TYRO3

Data demonstrated statistically significant and clinically meaningful reduction in risk of disease progression or death with Cabometyx® (cabozantinib) versus placebo in advanced pancreatic and extra-pancreatic neuroendocrine tumors (NETs)1,2Data presented at ESMO 2024 and published in New England Journal of Medicine Ipsen has submitted an extension of indication Marketing Authorization to the European Medicines AgencyLimited approved treatment options for advanced NETs dependent on primary site of disease, with no approved therapies in lung NETs upon progression after prior systemic therapy3,4 PARIS, FRANCE, 16 September 2024 - Ipsen (Euronext: IPN; ADR: IPSEY) announced today final data from the CABINET Phase III trial investigating Cabometyx® (cabozantinib) versus placebo in people living with advanced pancreatic neuroendocrine tumors (pNETs) or advanced extra-pancreatic neuroendocrine tumors (epNETs) whose disease had progressed after prior systemic therapy. These data demonstrated a statistically significant reduction in the risk of disease progression or death for Cabometyx versus placebo of 77% (hazard ratio (HR) 0.23) and 62% (HR 0.38) for people living with advanced pNETs and epNETs, respectively.1,2 Presentation of these data is taking place today at the 2024 European Society for Medical Oncology Congress (ESMO 2024) during the Proffered Paper Session: NETs and Endocrine Tumors at 2:45 p.m. CEST, and is published in the New England Journal of Medicine (NEJM). “People living with neuroendocrine tumors face many challenges, from securing a timely diagnosis to optimal treatment options which address the needs of the increasing number of people affected by this cancer worldwide,” said Teodora Kolarova, Executive Director, International Neuroendocrine Cancer Alliance. “These latest data reaffirm the possibilities of continuing scientific advancements in neuroendocrine tumors, offering the potential for new therapies which could significantly impact people’s everyday lives as they navigate this complex and life altering diagnosis.” Final results demonstrated progression-free survival (PFS) benefits in favor of Cabometyx versus placebo by blinded independent central review (BICR).1,2 In the pNET cohort, at a median follow-up of 13.8 months, median PFS was 13.8 months for Cabometyx versus 4.4 months for placebo (HR 0.23 [95% confidence interval (CI) 0.12-0.42] p<0.0001).1,2 In the epNET cohort, at a median follow-up of 10.2 months, median PFS was 8.4 months for Cabometyx versus 3.9 months for placebo (HR 0.38 [95% CI 0.25-0.59] p<0.0001).1,2 The safety profile of Cabometyx observed in each cohort was consistent with its known safety profile; no new safety signals were identified.1,2 “These latest data reinforce the potential of Cabometyx to deliver significant efficacy benefits at an advanced stage of disease,” said Christelle Huguet, EVP and Head of Research and Development at Ipsen. “Through our submission to the EMA, it is our ambition to evolve the treatment paradigm for people living with neuroendocrine tumors, harnessing our longstanding heritage in this area to deliver an effective new therapy where options are notably limited.” The number of people newly diagnosed with NETs is believed to be rising due to increasing awareness and better methods of diagnosis, with approximately 35 in every 100,000 people currently living with NETs globally.5,6 However, despite increasing awareness, the non-specific nature of NET symptoms often leads patients to be seen by multiple specialists and to undergo various forms of testing before an accurate diagnosis is achieved.5 As a result, almost a third of people take at least five years to be diagnosed with NETs, contributing to poorer patient outcomes.5 Most forms of NETs are indolent in nature and can develop in any part of the body,7 requiring multiple lines of therapy as people progress.3,4 Treatment options upon progression are often limited dependent on primary site of disease, resulting in challenges in identifying optimal care pathways specific to patients’ circumstances.3,4,8 ENDS About Cabometyx Cabometyx (cabozantinib) is a small molecule that inhibits multiple receptor tyrosine kinases, including VEGFRs, MET, RET and the TAM family (TYRO3, MER, AXL).9 These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis (the growth of new blood vessels that tumors need to grow), drug resistance, modulation of immune activities and maintenance of the tumor microenvironment.9,10,11,12 Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of Cabometyx outside of the U.S. and Japan. Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited (Takeda) for the commercialization and further clinical development of Cabometyx for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize Cabometyx in the U.S. In over 65 countries outside of the United States and Japan, including in the European Union, Cabometyx is currently indicated as:10 Monotherapy for advanced renal cell carcinoma (aRCC). as first-line treatment of adults with intermediate- or poor-risk disease.in adults following prior VEGFR-targeted therapy. A combination with nivolumab for the first-line treatment of aRCC in adults.Monotherapy for the treatment of adults living with locally advanced or metastatic differentiated thyroid carcinoma, refractory or not eligible to radioactive iodine who have progressed during or after prior systemic therapy.Monotherapy for the treatment of hepatocellular carcinoma in adults who have previously been treated with sorafenib. About neuroendocrine tumors NETs are relatively uncommon and develop from cells of the neuroendocrine system; thus, can arise from a variety of locations throughout the body.5,7 The most common sites of NETs include the gastrointestinal (GI) tract, lungs and pancreas.7,13 Most NETs take years to develop and grow slowly, however some NETs can be fast-growing.7 The five-year survival rate is dependent on the primary site of disease. For advanced GI-NET and lung NETs, where the cancer has spread to distant parts of the body, the five-year survival rates are 68% and 55%, respectively.14,15 For people diagnosed with advanced pNET, however, the prognosis is poor, with a five-year survival rate of 23%.16 About CABINET (Alliance A021602) CABINET (randomized, double-blinded Phase III trial of CABozantinib versus placebo In patients with advanced NEuroendocrine Tumors after progression on prior therapy) is sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology with participation from the NCI-funded National Clinical Trials Network, as part of Exelixis’ collaboration through a Cooperative Research and Development Agreement with the NCI’s Cancer Therapy Evaluation Program. The multicenter, Phase III CABINET pivotal trial enrolled a total of 298 patients in the US at the time of the final analysis. Patients were randomized 2:1 to Cabometyx or placebo in two separately powered cohorts (pNET, n=95; epNET, n=203). The epNET cohort included patients with the following primary tumor sites: gastrointestinal tract, lung, unknown primary sites and other. Each cohort was randomized separately and had its own statistical analysis plan. Patients must have had measurable disease per RECIST 1.1 criteria and must have experienced disease progression or intolerance after at least one U.S. Food and Drug Administration-approved line of prior therapy other than somatostatin analogues. The primary endpoint in each cohort was PFS per RECIST 1.1 by retrospective independent central review. Upon confirmation of disease progression, patients were unblinded, and those receiving placebo were permitted to cross over to open-label therapy with Cabometyx. Secondary endpoints included overall survival, radiographic response rate and safety. More information about this trial is available at ClinicalTrials.gov. About Ipsen We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience. Our pipeline is fueled by external innovation and supported by nearly 100 years of development experience and global hubs in the U.S., France and the U.K. Our teams in more than 40 countries and our partnerships around the world enable us to bring medicines to patients in more than 80 countries. Ipsen 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. Ipsen contacts Investors Craig Marks | +44 7584 349 193 Media Amy Wolf | +41 7 95 76 07 23 Emma Roper | +44 7711 766 517 Disclaimers and/or Forward-Looking StatementsThe forward-looking statements, objectives and targets contained herein are based on Ipsen’s management strategy, current views and assumptions. Such statements involve known and unknown risks and uncertainties that may cause actual results, performance or events to differ materially from those anticipated herein. All of the above risks could affect Ipsen’s future ability to achieve its financial targets, which were set assuming reasonable macroeconomic conditions based on the information available today. Use of the words ‘believes’, ‘anticipates’ and ‘expects’ and similar expressions are intended to identify forward-looking statements, including Ipsen’s expectations regarding future events, including regulatory filings and determinations. Moreover, the targets described in this document were prepared without taking into account external-growth assumptions and potential future acquisitions, which may alter these parameters. These objectives are based on data and assumptions regarded as reasonable by Ipsen. These targets depend on conditions or facts likely to happen in the future, and not exclusively on historical data. Actual results may depart significantly from these targets given the occurrence of certain risks and uncertainties, notably the fact that a promising medicine in early development phase or clinical trial may end up never being launched on the market or reaching its commercial targets, notably for regulatory or competition reasons. Ipsen must face or might face competition from generic medicine that might translate into a loss of market share. Furthermore, the research and development process involves several stages each of which involves the substantial risk that Ipsen may fail to achieve its objectives and be forced to abandon its efforts with regards to a medicine in which it has invested significant sums. Therefore, Ipsen cannot be certain that favorable results obtained during preclinical trials will be confirmed subsequently during clinical trials, or that the