FDA and EMA Accept Vorasidenib Regulatory Submissions for the Treatment of IDH-mutant diffuse glioma

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Feb 20, 2024, 07:00 ET

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 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.⁴Additionally, 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 Glioma⁸

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.

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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.

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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. https://doi.org/10.1093/neuonc/noab106. 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. https://doi.org/10.1093/neuonc/noac202. Accessed February 2024.
³ Isocitrate Dehydrogenase. Science Direct. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/isocitrate-dehydrogenase. 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. https://www.nccn.org/patients/guidelines/content/PDF/brain-gliomas-patient.pdf
⁶ U.S. Food and Drug Administration (FDA). Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review. Accessed February 2024.
⁷ European Medicines Agency (EMA). Accelerated assessment. https://www.ema.europa.eu/en/human-regulatory-overview/marketing-authorisation/accelerated-assessment. Accessed February 2024.
⁸ Neuro Oncology. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. https://academic.oup.com/neuro-oncology/article/23/8/1231/6311214. Accessed February 2024.