Shire announces new hypoparathyroidism data at the 2018

Shire announces new hypoparathyroidism data at the 2018 European Congress of Endocrinology

• New Burden of Illness survey data shows patients living with chronic hypoparathyroidism report significant symptom burden
• Shire furthers the understanding of chronic hypoparathyroidism with data presented on new hypotheses about long-term treatment effects in patients as well as with safety and efficacy data for rhPTH (1-84) from the Open-Label RACE Study

Dublin, Ireland - May 22, 2018 - Shire plc (LSE: SHP, NASDAQ: SHPG), the global leader in rare diseases, presents new data on recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) in patients with chronic hypoparathyroidism at the 20 ^th European Congress of Endocrinology (ECE 2018), from 19-22 May 2018, in Barcelona, Spain. The latest studies provide valuable insights into the burden of the disease and impact of treatment in patients with chronic hypoparathyroidism, a rare endocrine disease.

Hypoparathyroidism occurs when inadequate levels of parathyroid hormone (PTH) are secreted by the parathyroid glands, resulting in a mineral imbalance in the body which can have a significant impact on patients. ^1,2,3 The disease is considered chronic when patients have a low concentration of calcium in the blood and inappropriately low PTH levels for more than 6 months ^2,4 , and could be at increased risk of renal complications such as nephrolithiasis, nephrocalcinosis, and renal dysfunction. ^5,6,7

A hypothesis-generating retrospective analysis, presented for the first time at ECE 2018, showed that patients not treated with rhPTH(1-84) exhibited a greater decline in Glomerular Filtration Rates (GFR), a key indicator of renal function, ⁸ compared with patients receiving rhPTH(1-84). ⁹

"As with any chronic disease, it is important to understand the long-term impact of treatment," said Howard Mayer M.D., Senior Vice President and Chief Medical Officer, Shire. "Given the kidney's central role in maintaining homeostasis of calcium and phosphate in the body, this study provides some important insights about long-term disease management, potential effects on renal function, and opens up new avenues for the future study of novel therapies."

New data from a global survey of patient reported outcomes on the burden of illness of hypoparathyroidism were also presented. ¹⁰ The self-reported 12 country survey was conducted in patients with chronic hypoparathyroidism. Interim results from the survey, again presented at ECE 2018 for the first time, highlight that the magnitude of symptom severity as reported by patients correlated with impact on their daily life. ¹⁰

"Patients with chronic hypoparathyroidism can experience a range of problems which impact different parts of their daily lives," said Dr Heide Siggelkow, University of Göttingen, Göttingen, Germany, and lead author of the study. "By understanding the severity of these symptoms and how they can affect the ability to work, exercise, sleep and emotional experiences, we can look at advancing the understanding of this disease to help these patients."

Several other clinical and real-world studies were presented by Shire at the congress ^11,12,13,14 with the aim to help physicians increase their understanding of hypoparathyroidism and thus achieve better outcomes for their patients. This wealth of data continues to underscore the commitment the company has to improving the understanding of this rare condition.

The full list of Shire abstracts presented are as follows:

• Renal Function Change in Chronic Hypoparathyroidism Patients Treated With Recombinant Human Parathyroid Hormone (1-84) (rhPTH[1-84]) and in a Historical Control Cohort Treated With Standard Therapy OC3.4  
• Burden of Illness Among Patients With Chronic Hypoparathyroidism Not Adequately Controlled With Standard Therapy by Self-Perception

