Shire Receives Positive CHMP Opinion in Europe for Revestive® (Teduglutide) for Paediatric Patients with Short Bowel Syndrome

ZUG, Switzerland, May 27, 2016 /PRNewswire/ --

Shire plc (LSE: SHP, NASDAQ: SHPG) today announced that the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the extension of the approval of Revestive^[®*] (teduglutide) 5 mg powder and solvent for solution for injection in paediatric patients (aged one to 17 years) with short bowel syndrome (SBS). Teduglutide is an analogue of human glucagon like peptide 2 (GLP-2) that enhances key structural and functional adaptations in the intestinal mucosa.^[i]

The European Commission (EC) will now consider the CHMP positive opinion in its final decision of whether to extend marketing authorisation for teduglutide in paediatric patients with SBS in the European Union; a final decision from the EC is expected in August 2016.

"We are delighted that the CHMP has rendered a favorable recommendation for teduglutide in paediatric patients based on their evaluation of the data and benefit-to-risk balance," said Philip J. Vickers, Ph.D., Head of Research and Development, Shire. "We await the final decision of the EMA and the potential to bring a new treatment option for children and adolescents suffering from SBS in Europe."

SBS is a rare gastrointestinal condition characterised by a clinically significant reduction in intestinal absorptive capacity as a consequence of surgical resection of large portions of the intestine, commonly due to congenital abnormalities, disease or trauma.^{[vi],[ vii],[ viii]} 

Revestive is currently indicated in Europe for the treatment of adult patients with SBS, who should be stable following a period of intestinal adaptation after surgery, ^[i] in Canada for the treatment of adult patients with SBS who are dependent on parenteral support (PS),^[ii] and in the United States under the name GATTEX^® (teduglutide [rDNA origin]) for injection for the treatment of adult patients with SBS who are dependent on PS.^[iii]

Supportive Paediatric Data 
A 12-week, open-label, multicentre, safety, pharmacokinetic and pharmacodynamic study was conducted in 42 children aged 1-17 years who had SBS with Intestinal Failure (SBS-IF) for at least one year and had plateaued in PS reduction with minimal or no advance in enteral nutrition for at least three months. Of the participants, 37 received teduglutide 0.05 mg/kg/day (n=15); 0.025 mg/kg/day (n=14); 0.0125 mg/kg/day (n=8); and five received standard of care.^{[iv], [v]}

Of the 42 patients, 40 (95%) completed the study. Most adverse events were related to gastrointestinal complaints and/or central line-related issues. No deaths were reported, no serious drug-related adverse events were observed, and no patient discontinued the study due to adverse events. No safety signals related to fluid overload, obstruction, hepatobiliary system, or colonic polyps were seen in the study.^{[iv],[ v]}

*Revestive and GATTEX are registered trademarks of NPS Pharmaceuticals Inc., part of the Shire Group of Companies

Although the study was not powered for efficacy, the data showed that children treated with teduglutide 0.05 mg/kg/day and 0.025 mg/kg/day had reductions from baseline to week 12 in PS volume requirements, and increases from baseline in enteral nutrition volume. Four patients achieved independence from PS (three in the teduglutide 0.05 mg/kg/day group, one in the 0.025 mg/kg/day group). Despite PS reductions, clinical and nutritional status remained stable across the teduglutide treatment groups. ^{[iv],[ v]}

About Short Bowel Syndrome 
SBS is a rare and potentially life-threatening gastrointestinal condition. It is characterized by a clinically significant reduction in intestinal absorptive capacity as a consequence of surgical resection of large portions of the intestine commonly due to congenital abnormalities, disease or trauma. If intestinal adaptation is inadequate, the absorptive capacity of the residual intestine becomes insufficient to meet the nutritional, fluid and electrolyte needs to sustain the life and growth requirements of a child; this leads to Intestinal Failure (IF), which requires chronic dependence on PS to maintain adequate growth, hydration, protein, electrolyte, and micronutrient balances. ^[vi], ^{[vii], [viii]} SBS is the most common cause of IF in the paediatric population.^{[vi],[ viii]}

Estimates of the prevalence of SBS-IF in children vary markedly, largely due to the lack of standardised reporting and rarity of the disease.^{[vi],[ viii]} In a recent cross-sectional study in the Netherlands (the nationwide DRIFT registry study), the prevalence of chronic IF requiring home PS was 9.6 per million in children.^[ix] In the DRIFT registry population, 43.2% of children with chronic IF had SBS, which translates into a Dutch national prevalence of paediatric SBS-IF requiring home parenteral nutrition of 4.1 per million.^[ix]

Safety Information  
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Adverse reactions 

Very common adverse reactions (frequency ≥1/10) with Revestive treatment are abdominal pain and distension, respiratory tract infections, nausea, injection site reactions, headache, vomiting, oedema peripheral and gastrointestinal stoma complications.

Common adverse reactions (≥1/100 to <1/10) are influenza, decreased appetite, anxiety, sleep disorder, paraesthesia, cardiac failure congestive, flushing, dyspnoea, cough, pancreatitis, intestinal obstruction, cholestasis and cholecystitis, dermatitis allergic, arthralgia, renal colic, costovertebral angle tenderness, chest pain, night sweats, C-reactive protein increased.

Uncommon adverse reactions (≥1/100 to <1/10) are syncope.

Contraindications 
Hypersensitivity to the active substance or to any of the excipients, or trace residues of tetracycline; active or suspected malignancy; history of malignancies in the gastrointestinal tract including the hepatobiliary system within the last five years.

