Transforming treatment in the management of SHPT with etelcalcetide
Secondary hyperparathyroidism (SHPT) is a very common condition in patients with chronic kidney disease (CKD).1,2 Cinacalcet, a calcimimetic that is commonly used to treat patients with SHPT, has been recommended by well-recognized guidelines but appears to have some shortfalls with non-adherence issues.3,4 With the newly introduced etelcalcetide, a calcimimetic that is more potent than cinacalcet, there is a possibility that this new treatment can transform the management of SHPT by addressing the gap with the currently available treatment options. Dr. Yuen Sze Kit from the Chinese University of Hong Kong and Prof. John Cunningham from the University College London Medical School shared their insights on management of SPHT in the meeting held on October 11, 2018, in Hong Kong.
Why bother with SHPT?
Parathyroid hormone (PTH) is a hormone produced and secreted from the parathyroid glands. It regulates the homeostasis of calcium. 1 Overstimulation and pathological enlargement results in SHPT.1
SHPT is often seen in patients with CKD, caused by several changes as a result of decreased kidney function, such as a high blood phosphorus (P) level, a low level of active vitamin D produced by the kidney, and a low blood calcium level.1 If SHPT is left untreated, the high PTH level can lead to osteitis fibrosa cystica, calciphylaxis, cardiovascular (CV) complications, abnormal fat and glucose metabolism, pruritis, and anemia, with some of the outcomes being potentially life-threatening.2
As the first speaker of this meeting, Dr. Yuen Sze Kit discussed about the treatment options for SHPT that are currently available as well as the treatment challenges in the healthcare system.
High PTH and its outcomes
To highlight the importance of managing patients with SHPT, Dr. Yuen reminded the audience about the U-shaped correlation between intact PTH and the risk of mortality by quoting a study in Europe.5 The study showed that in patients on hemodialysis (HD), when their intact PTH falls between 300-600pg/mL, the risk of all-cause mortality increased by 28% as compared to those within the Kidney Disease Outcomes Quality Initiative (KDOQI) target range (150-300pg/mL), and the risk is further increased by 53% when intact PTH exceeded 600pg/mL.5
A retrospective study on United States Renal Data System Waves 1, 3, and 4 Study also confirmed the association between PTH levels and mortality as well as CV events.6 On top of that, the risks of CV events and all-cause mortality were the highest in patients with high PTH, P, and calcium (Ca),6 demonstrating the significance of SHPT and justifying the reason for treating it.
Challenges with cinacalcet for SHPT management
There are various types of treatment available to lower the PTH level in SHPT patients, which includes the use of calcitriol or other vitamin D analogs.3 Vitamin D analogs act by increasing Ca reabsorption, ultimately leading to less PTH being secreted by the parathyroid glands.1
Other than vitamin D analogs, there are also treatments that directly act on the parathyroid glands to lower the PTH level, with cinacalcet being one of them. Cinacalcet is a calcimimetic drug given orally that can mimic the action of calcium to increase the sensitivity of calcium-sensing receptors (CaSR) on the parathyroid glands to suppress PTH secretion.7 Cinacalcet reduces the need for parathyroidectomy in patients with CKD stage 5D,7 and it is recommended as a first-line treatment in the Kidney Disease Improving Global Outcome (KDIGO) 2017 guideline.3
Both vitamin D and calcimimetic lower PTH levels in patients with SHPT, but their different mode of action means their effects on the other biochemical parameters is different (summarized in Table 1). Since patients with SHPT consist of a heterogeneous population, the choice of treatment should be carefully assessed base on individual patient’s characteristics.8
Moreover, although cinacalcet is widely used in dialysis patients,7 there are still some concerns with the use of this drug. In a study that aimed to determine the compliance to cinacalcet, it was found that only 29% of the patients were adherent to the treatment regimen.4 Considering that cinacalcet is included in the Hong Kong Hospital Authority drug formulary as a funded drug,9 the low adherence to cinacalcet is merely adding the burden to the already overwhelmed health care system in Hong Kong. Together with the risk of impaired SHPT control running high in patients with poor cinacalcet compliance,4 there is a gap in the SHPT management that needs to be addressed.
Etelcalcetide – the new calcimimetic for SHPT
With the launch of etelcalcetide, a newly developed calcimimetic that is given as an injection for patients with CKD on HD,10 it is hoped that it could be the solution to the non-adherence problem associated with cinacalcet. The second speaker, Prof. John Cunningham continued by discussing etelcalcetide and how it may improve the management of SHPT.
