DP-001

2-Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ (DP001 or 2MD) is a novel, potent 1α-hydroxylated vitamin D analog that binds to the vitamin D receptor and suppresses parathyroid hormone synthesis and secretion with potential for an improved safety profile compared to existing active vitamin D analogs. The purpose of this study was to evaluate the pharmacokinetics of DP001 given orally after hemodialysis.

DP001 (550 ng) was given orally to 11 hemodialysis patients with secondary hyperparathyroidism after each dialysis session (3 times/week) for 4 weeks. Pharmacokinetic analyses were performed after the first and final dose.

After the first and final dose, the half-life of DP001 was similar (55.8 ± 13.0 and 50.8 ± 8.2 h, respectively). At 4 weeks, the time to maximum plasma concentration was 4.0 ± 0.8 h, with a concentration maximum of 3.4 ± 0.3 pg/mL. The area under the curve (0 to infinity) after the final dose was 204.3 ± 23.9 pg h/mL, and apparent volume of distribution was 2.03 ± 0.22 L/kg. At week 4, mean intact parathyroid hormone was suppressed 33% from the baseline (pre-dose) value (313 ± 52 vs 462 ± 39 pg/mL, respectively). No clinically significant changes from baseline values were found for vital signs, electrocardiogram measurements, or other laboratory parameters, including serum calcium and phosphorus.

In hemodialysis patients, DP001 has a longer half-life than existing vitamin D therapies and enables control of parathyroid hormone when administered every 2-3 days on the day of dialysis. It is effective at a lower concentration maximum and area under the curve than other clinically available vitamin D compounds. DP001 may represent a therapeutic improvement over existing compounds due to rapid and extensive distribution to its target and its long half-life enabling sustained parathyroid hormone suppression. These studies support further evaluation of DP001 in longer-term treatment of secondary hyperparathyroidism.

Background: Vitamin D analogs and calcimimetics are used to manage secondary hyperparathyroidism (SHPT) in dialysis patients. DP001 is an oral vitamin D analog that suppresses parathyroid hormone (PTH) in uremic rats, osteopenic women, and hemodialysis patients. The safety and effectiveness of DP001 suppressing PTH in dialysis patients previously managed with active vitamin D with or without a calcimimetic are presented. Methods: A multicenter, randomized, double-blind study compared DP001 to placebo in hemodialysis patients with serum-intact PTH (iPTH) ≥300 pg/ml. The primary efficacy endpoint was the proportion of patients achieving 2 consecutive ≥30% decreases in iPTH levels during the 12 weeks of treatment. Calcium, phosphorus, calcium × phosphorus product and safety were also evaluated. The responses to DP001 were compared in patients previously treated with both active vitamin D and a calcimimetic to those previously on active vitamin D alone. Results: Sixty-two patients were randomized (n = 34 DP001; n = 28 placebo). At week 12, 78% of all DP001-treated patients and 7% of all placebo-treated patients achieved the primary endpoint (p < 0.0001); iPTH fell 45% in the DP001 group and increased 37% in the placebo group. No patient exceeded the safety threshold of 2 consecutively corrected serum calcium levels ≥11.0 mg/dl. Patients previously on cinacalcet plus active vitamin D also responded to DP001 (n = 10) resulting in a 55% decrease in iPTH, while those on placebo (n = 9) increased by 70%. <b>Conclusion: DP001 safely and effectively suppressed iPTH in hemodialysis patients with SHPT that were previously managed with active vitamin D alone or with a calcimimetic (www.clinicaltrials.gov, NCT01922843).