results of clinical trials will be sufficient to demonstrate the safe and effective nature of the medicine concerned. There can be no guarantees a medicine will receive the necessary regulatory approvals or that the medicine will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Other risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and healthcare legislation; global trends toward healthcare cost containment; technological advances, new medicine and patents attained by competitors; challenges inherent in new-medicine development, including obtaining regulatory approval; Ipsen’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Ipsen’s patents and other protections for innovative medicines; and the exposure to litigation, including patent litigation, and/or regulatory actions. Ipsen also depends on third parties to develop and market some of its medicines which could potentially generate substantial royalties; these partners could behave in such ways which could cause damage to Ipsen’s activities and financial results. Ipsen cannot be certain that its partners will fulfil their obligations. It might be unable to obtain any benefit from those agreements. A default by any of Ipsen’s partners could generate lower revenues than expected. Such situations could have a negative impact on Ipsen’s business, financial position or performance. Ipsen expressly disclaims any obligation or undertaking to update or revise any forward-looking statements, targets or estimates contained in this press release to reflect any change in events, conditions, assumptions or circumstances on which any such statements are based, unless so required by applicable law. Ipsen’s business is subject to the risk factors outlined in its registration documents filed with the French Autorité des Marchés Financiers. The risks and uncertainties set out are not exhaustive and the reader is advised to refer to Ipsen’s latest Universal Registration Document, available on ipsen.com. References 1 Chan et al. Phase 3 Trial of Cabozantinib in Previously Treated Advanced Neuroendocrine Tumors. 2024 New England Journal of Medicine. Online ahead of print2 Cabozantinib Versus Placebo for Advanced Neuroendocrine Tumors (NET) after Progression on Prior Therapy (CABINET Trial/Alliance A021602): Updated Results Including Progression Free-Survival (PFS) by Blinded Independent Central Review (BICR) and Subgroup Analyses. As presented at ESMO Congress 2024 during the ‘Proffered Paper: NETs and Endocrine Tumors at 2:45 p.m. CEST Barcelona, Spain.3 Baudin E, et al. Ann Oncol. 2021 Nov;32(11):1453-1455.4 Pavel M, et al. Ann Oncol. 2020;31(7):844-860.5 Singh et al. Patient-Reported Burden of a Neuroendocrine Tumor (NET) Diagnosis: Results From the First Global Survey of Patients With NETs. J Glob Oncol. 2017 Feb; 3(1): 43–53.6 Durma et al. Epidemiology of Neuroendocrine Neoplasms and Results of Their Treatment with [177Lu]Lu-DOTA-TATE or [177Lu]Lu-DOTA-TATE and [90Y]Y-DOTA-TATE—A Six-Year Experience in High-Reference Polish Neuroendocrine Neoplasm Center. Cancers 2023, 15(22), 5466; https://doi.org/10.3390/cancers152254667 Neuroendocrine tumor (NET). https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-endocrine-tumor/carcinoid-tumor. Accessed September 2024.8 McClellan, K., Chen. E.Y, Kardosh A., et al. Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors. Cancers. 2022, 14(19), 4769.9 El-Khoueiry A. et al., Cabozantinib: An evolving therapy for hepatocellular carcinoma. Cancer Treatment Reviews. 2021 Jul;98:102221. DOI: 10.1016/j.ctrv.2021.102221.10 European Medicines Agency. Cabometyx® (cabozantinib) EU Summary of Product Characteristics. Available from: https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf. Last accessed: September 202411 Yakes M. et al., Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298–2308. DOI: 10.1158/1535-7163.MCT-11-026412 Hsu et al., AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review. Liver Cancer 2021 DOI: 10.1159/00052050113 Jamal et al. Neuroendocrine tumor of the kidney. Diagnostic challenge and successful therapy. Urology Annals 11(4):p 435-438, Oct–Dec 2019. DOI: 10.4103/UA.UA_169_1814 Survival Rates for Gastrointestinal Carcinoid Tumors. ACS website. Available at: https://www.cancer.org/cancer/types/gastrointestinal-carcinoid-tumor/detection-diagnosis-staging/survival-rates.html. Accessed September 2024.15 Survival Rates for Lung Carcinoid Tumors. ACS website. Available at: https://www.cancer.org/cancer/types/lung-carcinoid-tumor/detection-diagnosis-staging/survival-rates.html. Accessed September 2024.16 Survival Rates for Pancreatic Neuroendocrine Tumor. American Cancer Society Available at: https://www.cancer.org/cancer/types/pancreatic-neuroendocrine-tumor/detection-diagnosis-staging/survival-rates.html. Accessed June 2024. Accessed September 2024. Attachment Ipsen PR_ESMO CABINET_16092024

