Shire plc: Large-Scale European Review Suggests Disparity in Symptom Recognition and Standardized Treatment for Metastatic Adenocarcinoma of the Pancreas

Large-Scale European Review Suggests Disparity in Symptom Recognition and Standardized Treatment for Metastatic Adenocarcinoma of the Pancreas

• New analyses from the global phase III NAPOLI-1 study, also presented at the 20^th ESMO World Congress on Gastrointestinal Cancer 2018, highlights additional insights into use of nal-IRI in combination with 5-FU/LV in patients with metastatic pancreatic adenocarcinoma who have disease progression on gemcitabine-based treatment

[Dublin, Ireland] - [22 June 2018] - Shire plc (LSE: SHP, NASDAQ: SHPG), the leading global biotechnology company focused on rare diseases, announced today results from a retrospective review of more than 2,500 patient records with metastatic adenocarcinoma of the pancreas (mPAC) from nine countries. The results - presented on 20 June at the 20^th ESMO World Congress on Gastrointestinal Cancer 2018 (ESMO-GI) in Barcelona - showed variation across Europe in the symptoms reported at initial diagnosis, and in treatment decisions made in the first-line and second-line metastatic settings. The research suggests that enhanced recognition of symptoms and a standardized treatment approach, especially in the second-line setting, may help improve diagnosis, patient care and outcomes^[1],[2],[3]

"Pancreatic adenocarcinoma is typically diagnosed late in the course of the disease, when outcomes are generally poor," said Floris de Jong, Ph.D., Global Medical Franchise Lead Solid Tumors at Shire Pharmaceuticals. "These analyses from patient records and NAPOLI-1 collectively provide important new insights for the diagnosis and treatment of patients with this difficult-to-treat cancer. Specifically, the results of the retrospective review indicate that enhanced awareness of, and attention to symptoms both by health care providers and the public at large may help improve mPAC diagnosis, care and outcomes."

Researchers also presented new data from four subgroups of the global phase III NAPOLI-1 study in an oral session.^[4] These subgroups included: the presence of metabolism and nutrition disorders at baseline, including diabetes mellitus and decreased appetite; the location of the primary tumor site; the presence of a biliary stent at baseline and response to prior therapy.^{[5],[6],[7],[8]}

The search for innovative new therapies in pancreatic cancer remains a serious unmet need. Relatively little progress has been made in preventing, detecting and treating the disease relative to other leading cancer killers, and survival rates for pancreatic cancer remain one of the lowest among other types of cancer.^[9]

"While first-line treatments are approved for patients with pancreatic adenocarcinoma, disease progression after initial therapy is inevitable and patients with this disease have a poor prognosis and low survival rate,"^9,[10] said Teresa Macarulla Mercadé, M.D., Ph.D., Clinical Investigator, Gastrointestinal Tumor Program, Vall d'Hebrón Institute of Oncology, Barcelona. "To further our understanding of the use of nal-IRI in the treatment of mPDAC, we conducted four separate NAPOLI-1 subgroup analyses investigating the effect of selected baseline parameters. These analyses demonstrated that a consistent treatment benefit was observed in patients treated with nal-IRI in combination with 5-FU/LV across the subgroups tested."

The full list of Shire abstracts presented at the 20^th ESMO-GI in Barcelona includes:

• Geographic variation in systemic treatment of metastatic pancreatic adenocarcinoma (mPAC) patients in real world across Europe2
  O-002 (oral presentation)
   
• Selected subgroup analyses of liposomal irinotecan (nal-IRI) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in the global NAPOLI-1 phase III trial⁴
  O-004
   
• Baseline characteristics and second-line treatment for metastatic pancreatic adenocarcinoma (mPAC) patients receiving first-line FOLFIRINOX, gemcitabine+nabpaclitaxel or gemcitabine-monotherapy in routine clinical practice across Europe3
  PD-004 (poster presentation)
   
• Prognostic effect of primary tumor location in the NAPOLI-1 phase III study in metastatic pancreatic ductal adenocarcinoma (mPDAC)⁶
  P-150
   
• Prognostic value of baseline biliary stents on outcomes in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in the global NAPOLI-1 trial⁷
  P-151
   
• The effect of best response to prior anticancer therapy on efficacy outcomes in the NAPOLI-1 trial of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy⁸
  P-152
   
• Decreased appetite (DA) at baseline impacts prognosis in the NAPOLI-1 phase III study in metastatic pancreatic ductal adenocarcinoma (mPDAC)⁵
  P-153
   
• Symptoms reported at initial diagnosis of (metastatic) pancreatic adenocarcinoma ([m]PAC) in routine clinical practice and variation in frequencies across Europe1
  P-167 (poster presentation)

More detailed data on each abstract can be found by visiting: http://www.worldgicancer.com/sites/default/files/World_GI_Abstract_Titles_and_Authors.pdf 

