Shire plc 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.”

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.  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.

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%]).