ALAMEDA, Calif.--( BUSINESS WIRE )-- Exelixis, Inc. (Nasdaq: EXEL) today announced that its supplemental New Drug Application (sNDA) for cabozantinib (CABOMETYX ® ) has been accepted in the U.S. for: 1) the treatment of adults with previously treated, locally advanced/unresectable or metastatic, well- or moderately differentiated pancreatic neuroendocrine tumors (pNET), and 2) the treatment of adults with previously treated, locally advanced/unresectable or metastatic, well- or moderately differentiated extra-pancreatic NET (epNET). The U.S. Food and Drug Administration (FDA) also granted orphan drug designation to cabozantinib for the treatment of pNET. The FDA assigned a standard review with a Prescription Drug User Fee Act target action date of April 3, 2025. “ The FDA’s acceptance of this application marks another important milestone in our commitment to bringing cabozantinib to patients living with difficult-to-treat cancers and who have limited treatment options,” said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. “ We appreciate the opportunity to work with the FDA in the coming months as they review our application, with the goal to bring this new, effective treatment option to patients with advanced neuroendocrine tumors as quickly as possible.” The sNDA is based on the final results of the phase 3 CABINET pivotal trial evaluating cabozantinib compared with placebo in two cohorts of patients with previously treated NET: advanced pNET and advanced epNET. As previously announced , CABINET was stopped early for compelling activity; all patients were unblinded and those on placebo were given the option to cross over to active treatment with cabozantinib. This early stopping was due to a dramatic improvement in progression-free survival (PFS) observed at an interim analysis in both cohorts. The study demonstrated a statistically significant and clinically meaningful improvement in PFS with cabozantinib versus placebo, based on results of both local review and available independent blinded central radiology review. Initial results were presented at the 2023 European Society of Medical Oncology (ESMO) Congress; final results will be presented at the 2024 ESMO Congress on September 16 th in Barcelona, Spain. About CABINET (Alliance A021602) CABINET (Randomized, Double-Blinded Phase III Study of CAB ozantinib versus Placebo I n Patients with Advanced NE uroendocrine T umors After Progression on Prior Therapy) is sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology with participation from the NCI-funded National Clinical Trials Network as part of Exelixis’ collaboration through a Cooperative Research and Development Agreement with the NCI’s Cancer Therapy Evaluation Program. CABINET is a multicenter, randomized, double-blinded, placebo-controlled phase 3 pivotal trial that had enrolled a total of 290 patients in the U.S. at the time of the interim analysis. Patients were randomized 2:1 to cabozantinib or placebo in two separate cohorts (pNET, n=93; epNET, n=197). The epNET cohort included patients with the following primary tumor sites: gastrointestinal (GI) tract, lung and other. Each cohort was randomized separately and had its own statistical analysis plan. Patients must have had measurable disease per RECIST 1.1 criteria and must have experienced disease progression or intolerance after at least one U.S. FDA-approved line of prior therapy other than somatostatin analogs. The primary endpoint in each cohort was PFS per RECIST 1.1 by retrospective blinded independent central review. Upon disease progression, patients were unblinded, and those receiving placebo were permitted to cross over to open-label therapy with cabozantinib. Secondary endpoints included overall survival, radiographic response rate and safety. More information about this trial is available at ClinicalTrials.gov . About Neuroendocrine Tumors (NET) Neuroendocrine tumors (NET) are cancers that begin in the specialized cells of the body’s neuroendocrine system. 1 These cells have traits of both hormone-producing endocrine cells and nerve cells. 1 In the U.S., it is estimated that 161,000 to 192,000 people are living with unresectable, locally advanced or metastatic NET. 2 The number of people diagnosed with NET has been increasing in recent decades. 3 Functional NET release peptide hormones that can cause debilitating symptoms, like diarrhea, hypertension and flushing, which may require focused treatment, while symptoms of non-functional NET are related primarily to tumor growth. 4,5 Most NET take years to develop and grow slowly, but eventually, all patients with advanced or metastatic NET will develop refractory and progressing disease. 6,7 NET can develop in any part of the body but most commonly start in the gastrointestinal (GI) tract or in the lungs, where they have historically been referred to as carcinoid tumors and are more recently called epNET. 1 The five-year survival rates for advanced GI and lung NET are 68% and 55%, respectively. 8,9 NET can also start in the pancreas, where they tend to be more aggressive, with a five-year survival rate of only 23% for advanced disease. 1,10 For advanced NET patients, treatment options include somatostatin analogs, chemotherapy, targeted therapy and peptide-receptor radionuclide therapy. 11 About CABOMETYX ® (cabozantinib) In the U.S., CABOMETYX tablets are approved as monotherapy for the treatment of patients with advanced renal cell carcinoma (RCC) and in combination with nivolumab as a first-line treatment for patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen Pharma SAS exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S. CABOMETYX is not indicated as a treatment for NET. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena. Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation. Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention. Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis. Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose. Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE. Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids. With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity. Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity. Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC. Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency. Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome. Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose. Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS. Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients. Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated. Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN. In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients. Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity. Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose. ADVERSE REACTIONS The most common (≥20%) adverse reactions are: CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation. CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. DRUG INTERACTIONS Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice. Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort. USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose. Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment. Please see accompanying full Prescribing Information https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf . You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088. About Exelixis Exelixis is a globally ambitious oncology company innovating next-generation medicines and regimens at the forefront of cancer care. Powered by drug discovery and development excellence, we are rapidly evolving our product portfolio to target an expanding range of tumor types and indications with our clinically differentiated pipeline of small molecules, antibody-drug conjugates and other biotherapeutics. This comprehensive approach harnesses decades of robust investment in our science and partnerships to advance our investigational programs and extend the impact of our flagship commercial product, CABOMETYX ® (cabozantinib). Exelixis is driven by a bold scientific pursuit to create transformational treatments that give more patients hope for the future. For information about the company and its mission to help cancer patients recover stronger and live longer, visit www.exelixis.com , follow @ExelixisInc on X (Twitter), like Exelixis, Inc. on Facebook and follow Exelixis on LinkedIn. Forward-Looking Statements This press release contains forward-looking statements, including, without limitation, statements related to: the therapeutic potential of cabozantinib as a treatment for patients with previously treated, locally advanced/unresectable or metastatic, well- or moderately differentiated pNET and epNET; the regulatory review process, including the PDUFA target action date assigned by the FDA, and Exelixis’ plans to work with the FDA while the application is reviewed; and Exelixis’ scientific pursuit to create transformational treatments that give patients more hope for the future. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: complexities and the unpredictability of the regulatory review and approval processes in the U.S. and elsewhere, including the risk that the FDA may not approve cabozantinib as a treatment for pNET or epNET in a timely fashion, if at all; unexpected concerns that may arise as a result of the occurrence of adverse safety events or additional data analyses of clinical trials evaluating cabozantinib; Exelixis’ ability to protect its intellectual property rights; market competition, including the potential for competitors to obtain approval for generic versions of CABOMETYX; changes in economic and business conditions; and other factors affecting the ability of Exelixis to obtain regulatory approval for cabozantinib in new indications detailed from time to time under the caption “Risk Factors” in Exelixis’ most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, and in Exelixis’ future filings with the Securities and Exchange Commission. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law. Exelixis, the Exelixis logo and CABOMETYX are registered U.S. trademarks of Exelixis. 1 Neuroendocrine Tumors. Cleveland Clinic website. Available at: https://my.clevelandclinic.org/health/diseases/22006-neuroendocrine-tumors-net . Accessed August 2024. 2 Population Estimate: Unresectable, Locally Advanced or Metastatic Extra-Pancreatic NET. June 2024 (internal data on file). 3 Pathak S, Starr JS, Halfdanarson T, et al. Understanding the increasing incidence of neuroendocrine tumors. Expert Rev Endocrinol Metab. September 2023;18(5):377-385. 4 Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ ® )–Patient Version. NCI website. Available at: https://www.cancer.gov/types/pancreatic/patient/pnet-treatment-pdq . Accessed August 2024. 