Natpara Recommended by FDA Panel for Hypoparathyroidism

Troy Brown, RN

September 13, 2014

Recombinant human parathyroid hormone (rhPTH[1-84]) (Natpara, NPS Pharmaceuticals) has been recommended for approval for the long-term treatment of hypoparathyroidism by a Food and Drug Administration (FDA) advisory committee.

On September 12, the Endocrinologic and Metabolic Drugs Advisory Committee voted 8 to 5 in favor of recommending rhPTH(1-84) to replace endogenous parathyroid hormone in patients with hypoparathyroidism.

"This represents a novel therapy, which is an actual hormone replacement for a hormone-deficiency state. In the absence of its approval, this type of therapy option doesn't exist at all," committee chairperson and voting member Robert J. Smith, MD, professor of medicine (endocrinology), Alpert Medical School, Brown University; Ocean State Research Institute; and Providence Veterans Administration Medical Center, Rhode Island, said.

There are currently no therapies specifically for hypoparathyroidism, a rare endocrine disorder characterized by insufficient levels of parathyroid hormone that causes impaired mineral homeostasis, including hypocalcemia and hyperphosphatemia.

The standard of care at the moment is oral supplementation with calcium and active vitamin D, but this provides inadequate and inconsistent regulation of biochemical indices. It can also cause severe long-term complications and often requires patients to take large amounts of oral calcium and vitamin D, which can be inconvenient and cause gastrointestinal symptoms.

Recombinant human parathyroid hormone is not approved in the United States at this time for any indication; it is approved in Europe for the treatment of osteoporosis but not hypoparathyroidism.

The FDA panel decision follows a discussion of data from a randomized, double-blind, placebo-controlled, international clinical trial (REPLACE). This pivotal trial was published in December 2013 (Lancet Diabetes Endocrinol 2013;1:275-283). Three other clinical trials provided supportive data: RELAY, RACE, and REPEAT.

A similar drug, Forteo (Eli Lilly), used for osteoporosis, is associated with an increased risk for osteosarcoma and carries a boxed warning for this risk.

"I think it's very clear that replacing a missing hormone is the way to go with this disorder; it's the only endocrine disorder that we don't do that for," voting committee member Charles A. Stanley, MD, professor of pediatrics, Perelman School of Medicine, University of Pennsylvania, and division of endocrinology and diabetes, Children's Hospital of Philadelphia, said.

Dr. Stanley said he believes the risk for osteosarcoma seems to be quite small with rhPTH(1-84).

During the open public-hearing portion of the meeting, 14 men and women who have been affected by hypoparathyroidism implored the committee to recommend rhPTH(1-84). Many were patients who said that life as they knew it had ended with their diagnosis and that the drug had dramatically improved their symptoms and quality of life.

Pivotal Study Details and Results

The pivotal study — conducted at 33 sites in 8 countries, 20 of them in the US — included 134 eligible patients; they first underwent an optimization period of 2 to 16 weeks, during which calcium and active vitamin-D doses were titrated to maintain serum calcium levels of 8 to 8.5 mg/dL.

Next, patients were randomly assigned (2:1) to receive 50 µg daily of rhPTH(1-84) (n=90) or placebo (n=44) subcutaneously once daily.

The 6-month treatment phase of the trial was divided into a 12-week titration phase and a 12-week maintenance phase. The researchers progressively reduced active vitamin D and calcium and could titrate rhPTH(1-84) up from 50 µg to 75 µg and finally to 100 µg during weeks 0 to 5, maintaining it at that dose for the remaining 7 weeks.

Doses of rhPTH(1-84) were maintained for an additional 12 weeks.

Six patients in the rhPTH(1-84) group and 7 in the placebo group withdrew from the study before it ended.

The study's primary end point was the proportion of patients who achieved at least a 50% reduction from baseline in their daily dose of oral calcium and active vitamin-D metabolite/analog dose (investigator reported) while maintaining albumin-corrected total serum calcium concentration levels from 7.5 mg/dL or above without exceeding the upper limit of normal (10.6 mg/dL).

The study's secondary end points were the percent reduction in supplemental calcium dose at week 24 and the proportion of patients who achieved independence from vitamin-D metabolite/analog use and a supplemental calcium dose of < 500 mg/day by week 24.

The primary end point was met by 46 (54.8%) of patients in the rhPTH(1-84) group compared with 1 (2.5%) in the placebo group (percentage difference 52.3%, P < .001).

At week 24, there was a mean percent decrease in daily calcium dose of 51.8% in the rhPTH(1-84) group, compared with a small change in the placebo group (mean increase of 2.4%).

By week 24, 36/84 (43%) of rhPTH(1-84)-treated subjects achieved independence from supplemental active vitamin-D/vitamin D analog use and a calcium-supplementation dose of < 500 mg/day, compared with only 2/40 (5.4%) of the placebo group.

The proportions of patients who reported one or more adverse event were similar between patients in the rhPTH(1-84) group (92.9%) compared with patients in the placebo group (100%). The most common adverse events were hypocalcemia, muscle spasm, paresthesia, headache, and nausea.

A similar number of patients in both groups experienced serious adverse events: 10.7% of the active-drug group and 10% of the placebo group.

Not All Panel Members Convinced

Not every voting member on the board was convinced, however.

Temporary voting committee member Susan R. Heckbert, MD, PhD, professor, department of epidemiology, University of Washington, Seattle, said: "I didn't think the efficacy and safety findings presented supported the approval of Natpara right now."

But she added: "I would like to see recombinant [parathyroid hormone] eventually made available for patients and their endocrinologists. There's a tremendous need here, and I think it sounds promising."

The US FDA is expected to make a decision regarding the approval of Natpara by October 24, 2014. Natpara has been granted orphan-drug status for the treatment of hypoparathyroidism by the FDA and the European Medicines Agency.

The committee members have disclosed no relevant financial relationships.


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