`10K 1 form10k.htm 10K
`
`10K 2013 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, 2013
`
`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 $1,540,963,266 as of June
`30, 2013, based upon the closing price for the shares of common stock reported on The NASDAQ Global Market on such
`date.
`
`As of February 11, 2014, there were 102,801,552 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 2014 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.
`
` PDF provided as courtesy
`
`Item
`
`PART I
`
`1.
`
`Business
`
`TABLE OF CONTENTS
`
`1A.
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`1B.
`
`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`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
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`Page
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`3
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`26
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`41
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`41
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`41
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`43
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`44
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`8.
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`9.
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`9A.
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`9B.
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`10K 2013 DOC
`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.
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`13.
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`14.
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`15.
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`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
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`95
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`10K 2013 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
`
`Overview
`
`We are a biopharmaceutical company focused on pioneering and delivering therapies that transform the lives of patients
`with rare diseases worldwide. Our strategy is focused on the global development and commercialization of `firstin' or
``bestin' rare disease therapeutics. We incorporated in Utah in 1986 and reincorporated in Delaware in 1992. Our 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 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 expect commercial sales of Revestive to begin in certain exUS territories in 2014. We plan to begin
`pricing and reimbursement discussions in certain EU countries during the first half of 2014. In addition, namedpatient
`programs have been initiated in a number of countries and we are implementing our regulatory strategy for Japan, which
`includes filing for orphan drug status. We are also seeking to expand our SBS franchise by evaluating the safety and
`efficacy of Gattex/Revestive in a global registration study of pediatric patients with SBS patients.
`
`Our second product, Natpara® (rhPTH[184]) for injection, has been developed for hypoparathyroidism, a rare
`multidimensional disorder characterized by deficient or absent parathyroid hormone (PTH). The review of our Biologic
`License Application for Natpara is ongoing and the Prescription Drug User Fee Act (PDUFA) goal date for a decision by
`FDA is October 24, 2014. Within our Filing Review Notification, also referred to as the Day74 letter, the FDA told us
`they plan to discuss our Natpara application at an advisory committee meeting. We expect to file our Marketing
`Authorization Application (MAA) for Natpara in hypoparathyroidism with the European Medicines Agency (EMA) in
`2014.
`
`We are actively pursuing inlicensing opportunities to build a global pipeline of `firstin' or `bestin' therapies for rare
`disorders of high unmet medical need. Our lead clinicalstage product candidate is NPSP795, a calcilytic compound with
`potential application in rare disorders involving increased calcium receptor activity, such as autosomal dominant
`hypocalcemia (ADH).
`
`We have collaborations or royalty agreements with a number of pharmaceutical companies. In 2013, we recorded $123.8
`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.
`
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`Significant Developments
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`10K 2013 DOC
`
`In February 2013, we launched and initiated commercial sales of Gattex in the US and we reported net sales of $31.8
`million for the year ended December 31, 2013. At December 31, 2013, 530 Gattex/Revestive prescriptions had been
`received and 303 patients were on therapy in the U.S. We expect commercial sales of Revestive to begin in certain
`exUS territories during the first half of 2014 with meaningful sales to begin in the later part of the year.
`
`In March 2013, we entered into an agreement, with Takeda GmbH and Takeda Pharma A/S (together, Takeda),
`which, among other things, terminated our existing license agreements with Takeda with respect to teduglutide and
`rhPTH 184. As a result of the transaction, we now have the exclusive worldwide rights, excluding Israel, to develop
`and commercialize teduglutide and rhPTH 184. Takeda received 6.1 million shares of NPS common stock that were
`valued at $54.9 million as of the date of the transaction. Takeda will also earn a $30.0 million milestone, payable in
`cash or stock at our option, in the first calendar year that combined worldwide net sales of both products exceed
`$750 million.
`
`In May 2013, we completed a public sale of 6,900,000 shares of our common stock at a per share price of $14.53.
`We received net proceeds from the sale of approximately $93.5 million, after deducting expenses and the
`commission in connection with the offering.
`
`In January 2014, the FDA accepted and filed for review our BLA for Natpara. Under PDUFA, the goal date for a
`decision by the FDA is October 24, 2014. Within our Filing Review Notification, also referred to as the Day74
`letter, the FDA also noted that they plan to hold an advisory committee meeting to discuss our Natpara application.
`
`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)
`
`Natpara
`
`NPSP795
`
`
`
`
`U.S.
`
`EU
`
`Worldwide ex
`Israel
`
`Worldwide ex
`Israel
`
`U.S.
`
`
`
`ExU.S.
