Servier Group

VORANIGO is the first and only FDA-approved targeted treatment in Grade 2 IDH-mutant glioma VORANIGO demonstrated significant improvement in progression free survival with a favorable safety profile in a pivotal Phase 3 study of patients with Grade 2 IDH-mutant glioma VORANIGO is the sixth approval for Servier in the field of IDH-mutant targeted therapies BOSTON, Aug. 6, 2024 /PRNewswire/ -- Servier today announced that the U.S. Food and Drug Administration (FDA) has approved VORANIGO®, an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor, indicated for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery including biopsy, sub-total resection, or gross total resection. VORANIGO is available and offers glioma patients the ability to actively manage their disease with the convenience of a once-daily pill. Gliomas are types of brain cancer that can hinder normal brain function and cause a variety of symptoms. Diffuse gliomas with IDH mutations represent the most common malignant primary brain tumors diagnosed in adults younger than 50 years of age. They are not curable with current therapies and without treatment they continue to grow and infiltrate normal brain tissue. 1, 2, 3 "Today's approval of VORANIGO is an enormous leap forward in cancer care, and a defining moment for people living with Grade 2 IDH-mutant glioma," said Arjun H. Prasad, Chief Commercial Officer, Servier Pharmaceuticals. "VORANIGO, which is the first breakthrough in this specific disease area in nearly 25 years, offers patients unprecedented improvement in progression free survival. We are proud to deliver this first-of-its-kind therapy to patients in need, and we remain committed to bringing innovative targeted therapies to people with cancer." In healthy human cells, a family of genes called isocitrate dehydrogenases (IDH) help break down nutrients and generate energy for cells. Mutations in IDH1 and IDH2 are associated with a variety of cancers, where they prevent cells from differentiating, or specializing, into the kind of cells they are ultimately supposed to become. When cells cannot differentiate properly, they may begin to grow out of control.4 In IDH-mutant gliomas, VORANIGO works by reducing the activity of the mutant IDH1 and IDH2 enzymes, to help control the disease. "Patients living with Grade 2 IDH-mutant gliomas have long faced the harsh reality of an incurable disease with very limited post-surgery treatment options," said Ralph DeVitto, President & CEO, of the American Brain Tumor Association. "The FDA approval of VORANIGO marks a monumental breakthrough in glioma treatment, offering renewed hope for patients and their families living with this relentless disease." The approval of VORANIGO is supported by results from the pivotal Phase 3 INDIGO clinical trial published in The New England Journal of Medicine and presented during the Plenary Session at the 2023 Annual Meeting of the American Society of Clinical Oncology (ASCO), which showed that VORANIGO significantly extended progression free survival and time to next intervention, when compared to placebo. The INDIGO study showed that VORANIGO was well tolerated, and its safety profile was consistent with results from the Phase 1 studies. The most common (≥15%) adverse reactions were fatigue, COVID-19, musculoskeletal pain, diarrhea and seizure.5 "Glioma is a unique cancer. Many of the patients I've met are in their 30's and 40's and in the prime of their lives. They have small children and are at the height of their careers. A glioma diagnosis is devastating. VORANIGO can offer patients and their families hope for the future," said David K. Lee, CEO, Servier Pharmaceuticals. "As we advance more targeted therapies, identifying mutations and understanding how these mutations impact cancer and its progression are key to helping the right patients find the right treatment, at the right time. We are humbled to lead the field of IDH-mutant inhibition, and we are committed to researching its applicability in glioma and other cancers." About the INDIGO Phase 3 Trial (NCT04164901)5 INDIGO, the pivotal Phase 3 clinical trial, met its major efficacy outcome of progression free survival (PFS) per a blinded independent review committee (BIRC) and key secondary endpoint of time to next intervention (TTNI) at the prespecified second interim analysis. The major efficacy outcome, PFS was statistically significant and clinically meaningful in favor of the vorasidenib arm. Median PFS was 27.7 months in the vorasidenib group, compared with 11.1 months in the placebo group (Hazard Ratio [HR], 0.39; 95% Confidence Interval [CI], 0.27 to 0.56; 1-sided P<0.001). TTNI was also statistically significant (HR, 0.26; 95% CI, 0.15 to 0.43; 1-sided P<0.001). Median TTNI was not reached for vorasidenib and was 17.8 months for placebo. Vorasidenib was also shown to reduce the