New Data From REPLACE Study Show Initiation of Bone Remodeling for Natpara®-Treated Patients with Hypoparathyroidism
-- Bone data from REPLACE along with results from eight-week RELAY study presented at American Society for Bone and Mineral Research Annual Meeting --
BEDMINSTER, N.J.--(BUSINESS WIRE)-- NPS Pharmaceuticals, Inc. (NAS: NPSP) , a biopharmaceutical company developing innovative therapeutics for rare gastrointestinal and endocrine disorders, announced today new findings from the double-blind, placebo-controlled Phase 3 REPLACE study of Natpara® (recombinant human parathyroid hormone (rhPTH [1-84]) that show Natpara initiated bone remodeling as demonstrated by significant increases in bone turnover markers. Investigators also reported results from an eight-week study, known as RELAY, which evaluated lower doses of Natpara in hypoparathyroidism. The findings were presented in a poster session at the Annual Meeting of the American Society for Bone and Mineral Research (ASBMR) in Minneapolis, MN.
Natpara is a bioengineered replica of human parathyroid hormone that is being developed by NPS for adults with hypoparathyroidism, a rare endocrine disorder that is characterized by insufficient levels of parathyroid hormone, the body's principal regulator of calcium and phosphorus. NPS expects to submit its Biologic License Application for Natpara by mid-2013.
Abnormal bone structure with high bone mineral density is a well-recognized consequence of hypoparathyroidism that is likely caused by decreased bone turnover in the absence of parathyroid hormone. In a poster session on Monday, October 15, lead study investigator Dr. John P. Bilezikian and colleagues presented "Effect of Recombinant Human Parathyroid Hormone (rhPTH [1-84]) on Skeletal Dynamics and BMD in Hypoparathyroidism: the REPLACE Study." The presentation focused on the effects of Natpara on changes in bone turnover markers and bone mineral density after 24 weeks of treatment in REPLACE.
At baseline, a large percentage of Natpara-treated and placebo-treated patients in REPLACE had elevated bone mineral density (BMD) based on Z-scores and low bone turnover markers with no differences between the two groups. Rapid and statistically significant increases from baseline were observed at Week 24 in all bone turnover markers in the Natpara-treated group (P<0.001 versus baseline for all markers) with no statistically significant changes observed in the placebo-treated group.
A summary of the average changes in bone turnover markers is summarized in the table below.
* n=32 for BSAP at Week 24
BSAP: Bone-specific alkaline phosphatase
P1NP: N-terminal propeptide of type-1 collagen
Investigators also reported statistically significant decreases in Z-scores towards normal from baseline to Week 24 in the hip for the Natpara-treated group versus placebo (P<0.001).
Overall rates of adverse events during the 24-week treatment period were similar (90% vs. 96% Natpara and placebo, respectively). The spectrum of adverse events reflected underlying disease pathophysiology with most common being paresthesia, muscle spasms, headache, and hypocalcemia.
"Hypoparathyroidism is the only classic endocrine deficiency disease for which the missing hormone, in this case parathyroid hormone, is not yet an approved therapy," said lead study investigator, John P. Bilezikian, MD, professor of medicine, Division of Endocrinology, Columbia University College of Physicians and Surgeons. "Today, doctors manage symptoms with high doses of calcium and vitamin D supplementation, both of which can be associated with skeletal and other complications. Natpara has the potential to fill a major gap in the treatment of hypoparathyroidism, leading to smoother and better management."
"These positive data continue to show the potential for beneficial treatment effects of replacing the missing hormone and restoring mineral homeostasis in patients with this rare disorder," said Roger Garceau, MD, senior vice president and chief medical officer of NPS Pharmaceuticals. "The consequences of hypoparathyroidism can be severely disabling. Patients need new treatment options particularly given the complications associated with the long-term use of high-dose calcium and vitamin D and potential irreversible damage to the kidneys, heart, and brain."
Investigators also reported results from an eight-week study, known as RELAY, which evaluated lower doses of Natpara in hypoparathyroidism.
In a poster session on Monday, October 15, Vokes et al. presented "Efficacy and Safety of Low Dose Recombinant Human Parathyroid Hormone (rhPTH [1-84]) in Hypoparathyroidism: the RELAY Study." The RELAY study was a randomized, dose-blinded, fixed-dose, eight-week study that evaluated the efficacy and safety of lower doses of Natpara as a therapy for the treatment of patients with hypoparathyroidism. The study enrolled patients who were naïve to Natpara replacement therapy, as well as patients who previously participated in Natpara studies.
At Week eight, 18 percent (4/22) of patients treated with 25µg once daily Natpara and 25 percent (6/24) of patients treated with 50µg once daily Natpara achieved the primary efficacy endpoint, which was defined as a reduction in oral calcium supplementation to 500 mg or less per day and active vitamin D supplementation (calcitriol) of 25µg per day or less while maintaining albumin-corrected total serum calcium (≥7.5 mg/dL).
