`10K 1 form10k.htm 10K
`
`10K 2014 DOC
`
`UNITED STATES
`SECURITIES AND EXCHANGE COMMISSION
`Washington, D.C. 20549
`
`FORM 10K
`
` ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES
`EXCHANGE ACT OF 1934
`
`For the fiscal year ended December 31, 2014
`
`Commission File Number 023272
`NPS PHARMACEUTICALS, INC.
`(Exact Name of Registrant as Specified in its Charter)
`
`
`
`Delaware
` (State or Other Jurisdiction of Incorporation or Organization)
`
`870439579
`(I.R.S. Employer Identification No.)
`
`550 Hills Drive, 3rd Floor, Bedminster, NJ 07921
`(Address of Principal Executive Offices including Zip Code)
`(908) 4505300
`(Registrant's Telephone Number, Including Area Code)
`
`Securities registered pursuant to Section 12(b) of the Act:
`
`Title Of Each Class
`
`Common Stock, $.001 Par Value Per Share
`
`Name Of Each Exchange On Which
`Registered
`
`The NASDAQ Stock Market LLC
`(NASDAQ Global Market)
`
`Securities registered pursuant to Section 12(g) of the Act: None
`
`Indicate by check mark if the Registrant is a wellknown seasoned issuer, as defined in Rule 405 of the Securities
`Act. YES NO
`
`Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the
`Securities Exchange Act. YES NO
`
`Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the
`Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was
`required to file such reports), and (2) has been subject to such filing requirements for at least the past 90
`days. YES NO
`
`Indicate by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any,
`every Interactive Data File required to be submitted and posted pursuant to Rule 405 of Regulation ST (§232.405 of this
`chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit and post such
`files). YES NO
`
`Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation SK is not contained herein,
`and will not be contained, to the best of Registrant's knowledge, in definitive proxy or information statements incorporated
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`by reference in Part III of this Form 10K or any amendment to this Form 10K.
`
`Indicate by check mark whether the Registrant is a large accelerated filer, an accelerated filer, or a nonaccelerated filer, or
`a smaller reporting company. See the definitions of "large accelerated filer," and large "accelerated filer" and "smaller
`reporting company" in Rule 12b2 of the Exchange Act.
`
`Large accelerated filer
`
`
`Accelerated filer Nonaccelerated filer
`(Do not check if a smaller reporting
`company)
`
`Smaller reporting company
`
`
`Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b2 of the Exchange
`Act). YES NO
`
`The aggregate market value of the common stock held by nonaffiliates of the Registrant was $3,543,284,815 as of June
`30, 2014, based upon the closing price for the shares of common stock reported on The NASDAQ Global Market on such
`date.
`
`As of February 11, 2015, there were 108,581,155 shares of common stock, par value $0.001 per share, outstanding.
`
`DOCUMENTS INCORPORATED BY REFERENCE:
`
`Portions of the Registrant's definitive Proxy Statement for its 2015 Annual Meeting of Stockholders are incorporated by
`reference into Part II "Securities Authorized For Issuance Under Equity Compensation Plans" and Part III of this Form
`10K, or, in the event the Registrant does not prepare and file such Proxy Statement, will be provided instead by an
`amendment to this report containing the applicable disclosures within 120 days after the end of the fiscal year covered by
`this report. (With the exception of those portions which are specifically incorporated by reference in this report, any such
`Proxy Statement is not deemed to be filed or incorporated by reference as part of this report).
`
`TABLE OF CONTENTS
`
`Item
`
`PART I
`
`1.
`
`Business
`
`1A.
`
`1B.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`PART II
`
`Risk Factors
`
`Unresolved Staff Comments
`
`Properties
`
`Legal Proceedings
`
`Mine Safety Disclosures
`
`Market for the Company's Common Equity, Related Stockholder
`Matters and Company Purchases of Equity Securities
`
`Selected Financial Data
`
`Management's Discussion and Analysis of Financial Condition and
`Results of Operations
`
`7A.
`
`Quantitative and Qualitative Disclosures About Market Risk
`
`Page
`
`3
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`26
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`42
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`42
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`42
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`45
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`45
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`47
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`48
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`10K 2014 DOC
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`8.
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`9.
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`9A.
`
`9B.