tumor volume by a mean of 2.5% (TGR of –2.5%; 95% CI: -4.7% to -0.2%) every 6 months, while tumor volume increased by a mean of 13.9% (TGR of 13.9%; 95% CI: 11.1% to 16.8%) every 6 months for patients randomized to the placebo arm, as measured by a BIRC. The INDIGO study showed that vorasidenib was well tolerated, and its safety profile was consistent with results from the Phase 1 studies. INDIGO was a registration-enabling Phase 3 global, randomized, double-blind placebo-controlled study of vorasidenib in patients with residual or recurrent Grade 2 glioma with an isocitrate dehydrogenase 1/2 (IDH1/2) mutation who have undergone surgery as their only treatment. About Glioma 6 Gliomas are tumors that arise from glial or precursor cells within the central nervous system (CNS). The 2021 World Health Organization (WHO) classification recognizes four general groups of gliomas, one of which is adult-type diffuse gliomas. These diffuse gliomas are the most common primary malignant brain tumors in adults. The pathogenesis and prognosis of these tumors are tightly linked to mutations (or lack thereof) in the metabolic enzyme isocitrate dehydrogenase (IDH), and molecular testing is required for proper diagnosis. As of 2021, adult-type diffuse gliomas are sub-divided into only three categories: Astrocytoma, IDH-mutant (CNS WHO grades 2-4) Oligodendroglioma, IDH-mutant and1p19q-codeleted (CNS WHO grades 2-3) Glioblastoma, IDH-wildtype (CNS WHO grade 4) About Servier in Oncology Servier is a global leader in oncology, governed by a non-profit foundation. Servier approaches innovation with a long-term vision, free of influence from fiduciary responsibilities. Servier is the leader in IDH-mutant targeted therapies and devotes more than 65% of its research and development budget to Oncology. Servier aspires to advance more targeted therapies by identifying mutations and understanding how these mutations impact cancer and its progression. Servier believes we can serve more people by helping the right patients find the right treatment, at the right time. Servier takes a One Innovation Engine approach to R&D and is actively seeking alliances, partnerships and acquisitions at various stages of the portfolio. For more information about working with Servier to bring the promise of tomorrow to the patients it serves, visit Servier.us. Media Contact: Erin Smith 1-857-278-7921 [email protected] VORANIGO IMPORTANT SAFETY INFORMATION What is VORANIGO? VORANIGO (40 mg tablets) is a prescription medicine used to treat adults and children 12 years of age and older with certain types of brain tumors called astrocytoma or oligodendroglioma with an isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutation, following surgery. Your healthcare provider will perform a test to make sure that VORANIGO is right for you. It is not known if VORANIGO is safe and effective in children under 12 years of age. What are the possible side effects of VORANIGO? VORANIGO may cause serious side effects, including: Liver problems. Changes in liver function blood tests may happen during treatment with VORANIGO and can be serious. Your healthcare provider will do blood tests to check your liver function before and during treatment with VORANIGO. Tell your healthcare provider right away if you develop any of the following signs and symptoms of liver problems: yellowing of your skin or the white part of your eyes (jaundice) dark tea-colored urine loss of appetite pain on the upper right side of your stomach area feeling very tired or weak The most common side effects of VORANIGO include: increased liver enzyme levels in the blood lack of energy, tiredness headache COVID-19 muscle aches or stiffness diarrhea nausea seizure Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with VORANIGO if you have certain side effects. VORANIGO may affect fertility in females and males, which may affect the ability to have children. Talk to your healthcare provider if this is a concern for you. These are not all of the possible side effects of VORANIGO. Before taking VORANIGO, tell your healthcare provider about all of your medical conditions, including if you: have liver problems have kidney problems or are on dialysis smoke tobacco are pregnant or plan to become pregnant. VORANIGO can harm your unborn baby Females who are able to become pregnant: Your healthcare provider will do a pregnancy test before you start treatment with VORANIGO You should use effective nonhormonal birth control during treatment with VORANIGO and for 3 months after the last dose. VORANIGO may affect how hormonal contraceptives (birth control) work and cause them to not work well. Talk to your healthcare provider about birth control methods that may be right for you during treatment with VORANIGO Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with VORANIGO Males with female partners who are