NPS Pharmaceuticals, Inc. (NASDAQ: NPSP), a biopharmaceutical company pioneering and delivering therapies that transform the lives of patients with rare diseases worldwide, today announced that its pivotal Phase 3 study of Natpara® (recombinant human parathyroid hormone (rhPTH[1-84]), known as REPLACE, was published online in The Lancet Diabetes & Endocrinology. Study findings underscore Natpara’s potential as a replacement therapy for endogenous parathyroid hormone (PTH) in hypoparathyroidism, a rare endocrine disorder characterized by insufficient production of PTH, a principal regulator of the body’s mineral homeostasis. “Managing hypoparathyroidism can be challenging because it is limited to controlling symptoms, which does not address the underlying cause of the disorder and may have deleterious effects on major organs,” said Michael Mannstadt, MD, Massachusetts General Hospital and Harvard Medical School, and first author on the publication. “This is why we are encouraged by the findings from the REPLACE trial that confirm rhPTH (1-84) has the potential to be the first approved replacement therapy that addresses the underlying absence of parathyroid hormone, an approach long used in other classic endocrine disorders.” When the body is missing PTH, blood calcium levels drop while phosphate levels increase, which can cause a number of physical and mental symptoms, including fatigue, muscle spasms and cramps, tingling, tetany, seizures, brain fog/mental lethargy, anxiety, and depression. Hypoparathyroidism is the only classic endocrine-deficiency disorder without an FDA-approved replacement therapy. It is currently managed with large doses of calcium and active vitamin D to maintain the calcium levels in the blood and reduce the severity of symptoms. Over time, calcium may build up in the body and result in irreversible calcifications in the kidneys, arteries or brain. REPLACE, a 24-week international phase 3 study of efficacy and safety of daily subcutaneous Natpara in 134 patients with hypoparathyroidism, is the largest randomized, placebo-controlled clinical trial conducted to date in patients with this rare and complex endocrine disorder. Patients were randomized 2:1 to 50µg subcutaneous once daily Natpara or placebo. In the study active vitamin D and oral calcium were progressively reduced, while Natpara could be titrated up from 50 to 75 and then 100 µg. Patients self-administered treatment for 24 weeks and were then followed for four additional weeks after the completion of the treatment phase.
A range of desired effects of PTH replacement therapy were observed in the study. With Natpara, patients were able to achieve clinically meaningful reductions in oral calcium and active vitamin D while maintaining serum calcium without increasing mean urinary calcium excretion. Serum phosphate was also improved. Treatment was well-tolerated, as demonstrated by the high compliance rate in both groups, with 80 percent or greater compliance in 98 percent and 96 percent of Natpara and placebo patients, respectively.53 percent of Natpara-treated patients achieved the primary endpoint by decreasing doses of oral calcium and active vitamin D by 50 percent or more, while maintaining serum calcium levels by the end of the treatment phase. In contrast, only 2 percent of the placebo group (P<0.001) met the primary endpoint. Among secondary endpoints, by Week 24, 43 percent (36/84) of patients treated with Natpara were able to achieve independence from active vitamin D therapy and required only 500 mg/day or less of oral calcium, as compared to five percent (2/37) of patients treated with placebo (p<0.0001). From baseline, patients treated with Natpara reduced their oral calcium dose by an average of 52 percent (P<0.001), whereas those treated with placebo increased their average dose by 6 percent. In addition, the between-group differences in the average decrease from baseline for prescribed doses of both calcium and active vitamin D were apparent from week three until week 24 (p<0.002). Despite the large reductions in oral calcium and active vitamin D doses, serum calcium remained at or above baseline levels for the Natpara-treated patients without increasing mean urinary calcium excretion. Mean serum phosphate concentrations were similar (at the upper limit of normal) in both groups at baseline, but fell within normal in the Natpara group upon treatment and remained lower than in the placebo group throughout treatment (P<0.003 at all time points). At week 24, mean serum phosphate levels (±SD) had decreased by 0.46 (0.80) mg/dL and 0.09 (0.66) mg/dL for the Natpara and placebo groups, respectively (P<0.001). The beneficial effects of Natpara also included a reduced calcium-phosphate product, which could reduce the risk of soft tissue calcifications. Natpara was also able to replicate another effect of endogenous PTH by maintaining the serum level of 1,25-dihydroxyvitamin D despite a statistically significant mean reduction in active vitamin D doses.
The overall incidence of adverse events (AE) and percentage of patients with an AE was similar between placebo (100 percent) and Natpara (93 percent) groups. By study end, 93 percent (84/90) of patients in the Natpara group and 100 percent (44/44) in the placebo group had at least one adverse event. The spectrum of adverse events reflected the underlying disease with most common being hypocalcemia, muscle spasm, paresthesias, headache, and nausea. Serious adverse event (SAE) rates were also similar between the placebo-treated (9 percent) and Natpara-treated (11 percent) groups. Only one serious AE of hypercalcemia in the Natpara group was considered treatment-related, and did not lead to study discontinuation. Three of 90 (3 percent) patients in the Natpara group discontinued treatment due to an AE, but only one of these patients’ events were thought to be related to treatment.NPS expects to submit its Biologic License Application (BLA) to the U.S. Food and Drug Administration (FDA) for the treatment of hypoparathyroidism in the fourth quarter of 2013. The U.S. prevalence of hypoparathyroidism is estimated to be approximately 60,000 to 80,000. About NPS Pharmaceuticals NPS Pharmaceuticals is a biopharmaceutical company pioneering and delivering therapies that transform the lives of patients with rare diseases worldwide. The company’s lead product, Gattex® (U.S.)/Revestive® (EU) (teduglutide [rDNA origin]) for injection is approved for adult Short Bowel Syndrome (SBS) patients who are dependent on parenteral support. NPS has also developed Natpara® (rhPTH [1-84]) for the treatment of adult hypoparathyroidism and expects to submit its marketing application to the U.S. Food and Drug Administration in 2013. NPS's earlier stage pipeline includes NPSP795, a calcilytic compound with potential application in rare disorders involving increased calcium receptor activity, such as autosomal dominant hypocalcemia (ADH). NPS complements its proprietary programs with a royalty-based portfolio of products and product candidates that includes agreements with Amgen, GlaxoSmithKline, Janssen Pharmaceuticals, and Kyowa Hakko Kirin. Additional information about NPS is available through its corporate website, http://www.npsp.com. “NPS,” “NPS Pharmaceuticals,” “Gattex,” “Natpara,” “Revestive,” “Preotact,” and “NPS Advantage” are the company's trademarks. All other trademarks, trade names or service marks appearing in this press release are the property of their respective owners.
Disclosure noticeStatements made in this press release, which are not historical in nature, constitute forward-looking statements for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. These statements are based on the company's current expectations and beliefs and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Forward looking statements include, but are not limited to, statements concerning the company’s future financial performance. Risks associated to the company's business include, but are not limited to, the risks associated with any failure by the company to successfully commercialize Gattex (teduglutide [rDNA origin])for injection, including the risk that physicians and patients may not see the advantages of Gattex and may therefore be reluctant to utilize the product, the risk that private and public payers may be reluctant to cover or provide reimbursement for Gattex, the risk that the company will be unable to submit its BLA for Natpara, the risks associated with the company's strategy, global macroeconomic conditions, the impact of changes in management or staff levels, the effect of legislation effecting healthcare reform in the United States, as well as other risk factors described in the company's periodic filings with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K and Form 10-Qs. All information in this press release is as of the date of this release and NPS undertakes no duty to update this information, whether as a result of new information, future events or otherwise.