Shire plc : New Data Presented at the Endocrine Society's 2018 Annual Meeting Advances Understanding of the Rare Disease Chronic Hypoparathyroidism

New Data Presented at the Endocrine Society's 2018 Annual Meeting Advances Understanding of the Rare Disease Chronic Hypoparathyroidism

-       Clinical and real-world data on chronic hypoparathyroidism provides new insights into the burden of the disease
-       Hypothesis generating study investigates renal function in patients treated with recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) compared to a historical control cohort over 3 years
-       Five-year RACE study of rhPTH(1-84) provides long-term safety and efficacy data

Dublin, Ireland - March 20, 2018 - Shire plc (LSE: SHP, NASDAQ: SHPG), the global leader in rare diseases, announced new data on its recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) in patients with chronic hypoparathyroidism, at the Endocrine Society's 100^th Annual Meeting and Exposition (ENDO), in Chicago, Illinois.

Hypoparathyroidism is a rare endocrine disease that 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 Chronic hypoparathyroidism is diagnosed in patients with a low concentration of calcium in the blood and inappropriately low PTH levels; for postsurgical chronic hypoparathyroidism the features of hypoparathyroidism must persist for at least 6 months after surgery.²

"The new data we are presenting at ENDO demonstrates a step forward in our understanding of chronic hypoparathyroidism, providing us with new insights into the burden of illness and how it may impact patients living with this rare disease," said Howard Mayer M.D., Senior Vice President and Chief Medical Officer, Shire. "These clinical and real-world studies reflect our commitment to advancing our knowledge of rare diseases and improving patient care." 

Dolores M. Shoback M.D., lead author of the RACE study, commented:

"Hypoparathyroidism is a rare disorder of mineral homeostasis due to deficiency of parathyroid hormone. Recombinant human parathyroid hormone (rhPTH [1-84]) is a relatively new treatment in the management of the disease in its chronic form, and therefore it is important to further improve our understanding of the safety and efficacy profile, especially in longer-term management of the condition."

Presentations at ENDO focused on research into the renal function of patients with chronic hypoparathyroidism⁴, the impact of the disease on quality of life⁵, as well as an analysis of the long-term safety and efficacy of rhPTH(1-84), the RACE study⁶.

The following is a summary of each abstract presented at ENDO:

Poster #MON-453 / MON-453: Comparison of 3-Year Estimated Glomerular Filtration Rates Between Recombinant Human Parathyroid Hormone (1-84) (rhPTH[1-84])-Treated Patients With Chronic Hypoparathyroidism and a Historical Control Cohort4
Chronic hypoparathyroidism is associated with an increased incidence of renal complications, including nephrolithiasis, nephrocalcinosis, and renal dysfunction7. This analysis compared estimated Glomerular Filtration Rates (eGFR) between patients treated with rhPTH(1-84) versus a historical control cohort of patients not treated with rhPTH(1-84) over a 3 year period. Glomerular filtration rate is a key indicator of renal function and a lower eGFR indicates lower kidney function8.

A total of 119 patients were included, 43 with rhPTH(1-84) treatment, selected from the ongoing open-label phase 3 RACE trial, and 76 historical control patients identified from the MedMining database using similar enrolment criteria to RACE, not treated with rhPTH(1-84). The historical cohort of patients not treated with rhPTH(1-84) showed a greater decline in mean eGFR compared with patients on rhPTH(1-84), after taking known confounders into account.

This retrospective analysis is hypothesis generating and further research is warranted.

Poster #MON-452 / MON-452: Symptom burden and HRQoL reported among patients with chronic hypoparathyroidism: impact of treatment with rhPTH (1-84) and with standard therapy⁵

Chronic hypoparathyroidism is associated with a variety of symptoms and diminished health-related quality of life (HRQoL).³ This web-based patient survey provides further understanding of how patients with chronic hypoparathyroidism experience significant interference with their lives, including impact on work responsibilities as well as physical and mental conditions.

90 adult patients with hypoparathyroidism currently on rhPTH(1-84) and 47 adult patients with hypoparathyroidism on standard treatment completed the survey.

The results indicated that patients on rhPTH(1-84) treatment experienced an average of 9.1 symptoms (range 0-34), compared with patients on standard therapy (oral calcium and/or vitamin D supplements) who experienced an average of 20.2 symptoms (range 1-39) over a recall period of up to 12 months.

In addition, a numerically greater proportion of patients on standard therapy reported significant disease-associated interference with their lives (49%) and impact on work responsibilities (31%) compared with patients on rhPTH(1-84) (27% and 15%, respectively).

Conclusions drawn are limited by the nature of the study design. This cross-sectional real-world non-interventional study did not control for baseline characteristic differences that could impact treatment outcomes between cohorts. The survey responses were dependent on patient recall.

The web-based survey was developed with input from members of the Hypoparathyroidism Association and from physician experts.