able to become pregnant: You should use effective birth control during treatment with VORANIGO and for 3 months after the last dose Tell your healthcare provider right away if your partner becomes pregnant or thinks she may be pregnant during your treatment with VORANIGO Tell your healthcare provider if you are breastfeeding or plan to breastfeed. It is not known if VORANIGO passes into breast milk. Do not breastfeed during treatment with VORANIGO and for 2 months after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VORANIGO may affect the way other medicines work, and other medicines may affect how VORANIGO works. Please click here for full prescribing information. Disclosures This release contains general information about the Servier Group and its entities (hereinafter "Servier and its Affiliates") and is intended for informational purposes only. The information is thought to be reliable; however, Servier and its Affiliates make no representation as to the accuracy or completeness of the information contained herein or otherwise provided and accept no responsibility or liability, in contract, in tort, in negligence, or otherwise, should the information be found to be inaccurate or incomplete in any respect. Servier and its Affiliates are not acting as an advisor to the recipient of this information, and the ultimate decision to proceed with any transaction rests solely with the recipient of this information. Therefore, prior to entering into any proposed transaction, the recipient of this information should determine, without reliance upon Servier or its Affiliates, the economic risks and merits, as well as the legal, tax, and accounting characterizations and consequences, of the transaction and that it is able to assume these risks. This statement also contains forward-looking statements that are subject to varying levels of uncertainty and risk. Investigational new drugs and indications are subject to further scientific and medical review and regulatory approval. They are not approved for use by the FDA. Any reliance placed on this document is done entirely at the risk of the person placing such reliance. The information contained in this document is neither an offer to sell nor the solicitation of an offer to enter into a transaction. The content of this document is a summary only, is not complete, and does not include all material information about Servier and its Affiliates, including potential conflicts of interest. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates disclaim all representations, warranties, conditions and guarantees, whether express, implied, statutory or of other kind, nor does it accept any duty to any person, in connection with this document. Without prejudice to the generality of the foregoing, Servier and its Affiliates do not warrant or represent that the information or opinions contained in this document is accurate or complete. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates shall not be liable for any loss, damage or expense whatsoever, whether direct or indirect, howsoever arising, whether in contract, tort (including negligence), strict liability or otherwise, for direct, indirect, incidental, consequential, punitive or special damages arising out of or in connection with this document, including (without limitation) any course of action taken on the basis of the same. The estimates, strategies, and views expressed in this document are based upon past or current data and information and are subject to change without notice. 1 Mandonnet E, Delattre JY, Tanguy ML, et al. Continuous growth of mean tumor diameter in a subset of grade II gliomas. Ann Neurol 2003;53:524-528. 2 Rees J, Watt H, Jäger HR, et al. Volumes and growth rates of untreated adult low-grade gliomas indicate risk of early malignant transformation. Eur J Radiol 2009;72:54-64. 3 Miller JJ, Gonzalez Castro LN, McBrayer S, et al. Isocitrate dehydrogenase (IDH) mutant gliomas: a Society for Neuro-Oncology (SNO) consensus review on diagnosis, management, and future directions. Neuro Oncol 2023;25:4-25. 4 Julie Grisham Monday, J. 1. (2019, July 1). Research clarifies how IDH mutations cause cancer. Memorial Sloan Kettering Cancer Center. 5 Mellinghoff, I. K., van den Bent, M. J., Blumenthal, D. T., Touat, M., Peters, K. B., Clarke, J., Mendez, J., Yust-Katz, S., Welsh, L., Mason, W. P., Ducray, F., Umemura, Y., Nabors, B., Holdhoff, M., Hottinger, A. F., Arakawa, Y., Sepulveda, J. M., Wick, W., Soffietti, R., … Cloughesy, T. F. (2023). Vorasidenib in idh1- or IDH2-mutant low-grade glioma. New England Journal of Medicine, 389(7), 589–601. 6 Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021 Aug 2;23(8):1231-1251. doi: 10.1093/neuonc/noab106. PMID: 34185076; PMCID: PMC8328013. SOURCE Servier Pharmaceuticals