5 What Is a Pancreatic Neuroendocrine Tumor? ACS website. Available at: https://www.cancer.org/cancer/types/pancreatic-neuroendocrine-tumor/about/what-is-pnet.html . Accessed August 2024. 6 McClellan K, Chen EY, Kardosh A, et al. Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors. Cancers. 2022, 14(19), 4769. 7 What is a Gastrointestinal Carcinoid Tumor? ACS website. Available at: https://www.cancer.org/cancer/types/gastrointestinal-carcinoid-tumor/about/what-is-gastrointestinal-carcinoid.html . Accessed August 2024. 8 Survival Rates for Gastrointestinal Carcinoid Tumors. ACS website. Available at: https://www.cancer.org/cancer/types/gastrointestinal-carcinoid-tumor/detection-diagnosis-staging/survival-rates.html . Accessed August 2024. 9 Survival Rates for Lung Carcinoid Tumors. ACS website. Available at: https://www.cancer.org/cancer/types/lung-carcinoid-tumor/detection-diagnosis-staging/survival-rates.html . Accessed August 2024. 10 Survival Rates for Pancreatic Neuroendocrine Tumor. ACS website. Available at: https://www.cancer.org/cancer/types/pancreatic-neuroendocrine-tumor/detection-diagnosis-staging/survival-rates.html . Accessed August 2024. 11 Neuroendocrine Tumor (NET). NCI website. Available at: https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-endocrine-tumor/carcinoid-tumor . Accessed August 2024.

Decision adds to existing collaboration agreement with Exelixis, permitting Ipsen to seek potential marketing authorizations for Cabometyx® (cabozantinib) in advanced pancreatic and extra pancreatic neuroendocrine tumors outside of the U.S. and Japan Agreement based on CABINET Phase III trial, led by the Alliance for Clinical Trials in Oncology, which demonstrated improvements in progression-free survival for Cabometyx versus placebo1 Ipsen has engaged with regulatory authorities in the European Union and will submit a regulatory filing on the basis of these data PARIS, FRANCE, 2 July 2024 - Ipsen (Euronext: IPN; ADR: IPSEY) announced today confirmation of an expanded collaboration and license agreement with Exelixis, Inc. for the development of Cabometyx® (cabozantinib) in advanced pancreatic neuroendocrine tumors (pNETs) and advanced extra-pancreatic neuroendocrine tumors (epNETs). The agreement is based on positive outcomes from the CABINET Phase III trial, led by the Alliance for Clinical Trials in Oncology and sponsored by the National Cancer Institute (NCI), which investigated Cabometyx versus placebo in people living with advanced pNETs or advanced epNETs whose disease had progressed after prior systemic therapy. An independent Data and Safety Monitoring Board recommended to stop accrual to the study, unblind patients and allow crossover from placebo to Cabometyx. This was due to early efficacy demonstrated at an interim analysis in both of the trial’s cohorts, with clinically meaningful improvements in progression-free survival (PFS).1 “With many people diagnosed with neuroendocrine tumors at an advanced stage of disease and treatment options limited upon progression, the need for efficacious new therapies is extensive,” said Christelle Huguet, EVP and Head of Research and Development, Ipsen. “The positive results demonstrated for Cabometyx within the CABINET Phase III trial represent clinically meaningful improvements in progression-free survival at a challenging stage of disease where there are few or no available treatment options. We look forward to discussing these clinical findings with regulatory authorities.” Neuroendocrine tumors (NETs) are a group of uncommon tumors that develop in the cells of the neuroendocrine system throughout the body.2,3 The symptoms of NETs are often not distinct and difficult to identify, leading to delays in diagnosis, with 58% of people presenting with metastatic disease at diagnosis.3 The number of people newly diagnosed with NETs is believed to be rising due to increasing awareness and better methods of diagnosis, with approximately 35 in every 100,000 people currently living with NETs globally.3,4 The survival rate varies greatly depending on the primary site and stage of disease, however for people living with advanced pNETs which has spread to distant parts of the body, the prognosis is poor, with a five-year survival rate of 23%.5 CABINET Phase III trial Data from the study, which demonstrated PFS benefits at interim analyses, were presented at the European Society for Medical Oncology Congress 2023 by Professor Jennifer Chan, MD, MPH, Dana-Farber Cancer Institute, Boston:1 In the pNET cohort, at a median follow-up of 16.7 months, median PFS based on local radiology review was 11.4 months for Cabometyx versus 3.0 months for placebo (hazard ratio (HR) 0.27 [95% confidence interval (CI) 0.14-0.49] p<0.0001)1 In the epNET cohort, at a median follow-up of 13.9 months, median PFS based on local radiology review was 8.3 months for Cabometyx versus 3.2 months for placebo (HR 0.45 [95% CI 0.30-0.66] p<0.0001)1 The safety pro Cabometyx observed in each cohort was consistent with its known safety profile; no new safety signals were identified1 ENDS About Cabometyx Cabometyx (cabozantinib) is a small molecule