Half Yearly Report
`
`Shire plc
`
`Half Yearly Report 2015
`
`Registered in Jersey, No. 99854, 22 Grenville Street, St Helier, Jersey JE4 8PX
`CFAD Exhibit 1057
`CFAD v. NPS
`IPR2015-01093
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`2
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`Half Yearly Report
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`Contents
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`The “safe harbor” statement under the Private Securities Litigation Reform Act of 1995
`Trade Marks
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`Chief Executive Officer’s review
`Business overview for the six months to June 30, 2015
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`Results of operations for the six months to June 30, 2015 and June 30, 2014
`Principal risks and uncertainties
`
`Directors’ responsibility statement
`Unaudited consolidated balance sheets at June 30, 2015 and December 31, 2014
`Unaudited consolidated statements of income for the six months to June 30, 2015 and June 30, 2014
`
`Unaudited consolidated statement of comprehensive income for the six months to June 30, 2015 and
`June 30, 2014
`Unaudited consolidated statement of changes in equity for the six months to June 30, 2015
`Unaudited consolidated statement of cash flows for the six months to June 30, 2015 and June 30, 2014
`
`Notes to the unaudited consolidated financial statements
`Non GAAP Measures
`
`Independent review report to Shire plc
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`Page
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`Half Yearly Report
`THE “SAFE HARBOR” STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995
`Statements included herein that are not historical facts are forward-looking statements. Such forward-looking
`statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks
`or uncertainties materialize, Shire’s results could be materially adversely affected. The risks and uncertainties include,
`but are not limited to, that:
`Shire’s products may not be a commercial success;
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`product sales from ADDERALL XR and INTUNIV are subject to generic competition;
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`the failure to obtain and maintain reimbursement, or an adequate level of reimbursement, by third-party
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`payers in a timely manner for Shire's products may affect future revenues, financial condition and results of
`operations;
`Shire conducts its own manufacturing operations for certain of its products and is reliant on third party contract
`manufacturers to manufacture other products and to provide goods and services. Some of Shire’s products or
`ingredients are only available from a single approved source for manufacture. Any disruption to the supply
`chain for any of Shire’s products may result in Shire being unable to continue marketing or developing a
`product or may result in Shire being unable to do so on a commercially viable basis for some period of time;
`the manufacture of Shire’s products is subject to extensive oversight by various regulatory agencies.
`Regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or
`manufacturing processes could lead to significant delays, an increase in operating costs, lost product sales,
`an interruption of research activities or the delay of new product launches;
`Shire has a portfolio of products in various stages of research and development. The successful development
`of these products is highly uncertain and requires significant expenditures and time, and there is no guarantee
`that these products will receive regulatory approval;
`the actions of certain customers could affect Shire's ability to sell or market products profitably. Fluctuations in
`buying or distribution patterns by such customers can adversely affect Shire’s revenues, financial condition or
`results of operations;
`investigations or enforcement action by regulatory authorities or law enforcement agencies relating to Shire’s
`activities in the highly regulated markets in which it operates may result in significant legal costs and the
`payment of substantial compensation or fines;
`adverse outcomes in legal matters and other disputes, including Shire’s ability to enforce and defend patents
`and other intellectual property rights required for its business, could have a material adverse effect on Shire’s
`revenues, financial condition or results of operations;
`Shire faces intense competition for highly qualified personnel from other companies and organizations. Shire
`is undergoing a corporate reorganization and was the subject of an unsuccessful acquisition proposal and the
`consequent uncertainty could adversely affect Shire’s ability to attract and/or retain the highly skilled
`personnel needed for Shire to meet its strategic objectives;
`failure to achieve Shire’s strategic objectives with respect to the acquisition of NPS Pharmaceuticals Inc.
`(“NPS Pharma”) may adversely affect Shire’s financial condition and results of operations; and
`other risks and uncertainties detailed from time to time in Shire’s filings with the Securities and Exchange
`Commission, including those risks outlined in “Item 1A: Risk Factors” in Shire’s Annual Report on Form 10-K for the
`year ended December 31, 2014.
