Old and new calcimimetics for treatment of secondary hyperparathyroidism: impact on biochemical and relevant clinical outcomes

Old and new calcimimetics for treatment of secondary hyperparathyroidism: impact on biochemical... Secondary hyperparathyroidism (SHPT) is associated with increased bone turnover, risk of fractures, vascular calcifications, and cardiovascular and all-cause mortality. The classical treatment for SHPT includes active vitamin D compounds and phosphate binders. However, achieving the optimal laboratory targets is often difficult because vitamin D sterols suppress parathyroid hormone (PTH) secretion, while also promoting calcium and phosphate intestinal absorption. Calcimimetics increase the sensitivity of the calcium-sensing receptor, so that even with lower levels of extracellular calcium a signal can still exist, leading to a decrease of the set-point for systemic calcium homeostasis. This enables a decrease in plasma PTH levels and, consequently, of calcium levels. Cinacalcet was the first calcimimetic to be approved for clinical use. More than 10 years since its approval, cinacalcet has been demonstrated to effectively reduce PTH and improve biochemical control of mineral and bone disorders in chronic kidney patients. Three randomized controlled trials have analysed the effects of treatment with cinacalcet on hard clinical outcomes such as vascular calcification, bone histology and cardiovascular mortality and morbidity. However, a final conclusion on the effect of cinacalcet on hard outcomes remains elusive. Etelcalcetide is a new second-generation calcimimetic with a pharmacokinetic profile that allows thrice-weekly dosing at the time of haemodialysis. It was recently approved in Europe, and is regarded as a second opportunity to improve outcomes by optimizing treatment for SHPT. In this review, we summarize the impact of cinacalcet with regard to biochemical and clinical outcomes. We also discuss the possible implications of the new calcimimetic etelcalcetide in the quest to improve outcomes. Key words: calcimimetic agents, chronic kidney disease, cinacalcet, etelcalcetide, secondary hyperparathyroidism prevalence of 8–16% [1]. During the course of CKD, the decline in Introduction renal function is accompanied by the development of disorders Chronic kidney disease (CKD) is rapidly becoming a public health of calcium and phosphate metabolism, leading to the well- issue, with increasing incidence and estimated worldwide known condition ‘Mineral Bone Disease associated with CKD’ Received: July 6, 2017. Editorial decision: August 18, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Old and new calcimimetics | 81 Table 1. Effect of PTH-suppressive therapies on biochemical (CKD-MBD) [2]. This condition develops due to the inability of the parameters kidney to excrete phosphate properly, leading to its retention and accumulation, which stimulates fibroblast growth factor 23 (FGF- PTH Calcium Phosphorus FGF-23 23) and serum parathyroid hormone (PTH) [3]. FGF-23, a peptide hormone produced mainly in the osteocytes, is able to reduce Vitamin D analogues #" " " phosphate levels using three different pathways: increased renal Cinacalcet ## # # excretion, PTH stimulation and calcitriol synthesis inhibition. Etelcalcetide ## ## # ## The latter promotes decreased gastrointestinal absorption of phosphate and calcium, leading to hypocalcaemia. The low calci- triol levels and hypocalcaemia also stimulate PTH secretion in It was recently approved in Europe, and is regarded as a second the parathyroid glands and induce the development of parathy- opportunity to improve outcomes in CKD-MBD patients by roid gland hyperplasia and secondary hyperparathyroidism optimizing treatment for SHPT using this promising new (SHPT). calcimimetic [13]. SHPT is associated with increased bone turnover, risk of In this review, we summarize the impact of cinacalcet in bio- fractures, vascular calcifications and, most importantly, risk of chemical and relevant clinical outcomes such as cardiovascular cardiovascular and all-cause mortality [4]. Recent observational mortality, vascular calcifications and fractures. We also discuss data indicate that PTH >600 pg/mL is associated with a higher the possible implications of the new calcimimetic etelcalcetide risk of cardiovascular mortality as well as all-cause cardiovas- in the quest to improve outcomes for CKD patients. cular hospitalization [5]. It is interesting to note that patients have better outcomes the longer the time that they have PTH Cinacalcet effectively controls SHPT within recommended levels. Indeed, consistent control of bone metabolism parameters, including PTH, within published rec- Cinacalcet’s efficacy and safety has been tested in several ommended targets is a strong predictor of survival in haemo- randomized controlled trials (RCTs) [11, 12, 14]. Cinacalcet treat- dialysis patients [6]. ment in addition to active vitamin D in patients with SHPT that The classical treatment for SHPT includes active vitamin D is inadequately controlled despite standard therapy effectively compounds and phosphate binders (to limit its gastrointestinal decreases PTH levels, while also reducing serum calcium and phosphate absorption) [7]. However, achievement of optimal phosphorus. Post hoc analysis has demonstrated that treatment laboratory targets is often difficult because vitamin D sterols with cinacalcet improves the achievement of biochemical tar- suppress PTH secretion, but also promote calcium and phos- gets recomended by international societies [15]. In a meta- phate intestinal absorption. analysis [16] involving eight trials (1429 patients) comparing Calcium-sensing receptor (CaSR) is essential for the mainte- cinacalcet treatment plus standard therapy with placebo plus nance of systemic calcium homeostasis, and has become an standard therapy, end-of-treatment values for PTH [290.49 pg/ excellent target for the treatment of bone and mineral disor- mL, 95% confidence interval (CI) 359.91 to 221.07], calcium ders. Its ligands are called calcimimetics and can be classified (0.85 mg/dL, 95% CI 1.14 to 0.56), phosphorus (0.29 mg/dL, as Type 1 (agonists), such as ionized calcium and other divalent 95% CI 0.50 to 0.08) and calcium  phosphorus product anions that directly stimulate CaSR, or Type 2 (positive allos- 2 2 (7.90 mg /dL , 95% CI 10.25 to 5.54) were significantly lower teric modulators), which bind to a site that is distinct from the with cinacalcet compared with placebo. physiological ligand and increase the sensitivity of CaSR to ion- To allow an objective assessment of the effect of cinacalcet ized calcium, leading to the decrease of the set-point for sys- on lowering PTH, the vitamin D activator receptor agonist temic calcium homeostasis (homeostasis is achieved with (VDRag) dose was kept constant. However, subsequent clinical lower concentrations of ionized calcium). [8]. This enables a studies have confirmed the PTH-lowering effect of cinacalcet decrease in plasma PTH levels, and consequently of calcium used in varying or constant doses of VDRags. This is an impor- levels (Table 1). Additionally, lower levels of phosphorus and tant finding considering that, in clinical practice, cinacalcet is calcium  phosphorus are also seen [9], demonstrating the used often with VDRags [17]. Adverse effects of cinacalcet are capability of calcimimetics to improve the four critical disease described in Table 2. biomarkers associated with SHPT (the phosphorus- and cal- Besides its suppressive effect on PTH levels, data suggest cium-lowering effect distinguishes calcimimetics from active that cinacalcet treatment can induce a volume reduction of the vitamin D) [10]. enlarged parathyroid glands with nodular hyperplasia seen in First-generation compounds include phenylalkylamines R- SHPT patients [18]. 