The Effect of Recombinant Human Parathyroid Hormone (rhPTH [1-84]) on Phosphate Homeostasis in Patients with Hypoparathyroidism

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 234-256-Bone & Calcium Metabolism: Clinical Trials & Case Series
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-246
Bart Lyman Clarke*1, Dolores M Shoback2, Michael Mannstadt3, Tamara J Vokes4, Hjalmar Lagast5 and John P. Bilezikian6
1Mayo Clinic Rochester, Rochester, MN, 2University of California - San Francisco VA Medical Center, San Francisco, CA, 3Massachusetts General Hospital and Harvard Medical School, Boston, MA, 4University of Chicago, Chicago, IL, 5NPS Pharmaceuticals, Inc, Bedminster, NJ, 6College of Physicians & Surgeons, Columbia University, New York, NY
Patients with hypoparathyroidism tend to have high phosphate (PO4) levels due to the loss of effects of parathyroid hormone (PTH) on the renal proximal tubule to promote PO4 excretion.  Treatment of patients with hypoparathyroidism with calcitriol often exacerbates their hyperphosphatemia by enhancing intestinal PO4 absorption; this tends to worsen the calcium-PO4 product. PTH therapy is expected to improve serum PO4 levels in patients with hypoparathyroidism.  We previously showed that serum calcium can be maintained within a target range with lowered urinary calcium excretion in patients with hypoparathyroidism treated with rhPTH(1-84) (1). Here, we report the effects of rhPTH(1-84) on PO4homeostasis analyzed in 2 rhPTH(1-84) studies.

C09-002 was an acute open-label, phase I dosing study. Patients received 2 rhPTH(1-84) injections (50 or 100 μg per day), separated by >=7 day washout. REPLACE was a double-blind, phase III trial; patients received (2:1 randomization) daily injections of rhPTH(1-84)  at 50 μg/day (escalated to 75 and then to 100 μg/day, if needed) or placebo for 24 weeks. Serum and urine samples were collected at various pre-defined timepoints throughout the study for analyses.

Both studies demonstrated substantial effects of rhPTH(1-84) on serum and urinary PO4 levels. In the phase I study, rhPTH(1-84) injections (50-µg, n=6; 100-µg, n=7) acutely decreased mean serum PO4 levels by a maximum of 1.5 mg/dL within 5 hours. rhPTH(1-84) also increased total 24-hour urinary PO4 excretion by 51% (50-µg) and 60% (100-µg). In REPLACE,  a marked decrease in serum PO4 in the rhPTH(1-84) group followed initiation of study drug and was maintained throughout the treatment period, with serum PO4 declining from baseline of 4.53±0.7 to 4.08±0.7mg/dL at Week 24; serum PO4 did not change from baseline in the placebo group. The rhPTH(1-84) group showed a significantly greater decrease over placebo in serum PO4 values at all timepoints (P<=0.003); at Week 24, the mean change from baseline (least squares±SE) was −0.47±0.07 mg/dL for rhPTH(1-84) vs −0.06±0.10 mg/dL for placebo (P<0.001). In both groups, 24-hour urine PO4 excretion was reduced from baseline  at Week 24; these results were not statistically significant (P=0.07).

Changes in serum PO4 and urine PO4 excretion towards normal after single and chronic rhPTH(1-84) administration suggest that replacement therapy with rhPTH(1-84)  provides better control of PO4 homeostasis in addition to the improved control of serum and urinary calcium.

(1) Bilezikian J, et al. Efficacy of recombinant human parathyroid hormone (rhPTH[1-84]) for the treatment of adults with hypoparathyroidism: a randomized, double-blind, placebo-controlled study. Endocr Rev. 2012;33:S18-13.

Disclosure: BLC: Advisory Group Member, NPS. DMS: Advisory Group Member, NPS, Investigator, NPS. MM: Advisory Group Member, NPS. TJV: Advisory Group Member, NPS. HL: Employee, NPS. JPB: Advisory Group Member, NPS, Principal Investigator, NPS.

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