Merrimack Pharmaceuticals Inc, announced detailed results from NAPOLI-1, a large, randomised, three-arm Phase 3 study of MM-398, a nanoliposomal encapsulation of irinotecan, in patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy. The combination of MM-398 with 5-fluorouracil (5-FU) and leucovorin extended overall survival and significantly increased progression free survival (PFS) and overall response rate compared to the control arm of 5-FU and leucovorin alone.

Top line results of NAPOLI-1 released in May showed that the combination of MM-398 with 5-FU and leucovorin achieved an overall survival of 6.1 months versus the 4.2 month survival demonstrated by the control arm of 5-FU and leucovorin alone. The primary log-rank analysis of overall survival was statistically significant (p=0.012), with a corresponding hazard ratio of 0.67.

In combination with 5-FU and leucovorin, MM-398 also demonstrated a statistically significant advantage in PFS, with a median of 3.1 months compared to 1.5 months in the control arm (HR = 0.56, 95 per cent CI [0.41-0.75], p=0.0001). The combination arm also showed a statistically significant difference in overall response rate compared to the control arm (16per cent and 1per cent, respectively, p < 0.001). The most common non-hematologic grade 3 and higher adverse events in the combination arm were fatigue (14 per cent), diarrhea (13 per cent) and vomiting (11 per cent). Hematologic grade 3 and higher adverse events included neutropenia, which was observed in 20per cent of patients as determined by objective laboratory values, and febrile neutropenia, which was observed in 2per cent of patients.

Results of the study were presented today by Andrea Wang-Gillam, M.D., Ph.D., assistant professor of medicine, division of oncology, Washington University School of Medicine, at an oral session at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer (ESMO GI) held in Barcelona, Spain, and was featured in the official press programme. To access the clinical poster and slides presented at ESMO GI, click here.

"These positive results further strengthen our belief in the MM-398 combination and design of NAPOLI-1. Entering into a difficult disease with a history of clinical trial failures, the MM-398 combination has extended overall survival while striking an important balance between efficacy and toxicity in a setting where there is no current standard of care," said Eliel Bayever, MD., a vice president at Merrimack and the medical director for MM-398. "This Phase 3 success bolsters our confidence in our systems approach and continued commitment to engineering innovative therapies for difficult to treat cancers."

Merrimack expects to submit a New Drug Application to the US Food and Drug Administration for the MM-398 combination regimen in 2014.

NAPOLI-1: Randomised Phase 3 Study of MM-398 (nal-IRI), with or without 5-Fluorouracil and Leucovorin, versus 5-Fluorouracil and Leucovorin, in Metastatic Pancreatic Cancer Progressed on or Following Gemcitabine-based Therapy (Abstract #O-0003)

Patients on the combination therapy of MM-398, dosed at 80 mg/m2 Q2W with 5-FU and leucovorin, achieved an overall survival of 6.1 months versus 4.2 month survival demonstrated by the control arm of 5-FU and leucovorin alone (HR=0.67, 95per cent CI [0.49-0.92], p=0.01).

The combination arm demonstrated a statistically significant median PFS of 3.1 months compared to 1.5 months in the control arm (HR = 0.56, 95 per cent CI [0.41-0.75], p=0.0001).

Safety and efficacy data for patients treated with MM-398 were consistent with previously reported top line data and results from earlier MM-398 clinical studies. Hematologic grade 3 and higher adverse events in the combination arm included neutropenia, which was observed in 20per cent of patients as determined by objective laboratory values, and febrile neutropenia which was observed in 2per cent of the patients. The most common non-hematologic grade 3 and higher adverse events were fatigue (14per cent), diarrhoea (13per cent) and vomiting (11per cent).

The overall response rate in the combination arm was 16per cent versus 1per cent in the control arm which was statistically significant (p < 0.001).A reduction of CA19-9 levels was observed in 36per cent of patients in the combination arm versus 12per cent of patients in the control arm. The reduction of CA19-9, a pancreatic tumour marker indicative of patient response to MM-398, was defined by a greater than or equal to 50 per cent decrease in baseline CA19-9 levels.

