Suzhou, China, March 16, 2022 – The partner of CStone Pharmaceuticals (“CStone”, HKEX: 2616), Servier, announced that the U.S. Food and Drug Administration (FDA) has accepted the supplemental New Drug Application (sNDA) for TIBSOVO® (ivosidenib tablets) as a potential treatment for patients with previously untreated IDH1-mutated acute myeloid leukemia (AML). The sNDA was granted Priority Review, which accelerates the review and shortens the review time goal from 10 months to 6 months. Priority Review is typically given to drugs that may offer major advances in treatment or may provide a treatment where no adequate therapy exists. CStone is pursuing submission for this indication in China as well.
Meanwhile, Servier announced that it has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for TIBSOVO for two indications as a first line treatment, in combination with azacitidine, in patients with previously untreated IDH1-mutated acute myeloid leukemia (AML) and not eligible for intensive chemotherapy, as well as in previously treated, locally advanced or metastatic IDH1-mutated cholangiocarcinoma. TIBSOVO is the first IDH1 mutation specific targeted therapy to be submitted for registration in Europe.
Dr. Jason Yang, Chief Medical Officer of CStone, said, “We are very pleased to see these significant milestones in multiple indications for TIBSOVO in the U.S. and Europe. TIBSOVO is the first therapy targeting cancer metabolism to demonstrate improved event-free survival and overall survival in combination with azacitidine in patients with previously untreated IDH1-mutated AML. We will work closely with the National Medical Products Administration (NMPA) of China with an aim to bring this innovative therapy to more Chinese patients as soon as possible.”
The sNDA acceptance and the MAA submission are supported by results from the AGILE study, a global, Phase 3 trial in patients with previously untreated IDH1-mutated AML, which were presented at the 2021 American Society of Hematology Annual Meeting and Exposition. The data demonstrated that treatment with TIBSOVO in combination with azacitidine significantly improved event-free survival (EFS) (hazard ratio [HR] = 0.33, [95% CI: 0.16, 0.69], 1-sided P = 0.0011) 1,2. In addition, the combination of TIBSOVO with azacitidine showed a statistically significant improvement in overall survival (OS) (HR = 0.44, [95% CI : 0.27, 0.73], 1-sided P = 0.0005), with a median OS of 24.0 months.
On July 19, 2019, CStone announced that the first patient in China was dosed in AGILE, the global registrational Phase 3 study of TIBSOVO. 16 centers in China participated in this global study.
The MAA submission for cholangiocarcinoma is supported by data from the ClarIDHy study, the first and only randomized Phase 3 trial for previously treated IDH1-mutated cholangiocarcinoma. Results from the ClarIDHy study demonstrated a statistically significant improvement in the primary endpoint of progression-free survival (PFS) (hazard ratio [HR] =0.37, [95% CI: 0.25, 0.54], p<0.001) 10 . The median PFS (95% CI) for TIBSOVO and placebo was 2.7 (1.6, 4.2) and 1.4 (1.4, 1.6) months, respectively. Thirty-two percent and 22% of patients randomized to TIBSOVO remained free of progression or death at 6 and 12 months, respectively, versus none on the placebo arm.
The study protocol specified that patients randomized to placebo could cross over to TIBSOVO at the time of disease progression, and a high proportion of patients in the placebo arm (70.5%) crossed over to TIBSOVO. The study also showed the key secondary endpoint of overall survival (OS) favoring patients randomized to TIBSOVO compared to those randomized to placebo; however, statistical significance was not reached. OS results are based on the final analysis of OS (based on 150 events) which occurred 16 months after the final analysis of PFS. The median OS (95% CI) for TIBSOVO was 10.3 (7.8, 12.4) months; and placebo was 7.5 (4.8, 11.1) months without adjusting for crossover.
TIBSOVO is currently approved by the NMPA of China for the treatment of adult patients with R/R AML who have a susceptible IDH1 mutation. In the U.S., TIBSOVO is approved as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory acute myeloid leukemia (AML), and for adults with newly diagnosed IDH1-mutant AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. Recently, TIBSOVO was approved as a first and only targeted therapy for patients with previously treated IDH1-mutated cholangiocarcinoma.
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About Acute Myeloid Leukemia
Acute myeloid leukemia (AML) a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults, with approximately 20,000 new cases in the U.S., and 43,000 cases in Europe each year1,2,7. In China, there are about 75.3 thousand new cases of Leukemia each year and approximately 59% are AML patients. AML incidence significantly increases with age, and the median age of diagnosis is 681. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML3. The five-year survival rate is approximately 29.5%1 . For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia4.
