Abstract: TH-OR19
Initial Evaluation of High-Dose Extended-Release Calcifediol (ERC) in Patients with Stage 5 CKD on Hemodialysis (HD)
Session Information
- CKD-MBD Potpourri: Emerging Clinical and Basic Science in Mineral and Bone Disease
November 04, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
Category: Bone and Mineral Metabolism
- 402 Bone and Mineral Metabolism: Clinical
Authors
- Strugnell, Stephen A., OPKO Health Inc, Miami, Florida, United States
- Csomor, Philipp, Vifor Pharma Ltd, Glattbrugg, Zurich, Switzerland
- Ashfaq, Akhtar, OPKO Health Inc, Miami, Florida, United States
- Bishop, Charles W., OPKO Health Inc, Miami, Florida, United States
Background
ERC has been approved since 2016 for treatment of secondary hyperparathyroidism (SHPT) in adults with stage 3-4 CKD and vitamin D insufficiency at weekly doses of 210 or 420 mcg (30 or 60 mcg/day). Conversion of calcifediol to calcitriol by CYP27B1 is thought to occur primarily in the kidney despite expression elsewhere, supporting a belief that normal serum levels of 1,25-dihydroxyvitamin D (1,25D) cannot be maintained with advancing CKD. A phase 2a study explored treatment of end-stage renal disease patients with SHPT requiring regular HD with high strength ERC (150 mcg/capsule). The goals of the study were to: (1) evaluate whether these patients could tolerate a high dose of ERC (900 mcg/week); (2) ascertain whether ERC could normalize serum total 1,25D in the absence of functional kidneys; and (3) determine whether ERC could reduce intact parathyroid hormone (iPTH).
Methods
Adults with stage 5 CKD on regular HD with iPTH ≥150 and <600 pg/mL and serum total 25-hydroxyvitamin D (25D) <30 ng/mL were enrolled from U.S. dialysis centers. Subjects underwent an 8-week washout from previous iPTH-lowering therapies and were randomized to 26 weeks of open-label treatment with ERC (300 mcg thrice weekly during HD) or matching placebo. Serum 25D, 1,25D, calcium (Ca) and phosphorus (P) and plasma iPTH were monitored at the start of HD on a weekly or bi-weekly basis.
Results
A total of 44 subjects were enrolled (33 on ERC and 11 on placebo). ERC-treated subjects attained mean (±SE) steady-state levels of 25D of 161±11 ng/mL vs 30±5.6 with placebo treatment without significant increases in serum Ca or P or the incidence of adverse events compared to placebo. Serum total 1,25D rose into the normal range (62.0±8.3 pg/mL) from undetectable or low baseline levels (10.6±1.5 pg/mL) in direct proportion to elevation of serum total 25D above 50 ng/mL. Significant decreases in iPTH were observed, in particular in patients reaching 25D levels exceeding 50 ng/mL.
Conclusion
ERC was well tolerated at 900 mcg/week, readily activated to calcitriol despite the lack of functional kidneys, and capable of suppressing elevated iPTH levels. These data suggest that extra-renal production of 1,25D can be sufficient to lower iPTH when serum 25D is gradually raised to high levels exceeding 50 ng/mL.
Funding
- Commercial Support – OPKO Health