567 and R-568, which were tested in haemodialysis patients, but pharmacokinetics issues halted further clinical development [7]. Second-generation calcimimetic drugs include cinacalcet Cinacalcet reduces FGF-23 levels and others that have never achieved clinical use, such as calin- FGF-23 levels have been associated with adverse clinical out- dol and AC-265347. Cinacalcet hydrochloride was the first comes [19–24] such as progression of CKD, arterial calcification, Type 2 calcimimetic to be approved for clinical use [11]. left ventricle hypertrophy, cardiovascular events and increased Treatment with cinacalcet effectively reduces PTH, calcium mortality. Pharmacologic intervention capable of reducing FGF- and phosphorus [12]. More than 10 years since its approval, 23 would hold the promise of having a beneficial effect on these cinacalcet has been demonstrated to effectively reduce PTH and important clinical outcomes. improve biochemical control of CKD-MBD. Etelcalcetide is a new second-generation calcimimetic. As a CUPID (Cinacalcet Study for Peritoneal Dialysis Patients in Double Arm On the Lowing Effect of iPTH level), a prospective novel intravenous formulation with a pharmacokinetic profile that allows thrice-weekly dosing (at the time of haemodialysis), RCT that evaluated the effect of cinacalcet on FGF-23 levels [25], etelcalcetide was developed to improve efficacy and adherence, enrolled patients that had been on peritoneal dialysis for >3 and reduce gastrointestinal adverse effects relative to cinacalcet. months and had PTH >300 pg/mL. Patients were randomized to Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 82 | L. Pereira et al. Table 2. Lateral effects of calcimimetic agents and suggested actions to take Side effect Frequency Proposed action Gastrointestinal events Nausea Very common Give cinacalcet with main meal after dialysis/in the evening Vomiting Very common Decrease or fractionate the dose if symptoms appear after a dose Diarrhoea and dyspepsia Uncommon increase Anorexia Common Caution is advised with anti-emetics, including metoclopramide (QT prolongation) Hypocalcaemia and nervous system disorders Hypocalcaemia Common Withhold or reduce cinacalcet until serum calcium levels reach 8 mg/ Dizziness and paraesthesia Common dL or symptoms have resolved Seizures Uncommon Use of calcium-based phosphate binders, vitamin D sterols or adjust- ments of dialysis fluid calcium have been suggested by some authors, according to clinical judgement Others Skin and cutaneous disorders, rash Common Seek other causes; consider discontinuing drug Musculoskeletal, connective tissue Common Seek other causes; consider discontinuing drug and bone disorders, myalgia Immune system disorders, Uncommon Seek other causes; consider discontinuing drug hypersensitivity reactions cinacalcet therapy or vitamin D. The cinacalcet group had a risk of cardiovascular mortality (P < 0.001), sudden death (P < reduction in FGF-23 levels (3960–2325 RU/mL), whereas the con- 0.001) and heart failure (P ¼ 0.04). trol group had an increase in FGF-23 concentration (2085–2415 RU/mL). ACHIEVE (ACHIEVE: Optimizing the Treatment of SHPT: Cinacalcet and fractures A Comparison of Sensipar and Low Dose Vitamin D vs Patients with CKD have increased risk of fractures compared Escalating Doses of Vitamin D Alone)—a Phase 4, open-label, with the general population [30, 31]. There is also a high rate of placebo-controlled, multicentre, RCT—was designed to compare death and hospitalization following bone fracture among hae- treatment results with escalating doses of cinacalcet plus fixed modialysis patients [32]. Abnormalities in bone structure, which low-dose calcitriol (cinacalcet-D group) versus calcitriol alone affect bone quality, are observed in patients with CKD-MBD. (Flex-D group) [26]. Using the data of 91 subjects from this study, Malluche et al. demonstrated that bone with high turnover had Wetmore et al. verified that the percentage change of FGF-23 material and nanomechanical abnormalities such as a reduced between the two groups differed significantly (P ¼ 0.002) [27]. mineral to matrix ratio [33]. Such turnover-related alterations in In the cinacalcet-D group, the percentage change decreased bone quality may contribute to the diminished mechanical (9.7 6 18.2; P ¼ 0.021), while an increase was found in the Flex- competence of bone in CKD. D group; however, the results were not significant (4.1 6 16.5). In their single centre cohort study, Iimori et al. [34] demon- The mechanism underlying the ability of cinacalcet to strated a U-shaped correlation between PTH level and risk of decrease FGF-23 levels remains to be clarified. The CUPID inves- fracture; only decreased [PTH <150 pg/mL; hazard ratio (HR) tigators concluded that cinacalcet treatment was independently 3.27] or increased levels were related to a superior hazard of associated with FGF-23 reduction, and not related to the drug’s clinical fracture (PTH >300 pg/mL; HR 2.69). effects on PTH, calcium and phosphorus serum levels. Others To date, no RCT has been specifically designed to evaluate have observed that the decrease of FGF-23 levels is concomitant whether any compounds used in the treatment of SHPT (phos- with the decrease in phosphorus levels (but not to PTH or cal- phate binders, vitamin D analogues or calcimimetics) decrease cium levels) [28]. Wetmore et al. suggested that calcium and the risk of fracture in CKD patients. However, treatment with phosphorus are responsible for cinacalcet’s effect on FGF-23 lev- cinacalcet has been associated with reduced risk of fractures. A els [27]. Further investigation is needed in order to understand combined post hoc analysis of safety data from four Phase 3 exactly how cinacalcet therapy results in a greater reduction of RCTs enrolling 1184 patients with end-stage renal disease serum FGF-23 when compared with traditional drugs. (ESRD) and uncontrolled SHPT (defined as PTH >300 pg/mL) Recently, a post hoc evaluation of the EVOLVE (Evaluation of showed that randomization to cinacalcet, in addition to conven- Cinacalcet Hydrochloride Therapy to LowerCardiovascularEvents) tional treatment with active vitamin D, resulted in a significant study added some more information to the FGF-23 issue [29]. reduction in the risk of fracture [relative risk (RR) 0.46, 95% CI When analysing the results from the cinacalcet-treated patient 0.22–0.95, P ¼ 0.04] compared with placebo and conventional group (n ¼ 1338), a decrease in FGF-23 levels was seen (5555–2255 treatment [35]. pg/mL; P < 0.001), in contrast to the control group (n ¼ 1264), where In the EVOLVE trial, in the intention-to-treat (ITT) analysis, levels remained unchanged (5600–5580 pg/mL). Moreover, when cinacalcet did not significantly reduced the risk of fractures [36]. compared with the control group, a larger proportion of patients in During the study, more than two-thirds of patients in both the cinacalcet group had a meaningful decline (30%) of FGF-23 groups discontinued the treatment, so a predetermined lag- (28% versus 64%; P < 0.001). This finding is relevant because the censoring analysis (censoring time >6 months after stopping 30% reduction of FGF-23 levels was associated with a decreased the study drug) was performed and a relative hazard for fracture Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Old and new calcimimetics | 83 of 0.72 (95% CI 0.58–0.90; P ¼ 0.003) was obtained. When partici- vitamin D (n ¼ 180) or flexible doses of vitamin D alone pants were censored at the time of co-interventions, such as (n ¼ 180). The primary endpoint was a change in the Agatston parathyroidectomy and kidney transplant, the relative hazard Total CAC score (which uses the concept of plaque density and was 0.71 (95% CI 0.58–0.87; P ¼ 0.001). Moreover, when consider- therefore reflects the amount of calcium deposited within a cal- ing the risk of all clinical fractures (not only the first, but also cified lesion). The median percent increase in Agatston total subsequent ones) the multivariable-adjusted relative hazard CAC score was 24% for the cinacalcet plus vitamin D group and was 0.83 (95% CI 0.72–0.98; P ¼ 0.02). They concluded that, when 31% for in the vitamin D group (stratified median treatment dif- considering events prompting discontinuation of the study ference¼10.3%; 95% CI 22.6% to 0.8%; P ¼ 0.073). Similarly, drug, such as co-interventions and cumulative clinical frac- Agatston score changes in the thoracic aorta and mitral valve tures, cinacalcet reduced the rate of clinical fracture by 17–29% were not statistically significant. The aortic valve, on the other [36]. These data provide suggestive evidence that cinacalcet hand, had a stratified median treatment difference of 44.7% reduces the risk of fracture in patients with SHPT. (95% CI 85.8% to 