`
`Financial Statements and Supplementary Data
`
`Changes in and Disagreements with Accountants on Accounting and
`Financial Disclosure
`
`Controls and Procedures
`
`Other Information
`
`PART III
`
`10.
`
`Directors, Executive Officers and Corporate Governance
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`PART IV
`
`SIGNATURES
`
`Executive Compensation
`
`Security Ownership of Certain Beneficial Owners and Management
`and Related Stockholder Matters
`
`Certain Relationships and Related Transactions, and Director
`Independence
`
`Principal Accountant Fees and Services
`
`Exhibits and Financial Statement Schedules
`
`65
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`95
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`95
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`96
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`96
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`96
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`96
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`96
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`10K 2014 DOC
`PART I
`
`Unless the context requires otherwise, references in this report to "NPS", the "Company", "we", "us", "our" and similar
`terms mean NPS Pharmaceuticals, Inc. and its subsidiaries.
`
`This Annual Report on Form 10K and the documents incorporated by reference into this report contain certain forward
`looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements are based
`on our current expectations and are subject to uncertainty and changes in circumstances. We cannot guarantee the accuracy
`of such statements, and you should be aware that results and events could differ materially from those contained in such
`statements. You should consider carefully the statements set forth in Item 1A of this report entitled "Risk Factors" and
`Item 7 of this report entitled "Management's Discussion and Analysis of Financial Condition and Results of Operations".
`
`ITEM 1. Business
`
`Merger Agreement
`
`On January 11, 2015, we entered into an Agreement and Plan of Merger (Merger Agreement) with Shire Pharmaceutical
`Holdings Ireland Limited (Parent), a company incorporated in Ireland and a wholly owned subsidiary of Shire plc (Shire),
`a company incorporated in Jersey; Knight Newco 2, Inc. (Purchaser), a Delaware corporation and wholly owned subsidiary
`of Parent; and, solely for purposes of Section 12.14 of the Merger Agreement, Shire. Pursuant to the Merger Agreement,
`Purchaser has commenced a cash tender offer for all of the outstanding shares of the Company's common stock, upon the
`terms and subject to the conditions of the Merger Agreement. Consummation of the tender offer is subject to customary
`closing conditions, as set forth in the Merger Agreement. As soon as practicable following the consummation of the tender
`offer, and subject to the satisfaction or waiver of certain conditions set forth in the Merger Agreement, Purchaser will
`merge with and into the Company pursuant to the provisions of section 251(h) of the Delaware General Corporation Law,
`with no stockholder vote required to consummate the merger, and the Company will survive as a wholly owned subsidiary
`of Parent.
`
`The Merger Agreement contains representations, warranties and covenants of the parties customary for transactions of this
`type. Until the earlier of the termination of the Merger Agreement and the consummation of the merger, the Company has
`agreed to operate its business and the business of its subsidiaries in the ordinary course and has agreed to certain other
`operating covenants, as set forth more fully in the Merger Agreement. The Company has agreed not to solicit alternative
`acquisition proposals. However, the Company may, subject to the terms and conditions set forth in the Merger Agreement,
`furnish information to, and engage in discussions and negotiations with, a third party that makes an unsolicited acquisition
`proposal that the Board reasonably believes is or could reasonably be expected to lead to a superior proposal. Under
`certain circumstances and upon compliance with certain notice and other specified conditions set forth in the Merger
`Agreement, the Company may terminate the Merger Agreement to accept a superior proposal.
`
`The Merger Agreement contains certain termination rights for both Parent and the Company and further provides that,
`upon termination of the Merger Agreement under certain circumstances relating to competing acquisition proposals,
`including if the Company terminates the Merger Agreement to accept a superior proposal, or where our Board of Directors
`changes its recommendation in favor of the transaction, the Company may be required to pay Parent a termination fee of
`$155,939,696.
`
`Shire has secured an $850 million fully underwritten shortterm bank facility, which in addition to Shire's cash and cash
`equivalents and its existing $2.1 billion fiveyear revolving credit facility, is available to finance the transaction and pay
`related fees and expenses.
`
`Additional information about the merger is set forth in our filings with the U.S. Securities and Exchange Commission
`(SEC).
