U.S. FDA Accepts for Filing Shire’s Supplemental New Drug Application for GATTEX® (teduglutide [rDNA origin]) for Children with Short Bowel Syndrome

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U.S. FDA Accepts for Filing Shire’s Supplemental New Drug Application for GATTEX® (teduglutide [rDNA origin]) for Children with Short Bowel Syndrome

Seeking approval for the potential use of GATTEX to pediatric patients builds on Shire’s decade-long commitment to addressing needs in GI diseases    

Cambridge, Mass. – November 13, 2018 – Shire plc (LSE: SHP, NASDAQ: SHPG) the global leader in rare diseases, announced today the U.S. Food and Drug Administration (FDA) has accepted for filing the supplemental new drug application to extend the indication of GATTEX® (teduglutide [rDNA origin]) for Injection to pediatric patients (aged 1-17 years old) with Short Bowel Syndrome (SBS) who are dependent on parenteral support. GATTEX is a prescription medicine indicated for the treatment of adult patients with SBS who are dependent on parenteral support.1

Shire submitted the supplemental new drug application to the U.S. FDA on September 11, 2018. The U.S. FDA is expected to reach a decision in March 2019.

SBS is a serious, chronic and rare malabsorption disorder resulting from surgical resection. People with SBS are unable to absorb enough nutrients and fluids from what they eat and drink alone. Malabsorption puts people at risk for diarrhea, dehydration, electrolyte disturbances and malnutrition.2,[3],[4] Children with SBS have had a large portion of the intestine removed by surgery due to congenital or acquired conditions of the newborn or trauma.5 

“The filing acceptance of Shire’s supplemental new drug application by the U.S. FDA is an important milestone in our efforts to investigate the use of GATTEX as a potential treatment for children with SBS who are dependent on parenteral support,” said Howard Mayer, M.D., Senior Vice President and Chief Medical Officer, Shire. “Addressing unmet medical needs in rare disease is the focus of Shire’s work, and we are pleased to continue advancing our GI portfolio to help patients living with rare and specialized GI conditions.”

The application included data from two core, completed Phase 3 studies as well as interim data from two ongoing extension studies. The Phase 3 studies included a 24-week, double-blind, multi-center, multi-national trial (TED-C14-006) and a 12-week, open-label, multi-center study (TED-C13-003), both of which evaluated the efficacy, safety, and pharmacodynamics of GATTEX in children with SBS who were stable on their required parenteral nutrition (PN)/ intravenous (IV) support that provided at least 30% of caloric and/or fluid/electrolyte needs for at least three months prior to screening.6

“Many children who develop SBS as infants may remain dependent on parenteral support, which helps to address their nutrition and fluid needs,” said Beth Carter, M.D., Medical Director of Intestinal Rehabilitation and Nutrition Support, Children’s Hospital Los Angeles. “While the goal in SBS management is to ensure patients receive the right amount of nutrients and fluids, we also look for opportunities to reduce, and even help some of these patients wean off of parenteral support. The development of teduglutide for pediatric SBS patients age 1 year and older is important as the data from the Phase 3 studies suggest it might potentially address an unmet medical need in this patient population.”

Fifty-nine patients ages 1 to 17 years enrolled and completed the 24-week, double-blind study, which included children in the U.S., Canada, UK, Germany, Finland, Belgium, and Italy.6 Subjects elected to receive either teduglutide or SOC; patients receiving teduglutide were randomized to receive either the 0.025 mg/kg or 0.05 mg/kg dose (0.025mg/kg, n=24; 0.05 mg/kg, n=26; Standard of Care (SOC), n=9). The study found that 54.2% and 69.2% of patients treated with teduglutide (0.025 mg/kg and 0.05 mg/kg, respectively) vs. 11.1% receiving standard of care achieved a 20% or greater reduction in the volume of parenteral support at 24 weeks compared to baseline, the study’s primary efficacy endpoint.7 In addition, five children on teduglutide (0.025 mg/kg, n=2; 0.05 mg/kg, n=3) were completely weaned off parenteral support at week 24 compared to none in the standard of care arm.7 The most frequent treatment-emergent adverse events (teduglutide 0.025 mg/kg, 0.05 mg/kg, or standard of care, respectively), included: pyrexia (33%, 42%, 44%), vomiting (42%, 31%, 56%), upper respiratory tract infection (29%, 31%, 44%), cough (8%, 38%, 33%), diarrhea (33%, 12%, 11%), nasopharyngitis (17%, 23%, 22%), abdominal pain (17%, 23%, 0%), dehydration (33%, 4%, 0%), increased ALT (29%, 8%, 0%), headache (13%, 19%, 11%), and catheter site erythema (0%, 4%, 22%).7 The findings from this study were recently presented at the 10th International Pediatric Intestinal Failure and Rehabilitation Symposium.