About Cholangiocarcinoma
Cholangiocarcinoma, a cancer of the bile ducts, is a rare and aggressive tumor often linked to medical history such as cirrhosis or liver infection. Cholangiocarcinoma affects 1–3/100,000 inhabitants in Europe, i.e., approximately 10,000 new cases each year in Europe8. The five-year survival rate is 9%, but 0% if metastasized9. Only surgery can cure patients but is only possible for a limited number of patients and the risk of relapse remains high. Chemotherapy is the standard therapy for patients with cholangiocarcinoma not eligible for surgery or that has progressed after surgery. The development of immunotherapy and new targeted therapies is now increasing the life expectancy and quality of life of patients.
About TIBSOVO (ivosidenib tablets)
TIBSOVO is an oral targeted IDH1 inhibitor. The NMPA of China has approved the NDA of TIBSOVO for the treatment of adult patients with relapsed/refractory acute myeloid leukemia who have a susceptible IDH1 mutation.
TIBSOVO is currently approved in the U.S. as monotherapy for the treatment for the treatment of adults with IDH1-mutant relapsed or refractory acute myeloid leukemia (AML), and for adults with newly-diagnosed AML with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adult patients who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy. In 2021, TIBSOVO was the first and only targeted therapy approved for patients with previously treated locally advanced or metastatic cholangiocarcinoma with an IDH1-mutation as detected by an FDA-approved test.
The U.S. FDA has granted Breakthrough Therapy Designation for TIBSOVO in combination with azacitidine for this supplemental indication and Breakthrough Therapy Designation for TIBSOVO for the treatment of adult patients with relapsed or refractory myelodysplastic syndrome (MDS) with a susceptible IDH1 mutation.
Servier has granted an exclusive license to CStone to develop and commercialize the product in Mainland China, Taiwan, Hong Kong, Macau and Singapore.
About CStone
CStone Pharmaceuticals (HKEX: 2616) is a biopharmaceutical company focused on research, development, and commercialization of innovative immuno-oncology and precision medicines to address the unmet medical needs of cancer patients in China and worldwide. Established in 2015, CStone has assembled a world-class management team with extensive experience in innovative drug development, clinical research, and commercialization. The company has built an oncology-focused pipeline of 15 drug candidates with a strategic emphasis on immuno-oncology combination therapies. Currently, CStone has received seven NDA approvals for four drugs. CStone's vision is to become globally recognized as a world-renowned biopharmaceutical company by bringing innovative oncology therapies to cancer patients worldwide.
For more information about CStone, please visit: www.cstonepharma.com.
Forward-looking statement
The forward-looking statements made in this article only relate to events or information as of the date when the statements are made in this article. Except as required by law, we undertake no obligation to update or publicly revise any forward-looking statements, whether as a result of new information, future events or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. All statements in this article are made on the date of publication of this article and may change due to future developments.
References
1. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Acute Myeloid Leukemia (AML). https://seer.cancer.gov/statfacts/html/amyl.html. Accessed January 2022.
2. American Cancer Society. Acute Myeloid Leukemia (AML). https://www.cancer.org/content/dam/CRC/PDF/Public/8674.00.pdf. Accessed January 2022.
3. Kumar C. Genetic Abnormalities and Challenges in the Treatment of Acute Myeloid Leukemia. Genes Cancer. 2011; 2:95-107.
4. DiNardo C. Durable Remissions from Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. New England Journal of Medicine. 2018; 378:2386-98. Accessed January 2022.
5. Data on file. Servier. January 26, 2022.
6. ClinicalTrials.gov. Study of AG-120 (Ivosidenib) vs. Placebo in Combination with Azacitidine in Patients With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation (AGILE). Available at: https://clinicaltrials.gov/ct2/show/NCT03173248. Accessed January 2022.
7. Visser O. Incidence, survival and prevalence of myeloid malignancies in Europe. European Journal of Cancer. 2012; 3257-3266.
8. Valle JW, et al. Ann Oncol. 2016;27(Suppl. 5):v28–v37
9. Oliveira IS, et al. Abdom Radiol (NY). 2017;42(6):1637–1649
10. Zhu A, et al. Final results from ClarIDHy, a global, phase 3, randomized, double-blind study of ivosidenib vs placebo in patients with previously treated cholangiocarcinoma and an isocitrate dehydrogenase 1 (IDH1) mutation. Presented at Gastrointenstinal Cancer Symposium 2021. Available at: https://www.servier.us/sites/default/files/2021-04/ASCO-GI21 ClarIDHy.pdf.
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