Shire Granted EU Marketing Authorization of Onivyde®, in Combination With 5-Fluorouracil (5-FU) and Leucovorin (LV),for the Treatment of Metastatic Adenocarcinoma of the Pancreas in Adult Patients Who Have Progressed Following Gemcitabine-Based Therapy

DUBLIN, October 18, 2016 /PRNewswire/ --

ONIVYDE, in combination with 5-fluorouracil (5-FU) and leucovorin (LV), is the first and only treatment approved for this patient population based on pivotal Phase 3 data (NAPOLI-1) showing increased overall survival^[i],[ii] 

Shire plc (LSE: SHP, NASDAQ: SHPG) announced that the European Commission (EC) has granted Marketing Authorization of ONIVYDE^® (pegylated liposomal irinotecan hydrochloride trihydrate), also known as nal-IRI or MM-398, for the treatment of metastatic adenocarcinoma of the pancreas, in combination with 5-fluorouracil (5-FU) and leucovorin (LV), in adult patients who have progressed following gemcitabine-based therapy. ONIVYDE is the first and only approved treatment option for this patient population.

With this approval, Shire is authorized to market ONIVYDE in the 28 Member States of the European Union (EU), as well as in Iceland, Liechtenstein and Norway. ONIVYDE was previously approved in the U.S. by the Food and Drug Administration (FDA), in October 2015.

"As the only treatment for metastatic pancreatic cancer following gemcitabine-based therapy that may improve patient survival, ONIVYDE is the first innovation that offers the potential to improve outcomes for this challenging patient population," said Philip J. Vickers, Ph.D., Global Head of Research and Development at Shire. "The approval of ONIVYDE marks a significant step forward in Shire's focus to develop and commercialize treatments that represent the most promising science in oncology."

Pancreatic cancer is the fourth leading cause of cancer death in the region^[iii] and there are limited treatment options available.^[iv] In September 2015, the European Society of Medical Oncology (ESMO) stated that use of MM-398 (ONIVYDE) when available in all countries, may be the best option for patients following gemcitabine-based therapy.^[v] Gemcitabine-based therapy is commonly used as a first-line treatment for patients with metastatic disease or locally advanced disease that cannot be treated with surgery, or as adjuvant therapy.^[vi]

"The burden of pancreatic cancer for patients, their families and healthcare providers is profound and the treatment options available, especially to those with metastatic disease, have not substantially evolved for decades," said Alfredo Carrato, M.D., Professor of Medical Oncology at Alcala University and Director of the Medical Oncology Department at Ramon y Cajal University Hospital in Madrid, Spain. "With the approval of ONIVYDE, we have the first and only treatment approved for metastatic adenocarcinoma following gemcitabine-based therapy, and an option that may improve patient survival. This is an important advance for the field of oncology and the lives of those impacted by pancreatic cancer."

The Marketing Authorization is based on the data from the pivotal, Phase 3 NAPOLI-1 study that demonstrated ONIVYDE combined with 5-FU/LV significantly improved overall survival (OS) (primary endpoint), as well as progression-free survival (PFS) and objective response rate (ORR) relative to the 5-FU/LV control arm (secondary endpoints). In the trial, the most common Grade 3 or higher adverse events with greater than five percent difference in patients receiving ONIVYDE and 5-FU/LV, versus 5-FU/LV alone, were neutropenia, fatigue, diarrhoea, and vomiting.^[ii]

About Pancreatic Cancer 

Pancreatic cancer is a significantly underserved disease in Europe and is almost always fatal.^[vi] At the time of diagnosis, more than 80 percent of people diagnosed with pancreatic cancer have metastatic disease or locally advanced disease that cannot be removed with surgery.^[vii] The disease has a median five-year survival rate of about 5 percent,^[v] and an overall median survival of typically less than a year, as supported by real-world European systematic review.^[vi] The only curative treatment for pancreatic cancer is surgical resection in the primary stage, which can improve five-year survival to 10 percent.^[viii]

The signs and symptoms of pancreatic cancer are non-specific (common presenting symptoms include jaundice, abdominal pain, weight loss, steatorrhoea, and new-onset diabetes)^[v] and may not appear until the disease has spread locally or metastasized.^[vii] Therefore, most patients are not candidates for surgery upon diagnosis.^[vii]

Even though it accounts for less than three percent of all cancer cases,^[ix] pancreatic cancer is the seventh leading cause of cancer death worldwide,^[x] and the fourth in Europe.^[iv] Worldwide, pancreatic cancer prognosis is typically poor, with an estimated 337,900 new cases and 330,400 deaths each year.^[xi]

About ONIVYDE (nal-IRI) 

ONIVYDE is a first-of-its-kind formulation (encapsulation) of irinotecan in a long-circulating liposomal form designed to improve delivery of length of tumor exposure to irinotecan and its active metabolite SN-38. Studies have suggested that encapsulation helps to improve delivery of irinotecan to tumors, such as metastatic pancreatic cancer.^[xii]

In the pivotal Phase 3 NAPOLI-1 study, ONIVYDE demonstrated significantly improved overall survival in adult patients with metastatic ADENOCARCINOMA of the pancreas who have progressed following gemcitabine-based therapy.^[ii] Gemcitabine, both as monotherapy as well as in combination, is commonly used in the first-line treatment of locally advanced and/or metastatic pancreatic adenocarcinoma, as well as in the adjuvant (treatment after surgery) and neo-adjuvant (treatment before surgery) settings.^[ii]

Shire is responsible for the development and commercialization of ONIVYDE outside of the United States and Taiwan under an exclusive licensing agreement with Merrimack Pharmaceuticals, Inc. (NASDAQ: MACK). Merrimack markets ONIVYDE in the United States after having 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.

