Onivyde® Regimen Demonstrated Statistically Significant Improvement in Overall Survival in Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma

Regulatory News:

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Ipsen (Euronext: IPN; ADR: IPSEY) announced the Phase III NAPOLI 3 trial of Onivyde^® (irinotecan liposome injection) plus 5 fluorouracil/leucovorin and oxaliplatin (NALIRIFOX regimen) met its primary endpoint demonstrating clinically meaningful and statistically significant improvement in overall survival compared to nab-paclitaxel plus gemcitabine in 770 previously untreated patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and key secondary efficacy outcome of progression-free survival (PFS) also showed significant improvement over the comparator arm. The safety profile of Onivyde in the NAPOLI 3 trial was consistent with those observed in the previous phase I/II mPDAC study.

Ipsen intends to file a supplemental New Drug Application with the U.S. Food and Drug Administration for Onivyde in combination with oxaliplatin plus 5- fluorouracil/leucovorin for the treatment of patients with previously untreated mPDAC following the Fast Track Designation granted in 2020. The clinical trial results will be presented at an upcoming medical conference.

“The positive results from the NAPOLI 3 trial demonstrate that compared with the standard-of-care, the investigational Onivyde treatment regimen extended the lives of people living with metastatic pancreatic ductal adenocarcinoma who were previously untreated,” said Howard Mayer, Executive Vice President and Head of Research and Development for Ipsen. “The prognosis for people diagnosed with pancreatic cancer is extremely poor and we plan to submit these new findings to the regulatory authority as, if approved, we believe this regimen could offer up an important new treatment option for people living with an aggressive and hard-to-treat cancer. We thank the patients who participated in the study, their families and their healthcare teams.”

PDAC is the most common type of cancer that forms in the pancreas with approximately 60,000 people diagnosed in the U.S. each year and nearly 500,000 people globally.^1,2 Since there are no specific symptoms in the early stages, PDAC is often detected late and after the disease has spread to other parts of the body (metastatic or stage IV).³ Even in later stages, weight loss, abdominal pain and jaundice are the most common symptoms making PDAC difficult to detect.⁴ Currently, fewer than 20 percent of people diagnosed with PDAC survive longer than one year and overall, pancreatic cancer has the lowest five-year survival rate of all cancer types globally and in the U.S.^1,2

Phase III NAPOLI 3 Study

NAPOLI 3 is a randomized, open-label Phase III trial of Onivyde treatment regimen (NALIRIFOX) in patients who have not previously received chemotherapy for metastatic pancreatic ductal adenocarcinoma. Onivyde plus oxaliplatin and 5 FU/LV was administered twice in a month (days 1 and 15 of 28 day cycle) compared to an injection of nab-paclitaxel and gemcitabine administered three times a month (days 1, 8, 15 of a 28 day cycle). Approximately 770 patients were enrolled in the trial with the primary outcome measure of overall survival. Secondary outcome measures included progression-free survival, objective response rate, quality of life assessment, incidence of treatment-emergent adverse events, serious adverse events and laboratory abnormalities. Adverse events and laboratory analyses were also analyzed.

Onviyde® (irinotecan liposome injection)

Onivyde is a long-circulating, liposomal topoisomerase inhibitor designed to interrupt DNA replication in cancer cells. Onivyde enters cancer cells using a naturally occurring process (enhanced permeability and retention or EPR effect) and as macrophages unpack the liposomes, Onivyde is activated facilitating the release of the cytotoxic payload into the tumor, including irinotecan and its conversion into SN-38, its active metabolite. Ipsen has exclusive commercialization rights for the current and potential future indications for Onivyde in the U.S. Servier, an independent international pharmaceutical company with a strong international presence in 150 countries, is responsible for the commercialization of Onivyde outside of the U.S. and Taiwan. PharmaEngine is a commercial stage oncology company headquartered in Taipei and is responsible for the commercialization of Onivyde in Taiwan.

Onivyde is currently approved in most major markets including the U.S., Europe and Asia 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. Onivyde is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNINGS: 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 5-FU and 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 hydrochloride.

Warnings and precautions

Severe neutropenia: see boxed WARNING. 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: see boxed WARNING. Severe and life-threatening late-onset (onset >24 hours after chemotherapy [9%]) and early-onset diarrhea (onset ≤24 hours after chemotherapy [3%], sometimes with other symptoms of cholinergic reaction) were observed

Interstitial lung disease (ILD): Irinotecan HCl can cause severe and fatal ILD. Withhold Onivyde 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: Onivyde can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during and for 1 month after Onivyde treatment

Adverse reactions

• The most common adverse reactions (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%)
• The most common Grade 3/4 adverse reactions (≥10%) were diarrhea (13%), fatigue/asthenia (21%), and vomiting (11%)
• 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 (≥20%) were anemia (97%), lymphopenia (81%), neutropenia (52%), increased ALT (51%), hypoalbuminemia (43%), thrombocytopenia (41%), hypomagnesemia (35%), hypokalemia (32%), hypocalcemia (32%), hypophosphatemia (29%), and hyponatremia (27%)

Drug Interactions

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

Special 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 Onivyde treatment
• Lactation: Advise nursing women not to breastfeed during and for 1 month after Onivyde treatment

Please see full U.S. Prescribing Information including Boxed WARNING for Onivyde.

ENDS

About Ipsen

Ipsen is a global, mid-sized biopharmaceutical company focused on transformative medicines in Oncology, Rare Disease and Neuroscience. With Specialty Care sales of €2.6bn in FY 2021, Ipsen sells medicines in over 100 countries. Alongside its external-innovation strategy, the Company’s research and development efforts are focused on its innovative and differentiated technological platforms located in the heart of leading biotechnological and life-science hubs: Paris-Saclay, France; Oxford, U.K.; Cambridge, U.S.; Shanghai, China. Ipsen, excluding its Consumer HealthCare business, has around 4,500 colleagues worldwide and is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com.

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References

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

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

3. 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). https://doi.org/10.1186/s13014-019-1345-6

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

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