Merrimack And Baxalta Announce Publication Of The ONIVYDE (irinotecan liposome injection) NAPOLI-1 Study In The Lancet

November 23, 2015 |

15 min read

CAMBRIDGE, Mass. and BANNOCKBURN, Ill., Nov. 23, 2015 /PRNewswire/ -- Merrimack (Nasdaq: MACK) and Baxalta Incorporated (NYSE: BXLT) today jointly announced that The Lancet has published the article “Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomized, open-label phase 3 trial” online in advance of its print issue. The Lancet is considered one of the most prestigious peer-reviewed general medical journals in the world.

“The publication of the NAPOLI-1 data in TheLancet is significant, as it will provide physicians with comprehensive data on this recently approved treatment that has demonstrated improved overall survival for patients with metastatic adenocarcinoma of the pancreas who had progressed after gemcitabine-based therapy,” said Prof. Li-Tzong Chen, M.D., Ph.D., corresponding author, Investigator on the NAPOLI-1 trial and Director, National Institute of Cancer Research, National Health Research Institutes in Tainan, Taiwan. “We thank the patients and their caregivers, study sites, steering committee members and the chairs for their contributions to this important study.”

Andrea Wang-Gillam, M.D., Ph.D., lead author of the NAPOLI-1 article and Associate Professor of Medicine, Clinical Director of GI Oncology Program, Division of Oncology, at Washington University School of Medicine, St. Louis added, “ONIVYDE in combination with fluorouracil and leucovorin extends median overall survival to six months, a 45% increase, with a well-defined safety profile in patients with metastatic adenocarcinoma of the pancreas who previously received gemcitabine-based therapy, representing a new treatment option for this patient population.”

The NAPOLI-1 study results were the basis of the recent U.S. Food and Drug Administration (FDA) and Taiwan FDA approval of ONIVYDE (irinotecan liposome injection) in combination with fluorouracil (5-FU) and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. ONIVYDE is not indicated for use as a single agent. ONIVYDE, also known as MM-398 or “nal-IRI,” is the first and only FDA approved therapy in this setting. ONIVYDE is irinotecan encapsulated in liposome nanoparticles. The liposome is designed to keep irinotecan in the circulation -- sheltered from conversion to its active metabolite (SN-38) -- longer than unencapsulated irinotecan, which would increase and prolong intratumoral levels of both irinotecan and SN-38 compared with free irinotecan¹. Data from the NAPOLI-1 study were previously presented at the 2014 European Society for Medical Oncology World Congress on Gastrointestinal Cancer and the American Society of Clinical Oncology 2015 Gastrointestinal Cancers Symposium.

The NAPOLI-1 Study and Results¹

NAPOLI-1 was a randomized, open label Phase 3 study in patients with metastatic adenocarcinoma of the pancreas who received prior gemcitabine-based therapy, and was the largest Phase 3 study in this setting to date. Patients were enrolled at 76 sites in North America, South America, Europe, Asia and Oceania.

The study evaluated ONIVYDE, in combination with 5-FU and leucovorin administered every two weeks and as a monotherapy administered every three weeks. Each ONIVYDE containing arm was compared to a control arm of 5-FU and leucovorin. A total of 417 patients were randomized across the three arms. The primary endpoint of the study was overall survival. Key findings of the study as published in The Lancet include:

The ONIVYDE combination regimen demonstrated a significant increase in median overall survival versus 5-FU and leucovorin alone: 6.1 months vs 4.2 months (p=0.012, unstratified hazard ratio for death (HR) =0.67, 95% CI: [0.490.92]). The monotherapy regimen in this study did not show improvement over the 5-FU and leucovorin arm: 4.9 vs 4.2 months (p=0.94, HR=0.99, 95% CI: [0.771.28]).
ONIVYDE in combination with 5-FU and leucovorin achieved a longer progression-free survival compared with the 5-FU and leucovorin arm (3.1 months versus 1.5 months; unstratified HR=0.56 [95% CI, 0.410.75]).
Unconfirmed objective response rate was higher in the ONIVYDE in combination with 5-FU and leucovorin arm than in the 5-FU and leucovorin arm: 16% (19/117) versus 1% (1/119) (difference 15.4 percentage points, 95% CI, 8.5-22.3; p<0.0001).
The most common grade 3 or 4 adverse events that occurred more frequently in the ONIVYDE in combination with 5-FU and leucovorin arm (>2% incidence versus 5-FU and leucovorin) were neutropenia, diarrhea, vomiting, and fatigue.

Baxalta Incorporated is responsible for the development and commercialization of ONIVYDE outside of the United States and Taiwan under the exclusive licensing agreement with Merrimack. In May 2015, the European Medicines Agency accepted for review Baxalta’s marketing authorization application for ONIVYDE based on the same clinical results.

PharmaEngine, Inc. (Taipei, Taiwan) holds the rights to commercialize ONIVYDE in Taiwan. PharmaEngine filed a New Drug Application with the Taiwan FDA on May 29, 2015, and received the approval of ONIVYDE on October 22, 2015.