that inhibits multiple receptor tyrosine kinases, including VEGFRs, MET, RET and the TAM family (TYRO3, MER, AXL).6 These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis (the growth of new blood vessels that tumors need to grow), drug resistance, modulation of immune activities and maintenance of the tumor microenvironment.6,7,8,9 In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of Cabometyx outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited (Takeda) for the commercialization and further clinical development of Cabometyx for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize Cabometyx in the U.S. In over 60 countries outside of the U.S. and Japan, including in the E.U., Cabometyx is currently indicated as a:7 Monotherapy for advanced renal cell carcinoma (aRCC). as first-line treatment of adults with intermediate- or poor-risk disease. in adults following prior VEGFR-targeted therapy. In combination with nivolumab for the first-line treatment of aRCC in adults. Monotherapy for the treatment of adults living with locally advanced or metastatic differentiated thyroid carcinoma, refractory or not eligible to radioactive iodine who have progressed during or after prior systemic therapy. Monotherapy for the treatment of hepatocellular carcinoma in adults who have previously been treated with sorafenib. The detailed recommendations for the use of Cabometyx are described in the Summary of Product Characteristics (EU SmPC). About neuroendocrine tumors NETs are relatively uncommon and develop from cells of the neuroendocrine system; thus, can arise from a variety of locations throughout the body.2,3 The most common sites of NETs include the gastrointestinal (GI) tract, lungs and pancreas.2,10 Most NETs take years to develop and grow slowly, however some NETs can be fast-growing.2 The symptoms of NETs are often difficult to identify leading to patients being seen by multiple specialists and undergoing extensive testing before diagnosis is confirmed.3 As a result, almost a third of people take at least 5 years to be diagnosed with NETs.3 The five-year survival rate is dependent on the primary site of disease. For advanced GI-NET and lung NETs, where the cancer has spread to distant parts of the body, the five-year survival rates are 68% and 55%, respectively.11,12 For people diagnosed with advanced pNET, however, the prognosis is poor, with a five-year survival rate of 23%.5 About CABINET CABINET (randomized, double-blinded Phase III trial of CABozantinib versus placebo In patients with advanced NEuroendocrine Tumors after progression on prior therapy) is sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology with participation from the NCI-funded National Clinical Trials Network, as part of Exelixis’ collaboration through a Cooperative Research and Development Agreement with the NCI’s Cancer Therapy Evaluation Program. The multicenter, Phase III CABINET pivotal trial enrolled a total of 290 patients in the U.S at the time of the interim analyses. Patients were randomized 2:1 to Cabometyx or placebo in two separate cohorts (pNET, n=93; epNET, n=197). The epNET cohort included patients with the following primary tumor sites: gastrointestinal tract, lung, unknown and other. Each cohort was randomized separately and had its own statistical analysis plan. Patients must have had measurable disease per RECIST 1.1 criteria and must have experienced disease progression or intolerance after at least one U.S. Food and Drug Administration-approved line of prior therapy other than somatostatin analogs. The primary endpoint in each cohort was PFS per RECIST 1.1 by retrospective independent central review. Upon confirmation of disease progression, patients were unblinded, and those receiving placebo were permitted to cross over to open-label therapy with Cabometyx. Secondary endpoints included overall survival, radiographic response rate and safety. More information about this trial is available at ClinicalTrials.gov. About Ipsen We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience. Our pipeline is fuelled by external innovation and supported by nearly 100 years of development experience and global hubs in the U.S., France and the U.K. Our teams in more than 40 countries and our partnerships around the world enable us to bring medicines to patients in more than 80 countries. Ipsen 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. Ipsen contacts Investors Craig Marks | +44 7584 349 193 Media Joanna Parish | +44 7840 023 741 Emma Roper | +44 7711 766 517 Disclaimers and/or Forward-Looking Statements The forward-looking statements, objectives and targets contained herein are based on Ipsen’s management strategy, current views and assumptions. Such statements involve known and unknown risks and uncertainties that may cause actual results, performance or events to differ materially from those anticipated herein. All of the above risks could affect Ipsen’s future ability to achieve its financial targets, which were set assuming reasonable macroeconomic conditions based on the information available today. Use of the words ‘believes’, ‘anticipates’ and ‘expects’ and similar expressions are intended to identify forward-looking