MM-398, dosed at 120 mg/m2 Q3W, had a 4.9 month median overall survival compared to 4.2 months in the control arm (HR=0.99, 95per cent CI [0.77-1.28], p=0.942).Patients on the MM-398 monotherapy arm achieved a median PFS of 2.7 months versus 1.6 months in the control (HR = 0.80, 95per cent CI [0.62-1.04]).Neutropenia was observed in 16per cent of the patients on the monotherapy arm and febrile neutropenia was observed in 4per cent of patients. The most common grade 3 or higher adverse events included diarrhoea (21per cent), vomiting (14per cent) and hypokalemia (12per cent).The overall response rate of MM-398 alone was 6per cent versus 1per cent in the control arm.

A reduction of CA19-9 levels was observed in 31per cent of patients on the MM-398 monotherapy arm versus 12 per cent of patients in the control arm.

Merrimack will host an investor conference call and webcast at 8 a.m., Eastern Time, tomorrow, Thursday, June 26, 2014 where Dr. Wang-Gillam will review the data presented at ESMO GI. Investors and the general public are invited to listen to the call by dialing (877) 564-1301 (domestic) or (224) 357-2394 (international) five minutes prior to the start of the call and providing the passcode 61076181.Slides accompanying the call and a listen-only webcast of the call can be accessed in the Investors section of Merrimack's website, http://investors.merrimackpharma.com, and a replay of the call will be archived there for six weeks.

NAPOLI-1 (NanoliPOsomaL Irinotecan) is a randomised, open label Phase 3 study in patients with metastatic pancreatic cancer who received prior gemcitabine-based therapy. The study evaluated two MM-398 regimens, 80 mg/m2 combined with 5-FU and leucovorin every two weeks, and 120 mg/m2 as a monotherapy every three weeks. Each arm was compared to a control arm of 5-FU and leucovorin. A total of 417 patients were randomised across the three arms. Each MM-398 regimen was compared against the control arm on the primary endpoint of overall survival. Patients were enrolled at over 100 sites in North America, South America, Europe, Asia and Australia.

MM-398 (irinotecan liposome injection), also known as "nal-IRI," is a nanoliposomal encapsulation of the chemotherapeutic irinotecan. MM-398 has demonstrated extended circulation in comparison to free irinotecan in the clinical setting. The activated form of irinotecan is SN-38, which functions by inhibiting topoisomerase I (an essential enzyme involved in DNA transcription and replication) and promoting cell death.

MM-398 is an investigational agent which is also currently being evaluated in an ongoing Phase 2 study in patients with metastatic colorectal cancer and Phase 1 studies in Ewing's sarcoma and glioma. An additional Phase 1 clinical trial is assessing a potential companion diagnostic for MM-398 in patients with multiple cancer types to determine which patients are most likely to benefit from treatment with the drug.

Under a 2011 agreement with PharmaEngine, Inc. (Taipei, Taiwan), Merrimack consolidated the worldwide development and commercialisation rights to MM-398, with PharmaEngine, Inc. retaining commercialisation rights in Taiwan.

MM-398 is not approved for any indication by the US Food and Drug Administration (US FDA) or any other regulatory agency. Both the FDA and the European Medicines Agency have granted MM-398 orphan drug designation in metastatic pancreatic cancer.

In the United States alone, approximately 46,000 people are diagnosed with pancreatic cancer and about 40,000 patients die annually, making it the fourth most common cause of cancer death. The one year and five year mortality rates are 73 per cent and 94 per cent, respectively1. Because the signs and symptoms of pancreatic cancer may not appear until the disease has spread to other sites in the body, a majority of patients are not candidates for surgery and receive chemotherapy as the mainstay of their therapy. There is no consensus on the standard of care for metastatic pancreatic cancer patients previously treated with a gemcitabine-based therapy.