Type of information: Granting of a Market Authorisation in the EU
Product name: Natpara®/Natpar®
Compound: recombinant human parathyroid hormone
Therapeutic area: Rare diseases - Endocrine diseases - Hormonal diseases
Action mechanism: protein. Natpara® is a bioengineered replacement for endogenous parathyroid hormone (PTH) that NPS has developed for the treatment of hypoparathyroidism, a rare endocrine disorder in which the body produces insufficient levels of parathyroid hormone, a principal regulatory of the body’s mineral homeostasis.
Company: NPS Pharma UK (UK) NPS Pharmaceuticals (USA - NJ) now Shire (UK - USA)
- • adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism
- • adjunctive treatment for adult patients with chronic hypoparathyroidism who cannot be adequately controlled with standard therapy alone
- • On April 26, 2017, the European Commission (EC) has granted conditional marketing authorisation for Natpar® (rhPTH[1-84]), the first recombinant human protein with the full length 84-amino acid sequence of endogenous parathyroid hormone (PTH). Natpar® will be the first and only approved hormone therapy indicated as adjunctive treatment for adult patients with chronic hypoparathyroidism who cannot be adequately controlled with standard therapy alone. The conditional marketing authorisation is based on the outcomes from the Phase III efficacy and safety of rhPTH(1-84) clinical trial (REPLACE) in patients aged 19-74 years with chronic hypoparathyroidism. The trial showed that Natpar® maintained serum calcium while reducing oral calcium and active vitamin D supplemental doses.
- In the double-blind, placebo-controlled, randomized Phase III study 124 patients with hypoparathyroidism were randomized in a ratio of 2:1 to either 50 micrograms once daily of rhPTH(1-84) or placebo for 24 weeks. The primary endpoint was a 50 percent or greater reduction from baseline in their daily dose of oral calcium and active vitamin D while maintaining a stable albumin corrected serum calcium concentration greater than or equal to baseline concentration (baseline was 2.1 mmol/L for the rhPTH[1-84] group and 2.2 mmol/L for the placebo group) and less or equal to the upper limit of normal (normal range 2.1–2.6 mmol/L). At the end of the treatment period, 54.8 percent of the patients on rhPTH(1-84) achieved the primary endpoint compared with 2.5 percent of patients in the placebo group (p<0.0001). There were no differences in the proportion of patients maintaining a stable albumin corrected serum calcium concentration at the end of treatment between subjects randomized to rhPTH (1-84) and placebo.
- • On April 1, 2015, Shire announced that Natpara® (parathyroid hormone) for injection is now available in the United States. The FDA approved Natpara® as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism on January 23, 2015. Because of the potential risk of osteosarcoma, Natpara® is recommended only for patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone. Natpara® was not studied in patients with hypoparathyroidism caused by calcium-sensing receptor mutations or in patients with acute post-surgical hypoparathyroidism.
- Natpara® will be available through a Risk Evaluation and Mitigation Strategy (REMS) Program and a limited network of specialty pharmacies. Eligible patients who are prescribed Natpara will have access to patient support services through NPS Advantage. These services include access to NPS Advantage Care Coordinators who can provide: information about Natpara®, insurance authorization, appeals and financial assistance; assistance with ordering products; and, connect patients with a Nurse Educator. Because of the potential risk of osteosarcoma associated with Natpara therapy, Natpara® is available only through a restricted REMS program called the Natpara® REMS Program. Under the Natpara® REMS Program, only certified healthcare providers can prescribe and only certified pharmacies can dispense Natpara®. In Europe, the European Medicines Agency (EMA) has validated and initiated its review of the company’s marketing authorization application for Natpar™.