statements, including Ipsen’s expectations regarding future events, including regulatory filings and determinations. Moreover, the targets described in this document were prepared without taking into account external-growth assumptions and potential future acquisitions, which may alter these parameters. These objectives are based on data and assumptions regarded as reasonable by Ipsen. These targets depend on conditions or facts likely to happen in the future, and not exclusively on historical data. Actual results may depart significantly from these targets given the occurrence of certain risks and uncertainties, notably the fact that a promising medicine in early development phase or clinical trial may end up never being launched on the market or reaching its commercial targets, notably for regulatory or competition reasons. Ipsen must face or might face competition from generic medicine that might translate into a loss of market share. Furthermore, the research and development process involves several stages each of which involves the substantial risk that Ipsen may fail to achieve its objectives and be forced to abandon its efforts with regards to a medicine in which it has invested significant sums. Therefore, Ipsen cannot be certain that favorable results obtained during preclinical trials will be confirmed subsequently during clinical trials, or that the results of clinical trials will be sufficient to demonstrate the safe and effective nature of the medicine concerned. There can be no guarantees a medicine will receive the necessary regulatory approvals or that the medicine will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Other risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and healthcare legislation; global trends toward healthcare cost containment; technological advances, new medicine and patents attained by competitors; challenges inherent in new-medicine development, including obtaining regulatory approval; Ipsen’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Ipsen’s patents and other protections for innovative medicines; and the exposure to litigation, including patent litigation, and/or regulatory actions. Ipsen also depends on third parties to develop and market some of its medicines which could potentially generate substantial royalties; these partners could behave in such ways which could cause damage to Ipsen’s activities and financial results. Ipsen cannot be certain that its partners will fulfil their obligations. It might be unable to obtain any benefit from those agreements. A default by any of Ipsen’s partners could generate lower revenues than expected. Such situations could have a negative impact on Ipsen’s business, financial position or performance. Ipsen expressly disclaims any obligation or undertaking to update or revise any forward-looking statements, targets or estimates contained in this press release to reflect any change in events, conditions, assumptions or circumstances on which any such statements are based, unless so required by applicable law. Ipsen’s business is subject to the risk factors outlined in its registration documents filed with the French Autorité des Marchés Financiers. The risks and uncertainties set out are not exhaustive and the reader is advised to refer to Ipsen’s latest Universal Registration Document, available on ipsen.com. References 1 Chan et al. Alliance A021602: Ph 3, double-blinded study of Cabozantinib vs Placebo for advanced NETs after progression on prior therapy (CABINET). As presented at ESMO Congress 2023 during the ‘Proffered Paper session - NETs and endocrine tumours’ on 22 October 2023 08:40-08:50 CEST, Madrid, Spain. 2 Neuroendocrine tumor (NET). Accessed June 2024. 3 Singh et al. Patient-Reported Burden of a Neuroendocrine Tumor (NET) Diagnosis: Results From the First Global Survey of Patients With NETs. J Glob Oncol. 2017 Feb; 3(1): 43–53. 4 Durma et al. Epidemiology of Neuroendocrine Neoplasms and Results of Their Treatment with [177Lu]Lu-DOTA-TATE or [177Lu]Lu-DOTA-TATE and [90Y]Y-DOTA-TATE—A Six-Year Experience in High-Reference Polish Neuroendocrine Neoplasm Center. Cancers 2023, 15(22), 5466; 5 Survival Rates for Pancreatic Neuroendocrine Tumor. American Cancer Society Available at: Accessed June 2024. Accessed June 2024. 6 El-Khoueiry A. et al., Cabozantinib: An evolving therapy for hepatocellular carcinoma. Cancer Treatment Reviews. 2021 Jul;98:102221. DOI: 10.1016/j.ctrv.2021.102221. 7 European Medicines Agency. Cabometyx® (cabozantinib) EU Summary of Product Characteristics. Available from: . Last accessed: June 2024 8 Yakes M. et al., Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298–2308. DOI: 10.1158/1535-7163.MCT-11-0264 9 Hsu et al., AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review. Liver Cancer 2021 DOI: 10.1159/000520501 10 Jamal et al. Neuroendocrine tumor of the kidney. Diagnostic challenge and successful therapy. Urology Annals 11(4):p 435-438, Oct–Dec 2019. DOI: 10.4103/UA.UA_169_18 11 Survival Rates for Gastrointestinal Carcinoid Tumors. ACS website. Available at: Accessed June 2024. 12 Survival Rates for Lung Carcinoid Tumors. ACS website. Available at: Accessed June 2024. Attachment Ipsen PR_CABINET Opt-in_02072024