6.1%; P ¼ 0.014). This effect of cinacalcet in reducing fractures is not a sur- The ADVANCE study had some limitations. A substantial prising one considering two reports that used bone histomorph- number of patients assigned to the cinacalcet group received ometry from different groups to describe improved histology in doses of vitamin D that were higher than specified in the proto- patients treated with cinacalcet [37, 38]. In the BONAFIDE (Bone col. A post hoc analysis [46] comparing CAC progression among Biopsy Study for Dialysis Patients with SHPT of End Stage Renal protocol-adherent patients treated with cinacalcet showed that Disease) study [38], dialysis patients with PTH >300 pg/mL and the percentage increase in CAC and aortic valve calcification biopsy-proven high-turnover bone disease were treated with was significantly slower in the cinacalcet group. Other cinacalcet and a second bone biopsy was performed after 6–12 limitations included the open-label design and short period of months of cinacalcet treatment. Bone formation and bone reab- follow-up (12 months, which is unlikely to be sufficient for the sortion indices were improved; most impressive was that the detection of substantial changes in vascular calcification). number of patients with normal bone histology increased from Finally, the reduced observed calcification progression could none at baseline to 20 at 12 months. not be solely attributed to cinacalcet; the lower doses from vita- The role of bone mineral density (BMD) evaluation in chronic min D sterols in the cinacalcet group also have to be considered. kidney patients is evolving. Unlike previous versions, the cur- rent KDIGO (Kidney Disease: Improving Global Outcomes) Cinacalcet, cardiovascular disease and guidelines suggest that BMD testing is undertaken in patients with CKD G3a-G5D with CKD-MBD and/or risk factors for osteo- all-cause mortality porosis if results will impact therapeutic decisions [39]. Elevated serum levels of phosphorus, calcium, PTH and FGF-23 Evidence-based information is scarce about the effect of cina- have been linked to death and cardiovascular outcomes [47–49]. calcet on BMD in CKD patients. Some of the available data have In a post hoc analysis, Cunningham et al. [35] combined data on shown a positive effect of cinacalcet on BMD, namely on the clinical outcomes from four Phase 3 RCTs and showed that femoral neck [40] and proximal femur [41]. However, others treatment with cinacalcet resulted in a significant reduction in have revealed that cinacalcet therapy shows no effect on BMD the risk of cardiovascular hospitalization (HR 0.61; 95% CI 0.43– of the lumbar spine [41] or has a detrimental effect with associ- 0.86) and a non-significant tendency to reduce all-cause mortal- ated bone loss on the femoral neck and lumbar spine [42]. The ity. Another observational study, including 19 186 haemodialy- effect and significance of cinacalcet on BMD remains to be sis patients from a large dialysis provider [50] receiving clarified. intravenous vitamin D analogues (as a surrogate for the diagno- sis of SHPT), found that treatment with cinacalcet was associ- Cinacalcet and vascular calcification ated with significant reductions in all-cause and cardiovascular mortality, with more pronounced survival benefits found in SHPT is associated with vascular calcification. Once established patients with SHPT of greater severity. In a prospectively obser- in haemodialysis patients, it generally progresses much faster vational study, Block et al.[50] described a significant survival than in the general population, leading to increased risk of all- benefit associated with cinacalcet prescription. These observa- cause and cardiovascular mortality [2]. tions and those of others [51, 52] led to the development of a In a single-centre prospective cohort study (n ¼ 23), prospective RCT evaluating the effect of cinacalcet treatment on Nakayama et al. [43] evaluated the impact of cinacalcet on cardiovascular mortality. The EVOLVE [53] study was an RCT abdominal aortic calcification by calculating the aortic calcifica- that enrolled 3883 haemodialysis patients with moderate to tion area index (ACAI) before and after treatment (12, 0, 12, 24 severe SHPT (median PTH 693 pg/mL) assigned to receive cina- and 36 months). The mean ACAI values were not decreased dur- calcet (n ¼ 1948) or placebo (n ¼ 1935). All patients were eligible ing the observation period (21.4% at baseline, 23.9% at 12 to receive conventional treatment including phosphate binders months, 23.7% at 24 months and 24.3% at 36 months). In addi- and vitamin D sterols. The primary composite endpoint was tion, Tsuruta et al. [44] compared coronary artery calcification time until death, myocardial infarction, hospitalization for (CAC) in cinacalcet (n ¼ 8) and control (n ¼ 60) groups, verifying unstable angina, heart failure or a peripheral vascular event. In a decrease (0.094/year) in the CAC score when cinacalcet was an unadjusted ITT analysis, the primary endpoint was reached used, while opposite was seen in the control group the (þ0.034/ in 48.2% of patients in the cinacalcet group and 49.2% in the pla- year). However, the results were not statistically significant cebo group (relative HR in the cinacalcet group 0.93; 95% CI 0.85– (P ¼ 0.102). The ADVANCE (A Randomized Study to Evaluate the Effects 1.02; P ¼ 0.11). After adjusting for baseline characteristics, the relative HR for the primary composite endpoint was 0.88 (95% CI of Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects with CKD) study [45] compared vascular and cardiac 0.79–0.97; P ¼ 0.008). In fact, despite randomization, there was valve calcification progression in 360 adult haemodialysis an unexpected 1-year difference in age between groups (median patients with SHPT, treated either with cinacalcet plus low-dose age 55 years in the cinacalcet group and 54 years in the placebo Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 84 | L. Pereira et al. Table 3. Comparison between cinacalcet and etelcalcetide Cinacalcet Etelcalcetide Class Calcimimetic Calcimimetic Year of approval (Europe) 2004 2016 Mechanism of action Interacts with membrane-spanning segments of Peptide agonist of the CaSR that interacts with and CaSR and enhances signal transduction, thereby activates the receptor, thereby reducing PTH reducing PTH secretion secretion Mode of administration Daily oral IV at the end of dialysis Half-life 30–40 h >7 days Excretion Renal (80%), faecal (15%) Renal Interaction with CYPs Metabolized by CYP3A4, and to a lesser extent No significant interactions CYP1A2; inhibits CYP2D6 (caution is advised when prescribing potentially interacting drugs) Daily dosing (starting; maximal) 30–180 mg 2.5–15 mg/dialysis Efficacy endpoints >30% reduction from baseline in 63.9 77.9 mean serum PTH level during the EAP >50% reduction from baseline in 40 52 (P¼ 0.001) mean serum PTH during the EAP Adverse effects Nausea 22.6 18.3 Vomiting 13.8 13.3 Diarrhoea 10.3 6.2 Headache 7.0 6.5 Hypertension 6.7 6.2 Hypotension 2.9 6.8 Muscle spasms 5.9 6.5 Pain in extremity 4.1 5.0 Asymptomatic hypocalcaemia 59.8 68.9 Symptomatic hypocalcaemia 2.3 5.0 Values are expressed as percentage unless indicated otherwise. EAP, efficacy assessment phase. group). As age is one of the strongest predictions of death, this patients were derived from the EVOLVE trial and this meta- difference may have affected the results. Also, the statistical analysis only included the results from primary analysis, with power of the EVOLVE study was affected by high rates of treat- the potential setbacks discussed above. Also, all of trials ment crossover because of discontinuation in the cinacalcet included, except the EVOLVE trial, were small and not specifi- group (dropout) and use of commercially available cinacalcet in cally designed to assess clinically relevant outcomes such as the placebo group (drop-in). A prespecified lag-censoring analy- mortality or cardiovascular events. sis, in which data was censored 6 months after patients stopped cinacalcet, was performed. This analysis found a significant New calcimimetics: etelcalcetide, a step reduction in the risk of primary composite endpoint (HR 0.85; forward 95% CI 0.76–0.95; P ¼ 0.003) and risk of death (HR 0.83; 95% CI 0.73–0.96; P ¼ 0.009) in the cinacalcet