To expand its market reach in rare gastrointestinal and endocrine diseases and build on its manufacturing infrastructure in biologics, Dublin-based Shire is buying NPS Pharmaceuticals of Bedminster, New Jersey. The $5.2-billion deal was announced almost two weeks before the US Food and Drug Administration (FDA) on January 23 approved NPS's Natpara (recombinant human parathyroid hormone 1-84), which becomes the only bioengineered hormone replacement therapy for hypoparathyroidism.

NPS' Natpara treats parathyroid hormone insufficiency, a condition that affects calcium levels and can result in organ damage. Credit: Anatomical Travelogue/Science Source

Initially viewed as a potential bone-growth treatment, Natpara failed to win FDA approval for use in menopausal women with osteoporosis, partly due to serious excess calcium levels observed after treatment. In Europe, Natpara was available for that purpose until 2013 through NPS's partner at the time, Zurich-based Nycomed. By then, NPS had shifted its efforts with Natpara to hypoparathyroidism, a condition where the parathyroid glands fail to produce sufficient parathyroid hormone, which helps regulate calcium and phosphorus levels in the body.

Hypoparathyroidism affects roughly 60,000 people in the US. Acute symptoms may include muscle pain and tingling, a lack of focus or ability to concentrate, and anxiety and depression. Over time, insufficient calcium levels can result in organ damage as well as precipitation of calcium phosphate in soft tissue. Standard treatment is high-dose calcium and vitamin D, but this can entail taking up to 20 pills per day and may lead to high calcium levels in urine, increasing the risk of kidney failure in the long term.

Natpara, the recombinant parathyroid hormone, binds to and activates parathyroid hormone 1 receptors on bone and kidney cells. The goal of parathyroid hormone replacement therapy is to control hypocalcemia without producing excessive urinary calcium, but adjusting the dosing can be tricky. Preclinical rodent studies also suggest a potential risk of osteosarcoma. Both Natpara and a competitor product, Forteo (teriparatide, parathyroid hormone 1-34) which is approved for osteoporosis, contain warnings to that effect on the drug label.

Questions about dosing and other issues arose during NPS's pivotal trial. Those receiving the drug had a greater incidence of excessive urinary calcium, leading some members of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee, which reviewed the drug, to doubt the strength of the clinical effect of the drug as well as the company's choice of dose. The dose regimen NPS proposed—and that was ultimately approved—did reduce oral calcium and vitamin D requirements and control serum calcium, which were the primary endpoints of the trial.

The clinical benefit did not convince everyone. The advisory committee voted 8–5 in favor of approving Natpara, but the study “was nowhere geared towards clinical benefit in terms of what was measured and what was shown,” said committee member Daniel Gillen of the University of California, Irvine. But in the end, the majority felt that having a hormone replacement therapy available was paramount.

“Replacing a missing hormone is the way to go with this disorder,” said Charles Stanley of The Children's Hospital of Philadelphia. “It's the only endocrine disorder that we don't do that [for].”

“There is an unmet need for a very small set of patients for this orphan condition,” added Carola Arndt of the Mayo Clinic in Rochester, Minnesota. Shire expects to launch the drug in the US in the first quarter of the year, after the acquisition is completed; Natpara is also currently under review in the EU.NPS's other key asset is Gattex (teduglutide), an analog of glucagon-like peptide-2 that stimulates growth of the intestinal lining and is approved to treat short bowel syndrome, a rare condition in which the body is unable to absorb nutrients following resection of the small intestine. In endocrinology, NPS has also started trials of NPSP795, a selective calcium receptor antagonist, as a treatment for autosomal dominant hypocalcemia, a very rare genetic disorder that leads to increased renal calcium excretion, decreased renal phosphate excretion and abnormally high serum phosphate levels.