• Positive opinion based on Phase III NAPOLI 3 clinical trial in which Onivyde® regimen (NALIRIFOX) demonstrated statistically significant superiority and clinically meaningful improvements in overall survival and progression-free survival versus Nab-paclitaxel and Gemcitabine.

• NAPOLI 3 represents the first positive Phase III trial in first-line metastatic pancreatic adenocarcinoma to demonstrate superior overall survival versus the currently approved regimen of Nab-paclitaxel and Gemcitabine.

• Onivyde is the only approved treatment regimen to demonstrate efficacy in two Phase III trials across lines of therapy in metastatic pancreatic adenocarcinoma.

PARIS, France – 22 March 2024 – Servier, an independent international pharmaceutical group, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion and recommended granting a marketing authorization for ONIVYDE® (irinotecan liposome injection) plus oxaliplatin, fluorouracil and leucovorin (NALIRIFOX) as a first-line treatment in adults living with metastatic pancreatic adenocarcinoma. This is the second approval for an Onivyde regimen in metastatic pancreatic adenocarcinoma, following the approval in Europe in 2016 of Onivyde plus fluorouracil and leucovorin after disease progression with Gemcitabine-based therapy.

“Metastatic Pancreatic Adenocarcinoma remains a major therapeutic challenge with currently limited options. In this context any treatment progress in this aggressive form of cancer offers a new hope. Each innovation represents a significant step towards clinical improvement in this particular population,” stated Professor. Davide Melisi, at the Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Claude Bertrand, Executive Vice President of R&D at Servier, added, “We are delighted that the CHMP has recognized the value of NALIRIFOX as demonstrated in the NAPOLI 3 study. For patients, this represents an additional option in the therapeutic armamentarium against this hard-to-treat cancer. This positive opinion is also another step forward in Servier’s commitment to delivering innovative treatments for patients with cancers.”

The CHMP’s positive opinion on ONIVYDE® as a first-line treatment in adults living with metastatic pancreatic adenocarcinoma will be referred to the European Commission (EC) for final decision. The decision will be applicable to all 27 EU member states plus Iceland, Norway, Northern Ireland and Liechtenstein.

In 2018, Servier entered into an exclusive license agreement with IPSEN for the co-development and commercialization of ONIVYDE®. Servier is currently responsible for the commercialization of ONIVYDE® outside of the U.S., Canada and Taiwan. 

NAPOLI 3 Data

The CHMP’s positive opinion is based on efficacy and safety data from NAPOLI 3, a randomized, controlled, open-label, Phase III pivotal trial that enrolled 770 people living with metastatic pancreatic adenocarcinoma between the ages of 20 and 85 without prior medical anticancer treatments across 187 sites in 18 countries.

This study is the first positive clinical study in 1st line metastatic pancreatic adenocarcinoma to demonstrate a superior overall survival and progression free survival versus the currently approved regimen of Nab-paclitaxel and Gemcitabine¹.

No unexpected safety concerns were identified with the use of NALIRIFOX as first-line therapy in NAPOLI 3. The safety profile is consistent with the profiles of the treatment components.

About Onivyde (irinotecan liposome injection)

Onivyde is an anticancer medicine that inhibits an enzyme called topoisomerase I, involved in copying cell DNA needed to make new cells. By blocking the enzyme, cancer cells are prevented from multiplying and eventually die. In Onivyde, irinotecan is enclosed in tiny lipid particles called ‘liposomes’, which accumulate in the tumor and release slowly over time.

About metastatic pancreatic adenocarcinoma

Metastatic pancreatic adenocarcinoma is the most common type of cancer that forms in the pancreas, with more than 500,000 people diagnosed globally each year ^3,4. Since there are no specific symptoms in the early stages, this cancer is often detected late and after the disease has spread (metastatic)⁴. Characterized as a complex cancer due to rapid tumor growth, limited genetic targets, and multiple resistance mechanisms, metastatic pancreatic adenocarcinoma has a poor prognosis with less than 20% of people diagnosed with metastatic pancreatic adenocarcinoma surviving longer than one year and, overall, pancreatic cancer has the lowest five-year survival rate of all cancer types globally^2,3.

Press contact

presse@servier.com

About Servier in Oncology

Servier is a global leader in oncology focused on delivering meaningful therapeutic progress for the patients it serves. Governed by a non-profit foundation, Servier approaches innovation with a long-term vision, free of influence from investors and outside pressure to chase short-term monetary targets.

As a leader in oncology, Servier has significantly accelerated its investment in difficult and hard-to-treat cancers, with more than 50% of its research and development dedicated to delivering significant advances in areas of high unmet need throughout oncology with the potential to change the lives of the patients it serves. Within these areas, Servier is the leader in mutant IDH inhibition, with the first ever mutant IDH1 inhibitor approved in the U.S. and the European Union, and the company continues to drive the science behind targeted mutant IDH inhibition.

Servier’s commitment to therapeutic progress guides its collaboration strategy. While many companies across the industry are scaling back investments, Servier is actively building alliances, completing acquisitions, conducting licensing deals and entering new partnerships that can help to accelerate access to therapies for patients in need. With the company’s commercial expertise, global reach, scientific expertise and commitment to clinical excellence, Servier is dedicated to bringing the promise of tomorrow to the patients it serves.

IMPORTANT SAFETY INFORMATION

Indications

• ONIVYDE^® (irinotecan liposome injection) is indicated, in combination with oxaliplatin, fluorouracil, and leucovorin for the first-line treatment of adult patients with metastatic pancreatic adenocarcinoma.
• ONIVYDE is indicated, in combination with fluorouracil, and leucovorin, for the treatment of adult patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy.

