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. Plain-language Summary Secondary hyperparathyroidism (SHPT) is a common condition among hemodialysis patients. In this phase 1 study, we evaluated the efficacy and safety of SHR6508, a novel intravenous calcimimetic developed to reduce parathyroid hormone secretion in patients with SHPT. SHR6508 effectively lowered parathyroid hormone levels at single dosing of 5-30 mg or thrice weekly dosing of 5-15 mg, and the extent of reduction increased proportionally with increasing doses. Reductions in other disease-related pharmacodynamics biomarkers were also observed, indicating promising efficacy of SHR6508. The treatment was well tolerated, with most of the adverse events being mild in severity. This work supported SHR6508 as a promising treatment for hemodialysis patients with SHPT.