Etelcalcetide effectively reduces parathyroid hormone (PTH) levels in patients with poorly controlled secondary hyperparathyroidism (SHPT), according to 3 new studies published in Journal of the American Medical Association. The intravenous (IV), second-generation calcimimetic was recently approved in Europe and is currently under review by the FDA.
In parallel phase 3 trials, 1023 patients with PTH values above 400 pg/mL on conventional treatment were randomly assigned to receive etelcalcetide (titrated up to 15 mg) or placebo thrice-weekly after hemodialysis sessions for 26 weeks. In the first trial, mean PTH values declined from 849 to 384 pg/mL from baseline to weeks 20–27 in the etelcalcetide group compared with an increase from 820 to 897 pg/mL among placebo recipients, Glenn M. Chertow, MD, MPH, of Stanford University in California, and colleagues reported. In the second trial, mean PTH values declined from 845 to 262 pg/mL among etelcalcetide users and increased from 852 to 960 pg/mL in the placebo arm. Etelcalcetide also lowered phosphate and fibroblast growth factor 23 levels.
In both trials, etelcalcetide recipients were more likely to achieve a PTH level of 300 pg/mL or less. In the first trial, 49.6% of etelcalcetide-treated patients achieved this level compared with 5.1% of placebo recipients; in the second trial, the proportions were 53.3% and 4.6%, respectively.
Etelcalcetide recipients also were more likely to achieve the primary efficacy endpoint of a greater than 30% reduction in PTH levels: 74.0% vs 8.3% in the first trial and 75.3% vs 9.6% in the second trial.
In a third trial, the same investigators compared the oral calcimimetic cinacalcet (taken daily) and IV etelcalcetide over 26 weeks in 683 patients with PTH levels above 500 pg/mL. Etelcalcetide, which acts on a distinct site of the parathyroid gland’s calcium-sensing receptor, proved noninferior to cinacalcet in the proportion of patients achieving a more than 30% reduction in PTH: 68.2% vs 57.7%. In addition, 52.4% of etecalcetide patients attained a more than 50% reduction of PTH compared with 40.2% of cinacalcet patients, demonstrating superiority.
Whether greater than 30% reduction in PTH levels is associated with clinical benefits is unknown. The researchers noted that observational studies have shown higher mortality, cardiovascular events, and fractures, in patients with PTH values above 600 pg/mL compared with 150 to 300 pg/mL.
“Although it may be tempting to assume that lowering individual patients’ PTH levels by 30% to 50% or more (and simultaneously lowering serum phosphate and FGF23 levels) will result in commensurate reductions in risk, only randomized trials with hard clinical end points, including mortality, can provide clear answers,” John P. Middleton, MD, and Myles Wolf, MD, MMSc, commented in an accompanying editorial.
Use of cinacalcet in clinical practice has been limited by a high incidence of gastrointestinal side effects, such as nausea and vomiting. Etelcalcetide bypasses the intestines, but all 3 trials reported nausea and vomiting with the drug, including no significant difference with cinacalcet.
Etelcalcetide does not contain calcium as do some other SHPT treatments, which may prevent abnormal calcification. Nearly two-thirds of patients experienced low blood calcium with the drug, however, despite calcium supplements and related therapies. Hypocalcemia symptoms, such as muscle spasms, headache, and paresthesia, were reported by a minority of patients.
Investigators noted prolongation of the QT interval, which may be a result of the low calcium. Longer-term trials are needed to assess the cardiac safety of etelcalcetide. According to the investigators, physicians should use caution when using etelcalcetide with other drugs that may prolong the QT interval.
All of the trials were funded by Amgen, the manufacturers of Parsabiv (etelcalcetide) and Sensipar (cincalcet).
- Block GA, Bushinsky DA, Cheng S, et al. Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism Two Randomized Clinical Trials. JAMA.
- Block GA, Bushinsky DA, Cheng S, et al. Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial. JAMA 2017;317:156-164. doi:10.1001/jama.2016.19468.
- Middleton JP and Wolf M. Second Chances to Improve ESRD Outcomes With a Second-Generation Calcimimetic. JAMA