Merrimack Pharmaceuticals Presents Additional Analyses of Phase 3 MM-398 NAPOLI-1 Study at the American Society of Clinical Oncology (ASCO) 2015 Gastrointestinal Cancers Symposium

CAMBRIDGE, Mass., Jan. 20, 2015 (GLOBE NEWSWIRE) -- Merrimack Pharmaceuticals, Inc. (Nasdaq:MACK) announced that additional analyses were presented on January 16, 2015 from the Phase 3 NAPOLI-1 study of MM-398 (irinotecan liposome injection), also known as "nal-IRI," in patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy. The data were presented by Li-Tzong Chen, M.D., Ph.D. in an oral session at the American Society of Clinical Oncology (ASCO) 2015 Gastrointestinal Cancers Symposium in San Francisco, CA. Merrimack and Baxter International's biopharmaceutical business (NYSE:BAX) are collaborating on the development and commercialization of MM-398 outside of the United States and Taiwan. PharmaEngine, Inc. (Taipei, Taiwan) holds the rights to commercialize MM-398 in Taiwan. Additionally, Merrimack presented preclinical and clinical data from studies of its investigational agents MM-141 and MM-151 in pancreatic and colorectal cancer, respectively. An investigator-sponsored study of MM-398 in colorectal cancer was also presented.

The extended analyses for the global NAPOLI-1 Phase 3 trial presented at ASCO GI support the robustness of the overall survival benefit of MM-398 in combination with 5-fluorouracil (5-FU) and leucovorin presented in June 2014, at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer (ESMO GI).

The primary analysis, presented at ESMO GI, demonstrated a statistically significant advantage in overall survival with an unstratified hazard ratio of 0.67 (95% CI [0.49-0.92], p=0.0122), and a median of 6.1 months for the combination of MM-398 plus 5-FU and leucovorin compared to 4.2 months in the control arm. Data presented at ASCO GI showed:

• Stratified analysis, which accounts for pre-specified prognostic factors included in the study randomization stratification, resulted in an overall survival hazard ratio of 0.57 (95% CI [0.41-0.80], p=0.0009).
  • A forest plot sensitivity analysis of additional prognostic factors such as line of treatment, stage at diagnosis, prior lines of therapy, time since initial diagnosis, and time since last prior therapy, supported the primary efficacy results obtained.
  • Evaluation of the Per Protocol population (defined by patients who were able to remain on treatment for >6 weeks) supported the primary Intent to Treat analysis and demonstrated a median overall survival of 8.9 months for MM-398 in combination with 5-FU and leucovorin versus 5.1 months in the control arm (stratified HR=0.47, 95% CI [0.29-0.77], p=0.0018).
• The safety profile of the MM-398 combination was reported to be manageable and consistent with previously reported safety results, with the most frequent adverse events including neutropenia (20% in the combination arm vs. 2% in the control arm), fatigue (14% vs. 4%) and gastrointestinal effects such as diarrhea (13% vs. 5%) and vomiting (11% vs. 3%).

"We are pleased to present additional analyses on the NAPOLI-1 study for the first time in the United States. The data are continuing to mature and these analyses reinforce our conclusions about the potential for use of MM-398 in patients with metastatic pancreatic cancer who have previously received gemcitabine," said Li-Tzong Chen, M.D., Ph.D., Director, Investigator and Attending Physician at the National Institute of Cancer Research, National Health Research Institutes in Taiwan. "These results highlight the potential for MM-398, in combination with 5-FU and leucovorin, to contribute to addressing the unmet needs of patients living with this difficult to treat disease."

Merrimack is in the process of submitting a New Drug Application to the U.S. Food and Drug Administration for the MM-398 combination regimen. In September 2014, Merrimack licensed the rights to MM-398 outside of the United States and Taiwan to Baxter. Baxter is currently working to prepare a Marketing Authorization Application for the European Medicines Agency and other territories during 2015. PharmaEngine is preparing a New Drug Application for the Taiwan Food and Drug Administration.

To access clinical posters presented at ASCO 2015, click here.

Methodology and Results

Expanded Analyses of NAPOLI-1: Phase 3 Study of MM-398 (nal-IRI), with or without 5-Fluorouracil and Leucovorin, versus 5-Fluorouracil and Leucovorin, in Metastatic Pancreatic Cancer (mPAC) Previously Treated with Gemcitabine-based Therapy (Abstract #234)

• MM-398 in combination with 5-FU and leucovorin improved overall survival compared to 5-FU and leucovorin treatment as demonstrated (in the Intent to Treat population):
  • Patients on the combination therapy of MM-398 and 5-FU and leucovorin achieved an overall survival of 6.1 months versus 4.2 months in the control arm of 5-FU and leucovorin alone (stratified HR=0.57, 95% CI [0.41-0.80], p=0.0009);
  • Both unstratified and stratified hazard ratios achieved statistical significance; and
  • There was consistency in benefit across formal stratification factors (performance status, albumin and ethnicity), prognostic factors, tumor characteristics and previous treatments.
• In the Per Protocol population, MM-398 in combination with 5-FU and leucovorin demonstrated improved overall survival and tumor control to the control arm of 5-FU and leucovorin alone. In the pre-specified Per Protocol analysis, median overall survival for the combination therapy arm was 8.9 months versus 5.1 months in the control arm (stratified HR=0.47, 95% CI [0.29-0.77], p=0.0018).
• Significant differences were also observed in PFS (overall and at three months), ORR and CA19-9 response
  • The combination arm of MM-398 and 5-FU and leucovorin demonstrated a statistically significant median PFS of 3.1 months compared to 1.5 months in the control arm (stratified HR=0.51, 95% CI [0.37-0.70], p=0.0001).
• Although there were more dose modifications needed, patients receiving MM-398 and 5-FU and leucovorin were able to stay on treatment longer, and experienced improved survival compared to the control arm of 5-FU and leucovorin alone. The following percentage of patients in the combination arm versus the control arm reported treatment emergent adverse events resulting in dose reduction (33% vs. 4%), dose delays (62% vs. 32%) and treatment discontinuation (11% vs. 8%).
• MM-398 monotherapy, dosed at a 120 mg/m² Q3W regimen, did not show a statistically significant OS advantage.

