Astellas Announces Conditional Approval of Gilteritinib in China for Treatment of FLT3-Mutated Relapsed or Refractory Acute Myeloid Leukemia

TOKYO, Feb. 4, 2021 /PRNewswire/ -- Astellas Pharma Inc. (TSE: 4503, President and CEO: Dr. Kenji Yasukawa, "Astellas") today announced that the National Medical Products Administration (NMPA) of China has granted conditional approval to Xigduo^®(English brand name XOSPATA^®, with the generic name gilteritinib fumarate tablets (hereinafter collectively referred to as gilteritinib), is indicated for the treatment of adult patients with relapsed (disease recurrence) or refractory (treatment-resistant) acute myeloid leukemia (AML) who are found to carry FMS-like tyrosine kinase 3 (FLT3) mutations by a fully validated test. Gilteritinib was approved by the National Medical Products Administration of China in July 2020Priority Review Eligibility^[1], and was listed in November 2020List of the Third Batch of Overseas New Drugs Urgently Needed for Clinical Use^[2], has now been approved under the accelerated pathway.

Professor Ma Jun, Director of the Harbin Institute of Hematology and Oncology in China, stated: “Patients with relapsed or refractory acute myeloid leukemia (AML) harboring FLT3 mutations urgently need novel therapeutic options. As the first targeted therapy approved in China for the treatment of relapsed or refractory AML with FLT3 mutations, gilteritinib, approved via the accelerated pathway, enables patients in our country to rapidly access innovative treatment options.”

Gilteritinib has demonstrated significant inhibitory activity against two types of FLT3 mutations: FLT3 internal tandem duplication (FLT3-ITD) and FLT3 tyrosine kinase domain (FLT3-TKD). FLT3-ITD mutations affect approximately 30% of patients with acute myeloid leukemia.^[3], associated with a higher risk of relapse and shorter overall survival compared to wild-type FLT3^[4],[5]. FLT3-TKD mutations affect approximately 7% of patients with acute myeloid leukemia^[3]。During the treatment of acute myeloid leukemia (AML), and even after relapse, the FLT3 mutation status may change. Therefore, confirming the patient’s FLT3 mutation status at relapse helps identify appropriate and potentially effective targeted therapies.^[6]。

Professor Wang Jianxiang, Deputy Director of the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, stated: “FLT3 mutations have a significantly adverse impact on the prognosis of patients with acute myeloid leukemia. The approval of gilteritinib, supported by robust efficacy and safety data, provides an important new treatment option for patients in China with relapsed or refractory acute myeloid leukemia harboring FLT3 mutations.”

Professor Wu Depei, Chairman of the Hematology Branch of the Chinese Medical Association, stated, “In recent years, there has been rapid advancement in the diagnosis and treatment of hematologic malignancies. The application of various novel drugs and therapies has ushered certain diseases, such as lymphoma and myeloma, into the ‘chemotherapy-free’ era. The approval of gilteritinib for the treatment of relapsed or refractory acute myeloid leukemia (AML) with FLT3 mutations will also promote the transition of AML therapy toward a ‘chemotherapy-free’ era.”

Acute Myeloid Leukemia Is a Cancer That Affects the Blood and Bone Marrow^[7], with its incidence increasing with age^[8]Acute myeloid leukemia is one of the most common leukemias in adults.^[9]. It is estimated that approximately 80,000 people are diagnosed with leukemia annually in China.^[10]。

Dr. Andrew Krivoshik, Senior Vice President of Astellas Oncology Development and Global Therapeutic Area Head, stated, “Patients with relapsed or refractory acute myeloid leukemia (AML) harboring FLT3 mutations are in urgent need of novel therapeutic options, as their median survival following salvage chemotherapy is currently less than six months. The accelerated approval of gilteritinib represents a significant step toward providing new treatment choices for physicians and patients in China. Astellas is committed to developing innovative and breakthrough solutions for refractory cancers with limited treatment options, and we are highly enthusiastic about the approval and launch of gilteritinib in China, which fulfills part of this commitment.”

The aforementioned approval was based on the results of the phase 3 ADMIRAL trial, which have been published in The New England Journal of Medicine. Treatment with gilteritinib significantly prolonged overall survival (OS) compared with salvage chemotherapy. The median OS was 9.3 months for patients receiving gilteritinib versus 5.6 months for those receiving salvage chemotherapy [hazard ratio = 0.64 (95% CI 0.49, 0.83); P=0.0004].^[11]. Additional pharmacokinetic data from Chinese patients were derived from the ongoing Phase III COMMODORE trial and have also been reviewed.

The safety of gilteritinib was evaluated in 319 patients with relapsed or refractory acute myeloid leukemia (AML) harboring FLT3 mutations who received at least one daily dose of 120 mg of gilteritinib.^[11]The most common adverse reactions of all grades (incidence ≥ 10%) in patients receiving gilteritinib were increased alanine aminotransferase (ALT) (25.4%), increased aspartate aminotransferase (AST) (24.5%), anemia (20.1%), thrombocytopenia (13.5%), febrile neutropenia (12.5%), decreased platelet count (12.2%), diarrhea (12.2%), nausea (11.3%), increased blood alkaline phosphatase (11%), fatigue (10.3%), decreased white blood cell count (10%), and increased blood creatine phosphokinase (10%). One case of differentiation syndrome, an adverse reaction leading to death, occurred in patients receiving gilteritinib. The most common serious adverse reactions (incidence ≥ 3%) were febrile neutropenia (7.5%), increased ALT (3.4%), and increased AST (3.1%). Other clinically significant serious adverse reactions included QT interval prolongation on electrocardiogram (0.9%) and posterior reversible encephalopathy syndrome (0.3%).

