HOUSTON – Hypoparathyroidism may soon lose its status as the only endocrine deficiency disease for which the missing hormone isn’t available as an approved replacement therapy.
That change may come as a result of the positive findings of the REPLACE study of the investigational recombinant human parathyroid hormone (1-84), known as Natpara.
REPLACE was a double-blind, randomized, multinational, dose-escalation clinical trial of 134 adults with hypoparathyroidism. After an average 10-week stabilization period in which participants’ oral calcium and active vitamin D doses were adjusted to maintain optimal biochemical control of their disease as defined by serum calcium concentrations of 8.0-9.0 mg/dL for 2 weeks, they were randomized 2:1 to once-daily self-injected subcutaneous recombinant human parathyroid hormone (rhPTH) or placebo for 24 weeks.
The starting dose of rhPTH was 50 mcg. Subjects underwent staged reductions in their calcium and vitamin D supplementation while maintaining a serum calcium level in the target range. In order to accomplish this, patients could be up-titrated to 75 mcg and if need be 100 mcg per day over 6-8 weeks, Dr. Michael Mannstadt explained at the annual meeting of the Endocrine Society.
The primary end point in the REPLACE study was at least a 50% reduction in oral calcium and vitamin D requirements at week 24 compared with baseline, along with maintenance of serum calcium in the target range. This combined end point was achieved in 53% of patients on rhPTH, compared with 2% of controls, reported Dr. Mannstadt, of Harvard Medical School and Massachusetts General Hospital, both in Boston.
At week 24, 43% of patients in the rhPTH arm no longer required vitamin D supplementation and could be maintained on an oral calcium dose of 500 mg/day or less of calcipotriol. This secondary end point was achieved in only 5% of controls.
The mean dose of active vitamin D was reduced by 78% compared with baseline in the rhPTH group and by 30% in controls. The mean dose of oral calcium was lowered by 52% in the rhPTH group, compared with a 5.7% increase over baseline in controls.
Natpara was generally well tolerated, with adverse event rates and profiles similar to those of the placebo arm. An ongoing extension phase of the REPLACE trial is looking at the effects of treatment beyond 24 weeks.
The REPLACE participants were similar to the patients typically encountered in clinical practice. They averaged 48 years of age and had a 13-year history of hypoparathyroidism; 78% were women; and their hormone deficiency resulted from surgery in three-quarters of cases.
Symptoms of hypoparathyroidism include paresthesias, uncontrollable muscle spasms, fatigue, laryngospasm, depression, and even seizures. The impetus for developing Natpara as the first replacement therapy for hypothyroidism stems from the high rate of serious complications resulting from current therapy, which entails large doses of calcium and vitamin D. High-dose calcium supplementation can result in major swings in serum calcium levels and, long term, as calcium builds up extraskeletally, in coronary artery calcification, renal damage, and neurocognitive abnormalities, Dr. Mannstadt noted.
This study was sponsored by NPS Pharmaceuticals. Dr. Mannstadt reported that he is on the company’s advisory board.
*CORRECTION 8/2/12: Natpara was misspelled in the headline in a previous version of this story. This version reflects the corrected headline.