Parathyroid Hormone for Hypoparathyroidism: More Data

Becky McCall

May 09, 2014

WROCŁAW, Poland — Over half of patients with hypoparathyroidism treated with recombinant human parathyroid hormone, rhPTH(1-84) (Natpara, NPS Pharmaceuticals), were able to eliminate all active vitamin-D and oral calcium supplementation, according to the results of a new phase 3 study, an extension of the earlier pivotal trial.

"This physiological hormone replacement is effective and well tolerated in the long term," reported Peter Lakatos, MD, from Semmelweis University Medical School, Budapest, Hungary, who was the principal investigator for the open-label REPEAT study, which he presented for the first time at the European Congress of Endocrinology (ECE) 2014. Among the patients, 58% no longer required vitamin D and calcium, and almost everyone (96%) cut out vitamin D alone, he observed.

Importantly for patients, this is a biological replacement, he stressed. "The body responds the same whether the hormone is made naturally or comes from an injection. Because it is physiological, the body gets back what it is missing."

The REPEAT study follows on from the REPLACE study, which was the registration trial for rhPTH (1-84) and was reported in full at the American Association of Clinical Endocrinologists (AACE) 2013 Scientific & Clinical Congress and published in the Lancet in December 2013.

Commenting on the findings, ECE session moderator Hans Romijn, MD, professor of medicine at the University of Amsterdam, the Netherlands, said that the concept of rhPTH for the treatment of hypoparathyroidism is logical, since it is one of the few endocrine deficiencies that is not treated with the "missing" hormone. "Vitamin-D and calcium supplementation is a good symptomatic approach but does not normalize calcium homeostasis," he explained.

However, he added that there are several issues with chronic treatment with rhPTH that remain to be addressed, and so longer follow-up will be necessary to prove long-term safety. And if approval is ultimately granted, "the price will also be higher than that for vitamin D and calcium," he noted.

Others at the AACE meeting last year said that the dosing complexity and side effects seen with rhPTH(1-84) might limit its use but that the product may still be suitable for a subgroup of severely affected patients with hypoparathyroidism

rhPTH(1-84) is awaiting approval in the United States for hypoparathyroidism; the new drug application was submitted in October 2013, and NPS Pharmaceuticals says it is planning a submission to the European Medicines Agency (EMA) this year.

REPEAT Follows on From the Pivotal REPLACE Trial

When the parathyroid gland functions properly, parathyroid hormone regulates calcium, so if the serum level of calcium drops for any reason, the hormone increases reabsorption from urine, releases calcium from bone, and stimulates absorption from the gut.

But in patients with hypoparathyroidism, a rare disorder, there are inadequate levels of parathyroid hormone, resulting in hypocalcemia and often hyperphosphatemia.

The condition is currently the only recognized endocrine disorder for which there is no licensed hormonal treatment. Instead, "symptoms are usually managed by intake of large amounts of oral calcium and active vitamin D, but this does not address the underlying deficiency of parathyroid hormone. These supplements usually just resolve cramps but little else," explained Dr. Lakatos.

The pivotal REPLACE was a double-blind, placebo-controlled, randomized phase 3 study in 134 patients randomized to 50 µg per day of rhPTH(1-84) given subcutaneously in the outpatient setting or placebo for 24 weeks. The dose of rhPTH(1-84) was increased to 75 µg and then 100 µg per day if required during the first 5 weeks, then held constant, and doses of calcium and vitamin D were altered as needed.

The primary end point was the proportion of patients who achieved a 50% or greater reduction from baseline in their daily dose of oral calcium and active vitamin D while maintaining a serum calcium concentration the same as or greater than baseline concentrations.

Of those in the rhPTH(1-84) group, 53% achieved the primary end point, compared with one (2%) patient in the placebo group.

Dr. Lakatos noted that REPLACE was originally intended as a double-blind study, but the investigators immediately knew who had received the recombinant hormone because it made the patients much better visibly.

"As a result, REPEAT was partly an extension of REPLACE in that we took 16 patients from REPLACE and continued their therapy and added 8 more. Our study ran for another 24 weeks beyond the 24 weeks of REPLACE," he told Medscape Medical News.

The primary end point was a 50% or greater reduction from baseline in oral calcium and active vitamin D and maintenance of serum calcium within normal limits (total serum calcium level >1.87 mmol/L and less than or equal to the upper limit of normal). All 3 criteria needed to be fulfilled to qualify as a response.

In this study, 75% of patients achieved the primary end point by week 24. Furthermore, for the majority of patients who previously received rhPTH(1-84) in REPLACE, efficacy was sustained over the longer term of treatment (approximately 1 year).

Of those patients who did still require vitamin D and calcium, the doses needed were extremely low, Dr. Lakatos said.

He noted that dosing of rhPTH(1-84) in the trials was limited to approved levels (the agent is licensed in Europe for the treatment of osteoporosis), so although higher doses might be more effective, they were not studied.

Long-term Effects on Bone Remain to Be Determined

The most common adverse events seen were hypoesthesia in 50% of patients; muscle spasms and decreased vitamin D, both found in 25% of patients; and hypercalcemia in 21%. No serious adverse events occurred, and no patients discontinued due to side effects.

Dr. Lakatos said that they did not yet have enough experience with rhPTH(1-84) in terms of hypoparathyroidism to speak properly to the issue of adverse effects, but around 8 years of use of a similar product (rhPTH[1-34]) in osteoporosis has provided an indication of potential outcomes.

"In osteoporosis, we have only seen a few side effects, including lower leg cramps and hypercalcemia, but no major events," he explained.

"The main concern is…in the bone due to the anabolic effect; it can increase bone-mineral content very quickly, so only 2 years of therapy is permitted in osteoporosis."

Patients from the REPEAT study will continue to be monitored with regard to their bones, he concluded.

The REPEAT study was supported by NPS Pharmaceuticals. Dr. Lakatos and Dr. Romijn have reported no relevant financial relationships.

European Congress of Endocrinology 2014; May 5, 2014; Wrocław, Poland. Abstract OC6.4.

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