First-in-human study of MM-141: A novel tetravalent monoclonal antibody targeting IGF-1R and ErbB3 (Abstract #384)

MM-141 is an investigational fully human tetravalent antibody that targets signaling of the PI3K/AKT/mTOR pathway driven through activation of IGF-1R and ErbB3 (HER3). PI3K/AKT/mTOR is a major pro-survival pathway that tumor cells use as a resistance mechanism to anti-cancer therapies. MM-141 is designed to interfere with this pathway by blocking ligand-induced signaling through the IGF-1R and ErbB3 (HER3) receptors and degrading oncogenic receptor complexes.

• MM-141 monotherapy was well tolerated and translational analysis showed that MM-141 induced IGF-1R and ErbB3 (HER3) degradation in patient tumor tissue.
• The observed safety profile of MM-141 in combination with nab-paclitaxel and gemcitabine was comparable to expected toxicities reported with the chemotherapy combination alone.
• A subset of patients with elevated pre-treatment serum free IGF-1 levels remained on study longer than those with low levels of free IGF-1.
• Data from this Phase I study were used to inform the design of a Phase 2 study of MM-141 in combination with nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer patients. The Phase 2 study is scheduled to begin in Q1 2015.

Effect of MM-141 on gemcitabine and nab-paclitaxel potentiation in preclinical models of pancreatic cancer through induction of IGF-1R and ErbB3 degradation (Abstract #289)

• In preclinical models of pancreatic cancer, MM-141 significantly increased the activity of a nab-paclitaxel/gemcitabine regimen by blocking growth factor signaling and degrading oncogenic receptor complexes containing IGF-1R and ErbB3 (HER3).
• Data also demonstrated that patient tumors with active IGF-1 and/or heregulin signaling were more likely to respond to an IGF-1R and ErbB3 (HER3) polytargeted therapy.

HER3 as a potential prognostic biomarker in pancreatic cancer (Abstract #295)

• An increase in overall survival was seen in patients with early stage pancreatic cancer who had elevated tumor levels of ErbB3 (HER3).
• ErbB3 (HER3) and IGF-1R are dynamically expressed in early versus late stage pancreatic cancer, suggesting IGF-1R and ErbB3 (HER3) pathway activation at later stages of the disease.

Safety, pharmacology and preliminary clinical activity of MM-151: an oligoclonal anti-EGFR therapeutic in patients with cetuximab-resistant CRC and other refractory solid tumors (Abstract #647)

MM-151 is an investigational novel oligoclonal anti-EGFR antibody combination designed to target EGFR-driven tumor growth.

• Prolonged stable disease and radiographic responses (three monotherapy and three combination therapy partial responses) were observed in heavily pre-treated solid tumor patients, including those with prior cetuximab therapy.
• Results for patients treated with MM-151 alone and MM-151 in combination with irinotecan showed an acceptable safety profile for MM-151 monotherapy and MM-151 plus irinotecan.
• Updated biomarker data suggests potential for particular clinical benefit in EGFR-ligand positive colorectal cancer patients.

PEPCOL: A randomized noncomparative phase II study of PEP02 (MM-398) or irinotecan in combination with leucovorin and 5-fluorouracil as second-line therapy in patients with unresectable metastatic colorectal cancer – A GERCOR study (Abstract #751)

• This is an investigator-sponsored study by Groupe Coopérateur Muldisciplinaire en Oncologie (GERCOR) evaluating the effect of adding PEP02 to 5-FU and leucovorin (FUPEP regimen) when administered to patients with metastatic colorectal cancer after failure of an oxaliplatin-based first-line therapy.
• The primary endpoint of the study was overall response rate. Both arms met the prespecified first stage of response. The response rate of the FUPEP regimen was 14% (4/28), which compared favorably with FOLFIRI (4/38, 11%).
• The most common Grade 3 or higher adverse events occurring at a higher rate in the FOLFIRI arm compared to the FUPEP arm were neutropenia (30% vs. 11%) and diarrhea (33% and 21%). Other adverse events were similar between the two arms.

About MM-398

MM-398 (irinotecan liposome injection), also known as "nal-IRI," is a novel encapsulation of irinotecan in a long-circulating nanoliposomal formulation designed to increase drug deposition and prolong cytotoxic effects, with the goal of improving its anti-cancer properties. 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. In 2014, Merrimack and Baxter International's biopharmaceutical business (NYSE:BAX) entered into an exclusive licensing agreement to develop and commercialize MM-398 outside of the United States and Taiwan. PharmaEngine, Inc. (Taipei, Taiwan) holds the rights to commercialize MM-398 in Taiwan.

About Merrimack

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 multiple candidates in preclinical development. Merrimack's lead product candidate, MM-398, recently completed a Phase 3 trial in post-gemcitabine pancreatic cancer. Based on the results of this trial, Merrimack is currently preparing a New Drug Application for MM-398. For more information, please visit Merrimack's website at www.merrimackpharma.com or connect on Twitter at @MerrimackPharma.

Forward-Looking Statements

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 its investigational drugs either alone or in combination and the timing of submitting a New Drug Application to the FDA for MM-398. 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 November 10, 2014 and other reports Merrimack files with the SEC.