P241

• Symptom Burden and HRQoL Reported Among Patients With Chronic Hypoparathyroidism: Impact of Treatment With rhPTH (1-84) and With Standard Therapy GP176 Guided poster tour  
• Five-Year Efficacy and Safety of Recombinant Human Parathyroid Hormone 1-84 (rhPTH[1-84]) for the Treatment of Adults With Chronic Hypoparathyroidism: Analysis From the Open-Label RACE Study GP180 Guided poster tour  
• The Global, Prospective, Observational PARADIGHM(TM) Registry for Patients With Chronic Hypoparathyroidism Was Expanded to Capture Recombinant Human Parathyroid Hormone, rhPTH(1-84), Use Under Routine Clinical Care GP178 Guided poster tour  
• Maintenance of Key Biochemical Parameters With Recombinant Human Parathyroid Hormone (1-84) in Patients With Hypoparathyroidism: An Analysis of a Long-Term, Open-Label, Single-Centre Study GP177 Guided poster tour

All abstracts will be available on the ECE 2018 website at http://www.endocrine-abstracts.org/ea/0056 .

Shire also sponsored two symposia at the meeting, focusing on the challenges of inadequate control of hypoparathyroidism.

About Hypoparathyroidism Chronic hypoparathyroidism is diagnosed in patients with a low concentration of calcium in the blood and inappropriately low PTH levels; for postsurgical hypoparathyroidism, the features of hypoparathyroidism must persist for at least 6 months after surgery to be considered chronic. ^2,4  

About NATPAR ^® (parathyroid hormone) for Injection NATPAR is a recombinant human PTH available as a 25, 50, 75 and 100 micrograms once-daily injection as adjunctive treatment for adult patients with chronic hypoparathyroidism who cannot be adequately controlled with standard therapy alone.

Shire is authorised to market NATPAR in the 28 Member States of the European Union, as well as in Iceland, Liechtenstein and Norway. Natpar is currently commercially available in Germany, Austria, Sweden, Denmark, Norway and the UK.

NATPAR is approved in the United States under the tradename NATPARA ^® . Click here for the full US Prescribing Information: http://www.shirecontent.com/PI/PDFs/Natpara_USA_ENG.pdf

Natpar   Safety Information   for Europe Please consult the Natpar Summary Product Characteristics (SmPC) before prescribing. Natpar treatment should be supervised by a physician or other qualified healthcare professional experienced in the management of patients with hypoparathyroidism.

Contraindications Natpar is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients, who are receiving or who have previously received radiation therapy to the skeleton, with skeletal malignancies or bone metastases, who are at increased baseline risk for osteosarcoma, with unexplained elevations of bone-specific alkaline phosphatase, with pseudohypoparathyroidism.  

Warnings and Precautions   Monitoring of patients during treatment  pre-dose and in some cases post-dose serum calcium levels must be monitored during treatment with Natpar.

Hypercalcemia  this was reported in clinical trials with Natpar. Hypercalcemia commonly occurred during the titration period, during which doses of oral calcium, active vitamin D, and Natpar were being adjusted. Hypercalcemia may be minimized by following the recommended dosing, the monitoring information and asking patients about any symptoms of hypercalcemia. If severe hypercalcemia develops, hydration and temporarily stopping Natpar, calcium and active vitamin D should be considered until serum calcium returns to the normal range. Then consider resuming Natpar, calcium and active vitamin D at lower doses.

Hypocalcemia  a common clinical manifestation of hypoparathyroidism, was reported in clinical trials with Natpar. Most of the hypocalcemic events occurring in the clinical trials were mild to moderate severity. The risk for serious hypocalcemia was greatest after the withdrawal of Natpar. Temporary or permanent discontinuation of Natpar must be accompanied by monitoring of serum calcium levels and increase of exogenous calcium and/or vitamin D sources as necessary. Hypocalcemia may be minimized by following the recommended dosing, the monitoring information, and asking patients about any symptoms of hypocalcemia.

Concomitant use with cardia glycosides  Hypercalcaemia of any cause may predispose to digitalis toxicity, monitor serum calcium and cardiac glycoside levels and patients for signs and symptoms of digitalis toxicity.

Severe renal or hepatic disease  Natpar should be used with caution in patients with severe renal or hepatic disease because they have not been evaluated in clinical trials.

Use in young adults  Natpar should be used with caution in young adult patients with open epiphyses.

