Shire plc: Large-Scale European Review Suggests Disparity

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 trial ⁴ 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 trial ⁷ 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 therapy ⁸ 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/fi...uthors.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/m ² ), expressed as irinotecan hydrochloride trihydrate (which is the equivalent of 70 mg/m ² ONIVYDE expressed as irinotecan free base) 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. ^[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.

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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

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^[1] Melisi D, Westphalen B, Mellbring A, et. al. Symptoms reported at initial diagnosis of (metastatic) pancreatic adenocarcinoma ([m]PAC) in routine clinical practice and variation in frequencies across Europe. Presentation at ESMO-GI 2018. Barcelona. Abstract #P-167.

^[2] Taieb J, Carrato A, Mellbring A, et. al. Geographic variation in systemic treatment of metastatic pancreatic adenocarcinoma (mPAC) patients in real world across Europe. Presentation at ESMO-GI 2018. Barcelona. Abstract #O-002.

^[3] Prager G, Macarulla T, Mellbring A, et. al. Baseline characteristics and second-line treatment for metastatic pancreatic adenocarcinoma (mPAC) patients receiving first-line FOLFIRINOX, gemcitabine+nab-paclitaxel or gemcitabine-monotherapy in routine clinical practice across Europe. Presentation at ESMO-GI 2018. Barcelona. Abstract #PD-004.

^[4] Macarulla T, Lee KH, Lakatos G, et. al. Selected subgroup analyses of liposomal irinotecan (nal-IRI) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in the global NAPOLI-1 phase III trial. Poster and oral presentation at ESMO-GI 2018. Barcelona. Abstract #O-004.

^[5] Lee KH, Bodoky G, Blanc JF, et. al. Decreased appetite (DA) at baseline impacts prognosis in the NAPOLI-1 phase 3 study in metastatic pancreatic ductal adenocarcinoma (mPDAC). Poster presentation at ESMO-GI 2018. Barcelona. Abstract #P-153.

^[6] Macarulla T, Wang-Gillam A, Chen LT, et. al. Prognostic effect of primary tumor location (PTL) in the NAPOLI-1 phase 3 study in metastatic pancreatic ductal adenocarcinoma (mPDAC). Poster presentation at ESMO-GI 2018. Barcelona. Abstract #P-150.

^[7] Lakatos G, Chen LT, Siveke JT, et. al. Prognostic value of baseline biliary stents on outcomes in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in the NAPOLI-1 trial. Poster presentation at ESMO-GI 2018. Barcelona. Abstract #P-151.

^[8] Macarulla T, Wang Gillam A, Chen LT, et. al. 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 therapy. Poster presentation at ESMO-GI 2018. Barcelona. Abstract #P-152.

^[9] Ducreux M, Suhna AS, Carmella C, et. al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2015;26 (suppl_5): v56-v68.

^[10] 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.

^[11] 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. 

^[12] 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.

^[13] Jones OP, Melling JD, and Ghaneh P. Adjuvant therapy in pancreatic cancer. World J Gastroenterol, 2014; 20: 14733-46.

^[14] Worldwide data. World Cancer Research Fund Website.  http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/pancreatic-cancer-statistics.

^[15] 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.

^[16] Shire. ONIVYDE, irinotecan hydrochloride trihydrate. Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_...215029.pdf