[21-February-2024] If approved, vorasidenib would be the first targeted therapy in IDH-mutant diffuse glioma, a malignant and incurable brain tumor In clinical studies, vorasidenib has demonstrated strong blood-brain barrier penetrance alongside clinically meaningful and statistically significant improvements in progression-free survival and time-to-next intervention Approval of vorasidenib would mark Servier's sixth approval for a first-in-class treatment option in IDH-mutant cancers BOSTON and SURESNES, France, Feb. 21, 2024 /PRNewswire/ -- Servier, a global leader in oncology focused on delivering meaningful therapeutic progress for the patients it serves, today announced the FDA filing acceptance and priority review for a New Drug Application (NDA) for vorasidenib, as well as the EMA granting accelerated assessment for the vorasidenib Marketing Authorization Application (MAA). This innovative targeted therapy is an oral, selective, highly brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) enzymes for the treatment of IDH-mutant diffuse glioma. If approved, vorasidenib would become a first-in-class targeted therapy for patients with IDH-mutant gliomas and would mark Servier's sixth approval across IDH-mutant cancers. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) action date of August 20, 2024, while the European Commission approval is anticipated in the second half of 2024. "In the realm of glioma treatment, innovation has been stagnant for nearly a quarter-century, posing challenges for patients who, post-surgery, may opt to defer treatment due to concerns around potential toxic side effects. As a drug specifically designed to be highly blood-brain barrier penetrant, vorasidenib has demonstrated clinically meaningful efficacy in patients with IDH1/2 mutant gliomas alongside a consistently manageable safety profile," said Susan Pandya, M.D., Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier. "This promising outcome brings hope to patients grappling with IDH-mutant diffuse gliomas, offering a potential breakthrough for those eagerly awaiting a new therapeutic option." Adult-type diffuse gliomas represent approximately 81% of primary malignant brain tumors. Of those, approximately 20% harbor an IDH mutation, including 100% of grade 2 and grade 3 adult-type diffuse gliomas, as well as a much smaller portion of the grade 4 tumors.1,2 Testing for IDH mutations is essential for the accurate diagnosis of adult-type diffuse gliomas and can offer more information on the pathogenesis and prognosis of the disease.3 The 2021 WHO Classification includes disease defining histologic and molecular features, including IDH mutation status, to diagnose adult-type diffuse gliomas.4 Additionally, the National Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend IDH mutation testing in all patients with glioma, noting IDH mutation status impacts diagnosis, prognosis and treatment recommendations.5 "As a dedicated pioneer in the field of mutant IDH inhibition, Servier has consistently spearheaded the development of cutting-edge treatment options for various cancer types characterized by IDH mutations. The compelling efficacy results observed with vorasidenib in the INDIGO study underscore its full potential to emerge as the benchmark treatment for patients grappling with IDH-mutant diffuse glioma harboring IDH1/2 mutations," stated Claude Bertrand, Executive Vice-President of Research & Development and Chief Scientific Officer at Servier. "The submission of global regulatory filings for vorasidenib serve as validation of Servier's global oncology commitment while marking a possibly significant milestone for patients who have endured more than two decades without access to new therapeutic solutions." The submissions are based on results from the pivotal Phase 3 INDIGO clinical trial, which met its primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC) and key secondary endpoint of time to next intervention (TTNI) at the prespecified second interim analysis. The primary endpoint, PFS per BIRC, was statistically significant and clinically meaningful in favor of the vorasidenib arm (Hazard Ratio [HR], 0.39; 95% Confidence Interval [CI], 0.27 to 0.56; 1-sided P=0.000000067), median PFS for vorasidenib and placebo was 27.7 and 11.1 months, respectively. TTNI was also statistically significant (HR, 0.26; 95% CI, 0.15 to 0.43; 1-sided P=0.000000019). Median TTNI was not reached for vorasidenib and was 17.8 months for placebo. Vorasidenib was also shown to reduce the tumor volume by a mean of 2.5% (TGR of –2.5%; 95% CI: -4.7% to -0.2%) every 6 months, while tumor volume increased by a mean of 13.9% (TGR of 13.9%; 95% CI: 11.1% to 16.8%) every 6 months for patients randomized to the placebo arm, as measured by a blinded independent radiology committee. The INDIGO study showed that vorasidenib was well-tolerated, and its safety pro consistent with results from the Phase 1 studies. The