group. Etelcalcetide is a novel second-generation calcimimetic agent Another predetermined protocol analysis compared younger that was recently approved for the treatment of SHPT [13]. (<65 years) and older patients (65 years) [54]. Cinacalcet Etelcalcetide is a eight amino acid peptide agonist of CaSR, reduced the risk of death and major cardiovascular events in which binds to CaSR by a covalent disulphide bond that results older but not younger patients (HR 0.70; 95% CI 0.60–0.81 for in the allosteric activation of CaSR and consequently reduces older subjects and HR 0.97; 95% CI 0.86–1.09 for younger the circulating levels of PTH and calcium [56]. In contrast to subjects). cinacalcet, etelcalcetide functions as a direct agonist of CaSR, Although the primary analysis of the EVOLVE trial was nega- slightly activating CaSR even under calcium-free conditions tive, prespecified additional analysis showed significant reduc- (Table 3). However, downstream signalling is stronger in the tion of the risk of death or cardiovascular outcomes, which presence of calcium; thus, the main action of etelcalcetide is suggests a potential benefit of cinacalcet. mediated through its effects as an allosteric activator [57]. Palmer et al. [55] have published a meta-analysis of random- Etelcalcetide has a favourable pharmacokinetic profile, with ized trials that evaluated the effects of calcimimetic therapy on a longer elimination half-life than cinacalcet, and half-life elim- mortality and adverse events in adults with CKD. Including 18 ination that exceeds 7 days in ESRD patients [58]. It is adminis- trials and a total of 7446 patients, they found that cinacalcet tered intravenously at the end of a haemodialysis session; the had little or no effect on all-cause mortality (RR 0.97; 95% CI plasma concentration of etelcalcetide decreases over time but 0.89–1.05) and an imprecise effect on cardiovascular mortality remains relatively constant from 24 h post-dose to the next (RR 0.67; 95% CI 0.16–2.87). The results of this meta-analysis dialysis session [13]. It is a molecule that is dialysable during should be interpreted with caution. More than half of the haemodialysis and, with the doses of etelcalcetide reaching Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Old and new calcimimetics | 85 Fig. 1. Parathyroid hormone, calcium and phosphate concentrations in patients receiving cinacalcet or etelcalcetide. Reproduced with permission from Block et al. [62]. between 2.5 and 5 mg at the end of a dialysis session, plasma randomized to etelcalcetide were significantly more likely to concentrations of etelcalcetide reach steady-state by week 4. achieve a PTH level of 300 pg/mL or lower (49.6–53.3% in the Although clinical experience is of course currently limited, etelcalcetide group versus 4.6–5.1% in the placebo group). The in vitro data show that etelcalcetide is not an inhibitor, inducer median dose of etelcalcetide during the efficacy assessment or substrate of hepatic cytochrome (CYP) enzymes, nor is it an phase was 5.0 and 7.1 mg, respectively. Patients randomized to inhibitor or substrate of common efflux and uptake human etelcalcetide were more likely to experience substantial lower- transport proteins such as P-glycoprotein [59]. Thus, etelcalce- ing of FGF-23 despite more frequent provision of calcium and tide is expected to have a low risk for CYP or transporter- vitamin D. Treatment with etelcalcetide decreased bone- mediated drug interactions. specific alkaline phosphatase and collagen Type 1 cross-linked The immunogenicity risk of etelcalcetide has been evaluated C-telopeptide. Patients randomized to etelcalcetide had more [60]. While both preexisting anti-etelcalcetide antibodies and muscle spasms, nausea and vomiting than the placebo group. those that developed after treatment were detected, no conse- Hypocalcaemia occurred in 63.8% of patients, but symptomatic quences have been reported regarding the clinical exposure, hypocalcaemia was reported in only 7% of patients assigned to efficacy or safety of etelcalcetide. etelcalcetide. Similar results were obtained in a placebo- Pivotal trials testing etelcalcetide in the treatment of SHPT controlled trial from Japan, which tested the efficacy and safety were recently published [61, 62]. Two parallel Phase 3 placebo- of etelcalcetide [63]. controlled trials were conducted in 1023 haemodialysis patients A randomized double-bind, double-dummy active clinical with moderate to severe hyperparathyroidism. Intravenous trial has been conducted that compared intravenous etelcalce- administration of etelcalcetide (n¼ 503) or placebo (n¼ 513) after tide versus oral placebo and oral cinacalcet versus intravenous each haemodialysis session for 26 weeks was performed. placebo in 683 haemodialysis patients with PTH higher than 500 Patients randomized to etelcalcetide were significantly more pg/mL [62]. The primary efficacy endpoint was non-inferiority likely to achieve the primary efficacy endpoint (a reduction of etelcalcetide at achieving more than a 30% reduction from >30% in baseline PTH: 74.0–75.3% in the etelcalcetide group ver- baseline in mean predialysis PTH concentration, and secondary sus 8.3–9.6% in the placebo group). In addition, patients endpoints included superiority in achieving biochemical Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 86 | L. Pereira et al. endpoints (>50% and >30% reduction in PTH) and self-reported However, the effect of cinacalcet on hard outcomes remains to nausea or vomiting. Etelcalcetide was not inferior to cinacalcet be proved. in reducing PTH concentration and also met superior criteria. Etelcalcetide, a new second-generation calcimimetic, is superior to cinacalcet in achieving the reduction of PTH and The proportion of patients who achieved >30% PTH reduction FGF-23 concentrations in ESRD patients, but also leads to more was 68.2% in the etelcalcetide group and 57.7% in the cinacalcet frequent episodes of hypocalcaemia that could be more pro- group (Figure 1). There was also a significant difference in the nounced at beginning of treatment. Etelcalcetide is given at the proportion of patients who achieved >50% reduction of PTH. end of haemodialysis sessions, which improves medication Hypocalcaemia was more frequent in etelcalcetide group (68.9% adherence and reduces pill burden. However, etelcalcetide does versus 59.8%) and the mean number of days of vomiting or nau- not seem to cause fewer gastrointestinal symptoms despite sea were not significantly different. Overall safety and tolerabil- intravenous administration. ity between etelcalcetide and cinacalcet were similar. There In our view, etelcalcetide represents a significant advance in was a numerically higher number of heart failure episodes in the treatment of SHPT, via better control of PTH and FGF-23 lev- the etelcalcetide group, but overall the event rates were very els and improved adherence. However, whether this improved low and similar to those observed in the EVOLVE trial. biochemical control translates into improved clinical outcomes The effect of etelcalcetide on FGF-23 levels is also notewor- such as bone fracture rate and cardiovascular morbidity and thy. Etelcalcetide treatment yielded a more pronounced mortality remains to be elucidated by prospective randomized reduction in FGF-23 levels than cinacalcet. As discussed above, trials. FGF-23 is elevated in CKD patients and has been associated with adverse outcomes such as left ventricular hypertrophy and cardiac failure. In the EVOLVE trial, a 30% reduction of FGF-23 Conflicts of interest statement levels was associated with significant reduction of the primary None declared. composite endpoint, heart failure and death [29]. This promis- ing finding in the etelcalcetide group raises the possibility of a more pronounced impact on cardiovascular outcomes. 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Critical cysteine resi- dues in both the calcium-sensing receptor and the allosteric cimimetic, for secondary hyperparathyroidism in Japanese activator amg 416 underlie the mechanism of action. Mol haemodialysis patients. Nephrol Dial Transplant 2017; 32: Pharmacol 2015; 88: 853–865 1723–1730 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Old and new calcimimetics for treatment of secondary hyperparathyroidism: impact on biochemical and relevant clinical outcomes