`
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`Overview
`
`10K 2014 DOC
`
`We are a global biopharmaceutical company pioneering and delivering firstin or bestin disease therapies that transform
`the lives of patients with rare diseases. Our vision is a world where every person living with a rare disease has a treatment
`option. We incorporated in Utah in 1986 and reincorporated in Delaware in 1992. Our current therapeutic areas of focus
`are rare gastrointestinal and endocrine disorders. These include Short Bowel Syndrome, a potentially fatal gastrointestinal
`disorder in which patients may have to rely on parenteral support for their survival; Hypoparathyroidism, a complex
`endocrine disorder in which the parathyroid glands are either absent or damaged and the body produces insufficient or no
`parathyroid hormone; and Autosomal Dominant Hypocalcemia (ADH), an ultrarare genetic disorder of calcium
`homeostasis caused by mutations of the calciumsensing receptor gene.
`
`Our first marketed product, Gattex® 0.05 mg/kg/d (teduglutide [rDNA origin]) for injection, for subcutaneous use was
`approved by the U.S. Food and Drug Administration ("FDA") in December 2012 for the treatment of adult patients with
`Short Bowel Syndrome ("SBS") who are dependent on parenteral support. SBS is an ultrarare potentially fatal disorder in
`which the body is unable to absorb enough nutrients and fluids through the gastrointestinal tract. In the European Union
`("EU"), teduglutide (trade name: Revestive®) is approved for the treatment of adult patients with SBS; patients should be
`stable following a period of intestinal adaptation after surgery. We launched Revestive in Germany and Sweden in 2014
`and plan to launch in other EU countries in 2015. We also have orphan drug designation in Japan and a small local study in
`Japanese SBS patients is underway. In addition, a global development program in pediatric SBS is advancing and we are
`currently evaluating the results from the first study.
`
`Our second product, Natpara® (parathyroid hormone) for Injection was approved in January 2015 as an adjunct to calcium
`and vitamin D to control hypocalcemia in patients with hypoparathyroidism, a rare endocrine disorder characterized by
`insufficient levels of parathyroid hormone or PTH. Natpara, a bioengineered replica of human PTH, is expected to be
`available in the second quarter of 2015.
`
`Because of the potential risk of osteosarcoma, Natpara is recommended only for patients who cannot be wellcontrolled on
`calcium supplements and active forms of vitamin D alone. Natpara was not studied in patients with hypoparathyroidism
`caused by calciumsensing receptor mutations or in patients with acute postsurgical hypoparathyroidism.
`
`In the EU, the European Medicines Agency is currently reviewing our Marketing Authorization Application for Natpar®
`which is the European brand name for Natpara, in hypoparathyroidism.
`
`We have collaborations or royalty agreements with a number of pharmaceutical companies. In 2014, we recorded $122.9
`million of royalty revenue that was driven by (i) Amgen's sales of Sensipar® and Mimpara® (cinacalcet HCl), (ii) Kyowa
`Hakko Kirin's sales of REGPARA® (cinacalcet HCl) in Japan, and (iii) Janssen's sales of Nucynta® (tapentadol) in the
`U.S. As described further herein, we have partially monetized our royalty rights related to Sensipar and Mimpara under our
`agreement with Amgen through the issuance of nonrecourse debt and we have sold certain of our rights to receive royalty
`payments arising from sales of REGPARA under our agreement with Kyowa Hakko Kirin.
`
`We consider our operations to be a single reportable segment. Financial results of this reportable segment are presented in
`our audited consolidated financial statements.
`
`Significant Developments
`
`In January 2015, we entered into a merger agreement with Shire pursuant to which Shire will acquire all of our
`outstanding shares for $46 per share.
`In January 2015, the FDA approved our BLA for Natpara.
`
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`Product and Development Programs and RoyaltyBased Agreements
`
`The table below includes our proprietary product and development programs:
`
`Indication
`
`Product
`
`Gattex® (teduglutide) for injection
`
`Revestive (teduglutide)
`
`Gattex/Revestive (teduglutide)
`
`Gattex/Revestive (teduglutide)
`
`Natpara® (recombinant human parathyroid
`hormone 184)
`
`Natpar®
`
`NPSP795
`
`
`
`
`
` Commercial
`Adult SBS
`
`
`
`
` Commercial
`Adult SBS
`
`
`
`
`
`Phase 4
`SBS (Registry)
`
`
`
` Registration
`Pediatric SBS
`study
`
`
`
`Hypoparathyroidism Commercial
`
`
`
`Hypoparathyroidism MAA
`Accepted
`
`
`
`ADH
`
`Phase 2
`
`Status
`
` Market
`
`
`
`
`
`
`
`U.S.