Forty patients ages 1 to 17 years enrolled and completed the 12-week, open-label study (TED-C13-003). Patients either received teduglutide (0.0125 mg/kg, n=8; 0.025 mg/kg, n=14; 0.05 mg/kg, n=15) or standard of care (SOC) (n=5).  Between baseline and week 12 of the study, prescribed PN volume and calories changed, respectively, by a median of 41% and 45% in the 0.025 mg/kg/day group, 25% and 52% in the 0.05 mg/kg/day group, and 0% and 6% in the 0.0125 mg/kg/day group. Reductions in PN volume and calories, respectively, of 0% and 1% were seen in the SOC group. On the basis of patient diary data, daily parenteral nutrition infusion time decreased in patients receiving teduglutide 0.025 mg/kg (median decrease of 4.0 hours) and 0.05 mg/kg (median decrease of 3.0 hours) at 12 weeks; no changes in median daily infusion time were observed for teduglutide 0.0125 mg/kg or SOC at 12 weeks. Four patients receiving teduglutide achieved independence from parenteral nutrition: 3 of 15 in the 0.05 mg/kg group (achieved at weeks 4, 8, and 12) and 1 of 14 in the 0.025 mg/kg group (achieved at week 11). At week 16 (4 weeks after teduglutide discontinuation), 2 of these 4 patients had resumed parenteral nutrition and 2 remained independent. All patients experienced ≥1 treatment-emergent adverse event. No serious treatment-related adverse events were deemed to be teduglutide-related. The most commonly reported treatment-emergent side effects included GI-related AEs, upper respiratory tract infection, catheter-related complications, and pyrexia. Severe adverse events were reported in 30% of patients receiving teduglutide and 20% of patients receiving SOC.8

About Short Bowel Syndrome
In adults, SBS occurs after extensive surgical removal of the bowel due to conditions such as Crohn's disease, inadequate blood supply to the small intestines (mesenteric ischemia), trauma, or other conditions.5 In children and adolescents, SBS is commonly caused by either congenital abnormalities (birth defects) or severe intestinal diseases that require surgical removal of the intestines.9,[10]

SBS is a serious, chronic and rare malabsorption disorder resulting from surgical resection. Children with SBS are unable to absorb enough nutrients and fluids from what they eat and drink alone. Malabsorption puts people at risk for diarrhea, dehydration, electrolyte disturbances and malnutrition.2,3,4

Patients with SBS often require nutritional support, including parenteral nutrition (PN) and/or intravenous (IV) fluids to supplement and stabilize nutritional needs.11

Patients who are dependent on PN/IV are at risk for serious complications, including catheter-related infections, blood clots, or liver damage,4 and often experience disrupted sleeping, frequent urination, and a loss of independence.11

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About GATTEX® (teduglutide [rDNA origin]) for Injection
GATTEX® (teduglutide [rDNA origin]) is a recombinant analog of human glucagon-like peptide 2. In the U.S., GATTEX is indicated for the treatment of adult patients with short bowel syndrome who are dependent on parenteral support. The safety and efficacy of GATTEX in pediatric patients have not been established in the U.S.1

IMPORTANT SAFETY INFORMATION for adult SBS patients who are dependent on parental support

WARNINGS AND PRECAUTIONS

Neoplastic Growth
Colorectal polyps were identified during clinical trials. There is a risk for acceleration of neoplastic growth. Colonoscopy of the entire colon with removal of polyps should be done within 6 months prior to starting treatment with GATTEX and is recommended after 1 year. Subsequent colonoscopies should be done as needed, but no less frequently than every 5 years. In case of intestinal malignancy (GI tract, hepatobiliary, pancreatic), discontinue GATTEX. The clinical decision to continue GATTEX in patients with non-gastrointestinal malignancy should be made based on risk and benefit considerations.

Intestinal Obstruction
Intestinal obstruction has been reported in clinical trials. In patients who develop obstruction, GATTEX should be temporarily discontinued pending further clinical evaluation and management.

Biliary and Pancreatic Disease
Cholecystitis, cholangitis, cholelithiasis, and pancreatitis have been reported in clinical trials.  Patients should undergo laboratory assessment (bilirubin, alkaline phosphatase, lipase, amylase) before starting GATTEX. Subsequent laboratory tests should be done every 6 months. If clinically meaningful changes are seen, further evaluation is recommended including imaging, and continued treatment with GATTEX should be reassessed.

Fluid Overload
Fluid overload and congestive heart failure have been observed in clinical trials. There is potential for fluid overload while on GATTEX. If fluid overload occurs, especially in patients with underlying cardiovascular disease, parenteral support should be appropriately adjusted and GATTEX treatment reassessed.

Increased Absorption of Concomitant Oral Medication
Altered mental status in association with GATTEX has been observed in patients on benzodiazepines in clinical trials. Patients on concomitant oral drugs (e.g., benzodiazepines, phenothiazines) requiring titration or with a narrow therapeutic index may require dose adjustment while on GATTEX.