Oral presentation #OR20-3: Five-year efficacy and safety of rhPTH(1-84) for the treatment of adults with chronic hypoparathyroidism: analysis from the open-label RACE study⁶

RACE is an ongoing open-label study of rhPTH(1-84) for the treatment of chronic hypoparathyroidism in adults. The analysis outcomes revealed that the efficacy composite endpoint was achieved by 28 of 40 patients* (70.0%) at month 60.

Oral calcium and calcitriol doses were reduced by 53.4% and 75.7%, respectively, while albumin-adjusted serum calcium levels were maintained within the target range. Serum creatinine levels also remained stable at 60 months, as did eGFR.

Treatment-emergent adverse events (TEAEs) were reported in 48 of 49 patients (98.0%). The most common TEAEs (>25% of patients) reported were hypocalcemia (36.7%), muscle spasms (32.7%), paresthesia (30.6%), sinusitis (30.6%), and nausea (30.6%). Serious TEAEs occurred in 13 patients (26.5%).

All abstracts are available on the ENDO website at http://www.abstractsonline.com/pp8/#!/4482.

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.^2,9  

About NATPARA^® (parathyroid hormone) for Injection
NATPARA, available as 25, 50, 75, and 100 mcg per dose strength, is a parathyroid hormone indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism. Because of the potential risk of osteosarcoma, NATPARA is recommended only for patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone. NATPARA was not studied in patients with hypoparathyroidism caused by calcium-sensing receptor mutations. NATPARA was not studied in patients with acute post-surgical hypoparathyroidism.

NATPARA is approved in Europe under the tradename NATPAR^®. 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, and Norway.

Important Safety Information
WARNING: POTENTIAL RISK OF OSTEOSARCOMA: In male and female rats, parathyroid hormone caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. A risk to humans could not be excluded. Because of the potential risk of osteosarcoma, prescribe NATPARA only to patients who cannot be well-controlled on calcium and active forms of vitamin D and for whom the potential benefits are considered to outweigh the potential risk.

Avoid use of NATPARA in patients who are at increased baseline risk for osteosarcoma (including those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, patients with hereditary disorders predisposing to osteosarcoma or patients with a history of prior external beam or implant radiation therapy involving the skeleton). NATPARA is available only through a restricted program called the NATPARA REMS Program.

NATPARA Warnings and Precautions include: Severe Hypercalcemia -- monitor serum calcium when starting or adjusting NATPARA dose and when making changes to coadministered drugs known to raise serum calcium. Severe Hypocalcemia can occur with interruption or discontinuation of NATPARA treatment -- Monitor serum calcium and replace calcium and vitamin D. Hypercalcemia increases the risk of digoxin toxicity -- in patients using NATPARA concomitantly with digoxin, monitor serum calcium more frequently and increase monitoring when initiating or adjusting NATPARA dose.

The most common adverse reactions associated with NATPARA and occurring in greater than 10% of individuals were: paresthesia, hypocalcemia, headache, hypercalcemia, nausea, hypoaesthesia, diarrhea, vomiting, arthralgia, hypercalciuria and pain in extremity.

Drug Interactions: Alendronate - Coadministration of alendronate and NATPARA leads to reduction in the calcium sparing effect, which can interfere with the normalization of serum
calcium. Concomitant use of NATPARA with alendronate is not recommended.

Use in Specific Populations: There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The safety and efficacy in pediatric patients have not been established.

Click here for the full Prescribing Information:
http://www.shirecontent.com/PI/PDFs/Natpara_USA_ENG.pdf 

For further information please contact:

NOTES TO EDITORS

About Shire

Shire is the global leader in serving patients with rare diseases. We strive to develop best-in-class therapies across a core of rare disease areas including hematology, immunology, genetic diseases, neuroscience, and internal medicine with growing therapeutic areas in ophthalmics and oncology. Our diversified capabilities enable us to reach patients in more than 100 countries who are struggling to live their lives to the fullest.

We feel a strong sense of urgency to address unmet medical needs and work tirelessly to improve people's lives with medicines that have a meaningful impact on patients and all who support them on their journey.

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; 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.     Chen K, et al. ENDO, March 2018. Available at: http://www.abstractsonline.com/pp8/#!/4482/presentation/7293.
5.     Chen K, et al. ENDO, March 2018. Available at: http://www.abstractsonline.com/pp8/#!/4482/presentation/7291.
6.     Shoback DM, et al. ENDO, March 2018. Available at: http://www.abstractsonline.com/pp8/#!/4482/presentation/7268.
7.     Mitchell DM, et al. J Clin Endocrinol Metab. 2012;97(12):4507-14.
8.     National Kidney Foundation. Glomerular Filtration Rate (GFR). Available at: https://www.kidney.org/sites/default/files/docs/11-10-1813_abe_patbro_gfr_b.pdf.
9.     Brandi ML, et al. J Clin Endocrinol Metab. 2016;101(6):2273-83.

*      The study cohort consisted of 49 patients when the study started.