results of INDIGO were presented at the 2023 Annual Meeting of the American Society of Clinical Oncology (ASCO) and simultaneously published in The New England Journal of Medicine. The results of additional secondary endpoints, including vorasidenib's impact on tumor growth rate (TGR) of IDH-mutant gliomas, were presented at the 2023 Annual Meeting of the Society for Neuro-Oncology (SNO) among other presentations including results on health-related quality of life, seizure control, neurocognition, and preliminary molecular translational analyses. Priority Review is granted to FDA applications for medicines that, if approved, would provide significant improvements in the effectiveness or safety of the treatment, diagnosis or prevention of serious conditions.6 Vorasidenib was granted Fast Track Designation by the FDA in February 2023 and Breakthrough Therapy Designation by the FDA in August 2023. The EMA's accelerated assessment is granted if the Committee for Medicinal Products for Human Use decides the new medicine is expected to be of major public health interest, particularly from the viewpoint of therapeutic innovation.7 Servier has also submitted an application for project Orbis member countries, including Brazil, Canada, Australia, Israel and Switzerland. In addition, Servier plans to submit a Marketing Application in the United Kingdom if a positive CHMP opinion is received. More information about Project Orbis can be found on the FDA website. In its ongoing commitment to addressing patient's needs, Servier recognizes that patients and their physicians may believe that a patient with a serious or immediately life-threatening disease could benefit from Servier's investigational drugs. An Expanded Access Program, also known as "compassionate use," is a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product for treatment outside of clinical trials. More information about Servier's expanded access program can be found at clinicaltrials.gov. About the INDIGO Phase 3 Trial (NCT04164901) INDIGO was a registration-enabling Phase 3 global, randomized, double-blind placebo-controlled study of vorasidenib in patients with residual or recurrent grade 2 glioma with an isocitrate dehydrogenase 1/2 (IDH1/2) mutation who have undergone surgery as their only treatment. Results were published in The New England Journal of Medicine. About Glioma8 Adult-type diffuse gliomas represent approximately 81% of primary malignant brain tumors. Of those, approximately 20% harbor an IDH mutation, including 100% of grade 2 and grade 3 adult-type diffuse gliomas, as well as a much smaller portion of the grade 4 tumors.1,2 Establishing the IDH mutation status of these tumors is essential to both diagnosis and prognosis, per the 2021 WHO classification of CNS tumors and the NCCN treatment guidelines, respectively. As of 2021, adult-type diffuse gliomas are sub-divided into only three categories: Astrocytoma, IDH-mutant (CNS WHO grades 2-4) Oligodendroglioma, IDH-mutant and 1p19q-codeleted (CNS WHO grades 2-3) Glioblastoma, IDH-wildtype (CNS WHO grade 4) 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. Press Contacts Servier Group (Global) marion.breyer@servier.com Servier Pharmaceuticals (U.S.) Nathan Mellor nathan.mellor@servier.com Disclosures This release contains general information about the Servier Group and its entities (hereinafter "Servier and its Affiliates") and is intended for informational purposes only. The information is thought to be reliable; however, Servier and its Affiliates make no representation as to the accuracy or completeness of the information contained herein or otherwise provided and accept no responsibility or liability, in contract, in tort, in negligence, or otherwise, should the information be found to be inaccurate or incomplete in any respect. Servier and its Affiliates are not acting as an advisor to the recipient of this information, and the ultimate decision to proceed with any transaction rests solely with the recipient of this information. Therefore, prior to entering into any proposed transaction, the recipient of this information should determine, without reliance upon Servier or its Affiliates, the economic risks and merits, as well as the legal, tax, and accounting characterizations and consequences, of the transaction and that it is able to assume these risks. This statement also contains forward-looking statements that are subject to varying levels of uncertainty and risk. Investigational new drugs and indications are subject to further scientific and medical review and regulatory approval. They are not approved for use by the FDA. Any reliance placed on this document is done entirely at the risk of the person placing such reliance. The information contained in this document is neither an offer to sell nor the solicitation of an offer to enter into a transaction. The content of this document is a summary only, is not complete, and does not include all material information about Servier and its Affiliates, including potential conflicts of interest. