TAKEDA

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK ) (“Takeda”) this week shared new data revealing the burden of chronic hypoparathyroidism on patients and caregivers, as well as potential long-term risks of renal and cardiovascular complications that patients treated with conventional therapy may experience. Six-year results from the open-label long-term safety and efficacy RACE study were also announced. Data was presented at the Endocrine Society’s 2019 Annual Meeting (ENDO) from 23–26 March in New Orleans, Louisiana, USA.

“Results from the Burden of Illness Global Survey in 13 countries reveal the extent of the impact hypoparathyroidism has on patients and their caregivers throughout their daily lives,” said John Bilezikian M.D., Professor of Medicine at the Columbia University Irving Medical Center, New York, NY, USA. “This offers important insights and enables us to take a more holistic approach in the management of these patients due to a greater understanding of the potential cardiovascular risks patients may face, along with other complications of the kidneys,” he added.

“We are committed to further investigating this rare condition and collecting more data on the long-term implications,” said John Germak, Global Medical Team Lead at Takeda. “Gaining valuable insights directly from patients enhances our understanding of the complex nature of the disease and its management. The data presented at ENDO supports this cause.”

Three abstracts from the Burden of Illness Global Survey were presented for the first time at ENDO. The multi-country self-reported survey, the first large study of its kind, looked at physical and mental health components to characterise the burden and impact of the disease. Results showed substantial symptom burden and health-related quality of life impact in patients with chronic hypoparathyroidism not adequately controlled with conventional therapy, and their caregivers.^1,2,3

New data on the risk of chronic kidney disease (CKD) and its progression were also presented alongside a study investigating estimated glomerular filtration rate (eGFR) decline in patients with chronic hypoparathyroidism. Furthermore, results from a new study looking at the risk of cardiovascular conditions in patients with chronic hypoparathyroidism – an area of limited prior research – were shared.^4,5,6,7

Final results from the six-year RACE study, with efficacy endpoints of calcium dose reduction, reduction in calcitriol dose and normalization or maintaining serum calcium, reported data in key measurements of mineral homeostasis in chronic hypoparathyroidism patients treated with recombinant human parathyroid hormone rhPTH (1-84). In addition, results from this study reported a safety profile consistent with previous clinical trials results. ⁸

Takeda presented a total of eight abstracts at the congress further building on the company’s knowledge and experience of the disease.

All abstracts are available on the ENDO 2019 website at https://www.abstractsonline.com/pp8/#!/5752

About the Data

Burden of Illness Global Patient and Caregivers Survey ^1,2,3
The survey data showed patients experience substantial symptom burden including physical fatigue (97%), muscle cramps (86%), tingling (84%), brain fog (77%), anxiety (78%) and depression (76%). The magnitude of symptom severity correlated with the impact on the reduction in patients’ health-related quality of life.

Patients also reported an impact on their lifestyle through a symptom diary, showing an effect on sleep (78%), the ability to exercise (84%), ability to work (75%) as well as an impact on family relationships (63%). In turn, caregivers reported a major impact on their relationship with spouse/partner, family and friends.

Long-term Complications Associated with Chronic Hypoparathyroidism ^4,5,6,7,13
Four studies were presented. Results from a study investigating the risk of CKD and its progression, a retrospective controlled cohort study comparing risks in chronic and non-hypoparathyroidism patients, showed that patients with chronic hypoparathyroidism on conventional therapy had a significantly increased risk of developing CKD stage 3 and greater, as well as progression to end stage renal disease. In addition, eGFR – a key indicator of kidney function¹³ – was examined and an association with chronic hypoparathyroidism and increased rate of eGFR decline over time was observed in the subset of cohorts with laboratory data available. Moreover, hypoparathyroid patients had an increased risk of nephrolithiasis and nephrocalcinosis compared with matched controls of patients without hypoparathyroidism.

In another retrospective cohort study, to compare the risk of cardiovascular (CV) conditions in patients with chronic hypoparathyroidism and non-hypoparathyroidism patients, the database analysis showed that chronic hypoparathyroidism patients had an increased risk of experiencing a new occurrence of each of the cardiovascular conditions studied, as well as the composite cardiovascular endpoints of cerebrovascular disease, coronary artery disease, peripheral artery disease and heart failure, compared to patients without hypoparathyroidism.

These studies, presented for the first time at ENDO, employed a systematic way to examine risk associations between long-term complications and chronic hypoparathyroidism. Although considered hypothesis generating and further research is warranted, the findings provide valuable new data and additional learnings for this rare condition.

RACE 6-year Long-term Safety and Efficacy of rhPTH (1-84) ⁸
Six-year results from the open-label RACE study presented at ENDO showed that treatment with rhPTH (1-84) in patients with chronic hypoparathyroidism had a safety profile consistent with previous clinical studies, and impacted key measurements of mineral homeostasis, notably of urinary calcium. Albumin-corrected serum calcium levels remained within the target range, stable urinary calcium excretion, serum phosphate, serum creatinine, and eGFR was observed and doses of oral calcium and calcitriol were reduced by >40% and >70% compared to baseline.

About Hypoparathyroidism
Hypoparathyroidism is a rare endocrine disease which occurs when inadequate levels of parathyroid hormone (PTH) are secreted by the parathyroid glands in the neck, resulting in a mineral imbalance in the body.^9,10,11 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 to be chronic.^10,12 Chronic hypoparathyroidism can have a significant impact on patients’ health-related quality of life, as well as leading to serious long-term complications.

About NATPARA ^® (parathyroid hormone) for Injection in the U.S.
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.¹⁴ 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.