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Abstract

Secondary hyperparathyroidism (SHPT) is associated with increased bone turnover, risk of fractures, vascular calcifications, and cardiovascular and all-cause mortality. The classical treatment for SHPT includes active vitamin D compounds and phosphate binders. However, achieving the optimal laboratory targets is often difficult because vitamin D sterols suppress parathyroid hormone (PTH) secretion, while also promoting calcium and phosphate intestinal absorption. Calcimimetics increase the sensitivity of the calcium-sensing receptor, so that even with lower levels of extracellular calcium a signal can still exist, leading to a decrease of the set-point for systemic calcium homeostasis. This enables a decrease in plasma PTH levels and, consequently, of calcium levels. Cinacalcet was the first calcimimetic to be approved for clinical use. More than 10 years since its approval, cinacalcet has been demonstrated to effectively reduce PTH and improve biochemical control of mineral and bone disorders in chronic kidney patients. Three randomized controlled trials have analysed the effects of treatment with cinacalcet on hard clinical outcomes such as vascular calcification, bone histology and cardiovascular mortality and morbidity. However, a final conclusion on the effect of cinacalcet on hard outcomes remains elusive. Etelcalcetide is a new second-generation calcimimetic with a pharmacokinetic profile that allows thrice-weekly dosing at the time of haemodialysis. It was recently approved in Europe, and is regarded as a second opportunity to improve outcomes by optimizing treatment for SHPT. In this review, we summarize the impact of cinacalcet with regard to biochemical and clinical outcomes. We also discuss the possible implications of the new calcimimetic etelcalcetide in the quest to improve outcomes. Key words: calcimimetic agents, chronic kidney disease, cinacalcet, etelcalcetide, secondary hyperparathyroidism prevalence of 8–16% [1]. During the course of CKD, the decline in Introduction renal function is accompanied by the development of disorders Chronic kidney disease (CKD) is rapidly becoming a public health of calcium and phosphate metabolism, leading to the well- issue, with increasing incidence and estimated worldwide known condition ‘Mineral Bone Disease associated with CKD’ Received: July 6, 2017. Editorial decision: August 18, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Old and new calcimimetics | 81 Table 1. Effect of PTH-suppressive therapies on biochemical (CKD-MBD) [2]. This condition develops due to the inability of the parameters kidney to excrete phosphate properly, leading to its retention and accumulation, which stimulates fibroblast growth factor 23 (FGF- PTH Calcium Phosphorus FGF-23 23) and serum parathyroid hormone (PTH) [3]. FGF-23, a peptide hormone produced mainly in the osteocytes, is able to reduce Vitamin D analogues #" " " phosphate levels using three different pathways: increased renal Cinacalcet ## # # excretion, PTH stimulation and calcitriol synthesis inhibition. Etelcalcetide ## ## # ## The latter promotes decreased gastrointestinal absorption of phosphate and calcium, leading to hypocalcaemia. The low calci- triol levels and hypocalcaemia also stimulate PTH secretion in It was recently approved in Europe, and is regarded as a second the parathyroid glands and induce the development of parathy- opportunity to improve outcomes in CKD-MBD patients by roid gland hyperplasia and secondary hyperparathyroidism optimizing treatment for SHPT using this promising new (SHPT). calcimimetic [13]. SHPT is associated with increased bone turnover, risk of In this review, we summarize the impact of cinacalcet in bio- fractures, vascular calcifications and, most importantly, risk of chemical and relevant clinical outcomes such as cardiovascular cardiovascular and all-cause mortality [4]. Recent observational mortality, vascular calcifications and fractures. We also discuss data indicate that PTH >600 pg/mL is associated with a higher the possible implications of the new calcimimetic etelcalcetide risk of cardiovascular mortality as well as all-cause cardiovas- in the quest to improve outcomes for CKD patients. cular hospitalization [5]. It is interesting to note that patients have better outcomes the longer the time that they have PTH Cinacalcet effectively controls SHPT within recommended levels. Indeed, consistent control of bone metabolism parameters, including PTH, within published rec- Cinacalcet’s efficacy and safety has been tested in several ommended targets is a strong predictor of survival in haemo- randomized controlled trials (RCTs) [11, 12, 14]. Cinacalcet treat- dialysis patients [6]. ment in addition to active vitamin D in patients with SHPT that The classical treatment for SHPT includes active vitamin D is inadequately controlled despite standard therapy effectively compounds and phosphate binders (to limit its gastrointestinal decreases PTH levels, while also reducing serum calcium and phosphate absorption) [7]. However, achievement of optimal phosphorus. Post hoc analysis has demonstrated that treatment laboratory targets is often difficult because vitamin D sterols with cinacalcet improves the achievement of biochemical tar- suppress PTH secretion, but also promote calcium and phos- gets recomended by international societies [15]. In a meta- phate intestinal absorption. analysis [16] involving eight trials (1429 patients) comparing Calcium-sensing receptor (CaSR) is essential for the mainte- cinacalcet treatment plus standard therapy with placebo plus nance of systemic calcium homeostasis, and has become an standard therapy, end-of-treatment values for PTH [290.49 pg/ excellent target for the treatment of bone and mineral disor- mL, 95% confidence interval (CI) 359.91 to 221.07], calcium ders. Its ligands are called calcimimetics and can be classified (0.85 mg/dL, 95% CI 1.14 to 0.56), phosphorus (0.29 mg/dL, as Type 1 (agonists), such as ionized calcium and other divalent 95% CI 0.50 to 0.08) and calcium  phosphorus product anions that directly stimulate CaSR, or Type 2 (positive allos- 2 2 (7.90 mg /dL , 95% CI 10.25 to 5.54) were significantly lower teric modulators), which bind to a site that is distinct from the with cinacalcet compared with placebo. physiological ligand and increase the sensitivity of CaSR to ion- To allow an objective assessment of the effect of cinacalcet ized calcium, leading to the decrease of the set-point for sys- on lowering PTH, the vitamin D activator receptor agonist temic calcium homeostasis (homeostasis is achieved with (VDRag) dose was kept constant. However, subsequent clinical lower concentrations of ionized calcium). [8]. This enables a studies have confirmed the PTH-lowering effect of cinacalcet decrease in plasma PTH levels, and consequently of calcium used in varying or constant doses of VDRags. This is an impor- levels (Table 1). Additionally, lower levels of phosphorus and tant finding considering that, in clinical practice, cinacalcet is calcium  phosphorus are also seen [9], demonstrating the used often with VDRags [17]. Adverse effects of cinacalcet are capability of calcimimetics to improve the four critical disease described in Table 2. biomarkers associated with SHPT (the phosphorus- and cal- Besides its suppressive effect on PTH levels, data suggest cium-lowering effect distinguishes calcimimetics from active that cinacalcet treatment can induce a volume reduction of the vitamin D) [10]. enlarged parathyroid glands with nodular hyperplasia seen in First-generation compounds include phenylalkylamines R- SHPT patients [18]. 