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates disclaim all representations, warranties, conditions and guarantees, whether express, implied, statutory or of other kind, nor does it accept any duty to any person, in connection with this document. Without prejudice to the generality of the foregoing, Servier and its Affiliates do not warrant or represent that the information or opinions contained in this document is accurate or complete. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates shall not be liable for any loss, damage or expense whatsoever, whether direct or indirect, howsoever arising, whether in contract, tort (including negligence), strict liability or otherwise, for direct, indirect, incidental, consequential, punitive or special damages arising out of or in connection with this document, including (without limitation) any course of action taken on the basis of the same. The estimates, strategies, and views expressed in this document are based upon past or current data and information and are subject to change without notice. 1 Louis, D. et. al (2021). The 2021 WHO Classification of Tumors of the Central Nervous System: a summary, Neuro-Oncology, 23(8): 1231–1251. . Accessed February 2024. 2 Ostrom, Q. T., Price, M., Neff, C., Cioffi, G., Waite, K. A., Kruchko, C., & Barnholtz-Sloan, J. S. (2022). CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015-2019. Neuro-oncology, 24(Suppl 5), v1–v95. . Accessed February 2024. 3 Isocitrate Dehydrogenase. Science Direct. . Accessed February 2024. 4 Antonelli M, Poliani PL. Adult type diffuse gliomas in the new 2021 WHO Classification. Pathologica. 2022 Dec;114(6):397-409. doi: 10.32074/1591-951X-823. PMID: 36534419; PMCID: PMC9763975. 5 NCCN. Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Brain Cancer Gliomas 2021. © National Comprehensive Cancer Network, Inc. 2023. Accessed February 2024. 6 U.S. Food and Drug Administration (FDA). Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review. . Accessed February 2024. 7 European Medicines Agency (EMA). Accelerated assessment. . Accessed February 2024. 8 Neuro Oncology. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. . Accessed February 2024.

If approved, vorasidenib would be the first targeted therapy in IDH-mutant diffuse glioma, a malignant and incurable brain tumor In clinical studies, vorasidenib has demonstrated strong blood-brain barrier penetrance alongside clinically meaningful and statistically significant improvements in progression-free survival and time-to-next intervention Approval of vorasidenib would mark Servier's sixth approval for a first-in-class treatment option in IDH-mutant cancers BOSTON and SURESNES, France, Feb. 20, 2024 /PRNewswire/ -- Servier, a global leader in oncology focused on delivering meaningful therapeutic progress for the patients it serves, today announced the FDA filing acceptance and priority review for a New Drug Application (NDA) for vorasidenib, as well as the EMA granting accelerated assessment for the vorasidenib Marketing Authorization Application (MAA). This innovative targeted therapy is an oral, selective, highly brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) enzymes for the treatment of IDH-mutant diffuse glioma. If approved, vorasidenib would become a first-in-class targeted therapy for patients with IDH-mutant gliomas and would mark Servier's sixth approval across IDH-mutant cancers. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) action date of August 20, 2024, and the the European Commission approval is anticipated in the second half of 2024. "In the realm of glioma treatment, innovation has been stagnant for nearly a quarter-century, posing challenges for patients who, post-surgery, may opt to defer treatment due to concerns around potential toxic side effects. As a drug specifically designed to be highly blood-brain barrier penetrant, vorasidenib has demonstrated clinically meaningful efficacy in patients with IDH1/2 mutant gliomas alongside a consistently manageable safety profile, " said Susan Pandya, M.D., Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier. "This promising outcome brings hope to patients grappling with IDH-mutant diffuse gliomas, offering a potential breakthrough for those eagerly awaiting a new therapeutic option." Adult-type diffuse gliomas represent approximately 81% of primary malignant brain tumors. Of those, approximately 20% harbor an IDH mutation, including 100% of grade 2 and grade 3 adult-type diffuse gliomas, as well as a much smaller portion of the grade 4 tumors.1,2 Testing for IDH mutations is essential for the accurate diagnosis of adult-type diffuse gliomas and can offer more information