- • On January 23, 2015, the FDA approved Natpara® (parathyroid horomone) to control hypocalcemia (low blood calcium levels) in patients with hypoparathyroidism. The safety and effectiveness of Natpara® were evaluated in a clinical trial of 124 participants who were randomly assigned to receive Natpara or a placebo. The trial was designed to determine whether Natpara® can be used as a substitute for, or be used to help reduce the amount of, active forms of vitamin D or oral calcium taken by participants. Results showed 42 percent of Natpara®-treated participants achieved normal blood calcium levels on reduced doses of calcium supplements and active forms of vitamin D, compared to three percent of placebo-treated participants.
- Natpara® carries a boxed warning that bone cancer (osteosarcoma) has been observed in rat studies with Natpara®. It is unknown whether Natpara® causes osteosarcoma in humans, but because of a potential risk of osteosarcoma, Natpara® is only recommended for use in patients whose hypocalcemia cannot be controlled on calcium supplementation and active forms of vitamin D, and for whom the potential benefits are considered to outweigh this potential risk. Natpara® is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).
- The most common side effects observed in Natpara®-treated participants were sensations of tingling, tickling, pricking, or burning of the skin (paraesthesia); low blood calcium; headache; high blood calcium; and nausea.
- • On December 2, 2014, NPS Pharmaceuticals announced that the European Medicines Agency (EMA) has validated and initiated its review of the company's marketing authorization application (MAA) for Natpar® (parathyroid hormone (rDNA)) for the treatment of Hypoparathyroidism, a rare endocrine disorder characterized by insufficient levels of parathyroid hormone (PTH). If approved, Natpar® would be the first and only PTH replacement therapy in Europe for patients with Hypoparathyroidism.
- The MAA includes results from 13 pharmacology studies and four company-sponsored efficacy and safety studies. The pivotal Phase 3 study, known as REPLACE, was a multinational, randomized, double-blind, placebo controlled study and the largest clinical trial conducted to date in Hypoparathyroidism. Key findings from the study were published in The Lancet Diabetes and Endocrinology (2013; 1:275-283). The EMA granted orphan drug designation for Natpar for the treatment of hypoparathyroidism in December 2013. The FDA granted orphan drug status for the product for the treatment of Hypoparathyroidism in 2007 and a Biologics License Application to market it under the trade name Natpara® is currently under review by the FDA with a Prescription Drug User Fee Act action date of January 24, 2015 .
- • On January 7, 2014, NPS Pharmaceuticals has announced that the FDA has accepted and filed for review the company’s Biologics License Application (BLA) for Natpara® (recombinant human parathyroid hormone 1-84, (rhPTH[1-84])) for the treatment of hypoparathyroidism. Under the Prescription Drug User Fee Act (PDUFA), the goal date for a decision by the FDA is October 24, 2014. The clinical development program for Natpara includes 12 pharmacology studies, five efficacy and safety studies in hypoparathyroidism, and a supporting development program consisting of seven studies in osteoporosis. The pivotal Phase 3 study known as REPLACE, was a randomized, double-blind, placebo controlled study of 134 patients with hypoparathyroidism.
- • On January 3, 2014, NPS Pharmaceuticals has announced that the European Commission has granted orphan drug designation to Natpara® (recombinant human parathyroid hormone (rhPTH[1-84]) for the treatment of hypoparathyroidism. The company was also granted orphan drug status by the FDA in 2007. The company submitted its U.S. Biologic License Application to FDA in October 2013.
- • On 5-6 November 2013, the Committee for Orphan Medicinal Products (COMP) has recommended the granting of an orphan designation for recombinant human parathyroid hormone for treatment of hypoparathyroidism.
Submission of marketing authorization application USA : 2013-10-24
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2014-01-23
UE authorization: 2017-04-26
Favourable opinion UE: 2017-02-24
Favourable opinion USA:
Orphan status USA: 2007-08-31
Orphan status UE: 2013-12-18
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
Other news: On January 11, 2015, Shire and NPS Pharmaceuticals announced that the companies have entered into a merger agreement pursuant to which Shire will acquire all the outstanding shares of NPS Pharma for $46.00 per share in cash, for a total consideration of approximately $5.2 billion.