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`TRADE MARKS
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`All trade marks designated ® and ™ used in this press release are trade marks of Shire plc or companies within the
`Shire group except for 3TC® and ZEFFIX® which are trade marks of GlaxoSmithKline, PENTASA® which is a trade
`mark of FERRING B.V. Corp, LIALDA® which is a trade mark of Nogra International Limited, MEZAVANT® which is a
`trade mark of Guiliani International Limited, CALCICHEW® which is a trade mark of Takeda, DERMAGRAFT® which is
`a trademark of Organogenesis Inc., VANCOCIN® which is a trademark of ANI Pharmaceuticals Inc. and DAYTRANA®
`which is a trade mark of Noven Pharmaceutical Inc. Certain trade marks of Shire plc or companies within the Shire
`group are set out in Shire’s most recent Annual Report and Accounts for the year ended December 31, 2014.
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`Half Yearly Report
`Chief Executive Officer’s review
`
`We are pleased to enclose our financial results for the six-month period ended June 30, 2015. This Half Yearly Report
`includes condensed consolidated financial statements prepared in accordance with generally accepted accounting
`principles in the United States of America (“US GAAP”).
`
`Flemming Ornskov, M.D., Shire’s Chief Executive Officer, commented:
`
`“During the first half of 2015, we delivered double-digit underlying product sales growth (on a Non GAAP CER(1) basis
`and excluding INTUNIV) amid continued investment in our pipeline and future growth drivers.
`
`Total reported product sales in the first half of 2015 were $2.9 billion, up 4%, and Non GAAP EBITDA(2) reached $1.4
`billion, growing 5%. We are especially pleased by the performance of VYVANSE, with total product sales growing
`18% to $842 million. This includes the market expansion of VYVANSE for adults with ADHD and the launch of the
`new adult indication for moderate to severe Binge Eating Disorder. The Rare Disease Business Unit continues to be
`our largest, with product sales of approximately $1.1 billion. LIALDA has also performed well, gaining market share
`and generating product sales of $306 million, up 12%.
`
`During the first half of the year, we further strengthened our focus on rare diseases through the acquisition of NPS
`Pharma, the largest acquisition in Shire’s history. NPS Pharma enabled us to leverage our GI commercial capabilities
`and global footprint while gaining access to two exciting rare disease assets, GATTEX®/REVESTIVE® and
`NATPARA®. GATTEX/REVESTIVE is off to a strong start and we are pleased with the early progress of NATPARA.
`This positive momentum underscores the strength of our M&A capabilities to effectively identify, acquire and integrate
`assets and deliver value. The NPS Pharma commercial integration has been completed.
`
`Our innovative pipeline saw several key developments in the first half of 2015. We received a Priority Review
`designation for lifitegrast for Dry Eye Disease and in July 2015 we completed enrolment of the OPUS 3 study for
`lifitegrast. In addition, we initiated a Phase 3 study for SHP465 ahead of plan and we received favourable FDA
`feedback on a path forward for a potential Phase 3 study for maribavir. Shire now has the broadest and deepest
`pipeline in its history.”
`
`Flemming Ornskov, M.D.
`Chief Executive Officer
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`(1)
`(2)
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`The Non GAAP CER financial measures included within this release is explained on page 59.
`Non GAAP earnings before interest, tax, depreciation and amortization (“EBITDA”). A reconciliation to US GAAP net income is provided on page 60.
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`Half Yearly Report
`Business overview for the six months to June 30, 2015
`
`The following discussion should be read in conjunction with the unaudited condensed consolidated financial
`statements and related notes appearing elsewhere in this Half Yearly Report for Shire plc and its subsidiaries
`(collectively “Shire” or “the Group”).
`
`Significant events in the six months to June 30, 2015 and recent developments
`
`Products
`INTUNIV for the treatment of attention deficit hyperactivity disorder (“ADHD”) in the EU
`The Committee for Medicinal Products for Human Use (“CHMP”) of the European Medicines Agency (“EMA”)
`(cid:120)
`has adopted a positive opinion at its July 2015 meeting recommending marketing authorization approval of
`INTUNIV (guanfacine) extended release drug product, a non-stimulant indicated as part of a comprehensive
`treatment programme for ADHD in children and adolescents 6 to 17 years old for whom stimulants are not
`suitable, not tolerated or have been shown to be ineffective.
`The CHMP positive opinion will be reviewed by the European Commission (“EC”) with the expectation that the
`EC will then grant a centralized marketing authorization with unified labeling that is valid in the 28 countries
`that are members of the European Union, as well as European Economic Area members, Iceland,
`Liechtenstein and Norway.