on the pathogenesis and prognosis of the disease.3 The 2021 WHO Classification includes disease defining histologic and molecular features, including IDH mutation status, to diagnose adult-type diffuse gliomas.4 Additionally, the National Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend IDH mutation testing in all patients with glioma, noting IDH mutation status impacts diagnosis, prognosis and treatment recommendations.5 "As the pioneer in the field of mutant IDH inhibition, Servier has consistently spearheaded the development of cutting-edge treatment options for various cancer types characterized by IDH mutations. The compelling efficacy results observed with vorasidenib in the INDIGO study underscore its full potential to emerge as the benchmark treatment for patients grappling with IDH-mutant diffuse glioma harboring IDH1/2 mutations," stated Claude Bertrand, Executive Vice-President of Research & Development and Chief Scientific Officer at Servier. "The submission of global regulatory filings for vorasidenib serve as validation of Servier's global oncology commitment while marking a possibly significant milestone for patients who have endured more than two decades without access to new therapeutic solutions." The submissions are based on results from the pivotal Phase 3 INDIGO clinical trial, which met its primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC) and key secondary endpoint of time to next intervention (TTNI) at the prespecified second interim analysis. The primary endpoint, PFS per BIRC, was statistically significant and clinically meaningful in favor of the vorasidenib arm (Hazard Ratio [HR], 0.39; 95% Confidence Interval [CI], 0.27 to 0.56; 1-sided P=0.000000067), median PFS for vorasidenib and placebo was 27.7 and 11.1 months, respectively. TTNI was also statistically significant (HR, 0.26; 95% CI, 0.15 to 0.43; 1-sided P=0.000000019). Median TTNI was not reached for vorasidenib and was 17.8 months for placebo. Vorasidenib was also shown to reduce the tumor volume by a mean of 2.5% (TGR of –2.5%; 95% CI: -4.7% to -0.2%) every 6 months, while tumor volume increased by a mean of 13.9% (TGR of 13.9%; 95% CI: 11.1% to 16.8%) every 6 months for patients randomized to the placebo arm, as measured by a blinded independent radiology committee. The INDIGO study showed that vorasidenib was well-tolerated, and its safety profile was consistent with results from the Phase 1 studies. The results of INDIGO were presented at the 2023 Annual Meeting of the American Society of Clinical Oncology (ASCO) and simultaneously published in The New England Journal of Medicine. The results of additional secondary endpoints, including vorasidenib's impact on tumor growth rate (TGR) of IDH-mutant gliomas, were presented at the 2023 Annual Meeting of the Society for Neuro-Oncology (SNO) among other presentations including results on health-related quality of life, seizure control, neurocognition, and preliminary molecular translational analyses. Priority Review is granted to FDA applications for medicines that, if approved, would provide significant improvements in the effectiveness or safety of the treatment, diagnosis or prevention of serious conditions.6 Vorasidenib was granted Fast Track Designation by the FDA in February 2023 and Breakthrough Therapy Designation by the FDA in August 2023. The EMA's accelerated assessment is granted if the Committee for Medicinal Products for Human Use (CHMP) decides the new medicine is expected to be of major public health interest, particularly from the viewpoint of therapeutic innovation.7 Servier has also submitted an application for project Orbis member countries, including Brazil, Canada, Australia, Israel and Switzerland. In addition, Servier plans to submit a Marketing Application in the United Kingdom if a positive CHMP opinion is received. More information about Project Orbis can be found on the FDA website. In its ongoing commitment to addressing patient's needs, Servier recognizes that patients and their physicians may believe that a patient with a serious or immediately life-threatening disease could benefit from Servier's investigational drugs. An Expanded Access Program, also known as "compassionate use," is a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product for treatment outside of clinical trials. More information about Servier's expanded access program can be found at clinicaltrials.gov. About the INDIGO Phase 3 Trial ( NCT04164901 ) INDIGO was a registration-enabling Phase 3 global, randomized, double-blind placebo-controlled study of vorasidenib in patients with residual or recurrent grade 2 glioma with an isocitrate dehydrogenase 1/2 (IDH1/2) mutation who have undergone surgery as their only treatment. Results were published in The New England Journal of Medicine. About Glioma 8 Adult-type diffuse gliomas represent approximately 