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

WARNING: SEVERE Neutropenia and SEVERE DIARRHEA  Neutropenia Severe and life-threatening neutropenia, including fatal neutropenic sepsis and fatal neutropenic fever, has occurred in patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin and in combination with fluorouracil and leucovorin. Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment.   Diarrhea Severe and life-threatening diarrhea has occurred in patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin and in combination with fluorouracil and leucovorin. 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.

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

Severe Neutropenia: See Boxed WARNING. In NAPOLI 3, Grade 3 and 4 neutropenia occurred in 26% of patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) and fatal neutropenic fever in 0.3% of patients. In NAPOLI 3, the incidence of Grade 3 or 4 neutropenia was similar among Asian patients [6 of 20 (30%)] compared to White patients [76 of 289 (26%)]. Neutropenic fever/neutropenic sepsis was reported in 5% of Asian patients (1 of 20) compared to 2.3% of White patients (7 of 306). In NAPOLI-1, Grade 3 and 4 neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin (ONIVYDE/FU/LV). Neutropenic sepsis occurred in 3% and fatal neutropenic sepsis in 0.8%. In NAPOLI-1, the incidence of Grade 3 or 4 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients.

Severe Diarrhea: See Boxed WARNING. In NAPOLI 3, Grade 3 and 4 diarrhea (early-onset [within 24 hours of chemotherapy] and late-onset [more than 24 hours following chemotherapy]) occurred in 20% receiving NALIRIFOX. In NAPOLI-1, Grade 3 or 4 diarrhea occurred in 13% receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 late-onset diarrhea was 9% in patients receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 early-onset diarrhea was 3% in patients receiving ONIVYDE/FU/LV. To reduce the risk of severe diarrhea, patients should stop lactose-containing products, eat a low-fat diet, and maintain hydration during treatment with ONIVYDE. Withhold ONIVYDE for Grade 2-4 diarrhea. Local institutional guidelines should be followed for the treatment of diarrhea that does not improve within 48 hours and may include the addition of diphenoxylate hydrochloride plus atropine sulfate or octreotide. Following recovery to Grade 1 diarrhea, resume ONIVYDE at a reduced dose.

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

Embryo-Fetal Toxicity: 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 7 months after the last dose of ONIVYDE treatment.

ADVERSE REACTIONS FOR NALIRIFOX

• The most common adverse reactions (≥20% with a difference between arms of ≥5% for all grades or ≥2% for Grades 3 or 4 compared to nab-paclitaxel and gemcitabine) of NALIRIFOX were diarrhea (72%), fatigue (62%), nausea (59%), neutropenia (48%), vomiting (40%), decreased appetite (37%), abdominal pain (35%), hypokalemia (32%), mucosal inflammation (28%), constipation (25%) and weight decreased (22%).
• Permanent discontinuation of ONIVYDE due to an adverse reaction occurred in 17% of patients. Adverse reactions that resulted in permanent discontinuation of ONIVYDE in ≥1% of patients included neutropenia, thrombocytopenia, diarrhea, fatigue, infections and cerebrovascular accident.
• Dosage reduction of ONIVYDE due to an adverse reaction occurred in 52% of patients. Adverse reactions that required dosage reduction in ≥1% of patients included anemia, decreased appetite, diarrhea, fatigue, febrile neutropenia, hypokalemia, liver function test abnormalities, nausea, mucosal inflammation, neutropenia, peripheral neuropathy, vomiting, thrombocytopenia and weight decreased.
• Dosage interruptions of ONIVYDE due to an adverse reaction occurred in 1.9% of patients. Adverse reactions that required dosage interruption in ≥0.5% of patients included hypersensitivity and infusion related reaction.
• The most common laboratory abnormalities (≥10% Grade 3 or 4) were decreased neutrophils (26%), decreased potassium (22%), decreased lymphocytes (11%) and decreased hemoglobin (10%).

ADVERSE REACTIONS FOR ONIVYDE/5-FU/LV

• The most common adverse reactions (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%).
• Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/5-FU/LV; The most frequent adverse reactions resulting in discontinuation of ONIVYDE were diarrhea, vomiting, and sepsis.
• Dose reductions of ONIVYDE for adverse reactions occurred in 33% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia.
• ONIVYDE was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia.
• The most common laboratory abnormalities (≥10% Grade 3 or 4) were lymphopenia and neutropenia.

Postmarketing Experience: Immune system disorders: Hypersensitivity (including anaphylactic reaction and angioedema)

DRUG INTERACTIONS

• Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme inducing 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: See WARNINGS & PRECAUTIONS. Advise males with female partners of reproductive potential to use condoms during and for 4 months after the last dose of ONIVYDE treatment.
• Lactation: Advise nursing women not to breastfeed during and for 1 month after the last dose of ONIVYDE treatment.

To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information, including Boxed WARNING for ONIVYDE.

References

1. Wainberg, Z., et al. NALIRIFOX versus Nab-paclitaxel and Gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet. 2023 Oct 7;402(10409):1272-1281.

2. https://seer.cancer.gov/statfacts/html/pancreas.html

3. https://www.cancer.net/cancer-types/pancreatic-cancer/statistics

4. Orth, M., Metzger, P., Gerum, S. et al. Pancreatic ductal adenocarcinoma: biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat Oncol 14, 141 (2019).

5. https://www.cancer.org/cancer/pancreatic-cancer/detection-diagnosis-staging/signs-and-symptoms.html