567 and R-568, which were tested in haemodialysis patients, but pharmacokinetics issues halted further clinical development [7]. Second-generation calcimimetic drugs include cinacalcet Cinacalcet reduces FGF-23 levels and others that have never achieved clinical use, such as calin- FGF-23 levels have been associated with adverse clinical out- dol and AC-265347. Cinacalcet hydrochloride was the first comes [19–24] such as progression of CKD, arterial calcification, Type 2 calcimimetic to be approved for clinical use [11]. left ventricle hypertrophy, cardiovascular events and increased Treatment with cinacalcet effectively reduces PTH, calcium mortality. Pharmacologic intervention capable of reducing FGF- and phosphorus [12]. More than 10 years since its approval, 23 would hold the promise of having a beneficial effect on these cinacalcet has been demonstrated to effectively reduce PTH and important clinical outcomes. improve biochemical control of CKD-MBD. Etelcalcetide is a new second-generation calcimimetic. As a CUPID (Cinacalcet Study for Peritoneal Dialysis Patients in Double Arm On the Lowing Effect of iPTH level), a prospective novel intravenous formulation with a pharmacokinetic profile that allows thrice-weekly dosing (at the time of haemodialysis), RCT that evaluated the effect of cinacalcet on FGF-23 levels [25], etelcalcetide was developed to improve efficacy and adherence, enrolled patients that had been on peritoneal dialysis for >3 and reduce gastrointestinal adverse effects relative to cinacalcet. months and had PTH >300 pg/mL. Patients were randomized to Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 82 | L. Pereira et al. Table 2. Lateral effects of calcimimetic agents and suggested actions to take Side effect Frequency Proposed action Gastrointestinal events Nausea Very common Give cinacalcet with main meal after dialysis/in the evening Vomiting Very common Decrease or fractionate the dose if symptoms appear after a dose Diarrhoea and dyspepsia Uncommon increase Anorexia Common Caution is advised with anti-emetics, including metoclopramide (QT prolongation) Hypocalcaemia and nervous system disorders Hypocalcaemia Common Withhold or reduce cinacalcet until serum calcium levels reach 8 mg/ Dizziness and paraesthesia Common dL or symptoms have resolved Seizures Uncommon Use of calcium-based phosphate binders, vitamin D sterols or adjust- ments of dialysis fluid calcium have been suggested by some authors, according to clinical judgement Others Skin and cutaneous disorders, rash Common Seek other causes; consider discontinuing drug Musculoskeletal, connective tissue Common Seek other causes; consider discontinuing drug and bone disorders, myalgia Immune system disorders, Uncommon Seek other causes; consider discontinuing drug hypersensitivity reactions cinacalcet therapy or vitamin D. The cinacalcet group had a risk of cardiovascular mortality (P < 0.001), sudden death (P < reduction in FGF-23 levels (3960–2325 RU/mL), whereas the con- 0.001) and heart failure (P ¼ 0.04). trol group had an increase in FGF-23 concentration (2085–2415 RU/mL). ACHIEVE (ACHIEVE: Optimizing the Treatment of SHPT: Cinacalcet and fractures A Comparison of Sensipar and Low Dose Vitamin D vs Patients with CKD have increased risk of fractures compared Escalating Doses of Vitamin D Alone)—a Phase 4, open-label, with the general population [30, 31]. There is also a high rate of placebo-controlled, multicentre, RCT—was designed to compare death and hospitalization following bone fracture among hae- treatment results with escalating doses of cinacalcet plus fixed modialysis patients [32]. Abnormalities in bone structure, which low-dose calcitriol (cinacalcet-D group) versus calcitriol alone affect bone quality, are observed in patients with CKD-MBD. (Flex-D group) [26]. Using the data of 91 subjects from this study, Malluche et al. demonstrated that bone with high turnover had Wetmore et al. verified that the percentage change of FGF-23 material and nanomechanical abnormalities such as a reduced between the two groups differed significantly (P ¼ 0.002) [27]. mineral to matrix ratio [33]. Such turnover-related alterations in In the cinacalcet-D group, the percentage change decreased bone quality may contribute to the diminished mechanical (9.7 6 18.2; P ¼ 0.021), while an increase was found in the Flex- competence of bone in CKD. D group; however, the results were not significant (4.1 6 16.5). In their single centre cohort study, Iimori et al. [34] demon- The mechanism underlying the ability of cinacalcet to strated a U-shaped correlation between PTH level and risk of decrease FGF-23 levels remains to be clarified. The CUPID inves- fracture; only decreased [PTH <150 pg/mL; hazard ratio (HR) tigators concluded that cinacalcet treatment was independently 3.27] or increased levels were related to a superior hazard of associated with FGF-23 reduction, and not related to the drug’s clinical fracture (PTH >300 pg/mL; HR 2.69). effects on PTH, calcium and phosphorus serum levels. Others To date, no RCT has been specifically designed to evaluate have observed that the decrease of FGF-23 levels is concomitant whether any compounds used in the treatment of SHPT (phos- with the decrease in phosphorus levels (but not to PTH or cal- phate binders, vitamin D analogues or calcimimetics) decrease cium levels) [28]. Wetmore et al. suggested that calcium and the risk of fracture in CKD patients. However, treatment with phosphorus are responsible for cinacalcet’s effect on FGF-23 lev- cinacalcet has been associated with reduced risk of fractures. A els [27]. Further investigation is needed in order to understand combined post hoc analysis of safety data from four Phase 3 exactly how cinacalcet therapy results in a greater reduction of RCTs enrolling 1184 patients with end-stage renal disease serum FGF-23 when compared with traditional drugs. (ESRD) and uncontrolled SHPT (defined as PTH >300 pg/mL) Recently, a post hoc evaluation of the EVOLVE (Evaluation of showed that randomization to cinacalcet, in addition to conven- Cinacalcet Hydrochloride Therapy to LowerCardiovascularEvents) tional treatment with active vitamin D, resulted in a significant study added some more information to the FGF-23 issue [29]. reduction in the risk of fracture [relative risk (RR) 0.46, 95% CI When analysing the results from the cinacalcet-treated patient 0.22–0.95, P ¼ 0.04] compared with placebo and conventional group (n ¼ 1338), a decrease in FGF-23 levels was seen (5555–2255 treatment [35]. pg/mL; P < 0.001), in contrast to the control group (n ¼ 1264), where In the EVOLVE trial, in the intention-to-treat (ITT) analysis, levels remained unchanged (5600–5580 pg/mL). Moreover, when cinacalcet did not significantly reduced the risk of fractures [36]. compared with the control group, a larger proportion of patients in During the study, more than two-thirds of patients in both the cinacalcet group had a meaningful decline (30%) of FGF-23 groups discontinued the treatment, so a predetermined lag- (28% versus 64%; P < 0.001). This finding is relevant because the censoring analysis (censoring time >6 months after stopping 30% reduction of FGF-23 levels was associated with a decreased the study drug) was performed and a relative hazard for fracture Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Old and new calcimimetics | 83 of 0.72 (95% CI 0.58–0.90; P ¼ 0.003) was obtained. When partici- vitamin D (n ¼ 180) or flexible doses of vitamin D alone pants were censored at the time of co-interventions, such as (n ¼ 180). The primary endpoint was a change in the Agatston parathyroidectomy and kidney transplant, the relative hazard Total CAC score (which uses the concept of plaque density and was 0.71 (95% CI 0.58–0.87; P ¼ 0.001). Moreover, when consider- therefore reflects the amount of calcium deposited within a cal- ing the risk of all clinical fractures (not only the first, but also cified lesion). The median percent increase in Agatston total subsequent ones) the multivariable-adjusted relative hazard CAC score was 24% for the cinacalcet plus vitamin D group and was 0.83 (95% CI 0.72–0.98; P ¼ 0.02). They concluded that, when 31% for in the vitamin D group (stratified median treatment dif- considering events prompting discontinuation of the study ference¼10.3%; 95% CI 22.6% to 0.8%; P ¼ 0.073). Similarly, drug, such as co-interventions and cumulative clinical frac- Agatston score changes in the thoracic aorta and mitral valve tures, cinacalcet reduced the rate of clinical fracture by 17–29% were not statistically significant. The aortic valve, on the other [36]. These data provide suggestive evidence that cinacalcet hand, had a stratified median treatment difference of 44.7% reduces the risk of fracture in patients with SHPT. (95% CI 85.8% to 6.1%; P ¼ 0.014). This effect of cinacalcet in reducing fractures is not a sur- The ADVANCE study had some limitations. A