justice and autonomy). Biochemical results were analyzed to support the clinical-ethical choices. Results. In the context of a strict clinical and biochemical surveillance, the lack of side effects ensured “non-maleficence”; efficacy was at least similar to oral calcimimetic agents, but tolerance was better. Autonomy was respected through a shared decision-making model; all patients appreciated the reduction of the drug burden, and most acknowledged better control of their biochemical data. The ethical conflict resides in the balance between the clinical “beneficience, non-maleficience” advantage and “justice” (economic impact of treatment, potentially in attrition with other resources, since the drug is expensive and included in the dialysis bundle). The dilemma is more relevant when a patient’s life expectancy is short (economic impact without clear clinical advantages), or when non-compliance is an issue (unclear advantage if the whole treatment is not correctly taken). Conclusions. In a context of person-centered medicine, autonomy, beneficence and non-maleficence should weight more than economic justice. While ethical discussions are not aimed at finding “the right answer” but asking “the right questions”, this example can raise awareness of the importance of including an ethical analysis in the choice of “economically relevant” drugs.

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“…The low incidence of GI-related AEs reported in this study shows that evocalcet may be more tolerable and therefore more efficacious than other currently available therapies. In the context of calcimimetic drugs other than cinacalcet, the injectable therapy etelcalcetide is not currently approved for patients undergoing PD [18][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

Faculty Opinions recommendation of Efficacy and safety of evocalcet in Japanese peritoneal dialysis patients.

Rodríguez

2020

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

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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 ://clini caltr ials.gov/ct2/show/NCT02 54941 7; JAPIC: Japi-cCTI-153016, http://www.clini caltr ials.jp/user/showC teDet ailE.jsp?japic Id=Japic CTI-15301 6.

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Etelcalcetide for the treatment of secondary hyperparathyroidism

Cited by 33 publications

References 27 publications

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 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

New Intravenous Calcimimetic Agents: New Options, New Problems. An Example on How Clinical, Economical and Ethical Considerations Affect Choice of Treatment

Faculty Opinions recommendation of Efficacy and safety of evocalcet in Japanese peritoneal dialysis patients.

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