About NAPOLI-1^[ii]

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. NAPOLI-1 is the largest Phase 3 study in this setting to date showing overall survival benefit. Patients were enrolled at 76 sites in 14 countries across North America, Europe, Asia, South America, and Australia. The study evaluated ONIVYDE (80mg/m^[2]) in combination with 5-FU/LV administered intravenously every two weeks and as a monotherapy (120 mg/m^[2]) administered every three weeks. Each ONIVYDE containing arm was compared to a control arm of 5-FU/LV.

NAPOLI-1 met the following primary and secondary endpoints by demonstrating that ONIVYDE combined with 5-FU/LV significantly improved OS, progression-free survival (PFS) and objective response (OR) compared to 5-FU/LV alone in patients with metastatic pancreatic cancer.^[i] ONIVYDE plus 5-FU/LV demonstrated a significant increase in median overall survival versus 5-FU/LV alone: 6.1 months vs 4.2 months (based on a non-stratified hazard ratio [HR] of 0.67; 95% CI 0.49-0.92, p=0.012).^{[i],[ ii]}

Grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned ONIVYDE plus 5-FU/LV were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). ^[ii]

Important Safety Information  

The most common adverse reactions (incidence ≥20 percent) seen with ONIVYDE in combination with 5-FU/LV were: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia, stomatitis, and pyrexia.^[i] Early-onset (within 1 day of treatment) diarrhoea occurred in 30 percent of patients on ONIVYDE combined with 5-FU/LV and was usually transient.^[i] Early-onset diarrhoea was accompanied by cholinergic symptoms in 3.4 percent of patients taking ONIVYDE in combination with 5-FU/LV. ^[i] Median time to late-onset diarrhoea was 8 days following the ONIVYDE dose.^[i] Of patients taking ONIVYDE combined with 5-FU/LV, 11 percent of patients discontinued treatment.^[i]

ONIVYDE is a registered trademark of Merrimack Pharmaceuticals, Inc. (NASDAQ: MACK), and used under license.

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

Forward-Looking Statements 

Statements included herein that are not historical facts, including without limitation statements concerning 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:

• 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 conducts its own manufacturing operations for certain of its products and is reliant on third party contract manufacturers to manufacture other products and to provide goods and services.  Some of Shire's products or ingredients are only available from a single approved source for manufacture.  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 significant delays, an increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
• certain of Shire's therapies involve lengthy and complex processes, which 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;
• Shire's products and product candidates face substantial competition in the product markets in which it operates, including 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 combined company's revenues, financial condition or results of operations;
• inability to successfully compete for highly qualified personnel from other companies and organizations;
• failure to achieve the strategic objectives with respect to Shire's acquisition of NPS Pharmaceuticals, Inc., Dyax Corp. ("Dyax") or Baxalta Inc. ("Baxalta")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, as well as changes in foreign currency exchange rates and interest rates, that adversely impact the availability and cost of credit and customer purchasing and payment patterns, including the collectability of customer accounts receivable;
• failure of a marketed product to work effectively or if such a product is the cause of adverse side effects could result in damage to the Shire's reputation, the withdrawal of the product and legal action against Shire;
• investigations or enforcement action by regulatory authorities or law enforcement agencies relating to Shire'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;
• 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 incurred substantial additional indebtedness to finance the Baxalta acquisition, which may decrease its business flexibility and increase borrowing costs;
• 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 filings with the Securities and Exchange Commission, including those risks outlined in "ITEM 1A: Risk Factors" in Shire's Quarterly Report on Form 10-Q for the quarter ended June 30, 2016.

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.

i. SMPC

ii. Wang-Gillam A, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. The Lancet. 2016; 387(10018):545-557.

iii. Malvezzi M, Bertuccio P, Levi F, et al. European cancer mortality predictions for the year. Ann Oncol. 2014; 25:1650-1656.

iv. Sclafani F, Iyer R, Cunningham D, Starling N. Management of metastatic pancreatic cancer: Current treatment options and potential new therapeutic targets. Critical Reviews in Oncology/Hematology. 2015; (95) 318-336.

v. Ducreux M, Cuhna A, Caramella C, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26(5): 56-68.

vi. Carrato A, Falcone A, Ducreux M, et al. A Systematic Review of the Burden of Pancreatic Cancer in Europe: Real-World Impact on Survival, Quality of Life and Costs. J Gastrointest Canc. 2015; 46: 201-211.

vii. Walker EJ and Ko AH. Beyond first-line chemotherapy for advanced pancreatic cancer: An expanding array of therapeutic options? World J Gastroenterol, 2014; 20(9): 2224-36.

viii. Jones OP, Melling JD, and Ghaneh P. Adjuvant therapy in pancreatic cancer. World J Gastroenterol, 2014; 20: 14733-46.

ix. Worldwide data. World Cancer Research Fund Website.  http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/pancreatic-cancer-statistics . Accessed March 8, 2016.

x. Pancreatic cancer statistics. World Cancer Research Fund International. http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/pancreatic-cancer-statistics . Accessed October 17, 2016

xi. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.1, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2014. Available from: http://globocan.iarc.fr , accessed on 10/17/2016.

xii. Ko AH, et al. A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer. British Journal of Cancer. 2013; 109, 920-925

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