substantial prising one considering two reports that used bone histomorph- number of patients assigned to the cinacalcet group received ometry from different groups to describe improved histology in doses of vitamin D that were higher than specified in the proto- patients treated with cinacalcet [37, 38]. In the BONAFIDE (Bone col. A post hoc analysis [46] comparing CAC progression among Biopsy Study for Dialysis Patients with SHPT of End Stage Renal protocol-adherent patients treated with cinacalcet showed that Disease) study [38], dialysis patients with PTH >300 pg/mL and the percentage increase in CAC and aortic valve calcification biopsy-proven high-turnover bone disease were treated with was significantly slower in the cinacalcet group. Other cinacalcet and a second bone biopsy was performed after 6–12 limitations included the open-label design and short period of months of cinacalcet treatment. Bone formation and bone reab- follow-up (12 months, which is unlikely to be sufficient for the sortion indices were improved; most impressive was that the detection of substantial changes in vascular calcification). number of patients with normal bone histology increased from Finally, the reduced observed calcification progression could none at baseline to 20 at 12 months. not be solely attributed to cinacalcet; the lower doses from vita- The role of bone mineral density (BMD) evaluation in chronic min D sterols in the cinacalcet group also have to be considered. kidney patients is evolving. Unlike previous versions, the cur- rent KDIGO (Kidney Disease: Improving Global Outcomes) Cinacalcet, cardiovascular disease and guidelines suggest that BMD testing is undertaken in patients with CKD G3a-G5D with CKD-MBD and/or risk factors for osteo- all-cause mortality porosis if results will impact therapeutic decisions [39]. Elevated serum levels of phosphorus, calcium, PTH and FGF-23 Evidence-based information is scarce about the effect of cina- have been linked to death and cardiovascular outcomes [47–49]. calcet on BMD in CKD patients. Some of the available data have In a post hoc analysis, Cunningham et al. [35] combined data on shown a positive effect of cinacalcet on BMD, namely on the clinical outcomes from four Phase 3 RCTs and showed that femoral neck [40] and proximal femur [41]. However, others treatment with cinacalcet resulted in a significant reduction in have revealed that cinacalcet therapy shows no effect on BMD the risk of cardiovascular hospitalization (HR 0.61; 95% CI 0.43– of the lumbar spine [41] or has a detrimental effect with associ- 0.86) and a non-significant tendency to reduce all-cause mortal- ated bone loss on the femoral neck and lumbar spine [42]. The ity. Another observational study, including 19 186 haemodialy- effect and significance of cinacalcet on BMD remains to be sis patients from a large dialysis provider [50] receiving clarified. intravenous vitamin D analogues (as a surrogate for the diagno- sis of SHPT), found that treatment with cinacalcet was associ- Cinacalcet and vascular calcification ated with significant reductions in all-cause and cardiovascular mortality, with more pronounced survival benefits found in SHPT is associated with vascular calcification. Once established patients with SHPT of greater severity. In a prospectively obser- in haemodialysis patients, it generally progresses much faster vational study, Block et al.[50] described a significant survival than in the general population, leading to increased risk of all- benefit associated with cinacalcet prescription. These observa- cause and cardiovascular mortality [2]. tions and those of others [51, 52] led to the development of a In a single-centre prospective cohort study (n ¼ 23), prospective RCT evaluating the effect of cinacalcet treatment on Nakayama et al. [43] evaluated the impact of cinacalcet on cardiovascular mortality. The EVOLVE [53] study was an RCT abdominal aortic calcification by calculating the aortic calcifica- that enrolled 3883 haemodialysis patients with moderate to tion area index (ACAI) before and after treatment (12, 0, 12, 24 severe SHPT (median PTH 693 pg/mL) assigned to receive cina- and 36 months). The mean ACAI values were not decreased dur- calcet (n ¼ 1948) or placebo (n ¼ 1935). All patients were eligible ing the observation period (21.4% at baseline, 23.9% at 12 to receive conventional treatment including phosphate binders months, 23.7% at 24 months and 24.3% at 36 months). In addi- and vitamin D sterols. The primary composite endpoint was tion, Tsuruta et al. [44] compared coronary artery calcification time until death, myocardial infarction, hospitalization for (CAC) in cinacalcet (n ¼ 8) and control (n ¼ 60) groups, verifying unstable angina, heart failure or a peripheral vascular event. In a decrease (0.094/year) in the CAC score when cinacalcet was an unadjusted ITT analysis, the primary endpoint was reached used, while opposite was seen in the control group the (þ0.034/ in 48.2% of patients in the cinacalcet group and 49.2% in the pla- year). However, the results were not statistically significant cebo group (relative HR in the cinacalcet group 0.93; 95% CI 0.85– (P ¼ 0.102). The ADVANCE (A Randomized Study to Evaluate the Effects 1.02; P ¼ 0.11). After adjusting for baseline characteristics, the relative HR for the primary composite endpoint was 0.88 (95% CI of Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects with CKD) study [45] compared vascular and cardiac 0.79–0.97; P ¼ 0.008). In fact, despite randomization, there was valve calcification progression in 360 adult haemodialysis an unexpected 1-year difference in age between groups (median patients with SHPT, treated either with cinacalcet plus low-dose age 55 years in the cinacalcet group and 54 years in the placebo Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 84 | L. Pereira et al. Table 3. Comparison between cinacalcet and etelcalcetide Cinacalcet Etelcalcetide Class Calcimimetic Calcimimetic Year of approval (Europe) 2004 2016 Mechanism of action Interacts with membrane-spanning segments of Peptide agonist of the CaSR that interacts with and CaSR and enhances signal transduction, thereby activates the receptor, thereby reducing PTH reducing PTH secretion secretion Mode of administration Daily oral IV at the end of dialysis Half-life 30–40 h >7 days Excretion Renal (80%), faecal (15%) Renal Interaction with CYPs Metabolized by CYP3A4, and to a lesser extent No significant interactions CYP1A2; inhibits CYP2D6 (caution is advised when prescribing potentially interacting drugs) Daily dosing (starting; maximal) 30–180 mg 2.5–15 mg/dialysis Efficacy endpoints >30% reduction from baseline in 63.9 77.9 mean serum PTH level during the EAP >50% reduction from baseline in 40 52 (P¼ 0.001) mean serum PTH during the EAP Adverse effects Nausea 22.6 18.3 Vomiting 13.8 13.3 Diarrhoea 10.3 6.2 Headache 7.0 6.5 Hypertension 6.7 6.2 Hypotension 2.9 6.8 Muscle spasms 5.9 6.5 Pain in extremity 4.1 5.0 Asymptomatic hypocalcaemia 59.8 68.9 Symptomatic hypocalcaemia 2.3 5.0 Values are expressed as percentage unless indicated otherwise. EAP, efficacy assessment phase. group). As age is one of the strongest predictions of death, this patients were derived from the EVOLVE trial and this meta- difference may have affected the results. Also, the statistical analysis only included the results from primary analysis, with power of the EVOLVE study was affected by high rates of treat- the potential setbacks discussed above. Also, all of trials ment crossover because of discontinuation in the cinacalcet included, except the EVOLVE trial, were small and not specifi- group (dropout) and use of commercially available cinacalcet in cally designed to assess clinically relevant outcomes such as the placebo group (drop-in). A prespecified lag-censoring analy- mortality or cardiovascular events. sis, in which data was censored 6 months after patients stopped cinacalcet, was performed. This analysis found a significant New calcimimetics: etelcalcetide, a step reduction in the risk of primary composite endpoint (HR 0.85; forward 95% CI 0.76–0.95; P ¼ 0.003) and risk of death (HR 0.83; 95% CI 0.73–0.96; P ¼ 0.009) in the cinacalcet group. Etelcalcetide is a novel second-generation calcimimetic agent Another predetermined protocol analysis compared