ONIVYDE® Receives Positive CHMP Opinion for Treatment of Patients with Metastatic Adenocarcinoma of the Pancreas Who Have Progressed Following Gemcitabine Based Therapy

ZUG, Switzerland, July 25, 2016 /PRNewswire/ --

The positive opinion is based on a pivotal Phase 3 study showing that ONIVYDE combined with chemotherapy significantly increased overall survival (OS) in patients with metastatic pancreatic cancer after previous gemcitabine based therapy 

Shire plc (LSE: SHP, NASDAQ: SHPG) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending the marketing authorization for the use of ONIVYDE^® (irinotecan pegylated liposomal formulation) 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.

"There has been little improvement in the prognosis for patients with metastatic pancreatic cancer in over 20 years. We therefore welcome the CHMP positive opinion for ONIVYDE, a regulatory milestone which brings us a step closer to helping patients with this devastating disease." said Philip J. Vickers, Ph.D., Head of R&D, Shire. "At Shire, we are committed to research and development through innovation in order to identify unique methodologies for treating patients with high unmet needs."

Pancreatic cancer is the third leading cause of cancer death in the region and there are limited treatment options available. 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 second-line treatment of these patients following gemcitabine-based therapy. Gemcitabine-based therapy is commonly used as a first-line treatment for patients with metastatic disease or locally advanced disease who cannot be treated with surgery, or as adjuvant therapy.

"Guidance from ESMO indicates the use of ONIVYDE for the treatment of metastatic pancreatic cancer in patients who have progressed following gemcitabine-based treatment," said Volker Heinemann, M.D., Ph.D., a professor of medical oncology at the University of Munich, Germany. "The CHMP positive opinion for ONIVYDE is an important step for patients with this devastating disease."

The CHMP positive opinion is based on pivotal, Phase 3 NAPOLI-1 data that demonstrated nal-IRI combined with 5-FU and LV improved overall survival (OS) (primary endpoint), as well as progression-free survival (PFS) and objective response rate (ORR) relative to the 5-FU and LV control arm (secondary endpoints). The most common Grade 3 or higher adverse events with greater than five percent difference in patients receiving nal-IRI and 5-FU and LV were neutropenia, fatigue and diarrhoea, and vomiting.

"The CHMP positive opinion confirms the strength of the Phase 3 NAPOLI-1 data for the use of ONIVYDE to treat metastatic pancreatic cancer patients in the post-gemcitabine setting." said Professor Thomas Seufferlein, M.D., University of Ulm, Germany. "This data will allow physicians to better evaluate options for extending overall survival of patients diagnosed with a very difficult-to-treat cancer."

The CHMP's positive opinion will be submitted to the European Commission (EC), which is responsible for granting marketing authorizations for medicines in the European Union (EU). We anticipate a final decision later this year.

J. Marc Pipas, M.D., Senior Medical Director at Merrimack Pharmaceuticals Inc. commented: "We applaud the CHMP's positive opinion on ONIVYDE as it acknowledges the clinical significance of this therapy for a patient population with few treatment options. We look forward to continuing our work with Shire to expand the global availability of this important therapy to patients facing metastatic pancreatic cancer."

About Pancreatic Cancer 

Pancreatic cancer is a significantly underserved disease in Europe and almost always fatal. Half of people diagnosed with pancreatic cancer are diagnosed at Stage 4, which is advanced metastatic disease and no longer curable. The disease has a five-year overall survival (OS) rate of three percent, and a median OS typically less than a year, as supported by real-world European systematic review. The only curative treatment for pancreatic cancer is surgical resection in the primary stage, which can improve five-year survival to 10 percent.  

The signs and symptoms of pancreatic cancer are non-specific, (common presenting symptoms include jaundice, abdominal pain, weight loss, steatorrhoea, and new-onset diabetes) and may not appear until the disease has spread locally or metastasized. Therefore, approximately 80 percent of patients are not candidates for surgery upon diagnosis.

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

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 and the length of exposure of irinotecan. Studies have suggested that encapsulation helps to improve delivery of irinotecan to tumors, such as metastatic pancreatic cancer.

In the pivotal Phase 3 NAPOLI-1 study, nal-IRI demonstrated improved survival in patients with metastatic pancreatic cancer after previous gemcitabine-based therapy. 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.

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 currently 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. Approval of ONIVYDE in Taiwan was also received in October 2015, where PharmaEngine holds the commercialization rights.

About NAPOLI-1 

NAPOLI-1 is the first global, randomized open-label Phase 3 trial to show extended overall survival in metastatic pancreatic ductal adenocarcinoma cancer after gemcitabine-based therapy through treatment with nal-IRI combined with 5-FU and LV. NAPOLI-1 was the largest Phase 3 study in this setting to date. Patients were enrolled at 76 sites in 14 countries across North America, Europe, Asia, South America, and Australia. The study evaluated nal-IRI (80mg/m2) in combination with 5-FU and LV administered intravenously every two weeks and as a monotherapy (120 mg/m2) administered every three weeks. Each nal-IRI containing arm was compared to a control arm of 5-FU and LV.

NAPOLI-1 met the following primary and secondary endpoints by demonstrating that nal-IRI combined with 5-FU and LV significantly improved OS, progression-free survival (PFS) and objective response (OR) compared to 5-FU/LV alone in patients with metastatic pancreatic cancer. In a pivotal analysis, nal-IRI plus 5-FU/LV demonstrated a significant increase in median overall survival versus 5-FU and 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).

The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nal-IRI plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]).

Important Safety Information  

The most common adverse reactions (incidence ≥20 percent) seen with nal-IRI in combination with 5-FU and LV compared with 5-FU and LV alone were: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia, stomatitis, and pyrexia. Early-onset (within 1 day of treatment) diarrhoea occurred in 30 percent of patients on nal-IRI combined with 5-FU and LV and was usually transient. Early-onset diarrhoea was accompanied by cholinergic symptoms in three percent of patients taking nal-IRI in combination with 5-FU and LV. Median time to late-onset diarrhoea was eight days following the nal-IRI dose. Alopecia occurred in 14 percent of patients in the nal-IRI combined with 5-FU and LV arm versus five percent of patients in the 5-FU and LV arm. Of patients taking nal-IRI combined with 5-FU and LV, 11 percent of patients discontinued treatment versus seven percent of patients receiving 5-FU and LV alone. No significant deterioration in quality of life was observed in patients in either arm of the study compared to baseline.

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

NOTES TO EDITORS 

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:

• disruption from the acquisition and integration of Shire Incorporated ("Shire") may make it more difficult to conduct business as usual or maintain relationships with patients, physicians, employees or suppliers;
• the company may not achieve some or all of the anticipated benefits of Shire's spin-off from Baxter International, Inc. ("Baxter") and the acquisition may have an adverse impact on Shire'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 acquisition of Shire may adversely affect the 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 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 company's ability to sell or market products profitably, and fluctuations in buying or distribution patterns by such customers can adversely affect the company's revenues, financial condition or results of operations;
• investigations or enforcement action by regulatory authorities or law enforcement agencies relating to the 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, tax audits and other disputes, including the 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 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 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 Corp. ("Dyax") may adversely affect the company's financial condition and results of operations;
• the company 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 the company's revenues, financial condition or results of operations;
• the 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 Shire into Shire may lead to the 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 Shire's filings with the Securities and Exchange Commission, including those risks outlined in "ITEM 1A: Risk Factors" in Shire's and Shire's Annual Reports 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.

FOR FURTHER INFORMATION PLEASE CONTACT:

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SOURCE Shire plc

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