Shire plc : New Formulation of ONCASPAR® (pegaspargase)

New Formulation of ONCASPAR ^® (pegaspargase) Receives Positive CHMP Opinion in Europe for Patients with Acute Lymphoblastic Leukemia (ALL)

If approved, lyophilized formulation would offer three times longer shelf life vs. liquid ONCASPAR, enabling better supply management and improved product availability

Zug, Switzerland - October 13, 2017 - Shire plc (LSE: SHP, NASDAQ: SHPG), the global leader in rare diseases, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending the marketing authorization for lyophilized ONCASPAR (pegaspargase), as a component of antineoplastic combination therapy in acute lymphoblastic leukemia (ALL) in pediatric patients from birth to 18 years, and in adult patients. Lyophilized ONCASPAR is a freeze-dried formulation of ONCASPAR. The liquid form of ONCASPAR is currently approved for the same indication in ALL, and is part of the pediatric standard therapy in ALL in many European countries. ^[1] The CHMP's positive opinion will be submitted to the European Commission (EC), which is responsible for granting marketing authorizations for medicines in the EU.

Acute lymphoblastic leukemia (ALL) is a cancer of the white blood cells and is characterized by an overproduction and accumulation of lymphoblasts, immature white blood cells. ALL is the most common type (~75%) of cancer among children diagnosed with leukemia. ^[2] ALL can be curable within certain pediatric patient populations, with a 5-year survival rate of more than 90% in children treated with regimens including ONCASPAR. ^{[3] ,[4],[5]}

"Lyophilized ONCASPAR builds on more than a decade of data and research with liquid ONCASPAR, and with no change in dosing regimen, it offers a three-times longer shelf life," said Howard B. Mayer, M.D., SVP and ad-interim Head, Global Research and Development, Shire. "Prolonging shelf life to 24 months for this critically-important therapy facilitates management of product inventory by enabling greater flexibility and longer-term planning. Once approved, with the extended shelf life of lyophilized ONCASPAR, we also hope to improve access to the medicine for ALL patients in countries currently not offering liquid ONCASPAR."

Lyophilized ONCASPAR works the same way as the liquid formulation by rapidly depleting serum L-asparagine levels and interfering with protein synthesis, thereby depriving lymphoblasts of asparaginase and resulting in cell death. That is why asparaginase is a critical component of the treatment regimen for ALL patients as it is a proven approach to inducing leukemic cell death.4 ^{,[6], [7] , [8] , [9] , [10] , [11]}

About Lyophilized ONCASPAR Lyophilized ONCASPAR builds on more than a decade of data and research with liquid ONCASPAR, a pegylated asparaginase. The positive opinion is based on analytical and nonclinical studies, which demonstrate that the lyophilized formulation of ONCASPAR is comparable to the liquid formulation.  Once reconstituted, lyophilized ONCASPAR demonstrates similar pharmacokinetic (PK)/pharmacodynamics (PD) to liquid ONCASPAR. ¹ The new lyophilized formulation offers no change in dosing regimen but a longer shelf life that is three times that of the liquid formation. ¹

About ONCASPAR In Europe, ONCASPAR is indicated as a component of antineoplastic combination therapy in acute lymphoblastic leukemia (ALL) in pediatric patients from birth to 18 years, and adult patients.

ONCASPAR can be given by intramuscular injection or intravenous infusion. For smaller volumes of ONCASPAR, the preferred route of administration is intramuscular. When ONCASPAR is given by intramuscular injection the volume injected at one site should not exceed 2 ml in children and adolescents and 3 ml in adults. If higher volume is given, the dose should be divided and given at several injection sites. Intravenous infusion of ONCASPAR is usually given over a period of 1 to 2 hours in 100 ml sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution. The diluted solution of ONCASPAR can be given together with an already-running infusion of either sodium chloride 9 mg/ml or 5% glucose. Do not infuse other medicinal products through the same intravenous line during administration of ONCASPAR.

Safety Information ONCASPAR is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients, in patients with severe hepatic impairment, and in patients with a history of serious thrombosis, pancreatitis, or serious haemorrhagic events with prior L-asparaginase therapy.

Anaphylaxis or serious allergic reactions can occur; therefore, patients should be observed for 1 hour after administration having resuscitation equipment ready. Discontinue ONCASPAR in patients with serious allergic reactions. There have been reports of adverse reactions of pancreatitis. If pancreatitis is suspected ONCASPAR should be discontinued. ONCASPAR should also be discontinued in patients with serious thrombotic events.

Combination therapy with ONCASPAR can result in hepatic toxicity and central nervous system toxicity. Appropriate monitoring should be performed for liver impairment, blood and urine glucose levels as well as serum amylase for early signs of inflammation of the pancreas.

Very common adverse reactions reported in clinical trial data and the post-marketing experience of ONCASPAR in ALL patients include: hyperglycemia, pancreatitis, diarrhea, abdominal pain, nausea, vomiting, stomatitis, hypersensitivity, urticaria, anaphylactic reaction, weight decreased, decreased appetite, and rash.

Common adverse reactions include: febrile neutropenia, anemia, coagulopathy, hepatotoxicity, fatty liver, infections, sepsis, amylase increased, alanine aminotransferase increased, blood bilirubin increased, blood albumin decreased, neutrophil count decreased, platelet count decreased, activated partial thromboplastin time prolonged, prothrombin time prolonged, hypofibrinogenemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia, pain in extremities, seizure, peripheral motor neuropathy, syncope, posterior reversible leukoencephalopathy syndrome, hypoxia, and thrombosis.1

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NOTES TO EDITOR

About Shire Shire is the leading global biotechnology company focused on serving people with rare diseases. 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.

www.shire.com

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^[1] Lyophilized Oncaspar SMPC reference

^[2] American Cancer Society. https://www.cancer.org/cancer/leukemia-in-chi...kemia.html

^[3] American Cancer Society. http://www.cancer.org/cancer/leukemiainchildr...ival-rates

^[4] Angiolillo AL, Schore RJ, Devidas M, et. al. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. doi: 10.1200/JCO.2014.55.5763. Epub 2014 Oct 27.

^[5] Place AE, et al . Lancet Oncol 2015; 16: 1677-1690 + appendix.

^[6] Oncaspar (pegaspargase) Summary of Product Characteristics. (SmPC) EU 1/2016.

^[7] Wilson GJ, et al. Am J Physiol Endocrinol Metab 2013; 305: E1124-1133.

^[8] Story MD, et al. Cancer Chemother Pharmacol 1993; 32: 129-133.

^[9] Avramis VA and Panosyan EH, Clin Pharmacokinet 2005; 44: 367-393.

^[10] Schwarz JH, et al. Biochemistry 1966; 56: 1516-1519.

^[11] Graham ML, Adv Drug Deliv Rev 2003; 55: 1293-302.