`
`
`
` Worldwide
`
`
`
`
`Status
`
` Market
`
`
`
`
`
`
`
` Commercial
`Adult SBS
`
`
`
`
` Approved
`Adult SBS
`
`
`
`
`
`Phase 4
`SBS (Registry)
`
`
`
` Registration
`Pediatric SBS
`study
`
`
`
`Hypoparathyroidism BLA filed
`
`
`
`Hypoparathyroidism
`Phase 3
`
`
`
`ADH
`
`Phase 2
`
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`The table below includes certain of our royaltybased agreements:
`
`
`
`Indication
`
`
`
`Status
`
`Product
`Sensipar®/Mimpara®
`(cinacalcet HCl)1
`
`Sensipar® (cinacalcet
`HCl)1
`
`Cinacalcet HCl1
`
`REGPARA®
`(cinacalcet HCl)2
`
`NUCYNTA®
`(tapentadol) and
`Nucynta ER
`
`Ronacaleret (calcilytic
`compound)
`
`
`
` Secondary hyperparathyroidism
`
` Hypercalcemia in parathyroid cancer
`
` Primary hyperparathyroidism
`
`
`
`
`
` Commercial
`
`
` Commercial
`
`
`
`
` Commercial
`
`
`
`
`
`
`
` 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
`
` Rights
` Market
`Worldwide
`ExAsia Amgen
`
`
`
`Worldwide
`ExAsia Amgen
`
`
`
`Worldwide
`ExAsia Amgen
`
`
`
`Kyowa
`Hakko
`Kirin
`
`Janssen
`
`
`
`GlaxoSmith
`Kline
`
`Asia
`
`
`
`
`
`
`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 nonrecourse 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 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 US in February 2013 and we expect commercial sales of Revestive to begin in certain exUS
`countries in 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).
`
`In 2007, we granted Takeda, the rights to develop and commercialize teduglutide outside the United States, Canada,
`Mexico and Israel. We regained these rights in March 2013 and now have worldwide, excluding Israel, rights to
`teduglutide.
`
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`SBS Market Opportunity
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`10K 2013 DOC
`
`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).
`
`We have estimated that there are between 9,000 and 17,000 addressable SBS patients worldwide who are eligible for
`Gattex/Revestive therapy with an estimated 3,000 to 5,000 patients in the U.S. market. Gattex/Revestive is the first long
`term 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, 24 week, 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).
`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).
`
`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.
`
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`In October 2013, we reported new findings from our STEPS 2 study of Gattex/Revestive at the American College of
`Gastroenterology (ACG) Annual Scientific Meeting and Postgraduate Course. STEPS 2 was a twoyear openlabel
`extension study of 88 adult patients with SBS. Investigators reported that the longterm use of Gattex/Revestive in patients
`with SBS resulted in additional, clinically meaningful reductions in the volume and days per week of parenteral support
`requirements in this extension study. In addition, 10 of 13 patients who achieved complete independence from parenteral
`support were those who received 30 months of Gattex in the 6month STEPS pivotal study and the 24month STEPS 2
`study. Two patients who received placebo in STEPS and 24 months of Gattex/Revestive in STEPS 2 and one patient who
`bypassed STEPS and was enrolled directly into STEPS 2 also achieved independence from parenteral support. No new
`unexpected safety concerns were observed with longterm Gattex/Revestive treatment and the product's safety profile
`remains consistent with the product's label. We have submitted these data to the FDA and the EMA to include longterm
`data from STEPS 2 in our U.S. and EU prescribing information.
`
`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. In December 2013 we initiated an
`openlabel 4 cohort study that will enroll approximately 36 pediatric SBS patients between the ages of 1 and 17. Non
`randomized patients will receive Gattex/Revestive in 3 active cohorts. We are also planning to enroll additional patients
`into an observational fourth cohort who will receive standard of care. The three doses of Gattex/Revestive will be
`investigated for 12 weeks. The patients will be 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 would expect to report topline data from the
`study in late2014 or early 2015.
`
`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 US, 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.
`
`Natpara® (recombinant human parathyroid hormone 184 [rDNA origin] injection)
`
`Natpara is our bioengineered replacement for endogenous PTH that we have developed for the treatment of
`hypoparathyroidism, a rare endocrine disorder in which the body produces insufficient levels of PTH, a principal regulator
`of the body's mineral homeostasis.