`
`RESOLOR – for the Symptomatic Treatment of Chronic Constipation in Men
`(cid:120) On May 27, 2015, Shire received the EC decision amending the terms of the RESOLOR Marketing
`Authorisation to the use of RESOLOR in adults for the symptomatic treatment of chronic constipation for
`whom laxatives fail to provide adequate relief. In Europe, RESOLOR was initially approved for use in women
`only, so the new variation extends the use of this treatment to male patients.
`
`VYVANSE – for the treatment of moderate to severe Binge Eating Disorder (“BED”) in adults
`Topline results from a 39-week, long-term maintenance of efficacy study (SPD489-346) in adults with
`(cid:120)
`moderate to severe BED showed VYVANSE superior to placebo (p<.001) on the primary efficacy endpoint of
`time to relapse of binge eating symptoms. At the conclusion of the trial, patients continuing on VYVANSE had
`a lower proportion of relapse of 5/136 (3.7%) as compared to patients continuing on placebo 42/131 (32.1%).
`The results of a separate, 12-month open-label safety extension study (SPD489-345) were generally
`consistent with the safety profile currently outlined in the United States Prescribing information.
`Based on the results of these studies, the Group plans to submit a supplemental New Drug Application by
`year end to the US Food and Drug Administration (“FDA”). The FDA will evaluate adding this data to the
`current labeling for VYVANSE.
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`(cid:120)
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`(cid:120)
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`(cid:120) On January 30, 2015 Shire launched VYVANSE for the treatment of adults with moderate to severe BED.
`
`VYVANSE – for the treatment of ADHD
`
`(cid:120) On March 23, 2015 Shire announced VYVANSE was available in a 10mg strength capsule. This new titration
`dose, which was approved by the FDA on October 30, 2014, is the seventh VYVANSE dosage strength
`available in addition to the 20mg, 30mg, 40mg, 50mg, 60mg, and 70mg capsule strengths. On April 7, 2015
`Health Canada approved the 10mg dose strength for incremental titration adjustments.
`
`NATPARA – for the treatment of hypoparathyroidism
`
`(cid:120) On January 23, 2015 it was announced that the FDA had approved NATPARA as an adjunct to calcium and
`vitamin D to control hypocalcemia in patients with hypoparathyroidism. Hypoparathyroidism is a rare
`endocrine disorder characterized by insufficient levels of parathyroid hormone, or PTH. NATPARA is a
`bioengineered replica of human PTH. NATPARA was launched on April 1, 2015.
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`Half Yearly Report
`Pipeline
`SHP620 (maribavir) – for the treatment of cytomegalovirus (“CMV”) infection in transplant patients
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`(cid:120)
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`In late June 2015, Shire conducted an end of Phase 2 meeting with the FDA and received further clarity on
`the path forward. Based on this feedback, Shire is considering progressing the program into Phase 3 in 2016.
`
`SHP631 – for the treatment of both the central nervous system (“CNS”) and somatic manifestations in patients with
`Hunter syndrome (“MPS II”)
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`(cid:120)
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`In Q2 2015, a Phase 1 trial of SHP631 (also known as AGT-182) was initiated. SHP631 is an investigational
`enzyme replacement therapy for the potential treatment of both the CNS and somatic manifestations in
`patients with Hunter syndrome MPS II.
`
`SHP606 (lifitegrast) – for the treatment of the signs and symptoms of Dry Eye Disease
`
`(cid:120) Shire has fully enrolled a Phase 3 safety and efficacy study (OPUS-3) in support of potential US and potential
`international regulatory submissions. OPUS-3 is a multicenter, randomized, double-masked, placebo-
`controlled, parallel arm study with a 14 day open-label placebo screening run-in period followed by a 12 week
`randomized, masked treatment period with a primary efficacy endpoint in subjective patient reported
`symptoms of dry eye disease as measured by the eye dryness score.
`
`(cid:120) On April 9, 2015 Shire announced that the FDA accepted the New Drug Application for lifitegrast and granted
`a Priority Review designation. The FDA has set an action date of October 25, 2015, based on the Prescription
`Drug User Fee Act V.