Tachyphylaxis  the calcium-raising effect of Natpar may diminish over time in some patients. The response of serum calcium concentration to administration of Natpar should be monitored at intervals to detect this and the diagnosis of tachyphylaxis considered.

Adverse Reactions  

The most commonly observed adverse events  with Natpar treatment were hypercalcaemia, hypocalcaemia, headache, diarrhoea, vomiting, paraesthesia, hypoesthesia and hypercalciuria.

For further information please contact:

NOTES TO EDITORS

About Shire

Shire is the global biotechnology leader serving patients with rare diseases and specialized conditions. We seek to push boundaries through discovering and delivering new possibilities for patient communities who often have few or no other champions. Relentlessly on the edge of what's next, we are serial innovators with a diverse pipeline offering fresh thinking and new hope. Serving patients and partnering with healthcare communities in over 100 countries, we strive to be part of the entire patient journey to enable earlier diagnosis, raise standards of care, accelerate access to treatment, and support patients. Our Rare Disease and Neuroscience divisions support our diverse portfolio of therapeutic areas, including Immunology, Hematology, Genetic Diseases, Internal Medicine, Ophthalmics, Oncology, and neuropsychiatry disorders. Championing patients is our call to action - it brings the opportunity - and responsibility - to change people's lives.

www.shire.com Forward-Looking Statements Statements included herein that are not historical facts, including without limitation statements concerning future strategy, plans, objectives, expectations and intentions, projected revenues, the anticipated timing of clinical trials and approvals for, and the commercial potential of, inline or pipeline products, 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, the following:

• Shire's products may not be a commercial success;
• increased pricing pressures and limits on patient access as a result of governmental regulations and market developments may affect Shire's future revenues, financial condition and results of operations;
• Shire depends on third parties to supply certain inputs and services critical to its operations including certain inputs, services and ingredients critical to its manufacturing processes. 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, among other things, significant delays, an increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
• the nature of producing plasma-based therapies may prevent Shire from timely responding to market forces and effectively managing its production capacity;
• 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 conditions or results of operations;
• failure to comply with laws and regulations governing the sales and marketing of its products could materially impact Shire's revenues and profitability;
• Shire's products and product candidates face substantial competition in the product markets in which it operates, including competition from generics;
• Shire's patented products are subject to significant competition from generics;
• adverse outcomes in legal matters, tax audits 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 the Shire's revenues, financial condition or results of operations;
• Shire may fail to obtain, maintain, enforce or defend the intellectual property rights required to conduct its business;
• Shire faces intense competition for highly qualified personnel from other companies and organizations;
• failure to successfully execute or attain strategic objectives from Shire's acquisitions and growth strategy may adversely affect the Shire's financial condition and results of operations;
• Shire's growth strategy depends in part upon its ability to expand its product portfolio through external collaborations, which, if unsuccessful, may adversely affect the development and sale of its products;
• a slowdown of global economic growth, or economic instability of countries in which Shire does business, could have negative consequences for Shire's business and increase the risk of non-payment by Shire's customers;
• changes in foreign currency exchange rates and interest rates could have a material adverse effect on Shire's operating results and liquidity;
• Shire is subject to evolving and complex tax laws, which may result in additional liabilities that may adversely affect the Shire's financial condition or results of operations;
• if a marketed product fails to work effectively or causes adverse side effects, this could result in damage to Shire's reputation, the withdrawal of the product and legal action against Shire;
• Shire is dependent on information technology and its systems and infrastructure face certain risks, including from service disruptions, the loss of sensitive or confidential information, cyber-attacks and other security breaches or data leakages that could have a material adverse effect on Shire's revenues, financial condition or results of operations;
• Shire faces risks relating to the expected exit of the United Kingdom from the European Union;
• Shire incurred substantial additional indebtedness to finance the Baxalta acquisition, which has increased its borrowing costs and may decrease its business flexibility;
• Shire's ongoing strategic review of its Neuroscience franchise may distract management and employees and may not lead to improved operating performance or financial results; there can be no guarantee that, once completed, Shire's strategic review will result in any additional strategic changes beyond those that have already been announced;
• the potential uncertainty resulting from the announcement by Takeda Pharmaceutical Company Limited on 8 May 2018 of a recommended offer for Shire under the UK Takeover Code; and