`
`EU
`
`Worldwide ex
`Israel
`
`Worldwide ex
`Israel
`
`U.S.
`
`ExU.S.
`
`
`
` Worldwide
`
`
`
`
`
`
`The table below includes certain of our royaltybased agreements:
`
`Product
`Sensipar®/Mimpara®
`(cinacalcet HCl)1
`
`Sensipar® (cinacalcet
`HCl)1
`
`Indication
`
` Primary and Secondary
`hyperparathyroidism
`
` Hypercalcemia in parathyroid cancer
`
`
`
`
`Status
`
` Commercial
`
`
` Commercial
`
`
`
`REGPARA®
`(cinacalcet HCl)2
`
`NUCYNTA®
`(tapentadol) and
`Nucynta ER
`
`Ronacaleret (calcilytic
`compound)
`
` Secondary hyperparathyroidism
`
` Commercial
`
`
` Moderate to severe acute pain
` Moderate to severe chronic pain
` Neuropathic pain associated with
`diabetic peripheral neuropathy in adults
`
` Stem cell mobilization
`
`
`
` Commercial
`
`
`
`
`
`
` Phase 2
`
`Asia
`
`
`
`
`
`
`
`
`
`
`
`
` Rights
` Market
`Worldwide
`ExAsia Amgen
`
`
`
`Worldwide
`ExAsia Amgen
`
`
`
`Kyowa
`Hakko
`Kirin
`
`Janssen
`
`
`
`GlaxoSmith
`Kline
`
`
`
`
`U.S.
`
`
`
`
`
`
`
`
`
`
` Worldwide
`
`1We currently receive cash payments for royalties earned in excess of $8.0 million per quarter related to Amgen's sales of
`Sensipar and Mimpara. The $8.0 million per quarter services nonrecourse debt.
`2We currently do not receive cash payments related to our REGPARA royalties as we have sold certain of our rights to
`receive these payments to service our non recourse debt.
`
`Product and Development Programs
`
`Gattex/Revestive (Teduglutide [rDNA] origin]) for Injection
`
`Gattex is a novel recombinant analog of human glucagonlike peptide 2 (GLP2), a protein involved in the rehabilitation of
`the intestinal lining. SBS results from surgical resection, congenital defect or diseaseassociated loss of
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`absorption in the bowel in which patients are subsequently unable to maintain fluid, electrolyte, and nutrient balances on a
`conventional diet. Despite an adaptation that occurs generally in the two years after resection, many SBS patients require
`parenteral support to supplement and stabilize their nutritional and hydration needs.
`
`We launched Gattex in the U.S. in February 2013 and in certain exU.S. countries in late 2014. In December 2012, the
`FDA approved Gattex for the treatment of adult patients with SBS who are dependent on parenteral support. In August
`2012, the European Commission approved Revestive® for the treatment of adult patients with SBS; patients should be
`stable following a period of intestinal adaptation after surgery.
`
`Significant reductions in mean parenteral support volume from baseline to end of treatment were seen in the Phase 3
`studies of Gattex. In addition, some patients were able to achieve independence from parenteral support during these trials.
`The most common side effects of Gattex include stomach area (abdomen) pain or swelling, skin reaction where the
`injection was given, nausea, headache, cold or flu like symptoms, vomiting, and holding too much fluid in the body
`(swelling of face, ankles, hands or feet).
`
`SBS Market Opportunity
`
`SBS is a very rare and highly disabling condition that can impair a patient's quality of life and lead to serious life
`threatening complications. SBS typically arises after extensive resection of the bowel due to Crohn's disease, ischemia or
`other conditions. SBS patients often suffer from malnutrition, severe diarrhea, dehydration, fatigue, osteopenia, and weight
`loss due to the reduced intestinal capacity to absorb nutrients, water and electrolytes. Before the approval of
`Gattex/Revestive, the only longterm treatment available for SBS was parenteral support to supplement and stabilize
`hydration and nutritional needs.