About Pancreatic Cancer
Pancreatic adenocarcinoma is a disease with limited treatment options and is almost always fatal.^[11] At the time of diagnosis, more than 80 percent of people diagnosed with pancreatic adenocarcinoma have metastatic disease or locally advanced disease that cannot be removed with surgery.^[12] The disease has a median five-year survival rate of about five percent,⁹ and an median overall survival of typically less than a year, as illustrated by real-world European systematic review.¹⁰ The only curative treatment for pancreatic adenocarcinoma is surgical resection in the early stage, which can improve five-year survival to 10 percent.^[13]

The signs and symptoms of pancreatic adenocarcinoma are non-specific (common presenting symptoms include jaundice, abdominal pain, weight loss, steatorrhoea and new-onset diabetes).⁹ Clear symptoms may not appear until the disease has spread locally or metastasized. As a result, most patients are not candidates for surgery upon diagnosis.12

Pancreatic adenocarcinoma accounts for less than three percent of all cancer cases,^[14] yet is the seventh leading cause of cancer death worldwide and the fourth in Europe.⁹ Worldwide, pancreatic cancer prognosis is typically poor, with an estimated 338,000 new cases and 331,000 deaths each year.11

About NAPOLI-1
NAPOLI-1 is the first global, randomized open-label Phase 3 trial to show extended overall survival in metastatic pancreatic adenocarcinoma after gemcitabine-based therapy through treatment with ONIVYDE combined with 5-FU and LV. Patients were enrolled at 76 sites in 14 countries across North America, Europe, Asia, South America and Australia. The study evaluated ONIVYDE (80 mg/m²), expressed as irinotecan hydrochloride trihydrate (which is the equivalent of 70 mg/m² ONIVYDE expressed as irinotecan free base) in combination with 5-FU/LV administered intravenously every two weeks and as a monotherapy (120 mg/m²) administered every three weeks. Each ONIVYDE containing arm was compared to a control arm of 5-FU/LV.^[15]

About liposomal irinotecan (nal-IRI)
Liposomal irinotecan (nal-IRI) is approved in the EU under the name 'ONIVYDE.' ONIVYDE is approved for the treatment of metastatic adenocarcinoma of the pancreas, in combination with 5-FU/LV, in adult patients who have disease progression following gemcitabine-based therapy.^[16]

Shire is responsible for the development and commercialization of ONIVYDE outside of the United States and Taiwan under an exclusive licensing agreement with Ipsen Biopharmaceuticals, Inc., an affiliate of Ipsen, (Euronext: IPN; ADR: IPSEY). Ipsen markets ONIVYDE in the United States after completion of the acquisition from Merrimack Pharmaceuticals.

ONIVYDE received US Food and Drug Administration (FDA) approval in October 2015 for the treatment of patients with metastatic adenocarcinoma of the pancreas who have progressed following treatment with gemcitabine-based therapy. ONIVYDE product license was granted in Taiwan in March 2016, where PharmaEngine holds the commercialization rights.

Important Safety Information 
The most common adverse reactions (incidence greater than or equal to 20 percent) seen with ONIVYDE in combination with 5-FU/LV were: diarrhea, nausea, vomiting, decreased appetite, neutropoenia, fatigue, asthenia, anaemia, stomatitis and pyrexia.¹⁵ In the clinical study, Grade 3 or Grade 4 diarrhea occurred in 12.8 percent of patients receiving ONIVYDE in combination with 5-FU/LV. Early-onset (within one day of treatment) diarrhea occurred in 30 percent of patients on ONIVYDE combined with 5-FU/LV and was usually transient.¹⁵ Early-onset diarrhea was accompanied by cholinergic symptoms in 3.4 percent of patients taking ONIVYDE in combination with 5-FU/LV.¹⁵ Median time to late-onset diarrhea was eight days following the ONIVYDE dose.¹⁵ Of patients taking ONIVYDE combined with 5-FU/LV, 11 percent of patients discontinued treatment vs 7% of patients receiving 5-FU/LV alone.¹⁵

ONIVYDE^® and the ONIVYDE Logo are registered trademarks of Ipsen Biopharm Ltd., and are used under license.

For further information please contact:

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 Rare Disease and Neuroscience divisions support our diverse portfolio of therapeutic areas, including Immunology, Hematology, Genetic Diseases, Internal Medicine, Ophthalmics, Oncology, and neuropsychiatry disorders.

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;
• Shire's patented products are subject to significant competition from generics;
• 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 the 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;
• Shire faces intense competition for highly qualified personnel from other companies and organizations;
• failure to successfully execute or attain strategic objectives from Shire's acquisitions and growth strategy may adversely affect the 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 the 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;
• Shire's ongoing strategic review of its Neuroscience franchise may distract management and employees and may not lead to improved operating performance or financial results; there can be no guarantee that, once completed, Shire's strategic review will result in any additional strategic changes beyond those that have already been announced;
• the potential uncertainty 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.