`
`SHP625 – for the treatment of cholestatic liver disease
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`(cid:120)
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`(cid:120)
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`In June 2015, Shire also received preliminary results from an interim analysis of the INDIGO study, a 72 week
`open label Phase 2 study in PFIC. The interim analysis was based on the first 12 subjects who completed 13
`weeks of treatment per protocol. SHP625 was well tolerated but there was no statistically significant reduction
`in mean serum bile levels from baseline.A change from baseline analysis was planned as there is no placebo
`treatment arm in this study. The changes from baseline for pruritus did reach statistical significance. 5 of the
`20 patients who received the drug experienced sustained decreases from baseline in serum bile acids ranging
`from 86 to 99% and also experienced marked reductions in pruritus as evidenced by absence of or only mild
`scratching at their last evaluation in this ongoing study. In this subset of patients where biomarkers of liver
`damage were elevated at baseline, as assessed by Alanine transaminase and Total Bilirubin, these values
`were normalized during the study. Shire continues to analyze the totality of the data to determine an
`appropriate path forward.
`
`In late May 2015, Shire also received results from the CLARITY trial, a 13 week, double-blind, placebo-
`controlled Phase 2 study in combination with Ursodeoxycholic Acid in Primary Biliary Cirrhosis. SHP625 did
`not meet the primary endpoint as measured by change in pruritus or the secondary endpoint in level of liver
`disease as measured by alkaline phosphatase. However, there was a significant reduction in mean serum bile
`acid levels versus placebo.
`
`(cid:120) On April 9, 2015 Shire announced that the small 13-week Phase 2 IMAGO trial of its investigational compound
`SHP625 did not meet the primary or secondary endpoints in the study of 20 pediatric patients with Alagille
`syndrome. Given the topline results from the IMAGO study of SHP625 in pediatric patients with Alagille
`syndrome, we plan to analyze the totality of data to better understand the mixed results we have seen. Data
`for this and other indications will be important to fully understand the safety and efficacy of SHP625 in patients
`with cholestatic liver disease.
`
`SHP465 – for the treatment of adults with ADHD
`
`(cid:120) On April 7, 2015 Shire announced that it had reached an agreement with the FDA on a clear regulatory path
`for SHP465 (triple-bead mixed amphetamine salts), an investigational oral stimulant medication being
`evaluated as a potential treatment for ADHD in adults. Shire has begun dosing patients in a Phase 3 study
`designed to evaluate the efficacy of SHP465 administered as a daily morning dose compared to a placebo in
`the treatment of children and adolescents (6-17 years of age inclusive) diagnosed with ADHD.
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`SHP609 – for the treatment of Hunter syndrome with CNS symptoms
`
`(cid:120) On January 26, 2015 Shire announced that the FDA has granted Fast Track designation for SHP609 for the
`treatment of neurocognitive decline associated with Hunter syndrome (mucopolysaccharidosis II).
`
`SHP611 – for the treatment of the late infantile form of MLD
`
`(cid:120) SHP611 is in development as recombinant human arylsulfatase A (rASA) delivered intrathecally every other
`week for the treatment of the late infantile form of MLD. This product has been granted orphan drug
`designation in the US and the EU. The Group initiated a 24 patient Phase 1/2 clinical trial in August 2012. The
`primary endpoint of this trial is to determine the safety of ascending doses (10mg, 30mg, and 100 mg) of rASA
`over 40 weeks. Secondary and exploratory endpoints focused on efficacy and include decline in motor
`function as defined by change in baseline Gross Motor Function Measure (GMFM-88). Based upon interim
`data for the first 18 patients, SHP611 was safe and well tolerated at all doses. In addition, while not
`statistically significant and despite a decline in GMFM-88 score across all doses, the 100mg dose caused a
`slower decline over the 40 week study period compared to the other two treatment groups, most notably for
`those patients with GMFM-88 > 40-50 at baseline. Analysis of other exploratory efficacy measures were also
`encouraging. We will continue to analyze these interim results and determine an optimal path forward in this
`development program.
`
`Other developments
`Board and Committee Changes
`
`(cid:120) On June 11, 2015 Shire announced the appointment of Olivier Bohuon to the Shire Board of Directors as a
`Non-Executive Director. Olivier will also be a member of the Science & Technology Committee of the Shire
`Board. Both appointments were effective from July 1, 2015.
`
`Meritage acquisition
`
`(cid:120) On February 24, 2015 Shire announced that it had acquired Meritage Pharma, Inc., a privately-held Group, for
`an upfront payment of $75 million and additional contingent payments based on the achievement of
`development and regulatory milestones. With the acquisition, Shire has acquired the global rights to
`Meritage’s Phase 3-ready compound, Oral Budesonide Suspension (SHP621), for the treatment of
`adolescents and adults with eosinophilic esophagitis, a rare, chronic inflammatory GI disease. This acquisition
`further enhances Shire’s late-stage pipeline and leverages the Group’s rare disease and GI commercial
`infrastructure and expertise.