younger that was recently approved for the treatment of SHPT [13]. (<65 years) and older patients (65 years) [54]. Cinacalcet Etelcalcetide is a eight amino acid peptide agonist of CaSR, reduced the risk of death and major cardiovascular events in which binds to CaSR by a covalent disulphide bond that results older but not younger patients (HR 0.70; 95% CI 0.60–0.81 for in the allosteric activation of CaSR and consequently reduces older subjects and HR 0.97; 95% CI 0.86–1.09 for younger the circulating levels of PTH and calcium [56]. In contrast to subjects). cinacalcet, etelcalcetide functions as a direct agonist of CaSR, Although the primary analysis of the EVOLVE trial was nega- slightly activating CaSR even under calcium-free conditions tive, prespecified additional analysis showed significant reduc- (Table 3). However, downstream signalling is stronger in the tion of the risk of death or cardiovascular outcomes, which presence of calcium; thus, the main action of etelcalcetide is suggests a potential benefit of cinacalcet. mediated through its effects as an allosteric activator [57]. Palmer et al. [55] have published a meta-analysis of random- Etelcalcetide has a favourable pharmacokinetic profile, with ized trials that evaluated the effects of calcimimetic therapy on a longer elimination half-life than cinacalcet, and half-life elim- mortality and adverse events in adults with CKD. Including 18 ination that exceeds 7 days in ESRD patients [58]. It is adminis- trials and a total of 7446 patients, they found that cinacalcet tered intravenously at the end of a haemodialysis session; the had little or no effect on all-cause mortality (RR 0.97; 95% CI plasma concentration of etelcalcetide decreases over time but 0.89–1.05) and an imprecise effect on cardiovascular mortality remains relatively constant from 24 h post-dose to the next (RR 0.67; 95% CI 0.16–2.87). The results of this meta-analysis dialysis session [13]. It is a molecule that is dialysable during should be interpreted with caution. More than half of the haemodialysis and, with the doses of etelcalcetide reaching Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Old and new calcimimetics | 85 Fig. 1. Parathyroid hormone, calcium and phosphate concentrations in patients receiving cinacalcet or etelcalcetide. Reproduced with permission from Block et al. [62]. between 2.5 and 5 mg at the end of a dialysis session, plasma randomized to etelcalcetide were significantly more likely to concentrations of etelcalcetide reach steady-state by week 4. achieve a PTH level of 300 pg/mL or lower (49.6–53.3% in the Although clinical experience is of course currently limited, etelcalcetide group versus 4.6–5.1% in the placebo group). The in vitro data show that etelcalcetide is not an inhibitor, inducer median dose of etelcalcetide during the efficacy assessment or substrate of hepatic cytochrome (CYP) enzymes, nor is it an phase was 5.0 and 7.1 mg, respectively. Patients randomized to inhibitor or substrate of common efflux and uptake human etelcalcetide were more likely to experience substantial lower- transport proteins such as P-glycoprotein [59]. Thus, etelcalce- ing of FGF-23 despite more frequent provision of calcium and tide is expected to have a low risk for CYP or transporter- vitamin D. Treatment with etelcalcetide decreased bone- mediated drug interactions. specific alkaline phosphatase and collagen Type 1 cross-linked The immunogenicity risk of etelcalcetide has been evaluated C-telopeptide. Patients randomized to etelcalcetide had more [60]. While both preexisting anti-etelcalcetide antibodies and muscle spasms, nausea and vomiting than the placebo group. those that developed after treatment were detected, no conse- Hypocalcaemia occurred in 63.8% of patients, but symptomatic quences have been reported regarding the clinical exposure, hypocalcaemia was reported in only 7% of patients assigned to efficacy or safety of etelcalcetide. etelcalcetide. Similar results were obtained in a placebo- Pivotal trials testing etelcalcetide in the treatment of SHPT controlled trial from Japan, which tested the efficacy and safety were recently published [61, 62]. Two parallel Phase 3 placebo- of etelcalcetide [63]. controlled trials were conducted in 1023 haemodialysis patients A randomized double-bind, double-dummy active clinical with moderate to severe hyperparathyroidism. Intravenous trial has been conducted that compared intravenous etelcalce- administration of etelcalcetide (n¼ 503) or placebo (n¼ 513) after tide versus oral placebo and oral cinacalcet versus intravenous each haemodialysis session for 26 weeks was performed. placebo in 683 haemodialysis patients with PTH higher than 500 Patients randomized to etelcalcetide were significantly more pg/mL [62]. The primary efficacy endpoint was non-inferiority likely to achieve the primary efficacy endpoint (a reduction of etelcalcetide at achieving more than a 30% reduction from >30% in baseline PTH: 74.0–75.3% in the etelcalcetide group ver- baseline in mean predialysis PTH concentration, and secondary sus 8.3–9.6% in the placebo group). In addition, patients endpoints included superiority in achieving biochemical Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018 86 | L. Pereira et al. endpoints (>50% and >30% reduction in PTH) and self-reported However, the effect of cinacalcet on hard outcomes remains to nausea or vomiting. Etelcalcetide was not inferior to cinacalcet be proved. in reducing PTH concentration and also met superior criteria. Etelcalcetide, a new second-generation calcimimetic, is superior to cinacalcet in achieving the reduction of PTH and The proportion of patients who achieved >30% PTH reduction FGF-23 concentrations in ESRD patients, but also leads to more was 68.2% in the etelcalcetide group and 57.7% in the cinacalcet frequent episodes of hypocalcaemia that could be more pro- group (Figure 1). There was also a significant difference in the nounced at beginning of treatment. Etelcalcetide is given at the proportion of patients who achieved >50% reduction of PTH. end of haemodialysis sessions, which improves medication Hypocalcaemia was more frequent in etelcalcetide group (68.9% adherence and reduces pill burden. However, etelcalcetide does versus 59.8%) and the mean number of days of vomiting or nau- not seem to cause fewer gastrointestinal symptoms despite sea were not significantly different. Overall safety and tolerabil- intravenous administration. ity between etelcalcetide and cinacalcet were similar. There In our view, etelcalcetide represents a significant advance in was a numerically higher number of heart failure episodes in the treatment of SHPT, via better control of PTH and FGF-23 lev- the etelcalcetide group, but overall the event rates were very els and improved adherence. However, whether this improved low and similar to those observed in the EVOLVE trial. biochemical control translates into improved clinical outcomes The effect of etelcalcetide on FGF-23 levels is also notewor- such as bone fracture rate and cardiovascular morbidity and thy. Etelcalcetide treatment yielded a more pronounced mortality remains to be elucidated by prospective randomized reduction in FGF-23 levels than cinacalcet. As discussed above, trials. FGF-23 is elevated in CKD patients and has been associated with adverse outcomes such as left ventricular hypertrophy and cardiac failure. In the EVOLVE trial, a 30% reduction of FGF-23 Conflicts of interest statement levels was associated with significant reduction of the primary None declared. composite endpoint, heart failure and death [29]. This promis- ing finding in the etelcalcetide group raises the possibility of a more pronounced impact on cardiovascular outcomes. 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Critical cysteine resi- dues in both the calcium-sensing receptor and the allosteric cimimetic, for secondary hyperparathyroidism in Japanese activator amg 416 underlie the mechanism of action. Mol haemodialysis patients. Nephrol Dial Transplant 2017; 32: Pharmacol 2015; 88: 853–865 1723–1730 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/80/4711103 by Ed 'DeepDyve' Gillespie user on 16 March 2018

Journal

Clinical Kidney JournalOxford University Press

Published: Feb 1, 2018

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