About Pancreatic Cancer

Pancreatic cancer is a rare and deadly disease. There are approximately 49,000 patients diagnosed with pancreatic cancer each year in the United States², the overwhelming majority of whom have adenocarcinoma³. Globally there are approximately 338,000 new cases each year⁴. Most patients receive gemcitabine-based therapy during either adjuvant/neoadjuvant treatment for locally advanced disease or during first- or second-line therapy for metastatic disease⁵, but are left with no standard of care therapy upon progression. ONIVYDE in combination with 5-FU and leucovorin is now approved in the U.S. and Taiwan for these patients whose disease has progressed following gemcitabine-based therapy.

About ONIVYDE [pronounced \ ‘on - ih vide \]

ONIVYDE (irinotecan liposome injection), also known as MM-398 or “nal-IRI,” is a novel encapsulation of irinotecan in a liposomal formulation. 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. ONIVYDE was recently approved by the U.S. Food and Drug Administration in combination with fluorouracil and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. For full prescribing information, including Boxed WARNING, please visit www.ONIVYDE.com.

IMPORTANT SAFETY INFORMATION

INDICATION

ONIVYDE (irinotecan liposome injection) is indicated, in combination with fluorouracil (5-FU) and leucovorin (LV), for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA

Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil (5-FU) and leucovorin (LV). Withhold ONIVYDE for absolute neutrophil count below 1500/mm³ or neutropenic fever. Monitor blood cell counts periodically during treatment.

Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with 5-FU/LV. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity.

CONTRAINDICATION

ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl.

WARNINGS AND PRECAUTIONS

Severe Neutropenia

ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In a clinical study, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving ONIVYDE, occurring in 1/117 patients in the ONIVYDE/5-FU/LV arm and 1/147 patients receiving ONIVYDE as a single agent. Severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE/5-FU/LV vs 2% of patients receiving 5-FU/LV. Grade 3/4 neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving ONIVYDE/5-FU/LV, and did not occur in patients receiving 5-FU/LV.

In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia was higher among Asian (18/33 [55%]) vs White patients (13/73 [18%]). Neutropenic fever/neutropenic sepsis was reported in 6% of Asian vs 1% of White patients.

Severe Diarrhea

ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to patients with bowel obstruction. Severe and life-threatening late-onset (onset >24 hours after chemotherapy) and early-onset diarrhea (onset <24 hours after chemotherapy, sometimes with other symptoms of cholinergic reaction) were observed. An individual patient may experience both early- and late-onset diarrhea.

In a clinical study, Grade 3/4 diarrhea occurred in 13% of patients receiving ONIVYDE/5-FU/LV vs 4% receiving 5-FU/LV. Grade 3/4 late-onset diarrhea occurred in 9% of patients receiving ONIVYDE/5-FU/LV vs 4% in patients receiving 5-FU/LV; the incidences of early-onset diarrhea were 3% and no Grade 3/4 incidences, respectively. Of patients receiving ONIVYDE/5-FU/LV, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea.

Interstitial Lung Disease (ILD)

Irinotecan HCl can cause severe and fatal ILD. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.

Severe Hypersensitivity Reactions

Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.

Embryo-Fetal Toxicity

Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for 1 month after ONIVYDE treatment.

ADVERSE REACTIONS

The most common (>20%) adverse reactions in which patients receiving ONIVYDE/5-FU/LV experienced a >5% higher incidence of any Grade vs the 5-FU/LV arm, were diarrhea (any 59%, 26%; severe 13%, 4%) (early diarrhea [any 30%, 15%; severe 3%, 0%], late diarrhea [any 43%, 17%; severe 9%, 4%]), fatigue/asthenia (any 56%, 43%; severe 21%, 10%), vomiting (any 52%, 26%; severe 11%, 3%), nausea (any 51%, 34%; severe 8%, 4%), decreased appetite (any 44%, 32%; severe 4%, 2%), stomatitis (any 32%, 12%; severe 4%, 1%), pyrexia (any 23%, 11%; severe 2%, 1%).
Of less common (<20%) adverse reactions, patients receiving ONIVYDE/5-FU/LV who experienced Grade 3/4 adverse reactions at a 2% higher incidence of Grade 3/4 toxicity vs the 5-FU/LV arm, respectively, were sepsis (3%, 1%), neutropenic fever/neutropenic sepsis (3%, 0%), gastroenteritis (3%, 0%), intravenous catheter-related infection (3%, 0%), weight loss (2%, 0%), and dehydration (4%, 2%).
The laboratory abnormalities in which patients receiving ONIVYDE/5-FU/LV experienced a >5% higher incidence vs the 5-FU/LV arm, were anemia (any 97%, 86%; severe 6%, 5%), lymphopenia (any 81%, 75%; severe 27%, 17%), neutropenia (any 52%, 6%; severe 20%, 2%), thrombocytopenia (any 41%, 33%; severe 2%, 0%), increased alanine aminotransferase (any 51%, 37%; severe 6%, 1%), hypoalbuminemia (any 43%, 30%; severe 2%, 0%), hypomagnesemia (any 35%, 21%; severe 0%, 0%), hypokalemia (any 32%, 19%; severe 2%, 2%), hypocalcemia (any 32%, 20%; severe 1%, 0%), hypophosphatemia (any 29%, 18%; severe 4%, 1%), hyponatremia (any 27%, 12%; severe 5%, 3%), increased creatinine (any 18%, 13%; severe 0%, 0%).
ONIVYDE can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early-onset diarrhea. Grade 1/2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients.
Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of ONIVYDE administration were reported in 3% of patients receiving ONIVYDE or ONIVYDE/5-FU/LV.
The most common serious adverse reactions (>2%) of ONIVYDE were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.