`
`NPS Pharma acquisition
`
`(cid:120) On February 21, 2015 Shire completed the acquisition of NPS Pharma. Shire plans to accelerate the growth
`of NPS Pharma’s innovative portfolio through its market expertise in gastrointestinal (“GI”) disorders, core
`capabilities in rare disease patient management, and global footprint. The integration is progressing according
`to plan.
`
`Legal Proceedings
`See note 15 Commitments and contingencies of this Half Yearly Report for details of Shire’s legal proceedings.
`
`Dividend
`In respect of the six months ended June 30, 2015 the Board resolved to pay an interim dividend of 4.21 US
`(cid:120)
`cents per Ordinary Share (2014: 3.83 US cents per Ordinary Share).
`Dividend payments will be made in Pounds Sterling to holders of Ordinary Shares and in US Dollars to
`holders of ADSs. A dividend of 2.69(1) pence per Ordinary Share (an increase of 20% compared to 2014: 2.24
`pence) and 12.63 US cents per ADS (an increase of 10% compared to 2014: 11.49 US cents) will be paid on
`October 2, 2015 to shareholders on the register as at the close of business on September 4, 2015.
`
`(1)
`
`Translated using a GBP:USD exchange rate of 1.5631.
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`Half Yearly Report
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`Research and development
`
`Products in registration as of June 30, 2015
`
`INTUNIV for the treatment of ADHD in the EU
`The CHMP of the EMA has adopted a positive opinion at its July 2015 meeting recommending marketing authorization
`approval of INTUNIV (guanfacine) extended release drug product, a non-stimulant indicated as part of a
`comprehensive treatment programme for ADHD in children and adolescents 6 to 17 years old for whom stimulants are
`not suitable, not tolerated or have been shown to be ineffective.
`
`The CHMP positive opinion will be reviewed by the EC with the expectation that the EC will then grant a centralized
`marketing authorization with unified labeling that is valid in the 28 countries that are members of the European Union,
`as well as European Economic Area members, Iceland, Liechtenstein and Norway.
`
`SHP606 (lifitegrast) for the treatment of DED
`On April 9, 2015 Shire announced that the FDA had accepted for filing the NDA for lifitegrast and had granted a
`Priority Review designation. The FDA is expected to provide a decision on October 25, 2015, based on the
`Prescription Drug User Fee Act V action date. In parallel to the NDA submission, Shire has fully enrolled a Phase 3
`safety and efficacy study (OPUS-3) in support of potential US and potential international regulatory submissions.
`OPUS-3 is a multicenter, randomized, double-masked, placebo-controlled, parallel arm study with a 14 day open-label
`placebo screening run-in period followed by a 12 week randomized, masked treatment period with a primary efficacy
`endpoint in subjective patient reported symptoms of dry eye disease, as measured by the eye dryness score.
`On April 30, 2014 Shire announced top-line results from the prospective, randomized, double-masked, placebo-
`controlled SONATA trial which indicated no ocular or drug-related serious adverse events. The safety data indicated in
`the SONATA trial was entirely consistent with that observed in the Phase 2, OPUS-1 and OPUS-2 studies for
`lifitegrast.
`
`NATPAR for the treatment of HPT
`NATPAR (NATPARA in the US) is currently under review in Europe as an adjunct to calcium and vitamin D to control
`hypocalcemia in patients with HPT.
`
`Products in clinical development as of June 30, 2015
`
`Phase 3 and Phase 3-ready
`
`SHP465 for the treatment of ADHD in adults
`Shire’s NDA for SHP465 was previously submitted in 2006 to support the use of SHP465 as a longer-acting, once-
`daily treatment for ADHD in adults. With the growing adult ADHD population there is now a larger patient population
`and Shire expects a greater commercial need for this type of product than in 2006. SHP465 (mixed salts of a single
`entity amphetamine) capsules provide an extended-release of amphetamines to provide coverage of ADHD symptoms
`for adults throughout the day. On April 7, 2015 Shire announced that it had reached an agreement with the FDA on a
`clear regulatory path for SHP465. Shire has begun dosing patients in a Phase 3 study designed to evaluate the
`efficacy of SHP465 administered as a daily morning dose compared to a placebo in the treatment of children and
`adolescents (6-17 years of age inclusive) diagnosed with ADHD.