In contrast to cinacalcet which is given orally and bind to the transmembrane region of the CaSR,11 etelcalcetide is given intravenously (IV) that can activate the extracellular domain of the CaSR on the surface of the chief cell of parathyroid glands to enhance signal transduction, which reduces PTH secretion.10
Etelcalcetide has already been tested in two randomized placebo-controlled trials and a randomized head-to-head controlled trial with cinacalcet, and the results were very encouraging.12-14
The two placebo-controlled trials (trial A and trial B) in total recruited 1,023 (trial A, n=508; trial B, n=515) patients with moderate to severe SHPT who were on HD, randomized 1:1 to receive intravenous etelcalcetide or placebo after each HD session for 26 weeks.12 The combined analysis showed a significantly higher proportion in the etelcalcetide arm achieving more than 30% reduction from baseline in their mean PTH during weeks 20-27 (etelcalcetide, 74.7% vs. placebo, 8.9%, p<0.001).14 The proportion of patients who had their PTH level reduced to 300pg/mL or lower was also higher amongst the etelcalcetide arm (etelcalcetide, 51.5% vs. placebo, 4.9%, p<0.001).14,15
Etelcalcetide helped more patients to achieve PTH reductions
The efficacy of etelcalcetide was further supported by evidence from the head-to-head controlled trial, which recruited 683 patients with serum PTH level higher than 500pg/mL, randomized 1:1 to receive either an IV etelcalcetide plus an oral placebo or an oral cinacalcet plus an IV placebo, where the injections were given after each HD session, and the oral drugs were taken daily.13 The results showed that 68.2% of the patients in the etelcalcetide arm achieving PTH reduction of more than 30% during weeks 20-27, a significantly higher proportion than the cinacalcet arm which had 57.7% achieving the endpoint (p for noninferiority<0.001; p for superiority=0.004).13 Furthermore, a higher proportion of patients who received etelcalcetide had more than 50% PTH reduction than those who received cinacalcet (52.4% vs. 40.2%, p=0.001).13 Overall, etelcalcetide appears to be a more potent agent in reducing PTH than cinacalcet (Figure 1).1
Both cinacalcet and etelcalcetide are capable of reducing calcium and phosphate level as shown in the placebo-controlled trials and head-to-head controlled trial. As compared to cinacalcet, etelcalcetide demonstrated a greater Ca and P reduction in the head-to-head trial, presented in Figure 2.
Moreover, confirming the consistency and durability of the drug, a recent study from Japan has demonstrated that etelcalcetide maintained appropriate range of PTH, Ca, and P levels over 52 weeks.16
The safety profile of etelcalcetide
Equally important, etelcalcetide was also demonstrated in the clinical trials to be generally well tolerated with nausea, vomiting, hypocalcemia, and muscle spasms being the most common adverse events.12,13,16
Of note, Prof. Cunningham and his colleagues originally anticipated for less gastrointestinal symptoms than cinacalcet in the head-to-head trial due to the IV route of administration.13 However, the rates of self-reported nausea and vomiting were similar between patients receiving cinacalcet and etelcalcetide.13 “It was a self-reporting process but set up in a way that encourage the patients to report adverse events and gastrointestinal events, and patients were told to expect a gastrointestinal upset,” said Prof. Cunningham, who speculated that the observation could be augmented by the fact that the instrument encouraged over-reporting of these adverse events, whether it was treatment-related or not.
Etelcalcetide, a game changer in the management of SHPT
“[Based on my clinical experience with cinacalcet], probably 40% [of the tablets] actually get thrown away, and it is not taken by the patients for various reasons,” said Prof. Cunningham, who made the point that with cinacalcet, many tablets were wasted due to non-adherence, causing major concern in the health economic sense. However, with etelcalcetide, which is administered IV,10 the compliance will be 100% because health care providers will know whether the drug has been administered. Prof. Cunningham described this major factor as potentially the “game-changing” element of etelcalcetide.
To wrap up for the lecture, Prof. Cunningham asked a question to the audience regarding how long they would treat their patients with SHPT by using calcimimetics, and the results are presented in Figure 3. The results showed that the majority of the audience would treat their patients with calcimimetics for at least one to three months. As a follow-up to the question, Prof. Cunningham recommended that clinicians should consider stopping oral calcimimetics at the first sign of non-adherence, i.e., if good response in PTH level has not been seen after the second increment of the dose titration.
Managing SHPT patients with etelcalcetide
To conclude, etelcalcetide offers a new option for patients and clinicians to manage SHPT without having to worry about non-adherence issues.10 Clinical studies have shown the possibility that the pharmacokinetic difference between etelcalcetide and cinacalcet contributed to the superior efficacy demonstrated over 27 weeks in reducing PTH, as well as the effects on Ca and P. 13 Undoubtedly, etelcalcetide provide another option for patients with characteristics that made them not suitable for receiving vitamin D analogs. In addition to that, the gap created by non-adherence to cinacalcet perhaps can finally be filled with the launch of etelcalcetide.
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