`
`Parenteral support does not improve the body's own ability to absorb nutrients and it is associated with shortened life span,
`lifethreatening complications including sepsis, blood clots or liver damage, and reduced qualityoflife due to the time
`required for, and consequences of, frequent access to an intravenous pump. A National Institute of Health (NIH)
`publication reported that the annual mean costs of lifelong, complex home healthcare associated with PN/IV support
`ranged from $185,000 to $568,000, not including the indirect costs associated with disability and/or the dollar value that
`could be ascribed to the challenging daily living for these patients (Piamjariyakul 2010).
`
`Gattex/Revestive is the first longterm therapy approved for adult SBS patients. Currently two products somatropin
`(rDNA origin) for injection (human growth hormone) and Lglutamine powder for oral solution are approved for the
`treatment of SBS for up to four and 16 weeks, respectively. The goal of treatment with Gattex/Revestive is to enhance
`absorption by increasing villus height and crypt depth of the intestinal mucosa and to reduce or eliminate dependence on
`parenteral support.
`
`We believe the SBS market is attractive because of the lack of effective longterm drug therapies in this rare indication, the
`high cost of parenteral support, the serious complications and morbidities associated with parenteral support, and the
`clinical benefits and improvements that we believe patients will experience with Gattex/Revestive therapy.
`
`Gattex/Revestive for adult SBS
`
`Gattex/Revestive is the first and only analog of GLP2 proven to increase intestinal absorption and decrease or eliminate
`the need for parenteral support.
`
`Our clinical development program for Gattex/Revestive is the largest and most comprehensive conducted in adult SBS
`patients to date, consisting of 15 clinical studies. Across all clinical studies, 566 subjects were exposed to at least one dose
`of Gattex, of whom 134 had SBS and were treated with 0.05 mg/kg/day Gattex/Revestive. The U.S. and EU approvals of
`Gattex/Revestive were based on an international, 24week, doubleblind, placebocontrolled, pivotal Phase 3 trial, known
`as STEPS. The primary endpoint of STEPS was defined as a 20 percent or greater reduction in parenteral support volume
`demonstrated at week 20 and sustained at week 24. The study's other endpoints included reductions in parenteral support
`volume and additional days off therapy. Key findings from the STEPS trial include:
`
`In an intenttotreat analysis at weeks 20 and 24, 63 percent of patients treated with Gattex/Revestive achieved at
`least a 20 percent reduction in weekly parenteral support volume when compared to baseline, versus 30 percent of
`patients on placebo (p=0.002).
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`After 24 weeks of treatment, parenteral support volume declined by 32 percent (4.4 L/week) in Gattex/Revestive
`treated patients, versus 21 percent (2.3 L/week) in the placebo group (p<0.001).
`After 24 weeks of treatment, 54 percent of Gattex/Revestivetreated patients were able to reduce the number of
`infusion days per week by one or more days, compared to 23 percent of those treated with placebo (p=0.005).
`
`Ninetyseven percent (76/78) of subjects who completed STEPS elected to enroll in STEPS 2 (37 received Gattex; 39
`received Placebo). An additional 12 subjects entered STEPS 2, who had been optimized and stabilized but not randomized
`in STEPS because of closed enrollment.
`
`30 months exposure
`
`Thirty Gattex subjects completed a total duration of 30 months (STEPS followed by STEPS 2 treatment). Of these, 28
`subjects (93%) achieved a 20% or greater reduction of parenteral support. Of responders in STEPS who had completed 2
`additional years of continuous treatment with Gattex, 96% (21/22) sustained their response to Gattex. The mean reduction
`in PN/I.V. (n=30) was 7.55 L/week (a 65.6% reduction from baseline). Ten subjects were weaned off their PN/I.V. support
`while on Gattex treatment for 30 months. Subjects were maintained on Gattex even if no longer requiring PN/I.V. support.
`These 10 subjects had required PN/I.V. support for 1.2 to 15.5 years, and prior to Gattex had required between 3.5 L/week
`and 13.4 L/week of PN/I.V. support. At the end of study, 21 (70%), 18 (60%) and 18 (60%) of the 30 completers achieved
`a reduction of 1, 2, or 3 days per week in PN/I.V. support, respectively.