Special warnings and precautions for use 
Colo-rectal polyps; gastrointestinal neoplasia including hepatobiliary tract; gallbladder and bile ducts; pancreatic diseases; monitoring of small bowel, gallbladder and bile ducts, and pancreas; intestinal obstruction; cardiovascular; management of fluids during treatment with Revestive; concomitant medication; special clinical conditions; hepatic impairment; discontinuation of treatment; excipients.

For the current Revestive EU Summary of Product Characteristics, please click here. For the Revestive Product Monograph (Canada), please click here. For the GATTEX U.S. Prescribing Information, please click here.

Notes to editors 

Shire enables people with life-altering conditions to lead better lives.

Our strategy is to focus on developing and marketing innovative specialty medicines to meet significant unmet patient needs.

We focus on providing treatments in Rare Diseases, Neuroscience, Gastrointestinal and Internal Medicine and we are developing treatments for symptomatic conditions treated by specialist physicians in other targeted therapeutic areas, such as Ophthalmics.

http://www.shire.com

Forward-Looking Statements 

Statements included herein that are not historical facts, including without limitation statements concerning our announced business combination with Baxalta and the timing and financial and strategic benefits thereof, our 20x20 ambition that targets $20 billion in combined product sales by 2020, as well as other targets for future financial results, capital structure, performance and sustainability of the combined company, the combined company's future strategy, plans, objectives, expectations and intentions, 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:

• the proposed combination with Baxalta may not be completed due to a failure to satisfy certain closing conditions, including any shareholder or regulatory approvals or the receipt of applicable tax opinions;
• disruption from the proposed transaction with Baxalta may make it more difficult to conduct business as usual or maintain relationships with patients, physicians, employees or suppliers;
• the combined company may not achieve some or all of the anticipated benefits of Baxalta's spin-off from Baxter International, Inc. ("Baxter") and the proposed transaction may have an adverse impact on Baxalta's existing arrangements with Baxter, including those related to transition, manufacturing and supply services and tax matters;
• the failure to achieve the strategic objectives with respect to the proposed combination with Baxalta may adversely affect the combined company's financial condition and results of operations;
• products and product candidates may not achieve commercial success;
• product sales from ADDERALL XR and INTUNIV are subject to generic competition;
• the failure to obtain and maintain reimbursement, or an adequate level of reimbursement, by third-party payers in a timely manner for the combined company's products may affect future revenues, financial condition and results of operations, particularly if there is pressure on pricing of products to treat rare diseases;
• supply chain or manufacturing disruptions may result in declines in revenue for affected products and commercial traction from competitors; regulatory actions associated with product approvals or changes to manufacturing sites, ingredients or manufacturing processes could lead to significant delays, an increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
• the successful development of products in various stages of research and development 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 the combined company's ability to sell or market products profitably, and fluctuations in buying or distribution patterns by such customers can adversely affect the combined company's revenues, financial condition or results of operations;
• investigations or enforcement action by regulatory authorities or law enforcement agencies relating to the combined company's activities in the highly regulated markets in which it operates may result in significant legal costs and the payment of substantial compensation or fines;
• adverse outcomes in legal matters and other disputes, including the combined company's ability to enforce and defend patents and other intellectual property rights required for its business, could have a material adverse effect on the combined company's revenues, financial condition or results of operations;
• Shire is undergoing a corporate reorganization and was the subject of an unsuccessful acquisition proposal and the consequent uncertainty could adversely affect the combined company's ability to attract and/or retain the highly skilled personnel needed to meet its strategic objectives;
• failure to achieve the strategic objectives with respect to Shire's acquisition of NPS Pharmaceuticals Inc. or Dyax may adversely affect the combined company's financial condition and results of operations;
• the combined company will be 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 the combined company's revenues, financial condition or results of operations;
• the combined company may be unable to retain and hire key personnel and/or maintain its relationships with customers, suppliers and other business partners;
• difficulties in integrating Dyax or Baxalta into Shire may lead to the combined company not being able to realize the expected operating efficiencies, cost savings, revenue enhancements, synergies or other benefits at the time anticipated or at all; and

other risks and uncertainties detailed from time to time in Shire's, Dyax's or Baxalta's filings with the Securities and Exchange Commission ("SEC"), including those risks outlined in Baxalta's current Registration Statement on Form S-1, as amended, and in "ITEM 1A: Risk Factors" in Shire's Annual Report on Form 10-K for the year ended December 31, 2015.

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 republish revised forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events.

Date of preparation: May 2016

INTSP/C-ANPROM/TED/16/0036

S12179

i. Revestive EU Summary of Product Characteristics, August 2015. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002345/WC500132926.pdf .

ii. Revestive Canada Product Monograph, September 2015. Available at http://www.shirecanada.com/en/documents/REVESTIVE-PM-EN.pdf .

iii. Gattex U.S. Prescribing Information, June 2014. Available at: http://www.shirecontent.com/PI/PDFS/Gattex_USA_ENG.pdf .

iv. Carter BA, et al. Clin Nutr 2015;34(Suppl 1):S239.

v. Carter BA, et al. J Pediatr Gastroenterol Nutr 2015;61(Suppl 2):S46-47.

vi. Wales PW, Christison-Lagay ER. Semin Pediatr Surg 2010; 19(1): 3-9.

vii. Sulkowski JP, Minneci PC. Pathophysiology 2014;21(1):111-118.

viii. Kaufman SS, Matsumoto CS. Minerva Pediatr 2015;67(4):321-340.

ix. Neelis EG, Roskott AM, Dijkstra G, et al. Clin Nutr 2016;35(1):225-229.

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