Shire Granted EU Conditional Marketing Authorisation for Natpar[®] (Parathyroid Hormone) for the Treatment of Patients with Chronic Hypoparathyroidism

Zug, Switzerland (ots/PRNewswire) -

Natpar is the first and only licensed recombinant human
parathyroid hormone therapy for chronic hypoparathyroidism

Shire plc (LSE: SHP, NASDAQ: SHPG) today announced that the
European Commission (EC) has granted Conditional Marketing
Authorisation for Natpar (rhPTH[1-84]), the first recombinant human
protein with the full length 84-amino acid sequence of endogenous
parathyroid hormone (PTH). Natpar will be the first and only approved
hormone therapy indicated as adjunctive treatment for adult patients
with chronic hypoparathyroidism who cannot be adequately controlled
with standard therapy alone.[1] Hypoparathyroidism is a rare
endocrine disease resulting from an inappropriately low circulating
PTH concentration.[2]

''As the first and only licensed recombinant parathyroid hormone
treatment in Europe for chronic hypoparathyroidism, Natpar represents
a historical and timely innovation for patients who cannot be
adequately controlled on calcium and vitamin D alone," said Philip J.
Vickers, Ph.D., Global Head of Research and Development at Shire.
"The approval of Natpar offers an important advance in the management
of this rare endocrine disorder for patients in Europe."

The Conditional Marketing Authorisation is based on the outcomes
from the Phase III efficacy and safety of rhPTH(1-84) clinical trial
(REPLACE) in patients aged 19-74 years with chronic
hypoparathyroidism.[1] The trial showed that Natpar maintained serum
calcium while reducing oral calcium and active vitamin D supplemental
doses.[1]

"Chronic hypoparathyroidism can carry a significant disease
burden, and some patients are not well-controlled, showing
fluctuations in their serum calcium levels,[3]" said Professor Maria
Louisa Brandi, Department of Internal Medicine, University of
Florence, Italy. "Clinical studies have shown Natpar maintains serum
calcium while reducing the need for calcium and vitamin D for
patients with chronic hypoparathyroidism.[1]"

With this approval, Shire is now authorized to market Natpar in
the 28 Member States of the European Union (EU), as well as in
Iceland, Liechtenstein and Norway. Natpar falls under the scope of
European Commission Regulation as eligible for Conditional Marketing
Authorisation because it is designated as an orphan medicinal product
and fulfils an unmet medical need.

About hypoparathyroidism

Hypoparathyroidism is a rare disease that occurs when inadequate
levels of PTH are secreted by the parathyroid glands, resulting in a
mineral imbalance in the body expressed by a low concentration of
calcium (hypocalcemia) and a high concentration of phosphate
(hyperphosphatemia) in the blood.

Guidelines from the European Society of Endocrinology (ESE) state
that a diagnosis of chronic hypoparathyroidism should be considered
in a patient with hypocalcemia and an inappropriately low PTH
concentration. Guidelines recommend that treatment should aim to
restore mineral homeostasis and prevent symptoms of hypocalcemia
while optimizing overall well-being. Typical symptoms of hypocalcemia
include muscle spasms and cramping.

To date, management of chronic hypoparathyroidism has focused on
maintaining serum calcium with oral calcium and active vitamin D
supplements; however, some patients are not adequately controlled and
still have variations in their serum calcium levels.[3]-[6]

About Natpar

Natpar is a recombinant human PTH and will be 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.

Natpar is approved in the United States under the trade name
Natpara® (parathyroid hormone).

About the REPLACE study

In the double-blind, placebo-controlled, randomized Phase III
study 124 patients with hypoparathyroidism were randomized in a ratio
of 2:1 to either 50 micrograms once daily of rhPTH(1-84) or placebo
for 24 weeks. The primary endpoint was a 50 percent or greater
reduction from baseline in their daily dose of oral calcium and
active vitamin D while maintaining a stable albumin corrected serum
calcium concentration greater than or equal to baseline concentration
(baseline was 2.1 mmol/L for the rhPTH[1-84] group and 2.2 mmol/L for
the placebo group) and less or equal to the upper limit of normal
(normal range 2.1-2.6 mmol/L). At the end of the treatment period,
54.8 percent of the patients on rhPTH(1-84) achieved the primary
endpoint compared with 2.5 percent of patients in the placebo group
(p<0.0001).[1] There were no differences in the proportion of
patients maintaining a stable albumin corrected serum calcium
concentration at the end of treatment between subjects randomized to
rhPTH (1-84) and placebo.[7]

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, diarrhea, vomiting,
paraesthesia, hypoesthesia and hypercalciuria.

Very common

(frequency Hypercalcemia, hypocalcaemia, headache,
hypoesthesia,
greater than or paraesthesia, diarrhoea, nausea, vomiting,
arthralgia, and
equal to1/10): muscle spasms.
Common Hypomagnesaemia, tetany, anxiety, insomnia,
somnolence,
palpitations, hypertension, cough, abdominal
pain upper,
muscle twitching, musculoskeletal pain,
myalgia, neck pain,
pain in extremity, hypercalciuria, pollakiuria,
asthenia,
(greater than or chest pain, fatigue, injection site reactions,
thirst,
equal to1/100 to anti-PTH antibody positive, blood
25-hydroxycholecalciferol
<1/10): decreased, vitamin D decreased.

NOTES TO EDITORS

About Shire

Shire is the leading global biotechnology company focused on
serving people with rare diseases and other highly specialized
conditions. We strive to develop best-in-class products, many of
which are available in more than 100 countries, across core
therapeutic areas including Hematology, Immunology, Neuroscience,
Ophthalmics, Lysosomal Storage Disorders, Gastrointestinal / Internal
Medicine / Endocrine and Hereditary Angioedema; and a growing
franchise in Oncology.

Our employees come to work every day with a shared mission: to
develop and deliver breakthrough therapies for the hundreds of
millions of people in the world affected by rare diseases and other
high-need conditions, and who lack effective therapies to live their
lives to the fullest.

http://www.shire.com

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- Shire incurred substantial additional indebtedness to finance the
Baxalta acquisition, which may decrease its business flexibility
and increase borrowing costs; 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 "ITEM 1A: 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.

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References

1. Natpar® Summary of Product Characteristics.
2. Bilezikian JP, et al. J Clin Endocrinol Metab. 2016;101:2313-2324.
3. Mitchell DM, et al. J Clin Endocrinol Metab. 2012;97:4507-4514.
4. Bollerslev J, et al. Eur J Endocrinol. 2015;173:G1-G20.
5. Brandi ML, et al. J Clin Endocrinol Metab. 2016;101:2273-2283.
6. Hadker N, et al. Endocr Pract. 2014;20:671-679.
7. Mannstadt M, et al. Lancet Diabetes Endocrinol. 2013;1:275-283.

ots Originaltext: Shire Pharmaceuticals Group Plc
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Contact:
, please contact:

Investor Relations
Ian Karp
ikarp@shire.com
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annabel.cowper@shire.com
+41-79-630-8619

Debbi Ford
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