`
`24 month exposure
`
`Of the 39 placebo subjects from STEPS entering STEPS 2, 29 completed 24 months of treatment with Gattex. The mean
`reduction in PN/I.V. was 3.11 L/week (an additional 28.3% reduction) from the start of STEPS 2. Sixteen (55.2%) of the
`29 completers achieved a 20% or greater reduction of parenteral support. At the end of study, 14 (48.3%), 7 (24.1%) and 5
`(17.2%) achieved a reduction of 1, 2, or 3 days per week in PN/I.V. support, respectively. Two subjects were weaned off
`their PN/I.V. support while on Gattex. Of the 12 subjects entering STEPS 2 directly, 6 completed 24 months of treatment
`with Gattex. Similar effects were seen. One of the six subjects was weaned off their PN/I.V. support while on Gattex.
`
`The most common adverse reactions (≥10 percent) across all studies with Gattex/Revestive include stomach area
`(abdomen) pain or swelling, skin reaction where the injection was given, nausea, headache, cold or flu like symptoms,
`vomiting, and holding too much fluid in the body (swelling of face, ankles, hands or feet). In addition, vomiting and fluid
`overload were reported in the Phase 3 SBS studies at rates ≥ 10 percent. Gattex may cause serious side effects, including:
`making abnormal cells grow faster, polyps in the colon (large intestine), blockage of the bowel (intestines), welling
`(inflammation) or blockage of the gallbladder or pancreas, and fluid overload.
`
`The FDA and European Commission have granted orphan drug status for Gattex and Revestive, respectively for the
`treatment of SBS.
`
`Gattex/Revestive for pediatric SBS
`
`We are also evaluating the safety and efficacy of Gattex/Revestive in pediatric SBS. We recently completed an openlabel
`4cohort study that enrolled 42 pediatric SBS patients between the ages of 1 and 17. Nonrandomized patients received
`Gattex/Revestive in 3 active cohorts. We also enrolled additional patients into an observational fourth cohort who received
`standard of care. The three doses of Gattex/Revestive were investigated for 12 weeks. The patients were screened prior to
`the start of treatment to establish baseline characteristics including safety, eligibility and nutritional support. The primary
`outcome is safety, based on the number of reported adverse events after 12 weeks of teduglutide. In addition we will look
`at the pharmacodynamics based on the changes in parenteral and enteral support requirements after 12 weeks of treatment.
`We are currently analyzing the data from the study.
`
`Pediatric SBS is a complex and highly morbid condition with significant mortality rates. Patients suffer from repeated
`episodes of sepsis, dehydration, and metabolic derangements. Pediatric SBS is also associated with diarrhea or stomal
`output that can be traumatizing and socially debilitating. Researchers from the University of Michigan reported in a
`publication that in the U.S., over a fiveyear period the mean cost of care for a child with SBS is $1.6 million and over that
`same period pediatric SBS patients spend an average of 146 days in the hospital (Spencer et al. 2008). In December 2013,
`we initiated a global registration study of Gattex/Revestive in pediatric patients with SBS who are dependent on parenteral
`support.
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`Natpara® (parathyroid hormone) for Injection
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`10K 2014 DOC
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`Natpara is our bioengineered replica of human parathyroid hormone that is approved as an adjunct to calcium and vitamin
`D to control hypocalcemia in patients with hypoparathyroidism, a rare endocrine disorder in which the body produces
`insufficient levels of PTH, a principal regulator of the body's mineral homeostasis.
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`Natpara is recommended only for patients who cannot be wellcontrolled on calcium supplements and active forms of
`vitamin D alone. Natpara was not studied in patients with hypoparathyroidism caused by calciumsensing receptor
`mutations or in patients with acute postsurgical hypoparathyroidism.
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`Hypoparathyroidism is a rare endocrine disorder in which the parathyroid glands fail to produce sufficient amounts of
`parathyroid hormone (PTH) or where the hormone lacks biologic activity. PTH plays a central role in a variety of critical
`physiological functions in the body. Insufficient levels of PTH lead to low levels of calcium and high levels of phosphate
`in the blood, and an inability to convert native vitamin D into its active state, which helps the body properly absorb oral
`calcium. Parathyroid hormone increases serum calcium by increasing renal tubular calcium reabsorption, increasing
`intestinal calcium absorption (i.e., by converting native vitamin D (25 OH) into its active form (1,25 OH2 vitamin D)) and
`by increasing bone turnover which releases calcium into the circulation.
