US FDA Approves Natpara for Hypoparathyroidism

Disclosures

January 26, 2015

After delaying its decision by 3 months, the US Food and Drug Administration (FDA) has finally approved a once-daily subcutaneous injectable recombinant parathyroid-hormone (PTH) product (Natpara, NPS Pharmaceuticals) as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism.

Hypoparathyroidism is a rare endocrine disorder that affects approximately 60,000 people in the United States and is characterized by insufficient levels of PTH. Natpara has been granted an orphan-drug designation by the FDA and is expected to be available in the second quarter of 2015, says the manufacturer.

An FDA advisory panel recommended approval of Natpara in September last year, by a vote of 8 to 5, but the agency extended the review date and requested that NPS Pharmaceuticals submit a risk evaluation and mitigation strategy (REMS) for the drug to ensure that the benefits outweigh its risks.

One of the concerns is a potential risk for osteosarcoma, because an agent similar to Natpara approved for osteoporosis (Forteo , Eli Lilly) has been associated with a higher risk for this adverse effect and osteosarcoma has been observed in rat studies with Natpara. It is unknown whether Natpara causes osteosarcoma in humans, but because of this potential risk, it is recommended only for patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone.

The starting dose of Natpara is 50 μg once daily, and it will be available only through a REMS and will contain a boxed warning citing the potential risk for osteosarcoma.

"People with hypoparathyroidism have limited treatment options and face challenging symptoms that can severely impact their quality of life. This product offers an alternative to patients whose calcium levels cannot be controlled on calcium supplementation and active forms of vitamin," said Dr Jean-Marc Guettier, director of the Division of Metabolism and Endocrinology Products in the FDA's Center for Drug Evaluation and Research, in an FDA statement

First Specific Hormone Replacement for Hypoparathyroidism

There have previously been no therapies specifically for hypoparathyroidism, which occurs most commonly as a result of surgical removal of the parathyroid glands and more rarely as a result of autoimmune or congenital diseases; it 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.

Patients with hypoparathyroidism can experience numbness, tingling, muscle twitching, spasms or cramps, abnormal heart rhythm, and seizures as a consequence of low blood calcium levels.

Hypoparathyroidism is also associated with long-term complications such as renal damage, kidney stones, development of cataracts, and calcification of soft tissues.

In an NPS statement, James Sanders, president of the Hypoparathyroidism Association, says: "As someone who has endured the challenges of living with this rare disorder for more than 50 years and seen all five of my children diagnosed with it, I know firsthand how devastating hypoparathyroidism can be and how important it is to have new treatment options.

"It's critical that companies like NPS Pharma continue to research and develop medicines for people with rare diseases, as so many of us are often overlooked."

The FDA approval of Natpara was supported by four company-sponsored efficacy and safety studies, including REPLACE, the largest clinical trial conducted to date in patients with hypoparathyroidism. This pivotal trial was published in December 2013 (Lancet Diabetes Endocrinol .2013;1:275-283). The three other clinical trials that provided supportive data were: RELAY, RACE, and REPEAT.

The most common side effects observed in Natpara-treated participants were sensations of tingling, tickling, pricking, or burning of the skin (paresthesia); low blood calcium; headache; high blood calcium; and nausea.

In Europe, the European Medicines Agency (EMA) is reviewing NPS Pharma's marketing authorization application for hypoparathyroidism; recombinant parathyroid hormone is already available there, but only for the treatment of osteoporosis.

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