The impact of this approval on performance has already been reflected in Astellas' current fiscal year (ending2021Year3Month31day) are reflected in the financial projections.

AboutADMIRALTrial

Phase 3 ADMIRAL Trial (NCT02421939) is a global, multicenter, open-label, randomized controlled study designed to compare the efficacy of gilteritinib versus salvage chemotherapy in adult patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML). The primary composite endpoints of the trial were overall survival (OS) and the rate of complete remission with full or partial hematologic recovery (CR/CRh). The study ultimately enrolled 371 patients with relapsed or refractory AML who had FLT3 mutations detected in their blood or bone marrow. Participants were randomized in a 2:1 ratio to receive either gilteritinib (120 mg) or salvage chemotherapy.^[12] 。

AboutCOMMODORE Trial

Phase III COMMODORE trial (NCT03182244) is an ongoing, multicenter, open-label, randomized controlled study conducted in China and other countries to compare the efficacy of gilteritinib versus salvage chemotherapy in adult patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML). The primary endpoint of the trial is overall survival (OS). The study will also compare gilteritinib with salvage chemotherapy in terms of event-free survival (EFS) and complete remission (CR) rate to assess safety and determine overall effectiveness. Participants are randomized in a 1:1 ratio to receive either gilteritinib (120 mg) or salvage chemotherapy.^[13]。    

Regarding Gilteritinib (Gilteritinib）

Gilteritinib is a drug discovered through a research collaboration between Astellas and Kotobuki Pharmaceutical Co., Ltd. Astellas holds exclusive global rights for the development, manufacturing, and commercialization of gilteritinib. Gilteritinib (brand name: Xospata®) is available to patients in the United States, Japan, selected countries in the European Union, and other regions, for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) harboring FLT3 mutations.^[14]。

Gilteritinib is a FMS-like tyrosine kinase 3 (FLT3) inhibitor that exhibits significant inhibitory activity against both FLT3-ITD and FLT3-TKD mutations. FLT3-ITD is a common driver mutation associated with high disease burden and poor prognosis.^[15]。

About Astellas

Astellas Pharma Inc. is a pharmaceutical company with operations in more than 70 countries and regions worldwide. Currently, we are advancing our “Focus Area Approach,” which aims to identify opportunities for sustained new drug development by concentrating on physiological mechanisms and therapeutic modalities, thereby addressing unmet medical needs. At the same time, we are expanding our focus beyond prescription drugs, combining our specialized expertise and knowledge with cutting-edge technologies from external partners across diverse fields to create Rx+® healthcare solutions. Through these efforts, Astellas strives to remain at the forefront of the ever-evolving healthcare industry, translating scientific advancements into value for patients. For more information, please visit our website.https://www.astellas.com/en。

Precautionary Statement

In this press release, statements regarding current plans, estimates, strategies and beliefs, and other statements that are not historical facts, are forward-looking statements about the future performance of Astellas. These statements are based on current assumptions and beliefs formed by management in light of information currently available to it and involve known and unknown risks and uncertainties. Many factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and laws and regulations related to the pharmaceutical market; (ii) fluctuations in currency exchange rates; (iii) delays in launching new products; (iv) Astellas’ inability to effectively market existing and new products; (v) Astellas’ inability to continue to effectively research and develop products that are accepted by customers in a highly competitive market; and (vi) infringement of Astellas’ intellectual property rights by third parties.

The information contained in this press release regarding pharmaceutical products (including those currently under development) does not constitute advertising or medical advice.

References:

[1] Center for Drug Evaluation, NMPA. List of priority review varieties. Available at: http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=21. Last accessed December 2020.  
[2] Center for Drug Evaluation, NMPA. Notice on the release of the third batch of clinically urgently needed overseas new drugs. Available at: http://www.cde.org.cn/news.do?method=viewInfoCommon&id=5ed6430be031fc66. Last accessed December 2020.
[3] Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079-89.
[4] Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a Cancer and Leukemia Group B study. Cancer Res. 2001;61(19):7233-7239.
[5] Whitman SP, Maharry K, Radmacher MD, et al. FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood. 2010;116(18):3622-3626.
[6] Warren M, et al. Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients. Mod Pathol. 2012;25(10):1405-12.
[7] American Cancer Society. What is Acute Myeloid Leukemia (AML)? Available at https://www.cancer.org/cancer/acute-myeloid-leukemia/about/what-is-aml.html. Last accessed December 2020.
[8] American Cancer Society. Risk Factors for Acute Myeloid Leukemia (AML). Available at: www.cancer.org/cancer/acute-myeloid-leukemia/causes-risks-prevention/risk-factors.html. Last accessed December 2020.
[9] American Cancer Society. Key Statistics for Acute Myeloid Leukemia (AML). Available at https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. Last accessed December 2020.
[10] GLOBOCAN Cancer Today Database, International Agency for Research on Cancer, World Health Organisation. Population Fact Sheets in 2018. Available at: http://gco.iarc.fr/today/data/factsheets/populations/160-china-fact-sheets.pdf. Last accessed December 2020.
[11] Perl A, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-mutated AML. N Engl J Med 2019; 381:1728-40.
[12] ClinicalTrials.gov. A Study of ASP2215 Versus Salvage Chemotherapy in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation. Available at: https://clinicaltrials.gov/ct2/show/NCT02421939. Last accessed December 2020.
[13] ClinicalTrials.gov. A Study of ASP2215 Versus Salvage Chemotherapy in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) With FLT3 Mutation. Available at: https://clinicaltrials.gov/ct2/show/NCT03182244. Last accessed December 2020. 
[14] Data on file. Northbrook, IL. Astellas Pharma Inc.
[15] Daver N, Schlenk RF, Russel NH, Levis MJ. (2019). Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 33: 299-312.