MM-398 in combination with 5-fluorouracil and leucovorin shows statistically significant improvement in overall survival, progression free survival and overall response rate in patients with post-gemcitabine metastatic pancreatic cancer
Plan to file New Drug Application in 2014
Conference call to review data scheduled for 8:00 a.m. ET tomorrow, June 26th
CAMBRIDGE, Mass., June 25, 2014 (GLOBE NEWSWIRE) -- Merrimack Pharmaceuticals, Inc. (Nasdaq:MACK) today announced detailed results from NAPOLI-1, a large, randomized, 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% 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 (16% and 1%, respectively, p<0.001). The most common non-hematologic grade 3 and higher adverse events in the combination arm were fatigue (14%), diarrhea (13%) and vomiting (11%). Hematologic grade 3 and higher adverse events included neutropenia, which was observed in 20% of patients as determined by objective laboratory values, and febrile neutropenia, which was observed in 2% 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 program. 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, M.D., 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 U.S. Food and Drug Administration for the MM-398 combination regimen in 2014.
NAPOLI-1: Randomized 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)
Study results for MM-398 in combination with 5-fluorouracil and leucovorin
- 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, 95% 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% 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 20% of patients as determined by objective laboratory values, and febrile neutropenia which was observed in 2% of the patients. The most common non-hematologic grade 3 and higher adverse events were fatigue (14%), diarrhea (13%) and vomiting (11%).
- The overall response rate in the combination arm was 16% versus 1% in the control arm which was statistically significant (p<0.001).
- A reduction of CA19-9 levels was observed in 36% of patients in the combination arm versus 12% of patients in the control arm. The reduction of CA19-9, a pancreatic tumor marker indicative of patient response to MM-398, was defined by a greater than or equal to 50% decrease in baseline CA19-9 levels.
Study results for MM-398 as a monotherapy
- 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, 95% 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, 95% CI [0.62-1.04]).
- Neutropenia was observed in 16% of the patients on the monotherapy arm and febrile neutropenia was observed in 4% of patients. The most common grade 3 or higher adverse events included diarrhea (21%), vomiting (14%) and hypokalemia (12%).
- The overall response rate of MM-398 alone was 6% versus 1% in the control arm.
- A reduction of CA19-9 levels was observed in 31% of patients on the MM-398 monotherapy arm versus 12% of patients in the control arm.
Merrimack to Host Conference Call
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 Trial Design
NAPOLI-1 (NAnoliPOsomaL Irinotecan) is a randomized, 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 randomized 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 commercialization rights to MM-398, with PharmaEngine, Inc. retaining commercialization rights in Taiwan.
MM-398 is not approved for any indication by the U.S. Food and Drug Administration (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.
About 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 percent and 94 percent, 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.
1 American Cancer Society. Cancer Facts and Figures 2014. Atlanta: American Cancer Society; 2014.
Merrimack is a biopharmaceutical company discovering, developing and preparing to commercialize innovative medicines paired with companion diagnostics for the treatment of cancer. Merrimack seeks to gain a deeper understanding of underlying cancer biology through its systems biology-based approach and develop new insights, therapeutics and diagnostics to improve outcomes for cancer patients. Merrimack currently has six oncology therapeutics in clinical development and three additional candidates in late stage preclinical development. For more information, please visit Merrimack's website at www.merrimackpharma.com.
To the extent that statements contained in this press release are not descriptions of historical facts, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements include any statements about Merrimack's strategy, future operations, future financial position and future expectations and plans and prospects for Merrimack, and any other statements containing the words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue," "hope" and similar expressions. In this press release, Merrimack's forward-looking statements include statements about the potential effectiveness and safety profile of MM-398 either alone or in combination and the expected timeline for seeking regulatory approval for the MM-398 combination regimen. Such forward-looking statements involve substantial risks and uncertainties that could cause Merrimack's clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, availability of data from ongoing clinical trials, expectations for regulatory approvals, development progress of Merrimack's companion diagnostics and other matters that could affect the availability or commercial potential of Merrimack's drug candidates or companion diagnostics. Merrimack undertakes no obligation to update or revise any forward-looking statements. Forward-looking statements should not be relied upon as representing Merrimack's views as of any date subsequent to the date hereof. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to Merrimack's business in general, see the "Risk Factors" section of Merrimack's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 6, 2014 and other reports Merrimack files with the SEC.
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