                    a further list and description of risks, uncertainties and other matters can be found in Shire's most recent Annual Report on Form 10-K and in Shire's subsequent Quarterly Reports on Form 10-Q, in each case including those risks outlined in "ITEM1A: Risk Factors", and in Shire's subsequent reports on Form 8-K and other Securities and Exchange Commission filings, all of which are available on Shire's website.       All forward-looking statements attributable to us or any person acting on our behalf are expressly qualified in their entirety by this cautionary statement. Readers are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof. Except to the extent otherwise required by applicable law, we do not undertake any obligation to update or revise forward-looking statements, whether as a result of new information, future events or otherwise.

References

1. Shoback DM, et al. J Clin Endocrinol Metab . 2016;101(6):2300-12. 2.     Bollerslev J, et al. Eur J Endocrinol . 2015;173:G1-G20. 3.     Hadker N, et al. Endocr Pract. 2014;20(7):671-9. 4.     Brandi ML, et al. J Clin Endocrinol Metab . 2016;101(6):2273-83. 5.     Mitchell DM, et al. J Clin Endocrinol Metab . 2012;97(12):4507-14. 6.     Underbjerg L et al. J Bone Miner Res . 2013; 28(11): 2277-85. 7.     Underbjerg L et al. J Bone Miner Res . 2015; 30(9): 1738-44. 8.     National Kidney Foundation. Glomerular Filtration Rate (GFR). Available at: https://www.kidney.org/sites/default/files/do..._gfr_b.pdf . 9.     Chen et al. Renal function change in chronic hypoparathyroidism patients treated with recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) and in a historical control cohort treated with standard therapy. European Congress of Endocrinology May 2018. Available at: http://www.endocrine-abstracts.org/ea/0056/ea0056oc3.4.htm 10.  Siggelkow et al. Burden of Illness Among Patients With Chronic Hypoparathyroidism Not Adequately Controlled With Standard Therapy by Self-Perception European Congress of Endocrinology May 2018. Available at: http://www.endocrine-abstracts.org/ea/0056/ea0056p241.htm 11.  Chen et al. Symptom Burden and HRQoL Reported Among Patients With Chronic Hypoparathyroidism: Impact of Treatment With rhPTH (1-84) and With Standard Therapy. European Congress of Endocrinology May 2018. Available at: http://www.endocrine-abstracts.org/ea/0056/ea0056gp176.htm 12.  Clarke et al. Five-Year Efficacy and Safety of Recombinant Human Parathyroid Hormone 1-84 (rhPTH[1-84]) for the Treatment of Adults With Chronic Hypoparathyroidism: Analysis From the Open-Label RACE Study. European Congress of Endocrinology May 2018. Available at: http://www.endocrine-abstracts.org/ea/0056/ea0056gp180.htm 13.  Clarke et al. The Global, Prospective, Observational PARADIGHM(TM) Registry for Patients With Chronic Hypoparathyroidism Was Expanded to Capture Recombinant Human Parathyroid Hormone, rhPTH(1-84), Use Under Routine Clinical Care. European Congress of Endocrinology May 2018. Available at: http://www.endocrine-abstracts.org/ea/0056/ea0056gp178.htm 14.  Krasner et al. Maintenance of Key Biochemical Parameters With Recombinant Human Parathyroid Hormone (1-84) in Patients With Hypoparathyroidism: An Analysis of a Long-Term, Open-Label, Single-Centre Study. European Congress of Endocrinology May 2018. Available at: http://www.endocrine-abstracts.org/ea/0056/ea0056gp177.htm