`
`PTH plays a central role in a variety of critical physiological functions, including closely modulating serum calcium and
`phosphate, regulating renal excretion of calcium and phosphate, activating vitamin D, and maintaining normal bone
`turnover. In patients with hypoparathyroidism, insufficient levels of PTH lead to low serum calcium, high serum
`phosphate, increased urinary calcium excretion, and decreased urinary phosphorus excretion. PTH deficiency can also
`disrupt skeletal homeostasis, leading to bone abnormalities. In addition, patients with insufficient levels of PTH are unable
`to convert native vitamin D into its active state to properly absorb dietary calcium.
`
`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. In the absence of an approved parathyroid
`replacement therapy, the standard approach focuses on using high doses of calcium 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 and the longterm use of high doses of calcium and vitamin D may
`lead to serious complications, including longterm renal damage. In addition, because serum phosphate levels are elevated
`when PTH is missing, increasing serum calcium may lead to irreversible calciumphosphate deposits in the kidneys,
`arteries or brain. Further, supplements do not correct the abnormal bone metabolism due to PTH deficiency or enable the
`activation of vitamin D.
`
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`Hypoparathyroidism Market Opportunity
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`10K 2013 DOC
`
`Epidemiological data on hypoparathyroidism are limited given its rarity and the variability in the severity of the symptoms
`associated with this disorder. Based on market research we have conducted, we believe the prevalence of chronic
`hypoparathyroidism in our targeted global markets is 180,000 patients of which approximately 70,000 patients are
`considered highly symptomatic despite current management approaches, which represents our initial target. 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.
`
`Hypoparathyroidism is one of the few hormonal deficiency syndromes in which replacement therapy using the native
`hormone is not clinically available. Treatment of hypoparathyroidism is further complicated by the lack of national or
`international consensus management guidelines.
`
`In the absence of an approved parathyroid replacement therapy, the standard approach focuses on using high doses of
`calcium 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 and the longterm use of
`high doses of calcium and vitamin D may lead to serious complications, including longterm renal damage. In addition,
`because serum phosphate levels are elevated when PTH is missing, increasing serum calcium may lead to irreversible
`calciumphosphate deposits in the kidneys, arteries or brain. Further, supplements do not correct the abnormal bone
`metabolism due to PTH deficiency or enable the activation of vitamin D.
`
`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.
`
`A study of the longterm followup of 120 patients with hypoparathyroidism was recently published (Mitchell et al, 2012).
`Hypoparathyroidism was confirmed by documented hypocalcemia with a simultaneous low or inappropriately normal PTH
`level for at least 1 year. Of those with renal imaging (n = 54), 31% had renal calcifications, and 52% of those with head
`imaging (n = 31) had basal ganglia calcifications. Rates of chronic kidney disease Stage 3 or higher were 2 to 17 fold
`greater than ageappropriate norms.
`
`The risks of renal complication and cardiovascular disease in subjects with hypoparathyroidism were also evaluated in a
`case study gleaned from the Danish National Patient Registry and a prescription database. From 1988 to the present, 688
`patients were identified who manifested symptoms of hypocalcemia and inappropriately low PTH levels necessitating
`treatment with calcium and/or vitamin D supplementation following neck surgery. Compared with age and gender
`matched controls, patients with hypoparathyroidism had an increased risk of renal complications and hospitalization due to
`seizures (Underbjerg et al, 2013).
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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 approximately threefold those for
`unaffected persons of similar age/sex.
`
`The PARADOX study and other epidemiological research show that hypoparathyroidism has a significant impact on
`patients in many ways: physical, emotional, quality of life, social life, and productivity. Despite the currently available
`medical management, symptoms persist and occur frequently, even daily and, when experienced on a moderate or severe
`level, can negatively affect the patients' life. In addition to associated symptoms, patients report comorbidities that are
`directly related to their hypoparathyroidism. These concurrent conditions necessitate further medical treatment. Given the
`chronicity of hypoparathyroidism patients are faced with a lengthy affliction with chronic and debilitating symptoms and
`complications.
`
`To help illustrate the fundamental aspects of hypoparathyroidism, we initiated enrollment in a global natural history
`registry for patients with hypoparathyroidism. The objective of the study, known as PARADIGHM, is to characterize the
`natural history of chronic hypoparathyroidism, including its treatment, clinical outcomes, comorbidities and mortality as
`observed in a typical clinical setting. The ultimate goal for compiling the PARADIGHM registry is to assist healthcare
`practitioners in optimizing clinical decision making for patients with hypoparathyroidism. The registry is designed to help
`healthcare practitioners better understand the variability, progression and natural history of the disorder. Patients will be
`enrolled and followed for at least 10 years to characterize this rare, complex endocrine dis