About NATPAR ^® for Injection in Europe
NATPARA is approved in Europe under the tradename NATPAR^® . NATPAR is indicated as adjunctive treatment of adult patients with chronic hypoparathyroidism who cannot be adequately controlled with standard therapy alone. ¹⁵ Takeda 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, Greece, Austria, Denmark and Norway.

U.S. 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.

For more information about the NATPARA REMS program, call 1-855-NATPARA or go to www.NATPARAREMS.com .

Contraindications
NATPARA is contraindicated in patients with a known hypersensitivity to any component of NATPARA. Hypersensitivity reactions (e.g., anaphylaxis, angioedema, and urticaria) have occurred with NATPARA.

Warnings and Precautions
Hypercalcemia: Severe hypercalcemia has been reported with NATPARA. The risk is highest when starting or increasing the dose of NATPARA but can occur at any time. Monitor serum calcium and patients for signs and symptoms of hypercalcemia. Treat hypercalcemia per standard practice and consider holding and/or lowering the dose of NATPARA if severe hypercalcemia occurs.

Hypocalcemia: Severe hypocalcemia has been reported in patients taking NATPARA, including cases that resulted in seizures. The risk is highest with interruption or discontinuation of NATPARA treatment but can occur at any time. Monitor serum calcium and patients for signs and symptoms of hypocalcemia, and replace calcium and vitamin D if indicated in patients interrupting or discontinuing NATPARA to prevent severe hypocalcemia.

Digoxin Toxicity: 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.

Hypersensitivity: There have been reports of hypersensitivity reactions in patients taking NATPARA. Reactions included anaphylaxis, dyspnea, angioedema, urticaria, and rash. If signs or symptoms of a serious hypersensitivity reaction occur, discontinue treatment with NATPARA, treat hypersensitivity reaction according to the standard of care, and monitor until signs and symptoms resolve. Monitor for hypocalcemia if NATPARA is discontinued.

Adverse Reactions
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: Co-administration 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 U.S. Prescribing Information:
http://www.shirecontent.com/PI/PDFs/Natpara_USA_ENG.pdf

Click here for the full European Prescribing Information:
https://www.ema.europa.eu/en/documents/product-information/natpar-epar-product-information_en.pdf

About Takeda Pharmaceutical Company Limited
Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK ) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Gastroenterology (GI), Neuroscience, and Rare Diseases. We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people's lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions.
For more information, visit https://www.takeda.com

References
1. Impact of Chronic Hypoparathyroidism on Health-Related Quality of Life: Findings from a 13-Country Patient Survey. Siggelkow et al., ENDO, March 2019. Available at: https://www.abstractsonline.com/pp8/#!/5752/presentation/15405
2. Symptoms, Comorbidities and Treatment Satisfaction with Chronic Hypoparathyroidism: Findings from a 13-Country Patient Survey. Bollerslev et al., ENDO, March 2019. Available at: https://www.abstractsonline.com/pp8/#!/5752/presentation/15404
3. Impact of Chronic Hypoparathyroidism on Word, Productivity, and relationships: Findings from a 13-Country Patient and Caregiver Survey. Clarke et al. ENDO, March 2019. Available at: https://www.abstractsonline.com/pp8/#!/5752/presentation/15403
4. Risk of Chronic Kidney disease (CKD) and Its Progression in Patients with Chronic Hypoparathyroidism (HypoPT). Chen et al. ENDO, March 2019. Available at: https://www.abstractsonline.com/pp8/#!/5752/presentation/15406
5. Risk of Decline in Estimated Glomerular Filtration Rate (eGFR) in Patients with Chronic Hypoparathyroidism (HypoPT). Chen et al, ENDO, March 2019. Available at: https://www.abstractsonline.com/pp8/#!/5752/presentation/15408
6. Risk of Cardiovascular (CV) Conditions in Patients with Chronic Hypoparathyroidism (HypoPT). Chen et al. ENDO, March 2019. Available at: https://www.abstractsonline.com/pp8/#!/5752/presentation/15410
7. Risk of Nephrolithiasis and Nephrocalcinosis in Patients with Chronic Hypoparathyroidism (HypoPT). Chen et al. ENDO, March 2019. Available at: https://www.abstractsonline.com/pp8/#!/5752/presentation/15407
8. Safety and Efficacy of Recombinant Human Parathyroid Hormone 1-84 for the Treatment of Adults with Chronic Hypoparathyroidism: Six-Year Results of the RACE study. Bilezikian, et al. ENDO, March 2019. Available at: https://www.abstractsonline.com/pp8/#!/5752/presentation/16334
9. Shoback DM, et al. J Clin Endocrinol Metab. 2016;101(6):2300–12.
10. Bollerslev J, et al. Eur J Endocrinol. 2015;173:G1–G20.
11. Hadker N, et al. Endocr Pract. 2014;20(7):671–9.
12. Brandi et al. J Clin Endocrinol Metab. 2016;101:2273–83.
13. 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 Accessed: Jan 2019
14. Natpara® Highlights of prescribing information. Initial US approval: 2015. Available at: http://www.shirecontent.com/PI/PDFs/Natpara_USA_ENG.pdf. Accessed Jan 2019
15. Natpar® Summary of Product Characteristics.

View source version on businesswire.com: https://www.businesswire.com/news/home/20190326005139/en/

Contact:

Japanese Media Kazumi Kobayashi kazumi.kobayashi@takeda.com +81 (0) 3-3278-2095

Media outside Japan Annabel Cowper annabel.cowper@takeda.com +41 79 630 8619

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