DRUG INTERACTIONS

Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzymeinducing therapies >2 weeks prior to initiation of ONIVYDE. Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors >1 week prior to starting therapy.

USE IN SPECIFIC POPULATIONS

Pregnancy and Reproductive Potential

Advise pregnant women of the potential risk to a fetus. Advise males with female partners of reproductive potential to use effective contraception during and for 4 months after ONIVYDE treatment.

Lactation

Advise nursing women not to breastfeed during and for 1 month after ONIVYDE treatment.

Pediatric

Safety and effectiveness of ONIVYDE have not been established in pediatric patients.

DOSAGE AND ADMINISTRATION

The recommended dose of ONIVYDE is 70 mg/m² intravenous (IV) infusion over 90 minutes every 2 weeks, administered prior to LV and 5-FU. The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m² administered by IV infusion over 90 minutes. There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. Premedicate with a corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE. Withhold ONIVYDE for Grade 3/4 adverse reactions. Resume ONIVYDE with reduced dose once adverse reaction recovered to <Grade 1. Discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction and in patients with a confirmed diagnosis of ILD.

Do not substitute ONIVYDE for other drugs containing irinotecan HCl.

Please see full U.S. Prescribing Information for ONIVYDE.

About Merrimack

Merrimack is a fully integrated biopharmaceutical company that views cancer as a complex engineering challenge. Through systems biology, which brings together the fields of biology, computing and engineering, Merrimack aims to decrease uncertainty in drug development and clinical validation, and move discovery efforts beyond trial and error. Such an approach has the potential to make individualized treatment of patients a reality. Merrimack’s first commercial product, ONIVYDE (irinotecan liposome injection), was approved by the U.S. FDA on October 22, 2015. With four additional candidates in clinical studies, several in preclinical development and multiple biomarkers designed to support patient selection, Merrimack is building one of the most robust oncology pipelines in the industry. For more information, please visit Merrimack’s website at www.merrimack.com or connect on Twitter at @MerrimackPharma.

About Baxalta Incorporated

Baxalta Incorporated (NYSE: BXLT) is a $6 billion global biopharmaceutical leader developing, manufacturing and commercializing therapies for orphan diseases and underserved conditions in hematology, oncology and immunology. Driven by passion to make a meaningful impact on patients’ lives, Baxalta’s broad and diverse pipeline includes biologics with novel mechanisms and advanced technology platforms such as gene therapy. The Baxalta Global Innovation and R&D Center is located in Cambridge, Massachusetts. Launched in 2015 following separation from Baxter International Inc., Baxalta’s heritage in biopharmaceuticals spans decades. Baxalta’s therapies are available in more than 100 countries and it has advanced biological manufacturing operations across 12 facilities, including state-of-the-art recombinant production and plasma fractionation. Headquartered in Northern Illinois, Baxalta employs 16,000 employees worldwide.

Forward-Looking Statements

This release includes forward-looking statements concerning ONIVYDE and the related collaboration between Baxalta Incorporated and Merrimack, including expectations with respect to clinical studies, the timing of related data, regulatory filings and potential impact to patients. The statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: satisfaction of regulatory and other requirements; actions of regulatory bodies and other governmental authorities; additional clinical trial results; changes in laws and regulations; issues with product quality, manufacturing or supply; patient safety issues; and other risks identified in Baxalta’s and Merrimack’s most recent filings on Form 10-K and other SEC filings as well as the Form 10 filed by Baxalta Incorporated. Neither Baxalta nor Merrimack undertakes to update their forward-looking statements.

¹Wang-Gillam A, et.al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomized, open-label phase 3 trial. The Lancet. Published online in advance of print November 22, 2015.
²American Cancer Society. Cancer Facts and Figures 2015. Atlanta: American Cancer Society; 2015.
³American Cancer Society. Pancreatic Cancer Overview. Atlanta: American Cancer Society; 2015.
⁴World Health Organization. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012; Lyon, Fr.: International Agency for Research on Cancer; 2012.
⁵Data presented at ASCO 2014 (Abrams et al.).