Adverse Reactions
The most common adverse reactions (≥ 10%) across all studies with GATTEX are abdominal pain, injection site reactions, nausea, headaches, abdominal distension, upper respiratory tract infection. In addition, vomiting and fluid overload were reported in the SBS studies (1 and 3) at rates ≥10%.

To report SUSPECTED ADVERSE REACTIONS, contact Shire Medical Information at    1-866-888-0660 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For U.S. GATTEX Prescribing Information www.shirecontent.com/PI/PDFS/Gattex_USA_ENG.pdf

For further information please contact:

Investor Relations  
Christoph Brackmannchristoph.brackmann@shire.com+41 41 288 41 29
Sun Kimsun.kim@shire.com+1 617 588 8175
Scott Burrowsscott.burrows@shire.com+41 41 288 4195
   
Media  
Katie Joyce
Linda Calandra		kjoyce@shire.com
linda.calandra@shire.com 		+1 781 482 2779
+1 917 697 7543
   

NOTES TO EDITORS

About Shire

Shire is the global biotechnology leader serving patients with rare diseases and specialized conditions. We seek to push boundaries through discovering and delivering new possibilities for patient communities who often have few or no other champions. Relentlessly on the edge of what’s next, we are serial innovators with a diverse pipeline offering fresh thinking and new hope. Serving patients and partnering with healthcare communities in over 100 countries, we strive to be part of the entire patient journey to enable earlier diagnosis, raise standards of care, accelerate access to treatment, and support patients. Our diverse portfolio of therapeutic areas includes Immunology, Hematology, Genetic Diseases, Neuroscience, Internal Medicine, and Ophthalmics.
 
Championing patients is our call to action - it brings the opportunity - and responsibility - to change people’s lives.

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;
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  • 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 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;
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  • failure to successfully execute or attain strategic objectives from Shire’s acquisitions and growth strategy may adversely affect 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 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;
  • the potential uncertainty among our employees, customers, suppliers, and other business partners resulting from the announcement by Takeda Pharmaceutical Company Limited on May 8, 2018 of a recommended offer for Shire under the UK Takeover Code; 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.



1 GATTEX Prescribing Information. 2016. Available at: http://www.shirecontent.com/PI/PDFS/Gattex_USA_ENG.pdf. Accessed October 23, 2018.

2 Seidner DL, Schwartz LK, Winkler MF, Jeejeebhoy K, Boullata JI, Tappenden KA. Increased Intestinal Absorption in the Era of Teduglutide and Its Impact on Management Strategies in Patients With Short Bowel Syndrome Associated Intestinal Failure. JPEN J Parenter Enteral Nutr. 2013;37(2):201-211.

3 O'Keefe SJ, Buchman AL, Fishbein TM, Jeejeebhoy KN, Jeppesen PB, Shaffer J. Short Bowel Syndrome and
Intestinal Failure: Consensus Definitions and Overview. Clin Gastroenterol Hepatol. 2006;4(1):6-10.

4 Hofstetter S, Stern L, Willet J. Key Issues in Addressing the Clinical And Humanistic Burden of Short Bowel Syndrome in the U.S. Current Medical Research and Opinion. 2013;29:495-504.

5 Wales PW, Christison-Lagay ER. Short Bowel Syndrome: Epidemiology and Etiology. Semin Pediatr Surg. 2010; 19(1):3-9. doi: 10.1053/j.sempedsurg.2009.11.001.

6 Short Bowel Syndrome Research Study for Children Up To 17 Years of Age on Parenteral Nutrition – Tabular View. ClinicalTrials.gov, U.S. National Library of Medicine. Available at:  clinicaltrials.gov/ct2/show/record/NCT02682381?term=TED-C14-006&rank=2&view=record

7  Grimm A, Carter BA, Hill S, et. al. Teduglutide Reduced Parenteral Support in Children With Short Bowel Syndrome Associated-Intestinal Failure (SBS-IF): a Phase 3 Study. Abstract to be presented at the 10th International Pediatric Intestinal Failure and Rehabilitation Symposium. Pittsburgh, PA. September 20-22, 2018.

8  Carter, BA, Cohran VC, Cole CR, et al. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of
Teduglutide in Pediatric Short Bowel Syndrome.The Journal of Pediatrics. 2017; 181:102-16

9 Squires RH, Duggan C, Teitelbaum DH, et. al. Natural History of Pediatric Intestinal Failure: Initial Report from the Pediatric Intestinal Failure Consortium. J Pediatr. 2012;161:723-8.e2.

10 Duro D, Kamin D, Duggan C. Overview of Pediatric Short Bowel Syndrome. J Pediatr Gastroenterol Nutr. 2008;47: Suppl 1, S33-6.

11 G Kelly, Darlene et al. Short Bowel Syndrome: Highlights Of Patient Management, Quality Of Life, And Survival.
   JPEN. Journal Of Parenteral And Enteral Nutrition. 2014 May;38(4):427-37. doi: 10.1177/0148607113512678.