81% of primary malignant brain tumors. Of those, approximately 20% harbor an IDH mutation, including 100% of grade 2 and grade 3 adult-type diffuse gliomas, as well as a much smaller portion of the grade 4 tumors.1,2 Establishing the IDH mutation status of these tumors is essential to both diagnosis and prognosis, per the 2021 WHO classification of CNS tumors and the NCCN treatment guidelines, respectively. As of 2021, adult-type diffuse gliomas are sub-divided into only three categories: Astrocytoma, IDH-mutant (CNS WHO grades 2-4) Oligodendroglioma, IDH-mutant and 1p19q-codeleted (CNS WHO grades 2-3) Glioblastoma, IDH-wildtype (CNS WHO grade 4) 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. Press Contacts Servier Group (Global) [email protected] Servier Pharmaceuticals (U.S.) Nathan Mellor [email protected] Disclosures This release contains general information about the Servier Group and its entities (hereinafter "Servier and its Affiliates") and is intended for informational purposes only. The information is thought to be reliable; however, Servier and its Affiliates make no representation as to the accuracy or completeness of the information contained herein or otherwise provided and accept no responsibility or liability, in contract, in tort, in negligence, or otherwise, should the information be found to be inaccurate or incomplete in any respect. Servier and its Affiliates are not acting as an advisor to the recipient of this information, and the ultimate decision to proceed with any transaction rests solely with the recipient of this information. Therefore, prior to entering into any proposed transaction, the recipient of this information should determine, without reliance upon Servier or its Affiliates, the economic risks and merits, as well as the legal, tax, and accounting characterizations and consequences, of the transaction and that it is able to assume these risks. This statement also contains forward-looking statements that are subject to varying levels of uncertainty and risk. Investigational new drugs and indications are subject to further scientific and medical review and regulatory approval. They are not approved for use by the FDA. Any reliance placed on this document is done entirely at the risk of the person placing such reliance. The information contained in this document is neither an offer to sell nor the solicitation of an offer to enter into a transaction. The content of this document is a summary only, is not complete, and does not include all material information about Servier and its Affiliates, including potential conflicts of interest. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates disclaim all representations, warranties, conditions and guarantees, whether express, implied, statutory or of other kind, nor does it accept any duty to any person, in connection with this document. Without prejudice to the generality of the foregoing, Servier and its Affiliates do not warrant or represent that the information or opinions contained in this document is accurate or complete. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates shall not be liable for any loss, damage or expense whatsoever, whether direct or indirect, howsoever arising, whether in contract, tort (including negligence), strict liability or otherwise, for direct, indirect, incidental, consequential, punitive or special damages arising out of or in connection with this document, including (without limitation) any course of action taken on the basis of the same. The estimates, strategies, and views expressed in this document are based upon past or current data and information and are subject to change without notice. 1 Louis, D. et. al (2021). The 2021 WHO Classification of Tumors of the Central Nervous System: a summary, Neuro-Oncology, 23(8): 1231–1251. . Accessed February 2024. 2 Ostrom, Q. T., Price, M., Neff, C., Cioffi, G., Waite, K. A., Kruchko, C., & Barnholtz-Sloan, J. S. (2022). CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015-2019. Neuro-oncology, 24(Suppl 5), v1–v95. . Accessed February 2024. 3 Isocitrate Dehydrogenase. Science Direct. . Accessed February 2024. 4 Antonelli M, Poliani PL. Adult type diffuse gliomas in the new 2021 WHO Classification. Pathologica. 2022 Dec;114(6):397-409. doi: 10.32074/1591-951X-823. PMID: 36534419; PMCID: PMC9763975. 5 NCCN. Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Brain Cancer Gliomas 2021. © National Comprehensive Cancer Network, Inc. 2023. Accessed February 2024. 6 U.S. Food and Drug Administration (FDA). Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review. . Accessed February 2024. 7 European Medicines Agency (EMA). Accelerated assessment. . Accessed February 2024. 8 Neuro Oncology. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. . Accessed February 2024. 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