`
`SHP621 OBS, for the treatment of adolescents and adults with Esoinophilic Esophagitis (“EoE”)
`With the Meritage acquisition, Shire has acquired the global rights to Meritage’s Phase 3-ready compound, OBS, for
`the treatment of adolescents and adults with EoE, a rare, chronic inflammatory GI disease. EoE is a chronic disease
`that is increasingly being diagnosed in children and adults, with an estimated prevalence in the U.S. of ~181,000. It is
`characterized by inflammation and accumulation of a specific type of immune cell, called an eosinophil, in the
`esophagus. EoE patients may have persistent or relapsing symptoms related to esophageal dysfunction, which
`include dysphagia (difficulty swallowing) and food impaction.
`
`OBS is a proprietary viscous oral formulation of budesonide that is designed to coat the esophagus where the drug
`can act locally. Budesonide is the active pharmaceutical ingredient in several products approved by the FDA, including
`products for the treatment of asthma, allergic rhinitis, ulcerative colitis and Crohn’s disease. Budesonide is a
`corticosteroid and has an established safety profile in those diseases. The FDA has granted orphan drug designation
`to OBS for the treatment of patients with EoE.
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`Half Yearly Report
`FIRAZYR for the treatment of ACE inhibitor-induced Angioedema (“ACE-I AE”)
`A Phase 3 clinical trial to assess the efficacy of FIRAZYR for the treatment of ACE-I AE was initiated in the fourth
`quarter of 2013 and is ongoing.
`
`FIRAZYR for the treatment of Hereditary Angioedema (“HAE”) in Japan
`Shire plans to initiate a Phase 3 trial to evaluate the efficacy and safety of FIRAZYR for the treatment of HAE in
`Japanese patients in 2015.
`
`SHP555 (prucalopride; marketed as RESOLOR in the EU) for the treatment of chronic constipation in the US
`On January 10, 2012 Shire announced that it had acquired the rights to develop and market prucalopride in the US in
`an agreement with Janssen Pharmaceutica N.V. Discussions have been conducted with the FDA and an NDA
`submission pathway has been agreed. Planning is underway to confirm Phase 3 program activities and timelines.
`
`INTUNIV for the treatment of ADHD in Japan
`Under a collaboration agreement, Shionogi and Shire will co-develop and sell treatments for ADHD in Japan, including
`INTUNIV. A Phase 3 clinical program to evaluate the efficacy and safety of INTUNIV in Japanese patients aged 6 to
`17 was initiated in the second quarter of 2013 and is ongoing.
`
`SHP616 (CINRYZE) for routine prophylaxis against HAE attacks in adolescent and adult patients in Japan
`CINRYZE is indicated in the US for prophylaxis and in the EU for both prophylaxis and acute treatment of angioedema
`attacks in adolescent and adult patients with HAE. Based on feedback from the Pharmaceutical and Medical Devices
`Agency (“PMDA”), a Clinical Trial Notification (“CTN”) was resubmitted and approved on October 2, 2014.
`
`Phase 2
`
`LDX(1) for the treatment of ADHD in Japan
`Under a collaboration agreement, Shionogi and Shire will co-develop and sell ADHD products in Japan, including
`LDX. A Phase 2 clinical program to evaluate the efficacy and safety of LDX in Japanese patients aged 6 to 17 was
`initiated in the second quarter of 2013 and is ongoing.
`
`(1)
`
`Currently marketed as VYVANSE in the US and ELVANSE in certain countries in the EU for the treatment of ADHD.
`
`SHP607 for the prevention of Retinopathy of Prematurity (“ROP”)
`SHP607 is in development as a protein replacement therapy for the preventative treatment of ROP, a rare eye
`disorder associated with premature birth. In December 2014 Shire received notification that SHP607 was granted Fast
`Track designation by the FDA. In addition, this product has been granted orphan drug designation in both the US and
`EU. A Phase 2 clinical trial is currently ongoing.
`
`SHP609 for the treatment of Hunter syndrome with CNS symptoms
`SHP609 is in development as an enzyme replacement therapy (“ERT”) delivered intrathecally for Hunter syndrome
`patients with cognitive impairment. In January 2015 the FDA granted SHP609 Fast Track designation.
`In addition, this
`product has been granted orphan designation in the US. The Group initiated a pivotal Phase 2/3 clinical trial in the
`fourth quarter of 2013 which is ongoing.
