Parathyroid Hormone Replacement Effective, Safe Long Term

Miriam E. Tucker

April 04, 2019

NEW ORLEANS — Recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) (Natpara, Shire) was safe and effective over 6 years of continuous use for the treatment of adults with chronic hypoparathyroidism, new research shows.

Findings from the long-term, open-label RACE extension study were presented March 26 here at ENDO 2019: The Endocrine Society Annual Meeting by John P. Bilezikian, MD, professor of medicine at Columbia University, New York City.

Hypoparathyroidism is a disorder of mineral homeostasis characterized by deficient or absent parathyroid hormone. The associated clinical findings are hypocalcemia, hyperphosphatemia, and reduced tubular reabsorption of calcium, often leading to hypercalciuria.

Conventional treatment with oral calcium and activated vitamin D (calcitriol) doesn't always maintain normal serum calcium levels and also doesn't restore other physiologic actions of the missing parathyroid hormone, Bilezikian explained.

The once-daily subcutaneous injectable drug was approved by the US Food and Drug Administration in 2015 and European Medicines Agency (Natpar) in 2017.

The new follow-up data are important, Bilezikian told Medscape Medical News, because the original phase 3 trial lasted only 26 weeks.

"These are patients who have a lifelong disease. With an approved drug you'd like to have long-term safety and efficacy data. It continues to demonstrate efficacy and no safety concerns surfaced since the original study."

One new finding did arise in the 6-year data that was not seen in the original phase 3 REPLACE trial. Urine calcium levels eventually went down among the patients who received rhPTH(1-84), whereas those levels hadn't previously changed significantly over 26 weeks.    

Session moderator Suzanne Marie Jan De Beur, MD, associate professor of medicine at Johns Hopkins University, Baltimore, Maryland, told Medscape Medical News, "One of the main shortfalls of conventional therapy is that you get hypercalciuria and that can be damaging to the kidneys."

"So if this indeed holds up that the urine calcium concentration will eventually fall, that will mean this is a good way to go in those individuals in whom you can't control the urine calcium by conventional therapy and other adjunctive therapy that we use to try and bring the urine calcium down," she added.

Relentless Reduction in Urine Calcium Excretion Over 6 Years

The RACE study, an open-label extension of REPLACE and another phase 3 trial, enrolled 49 patients from 12 US centers, of whom 82% were women with a mean age 48 years and hypoparathyroidism duration of about 16 years.

Bilezikian reported findings for 34 of those patients who had completed 72 months of the study. They were started on 25 or 50 µg/day of rhPTH(1-84) and titrated up or down to a maximum of 100 µg/day depending on serum calcium, with the goal of maintaining albumin-corrected serum calcium between 8-9 mg/dL. Oral calcium and calcitriol supplementation doses were continued and also adjusted up or down to help achieve that target.   

The composite efficacy endpoint was the proportion of patients who achieved at least a 50% reduction from baseline in oral calcium dose (or calcium ≤ 500 mg/day) and at least a 50% reduction from baseline in calcitriol dose (or calcitriol ≤ 0.25 µg/day) while normalizing or maintaining albumin-corrected serum calcium compared with baseline and not exceeding the upper limit of normal for the central laboratory.

After the first year, 76% of patients had achieved the primary composite endpoint. By 72 months, 65% of the 34 patients who reached that timepoint met the primary endpoint. 

Among the 34 patients, there was a 40% reduction in oral calcium supplementation doses and a 72% reduction in calcitriol dose, while albumin-corrected serum calcium levels were maintained within the target range (mean 8.4 mg/dL at baseline and 6 years).

And there was a "very interesting, progressive, if not relentless," reduction in urinary calcium excretion, from hypercalciuric values (mean 357 mg/24 hours) at baseline to normal levels (213 mg/24 hours) at 6 years. At the same time, there were no significant changes in serum creatinine concentrations or estimated glomerular filtration rate, Bilezikian noted.

Average serum phosphorus levels also declined rapidly and significantly from 4.8 mg/dL at baseline and was maintained at about 4.0 mg/dL through the 6 years. Calcium phosphate product also dropped quickly, by an average of 9.5 mg2/dL2 lower than baseline at 6 years.

No Unexpected Adverse Events  

Adverse events were reported by most patients, and the most common drug-related adverse events were nausea, hypercalcemia, and hypocalcemia.

A quarter of the patients experienced serious adverse events, but none were believed to be because of the drug. "No new safety concerns were identified," said Bilezikian.

Continuous use of rhPTH(1-84) over 6 years resulted in a favorable safety profile, was effective, and improved key measurements of mineral homeostasis, notably normalization of urinary calcium, the authors concluded.  

Bilezikian has reported being an advisory board member, consultant for, and grant recipient from Shire. De Beur has reported no relevant financial relationships.

ENDO 2019. Presented March 26, 2019. Abstract OR30-1.

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