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`Acute symptoms of hypoparathyroidism are largely due to hypocalcemia and include fatigue, muscle spasms and cramps,
`tingling, tetany, seizures, brain fog/mental lethargy, anxiety, and depression. Prior to an approved parathyroid replacement
`therapy, treatment options were limited to calcium supplements and active vitamin D to increase calcium levels in the
`blood and reduce the severity of hypocalcemic symptoms. However, balancing the administration of supplements is
`challenging due to calcium fluctuations. In clinical trials, Natpara has been shown to reduce the amount of oral calcium
`and active vitamin D required to maintain serum calcium levels.
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`Hypoparathyroidism Market
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`Epidemiological data on hypoparathyroidism are limited given its rarity and the variability in the severity of the symptoms
`associated with this disorder. The most common cause of hypoparathyroidism is injury to or removal of the parathyroid
`glands during neck surgery. The definition of permanent postsurgical hypoparathyroidism is generally accepted to be
`insufficient parathyroid hormone to maintain normal calcium levels six months after surgery. Hypoparathyroidism can also
`be associated with autoimmune or other disorders or it can be idiopathic in nature.
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`Hypoparathyroidism is one of the few endocrine deficiency syndromes in which hormonal therapy is not clinically
`available. Treatment of hypoparathyroidism is further complicated by the lack of national or international consensus
`management guidelines.
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`As is the case for most rare diseases, the burden of illness for hypoparathyroidism has not been well described or studied.
`Considering the need to better understand the burden of illness associated with this condition, we conducted an extensive
`quantitative study known as PARADOX in conjunction with the Hypoparathyroidism Association and the Mayo Clinic.
`This study is the largest ever conducted in this condition and included 374 patients with hypoparathyroidism. Key findings
`from PARADOX suggest that patients with hypoparathyroidism have a high burden of illness, as 99% continue to
`experience multiple symptoms despite the use of calcium and vitamin D supplements and other medications. On average,
`patients reported experiencing a collection of 16 of the 38 symptoms reported in the analysis. The most common physical
`symptoms reported included fatigue (82%), muscle pain or cramping (78%), paresthesia (76%), tetany (70%), and joint or
`bone pain (67%), and pain/heaviness/weakness in extremities (53%). Cognitive and emotional symptoms were also
`prevalent. Brain fog/mental lethargy (72%), inability to focus or concentrate (65%), and memory loss or forgetfulness
`(61%), and sleep disturbances (57%) were common, while anxiety (59%) and depression (53%) were also reported. The
`findings also showed that symptoms persist for an average of 13 hours over the course of a day. While patients indicated
`that they were managing their symptoms with calcium and vitamin D, they continued to develop comorbidities of
`hypoparathyroidism and suffer from acute episodes requiring emergency care and/or hospitalization. Sixtynine percent of
`patients experienced comorbidities since diagnosis. Common comorbid conditions that were most frequently reported by
`patients in PARADOX included heart arrhythmias (66%) and kidney stones (36%). Bone fractures (16%) were also
`reported. Seventynine percent of patients reported hospital stays or emergency department visits, with the annualized rate
`for patients who classified their condition as severe exceeding those of patients with mild or moderate condition. Patients
`exceeded the national average for the general population for emergency department visits and hospital stays.
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`Calcium supplementation is associated with several challenges, including renal function deterioration, renal stones, and
`soft tissue calcifications. In the longterm followup study of 120 patients with hypoparathyroidism (Mitchell et al. 2012)
`adverse renal effects were observed. The risk of renal complications in patients with hypoparathyroidism was also
`evaluated in a case study using the Danish National Patient Registry and a prescription database. Six hundred and eight
`eight (688) patients were identified who manifested symptoms of hypocalcemia and inappropriately low PTH levels
`following neck surgery that required oral calcium and/or active vitamin D. Compared with age and sexmatched controls,
`patients with hypoparathyroidism had an increased risk of renal complications (hazard ratio: 3.67, 95% CI, 2.41 to 5.59)
`(Underbjerg et al. 2013). Experts recommend close monitoring of patients being treated for hypoparathyroidism with large
`amounts of calcium and vitamin D preparations (De Sanctis et al. 2012; Shoback 2008).
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`The direct and indirect health care costs for persons with hypoparathyroidism are substantial. In a study conducted by the
`Mayo Clinic, the mean and median costs for persons with hypoparathyroidism were approximat