In addition, 9 percent (2/22) of patients treated with 25µg once daily Natpara and 29 percent (7/24) of patients treated with 50µg once daily Natpara were able to demonstrate by week eight a 50 percent or greater reduction from baseline of both oral calcium supplementation and active vitamin D metabolite/analog therapy and a total serum calcium concentration that was normalized or maintained compared to baseline. Bone turnover markers were also studied. Increases were observed in CTX, OC and P1NP from baseline to Week 8 for both treatment groups.
Both dosages were well tolerated throughout the study with no treatment-emergent serious adverse events or unexpected safety events. The spectrum of adverse events reflected underlying disease pathophysiology with the most frequent AEs occurring in either group being paresthesia, nausea, muscle spasms, fatigue and headache.
Investigators concluded that for a small percentage of patients with hypoparathyroidism, lower dosages of Natpara may be sufficient to achieve mineral homeostasis. Efficacy and safety results are consistent with prior Phase 3 study indicating that 50 µg/day is an appropriate starting dose for most patients. 25µg once daily Natpara provides an additional dosage option.
About the REPLACE Study
REPLACE was a randomized, double-blind, dose-escalating, placebo-controlled Phase 3 registration study that investigated the use of Natpara for the treatment of adults with hypoparathyroidism at more than 30 sites in North America and Europe.
The study consisted of an average 10-week screening and stabilization period followed by a 24-week treatment period marked by randomization (2:1) to 50µg once daily Natpara or placebo. Following randomization, subjects underwent staged reductions in calcium and vitamin D supplementation, while maintaining stabilized serum calcium. If needed, step-wise up-titration of study drug (Natpara or placebo) to a dose of 75 µg and then if necessary to 100 µg over a six to eight week period was performed. Subjects continued on their final dose through Week 24. A follow-up period without study drug lasted from Week 24 to Week 28.
In an intent-to-treat analysis, 53 percent (48/90) of Natpara-treated patients achieved the primary endpoint versus 2 percent (1/44) of placebo-treated patients (P<0.001). The primary efficacy endpoint of REPLACE was to demonstrate by Week 24 at least a 50 percent reduction from baseline of both oral calcium supplementation and active vitamin D metabolite/analog therapy and a total serum calcium concentration that was normalized or maintained compared to baseline (≥7.5 mg/dL).
At Week 24, 43 percent (36/84) of patients treated with Natpara were able to achieve independence from active vitamin D therapy and required only a calcium supplementation dose of 500 mg/day or less, as compared to five percent (2/37) of patients treated with placebo (P<0.0001).
Despite the large reductions in supplementation, serum calcium remained at or above baseline levels for the Natpara-treated patients. In this study, Natpara was generally well-tolerated. Overall rates of adverse events during the 24-week treatment period were similar (90% vs. 96% Natpara and placebo, respectively). The spectrum of adverse events reflected underlying disease pathophysiology with most common being paresthesias, muscle spasms, headache, and hypocalcemia. Based on these study findings, Natpara may show promise as an effective replacement therapy for hypoparathyroidism.
Hypoparathyroidism is a rare endocrine disorder in which the body produces insufficient levels of parathyroid hormone, the principal regulator of calcium and phosphorus. When the body has too little parathyroid hormone, blood calcium levels drop and phosphorus levels increase, which can cause a number of physical and mental symptoms, including uncontrollable muscle spasms and cramps, tetany, seizures, fatigue, anxiety, and depression. It is the only classic endocrine disorder for which there are no FDA-approved replacement therapies. Current treatment approaches focus on symptom management through high doses of calcium and active vitamin D supplementation, which can lead to serious side effects and long-term consequences. Over time, calcium may build up in the body and result in serious health risks, including calcifications in the kidneys, heart or brain.
About NPS Pharmaceuticals
NPS Pharmaceuticals is a biopharmaceutical company focused on bringing orphan products to patients with rare disorders and few, if any, therapeutic options. NPS is advancing two late-stage registration programs. A New Drug Application is undergoing FDA review for Gattex® (teduglutide) as a treatment for adult short bowel syndrome (SBS) and a Phase 3 registration study has been completed for Natpara® (recombinant human parathyroid hormone (rhPTH [1-84]) in adult hypoparathyroidism. NPS' earlier stage pipeline includes two calcilytic compounds, NPSP790 and NPSP795, with potential application in rare disorders involving increased calcium receptor activity, such as autosomal dominant hypocalcemia with hypercalciuria (ADHH). NPS complements its proprietary programs with a royalty-based portfolio of products and product candidates that includes agreements with Amgen, GlaxoSmithKline, Janssen Pharmaceuticals, Kyowa Hakko Kirin, and Nycomed (acquired by Takeda Pharmaceutical Company Limited).
"NPS," "NPS Pharmaceuticals," "Gattex," and "Natpara" 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.
Statements 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. Risks associated to the company's business include, but are not limited to, the risks associated with any failure by the company to successfully complete its preclinical and clinical studies within the projected time frames or not at all, the risk of not gaining marketing approvals for Gattex and Natpara, the risks associated with the company's strategy, 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.
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