New Findings from REPLACE Study Support Potential of Natpara(TM) to Treat Adult Hypoparathyroidism

NPS Pharmaceuticals, Inc. (NASDAQ: NPSP), a specialty pharmaceutical company developing innovative therapeutics for rare gastrointestinal and endocrine disorders, announced today that new findings from the double-blind, placebo-controlled Phase 3 REPLACE study of Natpara™ (recombinant human parathyroid hormone (rhPTH [1-84])) support the drug’s therapeutic potential as the first parathyroid hormone replacement therapy for adults with hypoparathyroidism. The findings were presented in oral and poster sessions at the ENDO 2012 annual meeting of The Endocrine Society in Houston, TX. Natpara is a bioengineered replica of human parathyroid hormone that is being developed by NPS Pharmaceuticals as the first replacement therapy for adults with hypoparathyroidism.

"These presentations show the potential benefits of replacing the missing parathyroid hormone with Natpara and restoring and maintaining healthy serum calcium levels in patients with this rare and complex metabolic disorder,” said Roger Garceau, M.D., senior vice president and chief medical officer of NPS Pharmaceuticals. "The consequences of this disorder can be severely disabling, which is why the drug’s apparent treatment effects in this study – increased serum calcium levels, reductions in calcium and vitamin D supplementation, fewer disease symptoms and increased bone turnover – are so impressive. Natpara was also well tolerated, with no significant differences in adverse events compared to placebo. These findings reinforce our belief that Natpara represents a promising and important new treatment option for hypoparathyroidism.”

Hypoparathyroidism is characterized by hypocalcemia due to insufficient levels of parathyroid hormone, the body’s principal regulator of calcium and phosphorus. 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.

Treatment with Natpara resulted in significant reductions in calcium and active vitamin D supplements.

In an oral presentation on Saturday, June 23, lead study investigator, John P. Bilezikian, M.D., professor of medicine, Division of Endocrinology, Columbia University College of Physicians and Surgeons, presented an overview of the data from the REPLACE study.

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 was defined as a 50 percent or greater reduction in oral calcium supplementation and active vitamin D therapy and a total serum calcium concentration that was normalized or maintained compared to baseline after 24 weeks of treatment.

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. Treatment with Natpara also resulted in a small decrease in mean 24-hour urinary calcium excretion from baseline and patients experienced fewer hypocalcemic clinical symptoms during the maintenance phase of the study. Natpara was generally well-tolerated and shows promise as an effective replacement therapy for hypoparathyroidism.

"Parathyroid hormone has the potential to fill a major therapeutic gap in the effective management of hypoparathyroidism,” said lead study investigator, John P. Bilezikian, Professor of Medicine and Pharmacology, Director of the Metabolic Bone Diseases Unit, Division of Endocrinology, Columbia University College of Physicians and Surgeons. "Hypoparathyroidism is the only endocrine deficiency disease for which the missing hormone, namely parathyroid hormone, is not an approved therapy. These findings provide hope for patients with hypoparathyroidism who desperately need more options for their care. Many patients rely on the long-term use of high dose calcium and vitamin D to help alleviate symptoms. However, this approach is subject to uneven control in many patients with wide swings in their blood calcium levels and fluctuations in their symptoms. Moreover, long-term high dose calcium and vitamin D can be associated with serious complications, including calcifications in the kidneys, heart, and brain.”

Treatment with Natpara was well-tolerated and patients were highly compliant with fewer patients discontinuing treatment in the Natpara group compared to the placebo group.

In a poster session on Sunday, June 24, Shoback et al. presented the safety data from the REPLACE study.

Treatment with once daily Natpara (50µg with titration up to 100µg) was well tolerated. Patients were highly compliant with fewer patients discontinuing treatment in the Natpara group 6/90) compared with the placebo group (7/44). Ninety-eight percent of Natpara-treated patients were treatment compliant as determined from investigator records.

The overall rate of adverse events (AE) during the treatment period was similar in the Natpara and placebo groups (90 percent and 96 percent, respectively). The spectrum of AEs reflected the underlying disease pathophysiology with most common being nervous system, metabolism and nutrition, musculoskeletal and connective tissue, and gastrointestinal disorders. Overall, the hypocalcemic clinical symptoms during the maintenance phase were fewer with Natpara compared with placebo. The most commonly reported AEs with Natpara compared with placebo were nervous system disorders (paresthesia, headache, hypoesthesia, and dizziness) and metabolism and nutrition disorders (hypocalcemia, hypercalcemia, tetany, and hypomagnesemia). Three of the 90 randomized patients treated with Natpara discontinued the REPLACE study with reported AEs due to hypertension (n=1), stroke (n=1), and multiple events (n=1).

Patients with hypoparathyroidism represent a complex metabolic mineral disorder resulting from the lack of parathyroid hormone.

In a poster session on Sunday, June 24, Mannstadt et al. presented the REPLACE baseline demographics and characteristics. The mean age of study participants was 47.5 years. Seventy-eight percent of study participants were women. Hypoparathyroidism was the result of surgery in 74 percent of the patients. All patients were prescribed large daily doses of calcium and active vitamin D.

Bone mineral density was increased at the spine and hip in the majority of patients in the study. Abnormal bone structure with increased bone mineral density is a well-recognized consequence of hypoparathyroidism that is likely from decreased bone turnover in the absence of PTH. Along with low serum calcium and high serum phosphate, urinary calcium excretion was elevated.

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.

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).

About 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. There is currently no FDA-approved replacement therapy for hypoparathyroidism, which is currently managed with large doses of calcium supplementation and active vitamin D therapy to raise the calcium levels in the blood and reduce the severity of symptoms. 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.