`
`SHP610 for Sanfilippo A syndrome (Mucopolysaccharidosis IIIA)
`SHP610 is in development as an ERT delivered intrathecally for the treatment of Sanfilippo A syndrome, a Lysosomal
`Storage Disorder. The Group initiated a Phase 1/2 clinical trial in August 2010 which has now completed. Shire
`initiated a Phase 2b clinical trial for SHP610, which is designed to establish clinical proof of concept. The product has
`been granted orphan drug designation in the US and in the EU.
`
`SHP620 (maribavir) for the treatment of CMV infection in transplant patients
`SHP620 was acquired as part of the acquisition of ViroPharma. Shire has completed two Phase 2 studies in transplant
`recipients. The first trial was in first-line treatment of asymptomatic CMV viremia in transplant recipients and the
`results of this study showed that maribavir, at all doses, was at least as effective as valganciclovir in the reduction of
`circulating CMV to below the limits of assay detection (undetectable plasma CMV). The second study recently
`completed was for the treatment of resistant/refractory CMV infection/disease in transplant recipients. The purpose of
`this study was to determine whether maribavir is efficacious and safe in patients with disease which is resistant or
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`Half Yearly Report
`refractory to the standard of care CMV therapy (e.g., valganciclovir, foscarnet). This study also showed that maribavir,
`at all doses, was effective at lowering CMV to below the limits of assay detection. Approximately two-thirds of patients
`across the maribavir treatment groups achieved undetectable plasma CMV DNA (viral load) within 6 weeks. This
`product has been granted orphan drug designation in both the US and EU. In late June, 2015 Shire conducted an end
`of Phase 2 meeting with the FDA and received further clarity on the path forward. Based upon this feedback, Shire is
`considering progressing the program into Phase 3 in 2016.
`
`SHP625 for the treatment of cholestatic liver disease
`SHP625 was acquired as part of the recent acquisition of Lumena. Shire is currently conducting Phase 2 studies in the
`following indications: ALGS, PFIC, PBC, and Primary Sclerosing Cholangitis. This product has been granted orphan
`drug designation both in the US and EU.
`On April 9, 2015 Shire announced that the 13-week Phase 2 IMAGO trial of SHP625 did not meet the primary or
`secondary endpoints in the study of 20 pediatric patients with ALGS. Mean serum bile acid levels and pruritus at the
`end of the study were lower in both SHP625 and placebo treated groups as compared to baseline. However, in a post-
`hoc analysis, a positive correlation between percent changes from baseline in serum bile acid levels and pruritis was
`observed in the SHP625 treated group.
`In late May 2015, Shire also received results from the CLARITY study, a 13 week, doubled blind, placebo-controlled
`Phase 2 study in combination with UDCA in PBC. SHP625 did not meet the primary endpoint as measured by change
`in pruritus or the secondary endpoint in level of liver disease as measured by the ALP. However, there was a
`significant reduction in mean serum bile acid levels versus placebo.
`In June 2015, Shire received preliminary results from an interim analysis of the INDIGO study, a 72 week open label
`Phase 2 study in PFIC. The interim analysis was based on the first 12 subjects who completed 13 weeks of treatment
`per protocol. SHP625 was well tolerated but there was no statistically significant reduction in mean serum bile levels
`from baseline. A change from baseline analysis was planned as there is no placebo treatment arm in this study. The
`changes from baseline for pruritus did reach statistical significance. 5 of the 20 patients who received the drug
`experienced sustained decreases from baseline in serum bile acids ranging from 86 to 99% and also experienced
`marked reductions in pruritus as evidenced by absence of or only mild scratching at their last evaluation in this
`ongoing study. In this subset of patients where biomarkers of liver damage were elevated at baseline, as assessed by
`ALT and Total Bilirubin, these values were normalized during the study. Shire continues to analyze the totality of the
`data to determine an appropriate path forward.
`
`SHP616 (CINRYZE) for the treatment of Acute Antibody Mediated Rejection (“AMR”)
`A Phase 2 study for the treatment of AMR with SHP616 was completed in 18 patients. Shire has received FDA and
`EMA feedback and submitted an investigational new drug application (“IND”) in the second quarter of 2015. Shire
`plans to initiate a Phase 2/3 study in the second half of 2015.
`
`Phase 1
`
`SHP611 for the treatment of Metachromatic Leukodystrophy (“MLD”)
`SHP611 is in development as recombinant human arylsulfatase A (“rASA”) deli