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Secondary hyperparathyroidism (SHPT) is a chronic compensatory clinical manifestation, stimulated by long-term exposure to low blood calcium, low blood magnesium or high blood phosphorus. SHR6508, an allosteric modulator of calcium-sensing receptor, is developed to reduce parathyroid hormone (PTH) secretion among hemodialysis patients with SHPT. This first-in-patient study aimed to assess SHR6508 in Chinese patients with SHPT of chronic kidney disease on maintenance hemodialysis.
This is a multicenter, randomized, double-blind, placebo-controlled, single and multiple ascending dose (SAD/MAD) study (ClinicalTrials.gov, NCT05221008). Eligible patients with PTH of 400-1300 pg/mL and calcium of ≥2.1 mmol/L (8.4 mg/dL) were randomized in a 4:1 ratio to receive either SHR6508 or placebo by intravenous injection after hemodialysis. The dose levels studied were 5, 10, and 15 mg given three times a week (TIW) for 4 weeks in the MAD cohorts and 30 mg given once in the SAD cohort. Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PTH and calcium) were assessed.
Fifty-four patients were enrolled with mean baseline PTH concentrations ranging from 604.3 to 750.8 pg/mL in the SHR6508 groups and 678.9 pg/mL in the placebo group (placebo-treated patients from all cohorts). Treatment-emergent adverse events (TEAEs) occurred in 41 (95.3%) of 43 SHR6508-treated patients and in all 11 (100%) patients in the placebo group, most of which were mild and moderate in severity. The most commonly reported TEAEs were decreased blood calcium (83.7% for SHR6508 and 27.3% for placebo), hypocalcemia (67.4% and 18.2%) and decreased platelet count (4.7% and 27.3%).
PK parameters were found to be linear and dose-proportional across the evaluated dose range. Plasma SHR6508 showed a multiple exponential decay pattern, with rapid initial distribution followed by slow elimination. TIW dosing of SHR6508 generally resulted in a 3-fold accumulation, as measured by AUC0-t through day 27.
After a single SHR6508 dose, mean PTH levels reached the
SHR6508 was well tolerated and showed promising efficacy in hemodialysis patients with SHPT. A phase Ⅱ study comparing SHR6508 to cinacalcet has been initiated (NCT05663411).