Safety, Pharmacokinetics, and Pharmacodynamics of SHR6508, a Calcium-Sensing Receptor Agonist, in Maintenance Hemodialysis Patients With Secondary Hyperparathyroidism: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 1 Study.

RATIONALE &

OBJECTIVE

Secondary hyperparathyroidism (SHPT) is a common health problem among patients receiving maintenance hemodialysis. SHR6508, an allosteric modulator of calcium-sensing receptors, was developed to reduce parathyroid hormone secretion among Chinese hemodialysis patients with SHPT. This study aimed to evaluate the safety, pharmacokinetics, and pharmacodynamics of SHR6508 administered intravenously.

STUDY

DESIGN

This was a multicenter, randomized, double-blind, placebo-controlled single and multiple ascending dose phase 1 trial.

SETTING &

PARTICIPANTS

This study was conducted at 18 sites in China. Hemodialysis patients who had serum intact parathyroid hormone (iPTH) concentration 400-1,300 pg/mL and corrected calcium ≥8.4 mg/dL (2.1 mmol/L) were enrolled.

INTERVENTIONS: Patients were randomized in a 4:1 ratio to receive SHR6508 or placebo by intravenous injection after hemodialysis.

OUTCOMES: The primary outcomes were pharmacokinetic parameters and changes in iPTH and corrected calcium concentrations.

RESULTS

The plasma drug exposures (mean maximum plasma concentration, area under the concentration-time curve) increased proportionally with the dose after the administration of SHR6508. iPTH level declined markedly after a single dose of SHR6508 in all cohorts (5-30 mg). After multiple doses of 5-15 mg, the percentage of patients achieving a reduction in iPTH concentration ≥30% from baseline to week 2 (25.0%-90.9%) and week 4 (36.4%-100.0%) in the 5, 10, and 15 mg groups was higher than those observed in the placebo group (12.5% and 14.3%, respectively). Treatment-emergent adverse events, which were mostly mild or moderate, occurred in 41 (95.3%) SHR6508-treated patients and in all patients treated with placebo.

LIMITATIONS: This study had a relatively small sample size and short treatment and follow-up period.

CONCLUSIONS

SHR6508 showed promising efficacy and safety in Chinese hemodialysis patients with SHPT. A starting dose of 5 mg for titration was the best dose and will be used in the phase 2 study.